2011 Pediatric Anesthesia - Bissonnette

Bissonette-000FM-(F)
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Page i
Pediatric Anesthesia
Basic PrinciplesState of the ArtFuture
Edited by
Bruno Bissonnette, MD
Department of Anesthesia
Faculty of Medicine
University of Toronto
President and Founder
Children of the World Anesthesia Foundation
Toronto, Ontario, Canada
Subeditors
Brian J. Anderson, MB ChB, PhD - New Zealand
Adrian Bsenberg, MB ChB - USA
Thomas Engelhardt, MD, PhD - Scotland
Linda J. Mason, MD - USA
Joseph D. Tobias, MD - USA
Illustrator: Danny Aguilar - Canada
2011
PEOPLES MEDICAL PUBLISHING HOUSEUSA
SHELTON, CONNECTICUT
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Page ii
Peoples Medical Publishing House-USA

2 Enterprise Drive, Suite 509
Shelton, CT 06484
Tel: 203-402-0646
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2011 PMPH-USA, Ltd.
All rights reserved. Without limiting the rights under copyright reserved above, no part of this publication may be reproduced, stored in or introduced
into a retrieval system, or transmitted, in any form or by any means (electronic, mechanical, photocopying, recording, or otherwise), without the
prior written permission of the publisher.
11 12 13 14 15/PMPH/9 8 7 6 5 4 3 2 1
ISBN-13: 978-1-60795-093-6
ISBN-10: 1-60795-093-6
Printed in China by Peoples Medical Publishing House
Editor: Linda Mehta
Copyeditor/Typesetter: David Stockhoff, Spearhead Global
Cover designer: Bruno Bissonnette and Mary McKeon
Library of Congress CataloginginPublication Data
Pediatric anesthesia : basic principles, state of the art, future/[edited by] Bruno Bissonnette.
p. ; cm.
Includes bibliographical references and index.
ISBN-13: 978-1-60795-093-6
ISBN-10: 1-60795-093-6
1. Pediatric anesthesia. I. Bissonnette, Bruno.
[DNLM: 1. Anesthesiamethods. 2. Child. 3. Anestheticspharmacology. WO 440]
RD139.P418 2011
617.96083dc22
2010048079
Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and
drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly
change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes
recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs. Any treatment
regimen, particularly one involving medication, involves inherent risk that must be weighed on a case-by-case basis against the benefits
anticipated. The reader is cautioned that the purpose of this book is to inform and enlighten; the information contained herein is not intended as,
and should not be employed as, a substitute for individual diagnosis and treatment.
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To All the Children of the World We Care For

Also
To my dear mother Lilianne for her love and encouragement
and
to the loving memories of my father Raymond and my brother Luc Bissonnette
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Page vi
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Page vii
Contributors
Rita Agarwal, MD, FAAP [130]
Dean B. Andropoulos, MD, MHCM [106]
Associate Professor of Anesthesiology

Pediatric Anesthesia Program Director
The Childrens Hospital of Denver
Aurora, Colorado, USA
Professor of Anesthesiology and Pediatrics

Baylor College of Medicine
Chief of Anesthesiology
The Kurt D. Groten Sr Family Chair of
Pediatric Cardiovascular Anesthesiology
Attending Cardiovascular Anesthesiologist
Texas Childrens Hospital
Houston, Texas, USA
Swati Agarwal, MD [67]

Assistant Professor
Virginia Commonwealth University School of Medicine
Pediatric Critical Care Physician
Inova Fairfax Hospital for Children
Falls Church, Virginia, USA
Asim Ali, BASc, MD, FRCSC [102]

Assistant Professor of Ophthalmology
Department of Ophthalmology and Vision Sciences
Attending Ophthalmologist
Director of Pediatric Ophthalmology Fellowship Program
The Hospital for Sick Children
Kanwaljeet J. S. Anand, MB BS, DPhil, FAAP,

FCCM, FRCPCH [15]
Professor of Pediatrics, Anesthesiology and Neurobiology
University of Tennessee
St. Jude Childrens Research Hospital Endowed Chair of
Critical Care
Division Chief, Pediatric Critical Care Medicine
Le Bonheur Childrens Medical Center
University of Tennessee Health Science Center
Memphis, Tennessee, USA
Brian J. Anderson, MB ChB, PhD, FANZCA,

FJFICM [17, 18]
Honorary Associate Professor of Anaesthesiology
University of Auckland School of Medicine
Paediatric Anaesthetist and Intensivist
Department of Anaesthesia and Critical Care Medicine
Auckland Childrens Hospital
Auckland, New Zealand
Christian Apitz, MD [7]

Pediatric Cardiologist
Pediatric Heart Centre
University Childrens Hospital
Giessen, Germany
Glen S. Van Arsdell, MD [94]

Professor of Surgery
Head, Division of Cardiovascular Surgery
Department of Surgery
CIT Chair in Cardiovascular Research
Labatt Family Heart Centre
Karim Ashenoune, MD, PhD [63]

Professor of Anesthesiology and Intensive Care Medicine
University of Nantes
Attending Anesthesiologist
Departement of Anesthesiology and Intensive Care Medicine
Htel Dieu
Centre Hospitalier Universitaire de Nantes
Nante, France
Hanan Azzam, MD [82]

Assistant Professor of Clinical Pathology
Faculty of Medicine, Mansoura University Hospital
Department of Clinical Pathology
Mansoura University Hospital
Mansoura, Egypt
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Page viii
viii Contributors
Mette M. Berger, MD, PhD [124]
Gilles Boulay, MD [1]
Professor of Anesthesia and Critical Care Medicine

University of Lausanne School of Medicine
Consultant, Service of Intensive Care Medicine and Burns
Centre Hospitalier Universitaire Vaudois
Lausanne, Switzerland
Facult de Mdecine, AP-HP

Universit Paris Descartes
Hpital Saint-Vincent de Paul
Paris, France
Marc-Andr Bernath, MD, MER [124]
Nathalie Bourdaud, MD [53, 112]
Mdecin Associ
Universit de Lausanne
Chef du secteur de lAnesthsie Pdiatrique
Service dAnesthsiologie
Centre Hospitalier Universitaire Vaudois (CHUV)
Dominique A. Bettex, MD [73]

Assistant Professor of Anesthesiology
University of Zurich
Chief, Division of Cardiac and Vascular Anesthesia
University Hospital
Zurich, Switzerland

Praticien Hospitalier
Hpital Necker Enfants-Malades
Paris, France
Kenneth M. Brady, MD [15]

Associate Professor, Pediatrics and Anesthesia
Attending Anesthesiologist and Intensivist
Department of Anesthesia and Pediatrics
Houston, Texas, USA
Bruno Bissonnette, MD [6]

Professor of Anesthesia
Faculty of Medicine
President and Founder
Children of the World Anesthesia Foundation
David A. Blacoe, MbChB, MRCP(UK), FRCA [128]

Consultant in Anaesthesia
Anaesthetist
Monklands Hospital
Airdrie, Scotland
Christopher M. Bolton, MB BS, FANZCA, PhD [122]

Attending Anaesthesiologist
Department of Anaesthesia and Pain Management
The Royal Childrens Hospital
Melbourne, Victoria, Australia
Peter D. Booker, MB, BS, MD, FRCA [23, 95]

Senior Lecturer in Paediatric Anaesthesia
University of Liverpool
Honorary Consultant
Paediatric Anaesthetist
Alder Hey Childrens NHS Foundation Trust
Liverpool, England
Alain Borgeat, MD, PhD [44]

Professor of Anesthesiology
Chief, Department of Anesthesiology
Balgrist University Hospital
Zurich, Switzerland
Adrian Bsenberg, MB ChB, FFA(SA) [47,49,132]

University of Washington
Director, Division of Regional Anesthesia
Department Anesthesiology and Pain Management
Seattle Childrens Hospital
Seattle, Washington, USA
Karen A. Brown, MD, FRCP(C) [62]

McGill University
Queen Elizabeth Hospital of Montreal Foundation Chair in
Montreal Childrens Hospital
McGill University Health Center
Montreal, Quebec, Canada
Stephen C. Brown, MD, FRCPC [16]

Associate Professor of Anesthesia
Medical Director
Divisional Center of Pain Research and Pain Management
David Buckley, MBBChB, FANZCA, FCICM [42]

Paediatric Intensivist and Anaesthetist
Starship Children's Hospital
Sabine Kost-Byerly, MD [66]

Johns Hopkins University School of Medicine
Director, Pediatric Pain Management
Department of Anesthesiology and Critical Care Medicine
Baltimore, Maryland, USA
Xavier Capdevila, MD, PhD [45]

Professor of Anesthesiology and Critical Care Medicine
Montpellier School of Medicine
Montpellier University I
Chairman, Department of Anesthesiology and
Critical Care Medicine
Lapeyronie University Hospital
Montpellier, France
4/9/11
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Page ix
Contributors ix
Pierre Carli, MD [68]
Brian Chanpong, DDS, MSc [126]
Professeur dAnesthsiologie et de Ranimation Chirurgicale

Chef, Dpartement dAnesthsie et de Ranimation
Professor Hospitalier
Dpartement dAnesthsie-Ranimation
Directeur, SAMU de Paris
Hpital Necker Enfants Malades
Paris, France
Clinical Assistant Professor

Faculty of Dentistry
University of British Columbia
Attending Dental Anesthesiologist
Department of Dentistry
British Columbia Childrens Hospital
Vancouver, British Columbia, Canada
Alison S. Carr, MB BS, FRCA, MSc,

PGCertMEd (Dist) [99]
Consultant Paediatric Anaesthetist and
Honorary Senior Lecturer
Plymouth Hospitals NHS Trust
Derriford Hospital
Plymouth, England
Michael J. Casas, DDS, Dip.Paed, MSc, FRCD(C) [125]
Pierre-Guy Chassot, MD, PhD [73]

University Hospital of Lausanne
Head, Division of Cardiac Anesthesia
Director, Division of Intraoperative Transesophageal
Echocardiography
Farha Abd El-Aziz El-Chennawi, MD [82]
Associate Professor of Dentistry

Director of Dental Clinics
Department of Dentistry
Professor of Immunology
Vice-President of Mansoura University
Postgraduate Studies and Research
Faculty of Medicine, Mansoura University
Head of Immunology Unit and Clinical Pathology
Mansoura, Egypt
Neroli Chadderton, BHB, MBChB, FANZCA [23]
Olivier Choquet, MD [45]
Specialist Anesthetist
Hutt Valley Hospital
Wellington, New Zealand
Tristan M. B. de Chalain, MSc, MB Ch.B, FCS(SA),

FRCSC, FRACS [123]
University of Auckland
Director, Auckland Plastic Surgical Center
Consultant Plastic Surgeon
Starship Childrens Hospital
George A. Chalkiadis, MB BS, FANZCA,

FFPMANZCA, DA (London) [30]
Clinical Associate Professor
University of Melbourne
Consultant Paediatric Anaesthetist and Pain Medicine Specialist
Coordinator of the Childrens Pain Management Services
Attending Paediatric Anaesthetist
John Chandler, FDSRCS, FCARCSI [10]

Fellow in Pediatric Anesthesia
University of British Columbia
British Columbia Childrens Hospital
Vancouver, British Columbia, Canada

Montpellier University I
Lapeyronie University Hospital
Montpellier, France
Howard M. Clarke, MD, PhD, FRCS(C),

FACS, FAAP [123]
Active Staff Surgeon
Department of Surgery, Division of Plastic Surgery
John G. Coles, MD, FRCSC [105]

Attending Cardiovascular Surgeon
Mario J. da Coneicao, MD, PhD [34]

Professor of Surgical Techniques and Anesthesia
Blumenau Regional University Foundation
Instructor of Pediatric Anesthesia
Joana de Gusmao Childrens Hospital
Florianopolis, Brazil
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Page x
Contributors
Bairbre Connolly, MB BCh, BAO, FRCSI, MCh,

FFRRCSI, LMCC, FRCP(C) [121]
Associate Professor of Radiology
Department of Medical Imaging
Earl Glenwood Coulson Chair
Pediatric Interventional Radiology
Department of Diagnostic ImagingImage Guided Therapy
Isabelle Constant, MD, PhD [75]

Professeure dAnesthsiologie et de Ranimation
AP-HP, UPMC Paris 6
Chef du Service dAnesthsie-Ranimation Chirurgicale
Responsable du Ple Hospital-Universitaire de
Chirurgie-Anesthsie
Coordonnateur du Centre de Traitement des Grands Brls
Hpital Armand Trousseau
Paris, France
Robin G. Cox, MB BS, MRCP(UK), FRCA, FRCPC [36]

Professor of Anesthesia, University of Calgary
Pediatric Anesthesiologist
Department of Anesthesia and Critical Care Medicine
Alberta Childrens Hospital
Calgary, Alberta, Canada
Peter N. Cox, MBChB, DCH, FFARCS (UK),

FRCP(C) [64]
Professor of Anesthesia, Critical Care and Pediatrics
Associate Chief, Critical Care Unit
Clinical Director, Pediatric Intensive Care Unit
Fellowship Program Director
Department of Critical Care Medicine
Mary Cunliffe, MB BS, FRCA, FFPMRCA [91]

Honorary Clinical Lecturer in Anaesthesia
University of Liverpool
Consultant Paediatric Anaesthetist
Jackson Rees Department of Paediatric Anaesthesia
Alder Hey Childrens NHS Foundation Trust
Liverpool, England
Sharon L. Cushing, MD, MSc, FRCS(C) [98]

Assistant Professor of Surgery (ENT)
Attending Otolaryngologist
Souhayl Dahmani, MD, PhD [19]

Universit Paris VII
Service dAnesthsie-Ranimation et Douleur
INSERM U676, Hpital Robert Debr
Paris, France
Andrew Davidson, MBBS, MD, FANZCA [77]

Leonard Travers Professor of Anaesthesia
Department of Pharmacology
Associate Editor, Anesthesiology
Head, Clinical Research Development
Murdoch Childrens Research Institute
Attending Anaesthetist
Jayant K. Deshpande, MD, MPH [88]

Professor of Pediatrics and Anesthesiology
University of Arkansas for Medical Sciences
Senior Vice President/Chief Quality Officer
Arkansas Childrens Hospital
Little Rock, Arkansas, USA
John Doyle, MD, FRCPC, FAAP [113]

Department of Pediatrics
Head, Division of Blood and Marrow Transplant Program
R. Blaine Easley, MD [15, 58]

Associate Professor, Pediatrics and Anesthesiology
Attending in Cardiovascular Anesthesiology and Critical Care
Houston, Texas, USA
David Elliott, MB BS (Lon), MRCP(UK), FRCA,

PgClinUs [99]
Anaesthetic Registrar
Derriford Hospital
Plymouth, England
Steven T. Elliott, MD [89]

Surgery Resident
University of California Davis Medical Center
Sacramento, California, USA
Thomas Engelhardt, MD, PhD [5, 57]

Royal Aberdeen Childrens Hospital
Aberdeen, Scotland
Walid A. Farhat, MD, FAAP [109]

Associate Professor of Surgery (Urology)
Department of Surgery, Division of Urology
Associate Surgeon-in-Chief for Education
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Page xi
Contributors xi
Patrick T. Farrell, MD [97]
Steven Ganzberg, DMD, MS [126]
Conjoint Lecturer, University of Newcastle

Director of Anaesthesia, John Hunter Hospital
Newcastle, New South Wales, Australia
Professor of Clinical Anesthesiology

College of Dentistry
College of Medicine and Public Health
The Ohio State University
Residency Program Director
Department of Dental/Maxillofacial Anesthesiology
Columbus, Ohio, USA
Pierre Fayoux, MD, PhD [8]

Director of the Pediatric Otorhinolaryngology
Head-Neck Surgery
Department of Otorhinolaryngology
Jeanne de Flandre Childrens Hospital
University Hospital of Lille
Lille 2 University
Lille, France
Annie Fecteau, MD [107]

Associate Professor of Surgery
Division of General and Thoracic Surgery
Sick Kids Transplant Center
Zipporah Njeri Gathuya, MD [132]

Specialist Anesthesiologist
University of Nairobi
Director, Pediatric Anesthesia
Department Anesthesiology
Mary Gertrude Childrens Hospital
Nairobi, Kenya
J. Ted Gerstle, MD [96]

La Conception University Hospital
Marseille, France

Program Director, Division of General and Thoracic Surgery
Project InvestigatorProgram in Cell Biology
Research Institute
David M. Fisher, MB BCh, FRCSC, FACS [100]
Peter Gibson, MBBS, FANCZA [110]
Jean-Louis Feugeas, MD [45]
Associate Professor of Surgery (Plastics)

Medical Director, Cleft Lip and Palate Program
Clinical Lecturer in Anaesthesia

The University of Sydney
Staff Anaesthetist
Specialist Paediatric Anaesthetist
The Childrens Hospital at Westmead
Westmead, New South Wales, Australia
James Flowerdew, MD [101]
Jean-Louis Ginis, MD [11]
Director, Medical Student Electives in Anesthesia
Maine Medical Center
Portland, Maine, USA
Christopher R. Forrest, MD, MSc, FRCSC, FACS [116]

Professor of Surgery,
Chief, Division of Plastic Surgery
Medical Director, Craniofacial Program
Professor of Pediatrics
University of Angers
Attending Pediatrician
Pediatric Intensive Care Medicine
Centre Hospitalier Universitaire
Angers, France
Jean Godard, MD [71]

Praticien Hospitalier dAnesthsie-Ranimation
Service de Ranimation Pdiatrique
Hpital Femme-Mre-Enfant
Lyon, France
Manuel Garca Grriz, MD [12]
Clinical Senior Lecturer

University of Auckland
Assistant Professor of Anesthesia

Universitat Autonoma de Barcelona
Hospital Universitari Vall DHebron
Barcelona, Spain
Mohamed El-Gammal, MD [115]
Marie Granier, MD [103]
Michael J. Fredrickson, MD, MBChB, FANZCA [51]

King Saud bin Abdulaziz University for Health Sciences
Chairman Department of Anesthesia
Head, Division of Pediatric Anesthesia
King Abdulaziz Medical City
Riyadh, Saudi Arabia
Pediatric Anesthesiologist
Centre Hospitalier Universitaire Estaing
Clermont-Ferrand, France
xii
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Page xii
Contributors
Jean-Claude Granry, MD [11]
Brendan OHare, MB [119]
Professor of Anesthesia and Intensive Care

Chief, Department of Anesthesia and Intensive Care
Department of Anesthesia and Critical Care Medicine
Angers, France
Senior Clinical Lecturer

Trinity Medical School
Trinity College
Consultant in Paediatric Anesthesia and Critical Care Medicine
Our Ladys Childrens Hospital, Crumlin
Dublin, Ireland
George A. Gregory, MD [133]

Professor Emeritus, Anesthesia and Pediatrics
University of California, San Francisco
San Francisco, California, USA
Magalie Gurin, MD [40]

Facult de Mdecine de Marseille
Universit de la Mditerrane
Fellow, Department of Pediatric Anesthesia and
La Timone University Hospital
Marseille, France
Jean-Daniel Guieu, MD, PhD [76]

Professor Emeritus of Neurophysiology
University of Lille II
Department of Clinical Neurophysiology
Lille, France
Walid Habre, MD, PhD [61]

University of Geneva
University Hospitals of Geneva
Geneva, Switzerland
Gregory B. Hammer, MD [67]

Departments of Anesthesia and Pediatrics
Stanford University School of Medicine
Director of Pediatric Anesthesia Research
Lucile Packard Childrens Hospital at Stanford
Stanford, California, USA
Jamil Hamza, MD [1]

Head of Pediatric Surgical Intensive Care
Paris, France
Raafat S. Hannallah, MD [69]

The George Washington University Medical Center
Attending Pediatric Anesthesiologist
Department of Anesthesiology
Childrens National Medical Center
Washington, DC, USA
Jason A. Hayes, MD [25]

Elise Hon, MD, FRCS(C) [102]

Professor of Ophthalmology
Ophthalmologist-in-Chief
Associate Surgeon-in-Chief
Badr-Eddine Hmamouchi, MD [79]

Hassan II Ain Chok University of Casablanca
Department of Anesthesia and Critical Care
Casablanca Childrens Hospital
Casablanca, Morocco
Laura Holmes, BSc, CNIM [74]

Neurophysiology Technologist
Division of Intraoperative Neuromonitoring
Osami Honjo, MD, PhD [94, 105]

Assistant Professor of Surgery (Cardiovascular)
Staff Cardiovascular Surgeon,
Division of Cardiovascular Surgery
David J. Kenny, BSc, DDS (hons), PhD, Dip Ped,

FRCD(C) [125]
Professor of Dentistry
Attending Pediatric Dentist
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Page xiii
Contributors xiii
Rene Krivosic-Horber, MD [81]
Martin Jhr, MD [31]
Professeure dAnesthsie et Ranimation

Universit de Lille 2
Chef, Centre dHyperthermie Maligne de LilleHead,
Lille MH Center
Centre de rfrence des maladies rares neuro-musculaires
Centre Hospitalier Regional Universitaire
Lille, France
Professor of Anesthesia and Intensive Care Medicine

Department of Anesthesia, Intensive Care Medicine,
Emergency Medicine and Pain Therapy
Luzerner Kantonsspital
Luzerne, Switzerland
Rodrigo A. Iniguez, MD [111]

Pediatric Surgeon
Group for Improvement of Intestinal Function and Treatment
Transplant Center, The Hospital for Sick Children
Toronto, Ontario
Tel-Hashomer, Israel
Richard J. Ing, MBBCh, FCA(SA) [83]

Associate Professor of Anesthesia and Critical Care Medicine
Duke University
Division of Pediatric Anesthesia and Critical Care Medicine
Duke University Medical Center
Durham, North Carolina, USA
Lisa A. Isaac, MD, FRCP(C) [39]

Department of Anesthesia and Pain Medicine
Giorgio Ivani, MD [48]

University of Turin
Chairman, Department of Pediatric Anesthesia and
Intensive Care Medicine
Regina Margherita Childrens Hospital
Turin, Italy
Brenna L. Jacobson, MD [59]

Loma Linda University School of Medicine
Loma Linda, California, USA
Justin John, MD [113]

Assistant Professor of Anesthesiology and Pediatrics
Eastern Virginia Medical School
Medical Director of Sedation Services
Childrens Hospital of The Kings Daughters
Norfolk, Virginia, USA
Daisy T. Joo, MD, PhD [25]

North York General Hospital
Hans Jutzi, MD [44]

Consultant in Anesthesiology
Balgrist University Hospital
Zurich, Switzerland
Chaim Kaplinsky, MD [13]

Professor of Medicine (Hematology) and Pediatrics
The Sackler School of Medicine
University of Tel-Aviv
Department of Pediatric Hematology-Oncology
Safra Childrens Hospital
The Chaim Sheba Medical Center
Cengiz Karsli, BSc, MD, FRCPC [39]

Katherine Keech, MD [47]

Fellow in Pediatric Anesthesia
Department Anesthesiology and Pain Management
Cassandra M. Kelleher, MD [107]

Instructor in Surgery
Harvard Medical School
Assistant in Surgery
Mass General Hospital for Children
Boston, Massachusetts, USA
Gili Kenet, MD [13]

Professor of Medicine (Hematology) and Pediatrics
University of Tel-Aviv
Institute of Thrombosis and Hemostasis
The Thrombosis Unit and National Hemophilia Center
Department of Hematology
Safra Childrens Hospital
xiv
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Page xiv
Contributors
Sonia ben Khalifa, MD [90]
Wai-Ching Lam, MD, FRCS(C) [102]
Professor of Anesthesia and Intensive Care Medicine

Faculty of Medicine, Tunis El Manar University
Chairman
Department of Anesthesia and Intensive Care Medicine
University Children Hospital
Tunis, Tunisia
Associate Professor of Ophthalmology

Program Director
Toronto Western Hospital
University Health Network
Antoine E. Khoury, MD, FRCSC, FAAP [87]

Professor and Chief of Pediatric Urology
University of California, Irvine
Childrens Hospital of Orange County
Orange, California, USA
Jarmila Kim, MD, FRCPC [37]

University of Ottawa
Childrens Hospital of Eastern Ontario
Ottawa, Ontario, Canada
Peter C. W. Kim, MD, CM, PhD [85]
Frdric Lamy, MD [40]

Fellow, Department of Pediatric Anesthesia and
Marseille, France
Vincent P. Laudenbach, MD, PhD [19]
Staff Surgeon, Lead CIGITI
Hospital for Sick Children
Professor of Pediatric Anesthesiology and Neonatal

Intensive Care
Charles Nicolle University Hospital
Laboratory Deputy Head
EA 4309 NeoVasc Microvasculature and neonatal brain lesions
Normandy University Institute
Rouen, France
Hannu Kokki, MD, PhD [27]
Emmanule Laureau, MD, MsC [76]

University of Kuopio
Attending Anesthetist
Kuopio University Hospital,
Kuopio, Finland
Staff Neurophysiologist
Department of Clinical Neurophysiology
Lille, France
Peter C. Laussen, MBBS [119]

Charles D. Kurth, MD [129]
Professor of Anesthesia and Pediatrics
University of Cincinnati College of Medicine
Anesthesiologist in Chief
Chairman, Department of Anesthesiology
Cincinnati Childrens Hospital Medical Center
Cincinnati, Ohio, USA
Frdric Lacroix, MD [45]

Anesthsiste-Ranimateur Pdiatrique
Dpartment dAnesthsiologie et Ranimation
Centre Hospitalier Universitaire La Timone
Assistance PubliqueHpitaux de Marseille
Marseille, France
Carol L. Lake, MD, MBA, MPH [95]

Hummelstown, Pennsylvania, USA
DD Hansen Chair in Pediatric Anesthesia
Chief, Division Cardiovascular Critical Care
Childrens Hospital Boston
Charles Lee, MD [108]

Director of Acute/Perioperative Pain Service
Director of Organ Transplantation Anesthesia
Clinical Director of Pediatric Anesthesia
Loma Linda University Medical Center
Corinne Lejus, MD, PhD [63]

Professor of Anesthesiology and Surgical
University of Nantes
Chief of Department of Anesthesiology and Surgical
Htel Dieu
Centre Hospitalier Universitaire de Nantes
Nantes, France
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Page xv
Contributors xv
Mark F. Levine, MBBCh, FRCPC [117]
Barry Lyons, MB, FFARCSI [64]

Program Director
Consultant Anaesthetist
Department of Anaesthesia and Critical Care Medicine
Our Ladys Hospital for Sick Children
Dublin, Ireland
Jonathan de Lima, MBBS, PhD (UCL), FANCZA [110]

Clinical Senior Lecturer
The University of Sydney
Deputy, Department of Pain Medicine and Palliative Care
Senior Staff Anaesthetist
The Childrens Hospital at Westmead
Westmead, New South Wales, Australia
Tsz-Yan Milly Lo, MB ChB, DCH, MRCP (UK),

MRCPCH, PhD [64]
Honorary Senior Lecturer
University of Edinburgh
Consultant in Paediatric Intensive Care Medicine
The Royal Hospital for Sick Children
Edinburgh, Scotland
Justin L. Lockman, MD [58]

Fellow in Anesthesiology and Critical Care Medicine
Pediatric Critical Care Medicine and Anesthesiology
The Johns Hopkins School of Medicine
Fellow in Anesthesiology
Childrens Hospital
The Johns Hopkins Hospital
Per-Arne Lnnqvist, MD, DEAA, FRCA, PhD [86]

Professor of Pediatric Anesthesia and Intensive Care Medicine
Department of Physiology and Pharmacology
Karolinska Institute
Senior Consultant, Karolinska University Hospital
Stockholm, Sweden
Armando J. Lorenzo, MD, MSc, FAAP [109]

Assistant Professor of Surgery (Urology)
Department of Surgery, Division of Urology
Attending Surgeon
Igor Luginbuehl, MD [14]

Ruth Oelhafen Luginbuehl, MD, DTATI [2]

Pediatrician FMH
Medical Art Therapist DTATI
Jean Mantz, MD, PhD [19]

Professeur dAnesthsie-Ranimation
Universit Paris VII, Paris Diderot
Chairman, Service dAnesthsie-Ranimation
INSERM U676, Hpital Beaujon
Clichy la Garenne, France
Bruno Marciniak, MD [8]

Lille, France
Peter Marhofer, MD [46]

Medizinische Universitt Wien
Univ. Klinik fr Ansthesie, Intensivmedizin and
Schmerztherapie
Vienna, Austria
Giuseppe Marraro, MD [72]

Associate Professor of Anesthesia and
Intensive Care Medicine II Specialization
School of Anesthesia and Intensive Care
Faculty of Medicine and Surgery
University of Milan
Honorary Consultant in Anesthesia and
Director of Pediatric Anesthesia and Intensive Care Medicine
Pediatric Intensive Care Unit
Fatebenefratelli and Ophthalmiatric Hospital
Milan, Italy
Lynn D. Martin, MD, FAAP, FCCM [131]

Professor of Anesthesiology and Pediatrics (Adj.)
University of Washington School of Medicine
Director, Department of Anesthesiology and Pain Medicine
Medical Director, Bellevue Clinics and Surgery Center
Linda J. Mason, MD [59, 95]

Director of Pediatric Anesthesiology
Loma Linda University Medical Center
Lynne G. Maxwell, MD, FAAP [66]

Associate Professor Anesthesiology and Critical Care
University of Pennsylvania
Deputy Director, General Anesthesia Division
The Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania, USA
xvi
4/9/11
3:33 PM
Page xvi
Contributors
Jean Xavier Mazoit, MD, PhD [28]
Neil S. Morton, MD, FRCA, FRCPCH, FFPMRCA [41]
Dpartement dAnesthsie-Ranimation
Hpital Bictre AP-HP
Laboratoire dAnesthsie UMR788
Neuroprotection, rgnration des axones et de la myline
Universit Paris-Sud
Facult de Medecine du Kremlin-Bictre
Bictre, France
Reader in Paediatric Anaesthesia and Pain Management

University of Glasgow
Consultant in Paediatric Anaesthesia and Pain Management
Royal Hospital for Sick Children
Editor-in-Chief, Pediatric Anesthesia
Glasgow, Scotland
Craig D. McClain, MD, MPH, FAAP [93]

Associate in Anesthesia
Valeria Mossetti, MD [48]

Division of Pediatric Anesthesiology and
Regina Margherita Childrens Hospital
Turin, Italy
Etsuro K. Motoyama, MD [9]

Staff Anesthesiologist
Professor Emeritus of Anesthesiology and Pediatrics

University of Pittsburgh School of Medicine
Attending Anesthesiologist and Pulmonologist
Director Emeritus, Respiratory Physiology Laboratory
Childrens Hospital of Pittsburgh
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, USA
Patricia A. McGrath, PhD [16]
Isabelle Murat, MD, PhD [127]
Conor McDonnell, MD, MB [20]
Scientific Director
Chronic Pain Program Psychology
Research Institute
Senior Associate Scientist
Neurosciences and Mental Health
AP-HP, University Paris 6
Chairman, Departement of Anesthesia and
Armand Trousseau Hospital
Paris, France
Laura B. Myers, MD [120]
University of Helsinki
Hospital for Children and Adolescents
Helsinki, Finland

Research Associate in Anesthesia
Children's Hospital Boston
Staff Anesthesiologist
Newton-Wellesley Hospital
Hawa Keta-Meyer, MD, PhD [19]
Sif-Eddine Nejmi, MD [79]
AP-HP, University Paris 7
Director, Division of Anesthesia
Louis Mourier Hospital
Colombes, France

Hassan II Ain Chok University of Casablanca
Department of Anesthesia and Critical Care
Casablanca Childrens Hospital
Casablanca, Morocco
Gregory Moloney, MBBS, FANZCA [43]
David G. Nykanen, MD [118]
Attending Anaesthetist
Mater Childrens Hospital
Brisbane, Queensland, Australia
Associate Professor of Paediatrics (Cardiology)

University of Central Florida College of Medicine
Director, Cardiology and Cardiac Catheterization
Arnold Palmer Medical Center
Orlando, Florida, USA
Olli A. Meretoja, MD [27]
Victor H. Espinal Montoya, MD [65]

Cape Breton Regional Hospital
Sydney, Nova Scotia, Canada
Kar-Binh Ong, MBBS (London), FRCA(UK) [56]

Honorary Senior Lecturer (Institute of Child Health)
Consultant Anaesthetist (Great Ormond Street Hospital)
Great Ormond Street Hospital
London, England
4/9/11
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Page xvii
Contributors xvii
Gilles Orliaguet, MD, PhD [53, 112]
Aurelia Peraud, MD, PhD [92]
Professeur dAnesthsiologie et Ranimation

Universit Paris Descartes Facult de Mdecine, AP-HP
Vice Chairman
Dpartement dAnesthsie et Ranimation
Paris, France
Associate Professor of Surgery (Neurosurgery)

Ludwig-Maximilian University of Munich
Chief, Division Pediatric Neurosurgery
Attending Pediatric Neurosurgeon and Epilepsy Surgeon
Department of Neurosurgery
Klinikum Grosshadern
Munich, Germany
Nicholas Pace, FRCA, FRCP, MPhil, PhD [128]

Clinical Director
Department of Anaesthesia
Gartnavel General Hospital
Glasgow, Scotland
Greta M. Palmer, MBBS, FANZCA, FFPMANZCA [26]

Deputy Head, Childrens Pain Management Service
Paediatric Anaesthetist and Pain Management Specialist
Royal Childrens Hospital
Murdoch Childrens Research Institute
Blake C. Papsin, MD, MSc, FRCSC, FACS, FAAP [98]

Professor of Otolaryngology
Faculty of Medicine
The University of Toronto
Cochlear Chair in Auditory Development
Director of the Cochlear Implant Program
Attending Otolaryngologist
Associate Scientist, Neurosciences and Mental Health
The Research Institute
Catherine Paquet, MD, FRCPC [54]

McGill University
Montreal Childrens Hospital
Olivier Paut, MD [40]

Head, Department of Pediatric Anesthesia and
Marseille, France
Dilip Pawar, MBBS, DA, MD, FAMS, FAMS(S) [29]

All India Institute of Medical Sciences
New Delhi, India
Daniel A. Peters, MD, MBA, FRCSC [116]

Assistant Professor of Surgery (Plastic Surgery)
Telfer School of Management
Robert Plant, FCARCSI, FJFICM(Ireland),

FJFICM(Aus/NZ) [10]
Director of Intensive Care
Cork University Hospital
Cork, Ireland
David M. Polaner, MD, FAAP [130]

University of Colorado School of Medicine
Chief, Acute Pain Service
Anesthesia Informatics
The Childrens Hospital of Denver
Aurora, Colorado, USA
George D. Politis, MD, MPH [21]

Associate Professor of Anesthesiology and Pediatrics
University of Virginia
Co-Director of the University of Virginia
Outpatient Surgical Center
University of Virginia Health System
Charlottesville, Virginia, USA
Elizabeth Prentice, MBBS, FANZCA [70]

Attending Paediatric Anaesthetist
Carlos Hervs Puyal, MD [12]

Consultant Pediatric Anesthesiologist
Hospital Universitario Vall dHebron
Barcelona, Spain
Abdullah A. Al-Rabeeah, MD, FRCSC [114]

Minister of Health, Kingdom of Saudi Arabia
King Saud bin Abdulaziz University for Health Sciences
Senior Pediatric Surgeon
King Abdulaziz Medical City (National Guard Health Affairs)
Riyadh, Saudi Arabia
4/9/11
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Page xviii
xviii Contributors
Carmen T. Ramos, MD, MSc [85]
Sophie Saindon, MD, FRCP(C) [55]
Ad Honorem Associate Professor of Surgery

University of Puerto Rico
Chief, Division of Pediatric Surgery
San Jorge Childrens Hospital
San Juan, Puerto Rico
Clinical Assistant Professor of Anesthesia

University of Montreal
Centre Hospitalier Universitaire Ste-Justine
Mother and Child University Hospital Center
Sally E. Rampersad, MD [131]
Michela Salvadore, MBChB, FRCA [57]

University of Washington School of Medicine
Director, Quality Improvement
Department of Anesthesiology and Pain Medicine
Childrens Hospital and Regional Medical Center
Pramod P. Reddy, M.B.B.S. [87]

Associate Professor of Urology
University of Cincinnati
Director, Division of Pediatric Urology
Cincinnati Childrens Hospital Medical Center
Andrew N. Redington, MB, BS, MRCP (UK), MD, FRCP

(UK), FRCP (C) [7]
Professor of Pediatrics
BMO Financial Group Chair in Cardiology
Labatt Family Heart Centre
Head, Division of Cardiology
Senior Associate Scientist
Physiology and Experimental Medicine
The Hospital for Sick Children Research Institute
Bndicte Ringuier, MD [11]

Attending Pediatrician
Pediatric Anesthesia and Intensive Care
Angers, France
Allison Kinder Ross, MD [83]

Duke University
Chief, Division of Pediatric Anesthesia
Division of Pediatric Anesthesia and Critical Care Medicine
Duke University Medical Center
Durham, North Carolina, USA
Specialist Registrar in Anaesthesia

Royal Aberdeen Childrens Hospital
Aberdeen, Scotland
Paul J. Samuels, MD [129]

Associate Professor of Anesthesiology and Pediatrics
Director of Education
Cincinnati Childrens Hospital
Anthony D. Sandler, MBChB [89]

Diane and Norman Bernstein Chair
Professor of Surgery and Pediatrics
George Washington University
Chief, Division of Thoracic and Abdominal Surgery
Washington, DC, USA
Rosario Nuo Sanz, MD [12]

Pediatric Anesthetist
Hospital Universitario Vall dHebron
Barcelona, Spain
Frdrique Sauvat, MD, PhD [112]

Pediatric Surgeon
Centre Hospitalier Regional F. Guyon
Saint Denis de la Runion, France
Ahmed Mohamed Shalabi, MSC, MD [80]

Assistant Lecturer in Anesthesiology and
Surgical Intensive Care Medicine
Faculty of Medicine
Alexandria University
Alexandria University Hospitals
Alexandria, Egypt
Lionel Simon, MD (Deceased) [1]

Anesthesiologist
Hpital Saint-Vincent de Paul
Paris, France
David A. Rowney, MB ChB, FRCA [78]

Consultant in Paediatric Anaesthesia and
Royal Hospital for Sick Children
Edinburgh, Scotland
Craig Sims, MB BS FANZCA [35]

Clinical Senior Lecturer in Anaesthesia
School of Paediatrics and Child Health
University of Western Australia
Paediatric Anaesthetist
Princess Margaret Hospital for Children
Perth, Western Australia, Australia
4/9/11
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Page xix
Contributors xix
Jonathan H. Smith, BSc (Hons), MB, BS, FRCA [56]
Michael R. J. Sury, FFARCS [56]
Honorary Senior Lecturer in Anaesthesia

Portex Unit of Paediatric Anaesthesia
UCL Institute for Child Health
Great Ormond Street Hospital for Children
London, England
Honorary Senior Lecturer in Anaesthesia

PORTEX Unit of Paediatric Anaesthesia
Institute of Child Health
University College London
Consultant Anaesthetist
Department of Anaesthesia
Great Ormond Street Hospital NHS Trust
London, England
Raz Somech, MD, PhD [13]

Professor of Medicine (Immunology) and Pediatrics
Tel-Aviv University
Director, Division of Pediatric Immunology
Department of Pediatric
Edmond and Lily Safra Childrens Hospital
Institute of Hematology
The Sheba Cancer Research Center
Tel Hashomer, Israel
Sulpicio G. Soriano, MD, FAAP [93]

Childrens Hospital Boston Endowed Chair in
Pediatric Neuroanesthesia
William M. Splinter, MD, FRCPC [37]

Samuel Strantzas, MSc, D.ABNM [74]

Associate Clinical Neurophysiologist
Director, Division of Intraoperative Neuromonitoring
Pascal Stucki, MD, MER [124]

Mdecin Associ
Service de Soins Intensifs Mdicochirurcaux de Pdiatrie
Centre Hospitalier Universitaire Vaudois (CHUV)
Santhanam Suresh, MD [50]

Northwestern Universitys Feinberg School of Medicine
Vice Chairman
Director of Research and Pain Medicine
Childrens Memorial Hospital
Chicago, Illinois, USA
Dale F. Szpisjak, MD, MPH [54]

Uniformed Services University of the Health Sciences
Interim Chair, Department of Anesthesiology
Bethesda, Maryland, USA
Elsa Taylor, MBChB, FANZCA [24]

Starship Childrens Health
Nasrin Najm-Tehrani, MB BCh, MSc,

FRCS Ed (Ophth) [102]
Assistant Professor of Ophthalmology
Leader of ROP Program
Caroline Telion, MD [68]

Practicien Hospitalier
Dpartement dAnesthsie Ranimation
Hpital Necker Enfants Malades
Paris, France
Michael J. Temple, MD, FRCPC [121]

Assistant Professor of Radiology
Department of Medical Imaging
Attending Radiologist
Pediatric Interventional Radiology
Department of Diagnostic ImagingImage Guided Therapy
Priya Thalayasingam, MBBS, FANZCA [104]

Princess Margaret Hospital for Children
Perth, Western Australia, Australia
Joseph D. Tobias, MD [4, 15, 57]

The Ohio State University
Chairman, Department of Anesthesiology and Pain Medicine
Nationwide Childrens Hospital
Columbus, Ohio, USA
xx
4/9/11
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Page xx
Contributors
Dalia Mohamed Tohlob, MD [82]
Polina Voronov, MD [50]
Assistant Lecturer of Clinical Pathology

Faculty of Medicine, Mansoura University Hospital
Mansoura, Egypt

Northwestern Universitys Feinberg School of Medicine
Childrens Memorial hospital
Chicago, Illinois, USA
Jon Tomasson, MD [129]

Childrens Hospital and Clinics of Minnesota
Minneapolis, Minnesota, USA
Peter H. Tonner, MD [22]

Professor and Chairman
Klinikum Links der Weser, Bremen
Klinikum Bremen Nord
Bremen, Germany
Mehdi Trifa, MD [90]

Faculty of Medicine, Tunis El Manar University,
Attending Anesthetist and Intensivist
University Children Hospital
Tunis, Tunisia
Pedro Paulo Vanzillotta, MD [84]

Chief, Department of Anesthesia
Hospital Municipal Jesus
Rio de Janeiro, Brazil
Laszlo Vutskits, MD, PhD [3]

Senior Lecturer in Anesthesia
Faculty of Medicine
University of Geneva Medical School
Head, Neuroscience-Oriented Anesthesia Research Group
Department of Fundamental Neuroscience
Division of Pediatric Anesthesia
Department of Anesthesiology, Pharmacology and
Intensive Care
University Hospital of Geneva
Geneva, Switzerland
Samuel H. Wald, MD [59]

Clinical Professor, Pediatric Anesthesiology
Associate Vice-Chair of Education
Associate Director, Residency Program
David Geffen School of Medicine at UCLA
Los Angeles, California, USA
Paul W. Wales, BSc, MD, MSc, FRCSC, FACS [111]

The George Washington University Medical Center
Washington, DC, USA

Neonatal and Pediatric Surgeon
Director, Group for Improvement of Intestinal Function and
Treatment
Associate Scientist, Child Health Evaluative Sciences
Research Institute, The Hospital for Sick Children
Anne Laffargue Vetter, MD [52]
Robert Whitty, FCARCSI [33]
Susan T. Verghese, MD [69]
Director of Pediatric Anaesthesia Division

University of Lille
Lille, France
Francis Veyckemans, MD [38, 60]

Clinical Professor of Anesthesiology
Universit Catholique de Louvain (Woluw)
Cliniques Universitaires St-Luc
Brussels, Belgium
Daniel Vischoff, MD [55]

Clinical Assistant Professor of Anesthesia
University of Montreal
Centre Hospitalier Universitaire Ste-Justine
Mother and Child University Hospital Center
Consultant Pediatric Anesthetist

Childrens University Hospital
The Adelaide, Meath, and National Childrens Hospital
Dublin, Ireland
Suzanne Wiener, MD [4]

FMH Pediatrics
FMH Acupuncture
University of Geneva
Pediatric Pain Fellow
Department of Anesthesiology and Reanimation
University Hospital of Geneva, Switzerland
Geneva, Switzerland
Niall Wilton, MRCP, FRCA [42]

Clinical Director
Pediatric Anesthesia and Operating Rooms
Starship Childrens Health
4/9/11
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Page xxi
Contributors xxi
William Wisden, MA, PhD [5]
Myron Yaster, MD [66]
Professor of Molecular Neuroscience

Imperial College South Kensington, London
Head, Cell Biology and Functional Genomics Section
Blackett Laboratory
London, England
Richard J. Traystman Distinguished Professor of Pediatric

Anesthesia, Critical Care Medicine, and Pain Management
The Johns Hopkins University School of Medicine
Division of Pediatric Anesthesia
Departments of Anesthesiology, Critical Care Medicine and
Pediatrics
Childrens Hospital, The Johns Hopkins Hospital
Andrew R. Wolf, MA, MBBChir, MD, FRCA [15]

Honorary Professor of Anaesthesia
Faculty of Medicine
University of Bristol
Consultant in Paediatric Anesthesia and Intensive Care Medicine
Bristol Royal Hospital for Children (Bristol Childrens Hospital)
Bristol, England
Gordon T. C. Wong, MB BS, FANZCA [32]

Clinical Assistant Professor of Anesthesiology
University of Hong Kong
Honorary Associate Consultant
Queen Mary Hospital
Hong Kong, China
Maysaa El Sayed Zaki, MD, PhD [82]

Professor of Clinical Pathology
Faculty of Medicine, Mansoura University
Department of Clinical Pathology
Mansoura, Egypt
4/9/11
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Page xxii
4/9/11
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Page xxiii
Preface
Pediatric anesthesia is no longer a subspecialty of anesthesia; in
the twenty-first century, it is considered a professional entity. The
growing complexity of this specialty is well demonstrated in this
major addition to the medical and surgical literature. The academic
and scientific development in recent years can be well appreciated
through the exceptional contributions of the 220 collaborators
who invested a great deal of time to share their knowledge
and expertise in writing this textbook. They have successfully
demonstrated, once again, that children are not small adults in
modern anesthesia and surgery. I take this opportunity to express
to each and every one of them my sincere thanks for their
participation in this international venture.
Because of the extent of the information to be shared with
the readers, Pediatric Anesthesia: Basic PrinciplesState of the
ArtFuture is divided into six parts: Developmental Considerations; Pharmacology; Anesthesia Management and Techniques;
Special Monitoring and Resuscitation Techniques; Anesthetic,
Surgical, and Interventional Procedures Considerations; and
Specific Considerations. I hope that this approach will facilitate
consultation and optimize reading. To further demonstrate
the scientific importance of each section, an international group of
subeditors was invited to assist me with the giant task of providing
the highest quality and most in-depth information. Their
exceptional knowledge, based on a well-established international
reputation and recognized wisdom in academic pediatric
anesthesia, elevates the status of this book. I am profoundly grateful
to Drs. Brian Anderson, Adrian Bsenberg, Thomas Engelhardt,
Linda Mason, and Joseph Tobias for their extensive investment of
time and determination in making this exceptional book the
premier text in pediatric anesthesia. I wish to express to them all
my deepest gratitude for their support, enthusiasm and intellectual
generosity.
The children of the world we care for, represented by the

Children of the World Anesthesia Foundation, are the ultimate
recipients of Pediatric Anesthesia: Basic PrinciplesState of the
ArtFuture. This international organization, which I founded in
2005, is dedicated to the promotion and dissemination of
continuing education in pediatric anesthesia and critical care
medicine through the development and acquisition of basic
principles of safe practice of anesthesia for infants and children
around the world. This book will provide expanded knowledge
and substantial clinical information to healthcare professionals
to ensure that every child can aspire to the best care possible
wherever they live. The extensive electronic version of this book is
available on the Foundations website.
This unique textbook would not have been possible without
the contribution and dedication of numerous other professionals.
I would like to extend my very special thanks to Ms. Linda Mehta
and Mr. Martin Wonsiewicz at PMPH-USA for their enthusiasm,
support, and determination to make this project a reality. I am also
truly grateful to Mr. David Stockhoff and members of his team at
Spearhead Global, Inc. for their dedicated support in the making
of a book that is beyond compare. I also express my gratitude to
Mr. Danny Aguilar, medical graphic artist and illustrator, for his
unique contribution to the visual beauty of this book.
Finally, on behalf of the subeditors, collaborators, and everyone
else involved in this venture, I would like to express to each reader
our sincere thanks for your interest in pediatric anesthesia and
your intellectual curiosity. We hope you will find it a thoughtful
and useful resource in your everyday professional activities and
immediately adopt it as your best academic friend.
Merci!
Bruno Bissonnette
4/9/11
3:33 PM
Page xxiv
4/9/11
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Page xxv
Contents
PART I
DEVELOPMENTAL CONSIDERATIONS
Subeditor: Joseph D. Tobias
CHAPTER 1
Prenatal Normal and Abnormal Development
20
43
58
71
80
Bruno Bissonnette
CHAPTER 7
Normal and Abnormal Development
of the Heart and the Circulation
181
CHAPTER 13
Principles of Hematopoiesis,
Immunity, and Coagulation
203
CHAPTER 14
Temperature Regulation: Physiology
and Pharmacology
221
Igor Luginbuehl
Thomas Engelhardt and William Wisden
CHAPTER 6
Central Nervous System: Anatomy and Physiology
CHAPTER 12
Endocrine System
Chaim Kaplinsky, Raz Somech, and Gili Kenet
Suzanne Wiener and Joseph D. Tobias
CHAPTER 5
Central Nervous System:
Neurotransmitters and Anesthesia
170
Carlos Hervs Puyal, Manuel Garca Grriz,

and Rosario Nuo Sanz
Laszlo Vutskits
CHAPTER 4
Nociception and Pain Perception
in Infants and Children
CHAPTER 11
Digestive System, Metabolic
Functions, and Nutrition
Bndicte Ringuier, Jean-Louis Ginis,
and Jean-Claude Granry
Ruth Oelhafen Luginbuehl
CHAPTER 3
Anesthesia and the Developing Brain
140
John Chandler and Robert Plant
Gilles Boulay, Lionel Simon, and Jamil Hamza
CHAPTER 2
General Growth and Tissue
Development Throughout Childhood
CHAPTER 10
Renal Function, Acid-Base, and
Electrolyte Homeostasis
CHAPTER 15
Development and Evaluation of Pain
and the Stress Response
R. Blaine Easley, Kenneth M. Brady, Andrew R. Wolf,
Kanwaljeet J. S. Anand, and Joseph D. Tobias
CHAPTER 16
Chronic and Recurrent Pain in the
Pediatric Patient
91
259
273
Stephen C. Brown and Patricia A. McGrath
Christian Apitz and Andrew N. Redington
CHAPTER 8
Airway Development
PART II
PHARMACOLOGY
100
Pierre Fayoux and Bruno Marciniak
CHAPTER 9
Respiratory Physiology
Etsuro K. Motoyama
106
291
Subeditor: Brian J. Anderson
CHAPTER 17
An Introduction to the Intricacies
of Pharmacology in Pediatrics
Brian J. Anderson
291
xxvi
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Page xxvi
Contents
CHAPTER 18
Using Pharmacokinetics and Pharmacodynamic
Models to Prevent Adverse Events in Neonates,
Infants, and Children
CHAPTER 31
Pharmacology of Vagal Blockers and
Antagonist Agents
297
507
Martin Jhr
Brian J. Anderson
CHAPTER 19
Mechanisms of Action of General Anesthetics
CHAPTER 32
Anticoagulants
310
Vincent P. Laudenbach, Souhayl Dahmani,

Hawa Keta-Meyer, and Jean Mantz
CHAPTER 20
Nitrous Oxide
CHAPTER 33
Pharmacology of Vasopressive Agents
323
544
CHAPTER 35
Resuscitation Agents
552
Craig Sims
347
Peter H. Tonner
CHAPTER 23
Intravenous Agents
CHAPTER 34
Antiemetic Agents
Mario J. da Coneicao
George D. Politis
CHAPTER 22
Xenon and Anesthesia: Pharmacology
535
Robert Whitty
317
Conor McDonnell
CHAPTER 21
Volatile Anesthetics
525
Gordon T. C. Wong
PART III
ANESTHESIA MANAGEMENT
AND TECHNIQUES
355
Subeditor: Adrian Bsenberg
376
CHAPTER 36
Preoperative Evaluation, Laboratory Testing,
and Preparation for Anesthesia and Surgery
571
Peter D. Booker and Neroli Chadderton
CHAPTER 24
Ketamine
571
Elsa Taylor
Robin G. Cox
CHAPTER 25
Opioid Analgesic Agents
CHAPTER 37
Premedication, Sedation, and Preoperative Fasting 584
387
William M. Splinter and Jarmila Kim
Jason A. Hayes and Daisy T. Joo
CHAPTER 26
Non-Opioid Analgesic Agents
406
Greta M. Palmer
CHAPTER 27
Neuromuscular Blocking Agents in Children
416
Olli A. Meretoja and Hannu Kokki
CHAPTER 28
Pharmacology of Local Anesthetics
441
Jean Xavier Mazoit
CHAPTER 29
Adjuvants to Local Anesthetics
473
CHAPTER 38
Anesthesia Equipment
Francis Veyckemans
CHAPTER 39
Induction of Anesthesia
CHAPTER 40
Maintenance of Anesthesia: Inhalational Agents
690
Olivier Paut, Frdric Lamy, and Magalie Gurin
CHAPTER 41
Maintenance of Anesthesia: Total
Intravenous Anesthesia
Neil S. Morton
CHAPTER 30
Pharmacology of Premedication
and Sedative Agents in Children
CHAPTER 42
Modern Modes of Ventilation in
the Operating Room
491
669
Cengiz Karsli and Lisa A. Isaac
Dilip Pawar
George A. Chalkiadis
594
Niall Wilton and David Buckley
709
716
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Page xxvii
Contents
CHAPTER 43
Which Endotracheal Tube in Neonates,
Infants, and Small Children?
747
CHAPTER 56
Sedation and Anesthesia for Procedures
Outside Operating Theaters
Gregory Moloney
Jonathan H. Smith, Kar-Binh Ong, and Michael R. J. Sury
CHAPTER 44
Regional Anesthesia: Principles of
Localization Using Manual Approaches
CHAPTER 57
Acute Complications During Anesthesia
753
xxvii
886
905
Michela Salvadore, Thomas Engelhardt, and Joseph D. Tobias
Hans Jutzi and Alain Borgeat
CHAPTER 45
Regional Anesthesia: Principles of
Localization Using Electrical Stimulation
CHAPTER 58
Emergence and Postoperative Care
Justin L. Lockman and R. Blaine Easley
757
CHAPTER 59
Anesthesia for the Patient With
Coexisting Diseases
Jean-Louis Feugeas, Frdric Lacroix,

Olivier Choquet, and Xavier Capdevila
CHAPTER 46
Regional Anesthesia: Principles of Localization
Using Ultrasound Techniques
924
942
Brenna L. Jacobson, Samuel H. Wald, and Linda J. Mason
767
Peter Marhofer
CHAPTER 60
Anesthesia for Laparoscopic Procedures
968
Francis Veyckemans
CHAPTER 47
Regional Anesthesia: Upper Limb Blocks
783
Katherine Keech and Adrian Bsenberg
CHAPTER 48
Regional Anesthesia: Lower Limb Blocks
806
Adrian Bsenberg
CHAPTER 50
Regional Anesthesia: Head and Neck Blocks
823
CHAPTER 51
Regional Anesthesia: Thorax and Abdomen Blocks 833
Michael J. Fredrickson
843
Nathalie Bourdaud and Gilles Orliaguet
CHAPTER 54
Perioperative Blood Sparing Techniques
in Pediatric Patients
994
Corinne Lejus and Karim Ashenoune
CHAPTER 64
Pediatric Critical Care
1008
Barry Lyons, Tsz-Yan Milly Lo, and Peter N. Cox
1043
Victor H. Espinal Montoya
CHAPTER 66
Pediatric Pain Management
850
988
Karen A. Brown
CHAPTER 65
Intrahospital Patient Transportation
Anne Laffargue Vetter
CHAPTER 53
Transfusion for the Pediatric Patient
CHAPTER 62
A Pragmatic Approach to Pediatric
Obstructive Sleep Apnea
CHAPTER 63
Anesthesia for the Acutely Ill Patient
Polina Voronov and Santhanam Suresh
CHAPTER 52
Fluid Therapy for the Pediatric Surgical Patient
981
Walid Habre
793
Giorgio Ivani and Valeria Mossetti
CHAPTER 49
Regional Anesthesia: Central Neuraxial Blocks
CHAPTER 61
Anesthesia for Non-Cardiac Surgery
in Children With Congenital Heart Disease
1048
Sabine Kost-Byerly, Lynne G. Maxwell, and Myron Yaster
PART IV
SPECIAL MONITORING AND
RESUSCITATION TECHNIQUES
861
Subeditor: Bruno Bissonnette
873
CHAPTER 67
Cardiopulmonary Resuscitation
of the Infant and the Child
1065
Dale F. Szpisjak and Catherine Paquet
CHAPTER 55
Outpatient Anesthesia
Daniel Vischoff and Sophie Saindon
Swati Agarwal and Gregory B. Hammer
1065
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xxviii Contents
CHAPTER 68
Prehospital Cardiorespiratory
and Trauma Resuscitation
CHAPTER 81
Pediatric Features of Malignant Hyperthermia
1081
Rene Krivosic-Horber
1097
CHAPTER 82
Influence of Anesthesia on the Immune
System in Children
1362
Pierre Carli and Caroline Telion
CHAPTER 69
Peripheral Vascular Access
Susan T. Verghese and Raafat S. Hannallah
CHAPTER 70
Central Vascular Access
1114
Elizabeth Prentice
CHAPTER 71
Prolonged Vascular Access
1155
1167
1186
Dominique A. Bettex and Pierre-Guy Chassot
CHAPTER 74
Principles of Neuroelectrophysiology Monitoring
1213
Samuel Strantzas and Laura Holmes
CHAPTER 75
Brain Monitoring
1392
CHAPTER 84
Miscellaneous Techniques
1406
Pedro Paulo Vanzillotta
Giuseppe Marraro
CHAPTER 73
Transesophageal Echocardiography
in Congenital Heart Disease
CHAPTER 83
Specific Problems and Anesthesia Management
of Extremely Low Birthweight Infants
Richard J. Ing and Allison Kinder Ross
Jean Godard
CHAPTER 72
Airway Management
1379
Farha Abd El-Aziz El-Chennawi, Maysaa El Sayed Zaki,

Hanan Azam, and Dalia Mohamed Tohlob
PART V
ANESTHETIC, SURGICAL, AND
INTERVENTIONAL PROCEDURES:
CONSIDERATIONS
1421
Subeditor: Linda J. Mason
CHAPTER 85
Management of the Neonate:
Surgical Considerations
1421
Carmen T. Ramos and Peter C. W. Kim
1245
Isabelle Constant
CHAPTER 86
Management of the Neonate:
Anesthetic Considerations
1437
Per-Arne Lnnqvist
CHAPTER 76
Spinal Cord Monitoring
1262
Emmanule Laureau and Jean-Daniel Guieu
CHAPTER 87
Genitourinary Tract: Surgical Considerations
1476
Pramod P. Reddy and Antoine E. Khoury
CHAPTER 77
Depth of Anesthesia Monitoring
and Awareness
1285
1304
David A. Rowney
CHAPTER 79
Gastrointestinal Procedures
1334
CHAPTER 89
Digestive Tract Procedures:
CHAPTER 90
Digestive Tract Procedures:
Sonia ben Khalifa and Mehdi Trifa
CHAPTER 80
Patient Positioning and Precautions
During Anesthesia and Surgery
CHAPTER 91
Bone and Joint Surgery: Anesthetic
Considerations and Postoperative Management
1341
1501
Steven T. Elliott and Anthony D. Sandler
Sif-Eddine Nejmi and Badr-Eddine Hmamouchi
Ahmed Mohamed Shalabi
1496
Jayant K. Deshpande
Andrew Davidson
CHAPTER 78
Cardiovascular Monitoring and
Cardiothoracic Procedures
CHAPTER 88
Genitourinary Tract: Anesthetic Considerations
Mary Cunliffe
1520
1527
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Contents
CHAPTER 92
Neurosurgery and Neurotraumatology:
1551
CHAPTER 105
Heart and Lung Transplantation:
Aurelia Peraud
Osami Honjo and John G. Coles
CHAPTER 93
Neurosurgery and Neurotraumatology:
CHAPTER 106
Heart and Lung Transplantation:
1569
Craig D. McClain and Sulpicio G. Soriano
Dean B. Andropoulos
CHAPTER 94
Cardiovascular Procedures:
CHAPTER 107
Liver Transplantation: Surgical Considerations
1589
Osami Honjo and Glen S. Van Arsdell
CHAPTER 95
Cardiovascular Procedures:
1609
1641
1655
1668
CHAPTER 99
Otorhinolaryngology: Anesthetic Considerations 1699
Alison S. Carr and David Elliott
1722
David M. Fisher
CHAPTER 101
Plastic Procedures: Anesthetic Considerations
1728
1738
Priya Thalayasingam
CHAPTER 111
Intestinal and Pancreatic Transplantation:
1843
Rodrigo A. Iniguez and Paul W. Wales
CHAPTER 112
Intestinal and Pancreatic Transplantation:
1850
Nathalie Bourdaud, Frdrique Sauvat, and Gilles Orliaguet
CHAPTER 113
Bone Marrow Transplantation:
Hematological and Anesthetic Considerations
1859
CHAPTER 114
Conjoined Twins: Surgical Considerations
1867
CHAPTER 115
Conjoined Twins: Anesthetic Considerations
1877
Mohamed El-Gammal
CHAPTER 116
Craniofacial Malformations:
1757
Daniel A. Peters and Christopher R. Forrest
1768
CHAPTER 117
Craniofacial Malformations:
Marie Granier
CHAPTER 104
Anesthesia for Organ Retrieval
CHAPTER 110
Renal Transplantation: Anesthetic Considerations 1836
Abdullah A. Al-Rabeeah
Asim Ali, Nasrin Najm-Tehrani, Wai-Ching Lam,

and Elise Hon
CHAPTER 103
Ophthalmological Procedures:
1821
John Doyle and Justin John
James Flowerdew
CHAPTER 102
Ophthalmological Procedures:
CHAPTER 109
Renal Transplantation: Surgical Considerations
Jonathan de Lima and Peter Gibson
Blake C. Papsin and Sharon L. Cushing
CHAPTER 100
Plastic Procedures: Surgical Considerations
1807
Cassandra M. Kelleher and Annie Fecteau
Walid A. Farhat and Armando J. Lorenzo
Patrick T. Farrell
CHAPTER 98
Otorhinolaryngology: Surgical Considerations
1793
Charles Lee
J. Ted Gerstle
CHAPTER 97
Thoracic Surgery: Anesthetic Considerations
1781
CHAPTER 108
Liver Transplantation: Anesthetic Considerations 1816
Carol L. Lake, Linda J. Mason, and Peter D. Booker
CHAPTER 96
Thoracic Surgery: Surgical Considerations
xxix
Mark F. Levine
1891
1920
xxx
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Contents
CHAPTER 118
Interventional Cardiac Catheterization
Procedures: Cardiology Considerations
CHAPTER 126
Dental Procedures: Anesthetic Considerations
1934
2080
Steven Ganzberg and Brian Chanpong
David G. Nykanen
CHAPTER 119
Interventional Cardiac Catheterization
Procedures: Anesthetic Considerations
PART VI
SPECIFIC CONSIDERATIONS
1952
Subeditor: Thomas Engelhardt
1971
CHAPTER 127
Mortality, Morbidity, and
Outcome in Pediatric Anesthesia
2091
Peter C. Laussen and Brendan OHare
CHAPTER 120
Fetal Anesthesia
Laura B. Myers
Isabelle Murat
CHAPTER 121
Interventional Radiology:
Radiological Considerations
CHAPTER 128
Consent, Research, and Withdrawing Treatment
2002
2091
2109
Nicholas Pace and David A. Blacoe
Michael J. Temple and Bairbre Connolly
CHAPTER 122
Interventional Radiology: Anesthetic
Considerations and Postprocedural
Management
CHAPTER 129
Training and Education in Pediatric Anesthesia
2119
Paul J. Samuels, Jon Tomasson, and Charles D. Kurth
2015
Christopher M. Bolton
CHAPTER 130
Acute Pain Service
2132
Rita Agarwal and David M. Polaner
CHAPTER 123
Burns and Post-Burn Care:
2031
CHAPTER 131
Quality Improvement
Howard M. Clarke and Tristan M.B. de Chalain
Sally E. Rampersad and Lynn D. Martin
CHAPTER 124
Burns and Post-Burn Care:
CHAPTER 132
Special Problems in Developing Countries
2049
Marc-Andr Bernath, Pascal Stucki,

and Mette M. Berger
CHAPTER 125
Dental Procedures: Surgical Considerations
David J. Kenny and Michael J. Casas
2143
2155
Adrian Bsenberg and Zipporah Njeri Gathuya
CHAPTER 133
Implications for Humanitarian Anesthesia
2173
George A. Gregory
2071
Index
2183
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Developmental Considerations
P A R T
1
C H A P T E R
Prenatal Normal and Abnormal

Development
Gilles Boulay, Lionel Simon, and Jamil Hamza
INTRODUCTION
The subspecialties of pediatric anesthesiology and pediatric
intensive care medicine have seen remarkable growth since the
1980s. This growth has included the establishment of fellowship
programs, the establishment of guidelines for the accreditation of
these programs, the institution of a formal written examination
process for pediatric intensive care medicine leading to board
certification, and the plans for a written examination in pediatric
anesthesiology. There has also been increasing recognition of the
value of such training and the attainment of board certification
not only by pediatricians and pediatric surgeons but also by
physicians outside of our own subspecialty. The recognition that
neonates, infants, and children may require subspecialists to
provide their perioperative care has partly grown from the
acceptance that the anatomy, physiology, and pharmacology of
pediatric patients differ from those of their adult counterparts.
That being said, it becomes obvious that children are not just little
adults and that variability in the response to many pharmaceutical agents is just one of many variations that may exist in this
population.
When dealing with infants and children, the anesthesiologist
is faced with variations not only in size, gestational age, and anatomic parameters but also in metabolic, cellular, and subcellular
ones. Pediatric anesthesiologists are frequently called upon to
anesthetize children with various congenital anomalies and malformations. As outlined in the chapters that follow in this section,
a myriad of processes must occur for normal development to take
place. Given the intricacies of these processes, it is amazing that
the majority of these defects are relatively uncommon in the
general population. By understanding the processes that must
occur for normal development, we can gain an understanding of
how defects during the embryonic period can result in devastating
anatomic abnormalities. Given that numerous processes occur
simultaneously in various organ systems, congenital anomalies in
several organ systems may coexist. In addition to the deviations
from normal development that may result in congenital anomalies, even the normal developmental processes, which continue
following birth, have specific implications for the perioperative

care of infants and children. These normal developmental processes may affect the response of infants and children to various
anesthetic agents.
Knowledge of the normal and abnormal prenatal development
is necessary for the pediatric anesthesiologist who is becoming
increasingly involved in fetal-neonatal surgical procedures, which
may occur immediately after birth or even before with the growing
field of in utero surgery. The goals of this, the first chapter of this
textbook on pediatric anesthesiology, are to (1) describe the
normal and abnormal developmental stages of the embryonic and
fetal periods, (2) show how some maternal disorders (hypertension, diabetes) or drug ingestions (tobacco, alcohol, cocaine)
during this critical period can alter normal fetal development,
(3) discuss the fetal and neonatal problems associated with
intrauterine growth retardation (IUGR) and premature birth,
which remain the two primary causes of perinatal mortality and
morbidity, (4) explain why and how acute fetal distress can lead to
definitive neurologic impairment, and (5) develop a comprehensive approach to diagnosis and therapy.
NORMAL AND ABNORMAL

EMBRYOLOGIC DEVELOPMENT
The human pregnancy usually lasts 266 days (38 wk) from fertilization to birth. Prenatal growth can be divided in two periods:
(1) embryonic and (2) fetal. During the embryonic period, most
major organ systems are formed (organogenesis). During the fetal
period (from 8 wk to birth), functional development of organ
systems and maturation take place.
Normal Embryonic Development

(First 8 Weeks)15
The embryonic development begins when the zygote containing a
single diploid nucleus forms as a spermatocyte and an oocyte join
during the process of fertilization. While a series of cell divisions
occur, the embryo travels toward the uterus. Further cleavage
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Figure 1-1. Formation of the blastocyst.
results in the zygote with 16 cells that organize in two separate

groups of cells. The peripheral outer cell mass (trophoblast) will
yield the placenta and membranes, whereas the central inner cell
mass (embryoblast) will form the embryo. By the 30-cell stage, the
blastocyst cavity develops (morula). At the end of the first week,
the embryo enters the uterine cavity and implants into the
endometrial lining of the uterine wall. At this point, it is then
designated a blastocyst (Figure 11). At the beginning of the
second week, the embryoblast splits into the epiblast or primary
ectoderm and the hypoblast or primary endoderm, thus creating
a dorsoventral axis in the embryo (bilaminar embryo). The
trophoblast differentiates into two tissues: the cytotrophoblast and
the syncytiotrophoblast. During the second week, the amniotic and
chorionic cavities appear. Gastrulation begins at the third week as
the bilaminar germ disk becomes trilaminar with the formation
of the mesoblast (Figure 12). The neural plate and groove appear.
Figure 1-2. Formation of the trilaminar germ disk. (1) Amniotic

cavity. (2) Hensen node and primitive streak, then neural groove.
(3) Chorionic cavity. (4) Epiblast. (5) Hypoblast. (6) Migration of
epiblastic cells. (7) Mesoblast.
The caudal eminence and first somites form (Figure 13) while
neuromeres develop into the presumptive brain vesicles. At the
end of the third week, a primitive heart tube is formed and the
embryologic vasculature begins.
From the fourth to eighth week of gestation (organogenesis
period), the three primitive layers (ectoblast, mesoblast, and endoderm) differentiate into different tissues and organs. The
embryonic plate folds laterally; its cranial and caudal ends expand
and the limbs begin to develop. The embryonic plate acquires a
human-like shape. The ectoderm differentiates into tissues and
organs that will eventually have contact with the external environment (central and peripheral nervous system, skin, sweat glands,
mammary glands, teeth, and epithelial structures of the eyes, ears
and neck). The mesoderm yields the somites, dermis, epidermis,
cardiovascular system (heart, arteries, venous and lymphatic
vessels), urogenital system (kidney, gonads), spleen, and adrenal
cortex. The endoderm provides the epithelium of the digestive
system, respiratory tract, and bladder as well as forming the
parenchyma of the liver, pancreas, and some glandular structures
(thyroid, parathyroid, thymus, salivary). The myocardium develops and the heart begins to beat during the fourth week. The
process of neurulation converts the neural plate into a neural tube,
which begins the differentiation of the brain and spinal cord. At
the same time, the pulmonary primordium and hepatic plate
appear. The optic system begins to form (sulci, vesicles, and pit).
The somites divide into three structures: (1) myotomes,
which provide the segmental musculature of the back and the
Figure 1-3. The development of the somites and neural tube.

(1) Somite. (2) Neural tube.
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CHAPTER 1
anterolateral body wall; (2) dermatomes, which form the dermis
of the scalp, neck, and trunk; and (3) sclerotomes, which develop
into vertebral bodies and arches. Spinal defects such as scoliosis or
spina bifida result from the abnormal induction of the sclerotome
and the neural tube at the level of the first five somites (from day
22 onward). The two opposite orifices of the neural tube are
termed the cranial and the caudal neuropores. The cranial neuropore closes on day 24 and the caudal neuropore on day 26.
Neural crest cells migrate to several locations in the body where
they differentiate into different structures and cell types. The fifth
week is critical for the development of the peripheral nervous
system. At day 28, motor neurons appear in the central column of
the neural tube (starting in the cervical region). Spinal nerves
begin to sprout and grow into myotomes on day 32 and the three
main subdivisions of the brain (forebrain, midbrain, and hindbrain) become identifiable. At the end of the embryonic period,
the gross structure of the nervous system is developed.
Figure 1-4. Formation of the heart

(timeline). From Larsen WJ. Human
Embryology. 2nd ed. New York: Churchill
Livingstone; 1997. Chapter 7, p. 152.
The lung bud appears at approximately day 24. It elongates to

form the primordial trachea and branches to form the bronchial
tree and the epithelial lining of the lungs (including the alveoli).
Segmental bronchi develop and the diaphragm is complete at day
52. The primitive heart tube appears around day 20 and its folding
is completed by day 30. Between weeks 5 and 8, the primitive heart
tube undergoes a process of looping, remodeling, and septation
that transforms the single lumen into four cavities. During the
fifth and sixth weeks, a pair of septa (septum primum and
secondum) develop to separate the right and left atria. A pair of
foramina that perforate these septa (ostia primum and secundum)
allow the right-to-left shunting of blood. The mitral and tricuspid
atrioventricular valves develop during this period. They are
finalized by the third month. The coronary sinus is formed at day
52 (Figure 14). The gut tube is formed at day 24. By the fifth
week, the abdominal portion of the foregut divides into three
parts: esophagus, stomach, and proximal duodenum. During the
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sixth and seventh weeks, the stomach rotates. This rotation and
the secondary fusion of the duodenum to the dorsal body wall
create the lesser sac of the peritoneal cavity, and the remaining
cavity develops as the greater sac. By the fifth week, rapid elongation of the ileum produces a primary intestinal loop that herniates
through the umbilicus. This herniated organ fully retracts into the
abdominal cavity during the 10th week. The rotation of the midgut
produces the definitive configuration of the small and large
intestines (Figure 15). The distal hindgut gives rise to the rectum
and the urogenital sinus. The major stages of the embryonic
development from day 1 to day 56 are summarized in Table 11.
Normal Fetal Development

(From 8 Weeks to Term)
The embryo becomes a fetus at the beginning of the third month.
During the fetal period, there is an increase in cell number and
size and a remodeling of several organ systems concomitant with
their maturation. The growth in length is particularly rapid from
the third to the fifth month (~5 cm/mo). The weight of the fetus
increases from 8 g at the eighth week to 3400 g at birth (a 425-fold

increase) (Figure 16). Weight gain occurs in the third trimester,
mainly in the last 2 months of pregnancy (700 g/mo). Major
changes in body proportions occur concomitantly. The head
represents half of the crown-rump length at 9 weeks, one third
of this length at the end of the fifth month, and one fourth at
birth. Fetal life is supported by the placenta, an organ with
maternal (decidua basalis) and fetal (chorion) components. The
placenta provides the fetus with oxygen and nutrients from
maternal blood and eliminates the metabolic waste of the fetus.
By 10 weeks, there is a 180-degree counter-clockwise rotation of
the midgut returning from the umbilical cord into the abdomen,
bringing the stomach and the small and large intestine into their
normal positions.
By 12 weeks, the glandular stage of pulmonary development induces the formation of intrasegmental airways and
associated vessels. The gender of the external genitalia becomes
identifiable. From the 16th to the 24th week, the canalicular stage
involves growth of the liquid-filled airways. The lung develops a
viable gas-exchanging surface and surfactant production begins.
Figure 1-5. Herniation and

rotations of intestine. (1) Primary
intestinal loop. (2) Stomach.
(3) Aorta. (4) Superior mesenteric
artery. (5) Liver. (6) Small intestine.
(7) Colon. (8) Rectum. From
Larsen WJ. Human Embryology.
2nd ed. New York: Churchill
Livingstone; 1997. Chapter 9,
p. 241.)
Blastocyst
Upper limb bud

forms
Optic cup
Otic invagination
Closure of neural
tube
Lower limb bud
forms
Lens invagination
Otic vesicle
Olfactory
placodes
Thyrod and
parathyrods
develop
Nasal swellings
Secondary palate Early muscle is

formed
present
Facial swellings
fused
Metanephric
blastema appear
Secondary bronchi Ureteric bud enter

metanephric
buds
blastema
Major calyces form
Minor calyces form
Kidneys ascend
Stomach rotation
Duodenal lumen Tertiary bronchi
Aorta
obliterated,
Pulmonary artery
cecum rotates
Valves
Membrane
right
Ventricular
septum
Tracheal cartilage
Coronary sinus
formed
Anorectal canal
completed
Sympathetic trunks
begin to form
Limb buds are
innervated as
they form
Vagal fibers
innervate heart
Most of spinal
ganglia formed
34 (7)
38 (11)
52 (23)
Adapted from reference 6.
55 (28)
CHAPTER 1
44 (17)
24 (2)
Primary bronchi
Extremities
and Other
Ventral roots begin Complete folding

to form
30 (4)
Face
Optic evagination
Otic placode
Allantois
Urologic
Mandible
Hyoid arches
Gut tube
Lung
Mesonephric
ridge
Heart beats at
22 d
Yolk sac
Gut
Lung bud appears
Enlargement of
anterior neural
plate
Neural crest cells
migrated
Heart
4:17 PM
19 (1)
Central Nervous
System
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714 (0.1)
Appearance
Age, d
(Length, mm)
TABLE 1-1. Normal Embryonic Development and Malformation
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5
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TABLE 1-2. Relative Timing and Developmental Pathology of Some Malformations

Tissues
Cause Prior to
Comment
Central nervous Anencephaly

Meningomyelocele
system
26 d
28 d
Face
Closure of anterior neural tube

Closure in a portion of the
posterior neural tube
Cleft lip
Closure of lip
Cleft maxillary palate
Fusion of maxillary palatal
shelves
Branchial sinus and/or cyst Resolution of branchial cleft
Esophageal atresia and
Lateral septation of foregut into
tracheoesophageal fistula
trachea and foregut
Rectal atresia with fistula
Lateral septation of cloaca
into rectum and urogenital
sinus
Duodenal atresia
Recanalization of duodenum
Malrotation of gut
Rotation of intestinal loop
36 d
10 wks
Subsequent degeneration of
forebrain
80% lumbosacral
42% associated with cleft palate
Omphalocele
Return of midgut from yolk sac

to abdomen
Obliteration of vitelline duct
Closure of pleuroperitoneal
canal
Migration of infraumbilical
mesenchyme
Fusion of lower portion of
mllerian ducts
Fusion of urethral folds
Descent of testicle into scrotum
Directional development of
bulbus cordis septum
Closure of ventricular septum
Closure of ductus arteriosus
Genesis of radial bone
10 wk
Separation of digital rays

Prechordal mesoderm
development
Development of posterior axis
6 wk
23 d
Gut
Malformation
Meckels diverticulum
Diaphragmatic hernia
Genitourinary
system
Extroversion of bladder
Bicornuate uterus
Limb
Hypospadias
Cryptorchidism
Transposition of great
vessels
Ventricular septal defect
Patent ductus arteriosus
Aplasia of radius
Complex
Syndactyly
Cyclopia
Heart
Sirenomelia
Defect in
8 wk
30 d
6 wk
78 wk
10 wk
10 wk
6 wk
30 d
Associated incomplete or
aberrant mesenteric
attachment
May contain gastric and/or
pancreatic tissue
Associated mllerian and
wolffian duct defects
10 wk
12 wk
79 mo
34 d
6 wk
910 mo
38 d
23 d
Often accompanied by other

defects of radial side of distal
limb
Secondary defects of midface
and forebrain
Associated defects of cloacal
development
Abnormal Development69
Abnormal development may result from chromosomal anomalies
that cause approximately 40 to 50% of spontaneous abortions
(when the products of conception are examined) (Table 12).
Many chromosomal anomalies are not lethal and lead to abnormal
developmental syndromes (Down syndrome). Other chromosomal anomalies include monosomy, trisomy, mosaic, translocations, triploidy, or tetraploidy. They may result in any of three
types of developmental pathology including (1) malformation
(poor tissue formation), (2) deformation (because of altered
mechanical forces on a normal tissue), and (3) disruption (breakdown of a previously normal tissue). Apart from chromosomal
anomalies, several types of malformations can be observed.
Incomplete morphogenesis is due to an incomplete stage in the
development of a structure. To this group belong syndactyly
(incomplete separation of fingers), cleft palate (incomplete closure

of the palate), and malrotation of the gut (incomplete rotation of
the gut). Another type of malformation is the aberrant form,
which never exists at any stage of normal development. Accessory
tissues such as polydactyly or accessory spleens belong to another
type of malformation. The accessory tissue is initiated at the same
time as the normal tissue. Hamartomas are organizational defects
leading to an abnormal admixture of tissues. Somesuch as
hemangiomas, melanomas, fibromas, and adenomashave a
malignant potential.
Congenital Diaphragmatic Hernia

This malformation occurs in 1 of 2500 live births, affecting the left
side four to eight times more than the right side. It results from
closure anomaly of the pericardioperitoneal canal. Consequently,
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CHAPTER 1
abdominal organs develop in the pleural cavity, which impairs the
growth of the ipsilateral lung. Although surgical correction can be
achieved while the fetus is still in utero, in most cases, it is performed after birth.
Esophageal Atresia
This disorder seems to result from the failure of the esophageal
endoderm to proliferate rapidly enough during the fifth week to
coincide with the elongation of the embryo. Five different types
are described, with or without an esophagotracheal fistula. This
anomaly should be rapidly repaired at birth because of the risk of
aspiration.
Spina Bifida
Spina bifida is a closure anomaly of the spinal canal during the
third week. It occurs most frequently in the lumbosacral region.
The consequences of this defect in neural tube closure can be
severe, with the dura and/or the arachnoid protruding from the
vertebral canal (meningocele and/or meningomyelocele). The
mildest form of spina bifida is termed occulta; in this, the vertebral
arches of a single vertebra fail to fuse without protrusion of neural
structures from the spinal canal and any defect in the skin and
overlying structures.
Hirschsprung Disease
Hirschsprung disease is a congenital defect of neural crest migration giving rise to an area of constriction and paralysis of
the colonic segment. The consequence of this malformation is the
development of a characteristic dilated colon proximal to the
constricted area.
Omphalocele
Omphalocele occurs in 2.5 of 10,000 births and results from an
incomplete closure of the umbilicus. The gastrointestinal structures protrude through an unclosed umbilical ring. The omphalocele often occurs with defects in other organ systems (cardiac,
renal) or as a part of a chromosomal anomaly.
Gastroschisis
Gastroschisis occurs in approximately 1 of 10,000 births. In this
malformation, the umbilical ring closes normally. The abdominal
wall defect occurs between the developing rectus muscles just
lateral to the umbilicus, usually on the right side. The cause of this
anomaly is an abnormality in the involution of the right umbilical
vein during the fifth to sixth week. The visceral organs rarely
protrude through this defect. Gastroschisis is less often associated
with other defects than omphalocele and is not associated with
chromosomal anomalies.
MATERNAL DISORDERS:
INTRAUTERINE DEVELOPMENT
Pregnancy-Induced Hypertension
The diagnosis of preeclampsia is based on the triad of elevated
blood pressure accompanied by proteinuria and edema. This
pathology, which is unique to human pregnancy, is a complex
phenomenon characterized by an inadequate maternal vascular

response to the development of the placenta. In normal pregnancies, the development of uteroplacental arteries into spiral
arteries should convert the uteroplacental arterial bed into a lowresistance, low-pressure, and highblood flow system. The
mechanism responsible for such an evolution reflects important
and complex interactions between the trophoblastic and the
maternal endothelial cells.
In preeclampsia, a defect in trophoblastic invasion impairs the
normal development of uteroplacental arteries. The development
of large spiral arteries is limited to the decidua and a constricting
segment remains present in the external part of the myometrium.
Damage to endothelial cells, platelets, and trophoblast cells is
responsible for an intravascular activation of the coagulation
cascade and increased vascular resistance, leading to a decrease in
placental blood flow. The etiology of the original defect in trophoblastic invasion is unknown, although both genetic and immunologic factors may be involved. Vascular lesions are present in
uteroplacental arteries from the 16th week of pregnancy, long
before the development of maternal hypertension. It is postulated
that placental ischemia is a very early mechanism responsible for
the clinical manifestations of preeclampsia. No prophylactic
therapy has been shown to be effective in preventing preeclampsia.
The goal of the antihypertensive therapy in preeclampsia is to
avoid the occurrence of maternal complications of the hypertension. However, none of these treatments has clearly been shown
to improve fetal outcome. Although low-dose aspirin has been
recommended to prevent preeclampsia and to improve perinatal
outcome in women at risk for preeclampsia, such therapy has been
shown to be ineffective.10,11 Progressive deterioration in both
maternal and fetal conditions is usual in severe preeclampsia, and
delivery is the only effective treatment for this situation. Therefore,
cesarean section should be considered even at a very early stage to
avoid dramatic complications for both the mother and the infant.
Delivery of a preterm infant must be anticipated and, if the
hospital is not designed for this event, the mother should be
referred to a level III obstetric center that includes a neonatal
intensive care unit. The decision to deliver the patient is often easy
in cases of severe preeclampsia after 32 weeks of gestation.
Between 28 and 32 weeks, a short delay is often utilized before
delivery to accelerate fetal pulmonary maturation through the
administration of maternal steroid therapy.12
The incidence of growth retardation and perinatal morbidity
and mortality rates are increased in pregnancies complicated with
severe preeclampsia or eclampsia. Some authors have reported
high rates of stillbirth and/or severe neonatal complications
resulting in cerebral palsy and mental retardation in neonates born
to eclamptic women.13,14 In spite of this, several studies have
demonstrated a reduced incidence of cerebral hemorrhage in very
low birthweight (VLBW) infants when they were born to mothers
with preeclampsia. Nelson and Grether suggested that magnesium
sulfate therapy used in preeclamptic women may be responsible
for this protective effect against cerebral palsy in VLBW infants.15
The primary factors associated with a poor neonatal prognosis
include the early onset of preeclampsia (before 37 wk), prematurity, multiple pregnancy, severity of the disease, and previous
maternal hypertension or renal disease. Several authors have tried
to test the value of Doppler-derived patterns in determining fetal
prognosis in pregnancy complicated with preeclampsia.1618 These
studies have led to contradictory results because of a difficult
interpretation caused by to the complexity of the uteroplacental
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circulation. Absent or reversed end-diastolic velocity waveform in

the umbilical artery seems to be associated with a poor neonatal
outcome.17,19 Ultrasonography may also be useful to ensure fetal
well-being. Obstetric ultrasound can evaluate fetal movements,
breathing activity, and muscle tone20 as well as provide an assessment of fetal anatomy, fetal growth, and amniotic fluid volume.
Identification of other conditions associated with maternal
hypertension, such as trisomy 13 and 18, is also possible with the
use of ultrasound.19 IUGR is important to quantify, and oligohydramnios appears to be associated with a neonatal outcome.
Epilepsy
Two major risks have to be considered in an epileptic woman who
wants to become pregnant: (1) an increase in the incidence of
seizures may be observed during pregnancy and (2) the anticonvulsant medications may have teratogenic effects. These two
risks may be limited if pregnancy is correctly planned with good
patient information and counseling. An increase in the incidence
of seizures may be observed during pregnancy in 21 to 46% of the
women.21,22 Many factors have been involved to explain this
increase in the number and severity of seizures: (1) some women
discontinue or reduce the dose of their anticonvulsant medication
to limit the risk of teratogenicity23 and (2) the pharmacokinetics of
anticonvulsant medications can be impaired by pregnancy. However, the decrease in the plasma concentration of many anticonvulsant medications during pregnancy does not involve the
free fraction of these drugs,24 and when the patients are monitored,
an adjustment of these medications to maintain the plasma
concentration of antiepileptic drugs throughout pregnancy does
not necessarily prevent the increase in the incidence of seizures.25
Generalized convulsions can lead to hypoxemia and hemodynamic disorders and, as such, represent a serious risk to fetal wellbeing. Therefore, the optimal control of seizure activity and strict
compliance should be obtained before pregnancy.
The incidence of congenital malformations in infants born to
epileptic mothers is two to three times greater than in nonepileptic
mothers.21 Important differences exist in the teratogenic effects of
anticonvulsant medications. Neural tube defects such as spina
bifida are associated with first trimester exposure to valproic acid
or carbamazepine. Phenytoin21 and valproic acid26,27 are the two
treatments that appear to be associated with the higher risk of
malformation syndromes. A fetal hydantoin syndrome occurs in
10 to 30% of exposed pregnancies.23 Hydantoin exposure in pregnancy may be associated with multisystemic anomalies including
the prenatal onset of growth deficiency, central nervous system
malformations, craniofacial anomalies, and nail/digital hypoplasia.
Multiple malformations including lip and palatal malformations,
congenital heart disease, and facial and digital anomalies have also
been described after exposure to valproic acid, phenobarbital, and
carbamazepine.23 The risk for neural tube defect associated with
valproic acid and carbamazepine is increased by low folate
concentrations during pregnancy.28 Genetic factors also play a role
because the relative risk for giving birth to an infant with a neural
tube defect is increased by a factor of 10 in a woman who has
already delivered an affected infant in a previous pregnancy.29
When possible, monotherapy for seizure control is preferred
in a woman who may become pregnant because the risk of birth
defects dramatically increases with multiple treatments. The risk
has been reported to be as high as 58% when carbamazepine,
phenobarbital, and valproic acid were combined.29 The presence of
a neural tube defect in infants whose mothers are treated with

valproic acid or carbamazepine can be assessed with ultrasound
examinations27 or -fetoprotein blood level measurements. The
teratogenic risk of anticonvulsants is reduced by folic acid
supplementation throughout pregnancy and adaptation of the
anticonvulsant treatment to the lowest effective doses. An
increased rate of neonatal deaths has been suspected in infants
born to epileptic mothers. These newborns are more likely to need
hospitalization in a neonatal intensive care unit,21 but the incidence of prematurity, low birthweight (LBW), and neonatal head
circumference seems similar to that in normal neonates. Fortunately, most epileptic mothers have uncomplicated pregnancies
and normal babies.
Diabetes Mellitus
Insulin-dependent diabetes can seriously alter the prognosis of
pregnancy. Spontaneous abortions, stillborns, and congenital
malformations occur more often in fetuses of diabetic mothers.
The relative risk for major malformations in these infants is 7.9
times higher than in neonates born to mothers without diabetes.30
The percentage of newborns with a birthweight greater than the
90th percentile is increased in diabetic women. The factors
involved in maternal and fetal weight gain during pregnancy are
not fully elucidated.31 Leptin, a small peptide, usually produced by
adipocytes and involved in many endocrine regulations, is also
synthesized in the placenta. The placental production of leptin can
be regulated by insulin and may be involved in the fetal weight
control. The increased rate of high birthweights is also present in
women with gestational diabetes and those at increased risk of
diabetes including those with an abnormal oral glucose tolerance
test during pregnancy.32 The rigorous control of the blood glucose
levels in diabetic women attempting to become pregnant and
during pregnancy can reduce these risks. One study showed that
the incidence of spontaneous abortion and congenital malformations in diabetic women receiving intensive insulin therapy was
identical to that in nondiabetic women.33 Ideally, the intensive
therapy should begin before conception and maintain normal
blood glucose levels (fasting blood glucose level of 70100 mg/dL
and a 1-h postprandial level < 140 mg/dL).
Drug Abuse
Alcohol
Alcohol consumption impairs the pregnancy and offspring
outcome. Alcohol has a direct toxic effect on the fetus, whereas
malnutrition associated with alcoholism can also impact on the
normal course of pregnancy. Indirect fetal toxicity may result from
zinc deficiency, alterations in placental functions, and effects on
prostaglandins. The amount of alcohol consumption is critical for
fetal prognosis. Normal development is impaired when maternal
consumption exceeds 1 to 2 glasses of wine per day, with major
consequences when more than 3 glasses per day are consumed.
These anomalies, termed the fetal alcohol syndrome, include
IUGR, microcephaly with characteristic craniofacial anomalies,
and central nervous system anomalies with intellectual deficiency.34 Major congenital malformations of other organs (heart,
urinary tract) are also more frequent in infants of alcoholic
mothers, even though they are less specific for the syndrome.
Growth retardation is linked to the amount of alcohol consumption. At birth, infants born to alcoholic mothers weigh up to
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160 g less than those born to nonalcoholic women. Alcohol abuse
has also been linked to an increased incidence of placental abruption and spontaneous abortion. In utero exposition to alcohol
impairs postnatal development and is associated with school
problems in late childhood.
Tobacco
A 1995 French study showed that 25% of pregnant women smoked
cigarettes.35 Sixty percent of them smoked fewer than 10 cigarettes
per day, whereas only 10% smoked more than 20 cigarettes per
day. Although this French study did not show a link between
smoking and prematurity, many other studies performed in the
United States, England, and Australia found a positive correlation
between the risk of preterm birth and maternal tobacco consumption.36,37 These discordant results may be related to quantitative
differences in maternal smoking between the studied populations.
In the study of Schwartz and coworkers, the stillbirth rate was
increased in smokers especially in those who inhaled.38 In this
study, mothers who ceased smoking at the beginning of their
pregnancy enjoyed the same prognosis for their pregnancy and
their offspring as the nonsmokers. Cigarette smoking during
pregnancy has also been related to other obstetric complications
including ectopic pregnancy, placental abruption, and placenta
previa.34 At term, the mean birthweight is usually 150 to 300 g
lower in infants born to smokers than to nonsmokers. The rate of
congenital anomalies and especially orofacial clefts may be increased with maternal smoking. However, the teratogenic effects
of tobacco, if present, are probably minimal. Cigarette smoking
interacts with the efficacy of dietary folate in women whose intake
is low,23 and therefore, smokers are at risk for folate deficiency,
which may increase the incidence of birth defects.
Cocaine
Cocaine abuse is a serious health problem. In the United States,
its prevalence is estimated between 7.5 and 45% in the obstetric
population, resulting in a very high incidence in both maternal
and neonatal morbidity and mortality.39 Adverse effects on the
mother are multiple, many of them being related to hypertensive
effects. Women who abuse cocaine have higher rates of
spontaneous abortion and preterm labor. Burkett and colleagues
reported an incidence of 41% of spontaneous or therapeutic
abortions in 139 women who used cocaine during pregnancy.40
Cocaine abuse favors the occurrence of placental abruption even
if the use is limited to the first trimester of gestation.41 In the
absence of placental abruption, cocaine use can be associated with
chorionic villus hemorrhage and villus edema.42 The influence
of these placental abnormalities on the fetal outcome remains
to be determined. Other obstetric complications such as meconium staining, prolonged membrane rupture, and precipitous
deliveries are more frequent in women who abuse cocaine. The
development of fetus exposed to cocaine is impaired in several
different ways:
1. Cocaine induces uteroplacental vasoconstriction, resulting in
uteroplacental insufficiency and fetal hypoxemia. This may
cause reduced birthweight, IUGR, microcephaly, and prematurity. The rate of premature deliveries in women exposed to
freebase cocaine (crack) may exceed 50%.43
2. Different authors have suspected, both in experimental and
in human studies, an increased rate of fetal malformations
3.
4.
5.
6.
7.
8.
associated with cocaine exposure. The mechanism involved

can be either direct teratogenicity or a consequence of vasopressor effects of cocaine in both the mother and the fetus.
Congenital heart defects are associated with cocaine use and
can result from the lower intracardiac fetal blood flow with
subsequent impairment of the development of some parts of
the heart.
An increased incidence of neonatal distress with lower Apgar
scores at 1 minute (but not at 5 min) has been reported in
neonates exposed prenatally to cocaine.44 Cocaine exposure
during pregnancy may also produce LBW; however, this is not
observed if exposure is limited to the first trimester of gestation.41
Hyperreflexia, prolonged periods of scanning eye movements,
excessive irritability, and tachypnea in a neonate can reflect
acute cocaine intoxication.
Differences in neurobehavioral capabilities, clinical seizures,
and electroencephalographic abnormalities are also seen in
neonates who were (chronically) exposed to cocaine in utero.
Cerebral infarctions and hemorrhages are other possible
neonatal complications that can result from alterations in
cerebral blood flow induced by cocaine.
Gastrointestinal tract disorders and renal dysfunction have also
been reported in such neonates. Some authors reported a decreased incidence of respiratory distress syndrome in neonates
after prenatal exposure to cocaine.45 This is supported by experimental data showing enhanced maturation of the fetal lung
in animals exposed to cocaine.46,47
Benzodiazepines
Dysmorphic characteristics similar to those of fetal alcohol syndrome, growth aberrations, and central nervous system abnormalities have been reported in infants born to mothers consuming
benzodiazepines during pregnancy.48 However, a clear link between maternal use of benzodiazepine and teratogenicity has not
been clearly demonstrated. Bergman and associates reported that
6 of 64 infants with major exposure to benzodiazepines exhibited
clinical features of developmental teratogenicity49; however, many
mothers exhibited other potentially confounding factors such as
alcohol dependence, multiple-drugs dependence, or convulsions.
Addiction associated with other teratogenic drugs has also been
suspected.50 Even though more recent studies did not find any
teratogenic effects of benzodiazepine,29 massive use of benzodiazepines should be avoided during pregnancy. Sedation and withdrawal symptoms have been reported in neonates whose mothers
took benzodiazepines up to delivery.49
Infectious Diseases
Rubella
Primary infection with rubella virus during pregnancy can induce
fetal death, chromosomal alterations leading to IUGR, ocular
lesions, deafness, congenital cardiomyopathy, and other malformations. A rubella titer should be made in every woman before
pregnancy to know her immune status. Congenital rubella can be
avoided with a policy of preventive immunization of all seronegative women before pregnancy. In case of primary infection with
rubella virus during pregnancy, the incidence of fetal infection is
approximately 90% in the first trimester, decreasing to 25% if
infection occurs during the 23rd and the 26th week. If maternal
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infection occurs during the last trimester, fetal infection is very

frequent (>90%), but the consequences for the neonate will be
minimal or absent. The diagnosis of fetal infection is made by
detection of specific immunoglobulin M (IgM) antibodies in the
fetal blood after 22 weeks. Direct detection of the virus after
chorionic villus sampling using polymerase chain reaction is also
possible during the first trimester. The risk of severe congenital
abnormalities seems to be maximal (>90%) for the infant when
the infection occurs before the 11th week.
Toxoplasmosis
Humans can be incidental hosts for Toxoplasma gondii, a protozoan whose definitive host is the domestic cat. Toxoplasma
infection in humans is often asymptomatic and results in the
development of antibodies, first IgM 1 to 2 weeks after exposure,
then IgG after 3 to 4 weeks. In case of acute infection during
pregnancy of a nonimmune mother, the organism can be transmitted to the fetus in up to 60% of cases. Fetal infection may cause
IUGR, nonimmune hydrops, hydrocephalus, or microcephaly.
Some infected infants are asymptomatic at birth but develop
neurologic issues later in development.51 Nonimmune pregnant
women should be advised to eat only well-cooked or hard
frozen meat, wash every utensil or surface after contact with raw
meat, avoid contact with cats and their litterbox, and wash fruits
and vegetables thoroughly. When an acute infection occurs before
the third trimester of pregnancy, treatment with spiramycin if
started promptly and continued until delivery reduces the risk of
fetal transmission by 50%.
Human Immunodeficiency Virus

Pregnancy is a frequent event in young women infected by HIV.
Pregnancy does not appear to influence the course of HIV infection in asymptomatic women,52,53 although some studies have
suggested an impairment of the outcome in women with HIV/
AIDS after pregnancy.54 Although HIV transmission to the fetus
can occur very early in pregnancy, before 15 weeks, fetal transmission seems rare during the first trimester. The spontaneous
rate of fetal transmission of HIV from an infected mother is 12 to
30%,52,55,56 depending largely on the characteristics of maternal
infection (Table 13).57 Cesarean section may reduce the risk of
fetal contamination at delivery, but this is controversial and vaginal delivery is generally preferred whenever possible. A doubleblind, prospective study was designed in asymptomatic pregnant
women infected with HIV with T4 lymphocyte counts of 200/mm3
or greater to compare zidovudine therapy versus placebo during
pregnancy and delivery. The transmission rate of HIV from the
mother to the infant was significantly reduced in the zidovudine
group (8% vs 25%). Moreover, no teratogenic effect of zidovudine
has been reported despite its fetoplacental passage.58 Antiretroviral
drugs may also be indicated for maternal therapy, and these agents
should not be withheld during pregnancy. HIV-infected infants
look normal at birth, and early on, the diagnosis of HIV infection
is difficult because of the presence of maternal antibodies.
Detection of the P24 in the neonates serum is a very specific
method for the diagnosis of infection at birth, but its sensitivity is
only 18%. Its presence at birth seems to be associated with poor
prognosis. Viral culture can also allow an early diagnosis of neonatal HIV infection with excellent specificity, but the technique is
not easy. Its sensitivity is around 50% at birth and 80% between
TABLE 1-3. Maternal Factors That Significantly Influenced

the Perinatal HIV-1 Transmission in the French Cohort
Study
Maternal Factors Associated With an Increased
Rate of HIV Transmission to the Fetus
Clinical signs, AIDS
CDC stage I
II
III
IV
CD4+ lymphocyte counts
<200/mm3
200400/mm3
400600/mm3
>600/mm3
% of Infected
Children
18
19
26
35
43
26
20
15
P24 antigenemia
Negative
Positive
19
46
Age of the mother, y

<25
2530
3035
>35
16
21
24
30
AIDS = acquired immunodeficiency syndrome; CDC = Centers for Disease

Control and Prevention.
After pregnancy, breast feeding was also associated with an increased rate of
transmission.
1 and 3 months of age.59 The first signs of the disease usually

appear at 6 months of age, and the median survival rate is
approximately 38 months.60
Herpes
Neonatal infections with herpes simplex virus have a high morbidity and mortality rate. Therefore, maternal infections require
special attention to prevent fetal contamination at birth. Asymptomatic genital infections are responsible for two thirds of the
neonatal infections with herpes simplex virus at delivery. Four
situations can be individualized to decide the best policy to
identify and prevent neonatal infection with herpes simplex virus
(Table 14).
ABNORMAL FETAL DEVELOPMENT

IUGR
IUGR complicates 3 to 7% of all pregnancies and remains one of
the main causes of perinatal morbidity and mortality. The prognosis associated with IUGR depends on its cause. Up to 8% of
newborns with IUGR have a major malformation that will impair
their outcome. Head growth is of particular concern in the
determination of the prognosis, and harmonious IUGR with head
circumference lower than the 3rd percentile is associated with
poor neurodevelopmental outcomes.61
Hemodynamic changes and/or infectious diseases are often
involved in the pathophysiology of IUGR.62 In normal situations,
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11
TABLE 1-4. Relationship Between the Maternal Manifestations of Herpes Infection and the Risk for the Newborn to Develop
an Infection With HSV
Clinical Manifestations
in the Mother
Incidence in Mothers
of Infected Newborns
Risk for the Newborn to Develop

an Infection with HSV
Primary infection with HSV

in the month before delivery
Recurrent maternal infection
Antecedent of genital infection
with HSV
Rare
75%
+
++
25%
1/1000
None antecedent
+++
2/3
1/10,000
Management of Delivery
Cesarean section acyclovir for the
infant
Cesarean section
Vaginal delivery after disinfection
identification of HSV acyclovir
for the infant.
No possibility of oriented prevention
of neonatal infection with HSV
HSV = herpes simplex virus.
the oxygenated blood from the umbilical vein flows through the
ductus venosus to the right atrium to the left lobe of the liver and
to the portal vein, resulting in a preferentially mesenteric blood
flow. Impaired uteroplacental perfusion induces a reduction in
fetal oxygen delivery responsible for a progressive hemodynamic
adaptation of the fetus with differential shunting of blood to vital
organs such as brain, heart, or adrenals. The blood flow to these
vital organs can be increased to 300%, whereas the increase in the
vascular resistances in the other fetal organs can reduce the cardiac
output by 40%. This redistribution of flow is an adaptive phenomenon that does not imply fetal distress but a brain-sparing
effect. Placental insufficiency can result in metabolic disorders
often associated with IUGR. In spite of low levels of insulin
(hypoperfusion of the pancreas), hypoglycemia is often noted.63
Triglycerides and fatty acids levels are increased, whereas the ratio
of essential to nonessential amino acids is often low, reflecting
the reduced anabolism of the fetus. This ratio is negatively
correlated to the degree of fetal hypoxemia. Biologic signs of
hypothyroidism can appear in the hypoxemic fetus, whereas
hypervascularization of the adrenals increases cortisol levels in
response to hypoglycemia.
The diagnosis of IUGR can be assessed by ultrasonographic
examination. In the first trimester, measurements of the crownrump length and the biparietal diameter allow for precise dating
of pregnancy.64 In late pregnancy, the diagnosis of IUGR is much
more difficult when the gestational age is not precisely known.
Many Doppler and morphometric indices have been proposed to
detect a fetus who is smallforgestational age (SGA). Abdominal
circumference and estimated fetal weight appear to be accurate
predictive indicators of infants who are SGA.65 Doppler ultrasonographic examination also gives information on the fetal condition
and can predict fetal asphyxia.66 Compensatory redistribution of
arterial blood flow to the brain and myocardium and decreased
flow to peripheral organs are additional physiologic adaptive
changes beneficial in preventing brain hypoxemia rather than a
sign of impending brain damage.64 Loss of variability and late
decelerations are pejorative features. Absent or reversed enddiastolic velocity waveforms in umbilical arteries of fetuses who
are SGA indicate a serious risk of adverse outcome with a 28%
perinatal mortality rate.64,67 Absent end-diastolic blood flow
and/or anomalies in heart rate reactivity (nonstress test) have been
associated with fetal hypoxemia and acidosis.68 Fetal cardiac
function should be assessed in an IUGR infant. The ductus
venosus blood velocity may be used to assess the left ventricle
function,62 with absent or inversed flow signs being a sign of

imminent heart failure. Decreases in cardiac output and aortic and
pulmonary peak velocities are directly related to the umbilical pH
at birth.69
Delivery is probably the more efficient treatment for IUGR. Its
timing is based on an evaluation of the fetal heart rate (FHR),
biophysical profile including amniotic fluid volume, Doppler
velocimetry, and the level of fetal maturation.64 The progress of
neonatal care and the benefits of antenatal corticosteroids in
reducing the risks of prematurity allow early deliveries of fetuses
with progressively deteriorating IUGR status. Nevertheless, the
right time for delivery before progressive deterioration of the fetus
often represents a difficult choice for the obstetric team. Growthrestricted fetuses may benefit from repeated noninvasive tests such
as FHR, ultrasound examinations with Doppler sonograms, and
occasionally, fetal blood sampling that may help in determining
the fetal condition and the appropriate timing of delivery.
Prematurity: Main
Pathophysiologic Implications
The incidence of prematurity is approximately 6 to 11% of all life
births.7073 These infants have a high morbidity and mortality rate
because of the incompleteness of organ maturation. They are not
able to maintain their body temperature and have difficulties with
sucking, swallowing, eating, and sustaining ventilation. They are
prone to cerebral damage, intraventricular hemorrhage, respiratory distress syndrome, and necrotizing enterocolitis. However,
since the mid-1990s, major advances in the neonatal and perinatal
care of preterm infants have reduced the mortality rate, even in
very small infants.
Definitions
According to the World Health Organization nomenclature,
preterm labor (prematurity) is now defined as a gestational age less
than 37 completed weeks or less than 259 days, irrespective of
birthweight, because decreased weight per se can be due to IUGR.
Classification according to the gestational age:74
1.
2.
3.
4.
Preterm infant: born before 37 weeks of gestation (<259 days).

Moderately premature: born at 31 to 36 weeks of gestation.
Severely premature: born at 24 to 30 weeks of gestation.
Postterm infant: born after 42 weeks of gestation.
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Classification according to the birthweight:

1. An LBW infant is one weighing less than 2500 g irrespective
of the duration of pregnancy (only 54% of LBW infants are
preterm).
2. A VLBW infant is one weighing less than 1500 g.
3. VLBW is associated with maternal malnutrition, excessive
smoking, chronic alcohol ingestion, drug abuse, toxemia, or
placental insufficiency.
Mortality, Morbidity, and Outcome

In North America and Europe, preterm birth is the most important cause of perinatal mortality. In Great Britain, preterm birth
accounts for 85% of early neonatal deaths not caused by lethal
congenital malformations.72 In the United States, preterm birth
occurs in 7.5% of all deliveries and accounts for 75% of the
perinatal deaths.71 In another study, preterm infants weighing less
than 750 g accounted for 41% of early neonatal deaths and 25% of
infant deaths.73 There is a relationship between the survival rate
of premature infants and increasing gestational age. From 1979 to
1981, a survival rate above 90% was reported for neonates born
after 32 weeks of gestation, decreasing to less than 50% when the
gestational age was less than 26 weeks.75
Preterm birth is associated with a major increase in neonatal
and infant morbidity, including neurodevelopmental disorders,
chronic respiratory problems, intraventricular hemorrhage, infection, retrolental fibroplasias, and necrotizing enterocolitis.76,77 There
is a long-term risk of neurologic and developmental impairment.78
82
In one study, McCarton and associates found that, irrespective of
the degree of prematurity, SGA infants were at greater risk for
neurodevelopmental impairment than appropriateforgestational
age (AGA) infants. Cognitive impairment can be attributed to a
higher incidence of neurologic abnormalities in SGA infants at
each gestational age.83 Table 15 presents the immediate complications and the late sequelae of preterm infants. Prevention of preterm birth is, thus, a major public health goal in many developed
countries and is cost-effective.84 In France, there was a reduction of
the preterm birth rate from 8.2% in 1972 to 6.8% in 1976 and 5.6%
in 1981, with a parallel decrease in the incidence of infants
weighing less than 1500 g from 0.8% in 1972 to 0.4% in 1981.85
Risk Factors for Preterm Birth

The causes of prematurity are (1) low socioeconomic status,
(2) multiple gestation, (3) uteroplacental insufficiency, (4) maternal illness with preeclampsia, and (5) idiopathic IUGR.8691 These
risk factors are summarized in Table 16.
Problems and Complications Associated

With Preterm Birth
RESPIRATORY PROBLEMS: Respiratory distress is common in
preterm infants because of the immaturity of the respiratory
system (Table 17). The limit of viability is approximately 22 to
24 weeks when the lungs have developed a gas-exchanging surface
and surfactant production has begun. Anatomic issues are critical
at this stage. Breathing is exclusively nasal and nasal occlusion can
induce hypoxemia with a reduction of ventilation.92 Spontaneous
neck flexion can induce an airway obstruction with apnea.93
Pulmonary compliance is decreased in cases of hyaline membrane
disease (HMD) because of a reduction of the functional residual
TABLE 1-5. Immediate Complications and Late Sequelae

of Preterm Infants
Immediate Complication
Late Sequelae
Hypoxia, ischemia
Mental retardation, spastic diplegia,

microcephaly, seizures, poor
school performance
Mental retardation, spasticity,
seizures, hydrocephalus
Hearing, visual impairment,
retinopathy of prematurity,
strabismus, myopia
Bronchopulmonary dysplasia, cor
pulmonale, bronchospasm,
malnutrition, iatrogenic cleft
palate, recurrent pneumonia
Short bowel syndrome,
malabsorption, malnutrition,
infectious diarrhea
Cirrhosis, hepatic failure,
carcinoma, malnutrition
Osteopenia, fractures, anemia,
vitamin E, growth failure
Child abuse or neglect, failure to
thrive
Sudden infant death syndrome,
infections, inguinal hernia,
cutaneous scars, gastroesophageal
reflux, hypertension,
craniosynostosis, cholelithiasis,
urolithiasis, cutaneous
hemangiomas
Intraventricular
hemorrhage
Sensorineural injury
Respiratory failure
Necrotizing
enterocolitis
Cholestatic liver
disease
Nutrient deficiency
Social stress
Other
capacity.94 Chest wall compliance is higher in preterm infants

(6.4 mL/cmH2O/kg at 32 wk vs 4.2 mL/cmH2O/kg at term.95 Airway resistance is increased in premature infants because of a
smaller diameter of the bronchi.96 Accessory inspiratory muscles
are relatively inefficient because of an unfavorable anatomic rib
configuration, leading to easy distortion of the chest wall and
paradoxical ventilation. The diaphragm is the most important
respiratory muscle in preterm infants. There is a tendency for
respiratory muscle fatigue, which results from metabolic characteristics of the diaphragm with a reduction of the content of type
1 muscle fibers (slow-twitch, high oxidative capacity) that account
for only 10% in preterm infant versus 20 to 30% in the full-term
infant.97,98 The diaphragmatic work to maintain tidal volume in
preterm infants is increased and may lead to diaphragmatic
fatigue, respiratory distress, or apnea.99,100
At the end of the canalicular stage of pulmonary differentiation
(1624 wk), a reliable gas-exchanging surface appears and surfactant production begins.101103 During the alveolar stage of
differentiation (from 24 wk to term), surfactant secretion in the
amniotic liquid increases, providing a useful indicator of lung
maturity.104 The insufficiency in surfactant production explains
why preterm infants are predisposed to develop HMD. At this
stage, maternal administration of betamethasone or dexamethasone 48 hours before delivery increases surfactant production
and significantly decreases respiratory morbidity in preterm
infants born after 30 weeks of gestation.74,105,106
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TABLE 1-6. Risk Factors of Preterm Birth
Obstetric factors
Maternal factors
Socioeconomic
factors
Fetal factors
Iatrogenic
prematurity
Multiple gestation
Overdistention of the uterus
Placenta previa
Uteroplacental insufficiencies
Intrauterine growth retardation
Placental abnormalities
Gestational bleeding
Cervical and uterine anomalies (multiple
fibroids, septate uterus)
In utero diethylstilbestrol exposure
Trauma: spontaneous, precipitous
delivery, or iatrogenic (e.g., dilation and
curettage)
Premature rupture of the fetal membranes
Multiple second trimester spontaneous
abortions
In vitro fertilization pregnancy
Infection (vaginitis, cervicitis,
chorioamniotitis, or urinary tract
infection)
Preeclampsia
Severe cardiac disease
Severe renal disease
Thyrotoxicosis
Diabetes
Previous history of preterm labor
Smoking
Cocaine use
African origin
Single marital status
Low socioeconomic status
Poor antenatal care
Poor personal hygiene
Extremes of maternal age
Stress
Fetal anomalies
Hypercapnic ventilatory response is decreased in the preterm

infant, and hypoxia may depress this response in term or preterm
infants.107,108 There is also decreased ventilation during oral feeding
in preterm infants.109 Clinical apneas are frequent, occurring in as
many as 25% of all preterm infants, especially the most immature.
These events can be life-threatening. They are associated with a
decrease in arterial oxygen saturation, bradycardia, and loss of
muscle tone. Factors involved in these apneas include brainstem
immaturity, decreased hypercarbic and hypoxic responses, and
respiratory fatigue precipitated by chest wall distortion.110,111
Treatment of apnea is directed at increasing the central drive to
ventilation using theophylline or caffeine preparations, stabilizing
the chest wall (positive end-expiratory pressure), and stimulating
by rocking or stroking. The risk of apnea after general anesthesia
is inversely related to the gestational age, affecting mainly infants
with a postconceptional age of 50 weeks or less.112
CARDIOVASCULAR PROBLEMS: Preterm infants often have a

patent ductus arteriosus that appears 3 to 5 days after birth,
13
TABLE 1-7. Complications Associated With Preterm Infants

Respiratory
Cardiovascular
Neurologic
Hematologic
Gastrointestinal
Metabolicendocrine
Renal
Other
Respiratory distress syndrome hyaline

membrane disease
Bronchopulmonary dysplasia
Pneumothorax
Pneumomediastinum
Congenital pneumonia
Pulmonary hypoplasia
Pulmonary hemorrhage
Apnea
Patent ductus arteriosus
Hypotension
Hypertension
Bradycardia (with apnea)
Congenital malformations
Intraventricular hemorrhage
Periventricular leukomalacia
Hypoxic-ischemic encephalopathy
Seizures
Retinopathy of prematurity (retrolental
fibroplasia)
Hypotonia
Congenital malformations
Kernicterus (bilirubin encephalopathy)
Anemia
Hyperbilirubinemia (direct or indirect)
Subcutaneous or organ hemorrhage (liver,
adrenal)
Disseminated intravascular coagulopathy
Vitamin K deficiency
Hydrops
Necrotizing enterocolitis
Poor gastrointestinal function or motility
Hypocalcemia
Hypoglycemia
Hyperglycemia
Late metabolic acidosis
Hypothermia
Hyponatremia
Hypernatremia
Hyperkalemia
Renal tubular acidosis
Renal glycosuria
Edema
Infections (congenital, perinatal, or
nosocomial)
concurrently with the decrease in pulmonary vascular resistance

associated with recovery from HMD and normal postnatal
changes (see Table 17).113,114 The medical treatment of patent
ductus arteriosus includes fluid restriction, diuretics, and the
administration of either indomethacin or ibuprofen.115,116 Indomethacin and ibuprofen induce closure of patent ductus arteriosus
by inhibiting prostaglandin synthesis117; however, efficacy is not
always complete in extremely premature infants (<28 wk) and
surgical closure may be required.118,119 Heart rate is greater in
preterm than in full-term infants (160 vs 120 beats/min) and
decreases progressively from 160 to 130 beats/min from 26 to
40 weeks of gestation.120 Blood pressure is lower in preterm than
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in full-term infants. Cardiac output is higher in preterm than in

full-term infants, which may reflect their higher metabolic rate
and oxygen consumption when compared with adults.121,122
Diastolic function is insufficient and cardiac output is dependent
on heart rate. Therefore, any bradycardia decreases cardiac output.
There is also a limited left ventricular response to volume overload
in preterm infants.123 Autonomic control of the heart is predominantly mediated by the parasympathetic nervous system because
the sympathetic system is immature. There is a decreased responsiveness to vasoconstrictor and vasodilator agents.124 Hypoxia
(apnea) produces a bradycardia with a decrease of cardiac output
associated with an increase of systemic and pulmonary resistances,
which then further potentiates the hypoxemia. There is impairment of the autoregulation of cerebral blood flow.125 Perlman and
coworkers described a fluctuation of cerebral blood flow in
preterm infants with respiratory distress syndrome that correlated
with an increasing rate of intracerebral hemorrhage.126
GASTROINTESTINAL PROBLEMS: Necrotizing enterocolitis is a
RENAL PROBLEMS: Urine production begins in utero at 10 to
because the production of red blood cells is reduced (see Table

17). Anemia has been shown to increase the risk of apnea.139
Immaturity of hepatic function can explain the abnormalities of
coagulation with decreases of vitamin Kdependent factors
leading to prolongation of the prothrombin time.
12 weeks of gestation. Urinary flow is important to maintain the

amniotic fluid volume. Glomerular filtration is decreased in
preterm infants compared with full-term infants.127 Because the
fetus maintains its metabolic homeostasis through the placenta, it
is only after birth that the kidney assumes this function. Tubular
function begins to develop after 34 weeks of gestation.128 The renal
tubular threshold for sodium is decreased, which explains the
propensity for neonates, especially preterm ones, to develop
hyponatremia (see Table 17).129 The tubular threshold for glucose
is low and responsible for frequent glycosuria with dehydration
induced by an osmotic polyuria.130 Metabolic acidosis is common
owing to diminished renal tubular threshold for sodium bicarbonate.131 The infusion of sodium bicarbonate may be necessary to
control acidosis in preterm infants. These infants are at increased
risk of dehydration because insensible water loss is increased.132
Immaturity of distal tubular function and relative hypoaldosteronism can explain the risk of hyperkalemia in preterm infants.133
NEUROLOGIC PROBLEMS: Brain development differs from that in

other organs. The brain has two growth spurts: (1) neuronal cell
multiplication between 15 and 20 weeks of gestation and (2) a
phase of glial cell multiplication from 25 weeks of gestation to the
second year of life. Preterm blood vessel fragility is increased by
several respiratory or hemodynamic factors, thereby increasing
the risk of intracerebral hemorrhage during the first days of life
(see Table 17).125,126,134 Periventricular leukomalacia is an ischemic
cerebral complication with a risk of delayed neurologic development. Its incidence ranges from 12 to 25% in LBW infants less
than 1500 g to 8% in infants born after 34 weeks.135 Retrolental
fibroplasia is a complication depending on the gestational age, the
duration of oxygen therapy, and the partial pressure of oxygen in
the arterial blood.136
THERMAL PROBLEMS: Thermal regulation is immature in the

preterm infant. Exposure to cold may induce an elevation of metabolic rate and oxygen consumption that increases the risks of
hypoxemia, acidosis, apnea, or respiratory distress (see Table 17).
Body heat can be dissipated by conduction, convection, radiation,
and also evaporation, which is the most important mechanism.137
The surface-to-volume ratio is more important in preterm than
in full-term infants, increasing heat losses. It is essential to protect
these infants in an incubator, dry them off immediately after birth,
and provide them with warmed and humidified inspired gases.
major digestive problem that remains a frequent complication in

preterm infants (see Table 17). It generally occurs after the
beginning of enteral feedings, but may also occur in infants who
have never been fed.138 The usual clinical manifestations include
abdominal distention, vomiting, bloody stools, and shock.
METABOLIC-ENDOCRINE PROBLEMS: As mentioned previously,

metabolic acidosis is common in preterm infants (see Table 17).
In addition, hypocalcemia can also be seen because calcium
transfer occurs mainly during the third trimester of gestation and
because preterm infants have diminished concentrations of serum
proteins. Because of the immaturity of glucose regulation, preterm
infants tolerate glucose loads poorly. Therefore, excessive glucose
infusion can be deleterious to the central nervous system. There is
also a risk of hypoglycemia that requires appropriate correction.
HEMATOLOGIC PROBLEMS: Anemia is frequent in preterm infants
INFECTION: The development of infections such as pneumonia,

sepsis, or meningitis is common in the preterm infant because
of significant reduction in cellular and tissue immunity (see
Table 17).
Prevention of Premature Birth

The strategies to prevent preterm birth are reviewed in an article
from Goldenberg and colleagues.75 These factors are outlined in
Table 18. Two categories of strategies are used to reduce adverse
outcomes associated with prematurity: (1) those intended to
prevent or delay preterm birth and (2) those aiming at reducing
the morbidity and mortality of prematurity. The regionalization
of perinatal care ensures that most preterm infants are delivered
close to a neonatal intensive care unit with appropriate equipment
and trained personnel. In these units, specialized therapies can be
used such as specific methods of mechanical ventilation, exogenous surfactant therapy, and other supportive therapies (antibiotic
treatment, and fluid and electrolyte management). Effective
obstetric interventions include use of prenatal corticosteroids for
fetal pulmonary maturation, intrapartum antibiotics to reduce
neonatal sepsis, and prevention or prompt treatment of fetal
hypoxia. These interventions are effective in decreasing the
mortality of preterm infants.
Acute Fetal Distress

Fetal distress can be chronic (antepartum period) or acute (intrapartum period only). Clinical features of antenatal fetal distress
include IUGR, fetal hypoxia, increasing vascular resistance in fetal
blood vessels, and fetal acidosis. Antepartum fetal distress is
frequently associated with uteroplacental insufficiency. Acute fetal
distress occurs during labor. It is a nonspecific and imprecise
diagnosis often associated with surgical delivery. Parer and
Livingston define fetal distress as a progressive fetal asphyxia
which without treatment induces a decompensation of adapted
physiological responses and causes definitive neurologic impairment and other damage or death.140 If birth asphyxia is defined by
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TABLE 1-8. Interventions to Prevent Premature Birth
Prenatal care (routine or enhanced)
Risk-scoring systems
Cervical circling
Progestin supplementation
Programs for cessation of tobacco, drug, and alcohol use
Psychological support
Nutritional interventions
Counseling
Caloric supplementation
Protein supplementation
Vitamin or mineral supplementation
Patient education (to detect signs of preterm labor)
Home uterine-activity monitoring
Frequent contact with a nurse
Tocolytic therapy
Bed rest
Hydration
Screening for and treatment of infection (urinary tract infection
or bacterial vaginosis)
Antibiotics for preterm labor or premature rupture of
membranes
Low-dose aspirin
Calcium supplementation
From Goldenberg RL, Dwight JR. Prevention of premature birth. N Engl J Med.
1998;339:313320.
an Apgar score below 7, its incidence is 5.3%.141 If the definition is

the requirement of more than 1 minute of positive-pressure
ventilation at birth, the incidence decreases to 1.16%.142 However,
if measurements of blood gas and acid-base status in the umbilical
artery are used just after delivery, the incidence is 2%.143
The morbidity of acute fetal distress is most important. In 1979,
a consensus conference estimated that intrapartum events accounted for 20 to 40% of cerebral palsy and 10% of severe mental
retardation.144 Freeman in 1985 concluded that asphyxia played a
major role in cerebral palsy, but not in the occurrence of mild or
severe mental retardation with epilepsy.145 Currently, the incidence
of cerebral palsy caused by birth asphyxia is less than 10%.145147
The consequences of birth asphyxia are variable, because some
fetuses die or have severe and irreversible brain injury whereas
others survive without apparent neurologic deficiencies.148150 In
the absence of any history of chronic fetal distress, there are three
major causes of acute fetal distress:
1. Maternal arterial hypotension: Hypotension can occur when
analgesia for labor is established (epidural or spinal anesthesia)
or following uteroplacental hemorrhage. Hypotension can also
occur or be enhanced by maternal malposition.151
2. Umbilical cord compression: Cord prolapse is positionally
dependent. It is 20 times more frequent in abnormal than in
vertex presentation.152 Abnormal presentations are more frequent in preterm infants. At 28 weeks, 25% of fetus are found
in breech presentation.153 Cord prolapse is, therefore, also
indirectly related to gestational age.
3. Uterine hypertonia: Uterine hypertonia is responsible for a
decrease in umbilical blood flow. The most frequent cause
of hypertonia is an excessive exogenous oxytocin administration.
15
Fetal oxygen delivery depends on the umbilical blood flow and

umbilical venous oxygen content and tension. Although some
cases are caused to changes in cardiac output (fetal arrhythmias)
or to modifications of fetal oxygen content (fetal anemia), major
acute fetal distress is mainly related to a decrease of umbilical
blood flow. Three mechanisms are responsible for this decrease:
(1) increase of uterine venous pressure (mainly uterine hypertonia), (2) decrease of uterine arterial pressure (mainly maternal
hypotension), and (3) increase of uterine vascular resistance
(mainly maternal hypertension). The fetal response to hypoxia is
a redistribution of blood flow to vital organs (heart and brain).
Fetal hypoxia results in hypertension with bradycardia without
initial modification of the cardiac output. In severe or prolonged
hypoxemia, fetal cardiac output decreases. During moderate
hypoxemia, absolute umbilical blood flow tends to be maintained.
Blood flow to brain, heart, and adrenals can increase from 100 to
200% while the cardiac output of the fetus decreases to 30%.154 The
umbilical venous blood flow that returns from the placenta either
enters the hepatic circulation or bypasses the liver via the ductus
venosus. The double phenomenon of increasing myocardial blood
flow and redistribution of umbilical venous blood (increasing the
proportion of oxygen-rich blood) maintains oxygen delivery to
the myocardium of the fetus during hypoxemia.155157 Autoregulation of cerebral blood flow protects the brain by increasing oxygen
delivery via vasodilatation associated with the hypertensive
response to hypoxemia. Severe and prolonged hypoxemia induces
ischemic cerebral lesions by a phenomenon of alteration of the
cerebral blood flow associated with hypotension. The evolution of
these ischemic lesions depends on the severity and timing of
cerebral hypoxemia.
Antenatal fetal distress can be suspected in cases of (1) diagnosis of IUGR by ultrasound, (2) Doppler anomalies of the
umbilical artery or fetal aorta blood flow,158160 (3) alterations of
the FHR (spontaneously or during contractions), and (4) diagnosis
of hypoxia or acidosis during percutaneous umbilical venous
blood sampling. Acute fetal distress is suspected during labor
when there are (1) anomalies of the FHR (tachycardia or bradycardia), (2) low variability or abnormal evolution of FHR with
uterine contractions (decelerations), or (3) anomalies of the acidbase status from fetal scalp blood sampling. A pH less than 7.25
suggests fetal distress and a pH less than 7.20 is an indication for
early surgical delivery. Parer and Livingston suggest that adding
the determination of FHR variability to the FHR pattern interpretation is the best indicator of fetal vigor at birth.140 If FHR
variability is absent, then a fetal stimulation test or fetal blood
sampling for acid-base status determination may be indicated.
Chronic fetal distress can be responsible for premature delivery
or IUGR. Acute fetal distress in full-term infants without a
previous problem can be associated with immediate or delayed
complications. Neurologic injuries represent the major factor in
the morbidity of the child. Outcome after birth asphyxia is difficult
to predict because it varies from intrauterine death to normal
survival without any apparent deficit.
CONCLUSIONS
The knowledge of normal and abnormal development of the fetus
is increasingly necessary for the pediatric anesthesiologists who
are involved in the care of preterm and term neonates undergoing
surgical treatments of a congenital malformation or a specific
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complication of prematurity. Diagnosis of major malformations is

now more predictable and effective with the development of
reliable in utero evaluation techniques and better pregnancy
supervision. These anomalies should be evaluated as soon as
possible and can lead to the transfer of the obstetric patient to a
tertiary perinatal center where a suitable therapeutic strategy can
be decided. Many innovations have been made, thus reducing the
mortality rate even in very small infants. Much of this decrease in
mortality can be attributed to improvements in the neonatal and
perinatal care of preterm infants. Another consequence of this
improvement in neonatal care is a reduction of the viable gestational age compatible with long-term survival with an increase in the
number of preterm infants needing surgery. Therefore, the pediatric anesthesiologist must be fully trained in dealing with the
problems associated with extreme prematurity.
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17
venous blood gases measured at cordocentesis. Am J Obstet Gynecol.

1990;162:115120.
Karsdorp VHM, Van Vugt JMG, Van Geijn HP. Clinical significance
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Arias F, Tomich P. Etiology and outcome of low birth weight and
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Vohr BR, Oh W, Rosenfield AG, et al. The premature small for
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Commey JO, Fitzhardinge PM. Handicap in the preterm small for
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weight 500 to 999 gm: a regional study of 1979 and 1980 births.
J Pediatr. 1984;104:921927.
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of very low birth weight infants with intrauterine growth retardation:
comparison with control subjects matched by birth weight or for
gestational age. J Pediatr. 1990;116:1926.
McCarton CM, Wallace IF, Divon M, et al. Cognitive and neurologic
development of the premature, small for gestational age infant
through age 6: comparison by birth weight and gestational age.
Pediatrics. 1996;98:11671178.
Korenbrot CC, Aalto LJ, Laros RK. The cost effectiveness of stopping
preterm labor with -adrenergic treatment. N Engl J Med. 1984;
310:691696.
Rumeau-Rouquette C, Du Mazaubrun C, Rabarison Y, et al. Natre
en France: 10 ans dEvolution, 19721981. Paris: INSERM/Doin;
1984.
Gonik B, Creasy RK. Preterm labor: its diagnosis and management.
Am J Obstet Gynecol. 1986;154:38.
McKeown T, Record R. Observations on fetal growth in multiples
pregnancies. J Endocrinol. 1952;8:386401.
Linn S, Schoenbaum S, Manson R. The relationship between induced
abortion and outcome of subsequent pregnancies. Am J Obstet
Gynecol. 1983;146:136140.
Parisi VM. Cervical incompetence and preterm labor. Clin Obstet
Gynecol. 1988;31:585598.
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90. Gravett MG, Nelson HP, DeRouen T. Independent associations of

bacterial vaginosis and Chlamydia trachomatis infection with
adverse pregnancy outcome. JAMA. 1986;256:18991903.
91. Berkowitz GS, Papiernik E. Epidemiology of preterm birth.
Epidemiol Rev. 1993;15:414443.
92. Miller MJ, Carlo WA, Strohl KP, et al. Effect of maturation on oral
breathing in sleeping premature infants. J Pediatr. 1986;109:
515519.
93. Thach BT, Stark AR. Spontaneous neck flexion and airway obstruction during apneic spells in preterm infants. J Pediatr. 1979;94:275.
94. Bancalari E, Garcia OL, Jesse ML. Effects of continuous negative
pressure and lung mechanics in idiopathic respiratory distress
syndrome. Pediatrics. 1973;51:485.
95. Gerhardt T, Bancalari E. Chest wall compliance in full term and
premature infants. Acta Paediatr Scand. 1980;69:359364.
96. Stocks J, Godfrey S. Specific airways conductance in relationship
to postconceptional age in early infancy. J Appl Physiol. 1977;43:
144154.
97. Keens TG, Bryan AC, Levison H, et al. Development pattern of
muscle fiber types in human ventilatory muscles. J Appl Physiol.
1978;44:909913.
98. Muller NL, Gulston G, Cade D, et al. Diaphragmatic muscle fatigue
in the newborn. J Appl Physiol. 1979;46:688695.
99. Heldt GP. Development of stability of respiratory system in preterm
infants. J Appl Physiol. 1988;65:441444.
100. Guslits BG, Gaston SE, Bryan MH, et al. Diaphragmatic work of
breathing in premature human infants. J Appl Physiol. 1987;62:
14101415.
101. Boyden EA. Development and growth of the airways. In: Hodsen
WA, editor. Development of the Lung. New York: Marcel Dekker;
1977.
102. Hislop A, Reid L. Lung development in relation to gas exchange
capacity. Bull Physiopathol Respir. 1973;92:13171343.
103. Campiche MA, Gautier A, Hernandez EI, et al. An electron
microscope study of the fetal development of human lung. Pediatrics. 1963;32:976994.
104. Gluck L, Kulovich MV. Lecithin/sphingomyelin ratios in amniotic
fluid in normal and abnormal pregnancy. Am J Obstet Gynecol.
1973;115:539546.
105. Liggins GC, Howie RN. A controlled study of antepartum glucocorticoid treatment of the respiratory distress syndrome in premature
infants. Pediatrics. 1972;50:515525.
106. Morales WJ, Diebel D, Lazar AJ, Zadrosny D. The effect of antenatal
dexamethasone administration on the prevention of respiratory
distress syndrome in preterm gestations with premature rupture of
membranes. Am J Obstet Gynecol. 1986;154:591595.
107. Rigatto H, Brady JP, Chir B, et al. Chemoreceptor reflexes in preterm
infants: I: the effect of gestational age and postnatal age on the ventilatory response to inhaled carbon dioxide. J Appl Physiol. 1975;
55:604.
108. Rigatto H, Verduzco RT, Cates DB. Effects of O2 on the ventilatory
response to carbon dioxide in preterm infants. J Appl Physiol.
1975;39:896899.
109. Shivpuri CR, Martin RJ, Carlo WA, et al. Decreased ventilation in
preterm infants during oral feeding. J Pediatr. 1985;106:625.
110. Heldt GP, McIloroy MB. Distortion of chest wall and work of
diaphragm in preterm infants. J Appl Physiol. 1987;62:164169.
111. Henderson-Smart DJ, Pettigrew AG, Campbell DJ. Clinical apnea
and brainstem neural function in preterm infants. N Engl J Med.
1983;308:353357.
112. Kurtz CD, Spitzer AR, Broennle AM, et al. Postoperative apnea in
preterm infants. Anesthesiology. 1987;66:483488.
113. Siassi B, Blanco C, Cabal L, et al. Incidence and clinical features
of patent ductus arteriosus in low birth weight infants: a prospective analysis of 150 consecutively born infants. Pediatrics. 1976;
57:347.
114. Thibeault DW, Emmanouilides GC, Nelson RJ, et al. Patent ductus
arteriosus complicating the respiratory distress syndrome in preterm infants. J Pediatr. 1975;86:120.
115. Rudolph AM, Heymann MA. Medical treatment of ductus
arteriosus. Hosp Pract. 1977;12:57.
116. Stevenson JG. Fluid administration in the association of patent
ductus arteriosus complicating respiratory distress syndrome.
J Pediatr. 1977;90:257.
117. Heymann MA, Rudolph AM, Silverman NH. Closure of the ductus
arteriosus in premature infants by inhibition of prostaglandin
synthesis. N Engl J Med. 1976;295:530.
118. Merritt TA, Disessa TG, Feldman BH, et al. Closure of the patent
ductus arteriosus with ligation and indomethacin: a consecutive
experience. J Pediatr. 1978;93:639.
119. Mellander M, Leheup B, Lindstrom DP, et al. Recurrence of symptomatic patent ductus arteriosus in extremely premature infants
treated with indomethacin. J Pediatr. 1984;104:419425.
120. Siassi B, Hodgman J, Cabal L, et al. Cardiac and respiratory activity
in relation to gestation and sleep states in newborn infants. Pediatr
Res. 1979;13:1163.
121. Walther FJ, Siassi B, Ramadan NA, et al. Pulsed Doppler determination of cardiac output in neonates: normal standards for clinical use.
Pediatrics. 1985;76:829833.
122. Walther FJ, Siassi B, King J, et al. Echocardiographic measurements
in normal preterm and term neonates. Acta Paediatr Scand. 1986;
75:563568.
123. Romero TE, Friedman WF. Limited left ventricular response to
volume over load in the neonate period: a comparative study with
adult animal. Pediatr Res. 1979;13:910915.
124. Manders WT, Pagani M, Vatner SF. Depressed responsiveness to
vasoconstrictor and dilatator agents and baroreflex sensitivity in
conscious newborn lambs. Circulation. 1979;60:945955.
125. Lou HC, Lassen NA, Friis-Hansen B. Impaired autoregulation of
cerebral blood flow in the distressed newborn infant. J Pediatr.
1979;94:118.
126. Perlman JM, McMenamin JB, Volpe JJ. Fluctuating cerebral blood
velocity in respiratory distress syndrome. N Engl J Med. 1983;309:
204209.
127. Guignard JP. Assessment of renal function without urine collection.
Arch Dis Child. 1977;52:424.
128. Arant BS. Developmental patterns of renal functional maturation
compared in the human neonate. J Pediatr. 1978;92:705712.
129. Engelke SC, Shah BL, Vasan V, et al. Sodium balance in very low
birth weight infants. Pediatrics. 1984;74:259.
130. Stonestreet BS, Rubin L, Pollack A, et al. Renal functions of low birth
weight infants with hyperglycemia and glycosuria produced by
glucose infusions. Pediatrics. 1981;66:561.
131. Guignard JP, John EG. Renal function in the tiny, premature infant.
Clin Perinatol. 1986;13:377401.
132. Wu PYK, Hodgman JE. Insensible water loss in preterm infants:
changes with postnatal development and non ionizing radiant
energy. Pediatrics. 1974;54:704712.
133. Gruskay J, Costarino AT, Polin RA, et al. Nonoliguric hyperkaliemia
in the premature infant weighing less than 1000 grams. J Pediatr.
1988;113:381386.
134. Ment LR, Duncan CC, Ehrenkranz RA, et al. Intraventricular
hemorrhage in the preterm neonate: timing and cerebral blood flow
changes. J Pediatr. 1984;104:419425.
135. Fawer CL, Diebold P, Calame A. Periventricular leukomalacia and
neurodevelopmental outcome in preterm infants. Arch Dis Child.
1987;62:3036.
136. Kinsey VE, Arnold HJ, Kalina RE, et al. PaO2 levels and retrolental
fibroplasia: a report of the cooperative study. Pediatrics. 1977;60:655.
137. Hammarlund K, Stromberg B, Sedin G. Heat loss from skin of
preterm and fullterm newborn infants during the first weeks after
birth. Biol Neonate. 1986;50:110.
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138. Salle B, Berthier JC. Entropathie aigu ncrosante du nouveau-n.
Pdiatrie. 1979;34:461471.
139. Dallman PR. Anemia of prematurity. Annu Rev Med. 1981;32:
143160.
140. Parer JT, Livingston EG. What is fetal distress? Am J Obstet Gynecol.
1990;162:14211427.
141. Drage J, Kennedy C, Schwarz B. The Apgar score as an index of
neonatal mortality: a report from the Collaborative Study of
Cerebral Palsy. Obstet Gynecol. 1964;24:222.
142. MacDonald H, Mullingan J, Allen A, et al. Neonatal asphyxia.
I. Relationship of obstetric and neonatal complications to neonatal
mortality in 38,405 consecutive deliveries. J Pediatr. 1980;96:898902.
143. Low JA. The role of blood gas and acid-base assessment in the
diagnosis of intrapartum fetal asphyxia. Am J Obstet Gynecol. 1988;
159:12351240.
144. Antenatal diagnosis: Report of a Consensus Development Conference, National Institute of Child Health and Human Development.
Vol. 79. Washington, DC: Government Printing Office; 1979. p. 1973.
145. Freeman J. Summary in prenatal and perinatal factors associated
with brain disorders. Washington, DC: Government Printing Office;
1985. NIH Publication no. 85-1149.
146. Nelson K. What proportion of cerebral palsy is related to birth
asphyxia? J Pediatr. 1988;112:572574.
147. Blair E, Stanley FJ. Intrapartum asphyxia: a rare cause of cerebral
palsy. J Pediatr. 1988;112:515519.
148. Freeman JM, Nelson KB. Intrapartum asphyxia and cerebral palsy.
Pediatrics. 1988;82:240249.
149. Paneth N, Stark R. Cerebral palsy and mental retardation in relation
to indicators of perinatal asphyxia. Am J Obstet Gynecol. 1983;
147:960966.
19
150. Low JM, Gaibraith RS, Muir DW, et al. Motor and cognitive deficits
after intrapartum asphyxia in the mature fetus. Am J Obstet Gynecol.
1988;158:356361.
151. Eckstein KL, Marx GF. Aortocaval compression and uterine
displacement. Anesthesiology. 1974; 40:9296.
152. Johnson CE. Transverse presentation of fetus. JAMA. 1964;187:
642.
153. Collea JV. Current management of breech presentation. Clin Obstet
Gynecol. 1980;23:525.
154. Behrman RE, Lees MH, Peterson EN, et al. Distribution of the
circulation in the normal and the asphyxiated fetal primate. Am J
Obstet Gynecol. 1970;108:956969.
155. Cohn HE, Sacks EJ, Heymann MA, et al. Cardiovascular responses
to hypoxemia and acidemia in fetal lambs. Am J Obstet Gynecol.
1974;120:817824.
156. Goodlin R. Fetal cardiovascular responses to distress. Obstet
Gynecol. 1977;49:371381.
157. Cohn H, Piasecki G, Jackson B. The effect of fetal heart rate on
cardiovascular function during hypoxemia. Am J Obstet Gynecol.
1980;138:11901199.
158. Burke G, Stuart B, Crowley P, et al. Is intrauterine growth retardation
with normal umbilical artery blood flow a benign condition? Br
Med J. 1990;300:1044.
159. Nicolaides KH, Bilardo CM, Soothill PW, et al. Absence of end
diastolic frequencies in umbilical artery: a sign of fetal hypoxia and
acidosis. Br Med J. 1988;297:10261027.
160. Arduini D, Rizzo G, Romanini C, et al. Fetal haemodynamic response to maternal hyperoxygenation as predictor of fetal
distress in intrauterine growth retardation. Br Med J. 1989;298:
15611562.
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General Growth and Tissue

Development Throughout
Childhood
Ruth Oelhafen Luginbuehl
INTRODUCTION
Postnatal
The first two decades of a human life are characterized by

significant growth and changes in both form and function. As a
human being progresses through fetal life, infancy, childhood, and
adolescence towards adulthood, tremendous physical, cognitive,
and emotional maturation occurs. Therefore, a physician dealing
with a pediatric population will be confronted with remarkable
physical and psychological differences in development and maturity
based on the chronological age of a child. A proper understanding
of this developmental progression is crucial for an anesthesiologist
to provide optimal care. As a detailed review in developmental
pediatrics is beyond the scope of this chapter, a general overview of
issues relevant to the practice of anesthesia is presented.
Birth is a dramatic event during which the fetus must adapt rapidly
to the abrupt change from the intrauterine to the extrauterine
environment. However, it is merely the beginning of a long process
of changes during human growth and development. Physical
growth continues at a rapid pace during the first 6 months of
extrauterine life and slows down gradually by about 2 years of age,
only to accelerate eventually again during the pubertal growth
spurt. On average, birthweight is doubled by 6 months of age and
tripled by 1 year. Length is doubled by 4 years of age. Growth
curves, including head circumference and body mass index (BMI)
curves, for healthy boys and girls are presented in Figures 22 to
29. Significant changes in body proportion take place over the
course of childhood. At birth the head is large relative to body size
(approximately 1/4 of total body length compared with 1/8 in
adulthood), the trunk is long, and the limbs are short (trunk to
limb ratio of 1:1 compared with 3:4 in adulthood). The upper body
to lower body ratio of about 1.7:1 in newborns decreases to
approximately 1:1 in adulthood.3 As Figure 210 shows, the total
body water content is almost 70% of body weight in the term
newborn (80% in the preterm baby), 62% at 1 year of age, and 65%
in adulthood.4 The decrease in the proportion of total body water
between the premature neonate and the older infant is attributed
to an increase in the proportion of body fat. The body surface area
to volume ratio is highest in the preterm newborn and decreases
into adulthood. Because of their increased relative surface area,
neonates may become hypothermic more quickly if they are
unprotected. The higher relative surface area also results in greater
evaporative water loss. The skin of the premature infant is thin
and gelatinous, further increasing evaporative heat losses in the
first few days of life.5 Figure 211 illustrates the nomogram for
approximating body surface area based on height and weight.
Mostellers formula allows a more accurate calculation of body
surface area6:
GENERAL GROWTH
Prenatal
The most rapid growth in human development occurs during the
prenatal stage.1 Although well protected in the uterus, the human
embryo may be affected in a negative way by environmental
agents or so-called teratogens.2 Teratogens, in biological (such as
bacterial and viral infections), chemical (such as drugs), and
physical form (such as radiation) may cause developmental
disruptions following maternal exposure. The damage caused by
these agents is very much dependent on the prenatal stage at the
time of exposure. During the first 2 weeks of gestation, maternal
exposure to teratogens may result in embryonic death and
spontaneous abortion or full repair. During organogenesis,
which is completed by the end of the eighth gestational week, the
embryo is most vulnerable to environmental agents. During this
stage, teratogenic insults may give rise to major congenital
malformations. The fetal period (beginning at the ninth
gestational week and lasting until term) is characterized by a
striking rate of somatic growth with continued differentiation
of organ systems. Environmental insults during this phase may
cause functional defects of organ systems or impair general growth
and result in a small-for-gestational-age (SGA) infant. Other
conditions including genetic defects, maternal illness, tobacco use,
and malnutrition may also compromise growth. By contrast,
poorly controlled maternal diabetes mellitus may result in a baby
that is large for gestational age (LGA). Figure 21 illustrates the
approximate birthweight at various gestational ages.
Body surface area m 2 = Body length cm x body weight kg 36000
Adolescence, the developmentally transitional stage between

childhood and adulthood, marks a time of dramatic physical and
psychological changes. Growth and physical changes including the
development of secondary sexual characteristics (facial, axillary,
and pubic hair as well as breast, testicular, penile, and laryngeal
development) are the result of endocrine maturation.78 The first
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Figure 2-1. Growth percentiles for preterm neonates.

General Growth and Tissue Development Throughout Childhood 21
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Figure 2-2. Growth percentiles for boys aged 0 to 36 months.

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Figure 2-3. Growth percentiles for girls aged 0 to 36 months.

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Figure 2-4. Growth percentiles for boys aged 2 to 20 years.

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Figure 2-5. Growth percentiles for girls aged 2 to 20 years.

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Figure 2-6. Head circumference percentiles for boys aged 0 to 36 months.

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Figure 2-7. Head circumference percentiles for girls aged 0 to 36 months.

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Figure 2-8. Body mass index (BMI) percentiles for boys aged 2 to 20 years.
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Figure 2-9. Body mass index (BMI) percentiles for girls aged 2 to 20 years.
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Figure 2-10. Age dependent changes in body composition.

sign of pubertal onset in boys is testicular enlargement, beginning

as early as 9 to 10 years of age. The first visible sign of puberty in
girls is the appearance of breast buds, which general begins
between 8 and 12 years of age. Menarche (age of first menses)
typically follows 2.5 years later, and marks the onset of fertility.
Staging of puberty is based on the sexual maturity rating (SMR)
criteria described by Tanner (Table 21).9 On average, the peak
growth velocity during the pubertal growth spurt occurs in girls at
11 to 12 years of age and in boys at around 14 years of age. During
the 2 years following menarche, girls gain on average another 5
8 cm until finally reaching adult height.10
FLUIDS AND NUTRITION

Rapid growth and the relatively high maintenance rates due to
higher metabolic and nutrient turnover explain the significantly
higher caloric needs in infants and children compared with
adults.11 Lack or too low a caloric intake has a negative impact on
a childs development, causing the weight curve to decline first.
A more chronic situation will eventually have a negative influence
on body size, and later on psychomotor development (failure to
thrive [FTT:). During the first 5 to 6 months of life, nutrition of a
healthy infant is provided entirely by breast milk (preferably) or by
special infant formulas, which have been adapted to age-related
needs. Around the age of 6 months, infants are generally ready for
the introduction of complementary solid food. The timing and
order of the introduction of solids varies considerably and is
influenced by social and cultural factors. However, there are
recommendations for the introduction of solid food by the
World Health Organization (WHO).12 These recommendations
take into consideration not only the risk of nutrients to act as
potential allergens, but also their potential to negatively influence
the risk of cardiovascular problems later on in adulthood.1314
Complementary food should be introduced step by step. The age
when children become entirely self-feeding varies and depends
on sociocultural factors and the willingness of the parents to
tolerate a mess at mealtimes. Caloric intake per kilogram of body
weight falls steadily after the age of 1 year. Table 22 illustrates the
recommended energy intake in a healthy and active child. Caloric
requirements in a hospitalized child vary depending on the illness
and most often lie between the basal metabolic requirements
and the normal energy needs of an active child. Because the
metabolism of 1 calorie of energy results in net consumption of
1 mL of water, fluid requirements are thought to reflect caloric
requirements. A simple formula known as the HollidaySeger
method for calculating daily maintenance fluid requirements
based on body weight may also help to estimate the daily energy
needs.15
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Figure 2-11. Nomogram for estimation of body surface area. A: For patients of approximately normal body size, the surface area
can be estimated from the body weight alone. B: The intersection of the line connecting patients height (left column) with patients
weight (right columns) yields the patients body surface area.
0 to 10 kg body weight:
11 to 20 kg body weight:
20 kg body weight:
Daily fluid
requirement
100 mL/kg
1000 mL
50 mL/kg
1500 mL
20 mL/kg
Daily energy
requirement
100 kcal/kg
1000 kcal
50 kcal/kg
1500 kcal
20 kcal/kg
The body surface area method serves the same purpose, but is
based on the body surface area.16 Daily fluid requirements are 1500
mL/m2 per 24 hours and daily energy requirements are 1500
mL/m2 per 24 hours. Recommended daily allowances for
electrolytes, minerals, vitamins, and other nutrients can be found
in various references.11,1416
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TABLE 2-1. Classification of Sexual Maturity Rating in Boys and Girls

Girls
Sexual Maturity
Rating Stage
1
2
3
4
Boys
Breasts
Pubic Hair
Pubic Hair
Penis
Testes
Preadolescent
Brest and papilla
elevated as small
mound; areola
diameter increased
Breast and areola
enlarged, no contour
separation
Areola and papilla form
secondary mound
Preadolescent
Preadolescent
Sparse, lightly
Scanty, long, slightly
pigmented, straight,
pigmented
medial border of labia
Preadolescent
Slight enlargement
Darker, beginning to
curl, increased
amount
Coarse, curly, abundant
but amount less than
in adult
Longer
Preadolescent
Enlarged
scrotum,
pink texture
altered
Larger
Mature; nipple projects,

areola part of general
breast contour
Adult feminine triangle,

spread to medial
surface of thighs
Darker, starts to
curl, small
amount
Resembles adult
type, but less in
quantity; coarse,
curly
Adult distribution,
spread to medial
surface of thighs
Larger; glans
and breadth
increase in
size
Adult size
Larger, scrotum
dark
Adult size
Adapted from references 10, 11.
TABLE 2-2. Recommended Daily Energy Intake (kcal),

by Age
Age, Years
Per Kilogram Body Weight
Per Day
108
98
102
90
70
55
45
47
40
650
850
1300
1800
2000
2500
3000
2200
2200
00.5
0.51.0
13
46
710
1114 Males
1518
1114 Females
1518
SPECIFIC ORGAN SYSTEMS

Airway and Respiratory System
The respiratory system serves the two main functions of supplying
sufficient oxygen to meet metabolic demands and removing
carbon dioxide. A variety of processes including ventilation,
perfusion, and diffusion are involved in fulfilling these functions.
The development of the respiratory system begins during the
fourth week of gestation.1 The respiratory tree is formed by
successive branching of the airways. By 24 weeks of gestation,
some thin-walled primitive alveoli have developed at the end of
the respiratory bronchioles. These regions are well vascularized
and therefore, at this point, the conditions exist for effective gas
exchange and breathing. However, at 24 weeks, the primitive
alveoli are mainly lined by type I pneumocytes, which means there
is no surfactant production. Surfactant is produced by type II
pneumocytes and spreads out in the form of a monomolecular
film over the walls of the primitive alveoli. Its function is to
counteract surface tension forces and to facilitate alveolar
expansion. By 26 to 28 weeks of gestation, sufficient alveoli and
surfactant are present to permit survival of some infants without

exogenous surfactant. Infants born without adequate surfactant
develop infantile respiratory distress syndrome (RDS). If
premature delivery can be anticipated 48 hours ahead of time,
surfactant production may be induced by the administration of
glucocorticoids to the mother. More importantly, several
preparations of exogenous surfactant are now available and have
improved morbidity and mortality in this population.5, 17
Approximately 12% to 16% of the adult number of alveoli are
present at birth. The number and size of alveoli continue to
increase until the child is about 8 years of age, after which time
lung growth occurs only by increasing alveolar size.1 Before birth,
the lungs are filled with fluid. To make the transition to extra
uterine life and allow the lungs to take over their function, this
fluid must be replaced by air. The majority of the fluid is removed
from the lungs by compression of the highly compliant chest
wall in the birth canal during the birth process.18 The rest will
be absorbed into the pulmonary vascular system and removed
by the pulmonary lymphatic system.5 This process may require
several hours in the normal infant and transient tachypnea of
the newborn may be seen if there is ineffective removal of this
fluid. This is generally a benign process which resolves during
the first day of life. Therapy may include the administration of
supplemental oxygen or continuous positive airway pressure
(CPAP). The first breath may require a very high negative intrathoracic pressures to inflate the lung tissue and fill the alveoli with
air. This may result in a pulmonary air leak, which may cause a
pneumothorax or pneumomediastinum.19 Asymptomatic infants
generally do not require invasive therapy such as tube thoracostomy. However, ongoing observation and monitoring for signs of
respiratory deterioration are necessary.5
The respiratory rate is highest in the newborn period and
gradually falls to adult values by adolescence (Table 23). Young,
especially premature, infants may normally show an irregular
respiratory pattern. Even term infants may normally display
periodic breathing, which is characterized by a period of apnea
lasting from 3 to 10 seconds followed by a period of ventilation
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TABLE 2-3. Mean Respiratory Rates, by Age

Age
Respiratory Rate, breaths/min
Premature
03 months
36 months
612 months
13 years
36 years
612 years
Adult
4070
3555
3045
2540
2030
2025
1422
1218
for 10 to 18 seconds. It is rarely seen during the first 24 hours

after birth and disappears by 38 to 40 weeks of gestational age.20 It
is therefore important to count the respiration rate for a full
minute in this age group when performing an assessment.
This normal variation in respiration must be distinguished
from apnea of prematurity, which may require mechanical or
pharmacological therapy. Apnea in infancy is defined as an
unexplained episode of interruption of breathing for 20 seconds or
longer, or a shorter respiratory pause of any duration associated
with symptoms such as bradycardia, cyanosis, pallor, and/or
significant muscular hypotonia.21 Respiratory pauses of up to
20 seconds during sleep are considered to be normal in a healthy
infant.22 As the lungs in an infant are noncompliant and the
chest wall elastic, mild intercostal restractions may be a normal
occurrence and not necessarily indicative of intrathoracic or
pulmonary parenchymal disease. However, this finding must be
considered pathologic in the context of other signs of respiratory
distress such as tachypnea, cyanosis, stridor, wheezing, grunting,
nasal flaring, or retractions.18 Additionally, neonates and infants
are more dependent on the diaphragm for normal ventilatory
function. As such, they may normally display paradoxical or
abdominal breathing where the abdomen moves out while the
chest wall moves in and vice versa.
The larynx in neonates and young infants differs from older
children, adolescents and adults not only in size, but also in
relative dimensions and location.23 An infants glottis is relatively
small compared with an adult glottis, whereas the epiglottis is
proportionately larger. This relative difference in size and the
position of the larynx high in the neck are crucial in allowing
infants to simultaneously suck, swallow, and breath. Therefore,
most newborn infants are obligate nasal breathers. Significant
nasal obstruction presenting at birth such as bilateral choanal
atresia may be a life-threatening situation. The descent of the
larynx to a lower position in the neck begins around 2 years of
age. This change in position results in a confluence of the digestive
and the respiratory tract. Although the ability of breathing and
suckling simultaneously is lost, this change is necessary to elongate
the vocal tract, which in turn is crucial for the development of
complex speech and articulation.23
Cardiovascular System
The development of the cardiovascular system is essentially
complete by 8 weeks of gestation, the most critical period being
day 20 to 50.24 During fetal life, the placenta is providing the
function that the lungs provide after birth. This includes removal
of carbon dioxide and almost full oxygenation of blood, which

then returns to the fetus via the umbilical vein.25 There are three
shunts bypassing organs, which during fetal life do not have a
major function. First is the ductus venosus, serving as a connection
from the umbilical vein to the inferior vena cava, permitting half
of the umbilical venous (oxygenated) blood to bypass the hepatic
microcirculation. Second is the foramen ovale, a direct connection
between the right and the left atrium, allowing blood of the highest
possible O2 concentration (from the umbilical vein into the right
atrium to the left atrium) to perfuse the cerebral circulation.
Finally, the ductus arteriosus, which directs blood from the
right ventricle to the descending aorta, thereby bypassing
the pulmonary circulation. Only approximately 10% of the blood
flowing through the right ventricle circulates through the lungs,
which in utero do not participate in gas exchange. As the rightsided pressures are higher than left-sided pressures in the fetus
due to the high pulmonary vascular resistance, the right ventricle
is more muscular than the left ventricle.
At birth, the fetal circulation begins to transition to the
postnatal circulation. The critical event during this transition is
the establishment of lung inflation. With the first breath, the lungs
become aerated. The contact with air containing oxygen results
in vasodilatation of the pulmonary resistance vessels, which is
accompanied by a tremendous increase of the pulmonary blood
flow as pulmonary vascular resistance acutely falls. Left atrial
pressure becomes immediately higher than right atrial pressure,
causing the foramen ovale to functionally close. Increased
arterial oxygen tension causes constriction and closure of the
ductus arteriosus. The ductus venosus and the umbilical vessels,
which are no longer needed, also constrict and obliterate. These
changes occur gradually over the first few days of life. Therefore,
establishing vascular access through umbilical veins and arteries
for the administration of fluids and medications, or monitoring
in severely sick neonates is only possible for a short period of time
after birth.
The higher affinity of fetal hemoglobin (HbF) for oxygen is
crucial in utero, allowing O2 to be extracted from the maternal
blood. Placental oxygen transfer occurs at a much lower oxygen
tension than does alveolar oxygen transfer after birth. However,
ex utero, this higher affinity is a disadvantage, as it impairs oxygen
delivery at the tissue level. Resting cardiac output in the neonate
is high compared with that of the older child and adult.26 This
allows the infant to meet oxygen demands in the periphery, but as
a result, the ability of the newborn to further increase cardiac
output in conditions of stress is limited.
Accurate blood pressure measurement in children depends
on the selection of an appropriate sized cuff. As is the case with
adults, it is now generally agreed that diastolic blood pressure
corresponds with the disappearance of Korotkoff sounds, also
referred to as the fifth Korotkoff sound.27 In some children,
Korotkoff sounds may be heard down to 0 mmHg. Normal blood
pressure in newborns correlates with gestational age and
birthweight.28 Blood pressure curves for infants are provided in
Figures 212 and 213. Tables 24 and 25 summarize blood
pressure levels for boys and girls from 1 to 17 years of age. Table
26 shows the normal range of heart rate in relationship to the age
of the infant or child.
Electrocardiographic (ECG) findings in neonates and children
are different from that of adults.29 Because of the right-sided
predominance of the fetal heart, the neonatal ECG shows a
marked right axis deviation (30 to 180 degrees) compared
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Figure 2-12. Percentiles for blood

pressure in boys.
with that of adults (30 to 105 degrees). The electrocardiogram
also shows tall R waves in the right-sided leads and deep S waves
in the left-sided leads. There is a gradual shift toward the normal
left axis orientation over the course of childhood. This occurs most
rapidly in the first month of life. QRS duration is shorter in
children, ranging from an average of 50 ms in neonates to 80 ms
in adults. The PR interval is shorter, increasing from about 90
100 ms (upper limits of normal is 120 ms) in neonates to 150170
ms (upper limit of normal is 210 ms) in adults. T waves may be
inverted further toward the left in the precordial leads in children
than in adults.
Innocent (or functional) heart murmurs are common in
childhood and may be heard in 80% of children at some point in
life.29 They emanate from cardiovascular structures in the absence
of anatomic abnormalities and are accentuated or brought out in
a high-output state such as fever or feeding. Innocent heart
murmurs can be difficult to diagnose and have to be differentiated
from pathologic heart murmurs. If 1 or more of the following
criteria are present, cardiology consultation is suggested:
1) Symptoms or physical signs of heart failure on examination
(e.g., cyanosis, dyspnea, abnormal strong or weak pulses,
hepatomegaly)
2) Abnormal cardiac size or silhouette or abnormal pulmonary

vascularity on chest x-ray
3) Abnormal ECG
4) Diastolic murmur
5) A systolic murmur that is loud (more than 3/6 or with a thrill),
long in duration and transmits well to other parts of the body
6) Abnormal heart sounds
Innocent systolic murmurs include the vibratory Stills
murmur, the basal systolic ejection murmur, cardiorespiratory
murmur, and the murmur of physiologic peripheral pulmonary
stenosis. The venous hum is a continuous murmur heard
throughout the cardiac cycle. Other innocent heart sounds that
may be present in childhood include the carotid bruit and third
heart sound (S3).
Gastrointestinal System
At birth the gastrointestinal system is almost fully capable of
taking over its functions which include digestion, absorption,
and secretion, as well as endocrine and immunologic activities.
Meconium, the first bowel movement after birth, is of greenishblack color and with a sticky consistency. It is normally discharged
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Figure 2-13. Percentiles for blood

pressure in girls.
TABLE 2-4. Blood Pressure Levels for Boys Aged
1 to 17 Years
Age, Years
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Systolic Blood Pressure, Diastolic Blood Pressure,

mm Hg (2 SD)
mmHg (2 SD)
98 (94102)
102 (98106)
105 (100109)
107 (102111)
108 (104112)
110 (105114)
111 (106115)
112 (107116)
113 (109117)
115 (110119)
117 (112121)
119 (115123)
122 (117126)
125 (120128)
127 (123131)
130 (125134)
133 (128136)
53 (5055)
57 (5559)
61 ( 5963)
64 (6266)
67 (6569)
70 (6772)
72 (6974)
73 (7175)
74 (7277)
75 (7378)
76 (7478)
77 (7579)
77 (7580)
78 (7680)
79 (7781)
81 (7983)
87 (8589)
TABLE 2-5. Blood Pressure Levels for Girls Aged

1 to 17 Years
Age
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Systolic Blood Pressure, Diastolic Blood Pressure,

mmHg (2 SD)
mmHg (2 SD)
100 (97104)
102 (99105)
103 (100106)
104 (101108)
106 (103109)
107 (104111)
109 (106112)
111 (108114)
113 (110116)
115 (112118)
117 (114120)
119 (116122)
121 (118124)
122 (119126)
124 (121127)
125 (122128)
125 (122128)
54 (5356)
58 (5761)
62 (6164)
65 (6367)
67 (6569)
69 (6771)
70 (6972)
71 (7074)
73 (7175)
74 (7376)
75 (7477)
76 (7578)
78 (7680)
79 (7781)
79 (7882)
80 (7982)
80 (7982)
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TABLE 2-6. Mean Heart Rate, by Age

Age
Premature
03 months
36 months
612 months
13 years
36 years
612 years
Adult
Heart Rate, beats/min

120170*
100150*
90120
80120
70110
65110
6095
5585

*In sleep, infant heart rates may drop significantly lower, but if perfusion is
maintained, no intervention is required
within the first 24 to 48 hours of life. Overall, the gastrointestinal

transit time in the infant is shorter than that of an adult and
increases with increasing age. The normal physiologic range of
stool frequency varies greatly (from 10 times a day to 12 times a
week30). Breast-fed infants usually have stools more often than
do their formula-fed counterparts. The frequency of bowel
movements gradually declines over the first years of life, reaching
adult habits at about 4 years of age. The abdomen of the infant and
younger child is protuberant because of the relatively large volume
of the abdominal viscera. In infants the edge of the liver is
normally felt 12 cm below the right costal margin.31 The spleen
should be no more than 1 cm below the rib margin. In young
infants, an umbilical hernia is common, usually of no clinical
concern, and generally closes spontaneously as the muscles
develop toward the end of the first year.
In neonates and younger infants, the lower esophageal sphincter
tone is physiologically decreased and may lead to gastroesophageal
reflux. Other predisposing factors include a short esophagus,
large meals in relation to gastric capacity, frequent feeding
regimen, supine position, and Valsalva maneuvers during bowel
movements.32 Daily vomiting or spitting up may be seen in one
half of all infants between 0 and 3 months of age and up to two
thirds of 4- to 6-month-old infants.33 Most of these infants suffer
no ill effect (happy spitter) and grow well.31 This condition
usually begins in the first weeks of life and resolves spontaneously
by 9 to 24 months of age as solid food has been introduced and the
child becomes more upright. Only between 1:300 and 1:1000
infants have reflux significant enough to cause complications.34
Neonatal jaundice (physiologic hyperbilirubinemia) is a
common condition, which generally begins during the second
24 hours of life, has its peak around the third day of life, and
resolves itself by the end of the first week.35 It is caused by a high
rate of bilirubin production due to the shorter lifespan of the
newborns red blood cells and by a limited ability to effectively
eliminate bilirubin due to immaturity of the hepatic microsomal
enzyme systems. Typical physiologic newborn jaundice is an
unconjugated, or indirect-reacting hyperbilirubinemia. Preterm
and breast-fed newborn babies may show a protracted form of
this condition. Although it is generally a benign, self-limiting
condition, its course should be monitored to prevent missing an
indication for treatment (e.g., phototherapy). It should also be
differentiated from pathologic causes of jaundice such as those
related to blood type incompatibility or hepatic problems such as
biliary atresia.
Colic, an episodic pattern of seemingly inconsolable crying that

tends to occur in the evenings, may be seen in babies less than
3 months of age. The cause of this phenomenon is not completely
understood. Although it resolves spontaneously around the end
of the third month of life, it must be differentiated from organic
causes. It may represent a source of considerable concern and
frustration for parents and caregivers.
Although tooth formation begins in utero during the 4th
month of gestation, the first primary (deciduous) tooth does not
erupt until approximately 6 to 7 months of age.36 Deciduous
dentition (with 20 teeth) is complete between the age of 2 and
3 years. The permanent teeth begin to erupt around the age of
6 years, starting after the loss of the primary central incisors. The
last primary tooth is shed around the age of 12 to 14 years. The
anesthesiologist must be aware of the possibility of loose teeth at
any age during childhood when managing the airway. The set of
permanent teeth (32 teeth) may not be complete until the third
decade of life. The timing of appearance of the dentition is shown
in Table 27.
Renal System
Urine production begins at approximately 12 weeks of gestation
and continues throughout fetal life.1 The urine is excreted into the
amniotic cavity and forms the major part of the amniotic fluid.
However, because the elimination of fetal metabolic waste is a
function of the placenta, there is no need for the kidneys to work
TABLE 2-7. Chronology of Human Dentition

Average Age
of Eruption
Tooth
Deciduous Dentition
Maxillary
Mandibular
Permanent Dentition
Maxillary
Mandibular
Central Incisor
Lateral Incisor
Cuspid
First Molar
Second Molar
Central Incisor
Lateral Incisor
Cuspid
First Molar
Second Molar
7.5 months
9 months
18 months
14 months
24 months
6 months
7 months
16 months
12 months
20 months
Central Incisor
Lateral Incisor
Cuspid
First Bicuspid
Second Bicuspid
Second Molar
Third Molar
Central Incisor
Lateral Incisor
Cuspid
First Bicuspid
Second Bicuspid
Second Molar
Third Molar
78 years
89 years
1112 years
1011 years
1012 years
1213 years
1721 years
67 years
78 years
910 years
1012 years
1112 years
1113 years
1721 years
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CHAPTER 2
before birth. The fetal kidneys receive only 2% of the cardiac

output, compared with 20% for the mature kidney.37 One of the
major functions of the kidney is to maintain extracellular
homeostasis. Although the adult kidneys maintain precise balance
matching fluid and electrolyte excretion to intake, in growing
children this balance must be positive for a number of solutes to
make growth possible. This conveys a great challenge for the
kidneys during this period of life. Although the kidneys are
morphologically fully developed at 34 weeks of gestation, the
functional development is far from complete at birth. Postnatal
functional changes occur in renal blood flow, glomerular filtration
rate (GFR), and tubular function. The glomerular filtration rate is
low in newborn, increases dramatically during the first month of
life, and reaches adult values, corrected to body surface area, by
the age of 2 years. At birth, the serum creatinine concentration
reflects the maternal level and declines during the first days of life.
Since the serum creatinine at birth is a result of the placental
creatinine transfer, it does not reflect the neonatal renal function. Over the course of early childhood, creatinine clearance
increases, reaching adult values between 2 and 3 years. Due to the
rapid growth and increase in muscular mass, normal serum
creatinine values increase with age and are higher in men. In the
newborn the ability to concentrate urine is limited compared
with adults. A maximum urine concentration of 600 mOsm/kg
can be achieved in newborns versus 1200 mOsm/kg in adult
counterparts. In young children, the relative inability to handle
high solute loads is offset by the low solute content of breast milk
and infant formula.
Hematological System
The first blood cells produced by the embryo belong to the red
cell line, followed by granulocytes, platelets and lymphocytes.38
The anatomic site of hematogenesis undergoes developmental
changes during fetal life. At about 3 to 5 months of gestation, the
liver is the chief organ of hematopoiesis and continues to produce
red cells into the first postnatal week. During the last 3 months
of gestation, the bone marrow becomes the chief site of blood
cell formation. The term neonate has a higher hemoglobin
and hematocrit compared to the older child. At birth the infants

hemoglobin is primarily HbF, which has a higher affinity for
oxygen than the adult type (HbA). The initially high hematocrit
drops dramatically during the first days of life, due to decreased
production of hemoglobin and red blood cells combined with the
shorter lifespan of fetal erythrocytes.39 The more immature the
neonate, the shorter is the lifespan of red cells. This and a lower
total body iron store result in a more exaggerated neonatal
anemia in preterm infants compared to their term counterparts.
The nadir of the hemoglobin level is reached at approximately 8 to
12 weeks of age in term infants and 4 to 8 weeks in premature
infants. This physiologic drop of hemoglobin concentration
stimulates erythropoiesis. Hemoglobin produced postnatal is of
the adult type, which has largely replaced HbF by approximately
4 months of age. Besides blood loss, there are two major types of
anemia including the hypo- or aregenerative anemia, where the
production of red blood cells is decreased and hemolytic anemia
with an increased destruction of red blood cells. Table 28 shows
the normal hematologic values during childhood.
The white blood cell count is highest in the first days of life and
drops steadily throughout childhood to finally reach adult values
during adolescence. Leucocytosis is a sign of a possible infectious
process. The younger the child, the more limited is the ability
to react with leucocytosis to an infectious agent. In neonates,
leukopenia is generally more indicative of an infectious process.
This age group is also more likely to develop hypothermia rather
than a fever as a reaction to an infection. Table 29 illustrates
normal leukocytosis counts at different ages. The production of
platelets is regulated by thrombopoietin, which maintains a
normal blood platelet count of 150400 109/L with no age
related differences. Table 210 lists normal platelet counts and
Table 211 gives normal values for selected coagulation tests.
After the initial adjustment during the first hours of life, blood
volume maintains a relatively constant relationship to body weight
throughout most of the life. The average blood volume in term
newborns is 85 mL/kg and 90 mL/kg in preterm newborns. It
increases to an average of 105 mL/kg during the first days of life
and then decreases again over the course of the next few months.
At approximately 6 months of age, the average blood volume is
TABLE 2-8. Normal Hematologic Values in Children

Age
Birth (cord blood)
13 days (capillary)
1 week
2 weeks
1 month
2 months
36 months
0.52 years
26 years
612 years
1218 years:
Female
Male
1849 years:
Female
Male
Red Cell Count, 1012/L (2 SD)
Hemoglobin, g/dL (2 SD)
Hematocrit, % (2 SD)
16.5 (13.519.5)
18.5 (14.522.5)
17.5 (13.521.5)
16.5 (12.520.5)
14.0 (10.018.0)
11.5 (9.014.0)
11.5 (9.513.5)
12.0 (10.513.5)
12.5 (11.513.5)
13.5 (11.515.5)
51 (4260)
56 (4567)
54 (4266)
51 (3963)
43 (3155)
35 ( 2842)
35 (2941)
36 (3339)
37 (3440)
40 (3545)
4.7 (3.95.5)
5.3 (4.06.6)
5.1 (3.96.3)
4.9 (3.66.2)
4.2 (3.05.4)
3.8 (2.74.9)
3.8 (3.14.5)
4.5 (3.75.3)
4.6 (3.95.3)
4.6 (4.05.2)
14.0 (12.016.0)
14.5 (13.016.5)
41 (3646)
43 (3749)
4.6 (4.15.1)
4.9 (4.55.3)
14.0 (12.016.0)
15.5 (13.517.5)
41 (3646)
47 (4153)
4.6 (4.05.2)
5.2 (4.55.9)
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TABLE 2-9. Reference Ranges for Leukocyte Counts in Children

Age
Leukocytes, 103/mm3 (2 SD)
Neutrophils, 103/mm3 (2 SD) [%*:
18.1 (9.030.0)
22.8 (13.038.0)
18.9 (9.434.0)
12.2 (5.021.0)
11.4 (5.0(20.0)
10.8 (5.019.5)
11.9 (6.017.5)
11.4 (6.017.5)
10.6 (6.017.0)
9.1 (5.515.5)
8.5 (5.014.5)
8.3 (4.513.5)
8.1 (4.513.5)
7.8 (4.513.0)
7.4 (4.511.0)
11.0 (6.026.0) [61:

15.5 (6.028.0) [68:
11.5 (5.021.0) [61:
5.5 (1.510.0) [45:
4.5 (1.09.5) [40:
3.8 (1.09.0) [35:
3.8 (1.08.5) [32:
3.5 (1.58.5) [31:
3.5 (1.58.5) [33:
3.8 (1.58.5) [42:
4.3 (1.58.0) [51:
4.4 (1.58.0) [53:
4.4 (1.88.0) [54:
4.4 (1.88.0) [57:
4.4 (1.87.7) [59:
Birth
12 hours
24 hours
1 week
2 weeks
1 month
6 months
1 year
2 years
4 years
6 years
8 years
10 years
16 years
21 years
Lymphocytes, 103/mm3 (2 SD) [%*:

5.5 (2.011.0) [31:
5.5 (2.011.0) [24:
5.8 (2.011.5) [31:
5.0 (2.017.0) [41:
5.5 (2.017.0) [48:
6.0 (2.516.5) [56:
7.3 (4.013.5) [61:
7.0 (4.010.5) [61:
6.3 (3.09.5) [59:
4.5 (2.08.0) [50:
3.5 (1.57.0) [42:
3.3 (1.56.8) [39:
3.1 (1.56.5) [38:
2.8 (1.25.2) [35:
2.5 (1.04.8) [34:

*Percentages are proportion of leukocytes.
TABLE 2-10. Circulating Platelet Counts in Children

Platelet Count, 109/L
Age
288 53
303 48
338 59
343 72
365 49
314 78
304 66
303 65
295 58
251 40
234 48
Cord blood
2 days
5 days
1 month
211 months
12 years
34 years
56 years
710 years
1115 years
Adult
approximately 7577 mL/kg, similar to that of older children and

adults.40
Pharmacology and Therapeutics

Maturational changes in body size and composition, as well
as changes in metabolic, gastrointestinal, hepatic, and renal
function may affect the way pharmacologic agents perform in
infants and general and therefore how they should be prescribed
and administered. In different age groups, divergences may be
seen in absorption, distribution, and clearance of xenobiotics.

These factors should be kept in mind when calculating and
adjusting drug dosages in children, particularly in infants. As a
general rule, on a per kilogram body weight basis, drug doses are
lower in younger infants and higher in children (preadolescents)
than in adults.
Neurological System
Although the nervous system is anatomicly complete at birth,
functionally it remains immature with the continuation of
myelination and synaptogenesis.41 At birth, the cranial sutures are
still open and are easily palpable. There may be some overlapping
of skull bones for the first few days of life, caused by compression
of the head in the birth canal. This should be differentiated from
craniosynostosis (premature closure of 1 or more sutures). The
anterior fontanel is diamond shaped, less than 3.5 cm in diameter
at birth, soft and easily palpable. Its size gradually decreases
following birth, but is still palpable during the first year of life. It
closes at anywhere from 12 to 18 months of age. A bulging or tense
anterior fontanel with or without separation of the sutures may be
an indication of increased intracranial pressure. A sunken fontanel
may be a sign of severe hypovolemia from any of many causes
including dehydration. The posterior fontanel is triangular and
much smaller in size (fingertip). It may be difficult to palpate at
birth and is usually closed by 6 weeks of age. The sutures need to
stay open to allow the brain to grow. (The growth of the head
TABLE 2-11. Reference Values for Selected Coagulation Tests in Children

Age
PT, sec (2 SD)
INR(2 SD)
APTT,
sec (2 SD)
Fibrinogen,
g/L (2 SD)
Bleeding Time,
min (2 SD)
15 years
610 years
1116 years
Adult
11 (10.611.4)
11.1 (10.112.1)
11.2 (10.212.0)
12 (11.014.0)
1.0 (0.961.04)
1.01 (0.91 1.11)
1.02 (0.931.10)
1.10 (1.01.3)
30 (2436)
31 (2636)
32 (2637)
33 (2740)
2.76 (1.704.05)
2.79 (1.574.0)
3.0 (1.544.48)
2.78 (1.564.0)
6 (2.510)
7 (2.513)
5 (38)
4 (17)
PT prothrombin time; INR international normalized ratio; APPT activated partial thromboplastin time. Adapted from reference 48.
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CHAPTER 2
circumference is presented in Figure 26 for boys and Figure 27

for girls.) Further maturation of the nervous system (myelination
and synaptogenesis) continues rapidly during the first 2 years of
life and is accompanied by rapid development of motor and
behavioral skills. These advances occur in a rostrocaudal pattern.
Myelination is complete by 7 years of age.
Primitive reflexes such as the grasp, rooting, sucking, Moro,
and asymmetric tonic neck reflex are present in the neonate infant
and fade during the latter part of the first year of life in the course
of normal development. Tendon reflexes (biceps, patellar, ankle
jerks) are present at birth. They may be exaggerated with a
tendency to clonus in newborn infants; however, they should be
symmetric. Absent or asymmetric tendon reflexes may be an
indication of a significant central or peripheral nervous system
abnormality. In the newborn, flexor tone predominates, giving the
infant the typical flexed posture.
DEVELOPMENTAL PEDIATRICS
So far this chapter has listed the chronology of anatomic and
physiologic changes that occur in childhood. Of equal importance
are the developmental and behavioral changes featured during
growth of the human organism. The developmental stage of a
child has a remarkable influence on the general approach to
the patient, as well as specific issues related to assessment and
treatment. For example, knowledge of a childs level of cognitive
maturity helps to determine which pain rating scale is most
appropriate. Patient safety may also depend on knowledge of
child development. For instance, adequately high bed rails are
needed for children who might pull themselves to the standing
position. Child development involves several areas including
motor (fine and gross motor), communication, and socialization
skills. Some of the major developmental milestones during
childhood are illustrated in Table 212. It should be kept in mind
that these are only guidelines since children show considerable
variation in timing and succession of stages during normal
development. Chronic illness or frequent hospitalizations as well
as environmental factors, such as psychosocial issues, may delay
achievements of developmental milestones.
Newborn infants do not have predictable sleep schedules. Naps
are interspersed with feedings and periods of crying and quiet
wakefulness. Over time, naps coalesce and episodes of wakefulness
become longer. In general, by 18 months of age, children are only
taking one daytime nap and by 4 years of age children no longer
sleep during the day. Toilet training is a learned behavior whose
timing of onset is extremely variable. The ability to achieve
continence develops by about 20 months of age, so attempting toilet
training before this time is often fruitless. Most children are fully
toilet trained between the ages of 2 and 3 years. Daytime control is
generally achieved before nighttime control, so even children who
are continent during the day may require diapers at night. Primary
nocturnal enuresis, or bedwetting of unknown etiology, may occur
in 15% to 20% of children 5 years of age or more. Thereafter, the
incidence decreases by about 15% of the initial rate per year and
becomes stable at 1% by 15 years of age.42 It is believed to be related
to physiologic immaturity. A positive family history following
mainly the male lineage can often be observed. Primary nocturnal
enuresis may be a source of considerable anxiety for some children,
particularly when they must sleep in an environment other than
their own home, such as in a hospital.
TABLE 2-12. Developmental Milestones

Age
Gross Motor
Rolls from prone to supine
Sits without support
Rolls from supine to prone
Gets to sitting
Pulls self to stand
Stands without support
Walks well
Up and down stairs without support
Runs
45 months
7 months
56 months
8 months
9 months
12 months
15 months
2 years
2 years
Fine Motor
Brings hands together
Grasps object
Reaches for object
Transfers object from one hand to the other
Pincer (thumb-forefinger) grasp
Turns page
Scribbles
Tower of 2 cubes
3 months
3.5 months
4 months
6 months
8 months
12 months
13 months
14 months
Communication and Language

Cooing
Monosyllabic babbling
Imitates sounds made by others
Polysyllabic babbling
Follows 1-step commands
First words other than mama or dada
10-word vocabulary
2-word sentences
Complete sentences
Almost completely intelligible to strangers
24 months
58 months
912 months
912 months
1015 months
12 months
1518 months
1824 months
23 years
35 years
Social skills
Social smile
Separation anxiety / stranger awareness
Interactive games: e.g., peek-a-boo
Feeds self with cup and spoon
Recognizes self in mirror
Dresses self (except for buttons, etc.)
Parallel play
Cooperative play
Able to distinguish fantasy from reality
12 months
612 months
912 months
1518 months
2 years
3 years
12 years
34 years
5 years
Although the cognitive development during childhood is a

continuous process, it has been divided into a number of discrete
stages described by Freud, Erikson, Piaget and others. Table 213
offers an overview of the major schools of developmental theories,
including those proposed by Freud, Erikson, and Piaget. Piaget
believed that children perceive the world differently than adults
and that their perception is different in each stage. This thesis can
aid in the understanding the actions and reactions seen in different
age groups. Piaget postulated that children learn through active
interaction with the environment not only through their success,
but also by analyzing their mistakes.43 During the first stage of
Piagets theory of cognitive development (Sensorimotor stage: 0 to
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TABLE 2-13. Theories of Developmental Psychology

Age
Freud
Erikson
Piaget
Acquired Skills
Birth18 months
Oral phase
Basic trust vs.

mistrust
Sensorimotor
18 months3 years
Anal phase
Symbolic
preoperational
36 years
Oedipal phase
Autonomy vs.
shame,
doubt
Initiative vs.
guilt
612 years
Latency
1217 years
Adolescence
Industry vs.
inferiority
Identity vs. role
confusion
Concrete
operational
Formal
operational
Basic trust as feature for later bonding capacity;

Object permanence; Differentiation between
self and world
Verbal communication more sophisticated;
Predominant egocentricity; Control over body
function
Rich imagination and creativity; Symbolic
functioning; Confrontation with societys moral
values
Higher level of social skills in peer interaction;
Development of reasoning
Moving out of family core to gain autonomy and
independence; Abstract reasoning and thinking
Intuitive
preoperational
2 years of age), a childs view of the world is shaped by physical

interaction with the environment. Infants may use their mouths
for this purpose and their safety needs to be considered at all
times. It is the stage of establishment of basic trust between the
child and the primary caregiver, which eventually will be a basic
feature for the capacity of bonding and building relationships later
in life. At around 9 months of age, a phenomenon known as
stranger anxiety may be seen when babies are confronted with
unfamiliar individuals. As the preoperative stage approaches, the
concept of object permanence is achieved whereby a child learns
that an object exists even though it is no longer present or visible.
In the preoperative stage (2 to 6 years of age), thought is dominated
by egocentricity and symbolism. Fantasy play is common.
Although toddlers have some appreciation of cause and effect,
they exhibit magical thinking. They may believe that a bad deed
or thought has caused illness in themselves or in others.
This stage also sees the development and subsequent disappearance of temper tantrums, episodes of loss of control over the
environment that leads to loss of internal control. These may be
aggravated if the child is tired or in physical discomfort. As the
third stage approaches the child starts to identify with his parents
and their societys values and to develop an inner voice of selfobservation and self-guidance, the conscience as the cornerstone
of morality. In the third stage of concrete operations (6 to 11 years
of age), children develop the ability to consider different points of
view and to elaborate explanations based on observations.
However, thinking still tends to be dogmatic. The child can
understand causality beyond himself and his own perception.
They move out of egocentricity enough to understand that others
may have ideas, feelings and desires different from their own.
Through social interactions with peers, the child develops ways
to maintain self-esteem while developing increased ability to
tolerate frustration. In the final stage of formal operations (11 years
to adulthood), the ability to think about the world in abstract
terms evolves. Older children can weigh options and consider the
consequences of different courses of action. Adolescents display
an increasing need for autonomy and independence. If not met,
their need to participate in their own medical decision making
may lead to problems in patient compliance. Typical in this
age group are feelings of grandiosity and invulnerability, which
often leads to behaviors with unreasonable risk taking. A childs

understanding for the concept of illness and medical treatment is
influenced by sociocultural and religious factors, as well as by his
cognitive developmental stage. Table 214 illustrates the agerelated development of spirituality and concept of illness and death
and accordingly the adjustment of interventions.44
APPROACH TO HISTORY AND

PHYSICAL EXAMINATION
The approach to history taking in pediatrics varies according to
the age of the child. It is important for the consultant to be aware
of which historical features are of greatest interest in each age
group to avoid missing vital information and to streamline the
information-gathering process. In neonates, the history will of
course be heavily weighted toward pregnancy and delivery. During
infancy, attainment of developmental milestones provides valuable
information on the health status of the infant. As the child ages, his
own past medical history assumes greater and greater importance.
Issues such as medication, allergies, past surgical procedures, and
chronic conditions must be considered. Obviously, in the very
young child, the history will be obtained entirely from a parent or
caregiver. The older child will be able to provide information and
should be allowed to become involved in the process. They should
be given an opportunity to ask questions and raise concerns.
Preadolescents and adolescents may feel uncomfortable discussing
certain issues in front of their parents and therefore should
also be interviewed on their own to make sure a full history is
obtained (e.g., drug abuse, sexual activity, potential for pregnancy,
piercings). Confidentiality must be respected in these situations.
Children, particularly toddlers, are less able to localize symptoms
than are adults. Consequently, a wide range of complaints
including pharyngitis and pneumonia may present as nonspecific
abdominal pain or discomfort. Care must be taken not to miss the
true diagnosis in such cases. Toddlers are also suggestible and may
nod agreeably when asked about specific symptoms. It is usually
preferable to use open-ended questions such as Where does it
hurt? as opposed to leading questions such as Does it hurt
there? Whereas organization of the physical examination by
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TABLE 114 Spirituality and concepts of illness and death in children, and conclusions for interventions. Adapted from53
Age
Characteristics
Spiritual Development
Concept of Illness and Death
Interventions
0 2 years
Sensory and motor

relationship with
environment, Limited
language skills, Object
permanence,
Magical and animistic
thinking, egocentricity,
Thinking is irreversible,
Engages in symbolic
play
Faith reflects trust and

hope in others, Need for
sense of self-worth, love
and containment
None
Faith is magical and

imaginative,
Participation in rituals,
Need for courage
Concrete thinking,
Reasoning about
Causality
Faith concerns right and

wrong, Accepts external
interpretations as truth,
Believes illness and death

can be caused by thoughts
and actions, Death is
temporary and reversible
like sleep, Not
personalizing death
Interested in physiology and
details of illness,
Personalizes illness and
death,
Explores nonphysical
explanations for illness
and death
Provide maximal physical

comfort, familiar
persons and transitional
objects, consistency,
Use simple language
Correct perceptions of
illness as punishment,
Evaluate for sense of
guilt, Use precise
language
2 6 years
6 12 years
12 18 years Generality of thinking,

Reality becomes
objective, Body-image
and self-esteem
paramount, Sense of
invulnerability and
omnipotence
Accepts inner
interpretations as truth,
Searches for meaning,
purpose, and value of
life, Evolution of
relationship with Higher
power
system or by anatomy (head to toe examination) may be

appropriate in adults and older children, some adaptations are
required in infants and toddlers. An opportunistic approach is
usually the most effective strategy in these groups. For example, if
an infant is quiet, it usually makes sense to begin by auscultating
the chest and examining the abdomen and to leave other aspects
such as examination of the extremities until later. Distraction,
either by the parent or by the examiner, is often quite useful.
The value of observation in providing important data should not
be underestimated. The laying on of hands should be the last
part of any assessment. Whenever possible, children should be
examined in the presence of a parent or caregiver. Infants and
toddlers can often be examined in a parents lap. Finally, infants
should not be left exposed any longer than is absolutely necessary to prevent hypothermia. During the neonatal period, an
overhead warmer may be indicated. In older children, especially
adolescents, modesty becomes an important consideration and
should be respected. For the physical examination of adolescents
in the absence of a parent, a nurse as a third person should be
present. Children of all ages should have height, weight, and head
circumference measured, recorded, and plotted on standard
growth curves. These data may provide clues to an underlying
disease and they are needed for appropriate selection of equipment
and calculation of drug doses.
CONCLUSION
The challenges of childhood growth involve anatomic,
physiologic, and cognitive-behavioral developmental changes.
These changes may have a profound influence on a wide variety
of aspects of anesthetic and perioperative care including choice
of medications and equipment, pre- and postoperative evalu-
Provide concrete info, Be

truthful, Allow child to
participate in decision
making
Allow child privacy,
Promote childs
independence, Be
truthful, Allow child to
participate in decision
making
ation, intraoperative care, postoperative management, and patient

safety. A synopsis has been provided to assist the pediatric
anesthesiologist in providing exemplary care to all infants and
children. With a sound knowledge of general growth and
development, supplemented as appropriate with consultation from
other pediatric specialists, this goal is eminently achievable.
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Anesthesia and the

Developing Brain
Laszlo Vutskits
INTRODUCTION
The normal development of the central nervous system (CNS)
relies on the precise temporal and spatial orchestration of several
molecular pathways that guide the proliferation, migration, differentiation, and survival of neuronal cells. Interference with these
finely tuned developmental mechanisms can disrupt physiologic
developmental patterns and may, ultimately, lead to permanent
impairment of CNS functions. Anesthetics primarily operate via
ligand-gated ionotropic neurotransmitter receptors and, thus,
modulate the activity of different neurotransmitter systems.1 In
turn, it is now well established that, in addition to their role in
synaptic transmission in the CNS, neurotransmitters act during
development as epigenetic factors to control important biologic
processes including progenitor cell proliferation, neuroblast
migration, and neuronal differentiation.2,3 In addition, a delicate
balance between excitatory and inhibitory signals also has a key
role in the functional assembly of neuronal networks.4 Because
even small changes in the relative amounts of excitation and
inhibition can markedly alter information processing, the impact
of anesthesia on neuronal and CNS development is an intriguing
question. This chapter aims to provide a brief synopsis of the
ontogeny of the human CNS and to describe how neurotransmitter signaling contributes to shape the maturing brain and
reviews the accumulating evidence suggesting that anesthetic
agents may indeed interfere with neural development.
ONTOGENY OF THE HUMAN BRAIN

Cell Proliferation, Neurogenesis,
and Neuronal Migration
In the earliest phase of neural development, starting on the 15th
postconceptional day of human embryonic life, neural tissue is
induced and begins to form within the ectodermal layer of the
embryo.5 As a consequence of neural induction, the ectoderm
subsequently divides into three different regions: the neural
ectoderm or neural plate, which will give rise to the CNS; the
nonneural ectoderm, which will form the epidermis; and the cells
at the border between neural and nonneural ectoderm, which for
the most part will become the neural crest tissue. After the
ectoderm differentiates, the neural plate border cells bend to form
the neural folds. Before the closure of the neural tube, the neural
folds expand considerably in the cephalad region (head) as the
first indication of the future brain. In humans, the neural tube
closes at around embryonic day (E) 30.6 At this stage, its wall
consists of a single layer of columnar neuroepithelial cells (also
3
C H A P T E R
called neural stem cells), the direct descendants of cells of the

neural plate. Subsequent to the closure of the neural tube, intense
symmetrical proliferation of these neuroepithelial cells will give
rise to a homogenous pseudostratified epithelium, which is called
the ventricular zone (VZ).6 Early proliferation increases the surface
area and the thickness of the VZ. Consequently, the neural tube
starts to differentiate along several axes. Regional expansions
along its anteroposterior axis will shape the major subdivisions of
the CNS: (1) the spinal cord; (2) the rhombencephalon or hindbrain; (3) the mesencephalon or midbrain; and (4) the prosencephalon or forebrain. The vertical axis determines the dorsal and
ventral sides, whereas the horizontal axis establishes medial and
lateral structural growth. Appropriate differentiation of the axes
of the neural tube is dependent on the precise temporal and spatial
gradients of highly complex gene expression during the early
embryonic period. Defective patterns of gene expression are
known to induce major developmental anomalies in the fetal
nervous system.5
During the early embryonic stages, the first neurons of the
human brain are generated in the rostral part of the neural plate.7
However, the vast majority of neuronal cells are eventually derived
from neuroepithelial stem cells of the VZ. At the start of
neurogenesis, occurring approximately at E33 in the lateral part
of the cortical wall in humans,7 these stem cells down-regulate
their epithelial characteristics and switch from a symmetrical to an
asymmetrical mode of cell division. One daughter remains a
progenitor to give rise to future neuronal cells whereas the other
is a postmitotic cell that is destined to become a neuron. By
gestational weeks (GWs) 5 and 6, the VZ is the only proliferative
zone. In the developing hindbrain and midbrain, the majority of
neurons are generated during this period.8 In the developing
telencephalon, the first postmitotic neurons migrate in a radial
fashion out of the VZ and form the first recognizable cortical layer
(the preplate). Around the seventh and eighth GW, accumulating
postmigratory cells within the preplate form the cortical plate
(CP). This is divided into the marginal zone on the superficial side
and the subplate on the inner side. Parallel to the formation of the
CP, a secondary proliferative region, the subventricular zone
(SVZ) appears above the basal border of the VZ.6 By GWs 25 to 27,
when the SVZ is still proliferating, the human VZ has reduced in
size to a one-cell-thick ependymal layer. The subsequent development of the cerebral cortex during the second half of gestation in
primates is mainly related to cell proliferation in the SVZ. In
addition, whereas the VZ gives rise only to neurons, dividing
progenitors of the SVZ generate both neurons and glial cells.6
During GWs 10 to 25, there is a major wave of generation and
subsequent migration of cortical neurons in the human brain. Two
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major kinds of neurons can be distinguished in the cerebral cortex:

(1) projection neurons with pyramidal morphology, containing
the excitatory neurotransmitter glutamate; and (2) local circuit
neurons with extremely diverse morphology, containing gammaaminobutyric acid (GABA). Projection neurons are all derived
from the neocortical VZ and SVZ of the telecephalon. These cells
migrate radially to accumulate in the CP in an inside-out manner.
The earliest-born neurons are destined to become the future layer
6, and the last-born neurons will become layer 2. In humans, the
majority (~65%) of local circuit neurons are also born in the VZ
and SVZ and migrate radially to populate the CP. A significant
portion (~35%) of local circuit neurons are born in the VZ and
SVZ of the subcortical ganglionic eminence of the ventral
telencephalon from which they migrate tangentially above the
SVZ into the cerebral cortex.9 Peak migratory activity of both
projection and local circuit neurons is thought to occur between
the third and the fifth months of gestation. Migration is competed
during the third trimester. The period after GW 22 is the most
significant time for spatial, laminar, and cytologic differentiation
of the CP. By the seventh month of gestation, the cerebral cortex
is clearly divided into six layers.6 In humans, neurogenesis ceases
in most cerebral regions by the third trimester of pregnancy.
However, newly generated neurons are still continuously added
into discrete regions of the adult brain, such as the hippocampus10
and the olfactory bulb.11 The functional significance of this adult
neurogenesis is still a matter of debate, but it is thought to be
important for hippocampus- and olfaction-related memory
processing.12
Neuronal Differentiation and Synaptogenesis

Neuronal differentiation starts early during fetal life. By GW 8 to
9, neurons in the CP display a fusiform cell body, a descending
axon, and an apical dendrite with a dense terminal tuft in the
marginal zone. Using a variety of chemoattractor or chemorepellent axonal guidance cues, the growth cones of developing
axonal pathways navigate to their intermediate and final targets.
For example, corticospinal axons reach the lower cervical spinal
cord by GW 26. Thereafter, they progressively and extensively
innervate spinal neurons.13 Neuronal dendrites represent the
primary sites of synaptic contacts in developing neurons. It is now
well established that interference with the finely tuned molecular
mechanisms, guiding the formation of neuronal dendritic arbors
in the developing brain, can lead to persistent dysfunctions of the
CNS.14 Although the type-specific morphology of CNS neurons
appears to be specified genetically,15 these intrinsic programs act
in concert with extracellular signals during the differentiation of
the dendritic arbor.16 Dendritic development accelerates from the
third trimester of gestation, remains very active till the end of the
first postnatal year, and continues up to 5 years of age.1719 From
the very early stages of differentiation, neurons establish synaptic
contacts with neighboring neurons. In the spinal cord, the first
synaptic contacts are established around GW 8, whereas synapses
in the cerebral cortex can be detected beginning at GW 9 to 10.20,21
After the formation of the CP, synaptic density steadily increases
with a rate of about 4% per week in all cortical regions until GW
24 to 26.21 Synaptogenesis then considerably accelerates from GW
28, resulting in an approximately sixfold increase in the number
of cortical synapses between this period and the first few months
of postnatal life.22 Peak synaptic density is reached at the age of
3 months (postterm) in primary sensory areas, such as the

auditory and visual cortex, and at the age of 15 months in the
prefrontal cortex.22
Compared with the rodent brain, a distinctive feature of the
primate CNS is the intricate folds of the cerebral cortex. In fact,
during the last trimester of pregnancy, the human cerebral cortex
expands tangentially and folds to accommodate a large surface
area, measuring 1600 to 2000 cm2 in humans, three times larger
than the inner surface of the skull.23,24 Although several hypotheses
have been proposed to explain the folding process during development, the potential influence of genetic, epigenetic, and environmental factors is still poorly understood.
Glial Cell Development

and Myelin Formation
Glial cells in the CNS are from two ontogenetically different
categories. Microglia cells are macrophages residing in the CNS.
These cells are immigrants of the hematopoietic system that enter
the CNS during the early stages of development. Macroglia cells
(astrocytes and oligodendrocytes) are derived from precursors cells
of the SVZ.25 In humans, the majority of glial cells are produced
between GWs 20 and 40.26 Astrocytes have diverse functions
ranging from the regulation of extracellular matrix composition to
the regulation of energy metabolism in the brain.27 Oligodendrocytes are destined to form the myelin sheet around neuronal
axons in the CNS. Although myelination starts at GW 12 in the
spinal cord28 and around GW 14 in the telencephalon,29 it becomes
a vigorously active process only during the first year after term.30
Following the first year of life, myelination continues at a slower
rate and becomes completed only during the fourth decade of life.31
Regressive Phenomena During Development

In addition to progressive biologic events, such as neurogenesis
and differentiation, regressive phenomena also play a major role in
determining the form of the mature CNS.32 Among these regressive phenomena is programmed cell death or apoptosis, which
plays a fundamental role in the control of the final number of
neurons and glial cells during development.33 Two apoptogenic
periods take place during CNS development. The first wave,
observed between GWs 7 and 13 in the proliferative zones of the
human telencephalon, consists of an early neuronal death of
proliferating precursors and young postmitotic neuroblasts.33,34
The second wave affects postmitotic neurons at later stages and is
linked to cell differentiation and synaptogenesis. In the cerebral
cortex, this type of cell death peaks between GWs 19 and 33.
However, apoptosis in sensorimotor, prefrontal, and cingulated
cortices continues until the first month of postnatal life34,35
Axonal retraction without accompanying cell death is another
prominent regressive process in the CNS. Although little is known
about the extent of this phenomenon in humans, data from
primates indicate a considerable postnatal reduction in the
number of projection axonal fibers within the corticospinal,
thalamocortical, and callosal pathways during the first few months
of postnatal life.3638 Physiologic data of children with congenital
hemiplegia suggest that axonal elimination in the corticospinal
tract may be activity-dependent, because in these children, major
parts of the ipsilateral corticospinal projections are conserved.39
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Intense synaptogenesis during the third trimester of pregnancy
and the first 2 years of postnatal life is followed by a period of
synapse elimination during which synaptic density and number
significantly decrease. In the rhesus monkey, synaptic density in
the primary visual and the motor cortex decline to 50 to 60% of
peak values following sexual maturity, whereas the extent of
synapse elimination is significantly lower in the prefrontal and
cingulated cortex of these animals.4043 Human data indicate that
there is a region-specific first phase of decline in synaptic density
between 3 and 5 years of age followed by a plateau phase during
which synaptic density remains relatively constant. This plateau
phase ends around the time of puberty, and then the number of
synapses further declines to reach adult values.22
NEUROTRANSMITTERS AS SIGNALS
FOR CNS DEVELOPMENT
Neurotransmitters are primarily considered as the main actors of
synaptic transmission. However, it is important to note that these
molecules are also present in the chemical microenvironment of
neural cells beginning at the very early stages of CNS development.44,45 Furthermore, neural stem cells, migrating neuroblasts,
and immature neurons express specific receptors for neurotransmitters.45,46 Thus, in addition to their role in neurotransmission in
mature neuronal circuits, these same molecules can also serve as
chemical signals to orchestrate a variety of morphogenetic events
during brain development.47,48 These effects appear to be, at least
partially, mediated through a paracrine mode of action in which
neurotransmitters are nonsynaptically released into the early differentiating cortical environment and activate their cogent receptors.48 This type of early neurotransmitter signaling may mediate
a wide range of developmental effects including proliferation,
differentiation, and synapse formation. This is in contrast with the
more focused, rapid mode of operation at the synapse within the
developed CNS.
Ontogeny of Ligand-Gated Ion Channels

During development, the expression of ligand-gated ion channel
receptors follows a precise spatial and temporal pattern in the
CNS.4446 The specific ontogenic progression in the expression of
different receptor subunit genes characterizes the subunit assembly
of the majority of ionotropic receptors, suggesting that these
protein complexes might respond differently to endogenous and
exogenous ligands at distinct stages of neural development.4446
Several GABAA receptor subunits are expressed from the early
stages of embryonic development, and anatomic mapping of these
subunits in the developing rodent CNS reveals a complex, transient, and region-specific expression pattern of these proteins.4951
In fact, it is now well established that embryonic and early postnatal
GABAA receptors differ markedly from those expressed in the adult
brain.4952 For example, in most brain areas, the 3 subunits, along
with the 2, 3, and 2 subunits are the most prominent
components of the GABAA receptor complex throughout the preand early postnatal development.50 The 3 subunit content then
decreases, and this is accompanied by a concomitant increase in
the expression of the 1 subunit. For detailed region-specific and
temporal expression patterns of GABAA receptor subunit mRNAs
in the brain, the reader is referred to references 49 and 50.
Anesthesia and the Developing Brain 45
The GABAergic signaling system has the unique property of

ionic plasticity, which is based on short-term and long-term
changes in the Cl and HCO3 ion concentrations in the postsynaptic neurons. Although short-term ionic plasticity is caused by
activity-dependent, channel-mediated anion shifts, long-term
ionic plasticity depends on changes in the expression patterns and
kinetic regulation of molecules involved in anion homeostasis.53
During development in immature neurons, activation of GABAA
receptors leads to the depolarization of these cells because of the
high intracellular Cl concentrations. Thus, in addition to glutamate, GABA also acts as an excitatory neurotransmitter during
brain development. The functional switch toward the hyperpolarizing actions of this neurotransmitter and its subsequent
inhibitory properties is linked to the developmental expression of
the K+/Cl cotransporter (KCC2), which actively extrudes intracellular Cl from neurons.53 KCC2 appears in the early postnatal
period in rodents, although no data about the expression pattern
of this protein exist in humans yet.
Among the ionotropic glutamate receptors, AMPA and kainate
receptors are the first to be expressed during early mammalian
CNS ontogenesis.5456 In rodents, these receptors are expressed
from E10 in the neural tube57 and as early as the fifth gestational
week in human embryos.54 Spatiotemporal changes in the expression pattern of subunits (GluR14) forming the AMPA receptor
complex also occur during CNS development.46,5861 GluR1
subunit levels increase progressively during late embryonic and
early postnatal days with varying levels of expression according to
specific brain areas.62 The GluR2/3 subunits are also expressed in
embryonic development, whereas the presence of GluR4 is mainly
restricted to the late postnatal development and adult.46 Concerning the isoforms of AMPA receptors, expression of the flip variants
dominates before birth and continues to be expressed in adulthood, whereas flop variants are in low concentration before the
postnatal period and reach the same level as the flip form by
adulthood.63
Changes in receptor subunit composition affect the functional
properties of the receptor complex, such as Ca2+ permeability,
single-channel conductance, desensitization, and affinity for
agonists.64,65 For example, a developmental switch during the
postnatal period, due to the expression of the GluR2 subunit of
the AMPA receptor complex in neocortical layer V pyramidal
neurons, substantially modifies the Ca2+ permeability of these
cells.65 Similarly to AMPA receptors, kainate receptors also show
a spatial and temporal expression pattern during CNS development with a peak in their expression in the late embryonic and
early postnatal period.46,66,67
In the human embryo, functional N-methyl-D-aspartic acid
(NMDA) receptors can be detected from around the 10th
gestational week.56 The functional NR1 subunit is ubiquitously
present in the brain throughout pre- and postnatal development,
although the modulatory subunits (NR2A-D) are differentially
expressed.46,68,69 The NR2A subunit is expressed mainly during the
postnatal time, whereas the NR2B subunit is detected throughout
the embryonic period with a restricted expression to the forebrain
at the postnatal stages. The NR2C subunit appears postnatally and
is prominent in the cerebellum; the NR2D subunit is mainly
present in the diencephalons and the brainstem at embryonic and
neonatal stages. The NR3 subunit is abundant within late prenatal
and early postnatal brain development.70
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Glycine receptor subunits are expressed at high levels during

early cortical development.71 In newborn rats, the GlyR is 2homomeric and differs from the adult form, which includes three
1 and two subunits.72 As with prenatal GABA signaling,
activation of nonsynaptic Gly receptors during the embryonic
period is excitatory.73 In the developing brain, glycine is found at
very low concentrations,74 and Gly receptors are mainly activated
by another endogenous ligand, taurine.73
Neuronal nicotinic acetylcholine (nACh) receptors are widely
distributed in both the developing and the adult mammalian
CNS.75,76 In rats, functional receptors are present as early as E12,77
and it is now well established that, similar to the previously
mentioned ionotropic receptor complexes, nACh receptor subunit
expression is also developmentally regulated.7880 For example, in
the case of the cerebral cortex, a pair of subunit mRNAs (32)
is initially (E1213) expressed followed by a repression of the 3
subunit (E15) and the subsequent (E17E19) induction of the 4
subunit.80
Serotonin (5-HT3) acts through several different receptors,81
but only the 5-HT3 receptor is ionotropic and mediates rapid
excitatory responses through a ligand-gated ion channel that is
mainly permeable to Na+ and K+, with a variable permeability for
Ca2+ according to the receptor subunit assembly.8284 Both serotonin and the 5-HT3 receptors appear during early prenatal development.85,86 In the rat embryonic brain, 5-HT3 receptors are detected
in a number of proliferative regions as early as E12.5.86 Although
5-HT3 receptor subunits (5-HT3AE) have now been described,87
the developmental expression pattern of these subunits remains
to be determined.
Neurotransmitters and Cell Proliferation

GABAA receptor subunits 4, 1, and 1 are expressed in the rat
VZ during periods of neurogenesis, indicating that GABA may
directly regulate proliferation of CNS progenitors.88 Although the
impact of GABAA receptor activation on cell proliferation remains
to be determined in vivo, activation of this receptor complex can
control cell cycle kinetics in neuronal progenitors. GABA has been
shown to depolarize and decrease the proliferation rate of neuronal
progenitors isolated from the developing rat telencephalon during
the peak period of cortical neurogenesis (E16E19), whereas the
administration of GABAA receptor antagonists displayed opposite
effects.89 The actions of growth factors and GABA are heavily
interconnected, thereby providing a major feedback mechanism.2
In vitro, exposure of proliferating neuroepithelial cells to basic
fibroblast growth factor (bFGF) increased the expression of the 1
subunit on the cell surface. In turn, exposure of these cells to GABA
inhibited the proliferative effects of bFGF on neural progenitors,
suggesting that GABA regulates cell production by providing a
feedback signal that terminates cell division.90 Trophic factors can
also decrease GABA production.91 Accumulating evidence suggests
that the modulatory effect of GABA on cell proliferation depends
on the brain region.44,92 For example, in embryonic neocortical slice
cultures from mice, GABA increases cell proliferation in the VZ
but decreases it in the SVZ.92 This differential modulation of cell
proliferation could regulate the relative contribution of VZ and
SVZ progenitors to neocortical growth and, thus, could be of
significant importance for proper CNS development.92,93 Recent
results further extend our understanding regarding the regulatory
role of GABA on cell proliferation during development by
demonstrating the existence of nonsynaptic GABAergic signaling

between neuroblasts and glial progenitors in the postnatal SVZ.94
According to these data, spontaneous depolarization-induced
nonsynaptic GABA release in neuroblasts activates GABAA
receptors on adjacent astrocytes leading to a decreased proliferation
of these latter cell types. Functional ionotropic glutamate receptors
emerge during terminal cell division and the early neuronal
differentiation of rat neuroepithelial cells.95 Activation of AMPA/
kainite, but not of NMDA receptors, has been shown to shorten
the cell cycle of isolated cortical neuroblasts89 and to differentially
alter cell proliferation in the ventricular and subventricular cortical
germinal zones.92 A similar effect of non-NMDA receptor agonists
has also been observed in O-2A cells in culture.96 By contrast,
proliferation of striatal neuronal progenitors is promoted by an
NMDA-dependent mechanism, but not through AMPA/kainate
receptors in the ventral telencephalon.97 NMDA receptors are also
involved in the regulation of cell proliferation in the hippocampal
dentate gyrus throughout life.98 A single treatment with NMDA
receptor antagonists increases granule cell proliferation approximately twofold within 3 hours, although activation of this receptor
leads to a decrease in the proliferation rate.99 By contrast to what is
known about the importance of GABAA and ionotropic glutamate
receptors in neural progenitor proliferation, the involvement of
Gly, nACh, and 5-HT3 receptors in this process remains to be
determined.
Neurotransmitters and Cell Migration

Once generated, immature postmitotic cells leave the germinative
zones and migrate toward their final destination. The complex
cyto-architectural organization of the mature CNS reflects this
highly precise pattern of cell migration. Deficiency in migration
patterns, caused by genetic disorders, toxins, pharmacological
interventions, or other environmental insults, can result in major
brain malformations.100 There are two major modes of neuronal
migration in the cerebral cortex: (1) a radial mode for the principal
pyramidal cells and (2) a tangential mode for the interneurons.101
A growing body of evidence indicates that neurotransmitters and
their specific receptors are involved in the complex molecular
machinery that orchestrates the migration of immature neurons in
the brain during development and adulthood.102 The GABA
system, via various receptors, is involved at distinct phases of
radial migration of projection neurons. GABAAC receptors are
required for ventricular to intermediate zone migration, GABAB
receptors are required for intermediate zone to cortical plate
migration, and GABAA receptor activation is required for proper
termination of migration within the cortical plate.103105 GABAminergic interneurons, originating in the median ganglionic
eminence, also require GABAA receptor signaling to migrate
tangentially toward the cerebral cortex.106 Although GABA is
present at micromolar concentrations throughout their migratory
route, tangentially migrating interneurons show little response to
GABA stimulation upon leaving the median ganglionic eminence.
However, when these cells reach the proximity of the neocortex,
they change the number and the subunit composition of the
GABAA receptor complex on the cell surface. Changes in the 13subunit composition of the GABAA receptor correlates with the
ability of migrating interneurons to cross the corticostriatal
junction, indicating that these cells require a specific GABAA
receptordependent signal for entry into the cortex.106 GABA,
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through activation of the GABAA receptor, also promotes the
migration of young CA1 pyramidal cells and interneurons in the
developing hippocampus.107,108 Migrating cells, in either the radial
or the tangential pathways, also express functional ionotropic
glutamate receptors on the cell surface.102 Micromolar concentrations of glutamate have been shown to stimulate the chemotaxis of
immature embryonic neurons through an NMDA-dependent and
AMPA/kainate-independent mechanism.109 Conversely, glutamate
released within the hippocampus by glutamatergic neurons
modulates the tangential migration of hippocampal interneurons
through AMPA receptor activation108 and promotes the migration
of young pyramidal neurons via NMDA receptordependent
signaling.107 These latter results suggest that glutamatergic and
GABAminergic neurons could modulate their migration in a
synergistic and cooperative manner through the release of specific
neurotransmitters. Paracrine, nonsynaptic signaling by glutamate
and presumably other neurotransmitters, are also responsible to
shape hindbrain development. The pharmacologic blockade of
the NMDA receptors results in a reduced radial migration of
granule cells.110 The role of Gly, nACh, and 5-HT3 receptors in
neural progenitor proliferation remains to be determined.
Neurotransmitters and Early

Neuronal Differentiation
The initial formation of neuronal axons and dendrites is an important developmental step preceding the assembly of differentiating neurons into functional networks. Axons carry efferent
information from neurons, whereas dendrites represent the
primary sites of synaptic contacts for developing and mature
neurons. Elaboration of a highly complex and organized dendritic
arbor is a prerequisite for the establishment of neuronal circuitry.16
In turn, substantial evidence supports the view that afferent
synaptic and network activity plays a fundamental role in shaping
neuronal arbor development.111113 Although the particular morphology of CNS neurons appears to be specified genetically,15 these
intrinsic programs act in concert with extracellular signals during
the differentiation of the dendritic arbor.16 In several in vitro and
in vivo experimental models, exposure to GABA leads to an
increased dendritic length with increased branching and density
of synapses, whereas antagonism of the GABAA receptor, using
the selective GABAA receptor antagonist bicucullin, has opposite
effects.2 Importantly, blockers of the Ca2+/calmodulin kinase II
(CaMKII) or mitogen-activated protein kinase (MAPK) reduce
the trophic effects of GABA, suggesting that GABA exerts its
effects via activation of Ca2+-dependent kinases.114 Glycine has also
been shown to enhance neuritic outgrowth.115,116 However, these
effects do not seem to be mediated via Gly receptors, but rather
through the activation of the GABAA receptor complex.116 Among
the ionotropic glutamate receptors, activation of the NMDA
receptor has been shown to promote neurite elongation of immature cerebellar granule neurons117 as well as to enhance dendritic outgrowth and branching in differentiating hippocampal
neurons.44,118 By contrast, in embryonic spinal motoneurons,
AMPA and kainite, but not NMDA receptors, mediate dendritic
growth.119 Activation of the nACh receptor promotes neuritogenesis of immature, newly formed neurons in the rat olfactory
bulb and pharmacologic blockade of the 7 subunit of the receptor
complex abolishes this effect.120 Conversely, in cultured embryonic
mouse spinal cord, acetylcholine decreased both growth cone
motility and neurite outgrowth via the activation of nACh

receptors.121 Little is known about the effects of 5-HT3 receptor
mediated serotonin signaling during early phases of neuronal
differentiation. Recently, nerve growth factor (NGF)induced
neurite outgrowth in PC12 cells has been shown to be enhanced
by serotonin and this effect was abolished by pharmacologic
blockade of the 5-HT3 receptor.122 The biologic significance of
these data remains to be determined.
Neurotransmitters and Activity-Dependent

Neuronal Network Formation
The establishment of neuronal networks begins with growing
axons recognizing their postsynaptic targets with the formation of
synaptic contacts. The most active phase of neuronal differentiation, synaptogenesis and functional network formation in
the rodent brain take place between the first and the third postnatal
weeks (corresponding to a period extending from the last trimester
of pregnancy up to the first few years of life in humans), which
closely parallels to the onset of sensory input to the cortex.123,124
GABA and glutamate, as synaptically released neurotransmitters, are confirmed regulators of the activity-dependent
development of functional neuronal networks during critical
periods of early postnatal life.125,126 These critical periods represent
developmental time windows in which brain circuits are particularly receptive to acquiring certain types of information or even
need instructive signals for their continued development.45 A
delicate balance between excitatory and inhibitory signals has a
key importance in appropriate network development. In addition
to drastic pharmacologic perturbations of neuronal activity, even
small changes in the relative amounts of excitation and inhibition
can markedly alter information processing.4
Immature or developing neurons and neuronal circuits are
particularly sensitive to external stimuli during the synaptogenetic
period. As discussed in the section on Neurotransmitters and Cell
Migration, endogenous GABA and glutamate are clearly key
factors guiding CNS morphogenesis. Exogenous stimulation or
blockade of GABAminergic and glutamatergic signaling pathways
can also trigger cell death in the developing brain.127 It was shown
during the 1970s that subcutaneous injection of high doses of
glutamate induces acute neuronal necrosis in several brain regions
in newborn mice and monkeys.128,129 Blockade of the NMDA
receptor during synaptogenesis triggers widespread apoptosis in
the developing brain.129
Generation of transgenic mice presenting deficient GABAminergic or glutamatergic signaling pathways further improved
the understanding regarding the role of these molecules during
the critical periods of neuronal network development. GABA is
synthesized by glutamic acid decarboxylase, which is the product
of two distinct genes, Gad65 and Gad67. Although genetic
deletion of the GAD67 enzyme is lethal and eliminates most
cortical GABA content,130 Gad65-knockout mice are viable and
show poor GABA release upon stimulation from synaptic
vesicles.131 This decrease in GABA-mediated synaptic neurotransmission results in an impairment of activity-dependent refinement
of functional connections in the developing visual cortex, thereby
demonstrating the important role of GABAergic neurotransmission in synaptic plasticity.131
In transgenic animals lacking the NR1 subunit of the NMDA
receptor, thus, having no functional NMDA receptors, there is
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increased apoptosis in several brain areas during the period of

naturally occurring cell death and synaptogenesis132 and these
animals die soon after birth.133 Generation of region-specific
knockouts in which nonfunctional NMDA receptors are present
only in the cerebral cortex has allowed the study of the role of this
receptor in the formation of cortical circuits during the early
postnatal life.134 These experiments have revealed the important
role of NMDA receptors during the critical period in several
cortical systems including the formation of the somatosensory
barrel cortex134 and the shaping of ocular dominance columns in
the visual cortex.125
The mammalian neocortex is densely innervated by cholinergic
and serotoninergic fibers, suggesting roles for these neurotransmitters in synaptogenesis and neural circuit formation. Both
acetylcholine and serotonin have been shown to mediate fast
synaptic transmission in the visual cortex, and the early onset of
these mechanisms suggests a role during initial stages of circuit
formation and during subsequent experience-dependent remodeling of cortical connections.135 5-HT3 receptor activation decreases
the amplitude and lateral extent of excitation throughout postnatal
development. This effect peaks after eye opening, which indicates
a function for serotonergic modulation of circuit responses during
the period of refinement of cortical connections.136 nACh receptors are transiently up-regulated during the early postnatal period
in several brain areas.137 Synergistic actions mediated by 7 nACh
receptors and NMDA receptors may contribute to experiencedependent synaptic plasticity in the sensory neocortex during
early postnatal life, although nicotine-induced desensitization of
presynaptic 7 nACh receptors would allow an increased glutamate release onto postsynaptic NMDA receptors.138 Importantly,
altered stimulation of nACh receptors specifically during the
second postnatal week disrupts the development of glutamate
synapses in the rat auditory cortex.139
The fetal alcohol syndrome is a dramatic clinical demonstration of how exogenous perturbations of GABAminergic and glutamatergic signaling can affect brain development. Administration
of ethanol, having both NMDA antagonist and GABA-mimetic
properties, to pregnant rodents provokes disturbances of cortical
lamination and neuronal ectopia, and reduces the thickness of the
cortical mantle in the offspring.140 In fact, ethanol has been shown
to inhibit proliferation of neuronal precursors, to impair their
migration, and to induce neuronal death thereby providing the
potential neurobiologic bases for the reduced brain mass and
lifelong neurobehavioral disturbances associated with the human
fetal alcohol syndrome.140 By contrast to immature cells, differentiated neurons are less sensitive to pharmacologic modulation of
GABAminergic and glutamatergic signaling.127 These findings
suggest that the increased vulnerability of neurons is mainly
confined to the synaptogenetic period, and once this period is
over, transient pharmacologic manipulation of neuronal activity
will not affect neuronal survival and optimal network function.
EFFECTS OF ANESTHETICS
ON CNS DEVELOPMENT
On the basis of our increased understanding regarding the
important developmental role of the neurotransmitter systems, it
is not surprising that the past few years have yielded a veritable
explosion of publications claiming the potential for adverse effects
of anesthetic agents on the immature brain. The following section
reviews the existing laboratory data regarding this phenomenon

with a focus on drugs that have been clearly shown to affect some
aspects of CNS development either in vitro or in vivo.
Specific Anesthetic Agents

Ketamine
Ketamine is a noncompetitive antagonist to the phencyclidine
(PCP) site of the NMDA receptor. By preventing excitotoxic
actions of endogenous excitatory amino acids such as glutamate
and aspartate, it may have a neuroprotective role in ischemiainduced and seizure-related brain damage.141143 The first indications that, in addition to its potential benefits, ketamine can also
induce pathologic changes in the CNS came from the observations
that subcutaneous administration of PCP to adult rats induced
cytopathologic changes (vacuolization of neuronal cytoplasm) in
cerebrocortical neurons.144 These effects were detectable as soon as
2 hours after drug exposure; however, neuronal morphology
returned to normal when only a single dose of PCP was applied.
In this same work, ketamine mimicked the effect of PCP when
administered subcutaneously at 40 mg/kg, although lower doses of
this anesthetic did not induce vacuolar neurodegeneration.144
These observations were further extended to the developing brain
in a subsequent study in which a series of seven subcutaneous
injections of ketamine (20 mg/kg at each dose) spaced evenly over
9 hours induced extensive apoptotic neurodegeneration in 7-dayold rat pups.129 The potential relevance of these rodent data has
recently been confirmed in primates, in which ketamine induced
extensive neuronal cell death in the cerebral cortex of rhesus
monkey fetuses when the pregnant mother was exposed to this
anesthetic for 24 hours.145 These experiments thus support the
contention that long-term exposure to ketamine at anesthetic
concentrations could indeed exert neurotoxic effects on the
developing CNS.
Whether short-term ketamine exposure, as may be used in
current pediatric anesthesia practice, can induce cell death in the
developing brain is a controversial issue. Several independent
observations indicate that, by contrast to repeated injections of
ketamine aimed to produce long-term anesthesia, a single anesthetic dose of this drug does not induce neuronal apoptosis.144147
However, these results were challenged by other experiments
demonstrating that even relatively mild exposure to ketamine can
trigger apoptosis in the developing mouse brain.148 In this latter
study, using immunocytochemical labeling with a specific antibody against the early apoptotic marker, caspase 3; apoptotic cell
bodies could be detected in several brain areas as soon as 4 hours
after a single subcutaneous injection of ketamine to 7-day-old
mice at anesthetic and subanesthetic concentrations (40 mg/kg
and 10 mg/kg, respectively). Although clearly further experiments
are needed to elucidate the impact of a single-dose ketamine administration on neuronal responses, these results raise the intriguing possibility that even a brief apoptogenic stimulus might alter
neuronal development during the peak synaptogenetic period.
An important point of concern in terms of neurotoxicity is that
neuronal apoptosis is not the only parameter to be considered in
evaluating the potential adverse effects of ketamine or other
anesthetics on neuronal development. It is now well established
that interference with the finely tuned molecular mechanisms,
which guides the formation of neuronal dendritic arbors in the
developing brain, can lead to persistent dysfunctions of the CNS.14
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Thus, understanding whether anesthetics modify dendritic arbor
expansion during CNS development is of utmost interest. To
investigate this issue, we have developed an in vitro model in which
immature neuroblasts are isolated from the SVZ of newborn rats.149
This purified cell population develops into GABAminergic
interneurons in low-density cultures with a dendritic arbor. On the
basis of previous experimental and clinical studies measuring
ketamine plasma concentrations following single-shot or repeated
administration in rodents and humans,147,150,151 we have recently
explored the dose- and exposure timedependent effects of
ketamine on the differentiation and survival of GABAminergic
neurons in these cultures.152 We found that ketamine, but not the
noncompetititve NMDA receptor antagonist MK801, rapidly
induced apoptosis of developing neurons when administered at
concentrations previously reported to induce cell death in vivo
(10 mg/mL).147 Neither survival nor long-term dendritic development was altered when differentiating neurons were exposed to
lower, subanesthetic concentrations (2 mg/mL) of this anesthetic
for up to 8 hours. By contrast, long-term exposure (>24 h) of
neurons to ketamine at concentrations as low as 0.01 mg/mL
severely impaired dendritic arbor development. These new data
suggest that long-term use of even low concentrations of ketamine,
such as an adjuvant to postoperative sedation and pain control,
could potentially interfere with the dendritic development of
immature neurons.
Little is known about the molecular mechanisms involved in
ketamine-induced neurotoxicity. Recently, ketamine has been
shown to reduce phosphatidylinositol-3 kinase/Akt phosphorylation and, thus, increase glycogen synthase kinase-3 (GSK-3) levels
in neurons.153 In turn, GSK-3 phosphorylates Bax, a proapoptotic
Bcl-2 family member that stimulates the intrinsic (mitochondrial)
death pathway by eliciting cytochrome C release from the mitochondria, promotes its mitochondrial localization.154 In fact,
application of Akt phosphorylation-activating growth factors, such
as insulin-like growth factor-1 (IGF-1), as well as inhibitors of
GSK-3 has been shown to protect against ketamine-induced
apoptosis.153 In this context, it is important to note that blockade
of the NMDA receptor during the peak synaptogenetic period,
using ethanol, delays the developmental switch from NR2B to
NR2A subunits, thereby altering the function of NMDA signaling
in maturing neural networks.155,156 Another important issue to be
addressed in the future is whether neuronal sensitivity to ketamine
is dependent on the subunit composition of the NMDA receptor
complex. Ketamine-induced neurotoxicity is primarily confined
to the brain growth spurt period when NR1 and NR2B subunits
predominate and the proapoptotic effects of this drug decrease
with the progressive increase in the amount of the NR2A subunit
during this period.68,157
Little is known about the potential adverse effects of ketamine
on neuronal progenitor proliferation and cell migration. Some
observations indicate a possible role for ketamine in progenitor
proliferation in postnatal neurogenic zones. In adult rats receiving
subanesthetic concentrations of ketamine for 5 consecutive days,
the proliferation marker, bromodeoxyuridine, demonstrates enhanced neurogenesis in the hippocampal subgranular zone.158 To
our knowledge, there are no other studies regarding the role of
ketamine exposure on the immature brain before the synaptogenetic period. Given the important role of these earlier developmental stages in the proper formation of the CNS, further research
is needed to clarify these issues.
Propofol
Propofol (2,6-diisopropyl phenol) is an alkyl phenol that potentiates the effect of GABA in the CNS by inducing tyrosine kinase
mediated phosphorylation of the subunits of the GABAA
receptor complex.159 Selective toxicity of propofol for GABAminergic neurons, but not for astroglial cells, has been demonstrated in aggregated cell cultures of the fetal rat telencephalon.160
Propofol has also been shown to induce growth cone collapse and
to inhibit neurite outgrowth in immature peripheral, retinal, and
autonomic neurons in vitro.161 In line with these results, we have
shown that even low concentrations of this drug can impair
dendritic differentiation of GABAminergic neurons in vitro.162
Finally, recent in vivo experiments indicate that the intraperitoneal
injection of propofol (60 mg/kg) to 10-day-old mice pups induces
neuronal apoptosis in several brain areas and that these changes
were accompanied by persistent behavioral deficits.163
Benzodiazepines
Benzodiazepines bind selectively to the subunits of the GABAA
receptor and exert agonistic activity on this receptor complex.164
GABA is among the first neurotransmitters to appear in the
developing brain, and signaling through the GABAA receptor is
present from the very early developmental stages.165,166 Chronic
prenatal exposure of rat fetuses to diazepam results in long-term
functional deficits as well as alterations of stress-induced behavioral patterns in these animals.167169 Prolonged diazepam treatment during both the prenatal and the postnatal period induces
long-lasting changes in GABAA receptor as well as neurosteroid
levels.170 In turn, diazepam-induced alterations in GABAA receptor
function result in the impaired modulation of norepinephrine release from brain synaptosomes in response to stressful
stimuli.171,172 In addition to the effects of chronic benzodiazepine
exposure, results indicate that, as with ketamine,148,173 a single,
subanesthetic dose of midazolam can induce a significant neuroapoptotic response in the cerebral cortex as well as in the basal
ganglia of young mice.148 Whether this treatment paradigm also
induces long-term behavioral or cognitive deficits remains to be
determined.
Barbiturates
Barbiturates are also potent agonists of the GABAA receptor. In
line with reports using midazolam or propofol, exposure of 7-dayold rats to barbiturates for 5 hours has been shown to induce
widespread neuronal apoptosis in numerous brain regions.174 In
these experiments, neuronal death was associated with reduced
expression of neurotrophins and decreased concentrations of
survival-promoting proteins in the brain.174
Volatile Anesthetic Agents

Although the exact mechanisms of action of the volatile anesthetic
agents remain to be determined, all of these anesthetics have
GABAmimetic and/or NMDA antagonistic properties. During the
mid-1980s, halothane was among the first of the anesthetics
reported to alter brain development. When rats were chronically
exposed to halothane anesthesia during the entire gestational
period, dendritic length and branching as well as cerebral synaptic
density were severely impaired.175 The effect of halothane on
dendritic growth appeared to be enduring, and the delay in initial
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dendritic growth caused by halothane was not compensated for

by an increased rate of dendritic growth once the drug had been
withdrawn. The effect of halothane treatment on dendritic growth
was associated with learning impairment, decreased exploratory
behavior, and decreased nociceptive reactivity.176
Isoflurane (1.5%) has been shown to induce neuronal degeneration in organotypic hippocampal slice cultures.177 In these
experiments, isoflurane-induced cell death occurred in cultures
obtained from postnatal 7-day-old rats (PND7) but not in those
from PND4 or PND14 rat pups. Moreover, this effect was
observed only with an isoflurane exposure of at least 5 hours.
Recent in vivo data also point to the dose, exposure time, and agedependent toxicity of this volatile anesthetic agent.178,179 Altogether,
these studies further support the notion of both an age- and a
duration-dependent relationship between anesthesia administration and perinatal neuronal death. Interesting new data show that
even shorter exposure time (4 h) to isoflurane in neonatal rat pups,
although not affecting survival, can induce a significant decrease
in hippocampal stem cell proliferation, leading to the long-term
impairment of neurocognitive function revealed by the fear
conditioning test.180
Nitrous oxide (N2O) is a potent antagonist of the NMDA type
of glutamate receptor. When pregnant rats were exposed to 75%
N2O-25% O2 mixtures on gestational days 14 and 15 for 8 hours
per day, permanently altered behavioral deficits could be detected
in the offspring without any accompanying physical abnormalities.181 In line with results observed following ketamine administration, there is now evidence that a 3-hour exposure to N2O
can also trigger apoptosis in the developing brain.182
Opioid Analgesics
Opioid analgesics primarily act on -, -, and -types of opioid
receptors on the cell surface. Upon binding, these opioid receptor
subtypes recruit inhibitory G proteins (Gi/o) and thereby initiate
the activation of multiple intracellular signaling cascades.183,184 In
addition to inducing potent analgesic effects, these signaling
pathways are also implicated in a variety of other biologic events
including the modulation of proliferation, survival, and differentiation of cells expressing opioid receptors.184 In the developing rodent CNS, opioid receptors are expressed from early
developmental stages,185,186 suggesting a role for opioid receptor
mediated signaling in the developmental processes. In rats, chronic morphine exposure during the embryonic and the early
postnatal period induces significant reduction in brain volume,
neuronal packing density, and dendritic growth.187191 Animals
subjected to this treatment paradigm show long-term impairments in learning abilities and motor activity.192,193 By contrast to
the effects of exogenous opioid exposure, pharmacologic blockade
of endogenous opioid signaling by naltrexone induces an increase
in brain size, suggesting a modulator role for the endorphin and
opioid receptor system during development.194
It is now well established that opioids modulate cell proliferation in germinative zones of the developing brain in a receptor-,
brain region, and cell typespecific manner. Activation of the
and opioid receptors increases proliferation rate, whereas
agonists of the receptor decrease cell division in the germinal
zone of the late embryonic neocortex.195 Conversely, morphineinduced receptor activation inhibits DNA synthesis in the
developing cerebellum.196 Finally, signaling through the receptor
increases cell proliferation in oligodendrocytes197 but inhibits

mitosis in astrocytes and neuronal precursors.196,198
Although morphine has been reported to reduce chemotactic
responses in leukocytes199 and increase chemotaxis in microglia,200
the role of opioid signaling in neuronal cell migration in the
developing brain remains to be established. In this context, recent
observations reveal that by contrast to proliferative neural progenitors, migrating neuroblasts do not express opioid receptors
on the cell surface.198 Further work is needed to determine whether
opioids affect the migration of other cell types such as astroglial
cells during development.
Naltrexone-induced chronic pharmacologic blockade of opioid
signaling in the early postnatal period induces a significant
increase in the extent of dendritic arborization as well as in the
number of dendritic spines, indicating that endogenous opioid
systems are critical regulators of neuronal differentiation and that
they control growth through an inhibitory mechanism.201,202 In
vitro observations indicate a dual role for opioid signaling in
neurite growth. Although high-dose (1 mM) morphine inhibits
neurite elongation, low concentrations (<10 nM) of this drug
enhance neurite-promoting activity of NGF.203,204 Although no
data are available on whether pharmacologic blockade or enhancement of opioid signaling induces cell death or survival during CNS
development, application of selective receptor agonists increases
NGF-dependent survival of embryonic chick dorsal root ganglion
neurons, suggesting that growth factormediated neuronal survival might be modulated by opioid signaling.205,206 Conversely, in
the adult rat brain, high doses of opioid have been shown to induce
electoencephalographic seizure activity and cell death in several
brain regions.20,207
Combined Use of Anesthetic Agents

During the perioperative period, patients are usually exposed to a
combination of different anesthetic agents either simultaneously
or in a timely order. As the majority of these drugs have GABAmimetic and/or NMDA antagonistic properties, the question as to
whether combined use of anesthetic agents could act additively or
synergistically in terms of neurotoxicity is of great clinical
significance. Although one of the major arguments for providing
multimodal anesthesia or balanced anesthesia is to diminish
potential side effects linked to higher concentrations of individual
drugs, recent laboratory results would suggest the need for a risk/
benefit reevaluation of this practice.208 Indeed, a large amount of
experimental evidence suggests that concurrent use of several anesthetic agents can potentiate CNS damage. The co-administration of
even low concentrations of ketamine and N2O enhances the
neurotoxic reaction to a much greater degree that can be explained
by the simple additive effects of these agents.182 Recently, the coadministration of sedative concentrations of midazolam and
ketamine to the infant mouse brain was shown to be more effective
in inducing apoptosis than either of these drugs alone.148 The coadministration of ketamine with propofol or thiopental also
potentiates apoptotic neurodegeneration in young rodents.163
Importantly, exposure of 7-day-old rats to a combined midazolamN2O-isoflurane anesthesia for 6 hours led to widespread neurodegeneration in the developing brain and this was accompanied by
persistent learning deficits.209 Interesting new data from this same
research group provide some insights into the molecular mechanisms of anesthesia-induced activation of apoptotic pathways in
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immature neurons.210 Midazolam-N2O-isoflurane rapidly induced
significant changes in the expression pattern of brain-derived
neurotrophic factor (BDNF) in the brain of rat pups. BDNF is a
member of the neurotrophin family of growth factors and is
implicated in neuronal survival, differentiation, and synaptic
plasticity via activation of its high-affinity receptor, TrkB.211 This
neurotrophin also binds to the so-called low-affinity neurotrophin
receptor, p75NTR, leading to the activation of apoptotic cascades.211 In the cerebral cortex of 7-day-old rats, as little as a 2-hourlong anesthetic exposure significantly increased the amounts of
BDNF. This was accompanied by an increase in the expression of
the p75NTR receptor. By contrast, the anesthetic induced an
important decrease in BDNF levels without affecting p75NTR
receptor expression in the thalamus, leading to a reduced BDNFdependent activation of the TrkB receptor. These results suggest
that general anesthesia can perturb CNS development by interacting with the multifaceted molecular pathways of neurotrophin
signaling.
Protection Against AnesthesiaInduced Neurotoxicity

Deciphering the molecular pathways involved in anestheticinduced adverse effects on the developing CNS would allow us to
develop therapeutic strategies to prevent these unwanted complications. In this context, administration of -estradiol has been
shown to reduce anesthesia-induced apoptosis in the developing
brain.210 This sex hormone is known to activate the Akt serine/
threonine kinase, which is an important factor for neuronal
survival pathways. The midazolam-N2O-isoflurane anesthesiainduced apoptotic neurodegeneration has been reported to be
reduced in a dose-dependent manner by the co-administration of
melatonin. Melatonin, in addition to its sleep-promoting activity,
exerts antioxidant effects by improving mitochondrial homeostasis and stabilizing the inner mitochondrial membrane.212 Recent
data indicate that co-administration of L-carnitine, a quaternary
ammonium compound involved in fatty acid metabolism, also
protects against N2O-isoflurane-induced neuroapoptosis.213 In
vitro, ketamine-induced neurotoxicity is prevented by the coadministration of IGF-1, a growth factor known to activate the
phosphatidylinositol-3 kinase/Akt signaling pathway.153 Recently,
co-application of xenon during isoflurane and isoflurane-N2O
anesthesia has been shown to attenuate the neurotoxic effects of
these latter two agents during the early postnatal period.214 These
encouraging observations open a whole new line of research
aimed to counteract anesthesia-induced neurotoxicity. Further
studies should be conducted to address this important issue.
Extrapolation of Laboratory Results to

Clinical Practice
It is of course extremely difficult to evaluate the clinical relevance
of experimental observations claiming the possibility of anesthesiainduced neurotoxicity in the developing brain. A first important
question concerns the possibility of interspecies differences in
terms of drug effects.215 In this context, it is important to note that,
in addition to rodents, anesthetic and subanesthetic doses of
currently used anesthetics have now been shown to induce
apoptosis in other species such as pigs and monkeys.145,216 Another
essential criticism concerning the significance of animal

experiments in comparison with human anesthesia practice
concerns the relatively long exposure time needed to produce
detectable neurotoxic effects in the majority of laboratory
studies.217 In fact, from a developmental perspective, several hourlong exposures to anesthetics in rodents would be equivalent to
producing general anesthesia for days or even weeks in the human
neonate.8 However, recent results somewhat counteract these
arguments, showing that even a single exposure to subanesthetic
doses of anesthetics could trigger a two- to fourfold increases in
neuronal apoptosis in the mouse brain during the synaptogenetic
period.148 In addition, in vitro data indicate that short-term exposure to anesthetic agents can also impair neuronal development
by interfering with dendritic growth and branching without
inducing cell death.152,162 Given the utmost importance of neuronal
dendritic architecture in appropriate information processing, one
essential next step will be to determine how neuronal dendritic
arbor development is influenced by anesthetic agents in a more
complex and physiologic environment, using organotypic slice
cultures and in vivo animal experiments. These experiments,
combined with long-term assessment of behavioral outcome
following short-term anesthesia, may help us to better understand
the impact of anesthetic agents on CNS development.
Differences in concentrations of drugs needed to produce
anesthesia across different species further complicate the issue of
anesthesia-induced developmental neurotoxicity. Subanesthetic
plasma concentrations of ketamine in humans vary from 0.1 to
0.5 g/mL,218,219 whereas intravenous administration to children
at doses of 3 mg/kg to induce anesthesia results in blood levels
of 1 to 2 g/mL.150,151 Although no direct comparison in terms of
plasma concentrations exists with rodents; as much as 40 mg/kg of
subcutaneously injected ketamine is insufficient to produce
anesthesia in young mice.148 In laboratory animals, plasma levels
of ketamine are approximately 6 g/mL following a single 20 mg/
kg subcutaneous dose.147 These studies suggest that effective
plasma concentrations and probably on-site brain concentrations
of ketamine needed to produce anesthesia are significantly higher
in rodents than in humans, raising further difficulties in the
extrapolation of these experiments to human infants.
Finally, one can argue that experimental conditions in these
animal experiments are very different from those associated with
surgical anesthesia and complex perioperative management.217
First, based on the neuronal stimulation hypothesis,220 preoperative stress and painful stimuli during surgery can activate NMDA
and other excitatory receptors in the immature brain and anesthetic drugs could, thus, reduce extreme degrees of neuronal
excitation.221 In line with this hypothesis, application of ketamine
has been shown to reduce cell death following inflammatory pain
in the newborn rat brain.222 The average clinical situation is
by contrast to experimental settings in which anesthesia was
administered without painful stimuli and, consequently, the
effect of anesthetics on the suppression of basal neural activity is
evaluated. Second, human neonates and children routinely receive
nutritional support and metabolic monitoring in the perioperative period, thereby minimizing the risk for hypoglycemia and
impaired nutrition. By contrast, although this issue is controversial, rodent pups do not suckle well after general anesthesia,
resulting in a prolonged decrease in weight gain compared
with nonanesthetized littermates.146,223 Given that the role of
malnutrition in decreased brain growth and learning disabilities is
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well established,224,225 one cannot fully exclude the possibility that

the neurotoxic effects of anesthetic agents are, at least partially,
related to impaired nutrition in the perioperative period in these
animal studies.
Anesthesia-Related Neurotoxicity and

Clinical Evidence
Several human cohort studies have demonstrated an association
between surgery in the neonatal period and poor neurodevelopmental outcome. Neurodevelopmental outcome in extremely low
birthweight (ELBW) infants undergoing laparotomy for necrotizing enterocolitis (NEC) has been shown to be significantly
worse than in ELBW infants, with or without NEC, in the absence
of anesthesia and surgery.226 Children who required major neonatal surgery performed significantly less well at 1 year of age and
in early adolescence than with their peers.227,228 Children who
underwent surgical correction for congenital diaphragmatic
hernia or esophageal atresia during the neonatal period have more
learning, emotional, and behavioral problems than children in the
general population.229,230 Recent clinical observations indicate that
surgical closure of patent ductus arteriosus (PDA) in ELBW
infants is associated with significantly worse neurodevelopmental
and neurosensory outcome than indomethacin-induced successful closure without a need for surgery.231 Unfortunately, given the
high number of potentially confounding factors, none of these
studies provides evidence for an association between anesthesia
per se and poor outcome. In fact, the majority of infants included
in these studies have coexisting malformations, prematurity,
sepsis, and associated cardiovascular instability. Also, it is virtually
impossible to distinguish between the effects of anesthetic agents,
surgical stress, and postoperative issues in the clinical setting.
Upcoming clinical trials, attempting to focus on a specific neonatal
population that presents with limited comorbidity but requires
surgery, are necessary to further investigate this issue.232
One should not forget that multiple lines of evidence suggest
the necessity of providing anesthesia in infants. In preterm babies
undergoing surgery, perioperative stress hormone levels as well as
postoperative complications were significantly higher when only
N2O and curare were administered peroperatively compared with
infants who also received fentanyl or halothane.233,234 In neonates
undergoing cardiac surgery, deeper levels of anesthesia decreased
the incidence of postoperative sepsis, disseminated intravascular
coagulation, and mortality.235 Repetitive painful stimuli have been
shown to persistently alter pain processing in humans,217,236 and
epidemiologic studies reveal an association between perinatal
and neonatal complications and behavioral/emotional problems
in childhood, such as anxiety, depression, and even suicidal
tendencies.237241
CONCLUSIONS
Anesthesia-induced neurotoxicity remains a highly debated and
controversial issue. The important role of neurotransmitter
signaling in shaping CNS development raises the intriguing
possibility that interference with these signaling pathways, such
as exposing the developing organism to anesthetic agents, could
potentially alter physiologic developmental patterns during brain
maturation. However, the functional impact of anesthetic agents
on developing humans remains to be determined. At the current
state of our knowledge, we believe that no recommendations can

be made to change clinical practice. Nevertheless, in light of
accumulating experimental data, one should systematically
consider whether elective surgical procedures in infants could be
safely postponed to later periods. Also, when surgery or a
procedure is unavoidable, every effort should be made to limit the
duration of the intervention. Finally, it is important to note that
there is no evidence whether one anesthetic agents is better or
worse that the others in terms of potential for toxicity to the CNS.
Clearly, given the large number of human fetuses and infants
receiving anesthesia worldwide, there is no doubt that additional
experimental and clinical studies are needed to elucidate the
impact of anesthesia on the developing brain.
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209. Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure
to common anesthetic agents causes widespread neurodegeneration
in the developing rat brain and persistent learning deficits.
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210. Lu LX, Yon JH, Carter LB, Jevtovic-Todorovic V. General anesthesia
activates BDNF-dependent neuroapoptosis in the developing rat
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211. Teng KK, Hempstead BL. Neurotrophins and their receptors:
signaling trios in complex biological systems. Cell Mol Life Sci.
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212. Yon JH, Carter LB, Reiter RJ, Jevtovic-Todorovic V. Melatonin
reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain. Neurobiol Dis. 2006;21:
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213. Zou X, Sadovova N, Patterson TA, et al. The effects of l-carnitine
on the combination of, inhalation anesthetic-induced developmental, neuronal apoptosis in the rat frontal cortex. Neuroscience.
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214. Ma D, Williamson P, Januszewski A, et al. Xenon mitigates
isoflurane-induced neuronal apoptosis in the developing rodent
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215. Berde C, Cairns B. Developmental pharmacology across species:
promise and problems. Anesth Analg. 2000;91:15.
216. Rizzi S, Carter LB, Ori C, Jevtovic-Todorovic V. Clinical anesthesia
causes permanent damage to the fetal guinea pig brain. Brain Pathol.
2008;18:198210.
217. Anand KJ, Soriano SG. Anesthetic agents and the immature
brain: are these toxic or therapeutic? Anesthesiology. 2004;101:
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218. Roytblat L, Talmor D, Rachinsky M, et al. Ketamine attenuates the
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219. Zilberstein G, Levy R, Rachinsky M, et al. Ketamine attenuates
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220. Lipton SA, Nakanishi N. Shakespeare in lovewith NMDA
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221. Bhutta AT, Anand KJ. Vulnerability of the developing brain.
Neuronal mechanisms. Clin Perinatol. 2002;29:357372.
222. Anand KJ, Garg S, Rovnaghi CR, et al. Ketamine reduces the cell
death following inflammatory pain in newborn rat brai. Pediatr Res.
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223. Olney JW, Young C, Wozniak DF, et al. Anesthesia-induced developmental neuroapoptosis. Does it happen in humans? Anesthesiology.
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224. Dobbing J. Undernutrition and the developing brain. The relevance
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226. Chacko J, Ford WD, Haslam R. Growth and neurodevelopmental
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Nociception and Pain Perception

in Infants and Children
Suzanne Wiener and Joseph D. Tobias
INTRODUCTION
The study of pediatric pain from the underlying neurobiologic
mechanisms to its effective management has grown since the early
1990s into an extremely active and important field. A crucial
change has been the realization that infants experience pain and
demonstrate dramatic and robust pain behaviors. Before that
realization, there was the misconception that the immaturity of
the central and peripheral nervous systems was such that infants
did not feel pain, and consequently, analgesia for painful interventions was unnecessary. However, it is now fully accepted not
only that infants are capable of experiencing pain but that there
are potential acute and long-term adverse effects from the undertreatment of pain.1
Pain sensation involves a multilayered network of nociceptors,
nerve fibers, neurons, and glial cells distributed in multiple
peripheral, spinal, and supraspinal areas, forming diverse feedback
and feed-forward loops. The participation, function, and neurochemical profiles of these cellular elements are constantly modified by external and internal cues.2,3 Signaling of pain at any stage
of development depends not only on the context and characteristics of the painful stimulus but also on the behavioral state and
cognitive demands at that time.2
Current pain research shows that the neonate or infant is not a
merely a little adult. Structures and mechanisms used for pain
processing during early development are unique and different
from those used in adult pain processing. Many of these structures
or mechanisms are not maintained beyond specific periods of
early development.4,5 Thus, the immature pain system plays a
signaling role during each stage of development and uses neural
elements available at that time to fulfill this role.6 This plasticity of
the developing nervous system may allow for the greatest impact
of pain to occur in the most premature infants.5
To better understand the tremendous impact of pain on the
developing nervous system and its pervasive long-term effects, we
review the uniqueness of the nocioceptive pathway including
4
C H A P T E R
specific receptors, transduction, peripheral sensitization, phenotypic switches, transmission, ascending projections, supraspinal
centers, and the descending modulation systems. In addition
to the complex nervous pathways involved in nociception, the
sensing of pain, which occurs only after the integration of the
noxious message into supraspinal centers, can be affected by
numerous factors. These include psychological factors (sex,
age, cognitive level, previous pain experiences, family learning,
culture), situational factors (expectations, control, relevance), and
emotional factors (fear, anger, frustration). Furthermore, this
chapter reviews how chronic pain syndromes develop and how
painful procedures, at an early age, can have deleterious long-term
consequences.
THE NOCICEPTIVE PATHWAY

Nociceptors
A nociceptor is a sensory receptor that sends signals that cause the
perception of pain in response to potentially damaging stimulus.
These receptors are found in any area of the body that can sense
pain either externally (skin, cornea, mucosa) or internally (muscles, joint, bladder, gut, digestive tract). They have four major
functional components (Figure 41): (1) the peripheral terminal
that transduces external stimuli and initiates action potentials;
(2) the axon that conducts action potentials; (3) the cell body that
controls the identity and integrity of the neuron, and (4) the
central terminal that forms the presynaptic element of the first
synapse in the sensory pathway in the central nervous system
(CNS).7 The cell bodies of the first-order neurons are located in
either the dorsal root ganglia (DRGs) or the trigeminal ganglia.
The trigeminal ganglia are specialized nerves for the face, whereas
the dorsal root ganglia are associated with the rest of the body.
Nociceptors are silent receptors and do not sense normal stimuli.
Only when activated by a threatening response (high-threshold
receptors) do they invoke a reflex.
Figure 4-1. Operational components of the nocioceptor including the peripheral terminal that innervates the tissue,
the axon that conducts the impulse toward the central nervous system, the cell body that lies in the dorsal root ganglia, and a central terminal that conducts information to the synapse with the second-order neuron.
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Nociceptors develop from neural crest stem cells. The neural
crest is responsible for a large part of the early development in
vertebrates and, more specifically, for neuronal development. The
neural crest stem cells form the neural tube, and nociceptors grow
from the dorsal part of this tube in a rostrocaudal progression.
They form late during neurogenesis when compared with
proprioceptors (A) or low-threshold mechanoreceptors (A),
which form during the early stages of gestation.5,8 These are non
pain-sensing receptors, so the development of nociceptors late in
neurogenesis allows for their different sensing capabilities. All
embryonic nociceptors express the TrkA nerve growth factor
(NGF) receptor.8 The formation of most TrkA+ neurons is dependent on the proneural transcripition factor neurogenin 1
(Ngn1). The homebox gene Brn3a and the zinc finger gene Klf7
are required for maintenance of TrkA expression. However, these
transcription factors are not specific for nociceptors.911 Following
sensory neurogenesis, differentiation occurs and two different
types of nociceptors are formed. They are classified as either
peptidergic or nonpeptidergic nociceptors. These two sets of receptors express distinct ion channels and receptors. This specialization allows the receptors to innervate different peripheral and
central targets. This differentiation occurs in both the perinatal
and the postnatal periods.
Early embryonic nociceptors share similar molecular identity,
co-expressing both TrkA and Runx1.11 The nonpeptidergic
nociceptors switch off the TrkA NGF and begin expressing Ret.
Ret is a transmembrane signaling component that allows for the
expression of another growth factor, the glial cellderived growth
factor (GDNF). Most of these neurons bind isolectin B4 (IB4).
This transition is assisted by Runx1, which has proved to be vital
in the development of nonpeptidergic nociceptors and in the
coordination of afferent targeting to the spinal cord. The signals
that trigger Runx1 down-regulation in the peptidergic neurons
remain unclear. The peptidergic nociceptors continue to use TrkA,
after the loss of Runx1 in the DRGs. They express a completely
different type of growth factor (calcitonin generelated peptide
[CGRP], Substance P [SP])11,12 and they do not bind IB4. Ongoing
research is attempting to determine more specifically what creates
the differences between these nociceptors.7
Nociceptors sensory channels/receptors can be divided into
Runx1-dependent and Runx1-independent subgroups. Runx1dependent genes are further divided into three groups: (1) Retdependent, (2) Ret-independent and TrkA-dependent, and
(3) Ret-independent and TrkA-independent.1314 Runx1 is selectively required for thermal, but not mechanical pain sensitivity in
vivo, supporting the idea that development of nociceptive mechanical and thermal sensitivity is subject to separate genetic control.
The sensory specificity of nociceptors is established by their
high threshold to particular stimuli. Only when the high threshold
has been reached by either chemical, thermal, or mechanical
stimuli are the nociceptors triggered. The majority of nociceptors
are classified by the type of stimulus to which they respond. Some
nociceptors respond to more than one stimulus and are consequently designated polymodal nociceptors. Other nociceptors respond to none of these modalities and yet may respond to
stimulation under conditions of inflammation after tissue damage
or after sensitization. This latter group is known as sleeping or
silent nociceptors.
Nociceptors have two different types of axons. The first are the
A fiber axons. They are myelinated and allow a fast action
potential to be carried to the spinal cord and CNS. The other type
Nociception and Pain Perception in Infants and Children
59
is the C fiber axon, which has slower conduction because of the

light or nonmyelination of the axon. Therefore, pain comes in two
phases. The first phase (first, sharp pain) is mediated by the fastconducting A fibers and the second (second, dull pain) by
C fibers. If there is massive, repetitive, or prolonged input to a
C fiber, there is progressive buildup in the spinal cord dorsal horn.
This phenomenon is called wind-up, which may increase sensitivity to pain.14
Transduction
Transduction is the first stage of the nociceptive pathway and
involves the process of converting a noxious or painful stimulus,
which can be mechanical, thermal, or chemical, into a nervous
impulse. Specific nociceptor transducers are responsible for how
and whether the specific nerve ending responds to stimulus.
Members of the TRP channel family (transient receptor potential;
cation channels; TRPV1, TRPV2, TRPV3, TRPV4),15 all expressing a particular C-terminal domain, detect noxious heat.16 The
extent to which all of these TRPs are involved in heat-responsive
nociceptor neurons remains uncertain. Heat-evoked activity in
nociceptors may also be modulated by co-expression of heatsensitive potassium channels like TREK-1, whose activity is reduced by increased heat. Cool stimuli are sensed by the TRPM8
channel, whereas the molecular transducers for noxious cold
remain unclear, perhaps involving TRPM8, TRPA1, and others.
Interestingly, although tactile sensibility and motor function
deteriorate in the cold, pain perception persists. This is achieved
by expression in nociceptor peripheral terminals of the TTX-R
Nav 1.8 voltage-gated sodium channel (VGSC), whose inactivation, unlike TTX-S channels, is cold resistant.17 The ENaC/DEG
channel family (degenerin/epithelial sodium channel) detects
mechanical stimuli. Although there are several candidates for the
high-threshold (pinch) mechanotransducers, as of today, all of
those appear to be invalid. These include TRPs (TRPA1), ASICs,
and potassium channels.18 Noxious chemicals, such as capsaicin
or acid (extracellular protons, spider toxins), may be detected
through a common transducer (TRPV1). TRPV1 appears to be a
major intergrator of diverse chemical (wasabie, mustard, raw
garlic, bradykinin) and perhaps even of thermal and mechanical
noxious stimuli.19,20
A single type of stimulus can interact with multiple detectors,
as seen by the ability of extracellular protons to activate not only
TRPV1, but also ASICs, which are also members of the ENaC/
DEG channel family.21 Furthermore, some nociceptors have quite
low thresholds with maximal responses in the noxious range
(TRPV3-4); others have thresholds so high that they do not
normally respond to noninjurious stimuli (TRPV2) and are called
sleeping or silent nociceptors because they wake and become responsive only in the presence of inflammation.7 Thus, transduction
is mediated by high-threshold transducer ion channels that
depolarize the peripheral terminal activating voltage-dependent
sodium channels.
Mutations in the NGF TrkA receptor that result in a failure of
nociceptor survival in the embryo22 lead to loss of nociceptor
neurons in patients with hereditary sensory and autonomic
neuropathy type 4, producing congenital pain hyposensitivity.
A congenital indifference to pain without loss of nociceptor
neurons has been shown recently to occur with loss of functional
mutations in the SCN9A gene encoding the alpha subunit of
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Nav 1.7 VGSC.23,24 These two examples of mutations reveal the

crucial importance of nociceptors as a warning device.
Peripheral Sensitization
Peripheral sensitization represents a form of stimulus-evoked
functional plasticity of the nociceptor. The stimulus is the sustained presence of inflammatory mediators released from injured
and inflammatory cells that sensitize the nociceptor, reducing the
threshold and increasing the responsiveness (primary hyperalgesia). The peripheral nociceptive hyperexcitability is induced
through increased receptor (autosensitization) or cell membrane
(heterosensitization) reactivity to stimuli. As a result of the change
in the chemical milieu produced by the disruption of cells, degranulation of mast cells, secretion by inflammatory cells, and
induction of enzymes like cycloxygenase-2 (COX-2), nociceptors
are no longer exclusively noxious stimuli detectors. They also
become detectors of innocuous inputs. Thus, low-intensity stimuli
gain access to the nociceptive pathway and begin to produce pain.
Various sensitizers (kinins, amines, prostanoids, growth factors,
chemokines, cytokines) combined with protons and adenosine
triphosphate (ATP), forming an inflammatory soup, are detected
by the nociceptor terminal and, as a result, change the properties
of the transducer and sodium channels, mainly as a result of
phosphorylation. Transducer channel activity is, thus, heightened
by the diverse inflammatory agents that bind to their cell-surface
receptors to stimulate phospholipase C (PLC- or PLC-) signaling
pathways. This, in turn, leads to hydrolysis of plasma membrane
lipids and the subsequent stimulation of protein kinase C subforms
(PKC-). Both of these actions have been proposed to potentiate
TRPV1 receptor function. Prostaglandins (PGE2) and other inflammatory products that activate adenylyl cyclase (AC) through
G-coupled receptors also enhance nociceptor excitability. This
occurs, in part, by cyclic adenosine monophosphatedependent
protein kinase (cAMP-PKA)dependent phosphorylation of Na,
1.8, and/or 1.9. Furthermore, substance P and CGRP dilate blood
vessels, increasing the local inflammatory response and contributing to peripheral sensitization. Several new products have also
been identified as peripheral sensitizers including the transforming
growth factor- (TGF-) member activin,25 TNF,26 the chemokine CCL3,27 prokineticins,28 proteases that activate proteaseactivated GPCR receptors,29,30 and GDNF.31
From multiple knockout studies, it has been shown that both
TRPV1 and TRPA1 contribute to peripheral sensitization as do
the VGSCs, Nav1.8, Nav1.7, and Nav1.9. TRP receptor antagonists and sodium channel selective blockers may be a useful
approach for reducing peripheral sensitization and thereby inflammatory pain.32
Phenotypic Switches
In addition to driving peripheral sensitization, peripheral inflammation produces retrograde signals in nociceptor neurons that
increase the transcription of neuropeptides, brain-derived neurotrophic factor (BDNF), and sodium channels in the cell body as
well as increase the translation of TRP channels to augment both
central transmission and peripheral sensitization. Furthermore,
the expression of -opioid receptors is increased by inflammation
via NGF enhancing sensitivity to opioids. Transport of NGFactivated Trk receptors and perhaps those of other growth factors
from the periphery appears to be a major means whereby nociceptor cell bodies change in response to peripheral inflammation.
Inflammation tends to cause an increase in the expression of specific nociceptive ion channels/receptors. The underlying transcriptional mechanisms are unclear and may involve axonal transport
of transcripts and local translation.7
If the peripheral axon of nociceptors is severely injured, disrupting contact of the cell body with its terminal and its peripheral
target, profound changes in transcription are induced. Negative
signals such as a loss of target-derived growth factors and positive
signals like retrograde protein kinase G or a vimentin-dependent
translocation of activated ERK drive activation of multiple signaltransduction pathways in the cell body that alter transcription in
more than 1000 genes. These molecular reactions are attempts
either by the neuron to survive the major insult or for the axon to
regrow. However, many axotomy-induced transcriptional changes
are maladaptive and produce alterations in function that can result
in neuropathic pain. Injured neurons lose some normal nociceptor
features (a down-regulation of TRP and sodium channels),
although at the same time gaining a new molecular identity. One
example of this is the up-regulation in DRG neurons of enzymes
involved in the synthesis and recycling of tetrahydrobiopterin
(BH4) after peripheral axonal injury. BH4 is an essential cofactor
for aromatic amine hydroxylases and nitric oxide synthetases. Its
increase drives NO production in DRG neurons, which in turn
increases calcium influx in the neurons. Inhibition of BH4 synthesis produces analgesia, whereas increased synthesis of BH4
produces painlike behavior. A human variant of the rate-limiting
enzyme in the BH4 pathway (guanosine triphosphate [GTP]
cyclohydrolase, which produces less BH4 in response to stress or
injury), is associated with decreased chronic pain in patients after
surgery. Although changes in the injured DRG neurons show a
major phenotypic shift, alterations are also seen in their spared,
noninjured neighbors. These cells may also be involved in the
genesis of chronic pain.
Presynaptic Terminal and Transmission

Stimuli from the periphery are transmitted to the spinal cord
through the sensory afferent nerves (Figure 42). Afferent
nociceptive fibers travel back to the spinal cord where they form
synapses in its superficial dorsal horn (gray matter) for somatic
neurons and in the spinal nucleus of the trigeminal nerve for those
neurons innervating the face. The nociceptive fiber located in the
periphery is known as a first-order neuron. The first-order neuron
carries the sensory input to the dorsal horn of the spinal cord
where they synapse with second-order neurons. This synapse
transfers information carried by action potentials regarding the
intensity and duration of the peripheral noxious stimuli. The
rostrocaudal and mediolateral topography of the central terminal
reflects the spatial location of the peripheral nociceptor, whereas
their dorsoventral location reflects the identity of the nociceptor.
Thus, they evoke fast and slow excitatory postsynaptic potentials
that exhibit significant spatial and temporal summation.7 Unlike
low-threshold primary sensory neurons that use glutamate as their
unique neurotransmitter, nociceptors use various compounds
including glutamate, neuropeptides (substance P), acetylcholine
(ACh)_, CGRP, and proteins like BDNF as transmitters and
synaptic modulators.
N-Type (CaV2.2) voltage-gated calcium channels are key
mediators of nociceptive signaling. These channels control the
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Figure 4-2. Schematic representation of the central regulation of pain and nocioceptive transmission.
release in the spinal cord of glutamate and neuropeptides such as

substance P. Consequently, inhibition of N-type channels via
activation of opioid receptors or by N-type channel antagonists
mediates analgesia. CaV2.2 RNA undergoes alternative splicing,
producing multiple CaV2.2 channel isoforms with distinct
electrophysiologic properties, distribution, and physiologic role.
CaV2.2 e37a variant is responsible for thermal and mechanical
nociception in undamaged tissues and thermal and mechanical
hyperalgesia during both inflammatory and neuropathic pain.
Both N-type channel CaV2.2 e37a and e37b isoforms, differing by
their proximal C terminus, contribute to tactile neuropathic
allodynia. N-Type channels and its alternative splicing of CaV2.2
are, thus, significantly involved in chronic pain. The elucidation
and better understanding of the molecular complexity in splice
variants and their respective locations and roles in different pain
pathways will allow for the development of better therapeutic
strategies for the treatment of chronic pain.33,34
Transmitter-modulated reductions in transmitter release from
nociceptors are a prominent control mechanism in nociceptor
input to the CNS. Chemicals involved in this modulation include
endogenous opioids acting on - and -opioid receptors (DOR),
gamma-aminobutyric acid (GABA) acting on GABAB receptors,
glycine, serotonin, norepinephrine (NE), and endogenous cannabinoids acting on CB1 receptors. The density of these receptors
changes based on several dynamic factors. In the case of the opioid receptor, there is an increase after inflammation and a
decrease after axonal injury. The DOR has another form of
regulation. Very little of the receptor is normally inserted in the
nociceptor terminal membrane. The majority of DORs are located
within the membrane in peptide-containing, large dense-core
vesicles. Following nociceptor activation, fusion of the vesicles to
the terminal membrane during synaptic release results in
stimulus-triggered exocytosis and the introduction of the receptor
into the terminal. Therefore, DOR-mediated analgesia requires
previous activation of the nociceptor before analgesia can be
achieved. Cannabinoids exert their analgesic action primarily on
CB1 receptors expressed on the peripheral terminals of nocicep-
tors. This mechanism of action of the cannabinoids may enable

the development of peripherally acting cannabinoid analgesics
without central side effects.
Other agents act to increase nociceptor input to the CNS. PGE2
and bradykinin act to increase transmitter release at the central
terminal. PGE2 is produced following induction of the COX-2
enzyme in dorsal horn neurons in response to peripheral inflammation, whereas bradykinin is released in the spinal cord within
minutes of nociceptor input. Both agents act via their G protein
coupled receptors to increase transmitter release.
Ascending Pathway
Following a painful stimulus, if sufficient numbers of a particular
type or types of nociceptors are activated, an afferent volley will be
produced. This ascending pathway initiates the conscious sensation of pain. A fibers, conveying fast, spontaneous pain, form
synapses in lamina I of the dorsal horn of the spinal cord
(Hematopoietic Progenitor Cells [HPC], which are reactive to
heat, pinch, and cold) and lamina V (WDR cells [wide-dynamicrange] neurons, which have large receptive fields and receive input
from mechanoreceptors in addition to nociceptors). In these
laminae, a synapse is formed with a second-order neuron. After
being activated by mainly glutamate-activated AMPA (-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) type of
glutamate receptors, the second-order neurons crosses the midline
through the anterior white commissure and travel cephalad
through the lateral spinothalamic tracts (STTs) or the neospinothalamic tracts, located in the anterolateral quadrant of the
controlateral spinal cord white matter. The second-order neurons,
without making connections elsewhere, terminate in the ventroposterior nucleus of the thalamus. The ventroposterior nucleus
includes the ventral posterolateral (VPL), the ventral posteromedial (VPM) and the posterior (PO) nuclei of the thalamus.
Third-order neurons project from the thalamus to the cortex and
synapse with the dendrites of the primary somatosensory cortex
(S1) in the postcentral gyrus.
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S1 is organized somatotopically and is subdivided into four

parallel strips: Brodmanns areas 3a, 3b, 1, and 2. In each area,
different receptor types predominate. In area 3a, afferents from
muscle predominate, whereas in area 3b, afferents from the skin
predominate. From area 3b, information is sent to areas 1 and 2,
which are important in recognizing the texture and the size/shape
of objects, respectively. The body representation (homunculus) in
S1 is distorted because some body parts are overrepresented
(hand, face) whereas other body parts are underrepresented
(trunk, leg). The distorsion is related to discriminative properties
that are more prominent in some territories (hand, face) than in
others. From S1, somatosensory information is then sent to
areas 5 and 7 in the posterior parietal associative somatosensory
cortex (S2) where stereognosis takes place. Fast pain is felt within
0.1 sec from the application of the painful stimulus and is sharp
and acute. Pain is detected as soon as it reaches the thalamus,
yet physical awareness of the location, quality, intensity, and extent
of the painful stimulus becomes possible only when the somatosensory cortex is activated. This ascending path is responsible for the discriminative aspect of nociception. Because it has
mainly controlateral projections, the body representation is
contralateral.
Conveying slow, increasing pain, C fibers enter the spinal cord
and connect with interneurons in laminae I, II, and possibly III.
The interneurons that receive this input express different subtypes
of glutaminergic receptors, namely N-methyl-D-aspartic acid
(NMDA) and AMPA. High levels of afferent input depolarize the
interneuron first through the AMPA then through the NMDA
receptors. The interneurons then transmit the signal, mainly
by the release of substance P (essential for wind-up), to the STT
cells (second-order neurons) that reside mainly in laminae I
(nociceptive-specific [NS] neurons), IV, and V. The axons of the
STT cells project across the spinal cord to the STT, joining fibers
from the fast pathway. Whereas fast-pain fibers travel through the
neospinothalamic tract (lateral), slow-pain fibers travel through
the paleospinothalamic tract (anterior). Both neospinothalamic
tract and paleospinothalamic tract convey ascending monosynaptic tracts and constitute the anterolateral extralemniscal system.
The paleospinothalamic neurons terminate in the ventrolateral
medulla, in various areas throughout the brainstem (reticular
formation), in the periaqueductal gray matter (mesencephalon), in
the parabrachial nucleus (pons), and in the thalamus (intralaminar
nucleus and other midline nuclei), where they synapse with thirdorder neurons. However, C fiber impulses are not relayed to the
somatosensory cortex, but rather to the frontal association cortex.
Their impulses are responsible for the affect that accompanies pain
and, thus, allows a cognitive appraisal of the nociceptive input.
The appraisal of pain is likely closely linked to ones pain tolerance.
Slow pain is different from acute pain because it is poorly localized
(non-discriminative), has a bilateral body representation, and is
described as an aching, throbbing, or burning pain.
The paleospinothalamic neurons include several ascending
monosynaptic tracts involved in the nociceptive process. The
neurons of the spinoreticular tract (SRT) originate mainly in
laminae V, VII, and VIII, and also in laminae I and X, mostly from
NS and WDR neurons, although also involving nonnociceptive
(N-NOC) neurons. These neurons propagate noxious and
innocuous stimuli from skin, viscera, and muscles. The SRT has
two projections to the brainstem. The first of these is directed to
the precerebellar nucleus in the lateral reticular formation and is
involved in motor control. The other is directed to the medial

pontobulbar reticular formation and is involved in the mechanisms of nociception. Few branches project to the centromedian
and intralaminar nuclei of the thalamus. Most fibers project
ipsilaterally, unlike the STTs. The afferents of the SRT are involved
in the motivational and affective characteristics as well as the
neurovegetative responses to pain. This tract is an important
pathway for the modulation of the nociceptive segmental pathways by activating brainstem structures responsible for descending
suppression.
The neurons of the spinomesencephalic tract (SMT) originate
in the WDR, substantia nigra (SN), and N-NOC neurons mainly
in laminae I, II, IV, V, VI, but also in laminae VII and X and in the
ventral horn. They terminate in several structures of the midbrain,
especially the periaqueductal gray (PAG) matter and the deep
layers of the superior colliculus. The projections to the PAG matter
originate from WDR and SN and are functionally distinct. Those
that reach the PAG in the portion more dorsal to the limiting
sulcus have an excitatory characteristic in afferent nociceptive
transmission, and those that project more ventral to the limiting
sulcus activate inhibitory mechanisms responsible for the
inhibition of the afferents of this same pathway. This suggests
an autoregulatory function of the medulla and midbrain. Stimulation of regions innervated by the SMT produces different responses involved in nociceptive processing. Responses include
aversive behaviors in the presence of noxious stimuli as well as
motor, autonomic, cardiovascular, motivational, and affective
responses.
The parabrachial nucleus (PN), constituting the spinoparabrachial tract (SPBT), receives direct and indirect afferents from
nociceptive pathways. The lateral parabrachial region receives
projection from nociceptive SN neurons originating in lamina I.
This area in turn projects primarily to the amygdala and hypothalamus. The patterns of nociceptive connectivity suggest that
the parabrachial area plays an important role in the motivational
and affective components of pain sensation and/or autonomic and
endocrine responses to noxious stimulation. Neurons in the internal lateral parabrachial nucleus also respond to noxious stimulation. By contrast to the lateral parabrachial region, nociceptive
input to the internal lateral parabrachial nucleus is derived from
the deep dorsal horn (laminae V and VI). Its neurons send their
axons to the medial thalamus, to the paracentral nucleus.
The spinohypothalamic tract (SHT) originates from laminae I,
V, X and some other regions around the central medullary canal.
It is composed of SN, WDR, and N-NOC neurons. These neurons
respond to noxious and innocuous stimulation coming from
muscles, tendons, joints, skin, and viscera. Its projections contribute to the neuroendocrine, autonomic, motivational-affective,
and alertness responses of pain of both somatic and visceral
origin.35 Two polysynaptic tracts, the spinocervicothalamic and
the dorsal horn postsynaptic tracts, are also involved in ascending
nociception. The spinocervicothalamic tract originates mainly
from laminae III and IV and, to a lesser extent, from laminae I,
II, and V. Its neurons receive afferents from peripheral A and
A fibers, consisting mostly of WDR and N-NOC fibers, although
SN neurons have also been described. Projections ascend in
the ipsilateral lateral cervical nucleus (LCN) where they
synapse. LCN neurons project to the controlateral thalamus via
the medial lemniscus. The functions related to this tract concern
the sensory-discriminative, motivational-affective, and autonomic
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characteristics of pain, as well as playing a role as in sensory
integration and modulation of afferent inputs in the spinal cord.
The dorsal horn postsynaptic tracts originate mainly from
laminae III and V as well as laminae VI and VII. The input is composed mainly of WDR and N-NOC neurons with a few SN neurons. Ascending fibers are organized along two distinct pathways,
close to the midline of the spinal cord and at the junction of the
gracile and cuneiform bundles, originating from the lumbar sacral
region and the thoracic column, respectively. The gracile nucleus,
with extensive direct and indirect projections, plays an important
role in sensory integration of the projections from abdominal
organs and from the skin. After crossing completely, fibers form
the medial lemniscus, which in turn, projects to the ventrobasal
nuclear complex of the thalamus. The postsynaptic pathway of the
dorsal column represents the largest afferent pathway for information of visceral origin. This has been revealed in studies demonstrating the control of visceral cancer pain by means of
myelotomy techniques. Lesions in this region are more effective
in the control of visceral pain than in interruption of the pathway
of the anterolateral quadrant of the spinal cord. This pathway also
has functions related to proprioception, tactile discrimination, and
graphesthesia. Given its projections to various thalamic regions,
the postsynaptic pathway of the dorsal column is considered to be
involved in the sensory-discriminative and motivational-affective
components of pain.35
Supraspinal Centers of Nociception

It is now clear that there is no single pain center in the brain.
Ascending pain pathways are relayed either directly or indirectly
to cortical and subcortical brain regions. The regions that are
commonly activated by nociceptive stimulation are often referred
to as the pain matrix. The pain matrix is subdivided into a medial
and a lateral pain system. This distinction, which is based on the
projection sites from either medial or lateral thalamic structures to
the cortex, is an oversimplification of the networks involved but is
a useful means for grouping brain regions that appear to have
similar roles in pain processing.36 The lateral pain system is
primarily thought to have a sensory-discriminative function, comprising spatial, temporal, and intensity properties. The medial pain
system has an affective-motivational dimension, related to the
unpleasantness of the stimulus as well as the behavioral and autonomic reactions it evokes. Some regions encode both sensorydiscriminative and affective pain processing. All of these areas
communicate extensively and reciprocally with the prefrontal
cortex, which brings the situational and memory context to the
experience (cognitive-evaluative function). We present a more
detailed description of supraspinal centers of nociception,
subdivided according to their main function.
Lateral Pain System (Sensory-Discriminative)

The lateral thalamic nuclei function as a relay station by conveying
sensory information from the spinal cord and brainstem to
sensory-discriminatve processing regions. The VPM and the VPL
project to the primary somatosensory (SI) cortex and send minor
projections to the secondary somatosensory (SII) areas of the
cortex. The ventral posterior inferior (VPI) nucleus sends axons
mainly to the SII. Reaching the somatosensory cortex, physical
awareness of pain becomes possible. The posterior insular cortex
as well as its thalamic relay nucleus, the ventromedial nucleus
63
(VMpo) are also involved in the sensory-discriminative dimension. The insula, being a component of the limbic system, is also
involved in affective processing.36
Medial Pain System (AffectiveBehavioral-Autonomic)

The medial thalamic nuclei are the relay station for ascending
pathways, conveying essentially affective-motivational components
of pain. The limbic system (amygdala, cingulated gyrus, hippocampus, hypothalamus, thalamus) plays a crucial role in emotional behavior during painful experiences. The cingulate gyrus is
a major part of the anatomic limbic system and, thus, is involved in
emotion related to pain. The cingulate cortex also participates in
sensory, motor, and cognitive processes related to pain. The
anterior cingulate cortex (ACC), consisting of areas 25 and 24, has
been implicated in a wide variety of autonomic functions including
visceromotor, skeletomotor, and endocrine outflow. These processes include responses to the painful stimuli. Because all of these
activities have an affective component, it is likely that connections
with the amygdala are essential.37 ACC is also involved in rational
cognitive functions, such as anticipation and decision-making. By
contrast, the posterior cingulate cortex (PCC), consisting of areas
29, 30, 23, and 31, contains neurons that monitor eye movements
and respond to sensory stimuli. It is involved in spatial orientation
and memory. It is likely that connections between the PCC and the
parahippocampal cortex contribute to these processes.
The hypothalamus coordinates behaviors necessary for survival, including the emotional homeostasis and responses to pain.
It regulates the autonomic and humoral responses to pain, stress,
and emotional expression. Many other areas in the brainstem
mediate homeostatic changes in bodily functions associated with
pain while receiving active regulatory inputs from cortical,
subcortical, and thalamic areas. The reticular activating system
(reticular formation) is involved in the arousal effects of the
painful stimuli. The arousal may activate noradrenergic neurons
in the locus coeruleus (LC) and, thus, decrease the upward pain
transmission (see the section on Descending Inhibitory Systems
(Endogenous Pain Modulation)). The cathecholaminergic nuclei
of the brainstem receive input from lamina 1 (pain-specific)
pathways and regulate vigilance and attention through cortical
projections. Furthermore, they regulate bodily functions via the
autonomic nervous system and are involved in the descending
modulation of the spinal nociceptive afferents. The parabrachial
nucleus is involved in cardiovascular regulation. It has connections
to the ventral medial nucleus of the hippocampus and the central
nucleus of the amygdala. Both of these areas of the CNS are involved in the affective response to pain. The PAG area is involved
in endogenous analgesia and in automatic coping behavior such as
the fight or flight reaction. The superior colliculus may play a role
in pain-related visuomotor orientating, a reflex function that
allows turning of the upper body, head, and eyes in the direction
of a painful stimulus. The pretectal nuclei are involved in the
regulation of endogenous analgesia. The red nucleus is involved in
pain-related motor functions.
Cognitive-Evaluative Function
The intralaminar and reticular thalamic nuclei, the prefrontal
cortex, and the ACC are involved in the cognitive dimension of
pain.
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Descending Inhibitory Systems

(Endogenous Pain Modulation)
Modulation of nociceptive transmission occurs at multiple
(peripheral, spinal, supraspinal) levels. Endogenous opioids, found
at the peripheral, spinal, and supraspinal levels, act at G-coupled
protein opioid receptors by increasing potassium channel activity
(hyperpolarization) and by inhibiting the Ca2+ voltage-gated
channel, thereby inhbiting substance P release. These endogenous
opioids include -selective enkephalins, -selective dynorphins,
and -selective endomorphins. Endogenous opioids play an
important role in pain modulation and are found in the cerebral
cortex, hypothalamus, thalamus, hippocampus, basal ganglia,
amygdala, PAG, LC, reticular formation, and parabrachial nucleus.
At the spinal level, modulation of the pain input has been
viewed as the attenuation of dorsal horn transmission. Melzack
and Walls Gate Control Theory first suggested this theory in 1965.
Gate control regulation of pain occurs in the gelatinous substance
(lamina II) of the dorsal horn. The selective stimulation of large
cutaneous afferent A fibers from an injured area blocks activation
of the second-order neurons, which are stimulated by the
nociceptive A and C fibers. The nociceptive input will be sensed
as painful only if it can subtract itself from the inhibitory influence
of enkephalin interneurons activated by A fibers. This type of
control modulates the pain intensity (sensory-discriminative
modulation).
At the supraspinal level, multiple brain regions contribute to
the escending inhibitory pathways. These descending pain
inhibitory controls are immature at birth and do not become
functionally effective until postnatal day 10 in the rat, although all
descending projections are already present at birth. They may have
gender-specific and genetic-specific differences contributing to
individual variability in pain sensitivity. Each of the descending
inhibitory system has different neurochemistry (endogenous
opioids, serotonin, NE, GABA) and different neuroanatomic connections. Both the PAG, the RVM (nucleus raphe magnus), and
adjacent reticular formation including the nucleus gigantocellularis pars alpha and paragigantocellularis ventralis receive direct
projections from the spinal dorsal horn and control the ascending
nociceptive input by a feedback mechanism, thereby modulating
pain intensity (sensory-discriminative modulation). On the basis
of their physiologic response properties, spinally projecting RVM
neurons can be classified into three types. The on-cells give an
excitatory response to a noxious stimulus starting just before a
spinal nocifensive reflex (withdrawal reflex). The off-cells give an
inhibitory response to a noxious stimulus starting just before a
spinal nocifensive reflex. The neutral cells give variable responses
or are unresponsive to noxious stimuli. Morphine suppresses oncell activity, increases indirectly off-cell activity through a
GABAergic mechanism within the RVM, and has little effect on
neutral cell activity. A subgroup of neutral cells are serotoninergic
and project to the spinal cord where its receptor contributes to
descending antinociceptive action by modulating the effects induced by on- and off-cells.
At the spinal cord level, the dorsolateral funiculus is the main
descending pathway mediating antinocieptive effects from the
RVM to the spinal dorsal horn. The noradrenergic neuronal cell
groups of the brainstem, particularly the LC (LC-A6) as well as
pontine noradrenergic cell groups A5 and A7, receive projections
from the PAG. Descending axons originating in these noradrenergic neuronal cell groups, conveyed by the ventrolateral pathway,
are the source of spinal NE. NE is known to have a significant

antinociceptive influence through action on spinal presynaptic 2adrenergic receptors (subtype 2A, 2C). NE also exerts its
descending inhibition by direct catecholaminergic postsynaptic
innervation of STT neurons and by activating, in the superficial
laminae, a population of small, low-threshold units, likely to be
inhibitory interneurons. The latter enhance GABAergic and glycinergic inhibitory synaptic transmsission in the substantia gelatinosa. The LC also receives projections from the central nucleus
of the amydgala, preoptic area, paraventricular nucleus of the
hypothalamus, and lateral hypothalamus. NE systems have little
influence on baseline pain sensitivity; however, in persistent pain,
these systems have an important role. In conditions that cause
persistant pain (inflammation, injury), the function of descending
pathways may change considerably. These changes may enhance
the efficacy of descending inhibition by increasing turnover of NE
and by increasing the number of 2-adrenergic receptors in the
spinal cord. Increased efficacy of glutamatergic receptors of the
medulla, accompanied by a phenotypic switch of medullary
neurons, has also been observed following inflammation. In the
presence of sustained pain stimulation, a decrease of descending
inhibition or an increase of descending facilitation of pain may
also be seen.
Other brainstem, diencephalic, and telencephalic structures
modulate pain. The hypothalamus is involved in stress-induced
analgesia either by endocrine mechanisms (Corticotropin releasing
factor (CRF) released after activation of the hypothalamicpituitary-adrenal axis) or by spinal antinociception through axonal
projections from the hypothalamus to the PAG-RVM circuitry. The
limbic system and the frontal cortex are closely associated with
memory and emotions. With other brain structures, they have an
important impact on pain modulation and perception (emotiveaffective modulation).
Another inhibitory system is the diffuse noxious inhibitory
controls (DNICs). Some neurones in the dorsal horn of the spinal
cord are strongly inhibited when a nociceptive stimulus is applied
to any part of the body, distinct from their excitatory receptive
fields. DNICs influence only convergent neurones. The other cell
types that are found in the dorsal horn, including specific nociceptive neurones, are not affected by this type of control. In normal
conditions, these inhibitions can be triggered only by conditioning
stimuli, which are nociceptive. The inhibitions are extremely
potent, affect all the activities of the convergent neurones, and
persist, sometimes for several minutes, after the removal of the
conditioning stimulus. In fact, only activity of A or C peripheral
fibers can trigger DNICs. DNICs are sustained by a complex loop
that involves supraspinal structures because, unlike segmental
inhibitions, they are not observed in animals in which the cord
has previously been transsected at the cervical level. The ascending
and descending limbs of this loop travel, respectively through the
ventrolateral and dorsolateral funiculi, respectively. DNICs result
from the physiologic activation of the subnucleus reticularis
dorsalis (SRD) in the caudal medulla.
Perception and Chronic Pain

Perception is how pain actually feels to someone rather than pain
as a sensation. It is the cerebral cortical response to nociceptive
signals that are projected by third-order neurons to the brain. The
relief of nociception, the antinociception, is simply the blockade
of nociceptive inputs. This notion should be differentiated
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from analgesia, the relief of perception of noxious stimulus. The
relationship between the reported pain intensity and the peripheral stimulus that evokes it depends on many factors such as
past pain experience, depression, distraction, expectation or
anticipation, anxiety, the level of arousal, gender, and genetics.
Therefore, people have different pain thresholds. The prefrontal
cortex and the limbic system are responsible for learning and
memorization of painful experiences and the way an individual,
who coped with pain in the past, will cope with subsequent
episodes of pain. Individuals who are already suffering from an
illness or experience depression or insomnia are more likely to
have a lower pain threshold than healthy people. In reality, the
experience of pain is nothing more than the interpretation of
nociceptive inputs. If a dissociation between nociception and pain
appraisal occurred, the experience of pain would not influence
behavior because the affect is missing. This affect accounts for the
variability of pain tolerance among individuals.
Supraspinally mediated factors that fall into the cognitive domain may account for a significant amount of the interindividual
differences in the subjective experience of pain. For example,
distractions main effect appears to be increased activity within the
medial pain systems via the descending pain modulatory system
and a corresponding reduction in activation in the lateral pain
system. Other experiments have investigated the effect of anticipation of an impending painful stimulus on regional brain activity. The main effects of anticipation were found to be activation
of rostral anterior insula and medial prefrontal cortices during the
anticipation of pain, whereas during pain itself, insular activity
was more caudal and the prefrontal focus was replaced by activity
within the ACC. The hippocampal formation (entorhinal complex) is responsible for producing anxiety-induced increased pain
perception.
A few genes have been identified that are associated with the
perception of pain in humans. Single nucleotide polymorphisms
(SNPs) in genes that code for the melanocortin-1 receptor and
neuronal cytochrome P450 (PY2D6) are associated with alteration
in opioid analgesia. Congenital insensitivity to pain (CIP) type I
has been linked to the gene encoding a subunit of serine palmitoyltransferase, and type IV has been linked to the gene encoding
for a NGF-specific tyrosine kinase receptor. Furthermore, a
common SNP in codon 158 (val138met) of the gene that codes for
catecholamine-O-methyltransferase (COMT) has been proposed
to contribute to differences in the human experience of pain.
Recent studies have identified three genetic haplotypes of the gene
encoding COMT, designated low pain sensitivity (LPS), average
pain sensitivity (APS), and high pain sensitivity (HPS). These
haplotypes encompass 96% of the human population, and five
combinations of these haplotypes are strongly associated with
variation38 in the sensitivity to experimental pain. The presence
of even a single LPS haplotype diminishes, by as much as two to
three times, the risk of developing a chronic pain condition. The
LPS haplotype produces much higher levels of COMT enzymatic
activity than the APS or the HPS haplotypes. As shown in rat
studies, inhibition of COMT results in a profound increase in pain
sensitivity.38
The threshold for eliciting pain has to be high enough that it
does not interfere with normal activites but low enough that is can
be evoked before frank tissue damage occurs. This threshold is not
fixed and can be shifted either up or down, which may be either
adaptative or maladaptive. Shifts in pain threshold and responsiveness are an expression of neural plasticity, the neurobiologic
65
means by which changes in the nervous system can modulate the

response to any stimulus. Such plasticity or modifiability of the
sensory system characterizes pain syndromes.3,39
Chronic pain is not just a prolonged acute pain; it is a distinct
entity, with many functional and structural alterations of the
peripheral nervous system (peripheral sensitization or primary
hyperalgesia) and CNS (central sensitization or secondary hyperalgesia). Ongoing nociceptive input from the periphery is needed
to maintain central hyperexcitability, the key process in the
generation of chronic pain. Repetitive and intense activation of the
high-threshold C fibers and AMPA postsynaptic receptors results
in release of excitatory substances such as glutamate and substance
P. Early changes also include elimination of the voltage-dependent
magnesium blockade of NMDA receptors and Na channel
stimulation. These changes permit glutamate to activate NMDA
and non-NMDA postsynaptic receptors and cause a gradual
increase in the frequency of dorsal horn neurons firing, known as
the NMDA-mediated wind-up phenomenon. Activated receptors
increase intracellular calcium levels with subsequent activation of
calcium-dependent intracellular kinase and phosphorylation of ion
channels and NMDA receptors. Potential consequences of these
changes include altered synaptic transfer and transcriptional
changes with c-fos production in the second-order dorsal horn
projection neurons (marker of central sensitization).
Activation of the NMDA receptors represents the first step in
central sensitization (the transition from acute to chronic pain). As
such, adequate treatment of physiologic, nociceptive pain is the
most important goal of acute pain management because it may
prevent subsequent central sensitization. Other neurochemical
changes involved in central sensitization include sensitization of
WDR neurons to nonnociceptive stimuli and expression of
substance P by A fiber presynaptic terminals. Neuroanatomic
modifications include sprouting of A fiber terminals into the
superficial layers of the dorsal horn with synapses onto the
nociceptive second -order neurons. Additional modifications
include extensive reorganization of the somatosensory cortical
maps and remodeling in the brainstem, cerebellum, basal ganglia,
and motor cortical areas with subsequent dysfunctional descending inhibition. This central sensitization and neuroplastic remodeling are responsible for all the main features of chronic pain
including hypersensitivity to nociceptive stimuli (hyperalgesia),
perception of pain upon nonnociceptive stimulation (allodynia),
expansion of the pain-receptive fields to uninjured tissue (referred
pain), and prolonged pain after a transient stimulus (persistant
pain).
DEVELOPMENT OF
NOCICEPTIVE CIRCUITRY
Somatosensory processing comprises a fine balance of sensory
afferent input, local inhibitory and excitatory control on dorsal
horn projection neurons, and descending inhibitory and facilitatory modulation. The development and maturation of each of
these components will affect the nociceptive responsivity.
Primary Sensory Afferents

Development of primary sensory neurons is the first stage in the
development of the somatosensory pathways that will transmit
sensory stimuli from the periphery to the higher areas of the CNS.
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Nociceptive neurons develop without influence from either central

or peripheral targets.40 Primary sensory neurons that make up the
DRG appear at embryonic day 12 (E12). The future, cutaneous,
nonnociceptive A fibers expressing the neurotrophin receptors
TrkB and TrkC appear first, followed by the C fiber cells that
express TrkA. The development of these two populations is under
the control of separate transcription factors of the neurogenin
family. Ngn1) is required for small C fiber neurons and Ngn2 for
the larger A fibre cells.41 The number of neurons increases until the
time of birth and is followed by a 15 to 20% loss over the first few
postnatal weeks,42 coinciding with the final innervation of the skin
by the peripheral afferents of the DRG neurons. The survival of
the neurons is dependent upon the presence of neurotrophic
factors produced by both the peripheral (skin) and the central
targets.43
Growth of Axons Toward Peripheral

and Central Targets
Toward the periphery, outgrowth of axons from DRG sensory
neurons occurs before birth. Large-diameter A fibers form an
initial nerve plexus and are followed by the smaller-diameter C
fibers.44 This growth is extremely precise with each DRG innervating somatotopically appropriate dermatomes. There is an initial
hyperinnervation of the skin, extending beyond the dermis into
the epidermal surface. These projections subsequently withdraw,
resulting in a pattern of innervations similar to that found in the
adult.45 The first sensory neuronderived afferents to penetrate
the spinal cord are the A fibers at E15 to E17, followed by C fiber
projections at E18 to E20. Although the peripheral target skin
influences the pattern of projections in the CNS, it does not direct
cutaneous axons to specific populations of neurons in the dorsal
horn. The inhibitory growth cone collapsing molecule semaphorin
3A and the homeodomain protein, DRG11, seem to play an
important role in the specific growth of sensory axons.45
Spontaneous action potentials of fetal dorsal horn ganglia cells
during this period may also be responsible for appropriate
synaptic connections.
Functional Development of Nociceptors

Determinant characteristics of C fibers such as the expression
of the neurotrophin receptor TrkA and selective binding of IB4
can be seen at an early embryonic age. The sodium canal TTXresistant Nav 1.8 (SNS/PN3) that regulates the neuronal hyperexcitability is expressed in C fibers from E17 with adult levels
present from the seventh day of life.46 Within days of birth,
the receptor for the capsaicin TRPV1, which has a predominant
role in the detection of thermal and chemical stimuli, is expressed
in the dorsal ganglia at a percentage similar to that found in adults.
The ATP-gated P2X3 receptor, important for thermal and
mechanical hyperalgesia following inflammation or nerve injury,
is also expressed from an early age by cells of the DRG.
Cell Determination in the Dorsal Horn

The expression of the gene homeobox Lbx1 is required for both
the correct specification of substantia gelatinosa neurons and the
appropriate sensory afferent innervation of the dorsal horn.47 The
selection of postmitotic genes Tlx1 and Tlx3 seals the destiny of
embryonic dorsal horn cell, resulting in excitatory glutamatergic

or inhibitory GABA cells.48 It is interesting to note that the genesis
of projecting neurons of lamina I is completed before the local
interneuron circuitry,49 implying that direct transmission of
nociceptive activity from the spinal cord to the CNS may appear
before the development of the local modulation circuitry. At
postnatal days 18 to 27, the miniature excitatory postsynaptic
current (mEPSC) frequencies of lamina I are five times higher
than those in the interneurons. The relatively late maturation of
interneurons means that their axodendritic growth takes place
postnatally, which may be important for the activity-dependent
shaping of nociceptive circuits (see Section on Growth of Axons
Toward Peripheral and Central Targets).
Functional Maturation of
Nociceptive Circuitry
The appearance of connections between the afferent sensory and
the spinal neuronal cells leads to the first functional reflex
response to tactile and nociceptive stimluli. Although these spinal
reflexes are not proof of the consciousness of pain, they confirm
the presence of a functional connectivity of somatosensory circuitry, a prerequisite of any behavioral response to a peripheral
sensory stimulus. The study of pain behaviors in fetal and neonatal
animal is restricted to examination of reflex responses that can be
elicited only once the primary afferent, dorsal horn neuron, and
motor neuron circuitry synaptic connections are complete. Reflex
responses can be elicited to both tactile and noxious stimuli. The
presence of these responses is not evidence of pain perception, rather, it is an indication of the degree of maturation of
somatosensory ciruitry and sensitivity to peripheral stimuli. Even
though prevalent in rats at E15 to E-17,50 cutaneous reflex
responses, at birth, are diffuse and exaggerated with lowered
thresholds. Receptive fields of hind limb flexor muscles are large
and disorganized in younger animals, resulting in inappropriate
limb withdrawal responses to noxious stimuli.51 Despite their
importance in early behavior, reflex responses cannot be equated
with a true pain experience, which must involve the cortex and
cognitive brain function. These reflexes are likely to reflect the
absence of the normal inhibitory control that higher brain
structures exert at more mature stages of development to dampen
spinal excitability. These reflex responses decrease as the rat
matures, becoming more restricted to an isolated leg or foot
movement. The fine-tuning of both excitatory and inhibitory
synaptic connections with interneurons within lamina II during
the postnatal period allows a progressive modification and
adaptation of these behaviors. The early presence and maturation
of A fiber terminations witin lamina II during the first weeks of
postnatal life seem to influence considerably the neuronal responses of the dorsal horn, contributing to the high level of
cutaneous reflexes excitability. On the contrary, the activity
triggered in the dorsal horn by C fibers appears gradually during
the postnatal period with a lower percentage of neurons conveying
a nocicepive signal during the first weeks of life compared with
those in an adult.52
Balance Between Excitation and Inhibition

The dorsal horn cells of newborn animals are more excitable than
those of adults. A painful cutaneous stimulation at an early
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postnatal age (P03) frequently results in action potentials with a
prolonged activity of 30 to 90 sec beyond the end of the stimulus.
This effect diminishes with age in both amplitude and duration.53
The newborn dorsal horn cells high-response capacity demonstrates the immaturity of excitatory and inhibitory synaptic
transmission in the spinal cord of the newborn. The elimination
of some synapses (such as the A fiber input to lamina II) and the
strengthening of others (such as C fiber inputs) alter the balance
of postnatal transmission. This process may be linked to the
number of silent synapses which express only NMDA receptors
in neonatal superficial dorsal horn neurons.54 Repeated afferent
stimulation may convert silent synapses to functional ones by
rapid insertion of AMPA receptors. The parallel development of
inhibitory, organized synapses is crucial to the development of a
functional nociceptive system. The subtle equilibrium between
excitation and inhibition within the CNS determines the functionality of the system. The presence of inhibitory synpases can
determine the impact of adjacent excitatory synapses only if they
are localized on the same dentritic branch and are activated
simultaneously.55 As with the excitatory synapses, the inhibitory
GABA and glycinergic synapses are regulated in the dorsal horn
and go through important functional modifications during the
postnatal period.
The Development of Descending

Pain Pathways
Descending activity from the brainstem is another factor contributing to the balance between excitation and inhibition in spinal
nociceptive circuits. Brainstem fibers containing serotonin
innervate the PAG at birth, yet the pattern and the density of adult
terminals are not achieved in the lumbar spine until P21. This
observation explains why stimulus-produced analgesia from the
PAG is not effective until P21 in rats. The dorsolateral funiculus of
the spinal cord, which transmits the descending inhibitory
pathways, grows down the spinal cord early in fetal life but does
not extend collateral branches into the dorsal horn until P10.56 The
lack of descending inhibition in the neonatal dorsal horn means
that there is no endogenous analgesic system to dampen noxious
inputs as they enter the CNS, and their effects may, therefore, be
more profound than in the adult. The late functional maturation
of this system is due to either low serotonin levels in the synaptic
terminals or a delay in receptor maturation in the early postnatal
period. Although the low levels of serotonin may limit synaptic
transmission, they may still influence synaptic maturation, as the
exposure to serotonin causes rapid insertion of AMPA receptors
into the synaptic membrane of neonatal substantia gelatinosa
neurons. The descending noradrenergic inhibitory system seems
to mature earlier because the administration of a 2-adrenergic
receptor agonist produces analgesia following nociceptive mechanical or thermal stimuli in the newborn rat. Also, the intrathecal
administration of dexmedetomidine, a potent and selective 2adrenergic agonist, reverses inflammatory hyperalgesia at all
postnatal ages at doses that have no effect on baseline sensory
processing and that are lower than those needed in the adult.57
Early and Late Consequences of Pain

Nociceptive activity is not a normal physiologic event during the
neonatal period. After tissue injury, a strong and prolonged
67
activation of C fibers is observed. Nociceptive C fibers can be

sensitized by inflammatory chemicals even before birth. As soon
as the stimulation of peripheral C fibers begins to trigger cells of
the dorsal horn, a repeated stimulus creates a wind-up NMDA
receptordependent phenomenon.58 Hyperalgesia can be triggered
in the young animal from age P3 or even before, although its
magnitude may not be as great as in adults.59 The postnatal maturation of hyperalgesia may follow the development of signaling
by substance P, which has been shown to be important for this
form of central sensitization.
Whereas many of the nervous system responses to local tissue
damage resolve after the injury is healed, tissue damage during a
critical period in newborn rodents can cause prolonged alterations
in somatosensory function that persist into adult life. The
consequences of neonatal injury depend on the type of injury and
the modality of sensation.6062 The early-onset inflammatory
hyperalgesia and the later-onset basal hypoalgesia extend into
adulthood and appear only if the original inflammatory stimulus
is applied during the first 10 days of life. Although it is not known
how these long-term changes in pain signaling develop, potential
mechanisms include alterations in synaptic connectivity and
signaling in postnatal nociceptive pathways as well as changes in
the balance of inhibition versus excitation. In addition, tissue
injury in the newborn triggers the secretion of higher concentrations of growth factors, which may have various effects on the
development of peripheral nociceptors.63 The permanent expansion of the dorsal horn receptor field in the neonatal injured area
is evidence for the failed development of a directed inhibitory
system within the nociceptive circuitry.
SUMMARY
This chapter has concentrated on nociceptive processing and its
maturation at the peripheral and spinal level, the importance of
functional higher brain centers in the pain experience on the
early and late consequences of pain, and issues related to the
development of chronic pain. Neuroanatomic evidence demonstrates that pain and its perception are complex entities involving
multiple ascending pathways, different functional projections to
the thalamic area, a cortical circuit, and a crucial excitatory and
inhibitory synaptic transmission system. Clinical and laboratory
research has elucidated many of the physiologic, pharmacologic,
and neurobiologic/immune complex mechanisms involved in the
immature pain pathways. Research has also shown how the
developing pain circuitry depends on nonnoxious sensory activity
in the healthy newborn and how early injury can permanently
alter pain processing. The demonstration of interactions between
the nervous and the immune systems and the discovery of the
synthesis and release of immune chemical messengers secondary
to a noxious stimulus have been crucial in our understanding of
the pathophysiology of the nervous and nocioceptive systems.
These messengers are involved in the regulation of the activity of
CNS neurons (mainly those in the dorsal horn of the spinal cord)
in certain pathologic situations leading to inflammatory and
chronic neuropathic pain. Questions related to the affective and
cognitive aspects of the pain experience among different chronic
pain conditions in later ages still remain to be more extensively
explored. These studies should not only help us to better prevent
and assess pain but also contribute to rational design of analgesic
regimes that are specific to young infants.
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Neurotransmitters and Anesthesia
Thomas Engelhardt and William Wisden
INTRODUCTION
The conduct of general anesthesia has become safer. The incidence
of anesthesia-related mortality has decreased dramatically since
the 1970s and is now estimated at much less than 1 in 10,000.
However, the progress in safety has not been matched by the
understanding of the molecular basis of general anesthesia.
Despite considerable research efforts, the exact mechanisms of
general anesthesia remain to be elucidated. This chapter reviews
central nervous system (CNS) neurotransmitters and their role in
sleep-awake states and considers aspects of neurodevelopment
relevant to anesthesia.
ANESTHETICS AND THEIR

INTERACTION WITH CNS
NEUROTRANSMITTERS
The commonly used general anesthetic agents include both
inhalational and intravenous agents. The inhalational agents
include both gases such as nitrous oxide (N2O) and xenon as well
as the vapors of volatile liquids such as halothane, isoflurane,
sevoflurane, or desflurane. The intravenous agents include the
barbiturates (thiopental and methohexital), propofol, ketamine,
etomidate, and benzodiazepines. Although the clinically relevant
anesthetic agents are often small, highly lipid-soluble molecules,
the previously held hypothesis that these agents act by dissolving
within the membrane of nerve cells inducing structural changes of
the lipid bilayer has now been discarded.15 Current thinking
hypothesizes that anesthetic agents amplify and modulate neurotransmitter signals within the CNS. In addition, some anesthetic
agents (the volatile or inhalational agents) directly open ion
channels such as two pore domain K+ channels or, in the case of
propofol, inhibit cyclic nucleotidegated (HCN) channels.5
Although these latter effects on ion channels are important
anesthetic targets, this chapter focuses on how anesthetic agents
interact directly with neurotransmitter receptors. Because of the
huge diversity in molecular structure of the different classes of
anesthetic agents, it is not surprising that these drugs interact with
a variety of protein targets (i.e., receptors and ion channels).
Therefore, the concurrent use of anesthetic agents, analgesic
agents, and neuromuscular blocking agents results in the simultaneous modulation of multiple receptors and ion channels systems
during general anesthesia.
Neurotransmitters are small molecules that relay, amplify, and
modulate signals between neurons and other cells. In addition,
as discussed in Chapter 3, these agents may also control or regulate
5
C H A P T E R
the development of the CNS. Quanta of neurotransmitters

are released after membrane depolarization via an exocytotic
process. Following diffusion across the synaptic cleft and binding
to a transmembrane receptor, binding to the specific ligandreceptor complex then determines the subsequent effect. The
majority of neurotransmitters are removed from the synaptic
cleft via re-uptake processes, degradation, or diffusion. There
may also be neuromodulators that change the sensitivity of the
receptor to its (natural) ligand and are not re-absorbed by the
presynaptic neuron. The receptors in biochemistry terms
are proteins on the cell membrane or within the cytoplasm that
bind specific factors (ligands) and initiate a cellular response to
the ligand. They are divided into transmembrane and intracellular
receptors. Only the transmembrane receptors are relevant to
anesthesia. Transmembrane receptors are integral membrane
proteins and are normally composed of two or more subunits. In
general, transmembrane receptors are classified according to their
function (metabotropic or ionotropic) or structure (domains)
(Figure 51).
Ionotropic Receptors
The activity of ionotropic receptors is regulated by changes of
either the membrane potential (voltage-gated) or the ligands
(ligand-gated). Voltage-gated ion channels are normally closed at
resting membrane potential, and a change in the membrane potential of the cell causes conformational changes that result in the
opening of the pore and the transmembrane movement of ions. A
transitional change leads to an inactivated state. Ligand-gated ion
channels are primary targets for general anesthetic agents. These
ligand-gated ion channels contain an intrinsic ion channel and an
extracellular binding site(s) for the ligand(s). Ligand binding
causes a conformational change with an increase of opening
probability of the ion pore. Ligand-gated ion channels fall into two
families: (1) the Cys loop family, which includes the nicotinic,
serotonin (5-HT3), gamma-aminobutyric acid A (GABAA), and
glycine receptors; and (2) the glutamate-gated ionotropic receptors, which comprise the -amino-3-hydroxy-5-methylisoxazole4-propionic acid (AMPA), kainite, and N-methyl-D-aspartic acid
(NMDA) receptor subtypes. The Cys loop family is characterized
by a pentameric arrangement of subunits and can be subdivided
into excitatory (nicotinic, 5-HT3) and inhibitory (GABAA, glycine)
ligand-gated channels. The ionotropic glutamate receptors are
encoded from an entirely different gene family that encodes subunits with a different membrane topology from those of the Cys
loop family. Ionotropic glutamate receptors assemble as heteromeric tetramers.
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Figure 5-1. Classification of transmembrane

receptors. Only receptors potentially relevant
to anesthesia are displayed. GABAB =
gamma-aminobutyric acid B; 5-HT1A =
5-hydroxytryptamine; NMDA = N-methylD-aspartic acid.
Metabotropic Receptors
Metabotropic receptors constitute the largest family of cell-surface
receptors and are a subclass of transmembrane receptors that
amplify their signal through G proteins linked to the receptor.
Metabotropic receptors have seven membrane-spanning domains
and the signaling unit is referred to as G proteinlinked receptors
(GPLRs). G proteins comprise three subunits, , and and
are molecular switches that transduce a signal to an amplifying
enzyme whose activity produces a second messenger, resulting in
the activation or inhibition of an enzyme or ion channel. Agonists
bind to GPLRs that activate G proteins through the release of
guanosine 5 diphosphate (GDP) bound to the subunit initiating
the G protein cycle (Figure 52).
All subunits transduce signals and regulate a range of second
messenger production or destruction. G Proteins are traditionally
classified according to their subunits: s, i, q, and 12/13. In
general, Gs stimulates adenylate cyclase activity and regulates
calcium ion channels whereas Gi inhibits adenylate cyclase, activates cyclic guanosine monophosphate (cGMP)specific phosphodiesterases, and regulates potassium and calcium channels.
The family of Gq G proteins activates phospholipase C (PLC-),
and the function of G12/13 is likely to regulate chloride ion
channels. Individual receptors can activate more than one G protein, and variation in different stages of G protein activation and
deactivation can affect the regulation of intracellular signaling.
The guanosine triphosphate (GTP) hydrolysis and binding properties vary for individual G subunits, and accessory and regulatory proteins affect these processes. It is likely that anesthetic
agents interfere with GPLR and dependent enzyme systems;
however, evidence so far has been inconclusive.
ROLE OF NEUROTRANSMITTERS
IN SLEEP-AWAKE STATES
The principal mechanisms of natural sleep and the neurotransmitters involved are helpful in furthering our understanding of
the mechanisms of general anesthetic agents.5,6 The natural states
of consciousness include wakefulness and sleep. The latter is
commonly divided into two phases: rapid eye movement (REM)
sleep, often associated with high level of brain activity and vivid
dreaming, and nonrapid eye movement (NREM) sleep, with a
reduced level of brain activity.7,8 Although not universally accepted, it is likely that anesthetic agents interfere with the neuronal
circuitry underlying these processes.5
Wakefulness
The ascending reticular activating system projects from the
midbrain to the thalamus, hypothalamus, and neocortex. The
cholinergic neurons that project to the thalamus originate from
the pedunculopontine and laterodorsal tegmental nuclei and fire
Figure 5-2. G protein cycle. Following agonist binding and release

of guanosine diphosphate (GDP), subsequent binding of guanosine
triphosphate (GTP) leads to dissociation of the heterotrimer into its
component subunits. The GTPase activity of the subunit determines
the lifetime of this dissociated, now active G protein. Hydrolysis of GTP
back to GDP leads to re-association of the heterotrimer and completion
of the G protein cycle.
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CHAPTER 5
rapidly during wakefulness and REM sleep.9 Other neuronal types
involved in stimulating arousal include noradrenergic, serotinergic, and histaminergic, and/or exinergic neurons. The monoaminergic neurons from the locus ceruleus (LC; norepinephrine),
dorsal raphe nuclei (DRN; serotonin), and tuberomamillary
nucleus (TMN; histamine) fire rapidly during wakefulness, but
only infrequently during sleep. Orexins (also named hypocretins)
are peptide neurotransmitters originating in the perifornical
region of the lateral hypothalamus (PFLH) and are thought to be
involved in the pathogenesis of narcolepsy. The orexinergic
neurons display maximal activity during wakefulness and are only
minimally active during REM and NREM sleep.10,11 These neurotransmitters promote wakefulness and can be considered potential
targets for general anesthetic agents.6,12,13
Central Nervous System: Neurotransmitters and Anesthesia
73
thesis is supported by the reciprocal neuronal activity in POA on

one side and the LC, DRN, TMN, and PFLH on the other side18
(Figure 54).
CURRENT AND POTENTIAL TARGETS

FOR GENERAL ANESTHESIA
Ligand-activated receptor systems are important targets for general anesthetic agents. Their functional classification has been
previously discussed in the section on Ionotropic and Metabotropic
Receptors in this chapter. It is likely that only a very few subtypes
might be sensitive to general anesthetic agents when used at clinical
concentrations. The principal neurotransmitter systems relevant
to anesthesia are the inhibitory GABA and the excitatory glutamate
systems. Other receptor types may make a smaller contribution.12
REM and NREM Sleep

REM sleep time depends on the maturity of the nervous system.7
REM sleep time declines rapidly in early childhood from 50% at
birth to approximately 20% after 6 years.14,15 Characteristics of REM
sleep include irregular heart rate and breathing pattern as well as
muscle atonia. Transsection and pharmacologic studies on animals
suggest that the pons and caudal midbrain are fundamental for
REM activity, with cholinergic neurons acting as promoters and
monoaminergic neurons as suppressors of REM sleep.8 The
switching between NREM and REM sleep is poorly understood,
but may be regulated by REM-on/REM-off areas in the mesopontine tegmentum (Figure 53). Both areas contain inhibitory
GABAergic neurons heavily innervating each other. The REM-on
side also contains excitatory glutamatergic neurons projecting into
the basal forebrain, medulla, and spinal cord, which regulates electroencephalographic components and muscle atonia, respectively.16
The existence of NREM sleeppromoting structures in the
rostral hypothalamus as opposed to wake-promoting systems in
the posterior hypothalamus was postulated almost 80 years ago.17
Sleep-active neurons are located in several regions of the preoptic
area (POA) and are concentrated in the ventrolateral POA
(vlPOA) and the median preoptic nucleus (MnPN).18 Anatomic,
electrophysiologic, and immunohistochemical (c-FOS; surrogate
marker of neuronal activity) evidence supports a role of these
neurons in promoting NREM sleep onset and maintenance by
inhibiting and modulating multiple arousal systems.19 This hypo-
Figure 5-3. Reciprocal interaction model of

rapid eye movement (REM) sleep. 1: Positive
feedback of the REM-on neuronal population
results in gradual increased excitation of
REM-off neurons. 2: The REM-off neurons
inhibit the REM-on neurons, terminating
REM sleep (3). 4: The REM-off neurons are
self-inhibiting, terminating inhibition of
REM-on neurons and completing the cycle.
Cys Loop Receptors (GABAA,

Glycine, Nicotinic, and 5-HT3)
GABA is the major inhibitory neurotransmitter and is involved in
all aspects of brain function including the regulation of wakefulness, anxiety, memory, and motor output. GABAA receptors are
hetero-oligomeric chloride channels. The subunits are selected
from four principle families (, , , and ) (Figure 55), although
others have been identified. The receptors are important targets
for many classes of drugs in clinical use including anesthetic
agents. The most common mammalian CNS GABAA receptor
(60%) comprises two 1, two 2, and a single 2 subunit. Each
GABAA receptor isoform displays a distinct distribution in the
brain, suggesting specific physiologic functions.20,21
Binding of GABA to the GABAA receptor complex leads to the
movement of chloride ions into the postsynaptic neuron, resulting
in hyperpolarization of the cell membrane and inhibition.22 In the
developing nervous system, the Cl gradient is reversed, being
higher on the inside than on the outside of the neurons. Thus, in
young neurons (probably fetal stage in humans), GABAA receptors
produce depolarizing actions by opening of voltage-gated Ca2+
channels and excitation. GABAA receptors produce fast (phasic)
inhibition at central synapses and tonic inhibition (from ambient
GABA) at extrasynaptic sites.23 The 2 type receptors are
localized at synapses, and the 4 and 6 receptors are
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Figure 5-4. Simplified sleep switch. Reciprocal relationship between sleep-promoting area (POA) and
arousal systems (locus ceruleus [LC], dorsal raphe nucleus [DRN], tuberomamillary nucleus [TMN],
and perifornical region of the lateral hypothalamus [PFLH]). The flip-flop mechanisms prevent intermediate states. The cholinergic system contributes to arousal as well as rapid eye movement (REM) sleep.
GABA = gamma-aminobutyric acid; 5-HT = serotonin; IL-1b = interleukin-1; LDT = laterodorsal
tegmental nucleus; MnPN = median preoptic nucleus; NE = norepinephrine; PGD2 = prostaglandin D2;
PPT = pedunculopontine tegmental nucleus; VLPO = ventrolateral preoptic hypothalamic area.
Adapted from reference 19 and modified after references 18 and 7.
Figure 5-5. A: Subunit arrangement in 2 (synaptic) and (extrasynaptic) containing gamma-aminobutyric acid A (GABAA) receptors. B:
Schematic of an individual subunit topology. The pore-lining domain,
TM2, is shown in blue. Pink triangles represent GABA. The blue circle
represents a benzodiazepine ligand. C = cysteine; TM = transmembrane
domain. Reproduced with permission from reference 22.
extrasynaptic.23 The functional GABAA receptor system can be

probed with selective drugs.24 Drug specificity in vivo was established using knockin mice with point mutations in the GABAA
receptor subunit genes and from gene knockouts.24 Zolpidem acts
preferentially at 12 receptors (producing sedation and hypnosis); benzodiazepines act on 12/32 (producing sedation and
hypnosis), 22/32 (producing anxyliolysis and myorelaxation),
32 (producing anxyiolysis and myorelaxation), and 52
receptors (reducing memory). The latter receptor subtype is
mainly expressed in the hippocampus. Propofol and etomidate act
largely at 2- and 3-containing GABAA receptors.24 Point mutant
mice show that 2- and 3-containing GABAA receptors are largely responsible for the anesthetic actions of these two intravenous
anesthetic agents.
Other GABAA drugs are potent sleep inducers and act mostly
at extrasynaptic GABAA receptors. The GABAmimetic agent
gaboxodol exerts most of its effects (sleep induction) via 4
receptors.25 The extrasynaptic receptors remain a potentially
important target for new drug development. Steroids, including
steroid anesthetics, activate and modulate many GABAA receptor
subtypes.26 Recombinant GABAA receptors are activated potently
by inhalational anesthetic agents,27 and GABAA receptor modulation provides some component of the inhalational-induced
anesthesia. However, the in vivo contribution of these receptors
to the actions of inhalational anesthetic agents requires more
clarification.
GABAC receptors appear to represent a relatively simple form
of ligand-gated chloride channel made up of subunits. Many
argue that they are really a specialized GABAA receptor subtype
and that they should be reclassified as this. GABAC receptors are
insensitive to bicuculline and baclofen and are most prominent in
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the retina. They are not modulated by barbiturates or benzodiazepines. The superior colliculi also use GABAC receptors at some
synapses.
Together with GABA, glycine is a major inhibitory neurotransmitter in the spinal cord and brainstem. Very closely related to the
GABAA receptors, glycine receptors (GlyRs) are hetero-oligomeric
ligand-gated chloride channels and consist of three and two
subunits. Four subunit genes (14) are expressed, and coexpression of the subunits is essential for targeting the receptor
to the synapse. Strychnine is a major GlyR antagonist, whereas alanine and taurine are full or partial agonists. Glycine and GABA
are coreleased from interneuron terminals in the spinal cord and
the brainstem.2831 GlyRs may mediate some of the actions of
volatile anesthetic agents in the spinal cord and brainstem.5 Similar
to GABAA receptors, GlyRs undergo developmental changes in
their expression. As with GABAA receptors, the activation of GlyRs
in immature neurons induces the outflow of chloride ions,
membrane depolarization, neuronal excitation, calcium influx,
and transmitter release. This is in contrast to the inhibitory effects
these receptors have on mature neurons.32 The effect of anesthetic
agents on the GlyRs in the developing human brain is unclear.
The neurotransmitter acetylcholine exerts its pre- and postsynaptic effects on muscarinic and nicotinic receptors. Neuronal
nicotinic acetylcholine receptors (nAChRs) are principally ligandoperated cation channels (calcium, sodium, and potassium) and
modulate the activity of various transmitter systems. They are
widely distributed in various regions of the brain potentially
relevant to general anesthesia. In the brain, the pentameric
channels are formed from (210) and (24) subunits,
whereas the , , and subunits are present in muscle. The
subunit contains the acetylcholine binding site. In addition to the
acetylcholine binding site, nAChRs have associated modulatory
sites for neurosteroids and acetylcholine esterase inhibitors. The
predominant neuronal nAChRs are composed of the subunits
(4)2(2)3 and (7)5. Both receptor subtypes can be pre- or
postsynaptic. The 7 receptors are fast-inactivating nonselective
cation channels with high Ca2+ permeability. The (4)2(2)3
receptors are mainly permeable to Na+ and K+. The nAChRs may
be involved in Parkinson and Alzheimer diseases and the
pathophysiology of schizophrenia. The main interest of nAChRs
for the anesthesiologist is the potential as a target for analgesic
agents and neuropathic pain research. However, a narrow therapeutic window between analgesic efficacy and toxicity has hindered the development of nicotinic agonists as novel analgesics.33
An exciting new development is the potential neuroprotective
effect of nicotine following spinal cord injury.34
Very closely related to the neuronal nicotinic receptors,
the 5-HT3s are ligand-gated cation channels and targets for
commonly used antiemetics in anesthesia.35 The receptors are
expressed throughout the brain, especially on GABAergic interneurons.
Glutamate-Gated Ionotropic Receptors:

AMPA, Kainate, and NMDA
The glutamate receptor family mediates fast excitatory neurotransmission at the majority of synapses in mammals. Glutamate
receptors are widespread in the brain and are divided based on
their pharmacology into three major subtypes: NMDA, AMPA,
and kainate. AMPA receptors are responsible for most fast excitatory synaptic currents at glutamatergic synapses. AMPA recep-
75
tors are permeable only to Na+ and K+, although a specialized

AMPA receptor subtype also alters Ca2+ permeability. NMDA
receptors carry slower integrative excitatory currents and gate
calcium ions in addition to sodium and potassium ions. The
primary target for general anesthetic agents is the NMDA subtype,
which is a heterotetramer consisting of an NR1 subunit combined
with one or more NR2 (AD) subunits and, in some subtypes, an
NR3 subunit. The NR1 subunit is obligatory. Two ligand recognition sites must be occupied for channel opening; one for
glutamate and one for glycine. The channel is blocked by Mg2+
ions. The Mg2+ block is removed by membrane depolarization.
This property, together with the selective Ca2+ permeability of the
channel, means that NMDA receptors can, in some contexts,
function as coincidence detectors used in the formation of
memories. However, the slow integrative currents produced by
NMDA receptor activation is also used in other types of circuits
(e.g., those producing rhythm in breathing). Most inhalational
anesthetic agents variably inhibit NMDA receptors; ketamine is
an NMDA receptor antagonist, and the gases nitrous oxide and
xenon inhibit NMDA receptor currents.5
The intracellular C termini of the NMDA receptor subunits
couples the receptor to a huge complex of proteins termed the
postsynaptic density (PSD), a structure unique to glutamaterigic
synapses. The PSD comprises thousands of proteins, most of
whose function is uncharacterized. Nevertheless, some proteins
have been characterized. For example, the neuronal form of nitric
oxide synthase (nNOS or type I NOS) is coupled to the NMDA
receptor via the PSD protein 95 (PSD 95), which allows tight
regulation of calcium influx and regulation of type I NOS activity.36 The hippocampus is particularly rich in NMDA synapses
and appears to play a central role in learning and memory.
Plasticity within the hippocampus is mediated in part through
changes in synaptic strength and revealed by long-term potentiation and long-term depression. NMDA receptors are crucial for
inducing these plastic changes, and blocking these receptors
reduces plasticity and impairs learning. Intravenous and volatile
anesthetic agents appear to impair long-term potentiation and
enhance long-term depression development.37 One of the downstream effectors of the NMDA receptor is the second messenger
cGMP. General anesthetic agents interact with the receptor, cGMP
formation, and degradation (Figure 56).
cGMP has long been recognized as a secondary messenger, but
its importance in signal transduction was not been recognised
until the identification of the first messenger, now identified as
nitric oxide (NO). Low intracellular concentrations of cGMP
when compared with cyclic adenosine monophosphate (cAMP)
further challenge investigations into its biologic role. cGMP is
formed from GTP through the action of the enzyme guanylyl
cyclase (GC), which exists in either soluble or particulate forms,
with the soluble form being located within the cytosol and the
particulate form within the cell membrane. The particulate form
of GCs is activated through cell membranebound receptors such
as the natriuretic peptide receptors or intestinal peptidebinding
receptors. Binding of the ligand at the extracellular domain of
these receptors results in the production of intracellular cGMP.
Soluble GC is the most abundant form in the CNS. It exists as a
heterodimer consisting of and subunits and is activated by the
interaction with NO resulting in an up to 400-fold activation.
Clinically used activators of soluble GC are described as NO
donors and include pharmacologic agents such as glycerol trinitrate (nitroglycerin), sodium nitroprusside, or S-nitrosothiol
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Figure 5-6. Simplified pathways of formation and degradation of cyclic guanosine

3,5- monophosphate (cGMP) within the
brain. Anesthetic agents have been shown
to interact with the process of the formation of cGMP, namely nitric oxide synthase
(NOS-1) and N-methyl-D-aspartic acid
(NMDA) receptors (NMDAr). GC-s =
soluble guanylyl cyclase; NO = nitric oxide;
PDE = phosphodiesterase; PSD95 =
postsynaptic density protein 95. Adapted
from reference 38.
agents. Methylene blue is a direct inhibitor of soluble GC but has

also been shown to inhibit NOS directly.
The release of cGMP has effects at three levels by affecting
cGMP kinases (protein kinase G [PKG]), cGMP-regulated ion
channels, and phosphodiesterase (PDE) activity. The duration of
cyclic nucleotide signaling is dependent on the rate of cyclic nucleotide formation and on its rate of breakdown. The cyclic nucleotides, cAMP and cGMP, are hydrolyzed by PDE, of which 11
isoforms are currently described. Clinically relevant human PDE
isoforms and their distributions are summarized in Table 51.
Apart from the selective PDE inhibitors for PDE3 (milrinone),
PDE 4, (rolipram) and PDE 5 (sildenafil), there are several wellknown nonisoform specific inhibitors such as caffeine, theophylline, and pentoxifylline. PDE isoforms 1, 2, and 3 utilize both
cyclic nucleotides as secondary messengers, whereas PDE5 and 6
are specific for cGMP. PDE5 is cGMP-specific and is a wellestablished and important regulator of cGMP function. The
activity of the PDE enzymes is regulated by cAMP and cGMP and
is subject to feedback activation and inhibition.
The AMPA receptor subtype is a hetero-oligomer formed from
combinations of GluR14 subunits. When glutamate binds to the
receptor, the channels open to gate the movement of Na+ and K+
TABLE 5-1. Human Phosphodiesterase Characteristics,
Tissue Distribution, and Selective Inhibitors
Family
Main Characteristics
Primary Tissue Distribution
PDE 1
Calcium/calmodulinstimulated
cGMP-stimulated
cGMP-inhibited,
cAMP-selective
cAMP-specific,
cGMP-insensitive
cGMP-specific
cGMP-specific
Heart, brain, lung, smooth

muscle
Adrenal gland, heart, lung
Heart, lung, liver, platelets
PDE 2
PDE 3
PDE 4
PDE 5
PDE 6
Sertoli cells, kidney, brain

Lung, brain, smooth muscle
Photoreceptors
cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine

monophosphate.
ions. Nearly all AMPA receptors contain GluR2 subunits. AMPA

receptors that do not contain GluR2 are permeable to Ca2+ in
addition to Na+ and K+. These specialized Ca2+ permeable AMPA
receptors are mostly found on GABAergic interneurons. AMPA
receptors show little anesthetic sensitivity.5
The kainate receptor subtype consists of hetero-oligomers
comprising the GluR5-7 and KA1 and KA2 subunits. The relevance of the kainate receptor complex for general anesthesia is
unclear, but there is evidence for a presynaptic location in the
hippocampus. Antagonists of kainate, NMDA, and AMPA receptors are thought to be of therapeutic benefit in stroke, head
injuries, epilepsy, and pain.
Metabotropic Receptors
2-Adrenoreceptors are members of the G proteincoupled family
of membrane receptors and mediate the actions of the endogenous
catecholamines, epinephrine, and norepinephrine. Their distribution is widespread, and they are located at pre- and postsynaptic
sites. Three 2-adrenoceptor proteins have been identified,
designated 2a, 2b, and 2c, with the 2a being responsible for most
of the 2-adrenoceptormediated actions. The 2 adrenoreceptor
agonists exert their effects via coupled Gi proteins by inhibiting
adenylyl cyclase and modifying K+/Ca2+ channel activity. 2Adrenoreceptor agonists such as clonidine and dexmedetomidine
are used for the treatment of hypertension, sedation, and analgesia.
There are currently no in vitro selective agonists for the 2adrenoceptor subtypes.39
Serotonin (5-hydroxytryptamine [5-HT]) is a major neurotransmitter in the CNS, being involved in wakefulness (see Role of
Neurotransmitters in Sleep-Awake States). 5-HT is synthesized
from L-Tryptophan in serotonergic neurons and enterochromaffin
cells. To date, 13 human subtypes of the serotonin receptor have
been identified and are subdivided into seven different classes (5HT1 to 5-HT7). Serotonin transduces its effects via G protein
coupled receptors, with 5-HT1 utilizing Gi-mediated adenylyl
cyclase modulation and 5-HT2 signaling via Gq and phospholipase (PLC-). The 5-HT1A receptors are involved in depression
and anxiety, and selective serotonin re-uptake inhibitors (SSRIs)
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77
are widely used, whereas the 5-HT1B/D receptors have emerged as

targets for migraine treatment (sumatriptan). 5-HT2 receptors may
present future targets for treatment of schizophrenia and obesity,
whereas 5-HT3 receptors are targets for the control of perioperative nausea and vomiting.
DEVELOPMENTAL CONSIDERATIONS
The effects of general anesthesia on neuronal development in
humans are controversial. Some rodent animal studies have
suggested that prolonged exposure to anesthetic agents leads to
widespread apoptotic neurodegeneration in the developing brain,
deficits in hippocampal synaptic function, and persistent memory
and learning impairments.40,41 These studies need to be balanced
against evidence that withholding anesthesia during the perioperative period increases the incidence of intraoperative and
postoperative complications.42,43 The brain growth, synaptic differentiation, and cellular proliferation period occurs at different
times in different species. In humans, it is both a pre- and a
postnatal phenomenon (from the 6th mo of gestation to 24 mo
after birth), whereas in rats, mice, and other primates, it is mainly
a postnatal phenomenon, thereby suggesting that application of
the rodent model to human CNS development may not be appropriate.44
Neuronal cell death occurs via two2 mechanisms: apoptosis
and necrosis. Apoptosis, programmed cell death or cellular suicide,
is a kinetic event that can be triggered by a variety of stimuli such
as cytokines, hormones, viruses, and toxic neurologic insults.
Necrosis, in contrast to apoptosis, can affect a number of contiguous cells and trigger an inflammatory reaction and/or death of
cellular structures in the surrounding tissue. Necrosis, which
typically occurs as a result of neuronal injury or cytotoxic exposure, is a pathologic or an accidental mode of cellular death. It is
characterized by irreversible swelling of the cytoplasm and the
mitochondria (Table 52).
The mechanism of apoptosis is a highly complex network of
energy-dependent cascades. Characteristic morphologic features
that define apoptosis are dependent on caspase activation and
cleavage of specific cellular proteins or the liberation of death
provoking substrates within the cell. Apoptosis is, therefore,
considered a caspase-mediated form of cell death.45 There are
two main pathways of caspase-mediated cell death: the extrinsic
or death receptormediated pathway and the intrinsic or
mitochondria-dependent pathway.46 Apoptosis is induced in the
TABLE 5-2. Comparison of Contrasting Morphologic
Features of Apoptosis and Necrosis
Apoptosis
Necrosis
Chromatin condensation
Cell shrinkage
Preservation of organelles
and cell membranes
Rapid engulfment by
neighbouring cells
preventing pericellular
inflammation
Maintenance of integrity
Nuclear swelling
Cell swelling
Disruption of organelles
Rupture of cell membrane and
release of cellular contents
Inflammatory response
Ingested by phagocytes
Figure 5-7. Simplified illustration of the extrinsic apoptotic pathway.

The ligation or binding of CD95L (FasL) to its receptor CD95 (Fas)
leads to the recruitment of an adapter protein (Fas-associated death
domain [FADD]). The FADD recruits the procaspase-8, a deathinducing signaling complex (DISC). A high local concentration of
active caspase 8 activates the main downstream effector, caspase 3.
Caspase 3 triggers the characteristic cellular changes associated with
apoptosis. Courtesy of Dr. Morgan Blaylock.
extrinsic pathway through specialized death surface receptors,

whereas in the intrinsic pathway, apoptosis is induced from within
the cell, mainly through mitochondrial activation in response to
extracellular cues and internal insults such as DNA damage. The
extrinsic pathway plays a fundamental role in the maintenance of
tissue homeostasis, especially in the immune system. The extrinsic
signaling pathway initiates apoptosis by triggering a transmembrane receptormediated interaction (Figure 57). The
intrinsic apoptosis pathway is induced from within the cell, mainly
through activation of mitochondria in response to extracellular
stimuli and internal insults such as DNA damage.47,48
One of the first processes involved in the mitochondrial apoptotic pathway is increased permeability of the outer mitochondrial membrane releasing mitochondrial molecules, most
importantly cytochrome C, into the cytoplasm. The primary mechanism of the increased permeability of the outer mitochondrial
membrane during apoptosis involves members of the Bcl-2 family
of proteins such as Bax and Bid. Once released, cytochrome C binds
to an adaptor molecule termed Apaf-1, which recruits procaspase9, then designated the apoptosome. This is required for the cleavage
and activation of caspase-3, the main effector caspase, by caspase9 (Figure 58). It remains to be determined whether general
anesthesia demonstrates a preference to a particular pathway,
which may then influence the choice of general anesthetic agents.
FUTURE DEVELOPMENTS
The better understanding of the physiology of sleep and wakefulness, neurotransmitters, and neuronal networks has led to new
insights into possible targets of general anesthesia.5 Further
research will undoubtedly lead to the development of anesthetic
agents targeting specific neurotransmitter systems and potentially
allow real-time monitoring of its effects. If the current concern
regarding the impact of general anesthesia on neurodevelopment
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Figure 5-8. Simplified illustration of the intrinsic apoptotic pathway. Cytochrome C is

released from the mitochondria as a result of
Bax or of caspase 2 activation. The released
cytochrome C binds to an adapter molecule
termed Apaf-1, which via oligomerization of
procaspase 9 forms the apoptosome, ultimately
leading to caspase 3 activation and apoptosis.
Courtesy of Dr. Morgan Blaylock.
is verified, it remains to be seen whether this will change the current standard practice in pediatric anesthesiology. The integration
and translation of emerging evidence in basic neuroscience
research into clinical studies will guarantee an exciting future for
basic research in the field of pediatric anesthesiology.
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Anatomy and Physiology
Bruno Bissonnette
6
C H A P T E R
INTRODUCTION
It is important for anesthesiologists to understand the anatomic
and psychological differences between an adult and a newborn,
an infant, and a growing child.1 It is even more important when
the brain is involved. Challenges in neuroanesthesia are most often
the result of the lack of knowledge of the disturbances caused by
a pathologic process affecting the central nervous system (CNS).
These alterations can be significant in the anesthesia preparation
and perioperative management.
The CNS does not reach maturity until the end of the first year
of life. Many pathologic processes result from abnormal neuroembryologic development, which may affect the physiology of the
brain as a whole. The understanding of cerebral physiology is an
important part of both neuroanesthesia and intensive care in order
to reduce both the neuromorbidity and the mortality. It is essential
to know the embryology, anatomy, and physiology of this vital
system in order to provide good clinical care of the child with
intracranial or spinal pathology.
NEUROEMBRYOLOGY
AND DEVELOPMENT
The three major processes by which the CNS develops are
(1) neurulation, (2) canalization, and (3) retrogressive differentiation (Table 61).
Neurulation
Early Stage
Neural tube development occurs in the first 56 to 60 days after
fertilization25 (see Table 61). During stage 6 (second wk of development), the nervous system begins to appear with the
TABLE 6-1. Phases and Stages of Neural Development
During Gestation
Phases
Stages
Age, d
Outcome
1. Neurulation
1628
2. Canalization
1320
3052
Brain, spinal cord

through L24
Sacral, coccygeal
segments
Filum terminale
3. Retrogressive 18Birth 46after

differentiation
birth
Modified from reference 6, with permission.
development of the primitive streak and Hensens node. The

notochord extends rostrally from Hensens node (stage 7), and
during the next 48 hours, fusion of the neural folds occurs at the
level of the third or fourth somite (of which there are six or seven
by this stage). The rhombencephalon or hindbrain corresponds
to this area.6 By stage 11, neural folds extend to the level of the
colliculi. The terminal hole is distorted by the primordia of the
thalamus and the corpus striatum. The neuroectoderm is connected to the amniotic cavity through the posterior neuropore at
this stage.
Later Stage
After closure of the anterior neuropore (stage 11), an interval
occurs before differentiation of the telencephalon or forebrain.
Bilateral cerebral vesicles appear in stage 15; they connect later to
the neural tube, thus, creating the foramina of Monro. As these
structures enlarge, areas that will later develop into the lobes of
the brain become identifiable: frontal and parietal areas (stage 17),
occipital area (stage 19), and temporal pole (stage 23). The main
differentiation of the cerebral cortex occurs during the third
trimester.7 However, even at this stage of development, the CNS
bears no resemblance to its final anatomic configuration. As the
brain develops, the external appearance changes. The surface of
the brain begins to develop fissures and sulci. As gyri develop,
most of the surface of the cortex becomes buried. During stage 22,
a layer of neuroblasts derived from pyramidal cells migrates to the
marginal zone, forming the primordium of the cortical gray
matter. During stage 23, the caudate nucleus is divided from the
putamen and globus pallidus by the progressive development of
upper and lower fibers. The early development of the cerebellum
occurs mainly about 1 month after the embryonic period begins
even though, at this stage, the paired cerebellar primordia have
not developed an identifiable pattern. The anlage of the cerebellum may be found when the pontine and cervical flexures begin
to form (stage 13). The cerebral nuclei derived from the diencephalon or midbrain appear at various stages, with the thalamic
structure appearing at stage 15. As the embryo makes the transition to fetus, the CNS is still relatively primitive, with the
development of the brain occurring during the later phases of
gestation and into the postnatal period.
Canalization and Retrogressive

Differentiation
Canalization is the process of development of the neural tube
caudal to that created by neurulation, which forms the lower
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lumbar, sacral, and coccygeal segments. During this process, a
secondary phase of caudal neural tube development occurs with a
proliferation of cells in the wall of the neural tube. This leads to an
excess of segments. Retrogressive differentiation is the process by
which these excess segments are remodeled to form the cauda
equina and the filum terminale.8 Eventually, the conus medullaris
is brought to its adult level opposite L12.
Neural Tube Defects and Embryology

Any defect in the development of the CNS may be referred to as a
neural tube defect. These may be classified by the extent of
involvement of the CNS: (1) those involving the brain and spinal
cord, (2) those involving the brain alone, and (3) those involving
the spinal cord alone. If both the brain and the spinal cord fail to
undergo complete neurulation, a condition of total dysraphism or
craniorachischis occurs. Anencephaly results when the brain alone
fails to close. Many abnormalities associated with the later stages
of development of the nervous system may be of significance to
the pediatric neuroanesthetist. Migrational abnormalities are
associated with schizencephaly (clefts in the cerebral wall),
pachygyri (sparse, broad gyri), and polymicrogyria. Lissencephaly
(smooth brain) may result from migrational abnormalities or
earlier defects in development. Agenesis of the corpus callosum is
often associated with migrational abnormalities, although it is not
considered to be a migrational abnormality in itself. Myeloceles
result from caudally defective neurulation. If an enlarged subarachnoid space is present dorsally to the defective cord, the
condition of meningomyelocele is present.
The Ventricular and Cerebrospinal

Fluid Systems
During stage 12, the posterior neuropore closes and, at that point,
the ventricular system is closed. It now consists of the systems
within the prosencephalon, diencephalon, mesencephalon, rhombencephalon (metencephalon, nyencephalon), and central canal
of the spinal cord. The roof of the rhombencephalon thins during
stage 14 and evaginations of the cerebral hemispheres develop
(stage 15). The anlage of the lateral ventricles, third ventricle, and
the foramen of Monro become demarcated, and by stage 20, the
cerebral hemispheres have overlapped the diencephalons, with the
lateral ventricles becoming the largest of the ventricular system.
The foramen of Magendie is created from a perforation in the roof
of the fourth ventricle. About 10 weeks later in the development of
the CNS, the foramina of Luschka develop. As the tectum and
tegmentum enlarge, the aqueduct of Sylvius narrows. The choroid
plexuses differentiate and the brain mass increases, reducing the
volume of the ventricular system. The ventricular system normally
terminates after birth at the level of the obex of the caudal floor of
the fourth ventricle as the spinal canal is obliterated by cellular
proliferation within the spinal cord. In the Arnold-Chiari malformation complex, the embryologic development of the caudal cerebellum is abnormal; the central canal remains enlarged, causing
hydrosyringomyelia.
Cerebrovascular Development
There are five periods of development of the cerebral vasculature.9
Initially (up to stage 8 or 9), there are no arteries or veins. As the
Central Nervous System: Anatomy and Physiology 81
embryo develops, primordial endothelium-lined channels form a

plexiform network from which arteries and veins develop (second
period, stages 1013). Thus, circulation to the CNS is established.
In the third period, direct connections between the arterial side
and the primitive aorta and between the venous side and the
jugular system are formed. The arterial and venous systems are
divided in the fourth period (stage 19) and extend into fetal
development. The fifth and final stage extends into the postnatal
period and is characterized by late histologic changes in the vascular walls as they become adult in form. Most vascular malformations are believed to occur before the arterial walls thicken when
the embryo is about 40 mm long and represents a structural defect
in the primitive arteriolar-capillary network.10
NEUROANATOMY
Gross Anatomy
In order to understand the complex nature of the CNS, it is
essential to have a working knowledge of its anatomy. The
neuroanesthetist should have a clear understanding of the
effects of trauma and other pathologic processes on the function
of the brain and spinal cord in order to introduce management strategies to minimize the disruption to the functioning of
the CNS.
The CNS is protected by the calvarium and vertebral column.
At birth, the calvarium is composed of ossified plates covering the
dura mater, separated by fibrous sutures and the fontanelles
(Figure 61). Two fontanelles are present at birth. The posterior
fontanelle closes at 2 to 3 months, whereas the anterior fontanelle
closes between 10 to 18 months. This fibrous membrane will
normally become ossified during adolescence.11 The single
continuous space within the calvarium and the vertebral column
contains the brain parenchyma (neurons, glial tissue, and
interstitial fluid), cerebrospinal fluid (CSF; 10%), and the cerebral
blood volume (CBV). An increase in the volume of any of these
compartments results in compression and displacement of vital
components of the CNS because of a lack of extensibility (e.g.,
impedance) within the subdural space and low compliance of the
system as a whole. Any process that causes an increase in the
volume of the tissue compartments within the craniospinal system
(tumor growth, hydrocephalus, hemorrhage) may cause a rapid
rise in intracranial pressure (ICP). It is essential to note that the
ability to compensate for an acute rise in ICP even in presence of
an open fontanelle is virtually nonexistent because of the lack of
distensibility of the dura mater. The dura mater offers high resistance to a rapid rise in volume of any of the tissue compartments
enclosed within it.12 Conversely, a slow rise in ICP may allow a
more progressive expansion of the nonfused fontanelles and
separation of the fibrous sutures.13 It is possible to use the anterior
fontanelle to assess the ICP in the infant either by clinical
palpation or with the use of skin transducers.14,15
At birth, the brain weighs about 335 g (1015% of body weight)
and grows rapidly throughout the first year of life, doubling
its weight by 6 months. At 1 year of age, the brain weighs 900 g;
at 2 years, 1000 g; finally reaching its adult weight by 12 years
(12001400 g). At this point it makes up about 2 % of the bodys
weight.11 The intracranial space may be separated into two compartments by a layer of dura mater and the tentorium cerebelli.
These are the supratentorial compartment and the infratentorial
compartment.
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Figure 6-2. Midsagittal nuclear magnetic resonance imaging (MRI)

scan shows the supratentorial (A) and posterior fossa (B) structures.
The white arrow shows the tentoria cerebelli and the straight sinus.
Figure 6-1. Three-dimensional image constructed from a computed

tomography scan of a 7-month-old infant showing the craniofacial
contours. The face is smaller than the cranium. The V shape downward
of the face helps us to understand why the mouth of the infant is small.
The open anterior fontanelle is easily seen. The coronal and metopic
sutures are also visualized.
structures. Obstruction of the anterior cerebral artery may lead to

ischemia. As the pressure within the supratentorial compartment
increases, the diencephalon, cerebral peduncle, oculomotor nerves, posterior communicating artery, and uncus of the temporal
lobe, which sits in the middle cranial fossa adjacent to the incisura,
will herniated, leading to contralateral hemiplegia, ipsilateral large
irregular pupil, and abnormal posturing.
The Infratentorial Compartment

The Supratentorial Compartment
The supratentorial compartment is the larger compartment of the
craniospinal space and includes the anterior and middle cranial
fossae. It contains the cerebral hemispheres, which consist of three
lobes (frontal, parietal, and parieto-occipital) and the diencephalon, which comprises the thalamus, hypothalamus, epithalamus, and subthalamus. The diencephalon (rostral end of the
brainstem) occupies the central part of the supratentorial compartment, the size of which is determined by the calvaria and
tentorium cerebelli (Figure 62). The tentorium is a tent-shaped
dural septum forming a roof over the posterior cranial fossa
between the supratentorial compartment and the cerebellum. It
has an oval opening (tentorial incisura) between the anteromedial
aspects of the right and the left leafs through which the brainstem
passes from the middle to the posterior cranial fossa. The cerebral
hemispheres are separated by the falx cerebri, a sickle-shaped
portion of dura in the longitudinal fissure separating the hemispheres. If there is a primary brain injury severe enough to cause
major hemorrhage or edema, both the inferior edge of the falx
cerebri and the tentoria incisura become important sites of
secondary injury. A differential pressure may occur across the
incisura, leading to herniation of the brainstem and other vital
The infratentorial compartment, often described as the posterior

cranial fossa, comprises the cerebellum, the pons, and the medulla
oblongata. It is delineated by the anterior and posterior occipital
portions of the skull. The consequences of lesions in this area can
be very severe because of compression of many vital structures
such as the reticular activating system, the cardiac and respiratory
control centers, and the cranial nerves. The cerebellum, which is
the largest structure in the infratentorial compartment, is mainly
associated with the regulation of posture, muscle tone, and coordination. Hence, lesions to the cerebellum may lead to an unsteady
gait, hypotonia, and tremor. Increased pressure within the posterior fossa may lead to a pressure differential across the foramen
magnum, the pressure cone phenomenon. This leads to herniation
of the cerebellar tonsils (posteroinferior prolongations of the
cerebellum) through the foramen magnum. This condition is
commonly fatal and may be preceded by relatively subtle clinical
signs.
The Spinal Canal Compartment

The spinal canal compartment contains the spinal cord and the
CSF. The spinal cord is the continuation of the medulla oblongata
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Figure 6-3. Position of the distal end of the spinal cord in relation to the vertebral column and meninges according to
the age of development of the patient. The sacral nerve (S1) root must stretch upward significantly to accommodate the
upward change in position of the spinal cord. A: 24 Weeks. B: Newborn. C: 8-Year-old child. D: Adult.
and is a cylindrical object, flattened slightly anteriorly and

posteriorly where the vascularization occurs. Following retrogressive differentiation at birth, the spinal cord ends at the intervertebral level of L34, reaching the usual adult level of L12 at the
age of 8 (Figure 63). The adult spinal cord is 42 to 45 cm in length
and may actually terminate anywhere between T12 and L3. The
spinal cord occupies approximately 66% of the entire vertebral
space, the rest being occupied by the CSF. The intradural space
extends to the level of S2, and therefore, the segment of L2 to S2
consists of a reservoir of CSF. This may act as a mechanism to
compensate for increases in ICP. However, acute decompression of
the spinal compartment by lumbar puncture may lead to transforaminal herniation, because the spinal compartment is larger
than the posterior fossa and has greater compliance secondary to
the slight distensibility of the spinal dura mater and the compressibility of the venous plexuses.
The venous sinuses of the dura mater are the most important
components of the venous drainage of the brain. They are valveless
channels between the dura mater and the cranial periosteum.
Their endothelium is continuous with that of the veins draining
Vascular Anatomy
Blood flow to the brain is supplied by two sets of paired arteries,
the internal carotid and the vertebral arteries. Each of these four
arteries contributes to the circle of Willis or circulus arteriosus
cerebri formed by the posterior cerebral artery, the posterior
communicating artery, the internal carotid siphon, the anterior
cerebral artery, and the anterior communicating artery (Figure
64). The circle of Willis prevents cerebral ischemia and infarction
in the event of failure of one of these blood supplies to the brain;
however, this protective mechanism is incomplete. In most cases
of occlusion to one of the vessels of the circle of Willis, insufficient
blood is supplied by the collateral routes. Up to 28% of individuals
lack at least one anastigmatic component of the arterial circle, the
most commonly absent part being the anterior communicating
artery.
Figure 6-4. The cerebral arterial circle of Willis and its principal
branches in a 9-month-old child. 1 = Basilar artery; 2 = posterior
cerebral artery; 3 = posterior communicating artery; 4 = middle
cerebral artery; and 5 = anterior cerebral artery. The black arrow
shows the anterior communicating artery.
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into them. There is no muscle in the sinus walls, and hence, tears
to the venous sinuses during surgery may lead to severe hemorrhage. The superior sagittal sinus, situated in the midline, is particularly vulnerable during surgery for correction of craniosynostosis
and during a morcellation craniectomy. Most commonly, this
sinus ends by becoming the right transverse sinus, which runs
above the tentorium cerebelli to the S-shaped sigmoid sinus
laterally. Most of the blood in the venous sinuses of the dura enters
the sigmoid sinuses and then into the venous enlargements or
superior bulbs of the internal jugular veins. The blood of the
inferior petrosal sinuses enters the internal jugular veins directly.
The smallest sinus, the occipital sinus, communicates with the
internal vertebral plexus. The cavernous sinuses situated around
the sella turcica join the inferior petrosal sinuses.
Vascular Anatomy of the Spinal Cord

Blood supply to the spinal cord is separated into anterior and
posterior circulations with no collateral flow between them. Both
circulations arise from the vertebral arteries, supplemented by the
intercostal and lumbar vessels from the descending aorta (Figure
65). A single anterior spinal artery supplies the ventral two thirds
of the spinal cord, which includes the corticospinal tracts and the
motor neurons. The dorsal one third is supplied by paired
posterior spinal arteries that form a plexus on the surface of the
cord.16 The ventral spinal cord is supplied by the anterior spinal
artery and, to a variable extent, by collateral flow from radicular
arteries arising from the aorta. The anterior spinal artery may not
be continuous throughout its length. Its branches run circumferentially on the surface of the spinal cord or penetrate the
parenchyma and divide within the gray matter (sulcal branches).
Radicular arteries arise from intercostal and lumbar arteries on
the left side of the aorta. Of the 62 radicular arteries present during
intrauterine life, only 5 to 8 are still present in the adult. Forty-five
percent of the population has fewer than 5 radicular arteries (12
cervical, 23 thoracic, and 12 lumbar). Hence, there are certain
watershed areas of the cord (upper thoracic and lumbar levels)
that are very vulnerable to ischemia. The great radicular artery of
Adamkiewicz arising from the aorta between the eighth thoracic
and the third lumbar roots provides up to 50% of the entire spinal
cord blood flow and, therefore, is crucial to the blood supply to
the cord. It may be particularly vulnerable to damage during aortic
or spinal surgery and trauma.
Figure 6-5. Arterial blood supply to the spinal cord. 1 = posterior

spinal artery; 2 = radicular artery; and 3 = anterior spinal artery.
Venous drainage from the spinal cord is via two systems, the
internal and the external venous plexuses, which communicate
with each other and with the segmental systemic veins and the
portal system.17 The internal venous plexus surrounds the dura
and the posterior longitudinal ligament in a weavelike pattern of
thin-walled, valveless veins. At each segmental level, the plexus
receives veins from the cord plus a basivertebral vein from the
vertebral body. The occipital and basilar sinuses of the brain
communicate with this system via the foramen magnum. Venous
blood from the internal venous plexus drains into the intervertebral veins passing through the intervertebral and sacral foramina
to the vertebral, intercostal, lumbar, and lateral sacral veins. Veins
draining vertebral bodies form the external venous plexuses,
which join to form the anterior vertebral plexus. Veins draining
the ligamentum flavum form the posterior venous plexus.
NEUROPHYSIOLOGY
Cerebral Metabolism and Ionic Transport
The physiologic structure and function of the human brain
represent one of the most complex structures of all biologic
systems. A young adult has about 100 million neurons each
connected to other neurons through 100 to 1000 synapses. The
two major elements involved in this complex system are the
innumerable synaptic connections and the presence of several
intra- and intercellular messenger, the last ones acting as
interneuronal mediators.18 The energy required to maintain and
regulate these biologic systems is somewhat extensive. After
8 years of age, the human brain weighs only 2% of the total body
mass. However, it consumes more than 20% of all the adenosine
triphosphate (ATP) produced by the entire body. Although
metabolic activity is necessary to sustain the complex interactive
functions of the brain, it also renders the neuronal tissue
particularly vulnerable to any reduction of energetic reserve.
Under normal physiologic conditions, the main substance used
to produce cerebral energy is D-glucose (2-deoxyglucose being the
only molecular form capable of crossing the blood-brain barrier
[BBB] in both directions).19 D-Glucose is the only source of
metabolic energy used by the Krebs cycle to produce ATP. Any
important decrease in the supply of glucose leads to coma and
possibly to cellular and cerebral death. It is interesting to note that
the brain, despite its enormous glucose requirement (6.8 mg
glucose/100 g/min in a child as opposed to 5.5 mg glucose/100 g/
min in an adult), does not store glucose and does not elaborate
any glycogen. The muscular and hepatic reserves of glycogen are,
respectively, 10 and 100 times that of the brain. Thus, with normal
consumption of ATP, the brains glucose reserve secures only
3 minutes of energy supply to maintain normal cerebral function.
The brain depends almost, if not entirely, on blood perfusion for
a daily glucose consumption of 120 g. D-Glucose comes from the
aerobic glucogenesis of the liver and muscles. A minimum
quantity is synthesized de novo through amino acids, glycerol, and
intermediate metabolites of the Krebs cycle. In infants and young
children, the use of ketones (also an important source of energy in
the adult after prolonged starvation) contributes to the supply of
energy to the brain. The use of these metabolic products such as
beta-hydrobutyrate and acetoacetate is normal in the child. The
ability of the CNS to use ketones as substrate to energy is essential
when there is a drop in glucose supply. An adult requires a period
of 12 to 16 hours to increase ketone production and begins to
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utilize them as energy substrate. More than 50% of all oxygen used
by the brain during a period of starvation is used to oxidize ketone
bodies. However, ketones produce only enough energy to maintain vital cellular functions but, do not, for example, allow recovery
from a hypoglycemic coma.
D-Gglucose penetrates the brain through a transport mechanism assisted by a specific membrane transporter having saturability properties (first-order kinetics) and competitive affinity to the
receptor. Aerobic glycolysis and phosphorylative oxidation
produce ATP, CO2, and H2O. Aerobic glycolysis in the internal
membrane of the mitochondria creates 30 ATP directly whereas
6 ATP come from 2 NADH (nicotinamide adenine dinucleotide,
reduced form) generated in the cytosol during glycolysis. Aerobic
mitochondrial oxidative metabolism produces 18 times more ATP
per molecule of glucose than cytoplasmic anaerobic glycolysis in
which NADH cannot be retransformed into NAD (nicotinamide
acid dehydrogenase) because of the lack of O2. In case of anaerobic
metabolism, NAD is regenerated by the transformation of pyruvate into lactate. Basic glucose consumption by the brain is
approximately 0.3 to 0.8 mmol/100 g/min, which is higher than
that reported for the heart (69 mmol/min).20 The combustion of
1 glucose molecule requires 6 molecules of O2. In the presence of
O2, 90 to 95% of all carbohydrates are consumed by the brain
through the phosphor-oxidative pathway. The production of
cerebral lactate represents less than 4% of the glucose metabolized
in presence of O2.
Of all human organs, the brain is the organ that consumes the
second largest amount of O2, after the glomic cells of the carotid
body known as the ultimum moriens (the last cells to die). The
total O2 consumption of the brain or the cerebral metabolic rate
for oxygen (CMRO2) in a young man (average age, 21 y) is 3.5 mL
O2/100 g/min.21 It is almost the same in an elderly person (average
age, 71 y). However, children (average age, 6 y) have a significantly
increased CMRO2 (5.5 mL O2/100 g/min). This increase in O2
consumption is probably related to the energetic requirements of
growth. The brain is the organ most sensitive to lack of O2. For
this reason, it is capable of regulating the use of O2 according to its
needs.
O2 is necessary for the synthesis and maintenance of mitochondrial ATP. The ATP produced by aerobic glycolysis is almost
entirely utilized for maintaining transmembrane electric functions
and ionic gradients. It is also used to supply energy for the biosynthesis, liberation, and capture of synaptic neurotransmitters. The
most costly energetic mechanism is undoubtedly the transmembrane transport of ions. About 60% of ATP produced is used to
maintain the ionic transmembrane potential, mainly the Na+/K+ATPase pump.22 Following a period of depolarization and liberation of synaptic neurotransmitters, much energy is required to
ensure the neuronal recapture of K+ (repolarization) and neurotransmitters. Consequently, even the basic neurologic activity
requires a large O2 supply, which significantly increases during a
period of external stimulation (visual) or voluntary movement. In
the presence of ischemia or anoxia, any interruption of the ionic
pump will cause a loss of cellular regulation and intracellular acidbase balance. The anesthesiologist must try to maintain the energy
balance between cerebral supply and demand. Approximately 50%
of the CMRO2 is used by the astrocytes for the maintenance of
energy production (e.g., ATP-glutamatedependent pumps) and
synthesis of neurotransmitters (the functional metabolism of the
brain). The other 50% is used to maintain the structural characteristics and functional metabolism of the brain cells.18
Cerebral Blood Flow and CBV

The cerebral blood flow (CBF) is one of the variables that can be
modified by the anesthesiologist. It is indirectly linked to the
intracerebral blood volume. Manipulation of the CBF helps to
control ICP. Although the presence of intracranial pathology may
change or even paradoxically inverse the relationship between ICP
and CBF, in most cases, the use of an anesthetic technique to alter
CBF remains an efficient and powerful tool for the anesthesiologist.
An adult brain weighs 1400 g on average and receives about
20% of the cardiac output at rest. It controls its own O2 supply
according to its metabolic requirement for O2 and glucose (metabolism flow coupling). Current techniques used to measure CBF
do not give a precise estimation of global CBF. The use of positron
emission tomography (PET) confirmed that the mean CBF in
the adult is 50 mL/100 g/min with a variability of 30 to 90 mL/
100g/min.23 In the pediatric population, CBF is 42 to 48 mL/min/
100 g in term neonates, 90 mL/100 g/min between the ages of 4
and 6 months, peaks around 110 mL/min/100 g at 3 to 4 years to
subsequently decrease to approximately 78 mL/min100 g at
9 years2426 The global CBF of children from 6 months to 4 years
of age is twice than of the adult. An accelerated cerebral development during this period explains the important increase in CBF.
Nevertheless, it has been reported that CBF in children born
prematurely is much lower than adults, varying significantly from
5 to 23 mL/min/100g in 26 to 28 weeks premature newborns to
approximately 50 mL/100g/min at term.27,28 This reduction of CBF
is associated with the presence of decreased cerebral mass and
metabolism as well as the significant absence of cerebral development in the first few weeks of life. The CBF of gray matter is higher
than that of the corresponding white matter.29 The perfusion of
the cerebral white matter represents about one third of that of the
gray matter, and this ratio remains constant during the entire
lifetime.30 This implies that the age-related reduction of cerebral
metabolism and CBF is mainly because of a loss of synapses or a
drop in their activity rather than to a neuronal anatomic loss.
The interstitial cerebral compartment is maintained constant
by the presence of the astrocytes and the tight junctions (9 ) that
form the BBB (Figure 66). The BBB is impermeable to electrolytes and allows osmotic pressures to equilibrate by a water shift between the blood and the brain compartments. Therefore, normal
brain volume is physiologically controlled by plasma osmotic
pressure. Brain cells are resistant to osmotic variation and possess
powerful adaptation mechanisms that correct neuronal volume
within minutes. When cerebral injury occurs, the BBB can be
injured and water transfer across the BBB is dependent on hydrostatic pressure gradients. The interstitial pressure is high with tight
cell junctions. This also prevents the flux of water toward the
interstitium.
Cerebral Perfusion Pressure

The arteriovenous pressure gradients that are observed are much
more complex in the brain than in other organs because the brain
is confined in a closed cranial vault. The presence of a rigid box
brings about the formation of arteriovenous gradients that are
directly dependent on the variation of ICP, which is normally
higher than the atmospheric pressure and central venous pressure
(CVP).30 Consequently, neither the CVP nor the venous pressure
of the cerebral sinuses affect CBF. The relative absence of pressure
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Figure 6-6. Relevant anatomic characteristics of the brain vessel. The

neural vasculature differs from the peripheral systemic vessels by the
tight junctions, the presence of numerous mitochondria, and rare
pinocytic vesicles. Astrocyte feet surround the vessel and form the
blood-brain barrier.
inside the venous sinuses is a consequence of the very resistant

fibrous wall that protects them from most changes in ICP. The
hydrostatic pressure of the cerebral venous sinuses is determined
almost entirely by the CVP. However, contrary to the venous
sinuses, the pressure of the veins of the cerebral tissue is totally
dependent on ICP. However, this should always be higher than
ICP in order to avoid any extrinsic compression. Direct measurement of their pressure has demonstrated this hypothesis. For that
reason, cerebral perfusion pressure (CPP) is equal to the mean
arterial pressure (MAP) less CVP or ICP (the greater of the two):
CPP = MAP ICP (or CVP)
Cerebral Autoregulation
The term autoregulation is used to describe the phenomenon by
which the CBF is maintained constant despite important changes
in CPP (Figure 67). This control is limited in the adult to CPP
range between 50 and 150 mmHg of CPP.31 The lower and higher
thresholds of cerebral autoregulation in the infant and the young
child are not known. Animal models suggest that the lower and
higher limits of the autoregulation mechanism are lower than
those observed in the adult, 40 to 90 mmHg, respectively.32,33 It
has been shown in infants and young children undergoing balloon
dilation of coarctation of the aorta that the cerebral autoregulation
mechanism is present and capable of rapid response.34 However,
the effect of systemic arterial hypotension on cerebral autoregulation of the newborn remains unknown. It is reasonable to think
that CBF is rather well maintained despite low perfusion pressures.
CBF is matched to CMRO2. At rest, it is maintained at a
constant level of about 50 mL/min/100 g for a large range of MAP.
With decreasing MAP, cerebral vasodilatation occurs and CBV
increases. With hypertension, vasoconstriction leads to a decrease
in CBV and ICP. This autoregulation process is necessary to
maintain local tissue PCO2 (carbon dioxide pressure) constant.
Three mechanismsmyogenic, metabolic, and neurogenicare
involved in cerebral autoregulation.35 The rapid component (i.e.,
Figure 6-7. The effect of cerebral perfusion pressure (CPP) on cerebral

blood flow (CBF). CBF is autoregulated between 50 and 150 mmHg in
the adult. In the child aged 6 months to 12 years, CBF is maintained
constant to higher values than those in the adult, whereas for the premature baby and infant younger than 6 months of age, mean CBF is lower
and the inferior and superior limits of autoregulation are different.
the myogenic response) takes from 30 seconds up to 3 minutes to

respond. The myogenic mechanism is probably the most efficient
against severe and rapid changes in CPP, whereas the metabolic
control system is associated with slower changes caused by modification of the metabolic flow balance.34 The myogenic theory rests
on the concept that smooth endovascular muscles have an
intrinsic property capable of reacting to changes in CPP. The
presence of stretching receptors capable of recognizing changes in
transmural pressure rather than the locoregional variation of flow
has been confirmed (the Bayliss effect described in 1902).36 In
children, the myogenic response seems even faster than described
in adults. It is activated within the first 10 seconds after an abrupt
change in CPP and completed under 2 minutes.34,37 The second
component of this cerebrovascular autoregulatory control is the
fine-tuning response based on neurogenic and metabolic mediators. The control of CBF by direct innervation of the autonomous
nervous system remains a complex phenomenon.35 Several neurotransmitters have been identified as having a direct contribution
to the cerebral autoregulation mechanism. The presence of an
important sympathetic innervation, mainly noradrenergic, on the
major cranial vessels and the small arteries cannot be neglected,
1-, 2-, and -adrenergic receptors having been identified on
the cortical microcirculation.38 Scientific evidence suggests that
the microcirculation is mainly responsible for the fine-tuning of
the cerebral autoregulation.
The metabolic factors involved in this system are the levels of
CO2, K+, and adenosine.35 CO2 is the most powerful vasodilator of
the cerebral vessels. An increase in CO2 produces cerebral vasodilatation and causes an increase in CBF and CBV. When CO2
doubles from 40 to 80 mmHg, CBF also doubles and is the same
for a reduction in CO2, halving from 40 to 20 mmHg when CBF
is reduced by as much. In the adult, CBF varies in a linear way
with any change in PaCO2 (arterial pressure of carbon dioxide)
between 20 and 80 mmHg (Figure 68). A 1-mmHg fall in PaCO2
results in a 4% decrease in CBF. As PaCO2 falls, CSF pH rises and
periarteriolar changes in pH are reflected in vasoconstriction. The
use of prolonged hyperventilation to control ICP is effective only
for a period of 6 to 8 hours, after which, unless the CO2 has
dropped again, CBF will return to its prehyperventilation value.
The clinical implication for this physiologic observation is that, if
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Figure 6-8. Hypocapnia widens the autoregulation plateau, whereas

hypercapnia reduces it. Young WL. Clinical Neuroscience Lectures, Cathenart Publishing, Munster, IN 1993.
hyperventilation is maintained for a certain period and then

normoventilation and, thus, normocapnia are then restored
rapidly, the pH of the interstitial space will drop. This decrease in
pH will be linked to the increase in PaCO2 and CBF and CBV will
increase dramatically, which will cause an increase in ICP. Chronic
hyperventilation will result in slow movement of bicarbonate ions
out of the CSF with normalization of CSF pH and CBF within 24
hours.39 However, sudden increases in PaCO2 after chronic hyperventilation of more than 24 hours can result in cerebral vasodilatation and increases in ICP.40 Previous studies have suggested that
the immature brain is relatively unresponsive to small changes in
PaCO2,41 but investigations on fetal rabbit brain have demonstrated that CBF responds to changes in PaCO2.42 In the child, a
study using transcranial Doppler has shown that the mathematical
relationship, describing the relationship between CBF when CO2
varies between 20 and 80 mmHg, is a logarithmic curve, which
suggests that the maximum vasodilatation effect of CO2 is rapidly
reached at around 50 mmHg.43
Cerebrovascular reactivity to CO2 represents the first therapeutic line used by emergency physicians, anesthetists, and intensivists
to control ICP. However, the effect of CO2 on the cerebral vasculature seems to be transient. A sustained modification in the
CO2 level for 6 to 8 hours causes a resetting of CBF to its initial
value. This suggests that the cerebrovascular effect of CO2 is
mediated via changes in H+ concentration in the extracellular
space. The vascular effect of CO2 is about 6 hours because the
extracellular HCO3 needs 6 to 8 hours to reset the acid-base
balance and, thus, the extracellular pH. It is important to stress
the importance of mild hypocapnia, which widens the autoregulation plateau, whereas hypercapnia decreases this plateau (Figure
69). Hypotension (MAP decreases) impairs CO2 reactivity of the
cerebral vasculature, whereas normotension maintains its effect
(see Figure 69). Blood viscosity may also have a major impact on
cerebral autoregulation. A decrease in blood viscosity will cause a
temporary increase in CBF, which will be rapidly corrected by
metabolic adjustment.44
Cerebral O2 and glucose demands also directly influence cerebral vasoreactivity and CBF. The cerebral vascular response to
hypoxia is not well studied in children. Even in the presence of
Figure 6-9. Hypotension impairs CO2 reactivity of the cerebral vasculature when compared with normotension. With permission from W. L.
Young, 1993, USA.
adequate autoregulation, the global distribution of CBF is not

uniform, which implies the presence of a regional vascular regulation linked to the regional CMRO2. Adults show no change in CBF
until PaO2 (arterial oxygen pressure) falls below 50 mmHg, at
which time, CBF begins to increase exponentially. The CBF seems
to depend on the quantity of oxygen available for the mitochondrial phosphorylative oxidation mechanisms. However, hyperoxia
does not modify CBF. Below a certain autoregulation limit, the
CBF varies in parallel with changes in CPP. When CPP is lower
than the inferior limit of autoregulation, the regions most vulnerable to ischemia are the vascular transition zones between the gray
and the white matters as well as the vital subcortical structures and
the basal nuclei. When CPP is greater than the superior autoregulation limit, CBF increases and the hydrostatic force transmitted
on the vasculature already dilated to a maximum could cause
edema, thrombotic occlusion, and/or intracerebral (mainly of the
germinal matrix) and intraventricular hemorrhage. Occlusive
thrombosis seems to result from fibrinoid necrosis of the vascular
endothelium causing the formation of platelet aggregates.
The controlled hypertension concept is based on intact cerebral
autoregulation.45 In the case of brain injury, a decreased CPP leads
to cerebral vasodilatation, increasing CBV and further increasing
ICP. To counteract this process, increasing MAP leads to an increased CPP and reflex cerebral vasoconstriction. This vasoconstriction decreases CBF and CBV, thus, further decreasing ICP and
increasing CPP. This therapeutic approach, by vasoconstriction in
uninjured areas, leads to increased perfusion in injured areas
(Robin Hood effect).46,47 Clinically, it is achieved by expanding
plasma volume and the use of vasopressor agents if needed.
However, it must be stressed that controlled hypertension must be
progressive to allow autoregulation to occur and must stay within
the patients autoregulation range of 80 to 100 mmHg. Cerebral
autoregulation can be impaired in the newborn, presenting a state
of severe respiratory distress in the presence of an anoxic or a hypoxic episode48 or simply during the administration of vasodilator
agents such as CO2, nitroprusside, or inhalational anesthetic
agents. Abrupt MAP changes will transiently lead to changes in
CBF. The autoregulation window ranges from a mean CPP of 50
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to 150 mmHg in normal subjects and is shifted to higher values in

hypertensive patients and to lower values in hypotensive patients
or in the brain surrounding an arteriovenous malformation.
Several factors impair cerebral vasoregulation. The two of primary
concern are PaCO2 and volatile anesthetic agents. Intravenous
agents like thiopental, etomidate, and propofol are cerebral vasoconstrictors. When cerebral vasoreactivity is uneven, vasodilating
agents can increase blood flow to uninjured areas, thus decreasing
blood flow to injured areas (vascular steel effect), whereas vasoconstricting agents increase blood flow to injured areas (Robin
Hood effect).
Not surprisingly, medications such as acetazolamide and

furosemide, which can reduce the production of CSF, have a
minimal effect on ICP. Only patients with an marked decrease in
intracerebral compliance with a very high ICP may benefit from
this pharmacologic effect. In patients with ICP issues, it is
important to avoid using certain anesthetic agents such as
enflurane, which can increase the secretion of CSF, or alfentanil,
which can hinder its reabsorption. Finally, resorption rate depends
on the CSFtovenous pressure gradient and resorption resistance. The pressure gradient between the CSF and the venous
compartment is called effective CSF pressure.
CSF
Spinal Cord Blood Flow
The brain is highly sensitive to environmental changes, and any

change in the extracellular ionic concentration can modify its
activity. The CSF composition is controlled very strictly, which
differentiates CSF from other fluids in the body (Table 62). The
brain is protected by two barriers, the BBB and the blood-CSF
barrier, which is responsible for maintaining ionic homeostasis
between blood and CSF and, moreover, between blood and the
respiratory control centers. The CSF is largely secreted by the choroidian plexi (80%), which are located in the cerebral ventricles.
The capillaries of the choroidian plexi are equipped with openings
and intercellular spaces allowing the free passage of molecules
through this special endothelium that is responsible for the
secretion of CSF. The presence of an extrachoroidian site involved
in the production of CSF has not been clearly identified. However,
it has been suggested that the surface of the ependyma as well as
the cerebral parenchyma are potentially able to participate in the
production of CSF. In the adult, normal CSF volume varies
between 100 and 150 mL or 1.5 to 2.0 mL/kg. Under normal
conditions, the production and reabsorption of CSF are balanced.
The production of CSF in the adult is 0.35 mL/min or 500 mL/
day.49 In the child, it is slightly less or about 0.3 mL/min. Because
the total CSF reserve is lower in the child, the effect on cerebral
compliance is more pronounced, and because the total quantity is
lower, the total CSF volume can be replaced entirely three to four
times a day. CSF is mainly formed by the passive transport of Na
, Cl, and HCO3, which follows a simple concentration gradient
with water passively following these ions, whereas active transport
is necessary for glucose and amino acids. There are virtually no
proteins in the CSF (see Table 62). Arachnoidian villi are
responsible for the passive reabsorption process of CSF through
their endovenous outgrowth. This reabsorption mechanism has
not yet been fully understood. A reduction of 35% in the
production of CSF causes a reduction of only 1.1 mmHg in ICP.50
The use of the Doppler technology has simplified the noninvasive

evaluation of CBF. In the child, it has opened up the study of the
pathophysiology of the cerebral circulation and the circulation in
the spinal cord. Previously, almost all scientific data linked to the
circulation of the spinal cord came from animal studies.51 Despite
the fact that blood flow is evaluated in velocity rather than in
milliliters per minute, the studies on blood flow in the spinal cord
carried out on cats demonstrate an excellent statistical correlation
with the measurements obtained by Doppler velocimetry. Animal
studies confirm that the physiology of the blood flow in the spinal
cord is comparable with that of CBF. However, because the spinal
cord metabolism is proportionally lower than that of the brain,
blood flow in the spinal cord is lower. Blood flow in the gray spinal
matter is 50% of blood flow at the level of the gray matter of the
brain, whereas blood flow in the white matter represents only one
third of the perfusion of the white cerebral matter.
The equation of the perfusion pressure of the spinal cord
(PPSP) is: PPSP = MAP extrinsic pressure. At the spinal cord
level, it is the equivalent of the CPP at the brain level. This concept
is clinically useful because it highlights the factors influencing
blood flow at the spinal cord level. Extrinsic pressure can be the
result of a tumor, hematoma, CSF, and/or epidural venous congestion. The presence of autoregulation in the spinal cord secures
a constant flow as occurs in the brain. Although the limit values
are often described as 60 to 150 mmHg, an inferior limit of
45 mmHg and a superior limit of 180 mmHg have also been
reported. It is most difficult to rely on monitoring to evaluate the
impact of an extrinsic compression on the spinal cord. It is, thus,
recommended to maintain the PPSP above 50 mmHg by
maintaining a normal MAP.
Finally, vascular reactivity of the spinal cord to changes in
PaCO2 and PaO2 is very comparable with that of the brain. Thus,
a PaO2 higher than 60 mmHg does not affect spinal blood flow.
However, spinal cord blood flow significantly increases when PaO2
is lowered to below 60 mmHg. Studies suggest that PaCO2 affects
blood flow in a linear fashion between 20 and 80 mmHg, resulting in absolute variation from 0.5 to 1.0 mL/100 g/min.52 It has
been demonstrated that CBF in the adult changes from 1 to 2 mL/
100 g/min.31,53
TABLE 6-2. Composition of the Human Cerebrospinal

Fluid and Plasma
Constituants
1
Sodium (mEq/L )
Potassium (mEq/L1)
Calcium (mEq/L1)
Magnesium (mEq/L1)
Chloride (mEq/L1)
Glucose (mg/dL1)
Protein (g/dL1)
CSF = cerebrospinal fluid.
CSF
Plasma
138.0
2.8
2.4
2.7
124.0
60.0
0.05
140.0
4.0
4.6
1.8
99.0
99.0
7.1
CONCLUSION
Successful anesthesia for infants and children affected with a
neurologic disease depends on a good understanding of the anatomy and physiology of the CNS.54 Application of basic principles
facilitates the clinical management of intracranial or spinal pathologies during neurosurgical procedures. Ischemia and necrosis
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represent the ultimate consequence of physiologic imbalance.
Although the brain does no mechanical work, a substantial
amount of energy is needed to maintain its cellular integrity and
biologic functions. Cerebral protection is possible only if one
anticipates the physiologic changes triggered by a pathologic disturbance and applies fundamental concepts to restore the normal
physiology as soon as possible.55 This clinical management is the
exclusive domain of the anesthesiologist and the neurosurgeon
and will be discussed in Chapters 93 and 92.
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40. Muizelaar JP, van, der, Poel, Hg, Li ZC, et al. Pial arteriolar vessel
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Normal and Abnormal Development

of the Heart and the Circulation
Christian Apitz and Andrew N. Redington
INTRODUCTION
The development of the heart reflects a complex interaction of
genes, environment, biomechanical events, and chance. Although
the embryo is growing exponentially, the heart transforms from a
muscle-wrapped tube without valves, septums, conduction system, or coronary circulation into a four-chambered structure that
will pump blood to the lungs and body 60 to 160 times/min for
more than 80 years. In approximately 1% of pregnancies, this
usually well-orchestrated process fails and congenital heart disease
results. Even in the normal heart, important maturational changes
must be taken into account when caring for infants and children.
In this chapter, we explore some of the important issues that are of
clinical relevance to those providing anesthesia care for the
pediatric population.
THE SPECTRUM OF
CONGENITAL HEART DISEASE
AND ITS DESCRIPTION
No matter what the cause, the ability to describe any structural
cardiac abnormality in a cohesive and comprehensive manner
forms the basis of communication, management, and description
of outcomes. There have been two schools of, often hotly debated, nomenclature: (1) the Van-Praaghian and (2) the Andersonian systems, which are eponymously named after their advocates.
Both have evolved and became more aligned since the early 1980s.
They are based on the description of the heart as a series of
segments.14 Without wishing to enter the debate of superiority,
and in the interests of clarity, in this section, we describe the most
widely used system, the Andersonian system of sequential
segmental analysis. Although it is beyond the scope of this chapter
to explore all of this morphologic method in detail, what follows is
a usable synopsis of the main concepts.
7
C H A P T E R
extending between the AV and the ventriculoarterial junctions. In

terms of its own intrinsic morphology, this ventricular mass can be
divided into (1) inlet portions surrounding the AV valves and
extending to the attachments of their papillary muscles, (2) apical
trabecular components, and (3) outlet components supporting
the arterial valves. The atrial and ventricular chambers and the
great arteries are paired structures. Each member of the pair is
distinguishable by its morphologically right or morphologically
left characteristics. Congenitally malformed hearts can then
be analyzed in the way that these morphologically right and left
components are arranged and connected or, in some cases, not
connected.
The Atria
The part of the atrium most uniformly present and most distinctive of rightness and leftness is the appendage. The morphologically right appendage is triangular-shaped with a broad base at its
junction with the smooth-walled atrium, whereas the morphologically left appendage is a finger-like structure having a narrow
junction with the smooth-walled atrial component. The great
veins cannot be used to distinguish accurately between a left and
a right atrium because an anomalous drainage of the great veins is
not uncommon in complex congenital defects.
The Ventricles
The most characteristic pattern to distinguish morphologically
right and morphologically left ventricles is their trabecular components. Characteristically, the right ventricle has coarse apical
trabeculations whereas the left ventricle typically has fine trabeculations. Additional morphologic criteria for the right ventricle
are the moderator band crossing the ventricular cavity (this is an
especially useful feature for echocardiographic diagnosis) and the
presence of tendinous cords attaching the septal leaflet of the
tricuspid valve to the ventricular septum.
The Segments
The Great Arteries
The basis of segmental analysis is the concept that all congenital

heart malformations can be readily analyzed in terms of three
basic segments: (1) the atria, (2) the ventricular mass, and (3) the
great arteries. These segments have uniquely defining features and
discrete anatomic boundaries. The atria are separated from the
ventricles by the fibrous tissue plane of the atrioventricular (AV)
junction. The ventriculoarterial junction is marked by the attachment of the arterial wall to the ventricular mass. The ventricular
segment of the heart is, therefore, defined as the muscle mass
The description of the arterial trunks is made on the basis

of patterns of branching. An aorta can be distinguished as an
arterial trunk giving rise to systemic and coronary arteries. A
pulmonary trunk is one giving rise to pulmonary arteries. A
common arterial trunk is defined as a single arterial vessel from
which systemic, pulmonary, and coronary arteries arise directly.
The second step of the segmental analysis is to describe the
connections between the components of the different segments.
Usually, we start with the description of the arrangement of the
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Figure 7-1. Arrangement of the appendages.
heart. According to the classification of the bodily arrangements,

we distinguish four basic arrangements: (1) the usual arrangement
(situs solitus), (2) the mirror image (situs inversus), (3) right
isomerism, and (4) the left isomerism. Because the appendages
are the most constant component to distinguish between the right
and the left parts of segments, the arrangement of the heart is
defined by the arrangement of the appendages (Figure 71).
ARRANGEMENTS OF THE APPENDAGES: Usually, the morphologically right atrium is right-sided and the morphologically left
atrium is left-sided (situs solitus = usual). In the mirror-image
arrangement (situs inversus), the morphologically right atrium is
left-sided. There are two other atrial arrangements, right or left
isomerism of the atrial appendages, in which both appendages
have morphologically right or morphologically left characteristics.
THE AV JUNCTION:
We have to distinguish the more common

biventricular AV connection, in which each atrium is connected
to its own ventricle, and the univentricular AV connections, in
which the atria are connected to only one ventricle (Figure 72).
This could be seen as a double-inlet ventricle or one with absent
right AV connection or absent left AV connection. In this second
group of hearts, it is always necessary to describe the type and
mode of AV connection together with the ventricular morphology
and the size of a rudimentary ventricle if present.
VENTRICULAR TOPOLOGY: In situs solitus with AV concordance,
the morphologically right ventricle almost always wraps itself
Figure 7-3. Single outlet of the heart with a common arterial trunk.
around the left ventricle in a fashion comparable with the

observers right hand being placed upon the morphologically right
ventricular septal surface, with the palm against the septum, the
thumb in the inlet, the fingers in the outlet, and the wrist in the
trabecular component. This pattern of ventricular topology can
be termed a right-hand pattern, and is also almost always seen in
hearts with situs inversus and AV discordance. The complementary left-handed pattern is usually found in hearts with either situs
inversus and AV concordance or AV discordance in situs solitus.
THE VENTRICULOARTERIAL JUNCTION:
There are four different

types of ventriculoarterial connection. The first two of these are
ventriculoarterial concordance, in which the aorta is connected to
a left ventricle and the pulmonary trunk to a right ventricle, and
ventriculoarterial discordance, in which there is the reverse connection (most commonly referred to as transposition). The other
two connections describe arrangements that are neither concordant nor discordant, including double-outlet ventricle, in which
both great arteries are connected to the same ventricular chamber,
and single outlet of the heart, either with the ventricles draining
via a common arterial trunk or with one ventriculoarterial connection absent, either an atretic aortic or a pulmonary trunk
without connection to the ventricle (Figure 73).
CARDIOVASCULAR EMBRYOLOGY
Figure 7-2. Biventricular (A) and univentricular (B) atrioventricular

junction with usual arrangement of the appendages. B: An absent right
atrioventricular connection (tricuspid atresia).
Cardiovascular embryology offers the basis for understanding the

pathogenesis of many types of congenital heart defects and is
particularly relevant to the abnormal development of the cardiac
segments.5 However, as with sequential segmental analysis
previously addressed in the section The spectrum of congenital
heart disease and its description, a detailed discussion of this
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Normal and Abnormal Development of the Heart and the Circulation 93
complex area is beyond the scope of this chapter. Nonetheless, we

provide a brief overview of the key elements of cardiovascular
development in early fetal life.
Although ultimately becoming a contiguous and integrated
structure, the ventricular myocardium is now known to be derived
from several different embryologic origins. For example, even
though they ultimately come to share myofibers, elements of the
right and left ventricles derive from separate heart fields in very
early embryogenesis. The vascular system of a human embryo
starts to develop in the second and third weeks of gestation. At
this point, diffusion alone is not sufficient to provide oxygen and
other substrates to the developing organs. Consequently, angiogenic cell structures move toward the developing heart at the cranial
end of the embryo, forming the endocardial tubes. These tubes
form the dorsal aorta and the rudimentary venous system. As the
heart tube continues to develop, the dorsal aorta and the vitelloumbilical veins serve as anchors as the heart tube bulges and
loops. The looping of the heart tube serves to form the primordial
heart chambers with a sinus venosus, the paired primitive atria,
the AV sulcus, the primitive ventricle, and its developing interventricular sulcus. On the outflow of the tube, the bulbous cordis
is forming part of the right ventricle and its outflow tract. As the
heart tube forms its bulboventricular loop, a common atrium is
formed. Partitioning of the atrium, by the appearance of the
septum primum, occurs by about the 28th day. The primum septum fuses with the endocardial cushions with superior perforations that ultimately coalesce to form the ostium secundum. If
these perforations are too large, a secundum atrial septal defect
will result. At the same time as atrial septation is occurring, the
left atrium and pulmonary veins are becoming confluent with the
lung buds to allow pulmonary venous return to the left atrium. As
the atrial wall expands, the pulmonary veins become fully incorporated into the posterior wall of the left atrium. Failure of incorporation of the pulmonary veins will lead to forms of total
anomalous pulmonary venous connection (TAPVC) with drainage of the pulmonary veins to other structures. The most common form of TAPVC is supracardiac drainage (usually via
connection of the pulmonary veins to remnants of the left-sided
cardinal venous system, which usually disappears during early
fetal life). Other forms of TAPVC include connection to the splanchnic veins below the diaphragm (infradiaphragmatic TAPVC),
to cardiac veins (TAPVC to coronary sinus), or mixed types.
The formation of the ventricles initially occurs from separate
heart fields, but ultimately develops as a looping of the newly
formed heart tube. The interventricular sulcus grows to separate
the right and left ventricles, which continue to expand until the
seventh week of gestation. The inlet of the ventricles develops from
the AV canal, which gradually shifts to the right in order to allow
communication between the atrial mass and the developing right
ventricle. Fusion of the endocardial cushions is responsible for
completion of both the septation of the atrium and the ventricle
and is integral to the formation of the AV valves. A common AV
canal between the atria and the ventricles is present in the normal
heart as it develops, but may also persist as one of the most
common of all cardiac anomalies. Failure of ventricular septation
in the presence of normal separation of the AV junctions will
account for the remainder of ventricular defects, which can be
classified broadly as perimembranous, muscular, doubly committed,
and juxta-arterial.
The outflow tract of the ventricle is gradually partitioned to
form a separate aorta and pulmonary trunk. The ascending aorta
coalesces to develop continuity with the dorsal aorta and the

pulmonary trunk coalesces with six arch structures to form the
branch pulmonary arteries, supplying the lungs. Abnormal septation can lead to the development of a common arterial trunk
(truncus arteriosus) and other abnormalities such as aortopulmonary window, an anomalous origin of a branch pulmonary
artery from the ascending aorta.
ETIOLOGY OF CONGENITAL
HEART DISEASE
Fundamental to the understanding of the origin of cardiac defects
are the impressive advances in the understanding of developmental mechanisms of cardiac morphogenesis. In the following
section, we address the most important factors contributing to
maldevelopment of the heart.
Genetic Factors
Although there is increasing understanding of the role of genetic
influences on early cardiac development, our understanding
remains incomplete. A substantial part of cardiovascular diseases
is either directly caused by gene mutations (monogenic) or at least
modified by genetic variation (polygenic, multifactorial).6 Among
infants born with associated noncardiac anomalies, chromosomal
anomalies and single-gene disorders are more frequently identified, and conversely, cardiac anomalies are overrepresented in
many definable genetic syndromes. For example, approximately
50% of children with trisomy 21 will have an associated cardiac
anomaly.7 AV septal defect is the most frequent defect, followed
in decreasing order by ventricular septal defect, atrial septal defect,
tetralogy of Fallot, and patent ductus arteriosus.810 Although less
frequently encountered than trisomy 21, almost all infants with
trisomy 18 will have a congenital cardiac defect. Among the sex
chromosome abnormalities, Turners syndrome is the most
frequent, with 10 to 40% of these patients having coarctation of
the aorta and associated bicuspid aortic valve.11 It is likely that
many cardiac diseases will have more subtle genetic origins such
as point mutations or microdeletions. The most frequent microdeletion syndrome associated with congenital heart disease is
22q11 syndrome. The syndrome has a population prevalence of
approximately 1 in 2000 in the United States. It has drawn considerable attention because a number of common psychiatric
illnesses are phenotypic features including attention deficit disorder, schizophrenia, and bipolar disorder.12,13 These children are
born with a spectrum of conotruncal abnormalities including
tetralogy of Fallot, interrupted aortic arch, and common arterial
trunk.
Environmental Factors
It has long been known that maternal factors can modify cardiac
development. Maternal infection with rubella is rare in Western
populations, but it leads to severe abnormalities of the pulmonary
arteries. Maternal viral illness in the third trimester is often associated with myocarditis in the newborn infant, coxsackie being
the most common viral agent. Ingested teratogens can be equally
devastating. The potential risks caused by maternal drug intake
were brought to light by the thalidomide tragedy. Exposure of
mothers who took thalidomide during pregnancy resulted in a
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high risk of cardiac malformations, especially of the conotruncal

type, tetralogy of Fallot, and truncus arteriosus.14 In addition,
various anticonvulsants used by mothers for the treatment of
epilepsy such as barbiturates, valproic acid, or diphenylhydantoin
have been found to cause defects such as pulmonary stenosis and
tetralogy of Fallot. There are also more generic effects of maternal
disease. Maternal diabetes not only may lead to a specific form of
transient hypertrophic cardiomyopathy in the newborn15 but is
also associated with increased risk of structural heart disease via
mechanisms yet to be fully elucidated.16 Maternal phenylketonuria
may also be a cause of congenital heart disease in the offspring, in
which patent ductus arteriosus, coarctation of the aorta, and
tetralogy of Fallot are the most frequently reported lesions.17
Mothers with systemic lupus erythematosus, even if not obviously
ill, have a risk of congenital complete heart block in the offspring
because of isoimmune damage of the fetal cardiac conduction
tissue.18
Abnormalities of Intracardiac Blood Flow

A group of human congenital cardiac malformations are associated with abnormal blood flow patterns in the fetus. The fetal
flow hypothesis of congenital heart disease has long been debated,
because it is very difficult to separate chicken from egg (i.e., is it
a subtle structural abnormality that modifies flow or vice versa?).
However, there does appear to be some evidence that primary
abnormalities of flow can lead to structural defects. A good
example of this is the development of right ventricular outflow
tract abnormalities in the recipient of an in utero twin-to-twin
transfusion.19 The flow hypothesis for the development of left
heart hypoplasia is less well defined. Although experimental
preparations have shown that perturbations in left heart flow
such as closure of the foramen ovale in the developing fetus
can lead to the typical disease, the clinical pathogenesis is less
clear.20 Indeed, hypoplasia of the left ventricle may be present in a
variety of congenital heart defects.21,22 The severity of left
ventricular hypoplasia may range from mild hypoplasia to its most
severe form, hypoplastic left heart syndrome.23 Left ventricular
hypoplasia is not a distinct disorder, but rather represents the
common end point of a wide variety of different pathophysiologic mechanisms, all resulting in diminished flow through the
left ventricle in utero.24 Thus, diminution in flow may be the cause
or the consequence of anatomic obstruction (e.g., restrictive
foramen ovale, mitral or aortic stenosis), intrinsic left ventricular disease (fibroelastosis), or extrinsic compression (congenital
diaphragmatic hernia), genetics, or a combination of several
factors.
Closure of the Foramen Ovale

When the umbilical cord is clamped, the low-resistance placental
circulation is lost and the systemic vascular resistance (SVR)
increases. With the initiation of respiration, the pulmonary vascular resistance (PVR) begins to decrease and the lungs begin to
be perfused with a greater amount of blood. With the increased
flow to the lungs, blood return from the lungs to the left atrium
also increases. Clamping of the umbilical cord decreases return of
systemic blood to the right atrium. These events represent the
reverse of the situation that occurred in the fetus, when right atrial
return from the placenta exceeded left atrial return. Now, with
increased pulmonary blood flow and increased left atrial pressure
relative to right atrial pressure, the flap mechanism of the foramen
ovale results in functional closure.
Closure of the Ductus Arteriosus

In normal term infants, the ductus arteriosus functionally closes
within 24 hours after birth. One factor responsible for ductal
closure is the increase in oxygen tension related to conversion to
the lung as the organ of respiration. Another may be the change in
levels of local circulating prostaglandins. Final anatomic closure of
the ductus ateriosus by way of muscle contraction, thrombosis,
and fibrosis usually occurs within the first few months of life.
Factors that can delay ductal closure include prematurity, hypoxemia, and associated congenital heart disease.
Closure of the Ductus Venosus

The ductus venosus (which in utero is a conduit for oxygenated
blood from the placenta to bypass the liver and go directly to the
heart) functionally closes soon after birth, but there is evidence
that it may remain anatomically open for up to 20 days before
closing secondary to connective tissue proliferation that obliterates
the lumen. With clamping of the umbilical cord, venous return
in the inferior vena cava is composed only of blood returning from
the lower body and the abdominal organs. Reduction of flow
through the ductus venosus allows it to passively collapse and
functionally close. Sphincter-like structures appearing at the
junction of the ductus venosus and the umbilical vein have also
been proposed as mechanisms responsible for regulation of ductus
venosus blood flow and for facilitation of ductus venosus closure.
The practical importance of this is that umbilical vein catheterization is a convenient method of central catheter placement for the
administration of drugs and fluids in the newborn. In addition, it
allows a pathway through which balloon atrial septostomy can be
performed via the umbilicus in the first day or two of life in infants
with transposition of the great arteries.
THE NORMAL CIRCULATION

AT BIRTH
The Transitional Pulmonary Circulation
Even in the normal heart, important maturational changes must

be taken into account when caring for children. At birth, a transformation must be made from having a parallel circulation, a
placenta as a respiratory organ, and a liquid environment in the
lungs, to having a series circulation, a lung as a respiratory organ,
and a gaseous environment. This requires that the shunt pathways,
which were necessary for the placenta to function as the organ of
respiration, abruptly cease to operate and that the lungs quickly
begin their role as organs of gas exchange.
In early gestation, the PVR is very high. Therefore, the lungs

receive only a small portion of the combined ventricular output.
During the last weeks of gestation, pulmonary blood flow begins
to increase, reaching 8 to 10% of combined ventricular output by
term. This period of increased pulmonary blood flow coincides
with a period of growth of the pulmonary vascular bed and with
the beginning of release of surface active material. The immediate
postnatal decrease in PVR results from the independent effects of
mechanical expansion of the lungs and the increase in arterial
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oxygen pressure (PaO2). In the normal state in the human neonate,

the PVR is approximately one half that of the SVR at 24 hours
of age and continues to decrease until it reaches adult values by
6 weeks of age.25
Persistent Pulmonary Hypertension

of the Newborn
PVR will not fall at birth and persistent pulmonary hypertension
will result if the pulmonary vascular bed has not demonstrated
normal pharmacologic maturation or if some perinatal insult such
as hypoxia sustains the vasoconstricted state of the pulmonary
vascular bed. Persistent pulmonary hypertension of the newborn
may also result from structural abnormalities. For example,
following an intrauterine insult, peripheral, normally nonmuscular arteries may be muscularized and muscular arteries may
show medial hypertrophy. In conditions causing pulmonary
hypoplasia such as diaphragmatic hernia, a severe reduction in the
number of alveoli and pulmonary vascular hypoplasia appear to be
the cause of pulmonary hypertension. As a consequence of persistent pulmonary hypertension in the newborn, the ductus arteriosus and foramen ovale do not close after birth. This leads to
intracardiac or great arterial level shunting of blood away from
the lungs and severe hypoxemia unless the PVR can be reduced
relative to the SVR.
The Abnormal Transitional Circulation

Problems occur when fetal pathways that should close during the
transitional period stay open or reopen, as in a premature baby
with a ductus arteriosus. Reopening of the duct, as a result of a
hypoxic stimulus, may cause a large left-to-right shunt and pulmonary edema because of the relatively rapid fall in resistance in
the poorly muscularized pulmonary arteries of the premature
infant. Other potential shunt pathways may exist or remain open
in the full-term newborn, but without causing apparent problems
in early life. This is because the PVR falls more slowly in these
infants. Consequently, symptoms from left-to-right shunting
through a ductus arteriosus or ventricular septal defect may not
become evident for several weeks after birth.
All of the normal physiologic responses that occur immediately

following birth may themselves be modified by the presence of
congenital heart disease. The various shunt pathways present in
the fetus that allow a parallel circulation to exist also permit many
fetuses with congenital cardiac malformations to grow and
develop normally in utero. Problems arise at birth and during the
transitional period only when the shunt pathways begin to close.
For example, a newborn infant with hypoplastic left heart syndrome does well during the transitional period until the ductus
arteriosus closes, leaving the infant with no means for systemic
cardiac output. In the following section we describe common
physiologic variants of transition in the presence of congenital
heart disease.
CONGENITAL HEART DISEASE

Left-to-Right Shunts at the
Ventricular and Arterial Level
The physiologic alterations associated with left-to-right shunt
lesions at the ventricular or great artery level are determined
principally by the size of the defect and the postnatal changes in
SVR and PVR (Figure 74). During fetal life, a large defect at the
ventricular level has no major physiologic effect. This is due
mainly to the presence of a high PVR in the fetus, which limits
any shunting into the pulmonary circulation, and the low
resistance of the placental circuit. However, following birth, the
decrease in PVR at the same time that the SVR is increasing
becomes the major determinant of left-to-right shunt flow. As
discussed in the section on The normal circulation at birth, the
normal decline in PVR to adult levels takes place within the first
6 weeks after birth. In the presence of a large communication, this
decline may be delayed by 1 to 3 months. Nonetheless, there is a
gradual increase in pulmonary blood flow with increasing
symptoms of congestive heart failure and failure to thrive. The
marked volume overload results in left atrial and pulmonary
venous hypertension and dilatation of the left and right ventricles.
The former contributes to the production of pulmonary edema,
and the latter stimulates an increase in ventricular mass. The need
for intervention is governed by symptoms and/or the presence of
Figure 7-4. Examples of left-to-right shunts at the ventricular and arterial levels. Ventricular septal defect (A), aortopulmonary window (B), and
persistent ductus arteriosus (C).
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pulmonary hypertension. For nonlimiting defects (large ventricular septal defect, aortopulmonary window, large patent ductus
arteriosus), the risk of irreversible pulmonary hypertension
(pulmonary vascular disease) rises steeply after the first year of
life. Therefore, elective intervention is usually planned in the first
3 to 6 months of life. The onset of pulmonary vascular disease may
be accelerated in some, and there may be a lack of signs or
symptoms even when the defect is large. Important causes of
accelerated pulmonary hypertension include the coexistence of
pulmonary parenchymal disease or upper airway obstruction, the
latter of which is particularly common in infants with trisomy 21.
For that reason, it is recommended that all children with trisomy
21 undergo echocardiographic screening early in life.26 When
present, pulmonary hypertension with incipient pulmonary
vascular disease represents a risk factor for adverse outcomes after
surgery. The risk of overt pulmonary hypertensive crisis in the
postoperative period has receded with the trend toward earlier
surgical correction, but the degree of postoperative elevation of
PVR still predicts the rate of postoperative recovery.27
Left-to-Right Shunts at the Atrial Level

By contrast with left-to-right shunts at the ventricular or arterial
level, shunting at the atrial level appears to be determined principally by the relative compliances of the right and left ventricles and
not necessarily by the size of the defect, unless the communication
is very small. The direction of blood flow through the defect is
determined by left and right atrial pressure differences during the
cardiac cycle. The latter, in turn, reflect the relative compliances of
the ventricles. In utero, atrial communications permit flow relations that mimic normal shunting across the foramen ovale.
Because the right ventricle is relatively stiff and noncompliant, leftto-right shunting is minimal early in life. As PVR falls and the
right ventricle becomes more compliant, the left-to-right shunt
increases gradually. The development of congestive heart failure
from increases in pulmonary blood flow secondary to atrial level
shunts is relatively rare. Despite large communications, pulmonary
artery pressures and resistances with few exceptions tend to be
low, hence, closure (nowadays, usually by transcatheter device)
can be delayed for several years.
Transposition of the Great Arteries

There appears to be little, if any, effect of transposition of the
great arteries on the fetal flow pathways or circulatory dynamics
(Figure 75). However, soon after birth, transposition of the
great arteries with limited mixing of pulmonary venous and
systemic venous streams is an acutely life-threatening condition
because of the sudden imposition of an extremely low level of
systemic arterial oxygen saturation. Early treatment with prostaglandin E2 therapy to maintain ductal patency is life-saving, but
is ineffective in the absence of an intracardiac shunt. Contrary to
popular belief, the effect of ductal reopening has little to do with
mixing of desaturated and oxygenated blood at the level of the
great arteries, but rather has its effects by increasing pulmonary
venous return, increasing left atrial pressure, and thereby
improving mixing at the atrial level. All of this will be further
improved by the performance of a balloon atrial septostomy,
which is performed in most newborns with transposition before
surgical repair.
Figure 7-5. Transposition of the great arteries with intact ventricular septum. Mixing of blood occurs at the atrial level (arrow) and
is increased by maintaining patency of the ductus arteriosus.
Single-Ventricle Physiology
Single-ventricle physiology is shared by several anatomic substrates. The most common is the hypoplastic left heart syndrome
(in which the systemic ventricle is the right ventricle), but similar
physiology is seen in those with absent right AV connection
(classic tricuspid atresia), unbalanced AV septal defect (in which
either the left or the right ventricle is too small to support the
circulation), and pulmonary atresia with intact ventricular septum. Although the details of the specific management of each of
these conditions are beyond the scope of this chapter, some
general rules are common to each of these conditions.
Some of these lesions manifest ductal-dependent pulmonary
perfusion. In the setting of hypoplastic right heart lesions, the right
ventricle is essentially bypassed with right-to-left shunting at the
atrial level. In the case of tricuspid atresia, pulmonary blood flow
may take place via a ventricular septal defect to the pulmonary
artery or via the ductus arteriosus. In the case of pulmonary atresia
with intact septum, pulmonary blood flow depends totally on
patency of the ductus arteriosus. These lesions appear to have little
effect on fetal growth and development. Postnatally, the dominant
physiologic theme is hypoxemia except where there is unobstructed flow into the pulmonary circulation. Early treatment
includes prostaglandin E2 therapy to maintain patency of the ductus arteriosus and surgical creation of a systemictopulmonary
artery anastomosis usually during the first weeks of life. The longterm palliative strategy is the creation of the so-called Fontan
circulation (see Ductal-dependent systemic perfusion).
Ductal-Dependent Systemic Perfusion

These defects include variations on the theme of hypoplastic
left heart syndrome including aortic atresia, interruption of the
aortic arch, and coarctation of the aorta (Figure 76A). During
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Figure 7-6. Hypoplastic left heart syndrome

before (A) and after (B) Norwood palliation.
intrauterine development, systemic perfusion is not compromised,

being maintained by the ductal flow from right ventricle to aorta.
Postnatally, systemic perfusion falls as the ductus arteriosus
constricts. In the case of aortic atresia, the entire systemic circulation depends on an open duct, whereas with interruption of
the arch and coarctation of the aorta, lower body perfusion is
acutely curtailed. Although coarctation of the aorta and interruption of the aortic arch can usually be surgically corrected
so that the circulation is restored to near-normal during the
first week of life, the classic hypoplastic left heart will be treated
by a series of palliative procedures extending over the first 2 or
3 years of life, starting with the so-called Norwood procedure (see
Figure 76B). Be it with the traditional or the new hybrid
approach,28,29 the goals of the initial Norwood procedure include
providing unobstructed systemic blood flow, unobstructed pulmonary venous return to the single ventricle (usually via atrial
septectomy), and limitation of pulmonary blood flow. An acceptable balance between the pulmonary and the systemic output
provides enough pulmonary flow for adequate oxygen delivery
to prevent acidosis without an excessive volume load to the
single ventricle or physiologic steal of blood away from the
systemic circulation. Assuming a mixed venous oxygen saturation
of 65% and a pulmonary venous oxygen saturation of 95%, arterial
oxygen saturation should be 80%. For the patient with either
excessive cyanosis (oxygen saturation < 75%) or relatively high
(>8588%) systemic oxygen saturations, the postoperative physiology must be carefully evaluated. Excessive cyanosis is caused
mainly by pulmonary issues such as pneumothorax or pleural
effusion, and decreased pulmonary blood flow is caused by
a restrictive systemictopulmonary artery shunt or elevated
PVR. The patient who is too pink typically has low PVR and
pulmonary blood flow far in excess of systemic blood flow. This
may result in inadequate systemic perfusion, renal dysfunction,
and an inability to wean the patient from mechanical ventilation.
The management of such neonates has considerably evolved since
the early 1990s, with a move away from ventilatory maneuvers to
increase PVR (breathing of subatmospheric concentrations of
oxygen or additional inhaled CO2) to pharmacologic therapy to
lower SVR (phenoxybenzamine or milrinone).30,31 Nonetheless,
permissive hypercapnia may increase systemic blood flow and

lower total body oxygen consumption.32
Further surgical intervention in patients with hypoplastic left
heart syndrome is necessary to avoid the chronic volume overload
state of the single ventricle. Following the Glenn procedure, the
superior vena cava venous return passes directly to and through
the lungs, thereby increasing effective pulmonary blood flow and
reducing cardiac work. Thus, the pulmonary blood flow equals
the brachiocephalic arterial flow, which is typically approximately
half of the total
output. The pulmonary to systemic
. ventricular
.
flow ratio (Q p:Q s) ratio is therefore approximately 0.5. This
typically results in a decrease in the ventricular volume load,
improved ventricular function, and improved AV valve function.
Patients with clinical signs of significantly elevated superior vena
cava pressure may have obstruction at the anastomosis, distal
pulmonary artery distortion, or marked elevations in PVR.
Excessive cyanosis (oxygen saturation < 75%) should be
investigated promptly. Etiologies include pulmonary or systemic
venous desaturation or decreased pulmonary blood flow because
of venous collaterals. Transient, or rarely permanent, sinus node
dysfunction is common and responds well to chronotropic agents
or temporary atrial pacing.33
The Glenn procedure is followed by the third state of the repair
of total cavopulmonary anastomosis or the Fontan circulation,
whereby the inferior vena cava is connected to the pulmonary
artery (Figure 77). Postoperative management after the Fontan
operation must be specifically tailored to the preoperative anatomy
and physiology as well as to the specific type of surgical procedure
performed. In general, it is geared toward optimizing cardiac
output at the lowest central venous pressure possible. Low cardiac
output may be caused by inadequate preload due to hypovolemia
(low right atrial and left atrial pressures), elevated PVR (low left
atrial and high right atrial pressures), or anatomic obstruction in
the systemic venous pathway. Alternatively, low cardiac output
in the face of high left atrial pressure is an ominous sign and
may be due to ventricular dysfunction, loss of AV synchrony, AV
valve regurgitation, or ventricular outflow obstruction. Significant
arrhythmias (e.g., junctional ectopic tachycardia) are particularly
poorly tolerated in this patient population. Mechanical positive-
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Figure 7-7. Hypoplastic left heart syndrome after establishment of a

total cavopulmonary anastomosis.
pressure ventilation with increased mean airway pressures may

adversely affect PVR and ventricular filling. Early institution of
spontaneous ventilation may improve hemodynamic function in
the awake state. The duration and frequency of pleural and pericardial effusions, typically the most frequent postoperative problem requiring prolonged hospitalization, have been reduced with
the use of baffle fenestrations and the adjustable atrial septal
defect.34
SUMMARY
The wide spectrum of diseases, resulting physiologic responses,
and modes of treatment make the care of infants with congenital
heart disease particularly challenging. The relationship between
pulmonary physiology, ventilation, and cardiac physiology is
almost ubiquitous and must be taken into account when assessing
and managing these patients. Those providing anesthetic care for
patients with congenital heart disease may be called upon to
provide anesthetic care for surgical correction or palliation directly
related to the congenital heart disease, during diagnostic and
therapeutic cardiac catheterization, or for surgical procedures
unrelated to the congenital heart disease. Given the frequent
occurrence of multiple congenital anomalies, these patients
frequently require anesthetic care at various stages of their lives
for procedures outside of the cardiovascular system. The care of
children with complex abnormalities should be in specialized
units staffed by subspecialty experts, at all levels, in the management of children with congenital heart disease.
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16. Ferencz C, Rubin JD, McCarter RJ, Clark EB. Maternal diabetes and
cardiovascular malformation: predominance of double outlet right
ventricle and truncus arteriosus. Teratology. 1990;14:313326.
17. Rouse B, Azen C, Koch R, et al. Maternal Phenylketonuria Collaborative Study (MPKUCS) offspring: facial anomalies, malformations,
and early neurological sequelae. Am J Med Genet. 1997;69:8995.
18. Lee LA. The clinical spectrum of neonatal lupus. Arch Dermatol Res.
2009;301:107110.
19. Lougheed J, Sinclair BG, Fung Kee Fung K, et al. Acquired right
ventricular outflow tract obstruction in the recipient twin in twintwin transfusion syndrome. J Am Coll Cardiol. 2001;38:15331538.
20. Schall SA, Dalldorf FG. Premature closure of the foramen ovale and
hypoplasia of the left heart. Int J Cardiol. 1984;5(1):103107.
21. Tchervenkov CI, Jacobs ML, Tahta SA. Congenital Heart Surgery
Nomenclature and Database Project: hypoplastic left heart syndrome.
Ann Thorac Surg. 2000;69:S170S179.
22. Corno AF. Borderline left ventricle. Eur J Cardiothorac Surg. 2005;
27:6773.
23. Tchervenkov CI, Jacobs JP, Weinberg PM, et al. The nomenclature,
definition and classification of hypoplastic left heart syndrome.
Cardiol Young. 2006;16:339368.
24. Cohen MS, Rychik J. The small left ventricle: how small is too small
for biventricular repair? Semin Thorac Cardiovasc Surg Pediatr Card
Surg Annu. 1999;2:189202.
25. Rudolph AM. Fetal and neonatal pulmonary circulation. Am Rev
Respir Dis. 1977;115:1118.
26. Wren C, Richmond S, Donaldson L. Presentation of congenital heart
disease in infancy: implications for routine examination. Arch Dis
Child Fetal Neonatal Ed. 1999;80:F49F53.
27. Schulze-Neick I, Li J, Penny DJ, Redington AN. Pulmonary vascular
resistance after cardiopulmonary bypass in infants: effect on postoperative recovery. J Thorac Cardiovasc Surg. 2001;121:10331039.
28. Calderone CA, Benson L, Holtby H, et al. Initial experience with
hybrid palliation for neonates with single-ventricle physiology. Ann
Thorac Surg. 2007;84:12941300.
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29. Akinturk H, Michel-Behnke I, Valeske K, et al. Hybrid transcathetersurgical palliation: basis for univentricular or biventricular repair:
the Giessen experience. Pediatr Cardiol. 2007;28:7987.
30. De Oliveira NC, Ashburn DA, Khalid F, et al. Prevention of early
sudden circulatory collapse after the Norwood operation. Circulation.
2004;110(11 Suppl 1):II133II138.
31. Guzzetta NA. Phenoxybenzamine in the treatment of hypoplastic left heart syndrome: a core review. Anesth Analg. 2007;105:
312315.
32. Li J, Zhang G, Holtby H, et al. Carbon dioxidea complex gas in a

complex circulation: its effects on systemic hemodynamics and oxygen transport, cerebral, and splanchnic circulation in neonates after the
Norwood procedure. J Thorac Cardiovasc Surg. 2008;136:12071214.
33. Cohen MI, Wernovsky G, Vetter VL, et alA. Sinus node function after
a systematically staged Fontan procedure. Circulation. 1998;98
(19 Suppl):II352II358.
34. Mott AR, Spray TL, Gaynor JW, et al. Improved early results with
cavopulmonary connections. Cardiol Young. 2001;11:311.
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Airway Development
Pierre Fayoux and Bruno Marciniak
INTRODUCTION
During the course of development, the upper airway undergoes
significant anatomic restructuring from the neonatal period to
adulthood. Anatomic restructuringincluding changes in size
and shape and the anatomic relationship between the various
componentsis particularly prominent during the first few years
of life. Many of the specific anatomic variations and differences of
the newborn and premature airway are important to outline and
consider because of their implications for airway management.
This chapter separates the discussion of airway development into
three parts: the face and the nasal chamber, the oropharynx including the tongue, and the laryngotracheal lumen. For each part,
the embryologic development and the morphologic modification
during the fetal period, infancy, and childhood are detailed.
THE FACE
Embryologic Considerations
The development of the skull can be divided into two major parts:
the development of the neurocranium, which forms the cranial
vault and skull base, and the viscerocranium, which forms the
skeletal part of the face. Most of the structures of the face and neck
originate from the first two branchial (pharyngeal) arches,
consisting of an outer layer of ectodermal tissue and an inner layer
of epithelium of endodermal origin. Both of these enclose the core
of mesenchymal tissue. The mesenchyma for the formation of the
cranial structures is from the para-axial and lateral plate mesoderm, together with a substantial part from neural crest cells.
These neural crest cells of the developing 3- to 4-week embryo,
composed of ectoderm, are found at the junction of the neural
plate and surface ectoderm. Neural crest cells migrate to the
branchial arch mesoderm. The face develops as a result of this
massive cell migration and their interactions with differentiating
cells of mesodermal origin, which contribute to the skeletal
components of the face.
The dorsal portion of the viscerocranium, originating from the
first pharyngeal arch, forms the maxillary process. This process
extends forward and forms the premaxilla, maxilla, zygomatic
bone, and part of the temporal bone. The anterior part also forms
the mandibular process and gives rise to the mandible. The dorsal
part of the mandibular process, together with the structures originating from the second pharyngeal arch, forms the ossicles of the
middle ear.
The caudal boundary of the oral cavity is less complex, consisting of the paired primordium of the mandibular arch. Appearing
8
C H A P T E R
first on either side of the midline are marked local thickenings

resulting from the rapid proliferation of mesenchymal tissue. Until
these thickenings have extended from either side to merge in the
midline, a conspicuous midline notch remains. With their merger,
the arch of the lower jaw is completed.1 The primitive mouth
(stomodeum) appears as a slight depression in the surface ectoderm separated by the oropharyngeal membrane. This membrane
ruptures at 24 to 26 days of gestation. With rupture of the membrane, the primitive gut communicates with the amniotic cavity.2
At 28 days of gestation, the face begins to show its eventual
relationship to the five primordia from which it is derived: the
frontonasal prominence (the cranial boundary of the stomodeum
or primitive mouth); the paired maxillary prominences (first
branchial arch); and the paired mandibular prominences (also
derived from the first branchial arch). The mandibular prominences grow medially and begin to merge with each other by the
end of the fourth week of gestation, forming the lower lip, the chin,
and the mandible.2 The midface is formed through the proliferation of the facial primordial tissue between 4 and 8 weeks of
gestation. The nasomedial prominence expands and displaces the
forebrain prominence from the forming mouth by merging in the
midline. The nasomedial prominences also fuse with the rapidly
elongating maxillary processes to complete the formation of the
tissues that constitute the upper jaw and lip. The segment of the
upper jaw, which is of medial nasal origin, gives rise externally to
the upper lip in the region of the philtrum. A deeper triangular
portion of the fused nasomedial prominence becomes the premaxillary portion of the dental arch as well as the median (primary) part of the palate. The intermaxillary segment in the central
portion of the upper lip area consists of three parts: the labial component, forming the philtrum; a maxillary component associated
with the four upper central incisor teeth; and a palatal component,
which becomes the primary palate. The upper lip is formed by the
merging of the maxillary prominences with the nasomedial
prominences.
During the second month of gestation, the development of the
palate separates the nasomaxillary complex from the oral cavity.
The premaxilla forms from the fusion of the globular processes of
the nasomedian process forming a small triangular median
portion of the palate (primary palate). The main part of the palate
(secondary palate) is derived from the maxillary process. It
develops in a medial direction, fusing in the midline, and unites
with the premaxilla and the developing nasal septum. The soft
palate forms from continued growth of the posterior edge of these
palatal processes, ending with the formation and fusion of the two
halves of the uvula.
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The nose originates in the cranial ectoderm, which subsequently develops into the frontonasal prominence, with the formation of nasal placodes during the third week of development. The
superior portion of the nose is formed from the nasolateral processes, whereas the inferior portion of the nasal cavity is incomplete until the paired maxillary processes of the first branchial arch
grow anteriorly and medially to fuse with the nasomedial processes. The nasomedial processes merge on the midline to form
the upper lip and the septum of the nose, which serves to separate
the two nasal chambers. The nasal chambers extend posteriorly
during development under the influence of the posteriorly directed fusion of the palatal processes. As this occurs, the membrane
that separates the two nasal chambers from the oral cavity thins.
By the 38th day of development, the two-layer oronasal membrane, consisting of nasal and oral epithelium, ruptures, forming
the choanae. The principal stages of craniofacial and nasopharyngeal development are illustrated in Figure 81.
Morphologic Considerations
The development of the face is influenced by the development of
the system of paranasal sinuses. Originally, because the sinuses are
absent, the facial structures are small compared with the neurocranium. The first signs of the development of the maxillary sinus
are evident at approximately the 10th week of gestation as a pouch
in the lateral wall of the ethmoidal infundibulum. The other
paranasal sinuses also begin their formation during the fetal
period as diverticuli of the lateral nasal wall and gradually differentiate inside the cranial bones to form the ethmoid, frontal,
and sphenoid sinuses. The sinuses develop postnatally. Their
maturation is not complete until adolescence or early adulthood.
The maxillary and ethmoidal sinuses are present at birth, whereas
the frontal and sphenoidal sinuses are not clinically detectable at
birth. Development begins around 2 years of age. Frontal sinuses
can usually not be detected radiographically until about 7 years of
age. The paranasal sinuses will not reach their final shape and size
until the end of puberty, giving the final appearance to the face.35
The skull base grows rapidly until 6 years of age, with relatively
slower growth thereafter.6 In addition, the cranial base flexes
postnatally during the rapid growth trajectory that is complete by
2 years of age. Modification of this angulation can occur as a result
of growth within the sphenooccipital, midsphenoidal, and sphenoethmoid synchondroses as well as from differential drift and
rotation of the components of the basioccipital, sphenoid, and
ethmoid relative to each other.7 The depth of the nasopharynx
increases because of remodeling of the palate as well as changes
in the angulation of the skull base.2 The soft tissues of the pharyngeal structures surrounding the upper airway grow proportionally
to the skeletal structures during the chilhood.8 Postnatally, the
dimensions of the nasal cavity increase very quickly. During the
first year of life, the total minimal cross-sectional area increases
by 67%, and the volume of the nasal airways increases by 36%
when measured by acoustic rhinometry.9 Choanal diameter also
undergoes rapid growth until 2 years of age and does not reach
its maximum size until 14 years of age.10 The volume of the
newborn oral cavity is proportionally less than that of an adult,
owing to the significantly shorter mandibular rami. The volume of
the oral cavity increases during the first 12 months of life because
of rapid growth in the height of the mandibular rami and eruption
of the dentition, which leads to enlargement of the lower face
(Figure 82).11
Figure 8-1. Embryologic development of the upper airway. The

principal stages of airway development during the embryologic period
are shown. Right column, Craniofacial development. Left column,
Nasopharyngolaryngeal development.
OROPHARYNX AND TONGUE

The primordial areas involved in forming the covering of the
tongue appear early during the second month of development.1
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With all of the shiftings of the components that occur as the
tongue develops, a small pit known as the foramen cecum delineates the border between the parts of the tongue that are formed
from the first and second branchial arches. The foramen cecum
is a vestige of the invagination from the floor of the pharynx that
gives rise to the thyroid primordium.
Compared with the adult tongue, the neonatal tongue12 contains
considerably less fat and soft tissue, a relatively enlarged extrinsic
musculature, and a less-developed superior longitudinal muscle,
resulting in a flatter dorsal surface and a larger tongue than that of
the adult configuration. Attachments between the extrinsic muscles and the transverse muscle, present only in the neonatal
tongue, may explain the poor lateral mobility of this structure.
LARYNX AND TRACHEA

Figure 8-2. Maturation of craniofacial and mandibular structures,

based on three-dimensional reconstructions of images from a computed tomography (CT) scanner (Osirix software). The volume of the
newborn oral cavity is proportionally lower than that of the adult
because of the significantly shorter mandibular ramus. The volume of
the oral cavity increases significantly during the first 12 months of life
because of rapid growth in the height of the mandibular ramus and
eruption of the dentition, which lead to enlargement of the lower face.
The tongue surface arises primarily from the mesenchyma of the

first arch, with significant contributions from the third and fourth
arches. In 5-week-old embryos, paired lateral thickenings, the
lateral lingual swellings, arise as a result of the rapid proliferation
of the mesenchyma beneath the overlying epithelium. These
structures border a posterior small median elevation known as the
tuberculum impar. Behind the tuberculum impar, the copula,
another median elevation, unites the second and third second
arches into a midventral prominence. The copula extends in a
cephalocaudad direction from the tuberculum impar to the
primordial swelling that marks the beginning of the epiglottis.
The larynx is developed embryologically from ectodermal,

endodermal, and mesodermal tissues that are derived from the
third, fourth, and sixth branchial arches and pouches.1,3,4,13 The
laryngeal cartilages and muscles form from the mesenchyma of
the fourth and sixth pharyngeal arches. Cartilaginous tissues from
these pharyngeal arches fuse to form the cartilaginous structures
of the airway including the arytenoid, thyroid, cricoid, corniculate,
and cuneiform cartilages. The hyoid bone is derived from the
second branchial arch (lesser horn and superior portion of the
body) and the third branchial arch (greater horn and inferior part
of the body). During the fourth week of embryonic life, a ventral
and midline diverticulum arises from the foregut, referred to as
the respiratory primordium. As this primordium deepens, it
becomes the laryngotracheal tube. The laryngotracheal groove
fuses from the caudal to the cephalic end, forming a tracheoesophageal septum that separates the laryngotracheal groove from
the esophagus. In the fifth to sixth embryologic week, three masses
of tissue appear around the primordial glottic slit at the base of
the third and fourth branchial arches.13 At approximately 6 weeks
of embryonic age, with the rapid proliferation of the mesenchyma
at the end of the laryngotracheal tube into the arytenoid prominences, the laryngeal entrance develops from a simple slit to a
T-shaped opening located directly below the epiglottal swelling.
The epiglottis itself develops from the caudal part of the eminentia
hypobranchialis (anterior parts of the third and fourth pharyngeal
arches). Between the arytenoid prominences is the epithelial
lamina, limited cephalad by the vestibulotracheal canal and
caudad by the pharyngotracheal canal. The rapid proliferation of
the laryngeal epithelium leads to temporary occlusion of the
lumen (Figure 83). After recanalization of the lumen at about
10 weeks of gestation, a pair of lateral recesses (laryngeal ventricles) remains. Around the lateral recesses, the true and false
vocal cords can be recognized as mesenchymal bands. During the
next 6 weeks, the larynx develops almost to its definitive appearance with the formation of thyroid, cricoid, and arytenoid
cartilages from the mesenchyma and further differentiation of the
epiglottis.5 At the end of the embryologic period, the larynx
structures are macroscopically differentiated. The fetal period is
characterized by the maturation of laryngeal ultrastructures,
particularly at the glottic level.14
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Airway Development
103
Figure 8-3. Median cross-section through the neck of a human embryo at 8 weeks. The laryngeal cartilages can be identified. The epithelial
lamina is limited cephalad by the vestibulotracheal canal and caudad by
the pharyngotracheal canal. At this stage, the glottic lumen is occluded.
Figure 8-4. Evolution of

laryngeal lumen morphology.
The neonatal larynx has a
conical shape, wider at the
supraglottic level and narrower in the subglottic level.
The larynx of an older infant
or adult larynx has a symmetrical cylindrical shape. The
hyolaryngeal descent leads to
a decrease in the pharyngolaryngotracheal angle.
Neonatal laryngeal morphology differs significantly from that of

the adult and major postnatal changes occur during the first year
of life. The larynx has a conical shape in infants and children,
wider at the supraglottic level and narrower at the subglottic level.
The adult larynx has more of a symmetrical cylindrical shape
(Figure 84).15,16 The neonatal supraglottic area has larger ventricular bands, larger arytenoids, and a shorter epiglottis, the latter
frequently configured in a U or an (omega) shape (Figure 85).
The angle between the epiglottis and the glottic plane is more
acute than in the adult. Neonatal vocal cords are shorter than those
of the adult, representing only the anterior half of the glottis, the
posterior half being covered by vocal process of arytenoids (Figure
86).17 The maturational descent of the larynx, considered as an
essential event in the transition from an obligate nasal to oral
breather, results in the further separation of the epiglottis from the
soft palate.
At 23 to 25 weeks of embryonic life, the fetal hyoid and larynx
are high relative to the cervical vertebrae, with the larynx extending from the basioccipital level to the level of the third and fourth
cervical vertebrae (C34).18,19 In the neonate, the hyoid lies opposite the junction between C2 and C3, just inferior to the mandible, with the larynx extending down to C3 to C4.18,20 By 2 years of
age, the hyoid and larynx have attained their adult position relative
to the cervical vertebrae, with the superior margin of the hyoid
body opposite the junction between C3 and C4 (Figure 87).21,22
During the majority of postnatal growth, the hyolaryngeal complex descends relative to the face and cranial base, but not relative
to the vertebral column.11 However, the hyoid descends relative to
the palatal plane during the first year of life, presumably because
of rapid growth in the height of the mandibular ramus. The
maturational position of the tip of the epiglottis relative to the
vertebral level is controversial, with a biphasic pattern according
to Sasaki23 and Westhorpe22 or a gradual linear descent according
to Schwartz and Keller.24 Schwartz and Keller reported that the tip
of the epiglottis is opposite the middle of the body of C2 in
children 1 day to 24 months of age, at the inferior end of the plate
of C2 in children 25 months to 10 years of age, and at the C23
intervertebral disk in adolescents.24 The hyolaryngeal descent
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Figure 8-5. Morphologic changes of the supraglottic structures

Endoscopic views of the supraglottic larynx. The supraglottic area
of a neonate has larger ventricular bands, larger arytenoids, and a
shorter epiglottis, which is frequently U or (omega) shaped.
relative to the craniovertebral structures leads to a decrease in the

orolaryngopharyngeal angle25 and the laryngotracheal angle (see
Figure 84).
Laryngotracheal measurements grow in a quasilinear fashion
during the fetal period, with a linear relationship observed between the laryngotracheal measurements and either body weight
or height.2628 The exception is the glottis, which has a curvilinear
growth pattern.26,28 The cricoid lumen is significantly less than the
tracheal and glottic lumens during perinatal period, thereby
representing the narrowest section of the airway.17,28 Sasaki23 and
Wailoo and Emery29 suggested that there were three phases of
laryngotracheal lumen growth (fetal period, birth to prepubertal
period, and postpubertal period), with the greatest growth occurring during the earliest period and decreasing thereafter.
Litman and colleagues30 and Arens and associates8 reported a
linear growth pattern of the laryngotracheal lumen during childhood. The evolution of cricoid and tracheal luminal dimensions
during childhood reported is outlined in Table 81.10,23,2634
Consequences of Anatomic Differences in

Pediatric Airway Management
Anatomic differences of the neonatal airway suggest the need for
the consideration of modifications of technique and equipment
Figure 8-7. Maturational descent of the larynx. The maturational

descent of the larynx is shown on parasagittal CT images. In the
newborn, the hyoid lies opposite the junction between C2 and C3, and
the glottis lies opposite the junction between C3 and C4. After 2 years
of age, the hyoid and larynx have attained their adult position relative
to the cervical vertebrae, as illustrated by this 13-year-old patient. The
hyoid body projects opposite the junction between C3 and C4 and the
glottis is opposite C5.
during airway management in the premature and neonatal population. The management of the neonatal pediatric airway is
discussed in detail in chapters 43 and 72. However, the specific
implications of some of the anatomic and morphologic differences
are reviewed.
The development of the mandibulofacial skeleton and modifications of the relationship between the soft palate and the tongue
make classic predictive tools of intubation such as the Mallampati
score inappropriate in pediatric population. The high position of
the neonatal larynx leads to a more anterior location of the glottis
during laryngoscopy. Because of the supraglottic morphology,
high position of the larynx, and acute glottoepiglottic angle, the
direct visualization of the glottic plane is more difficult in neonates. As such, the Cormak classification is also not applicable.
Moreover, the frequency of laryngomalacia in this age group may
further decrease the visualization of the glottis. In this case, the
most effective landmark for placement of an endotracheal tube is
the triangle formed by the arytenoid cartilages and the epiglottis.
The more acute laryngotracheal angle, related to the high position
TABLE 8-1. Development of Laryngotracheal Lumen*
Age
<28 GA
2834 GA
3438 GA
3841 GA
1y
3y
5y
10 y
Figure 8-6. Evolution of the glottis. The vocal cords of a neonate make
up only the anterior half of the glottis whereas the posterior half makes
up the vocal process of the arytenoids. This is compared with the glottis
of a 12-year-old in which the vocal cords make up two thirds of the
glottis.
Laryngeal Diameter,
mm
2.23.1
2.93.5
2.75.5
3.76.4
4.510
612
712
716
Tracheal Diameter,
mm
2.55
2.75.5
36
3.76.5
5.27.8
6.39
810
12
*
The growth of the laryngotracheal lumen according to anatomic and radiologic
studies reported from the literature. See references 10, 23, 2634. The mean
diameters reported in studies of Wailoo and Emery29 and Eckel and coworkers17
were recalculated based on the results expressed, respectively, in perimeter and
surface area of the subglottic cross-section.
GA = gestational age in weeks.
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of the neonatal larynx, not only is associated with a higher
incidence of difficulties during endotracheal intubation but also
results in a higher risk of anterior laryngotracheal injury such as
cricotracheal or cricothyroid dislocation.
The laryngeal structures have some degree of elasticity before
36 weeks of gestation, thereby permitting placement of an
endotracheal tube (ETT) that is larger than that predicted by direct
anatomic measurement.35 Therefore, in the premature population,
the risk of injury is greatest to the posterior glottic region. This
elasticity disappears around term, and the site of injury is then
predominantly in the subglottic area. The traumatic risk is correlated to the outer diameter (OD) of the ETT. Therefore, guidelines regarding sizing of the ETT should focus on the OD and not
the inner diameter (ID). The relationship between the OD and the
ID is different according to different manufacturers because of
differences in the thickness of the wall of the ETT. For similar ODs
of various ETTs, the ID may vary up to 1 mm. This is important
when considering the risk of airway trauma related to the OD of
the ETT and the respiratory resistance during spontaneous
ventilation, which is dependent on the ID of the ETT.
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obstructive anomalies of the upper respiratory-digestive tract. Prenat
Diagn. 1999;19:211218.
28. Fayoux P, Marciniak B, Devisme L, Storme L. Prenatal and early
postnatal morphogenesis and growth of human laryngotracheal
structures. J Anat. 2008;213:8692.
29. Wailoo MP, Emery JL. Normal growth and development of the
trachea. Thorax. 1982;8:584587.
30. Litman RS, Weissend EE, Shibata D, Westesson PL. Developmental
changes of laryngeal dimensions in unparalyzed, sedated children.
Anesthesiology. 2003;98:4145.
31. Too-Chung MA, Green JR. The rate of growth of the cricoid cartilage.
J Laryngol Otol. 1974;88:6570.
32. Tucker GF, Tucker JA, Vidic B. Anatomy and development of the
cricoid. Serial section whole organ study of perinatal larynges. Ann
33. Fishman RA, Pashley NRT. A study of the premature neonatal airway.
Otolaryngol Head Neck Surg. 1981;89:604607.
34. Sellars I, Keen EN. Laryngeal growth in infancy. J Laryngol Otol.
1990;104:622625.
35. Fayoux P, Devisme L, Merrot O, Marciniak B. Determination of
endotracheal tube size in a perinatal population. An anatomical and
experimental study. Anesthesiology. 2006;104:954960.
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Respiratory Physiology
Etsuro K. Motoyama
INTRODUCTION
Pediatric anesthesia involves perioperative and critical care of
patients of all sizes between preterm infants weighing less than
1 kg and teenagers weighing well over 100 times that of small
infants. Physiologic differences between the two extremes of
pediatric patients may even be more significant than their
differences in body size. In order for an infant to survive in the
extrauterine environment, the circulatory and respiratory systems
must undergo the most drastic changes during the first few
minutes of life. The neonate must exercise the effective neural
drive and respiratory muscles to displace the fluids filling the
airways and pulmonary alveoli and introduce sufficient air into
the lungs against the surface tension to establish sufficient alveolar
surface for pulmonary gas exchange. In response to rapid increases
in blood O2 tensions, pulmonary vascular beds must dilate rapidly
and increase pulmonary blood flow so as to establish regional
alveolar ventilation-pulmonary perfusion balance and maintain
adequate pulmonary gas exchange. Simultaneously, the pattern of
circulation must change from fetal placental circulationin which
the right and left heart outputs function in parallel, perfusing the
lower and upper portions of the body, respectivelyto the adulttype circulation with the circulation of blood through the right
and left sides of the heart in series.
Neonatal adaptation of the medullary respiratory control and
lung mechanics evolves much more slowly than circulatory
adaptation, which takes at least several weeks. Even beyond this
period of adaptation, the maturation of the infants lungs and the
chest wall, which support the stability of lung inflation, continues
during the first year and beyond. These different cardiorespiratory
characteristics in infants and young children make anesthetic
management quite different and extremely challenging for
pediatric anesthesiologists.
In this chapter, we first review the prenatal development of the
lungs and neonatal adaptation. We then review the postnatal
development and growth of the lung and thorax. We also discuss
some essential and practical aspects of respiratory physiology in
infants and children that have direct and indirect relevance to
pediatric anesthesiology. Such information is indispensable for a
better understanding of the complexity of neonatal physiology and
for the proper care of infants and young children during the
perioperative period.
C H A P T E R
DEVELOPMENT OF THE
RESPIRATORY SYSTEM
Prenatal Development of the Lung
The morphologic development of the human lung is seen as early
as several weeks into the embryonic period and continues well into
the first decade and beyond of the postnatal life (Figure 91).1 The
entire endodermal structure of the lung arises from the primitive
foregut as a ventral pouch in the third week of embryonic
development when the fetus is only 3 mm in length. The outgrowth
of the endodermal cavity together with surrounding mesenchymal
tissue projects into the pleuroperitoneal cavity to form lung buds.
The future airway and alveolar membranes including mucous
glands are derived from the endoderm; whereas the smooth
muscle, cartilage, connective tissues, lymph, and blood vessels
originate from the mesenchymal elements surrounding the lung
buds.2 During the pseudoglandular period, which extends into the
17th week of gestation, the budding of bronchi and the growth of
lung tissues progress rapidly. At the end of this period, preacinar
branching of the future airways down to the terminal bronchioles
are all but completed.3 Any disturbance of the free expansion of the
developing lung in this period, as seen in congenital diaphragmatic
hernia, results in hypoplasia of the lung and airway branching.4
The canalicular period, which extends into the 24th week of gestation, is characterized by airway branching into future respiratory
bronchioles, as the relative amount of the connective tissues
diminishes. At the same time, there is increased secretory gland
and capillary formation around the airways.2
At approximately the 24th week of gestation, at the beginning
of the terminal sac (alveolar) period, clusters of terminal air sacs
appear with flattened epithelia.5 These terminal air sacs (saccules)
are larger with relatively thicker walls with fewer capillaries than
future alveoli.6 Type II pneumocytes, which produce pulmonary
surfactant, appear at 24 to 26 weeks of gestation but occasionally
as early as the 20th week.7 At 26 to 28 weeks of gestation, the
proliferation of the capillaries surrounding the saccules becomes
sufficient for pulmonary gas exchange.8 These morphologic and
biochemical developments may occur earlier in some extremely
premature infants born before the 25th week of gestation who
survive with neonatal intensive care.
From the 28th week of gestation onward, the wall thickness of
the saccules decreases rapidly with increasing septal capillary
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Respiratory Physiology 107
Figure 9-1. Stages of human lung development and their timing. Note overlapping between stages, particularly between the alveolar stage and the stage of microvascular maturation. Open-ended bars indicate uncertainty as to exact
timing. From Zeltner TB, Burri PH. The postnatal development and growth of the human lung. II. Morphology. Respir
Physiol. 1987;67:269, with permission.
networks. There is further lengthening of terminal air sacs with

the possible additional development of air spaces. The formation
of alveoli from the terminal saccules occurs in some human fetuses
as early as the 32nd week of gestation. By the 36th week of
gestation, alveoli are consistently present,9 although the majority
of the terminal air sacs are primarily saccules at the time of birth
with further growth of alveoli during the postnatal period.
The lung produces a large quantity of liquid, which expands the
airways while the larynx is closed. This expansion helps to stimulate
lung growth and development. The lung fluid is periodically
expelled into the uterine cavity, contributing approximately one
third of the total amniotic fluid. During the 1990s, prenatal ligation
or occlusion of the trachea was thought to be a potential treatment
of the fetus with congenital diaphragmatic hernia (CDH).10 This
treatment causes the expansion of the fetal airways and results in
accelerated growth of the otherwise hypoplastic lung. Fetal surgery
for the repair of CDH was eventually abandoned.11
Idiopathic respiratory distress syndrome (IRDS) or hyaline
membrane disease (HMD) occurring in prematurely born infants
is the most common cause of neonatal maladaptation and is caused
by the immaturity of the lung, with its insufficient pulmonary
surfactant production and inactivation. Experimental studies in
animals have shown that certain hormones, such as cortisone12,13
and thyroxine,14 enhance lung maturation, as evidenced by the
earlier appearance of type II pneumocytes and surfactant
production. In 1972, Liggins and Howie15 reported the first clinical
study that demonstrated an acceleration of lung maturation in the

fetus after the administration of corticosteroids to mothers 24
to 48 hours before the delivery of premature infants. Prenatal
glucocorticoid therapy has been used routinely since the 1980s to
induce lung maturation and surfactant synthesis in mothers at risk
of premature delivery.
Perinatal Adaptation
At birth, the infant must overcome the high surface tension within
the alveoli with its first several breaths to introduce air into the
liquid-filled lung. Even a normal full-term infant with sufficient
surfactant available must exert a large negative pleural pressure
(80 cmH2O) to overcome the surface force/tension (Figure
92).16 The fluid in the trachea and the rest of the airways is
expelled quickly through the upper airways, whereas residual fluid
leaves the lung more slowly through the lymphatic system and the
pulmonary circulation. With the expansion of the lung, arterial
oxygen tension (PaO2) increases, dramatically reducing pulmonary vascular resistance. The resultant large increase in pulmonary
blood flow and the increase in left atrial pressure and the decrease
in right atrial pressure reverse the pressure gradient across the
atria and functionally close the foramen ovale. The accelerated
production of pulmonary surfactant and its abundant presence on
the alveolar surface is essential for the smooth transition from the
fetal to the neonatal state.
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Figure 9-2. A: A pressure-volume curve of expansion of a gas-free lung. AB represents the initial expansion. In the example,
approximately 13 cmH2O pressure will be necessary to overcome surface forces. C represents deflation to zero pressure with
gas trapping. B: Pressure-volume relationships during the first breath of a newborn weighing 4.3 kg. Here, 60 to 70 cm H2O
pressure was necessary to overcome the surface forces. A and B: From reference 16, with permission.
Postnatal Development of
the Lung and Thorax
The development and growth of the lung and surrounding thorax
continue with amazing speed during the first year of life; the
morphologic development of the lungs, however, continues
throughout the first decade of life. Although the formation of the
airway system, down to the terminal bronchioles, is completed by
the 16th week of gestation,3 alveolar formation in human fetuses
begins only at about the 36th week of gestation. At birth, the
number of terminal air sacs (most of which are saccules) is
between 20 and 50 million, less than one tenth that of adults. The
postnatal development of alveoli from primitive saccules occurs
more rapidly than previously assumed and is essentially completed
by 18 months of age.9
During the early postnatal period, the lung volume of infants is
disproportionately small in relation to body size. In addition,
because of higher metabolic rates in infants (O2 consumption per
unit body weight is twice as high as that of adults), the ventilatory
requirement per unit of lung volume in infants is markedly
increased. Thus, infants have much less reserve of lung surface area
for gas exchange. This is an important reason why infants and
young children develop rapid O2 desaturation with hypoventilation
or apnea of a relatively short duration.
In the neonate, static (elastic) recoil pressure of the lung is very
low (i.e., compliance is high), not unlike that of geriatric or
emphysematous lungs with diminished elastic recoil, because the
development of elastic fibers does not occur until the postnatal
period.1719 Perhaps more important clinically, the elastic recoil
pressure of the thorax (chest wall) is extremely low because of the
infants very compliant cartilaginous rib cage with its limited
thoracic muscle mass (see Control of Breathing). These unique
characteristics make infants more prone to lung collapse and
respiratory insufficiency, especially under general anesthesia (see
Anesthetic Effect on Respiratory Muscles). Throughout infancy
and childhood, static recoil pressure of the lung steadily increases
(compliance, normalized for size, decreases) toward normal values
for young adults.20,21
The actual size of the airway from the larynx to the bronchioles
in infants and children, of course, is much smaller than that in
adolescents and adults, and flow resistance in absolute terms is

higher. However, when normalized for per unit lung volume or
body size, infants airway size as well as airway resistance is
generally lower than in adults.22,23 For example, the upper airway
caliber of a 3.5-kg neonate (3.5 mm endotracheal [ET] tube size)
is relatively larger than that of a 70-kg adult (89 mm ET tube).
These findings do not necessarily conflict with the clinical
evidence that infants and toddlers are more prone to severe
obstruction of upper and lower airways. The absolute (not relative)
airway diameters in infants are much smaller than those in
adults, and young children develop upper airway obstruction
more often and more severely than do adults. Given the smaller
cross-sectional area of the pediatric airway, relatively mild
airway inflammation, edema, or secretions can lead to far-greater
degrees of obstruction in the subglottic (croup) to bronchiolar
(bronchiolitis) airways in infants than in adults.
CONTROL OF BREATHING
Prenatal Development
Respiratory rhythmogenesis occurs long before parturition.
In 1970, Dawes and coworkers24 were the first to demonstrate
breathing activities with rhythmic diaphragmatic contractions in
fetal lambs. Rhythmic movement of the human fetal thorax was
recorded soon afterward by means of ultrasound techniques.25
More recent studies have demonstrated that breathing activities
in human fetuses occur regularly during the last trimester of
pregnancy. Fetal breathing activities naturally occur only during
REM (rapid eye movement) sleep and are most active with
increased levels of maternal blood sugar a few hours after a
maternal meal.26
Hypoxia depresses, rather than stimulates, fetal respiratory
movement. This suppression may be related to decreased REM
sleep with hypoxia.27 Normally, low fetal arterial PaO2 (carotid
PaO2, 1925 mmHg) may be a physiologic mechanism that
suppresses fetal breathing activities.28 Severe hypoxia induces
gasping, which is independent of the peripheral chemoreceptors
and is unrelated to rhythmic fetal breathing. The near-term fetus
is relatively insensitive to arterial carbon dioxide tension (PaCO2)
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changes. In the fetal lamb, however, extreme hypercapnia (PaCO2
> 60 mmHg) can induce rhythmic breathing movement that is
preceded by a sudden activation of inspiratory muscle tone with
expansion of the thorax and inward movement (inhalation) of
amniotic fluid in amounts of up to 30 to 40 mL/kg (an apparent
increase in functional residual capacity [FRC]) (Motoyama,
unpublished observation). When PaCO2 was reduced, breathing
activities ceased, followed by a reversal of the sequence of events
noted above (i.e., relaxation of the thorax and outward flow of
amniotic fluid).
Perinatal Adaptation
Before the 1980s, the traditional view of the mechanism that
triggers the onset of breathing at birth was that transient fetal
asphyxia during labor and delivery stimulates fetal gasping
followed by rhythmic breathing that is maintained by tactile,
auditory, thermal, and other sensory stimuli. However the onset of
breathing activity occurs weeks before parturition and the onset of
air breathing. It is not clear why and how the fetus must breathe
in utero when respiratory gas exchange is handled by the placenta.
One reason may be prenatal practice or exercise of the respiratory
muscles by the fetus suggested by Dawes.29 Another reason is that
the stretching of the airways and lung parenchyma is an important
stimulus for lung development. Experimental blockade of fetal
breathing with bilateral phrenic nerve sections in the fetal lamb
results in hypoplasia of the lung.30
The current concept of the mechanism of continuous neonatal
breathing may be summarized as follows31,32:
1. Neonatal breathing is but a continuation of breathing activity,
which is present weeks before parturition.
2. The clamping of the umbilical cord is an important factor
initiating or restarting rhythmic breathing.
3. Relative hyperoxia (PaO2 > 4060 mmHg) with air breathing
compared with the low fetal PaO2 (2030 mmHg) augments
and maintains rhythmicity.
Figure 9-3. Effect on breathing 14% O2 (hypoxemia)

from room air and then 100% O2 (hyperoxia) in
three newborn infants. Ventilation (mean standard
error of the mean [sem]) is plotted against time.
During acute hypoxia, there was a transient increase
in ventilation followed by depression. Hyperoxia
increased ventilation. Modified from reference 101.
4. Continuous rhythmicity is independent of PaCO2; it is

unaffected by carotid denervation.
5. Hypoxia depresses or abolishes, rather than stimulates,
continuous breathing.
Control of Breathing in Neonates

and Infants
Response to Hypoxemia
During the first several weeks of life, both full-term and preterm
neonates respond to moderate hypoxemia (15% inhaled O2) with
a transient (a few minutes) increase in breathing followed by
sustained respiratory depression33 (Figure 93). However, in cold
environments, the initial period of transient hyperventilation is
abolished in neonates born between 32 and 37 weeks of gestation,
indicating the importance of maintaining a neutral thermal
environment.34,35 By contrast, when 100% O2 is given, a transient
decrease in ventilation is followed by sustained hyperventilation in
neonates. This ventilatory response to hyperoxia, similar to that of
the fetus, is distinctly different from that of the adult, in whom
ventilation continues to be decreased. 36 By 3 weeks after birth,
hypoxemia induces a sustained increase in ventilation, as is seen
in older children and adults.33
The biphasic depression of ventilation in hypoxemic neonates
has been attributed to central depression, rather than to the
depression of the peripheral chemoreceptors.37 Conversely, in the
study of newborn monkeys under hypoxemia, both tracheal
occlusion pressure (an index of central neuronal drive) and
diaphragmatic electromyogram (EMG) studies increased above
the control levels, during both the initial increase in ventilation
and the subsequent sustained ventilatory depression.38 These
findings imply that the biphasic ventilatory response to hypoxemia
in the neonate results from changes in the mechanics of the
respiratory system (such as increased stiffness or fatigue of the
thoracic muscles or upper airway obstruction), rather than
neuronal depression, as has been assumed.39
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at 10 to 12 months of age.41,43 An addition of 2 to 4% CO2 to the
inspired gas mixture abolishes periodic breathing, probably
because of respiratory stimulation.44
Central apnea of infancy is the cessation of breathing activity
lasting longer than 15 to 20 seconds or a shorter period of apnea
associated with bradycardia (heart rate < 100 beats/min), cyanosis,
or pallor.45 The mechanism of apnea in preterm infants is not well
understood but is related to an immature respiratory control
mechanism.46 Central apnea is relatively rare in full-term neonates
but occurs in the majority of premature infants.41,42 In a more
recent study with data on home monitoring involving more than
1000 infants with sudden infant death syndrome (SIDS), their
siblings, and controls who were monitored consecutively for 180
days (Collaborative Home Infant Monitoring Evaluation or
CHME Study), prolonged central apnea among full-term infants
was shown to be less common than was previously thought. Two
to 3% of healthy full-term infants developed central, obstructive,
or mixed apnea lasting more than 30 seconds during sleep. In
addition, prolonged obstructive sleep apnea (OSA) was observed
in a few normal-term infants with a simple upper respiratory
infection (URI), whereas 15 to 30% of preterm infants developed
prolonged apnea and severe desaturation with a URI.47
Figure 9-4. Mean steady-state CO2 response curves at different inspired oxygen concentrations in eight preterm infants. The slope of
the CO2 response curve decreases with decreasing oxygen. The slope increases with increasing oxygen. From Rigatto H, De La Torre Verduzco
R, Cates DB: Effects of O2 on the ventilatory response to CO2 in
preterm infants. J Appl Physiol. 1975;39:8969.
Response to CO2
Both full-term and preterm neonates respond to increased PaCO2
by increasing ventilation, but to lesser extents than in older infants.
The slope of the CO2 response curve is less in preterm than in
full-term neonates. The CO2 response (slope) increases with
postnatal age, independent of postconceptional age.32,40 Although
this increase in CO2 sensitivity may represent an increase in
chemosensitivity, it may also be due to the improved mechanics of
the respiratory system. In adults, the CO2 response curve increases
in slope as well as shifts to the left with the severity of hypoxemia.
By contrast, in neonates breathing a hypoxic mixture, the CO2
response curve is shifted to the right and the slope decreased.
Furthermore, hyperoxia (breathing 100% O2) shifts the curve to
the left and increases the slope (Figure 94).33
Periodic Breathing and Central Apnea

Full-term neonates sleep most of the time and spend 50% of their
sleep time in active (REM) sleep, compared with the 20% of REM
sleep of adults. Premature neonates stay in REM sleep most of
the time.28,32 Both full-term and premature neonates breathe
irregularly. Periodic breathing, in which rhythmic breathing is
interposed with a series of short apneic spells lasting less than
10 seconds without cyanosis or bradycardia, occurs during both
active and quiet (non-REM) sleep and even during wakefulness.
Although breathing is more irregular in REM sleep than in nonREM sleep, periodic breathing occurs mostly during quiet sleep.41
The incidence of periodic breathing in full-term neonates is about
80%, whereas it is nearly 100% in premature neonates.41,42 The
frequency of periodic breathing diminishes after 44 weeks
postconception and thereafter with maturation during the first
year of life. It is still present at sometime in nearly 30% of infants
Postoperative Apnea in Premature Infants

With advances in neonatal intensive care and improved survival
of prematurely born infants since the early 1980s, postoperative
apnea has become an important clinical issue in pediatric
anesthesia. There have been controversies regarding the age
at which these expremature infants can be safely discharged
from the hospital after simple surgical procedures such as inguinal
herniorrhaphy. The classic paper by Liu and colleagues and a
number of subsequent studies have shown that prematurely
born infants less than 44 weeks postconception, especially those
with a history of apnea, are at a high risk (2040%) of developing
postoperative apnea.48 Apnea occurs mostly within 12 hours
postoperatively.49 Conversely, Kurth and associates reported
that postoperative apnea could occur as late as 56 weeks postconception.50
More recent studies indicate that a number of compounding
factors are associated with the development of postoperative
apnea, such as the extent of surgery, anesthetic techniques, anemia,
and postoperative hypoxemia.51 It appears that the probability of
postoperative apnea between 44 and 60 weeks postconception is
less than 5%.52,53 The only important exception is the anemic infant
(hematocrit 30%) in whom the risk of developing apnea remains
high regardless of the postconceptional age.51,53
Most of the patients in these reports of postoperative apnea in
preterm infants were anesthetized with halothane and isoflurane,
agents with relatively high lipid solubility that remain in the
body tissues for a prolonged period of time. In the era of newer
anesthetic agents with a much lower lipid solubility (sevoflurane
and desflurane), increased use of total intravenous anesthesia, as
well as the use of regional block, the incidence of postoperative
apnea in preterm infants seems to have decreased.54 Indeed,
postoperative apnea is reported to be significantly lower with
sevoflurane or desflurane anesthesia than with other inhalational
anesthetic agents.55
Both theophylline and caffeine have been known to be effective
in reducing the incidence of apnea in premature infants.42,56
Caffeine is especially useful for prematurely born infants for the
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prevention of postoperative apnea.57 In addition, xanthine

derivatives, including theophylline and caffeine, are known to
strengthen muscle contractility and prevent fatigue.58 Therefore,
respiratory stimulation in the premature infants may occur by
both central and peripheral mechanisms. It is important to note
that hypoxemia or hypoxia induced by upper airway obstruction
(OSA) can trigger central apnea, because cerebral hypoxia is a
potent respiratory depressant. Indeed, many apneic episodes are
found to be mixed apnea and are often triggered by upper airway
obstruction.47
Postoperative Apnea in Children

Postoperative apnea is not limited to expremature infants. Apnea
or hypoventilation can occur in infants and children of all ages as
well as adults who are predisposed to upper airway obstruction
(OSA), not related to neuronal or central apnea. Surgical
correction of upper airway obstruction caused by obstructive
lesions such as micrognathia, macroglossia, adenotonsillar
hypertrophy, and nasal polyps can improve OSA. Children with
Down syndrome (trisomy 21) have an increased incidence of OSA,
which is often exaggerated during the perioperative period
because of the residual depressant effect of anesthetic agents,
opioids, or sedatives.39 With increasing obesity among adolescents
and even among younger children since the later 1990s, especially
in the United States, perioperative OSA has become a more
frequent and important clinical entity for pediatric anesthesiologists.59
Neural Control of Breathing

The mechanism that regulates and maintains pulmonary gas
exchange is remarkably efficient in healthy individuals in whom
PaCO2 is kept within a very narrow range (40 2 mmHg), whereas
O2 consumption and CO2 production vary greatly between states
of rest and exercise. Breathing is achieved by the coordinated
action of a large number of inspiratory and expiratory muscles.
Inspiration is produced mainly by the contraction of the
diaphragm and, to a lesser extent, the external intercostal muscles
and other thoracic muscles, which generate negative pleural
pressure and draw air through the airways to the lung. Expiration
is primarily produced by the elastic recoil of the lung and
the thorax while the sustained contraction (with diminishing
intensity) of the diaphragm and the upper airway muscles
(expiratory braking) impedes and smoothens the expiratory
phase of breathing. Rhythmic contraction and relaxation of the
respiratory muscles are governed by the respiratory centers in
the brainstem and are tightly regulated with multiple feedback
systems that match the level of alveolar ventilation to the
metabolic needs. These feedback mechanisms include central and
peripheral chemoreceptors, stretch receptors in the airways and
lung parenchyma with vagal afferenta, and segmental reflexes in
the spinal cord regulated by muscle spindles.60
Respiratory neurons in the medulla have inherent rhythmicity
even without the rostral brain or sensory afferents. Respiratory
neurons are concentrated in two bilaterally symmetrical areas
(dorsal and ventral groups) near the level of the obex in the
medulla. The dorsal respiratory group (DRG) of respiratory
neurons is located in the dorsomedial medulla and contains
mostly inspiratory neurons. The ventral respiratory group (VRG)
Figure 9-5. Schematic representation of the respiratory neurons on the

dorsal surface of the brainstem. Cross-hatched areas contain predominantly inspiratory neurons, blank areas contain predominantly expiratory neurons, and dashed areas contain both inspiratory and expiratory
neurons. Bt C = Btzinger complex; C1 = first cervical spinal nerve;
CP = cerebellar peduncle; DRG = dorsal respiratory group; 4th Vent =
fourth ventricle; IC = inferior colliculus; NA = nucleus ambiguus; NPA
= nucleus para-ambigualis; NPBL = nucleus parabrachialis lateralis;
NPBM = nucleus parabrachialis medialis; NRA = nucleus retroambigualis; PRG = pontine rerspiratory group; VRG = ventral respiratory
group. Courtesy of Dr. M. Tabatabai.
of neurons is located in the ventrolateral medulla. It consists of

both inspiratory and expiratory neurons61 (Figure 95).
The respiratory rhythm or cycle generated by the respiratory
neurons is composed of three phases: inspiration, postinspiration
(or early expiration), and late expiration. During the inspiration
phase, inspiratory neurons, which are premotor to the phrenic and
intercostal motor nuclei, display an augmented discharge.60 At the
end of the inspiratory phase, inspiratory neurons receive a
transient inhibition (off-switch) that terminates the increase of
inspiratory neuronal activity.61 Afferent inputs to the inspiratory
neurons, especially those from the pulmonary stretch receptors,
which are highly concentrated in the upper trachea, affect the
timing of the off-switch. The larger the airway inflation or tidal
volume (VT), the shorter the duration of inspiration62. During the
postinspiration (or early expiration) phase, the inspiratory
neurons receive both excitatory and inhibitory impulses associated
with active braking of expiratory airflow as the contraction of the
diaphragm gradually diminishes.60 After the postinspiration phase
of the respiratory cycle, lung volume decreases passively to the
preinspiratory level or to FRC. Under certain conditions, such as
during exercise or during the administration of inhalational
anesthetic agents, expiratory muscles may undergo active contractions. In this phase of the respiratory cycle, inspiratory neurons
receive inhibitory postsynaptic potentials in an augmented
pattern. Throughout the expiratory phase of the respiratory cycle,
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decreasing inhibitions of the onset of subsequent inspiration exist.

In addition, various afferent inputs affect the onset of inspiration
or prolong the duration of expiration. More specifically, respiratory neurons are grouped together as follows:
DRG of Neurons
The DRG is spatially associated with the tractus solitarius, the
principal tract for the 9th and 10th cranial nerves. These nerves
carry afferent fibers from the airways and lungs, heart, and
peripheral arterial chemoreceptors. The DRG functions as an
important primary and possibly secondary relay site for visceral
sensory inputs via the glossopharyngeal and vagal afferent fibers.
Furthermore, because many of the inspiratory neurons in the DRG
project to the ipsilateral and contralateral spinal cord and make
excitatory connections with phrenic motor neurons, the DRG
serves as a source of inspiratory drive to phrenic and possibly
external intercostal motor neurons.63
VRG of Neurons
The VRG extends from the rostral to the caudal end of the medulla
and has three subdivisions (see Figure 95). The Botzinger
complex, located in the most rostral part of the medulla in the
vicinity of the retrofacial nucleus, contains mostly expiratory
neurons. These neurons send inhibitory signals to DRG and
VRG neurons and project into the phrenic motor neurons in the
spinal cord, causing inhibition and contributing to the inspiratory
off-switch mechanism.64,65 The middle portion of the VRG is
occupied by the nucleus ambiguus (NA) and nucleus paraambigualis (NPA), which are located side by side. Axons of the
motor neurons originating at the NA project along with other
vagal nerve fibers and innervate laryngeal abductor (inspiratory)
and adductor (expiratory) muscles via the recurrent laryngeal
nerve.66 The NPA contains mostly inspiratory neurons, which
respond to lung inflation. The axons of these neurons project to
both the phrenic and the external intercostal motor neurons in
the spinal cord. The nucleus retroambigualis occupies the caudal
portion of the VRG and contains expiratory neurons whose axons
project into the spinal motor neuron pools of the internal
intercostal and abdominal expiratory muscles.67 The inspiratory
neurons of the DRG send collateral fibers to the inspiratory
neurons of the NPA in the VRG. These connections may provide
ipsilateral synchronization of the inspiratory activity between the
neurons in the DRG and those in the VRG. Furthermore, the
neurons in the NPA send collateral fibers to the contralateral NPA,
and vice versa.65 These connections may be responsible for the
bilateral synchronization of the medullary inspiratory motor
neuron output.
Pontine Respiratory Group of Neurons

An additional group of inspiratory and expiratory neurons exists
in the dorsolateral portion of the rostral pons, although their
function appears to be secondary or ancillary to DRG and VRG of
the medulla. Inspiratory neurons are concentrated ventrolaterally
in the region of the nucleus parabrachialis lateralis, whereas the
expiratory neurons are located more medially in the vicinity of the
nucleus parabrachialis medialis.68 These respiratory neurons are
referred to as the pontine respiratory group (PRG), which, in the
past, was called the pneumotaxic center, a term now considered
obsolete. There are reciprocal projections between the PRG
neurons and the DRG and VRG neurons in the medulla. Electrical
stimulation of the PRG produces rapid shallow breathing, whereas
transection of the brainstem at a level caudal to the PRG results
in prolonged inspiratory time (TI) or apnea with sustained
inspiration (apneusis).63 The PRG probably plays a secondary role
in modifying the inspiratory off-switch mechanism.69
Respiratory Rhythm Generation

Rhythmic breathing can be maintained without the brain rostral
to the pons and in the absence of feedback from peripheral
chemoreceptors. Thus, respiratory rhythmogenesis apparently
takes place in the brain stem. The PRG, DRG, and VRG have all
been considered as possible sites of the central respiratory
pacemaker or pattern generator.70,71 The prevailing view is that
rhythmicity is a property of the synaptic interactions among the
various groups of respiratory, motor, and sensory neurons in the
network.60,72 Studies in neonatal and fetal rats have indicated that
respiratory rhythm is generated in the small cluster of pacemaker
neurons in the ventrolateral medulla near the Boetzinger (preBoetzinger) complex.73,74 Such respiratory rhythmogenesis may be
uniquely needed for the fetus to initiate and maintain breathing
activities when there is little or no feedback from chemoreceptors
to the medulla.
Pulmonary and Thoracic Receptors

The respiratory tract (the upper airways, trachea, and bronchi),
lung, and chest wall have a number of sensory receptors that
respond to mechanical and chemical stimuli. These receptors affect
not only ventilation but also circulatory and other nonrespiratory
functions.
Upper Airway Receptors

The major role of the receptors in the pharynx is associated with
the swallowing function. It involves the inhibition of breathing,
closure of the larynx, and coordinated contractions of the
pharyngeal muscles.75 The larynx has a rich concentration of
various receptors. Activation of these receptors can cause apnea,
coughing, closure of the glottis, laryngospasm, and changes in the
ventilatory pattern.76 These reflexes, which affect the patency of
the upper airway, respond to transmural pressure or airflow
changes. Three types of receptors stimulate the superior laryngeal
nerve: pressure receptors, drive (irritant) receptors, and flow
(or cold) receptors.77 The laryngeal flow receptors produce
inspiratory modulation while breathing room air, but become
silent when inspired air is warmed and fully saturated. The activity
of pressure receptors increases markedly with upper airway
obstruction.77,78
Newborn animals are particularly sensitive to the stimulation
of the superior laryngeal nerve either directly or through the
receptors, which results in ventilatory depression or apnea. In
puppies anesthetized with pentobarbital, water in the laryngeal
lumen produced apnea whereas normal saline with neutral pH did
not. The principal stimulus for the apneic reflex was reduced or
absent chloride ion concentrations.79 The strong inhibitory
responses of various upper airway receptors in the newborn have
been attributed to immaturity of the central nervous system.79
Infants, particularly premature neonates, exhibit a clinically
important airway protective reflex response to fluid at the entrance
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to the larynx.80,81 This reflex seems to trigger prolonged breathholding and apnea in neonates and young children during
inhalation induction of anesthesia. When a small quantity of
warmed saline solution is dripped into the nasopharynx in
sleeping neonates, it pools in the piriform fossa and then overflows
into the interarytenoid space at the entrance to the larynx. This
area is densely populated with various nerve endings and
receptors. The most common response to fluid accumulation is
swallowing. These neonates also respond by central apnea, with
the glottis either open or gently closed. Coughing or awakening
may also occur, but these are infrequent. An apneic response is
more prominent with water than with normal saline solution.80
These findings appear clinically relevant and particularly
important in pediatric anesthesia. During inhalation induction,
pharyngeal reflexes (swallowing) are abolished while laryngeal
reflexes remain intact.82 Secretions would, therefore, accumulate in
the hypopharynx without swallowing, which would cause breathholding or central apnea. Positive-pressure breathing with a mask
and bag, in an attempt to support ventilation, instead of suctioning
the secretions in the larynx, would push secretions further down
into the larynx, stimulating the superior laryngeal nerve and
triggering true laryngospasm.39
The upper airway protective mechanism involves both the
pharynx and the larynx and includes sneezing, swallowing,
coughing, and laryngeal closure. Laryngospasm is a sustained tight
closure of the vocal cords caused by contraction of the adductor
(cricothyroid) muscles that persists beyond the removal of the
initial stimulus triggering the glottic closure. In puppies, it is
elicited by repetitive stimulation of the superior laryngeal nerve.83
By contrast, hyperventilation and hypocapnia as well as light
anesthesia increase the activity of adductor neurons and reduce
the mean threshold of the adductor reflex.75 Hyperthermia and
decreased lung volume also facilitate laryngospasm elicited by
the stimulation of the superior laryngeal nerve.83 By contrast,
hypoventilation and hypercapnia, positive intrathoracic pressure,
and deep anesthesia depress excitatory adductor after-discharge
activity and increase the threshold of the reflex that precipitates
laryngospasm.84 It is interesting to note that hypoxia (PaO2 <
50 mmHg) also increases the threshold for laryngospasm. These
findings are consistent with clinical impressions that laryngospasm occurs most frequently under light anesthesia and that it can
be broken by deepening anesthesia or by awakening the patient. In
addition, laryngospasm can also be broken when the patient
becomes severely hypoxemic, suggesting a fail-safe mechanism by
which asphyxia tends to prevent sustained laryngospasm.39
Furthermore, in puppies, positive upper airway pressure inhibits
the glottic closure reflex and laryngospasm. This finding also
supports the clinical observation that, during emergence from
anesthesia in infants and young children, the maintenance of
positive end-expiratory pressure (PEEP) and inflation of the lung
at the time of extubation seem to reduce both the incidence and
the severity of laryngospasm.39
Tracheobronchial and Pulmonary Receptors

There are three types of major receptors: slowly adapting (pulmonary stretch) receptors (SARs) and rapidly adapting (irritant)
receptors (RARs), both of which are innervated by myelinated
vagal afferents, and unmyelinated C fiber endings or J (juxtaalveolar) receptors.
SARs
SARs are mechanoreceptors that lie within the submucosa of
smooth muscles in the membranous posterior wall of the trachea
and major bronchi.85 SARs are stimulated by the distention of the
airways during inspiration (periodic lung inflation). They inhibit
inspiratory activity (Hering-Breuer inflation reflex) and show little
response to steady levels of lung inflation. Although SARs are
predominantly mechanoreceptors, hypocapnia stimulates and
hypercapnia inhibits their discharge.86
The inflation reflex is important in human newborn infants
as well as in cats in adjusting the pattern of breathing.62,87 In
anesthetized cats, TI is decreased with increasing VT with
hypercapnia, indicating the presence of the inflation reflex in the
normal VT range. Vagotomy abolishes this reflex and TI is
prolonged (Figure 96). In the human adult, TI is independent
of VT until the latter increases to about twice the normal VT, when
the inflation reflex appears. Apnea that is often observed in adult
patients during the emergence from general anesthesia with the
endotracheal tube cuff inflated may be related to the inflation
reflex, because deflation of the cuff often establishes rhythmic
breathing. The upper trachea has a high concentration of stretch
receptors.
RARs
RARs are located within the airway epithelial cells and are most
concentrated in the regions of the carina and large bronchi.88 RARs
react to both mechanical and chemical stimuli and, unlike SARs,
respond rapidly to large inflation, deflation, and distortion of
the lung. In addition, RARs are stimulated by cigarette smoke,
Figure 9-6. Relation between tidal volume (VT) and inspiratory time
(TI) as ventilation is increased in response to respiratory stimuli. Note
that in region I, VT increases without changes in TI. Also shown as
dashed lines are the VT trajectories for three different tidal volumes
in region II. From Berger AJ: Control of breathing. In: Murray JF,
Nadel JA, editors. Textbook of Respiratory Medicine. Philadelphia:
WB Saunders; 1988, with permission.
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ammonia, and other irritant gases, including inhaled anesthetics,

with considerable interindividual variability. RARs are more
consistently stimulated by histamine, prostaglandins, and leukotrienes, suggesting their role in response to pathologic states,
such as bronchial asthma.63 The stimulation of RARs in the large
airways may be responsible for reflexes such as coughing, bronchospasm, and tracheal mucus secretion. Activation of RARs in
the periphery of the airways may produce hyperpnea.
When the vagal afferents are partially blocked by cold temperature, inflation of the lung produces a sustained contraction of the
diaphragm and prolonged inflation of the lung (the paradoxical
reflex of Head). This reflex is most likely mediated by RARs. It may
also be related to the sigh mechanism, which may be triggered by
the collapse of some parts of the lung with quiet breathing and
increasing surface force. In the neonate, mechanical inflation of
the lung initiates a deep, gasping breath, which may be related
to the paradoxical reflex, and helps expand unaerated portions of
the lung.89
C Fiber Endings (J Receptors)

Most afferent axons arising from the lung, heart, and abdominal
viscera are slow-conducting unmyelinated vagal fibers. Studies by
Paintal90 have suggested the presence of such receptors located near
the pulmonary or capillary wall (juxtapulmonary or J receptors).
C fiber endings are stimulated by pulmonary congestion, edema,
or microemboli as well as irritant gases, including inhalational
anesthetic agents. Such stimulation of J receptors causes apnea
followed by rapid shallow breathing as well as bronchoconstriction,
hypersecretion, hypotension, and bradycardia. In addition, stimulation of C fiber endings can provoke severe reflex contraction of
the laryngeal muscles, which may be partially responsible for the
laryngospasm observed during inhalational induction with isoflurane or desflurane. Inhalation of irritant gases or particles causes
a sensation of tightness of the chest, or dyspnea, probably by
activation of pulmonary receptors. Bilateral vagal blockade in some
patients with lung disease abolishes dyspneic sensation and
increases breath-holding time.91
of isolated upper airways to halothane resulted in depression

of respiratory-modulated pressure receptors, whereas irritant
receptors and cold (flow) receptors were consistently stimulated in
a dose-dependent manner.75 Laryngeal pressure receptors may be
a part of the feedback mechanism that maintains the patency of
the upper airways. The depression of this feedback mechanism,
together with the activation of irritant receptors, may play an
important role in the collapse of the upper airways during the
induction of inhalational anesthesia.
Chemical Control of Breathing

Regulation of alveolar ventilation and maintenance of normal
PaCO2 within a very narrow range are the principal functions of
the central (medullary) and peripheral (carotid) chemoreceptors.
Central Chemoreceptors
The central or medullary chemoreceptors, located near the surface
of the ventrolateral medulla, are spatially separated from the
medullary respiratory centers. The central chemoreceptors
respond primarily to changes in hydrogen ion concentration in
the adjacent interstitial fluid and cerebrospinal fluid (CSF), rather
than to changes in PaCO2.93 Because CO2 rapidly passes through
the blood-brain barrier into the CSF, which has a poor buffering
capacity, central chemoreceptors are readily stimulated by
increases in PaCO2. By contrast, ventilatory responses to acute
metabolic acidosis and alkalosis are limited because changes in
hydrogen ion concentration are not rapidly transmitted to CSF.
In chronic acid-base disturbances, the pH of CSF surrounding
the chemoreceptors is generally maintained close to the normal
value of approximately 7.3, regardless of arterial pH.94 Under these
circumstances (patients with chronic obstructive pulmonary
disease or high altitude dwellers), the maintenance of alveolar
ventilation becomes more dependent on the hypoxic stimulation of
the peripheral chemoreceptors (see Peripheral Chemoreceptors).
Peripheral Chemoreceptors
Chest Wall Receptors
The chest wall muscles, especially intercostal muscles (and, to a
lesser extent, the diaphragm), contain various types of mechanoreceptors that can produce respiratory reflexes.92 The two types of
receptors most extensively studied are muscle spindles, which lie
parallel to the extrafusal muscle fibers, and the Golgi tendon
organs, which lie in series with the muscle fibers.63 The muscle
spindles are slowly adapting mechanoreceptors and are innervated
by motor neurons that excite intrafusal fibers of the spindle. The
arrangement of muscle spindles is appropriate for the respiratory
muscle load-compensation mechanism.63 The Golgi tendon
organs are located at the point of insertion of the muscle fiber into
its tendon and are also a slowly adapting mechanoreceptor.
Anesthetic Effects on the Upper Airway Receptors

Inhalation induction of anesthesia in children is often associated
with reflex responses such as breath-holding and laryngospasm.
Studies in animals have demonstrated that inhaled anesthetic
agents stimulate upper airway receptors directly and affect
breathing. In dogs under urethane-chloralose anesthesia and
breathing spontaneously through a tracheostomy, the exposure
The primary site of peripheral chemoreceptors affecting ventilation is in the carotid bodies, located at the bifurcation of the
common carotid artery. Peripheral chemoreceptors react rapidly
to changes in PaCO2 and pH. Their contribution to the ventilatory
drive has been estimated to be about 15% of resting ventilation,
but may be much larger when ventilation is increased.95 The
carotid body has three types of neural components: type I
(glomus) cells, type II (sheath) cells, and sensory nerve fiber
endings.96 Sensory nerve fibers originate at the terminals in
apposition to the glomus cells and travel through the carotid
nerve, which enters the glossopharyngeal nerve. The sheath cells
envelope both the glomus cells and the sensory nerve terminals.63
The carotid bodies are perfused with an extremely high level of
blood flow through a very short artery arising directly from the
internal carotid artery. They rapidly respond to an oscillating
PaCO2, rather than to a constant PaCO2. This mechanism may, in
part, be responsible for exercise-induced hyperventilation.97
The primary and unique role of peripheral chemoreceptors,
however, is their response to decreases in PaO2. Moderate-tosevere hypoxemia (PaO2 < 60 mmHg) results in significant increases in ventilation in a dose-dependent fashion.98 Ventilatory
stimulation, however, is absent in certain hypoxemic or hypoxic
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states, such as moderate-to-severe anemia and carbon monoxide
poisoning. Under these conditions, as PaO2 is kept near normal,
the chemoreceptors are not stimulated despite decreased arterial
O2 content and possible tissue hypoxia. In neonates during the
first several weeks of age, ventilation is depressed, rather than
stimulated, by hypoxemia caused by direct hypoxic suppression or
depression of medullary respiratory centers, although peripheral
chemoreceptor activities are present (see Central Chemoreceptors).
In acute hypoxemia, the ventilatory response via the carotid
chemoreceptors is partially opposed by the effect of hypocapnia
and respiratory alkalosis, which suppresses the central chemoreceptors. Acidification of the CSF by means of medication, such
as acetazolamide, restores hyperventilation (the method used for
acute ascent to high altitude by mountain rescuers). When a
hypoxic environment persists for more than several days or
weeks, for example, during a sojourn to high altitude, ventilation
increases further as CSF bicarbonate decreases and pH returns
toward normal despite continuous hypocapnia.99 In chronic
hypoxemia lasting for years, the carotid bodies gradually lose their
hypoxic response. In high-altitude-dwelling natives of the Andes
and Himalayas, the blunted response of carotid chemoreceptors
to hypoxemia takes 10 to 15 years to develop and is sustained for
a long time.100,101 In cyanotic heart disease in children, the hypoxic
response is lost within a few years, but returns after surgical
correction of right-to-left shunts and restoration of normoxia.102
In patients with chronic respiratory insufficiency and hypercapnia, hypoxemic stimulation of carotid chemoreceptors provides the primary stimulation of the medullary respiratory
centers. If these patients are given O2 and PaO2 increases rapidly,
as in the immediate postoperative period, stimulus by hypoxemia
is removed, ventilation may decrease or cease, and PaCO2
increases further. This is particularly the case in patients with
chronic hypercapnia. These patients may become comatose with
extremely high PaCO2 values (CO2 narcosis), and cardiorespiratory catastrophe may follow. Instead of O2 therapy alone, these
patients need their ventilation improved artificially with or without added O2.
CO2 Response Curve
Figure 9-7. Effect of acute hypoxemia on the ventilatory response to

steady-state arterial carbon dioxide pressure (PaCO2) in one subject.
Inspired oxygen was adjusted in each experiment to keep arterial oxygen pressure (PaO2) constant at the level as indicated. From reference
98, with permission.
The graphic presentation of the relationship

arterial or
. between
.
end-tidal PCO2 and minute ventilation (VI or VE) is commonly
known as the CO2 response curve. This curve normally reflects the
response or sensitivity of the medullary respiratory centers to
PCO2. The CO2 response curve is a useful and practical means for
evaluating the chemical control of breathing, provided that the
mechanical properties of the respiratory system, including
neuromuscular transmission, the respiratory muscles, chest wall
and lungs, and airways, are intact. Normally, ventilation increases
linearly with increasing PCO2, up to 10% or so, when ventilation
starts to decrease (CO2 narcosis). Under hypoxemic conditions,
the CO2 response is potentiated, primarily by the stimulation of
carotid chemoreceptors, resulting in the shift to the left of the
curve (Figure 97).98 An exception is during the newborn period
when hypoxemia causes respiratory depression and the rightward
shift of the curve (see Figure 93).40 By contrast, inhalational
anesthetic agents, opioids, and sedatives in general depress the
medullary respiratory centers and result in the rightward shift of
the CO2 response curve (Figure 98).103
Depression or a shift to right of the CO2 response curve occurs

in patients whose carotid bodies have been removed.104 This may
also occur in patients with lung disease in whom increases in
intact neural stimulation cannot be translated into increased
ventilation. Under these circumstances, it had long been difficult
to separate out neural components from mechanical failure of
the respiratory apparatus.105 In 1975, Whitelaw and coworkers
demonstrated that negative mouth pressure generated against
occlusion (occlusion pressure) at 0.1 s (P0.1) correlates well with
neural (phrenic) impulse and is unaffected by the mechanical
properties of the respiratory system.106 Milic-Emili and Grunstein
proposed that the ventilatory response to CO2 be analyzed not as
the product of tidal volume (VT) and respiratory rate (f) but rather
in terms of the product of mean inspiratory flow rate (VT/TI,
where TI is inspiratory time), as an indication of neural drive, and
the duty cycle of breathing (TI/TTOT, where TTOT is the respiratory
cycle duration) as follows107:
.
VI = VT f = VT/TI TI/T TOT
Assessment of Respiratory Control
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Anesthetic Effect on Respiratory Muscles
Figure 9-8. CO2 response curve with halothane. Family of steadystate CO2 response curves in one subject awake and at three levels of
halothane anesthesia. Note progressive decrease in ventilatory response
to PaCO2 with increasing anesthetic depth (minimum alveolar concentration [MAC]). The ventilatory response in awake state was measured
in response to end-tidal carbon dioxide pressure (PCO2). Courtesy of
Dr. Edwin S. Munson; data based on reference 103.
The distinct advantage of analyzing the ventilatory response in

this way is that VT/TI is an index of the inspiratory drive,
independent of the timing element. Conversely, VT is time
dependent, because VT = VT/TI TI. The second parameter,
TI/TTOT, is a dimensionless index of effective timing (respiratory
duty cycle) that is determined by the vagal afferent and central
inspiratory off-switch mechanism.108 It is apparent from this
equation that a reduction in ventilation in a patient under general
anesthesia or with lung disease is caused either by changes in the
drive (VT/TI) or the timing component (TI/TTOT) or both.
Anesthetic Effects on Respiratory Control

Anesthetic Effect on the CO2 Response Curve
Most anesthetic agents, opioids, and sedatives depress ventilation,
either by themselves or in combination
. with other agents. They
invariably affect minute ventilation (V I) and its components, VT,
frequency, VT/TI, TI/T TOT, or their combinations. All inhaled
anesthetics (perhaps with the exception of diethyl ether, which has
not been in clinical use since the 1970s) depress ventilation
profoundly in a dose-dependent fashion (see Figure 98). This
subject has been extensively studied in adults.109 Information on
the effects of anesthetic agents on the CO2 response in infants and
children, however, has been limited.
Under normal circumstances, inspiration of air into the lung is

produced by coordinated contractions of inspiratory muscles and
exhalation is accomplished passively by the elastic recoil of the
lung and chest wall. General anesthesia affects ventilation by
decreasing the intensity of motor neuron impulses to inspiratory
muscles, but with different degrees of depression. Three groups
of muscles coordinate the inspiratory phase of breathing: the
diaphragm, the external intarcostal muscles (pump muscles), and
the upper airway muscles, which maintain the patency of the
pharynx and larynx during inspiration. In quiet breathing, the
contraction of the diaphragm is the primary force producing tidal
ventilation, whereas the intercostal muscles stiffen the chest wall
and resist negative intrathoracic pressure from sucking the thorax
inward, which would result in thoracoabdominal asynchrony, as
seen in the neonate with labored breathing with or without upper
airway obstruction. By contrast, an increase in ventilation during
exercise or hypercapnia is accomplished primarily by increased
intercostal activity.
Sensitivity to anesthetics differs among various inspiratory
muscles and their neurons. Froese and Bryan were the first to
compare the depressant effects of anesthesia on the diaphragm
and intercostal muscles in children and adults.110 Using twodimensional magnetometers to measure chest wall and abdominal
circumferences, they demonstrated that light halothane anesthesia
depressed intercostal muscle activities disproportionately more
than it did the diaphragm. Subsequently, Ochiai and colleagues,
in their electromyographic studies in cats, demonstrated that the
phasic inspiratory activity of the genioglossus muscle (which
moves the tongue anteriorly and maintains the patency of the
pharyngeal airway) was most sensitive to the depressant effect of
halothane at a given concentration.111 The diaphragm was most
resistant or least sensitive whereas the sensitivity of the intercostal
muscles to halothane was intermediate (Figure 99). Furthermore,
the same group of investigators found that, in kittens, phasic
activity of the genioglossus was more readily depressed than in
adult cats.112
Unlike the laryngeal airway, the pharyngeal airway is not
supported by a rigid cartilaginous or bony structure. Its wall
consists of soft tissues surrounded by the upper airway muscles
and is kept patent with sustained and cyclic contractions of the
pharyngeal dilator muscles (the genioglossus, geniohyoid, tensor
palatine, and others).39,113 Anesthesia-induced depression of these
pharyngeal dilator muscles seems responsible for upper airway
obstruction that is often seen in infants and young children.
The work of breathing increases significantly in anesthetized
children breathing spontaneously without an oral airway when
compared with those with an oral airway or laryngeal mask airway in place, thereby indicating the presence of partial upper
airway obstruction. The addition of low continuous positive
airway pressure (CPAP of 56 cmH2O) further decreases the work
of breathing even in those with an oral airway or laryngeal mask
airway.114
In healthy awake patients, exhalation of VT is produced
passively by elastic recoil of the lung and chest wall. Under
halothane anesthesia, however, there have been reports of active
contractions of abdominal expiratory muscles.115 If this active
expiration occurs in anesthetized, spontaneously breathing
patients, it would further contribute to the reduction of FRC at
end-expiration, airway closure, and possibly, increased venous
admixture.
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CHAPTER 9
Figure 9-10. Total lung capacity (TLC) and lung volume subdivisions.
ERV = expiratory reserve volume; FRC = functional residual capacity;
IC = inspiratory capacity; IRV = inspiratory reserve volume; RV =
residual volume; VC = vital capacity; VT = tidal volume.
Figure 9-9. Decrease in phasic inspiratory muscle activity, expressed
as peak height of moving time average (MTA), in percent change from
control (1% halothane), during halothane anesthesia in adult cats. Values
are mean sem. *P < .05 compared with the diaphragm (DI); **P <.05
compared with the genioglossus muscle (GG). From reference 111.
LUNG VOLUMES AND

MECHANICS OF BREATHING
Lung Volumes
Total lung capacity (TLC) is the maximum lung volume during
inspiration with maximal contraction of inspiratory muscles. TLC
is subdivided into inspiratory capacity (IC) and FRC. IC and FRC
are further subdivided as shown in Figure 910. FRC is the lung
volume at the end of normal expiration when inspiratory muscles
are totally relaxed. It is normally about 50% of TLC (FRC/TLC
ratio, 0.5) in the upright position and 40% of TLC in the supine
position. Residual volume (RV) is the amount of air remaining in
the lung after maximum expiration and is roughly 25% of TLC
(RV/TLC ratio, 0.25). FRC is determined by the balance between
the outward recoil (expansion) of the thorax and the inward
recoil of the lung. The two opposing forces result in a negative
interpleural pressure of approximately 5 cmH2O in older children
and adults. In infants, interpleural pressure is at or slightly below
the atmospheric pressure.
In infants, the chest wall is extremely compliant (outward recoil
is low) whereas the inward recoil of the lung is only mildly lower
than that of adults.19,116 Consequently, FRC or relaxation volume
(VR) of young infants at complete relaxation (such as central
apnea, general anesthesia, or the use of neuromuscular blocking
agents) decreases to a mere 10 to 15% of TLC.116 This low VR is
substantially below the closing capacity (CC) and results in small
airway closure, atelectasis, ventilation/perfusion imbalance, and
hemoglobin desaturation.
TLC measured with the tracer gas washout technique

was reported to be relatively small (~60 mL/kg) in infants,
although air spaces in the lung might not have been fully
recruited (the lung inflated with relatively low pressure of 2025
cmH2O).117 TLC in children who are older than 18 months
(measured with an adequate inflation pressure of 3540 cmH2O)
increases with growth until 5 years of age, when it reaches
90 mL/kg, the value for older children and adults.117 In normal
children and adolescents, lung volume is correlated well with body
size, especially height.39
Elastic Properties
Compliance of the Lung, Thorax,
and Respiratory System
In order to expand the lung and achieve tidal ventilation by
contraction of the inspiratory muscles (or with positive pressure
applied to the airway system), one has to overcome the elastic
recoil of the lung and thoracic structures, which resist the
expansion. This elastic recoil pressure is fairly constant over the
range of normal V T, but it increases at the extremes of lung
inflation or deflation. The elastic recoil pressures of the lung, chest
wall, or respiratory system (lung and thorax) are expressed
as compliance of the lung (CL), thorax or chest wall (CW), or
respiratory system (CRS) and are expressed in units of lung volume
per units of pressure change as follows:
CL = V/
P
where V is usually the VT and P is the transpulmonary
pressure (pressure difference between the airway and the
interpleural pressure). In the case of CW, P is the pressure
difference across the chest wall (interpleural and atmospheric
pressures) and for CRS, the pressure difference between the airway
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and the atmospheric pressures. The reciprocal of compliance is

elastance (E = 1/C) and E can be added as follows:
ERS = EL + EW
1/CRS = 1/CL + 1/CW
The measurement of compliance is usually made at the extreme
of tidal breath where there is no airflow (static compliance, CST(L),
CST(W), and CST(RS)). Even without any inherent changes in
the pressure-volume characteristics of the lung, compliance of
the lung (CL) (or that of the respiratory system, CRS) decreases as
the end-expiratory volume increases from the midpoint of TLC
(as with air-trapping or with excessive levels of PEEP). CL also
decreases when FRC decreases to below normal at the midpoint of
TLC (as with general anesthesia or administration of neuromuscular blocking agents, see Effects of Anesthesia on Respiratory
Mechanics). Therefore, the measurement of the pressure-volume
relationship over the entire range of TLC provides a more accurate
description of the elastic properties of the lung and respiratory
system39 (Figure 911).
In normal lungs, compliance measured during the respiratory
cycle (dynamic compliance [CDYN]) is approximately the same as
static compliance. Conversely, when there is airway obstruction
with an increased pressure swing during tidal ventilation, CDYN
is relatively decreased, whereas static compliance is relatively
unaffected. This difference between static compliance and CDYN
increases with increasing respiratory frequency (frequency
dependence of compliance) and is a sign of airway obstruction.118
After several days of postnatal adaptation with the concomitant
removal of lung fluid, lung compliance of the neonate is extremely
high (elastic recoil, low),21 because of poorly developed elastic
fibers119 (Figure 912). These functional characteristics of pressurevolume relationships are not too dissimilar to those of geriatric
patients with pulmonary emphysema with the loss of functioning
elastic fibers (Figure 913). At both extremes of human life (e.g.,

neonatal and geriatric), the lung is prone to premature airway
closure.18 Elastic recoil pressure of the lung at 60% of TLC increases
from approximately 1 cmH2O to 7 cmH2O at 7 years and as high
as 9 cmH2O during the latter half of the teenage years.119,120
Developmental Changes in Compliance

of the Lung and Thorax
In infants, outward recoil of the thorax is extremely low (compliance, high)116 because of the soft cartilagenous rib cage and
poorly developed thoracic musculature. In comparison, inward
recoil of the lung is only mildly diminished compared with that
in adults. In the neonate, the CW is three to six times higher than
CL. Consequently, static balance of these opposing forces would
shift and decrease FRC to very low levels. This decrease in FRC
would make parenchymal airways unstable and prone to collapse.
This situation does occur under general anesthesia or muscle
paralysis and, to a lesser extent, during apnea and active (REM)
sleep when inspiratory muscles are relaxed.117,121,122
When does the chest wall of infants become stiffer and
CW decrease to the level of CL? Papastamelos and associates
have shown that the development of the chest wall occurs much
sooner than was previously believed.123 In their study, both CL
and CW were very high in young infants and CW was two to three
times higher than CL. However, the chest wall developed rapidly
with increasing rigidity and, by 9 to 12 months of age, CW
decreased to the level of CL. Both CW and CL continued to
decrease (elastic recoil, increase) thereafter for the entire study
period of 3 years. This rapid development of the chest wall (with
resultant stiffening and a decrease in CW) in young infants was
attributed to the shift from the horizontal to the upright posture
in early infancy, which presumably requires stronger thoracic
musculature.123
Figure 9-11. Schematic representation of the pressure volume (P-V) curve and compliance of the respiratory system. At the midpoint of the P-V curve
(indicated as FRC awake), the slope and compliance
(Crs = P/
V) is the highest. When functional
residual capacity (FRC) is decreased to the lower,
flatter portion of the P-V curve under general anesthesia or paralysis (indicated as FRC anesthetized),
Crs decreases even without changes in the mechanics
of the lung.
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Figure 9-12. Pressure-volume curves obtained from excised lungs at autopsy. Data are grouped by postnatal
ages as shown by symbols. It is evident that elastic recoil pressure (horizontal distance between nil distending
pressure and the curve at a given distending volume) increases with postnatal development of the lungs.
Based on data from references 17 and 119, with permission.
Figure 9-13. Static pressure-volume curves (deflation limbs) of the lungs in various conditions as
indicated. From Bates DV, editor: Respiratory Function in Disease: An Introduction to the Integrated
Studies. 3rd ed. Philadelphia: WB Saunders; 1989. p. 558.
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The breathing pattern of infants younger than 6 months of age

is predominantly diaphragmatic (abdominal) and the intercostal
(rib cage) contribution to VT is relatively less than that in adults.
After 9 months of age, the rib cage portion of V T increases to
approximately 50%, the level seen in older children and adults,
This increase in the thoracic portions of VT is brought about by
changes in the shape of the rib cage (from a horizontal to a V
shape) and the maturation of the thoracic musculature.124
airways, the tissue viscoelastic resistance or the resistance of

the lung and thoracic tissues themselves to deformation, and
inertial resistance (inertance) resulting from the movement of
gas molecules within the airways, especially at high velocities.
By contrast to compliance (or elastance), which is measured at
points of no flow, flow resistance is present only when the lung is
in motion.
Airway Resistance
Maintenance of FRC in Infants
In spite of an excessively compliant chest wall and the tendency
for static FRC (VR) to fall, dynamic FRC in awake, spontaneously
breathing infants is well maintained near the values seen in older
children and adults because of a number of mechanisms that
prevent FRC from collapsing. These mechanisms include
1. Breaking of expiration with continual (although diminishing) diaphragmatic activity in the early expiratory phase.
2. Tachypnea with short expiratory time and the initiation of
inspiration before the end of passive expiration. The resultant
intrinsic PEEP (PEEPi) maintains dynamic FRC higher than
relaxed FRC or VR.
3. Sustained tonic activities of the inspiratory muscles throughout
the respiratory cycle (especially external intercostal muscles).
How long does dynamic FRC continue postnatally? A study by
Colin and coworkers has demonstrated that the transition from
dynamic to relaxed FRC in infants occurs between 6 and 12 months
of age.125 By 1 year of age, the breathing pattern is predominantly
that of relaxed end-expiratory volume, as in older children and
adults. Perhaps the most important of all these mechanisms that
sustain FRC is the tonic activity of the external intercostal muscles,
the diaphragm, and other inspiratory muscles,126 the diaphragm,
and other inspiratory muscles. This mechanism effectively stiffens
the chest wall and maintains higher levels of FRC at end-expiration.
Anesthetic Effect on FRC

General anesthesia with or without muscle relaxants markedly
diminishes or abolishes inspiratory muscle tone and results in
a reduction in FRC. In healthy young adults, a reduction in
FRC following the induction of anesthesia has been reported
to be between 9 and 25%.127,128 In older individuals, the average
reduction in FRC is greater (30%), probably due to decreased
elastic recoil of the lung.129 The effect on FRC of general anesthesia
is more pronounced in infants and young children because their
thorax is more compliant,130 as discussed in more detail in the
section Effects of Anesthesia on Respiratory System Mechanics.
A reduction in FRC is not limited to general anesthesia or muscle
paralysis alone.131 Henderson-Smart and Read have reported a
30% reduction in thoracic gas volume (FRC measured with body
plethysmograph) in infants when their sleep pattern changed from
quiet (non-REM) to active (REM) sleep with the relaxation of
respiratory muscles.129
Dynamic Properties
Breathing involves cyclic contractions of respiratory muscles and
the generation of force, which must overcome resistive and elastic
properties of the lung and chest wall. The resistive properties of the
respiratory system include the resistance to airflow within the
The pressure required to overcome frictional resistance and

produce flow between the airway opening (Pao) at the mouth and
alveoli (PALV) is proportional to flow rate.132 Airway resistance
(Raw) is expressed as pressure gradient across the airways:
.
(P = Pao PALV) per unit flow (V):
.
Raw = P/V (cmH2O/L/s)
If the respiratory system is assumed to have a single
compartment with a constant elastance or compliance (E = 1/C)
and a constant resistance (R), the equation of forces acting on the
respiratory system can be expressed:
.
.
.
P = EV + RV + IV
where inertance (I) is very small in tidal breathing and can be
ignored. During normal tidal breathing, approximately 90% of the
pressure gradient required is needed to overcome the elastic forces
and the remaining 10% of the pressure is expended to counter the
flow resistance.133
Flow resistance is related to the length (l), the radius of the tube
(r), and the viscosity of the gas () as follows:
r = 8l/r4
Assuming a laminar flow (as seen in small or peripheral
airways), it is apparent from this equation (Poiseuilles law) that
the most important factor affecting flow resistance is the change
in the radius of the tube (airways), because resistance is inversely
proportional to the fourth power of the radius. When the flow is
turbulent, as occurs in large airways, the flow resistance increases
approximately with r5. Therefore, R aw in infants with smaller
airway diameters is much higher, in absolute terms, than Raw in
older children and adults. In terms of body size, however, the
caliber of airways in general is wider and Raw is lower in infants
and children than in adults.21,23
Upper Airway Resistance

The airway system extends from the airway opening at the naris or
the mouth to the alveolar duct at the periphery of the lung.
Functionally, the airway system can be subdivided into the upper
(extrathoraic) and lower (intrathoracic) airways. During quiet
breathing, airflow resistance through the nasal passages accounts
for approximately 65% of total Raw in adults.134 Stocks and Godfrey
found that nasal resistance accounted for approximately 49%
of the total Raw in European infants, whereas it was significantly
less in infants of African origin (31%).135 Overall, upper R aw is
approximately two thirds of the total Raw.
Except when crying, newborn infants are obligatory nasal
breathers. The cephalad position of the epiglottis and the close
approximation of the soft palate to the tongue and epiglottis in
neonates may be a reason why mouth breathing is more difficult
than nasal breathing.136 When the nasal airway is occluded, some
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infants, especially during REM sleep, do not respond sufficiently
to initiate adequate mouth breathing and OSA ensues. In infants,
insertion of a nasogastric tube significantly increases total
resistance by as much as 50% and may compromise breathing.137
If the upper airway is narrowed by either compression, increased
wall thickness (inflammation), or luminal obstruction (secretions),or their combinations, the resultant increase in Raw would
be far greater in infants than in adults. Life-threatening upper
airway obstruction, such as croup (laryngotracheobronchitis)
and epiglottitis (supraglottitis), are seen almost exclusively in
infants.
Lower Raw
Between the trachea and the alveolar duct, there are an average of
23 airway generations138 (Figure 914). As gas molecules move
from the trachea toward the terminal airways during inspiration,
the radius of the successive generations of airways becomes
smaller and, therefore, the resistance to flow is expected to
increase. In reality, however, the total cross-sectional area of the
airway segments increases dramatically toward the periphery,
although the diameter of successive single airways decreases.
This is because the number of airways increases markedly
and, consequently, the resistance to flow of the airways decreases
toward the periphery138 (see Figure 914). Indeed, using a retrograde catheter technique, Macklem and Mead demonstrated that
the peripheral airways, less than about 1 mm in diameter (around
the 14th generation), contribute less than 10% of the lower Raw or
3% of the total Raw.139
On the basis of physiologic studies of the lungs using the
retrograde technique at autopsy, Hogg and colleagues reported
that peripheral airways in children younger than 6 years of age
were disproportionately small and Raw high, compared with

adults.140 They postulated that the diameters of peripheral airways of the same generation were disproportionately smaller
in infants than in older children and adults. However, Motoyama has demonstrated in healthy infants and children under
general anesthesia that the conductance of the upstream segment,
normalized for lung volume, is disproportionately high (parenchymal Raw, low) in infants and decreases with age.21 This study,
based on the measurements of maximum expiratory flow-volume
curves, indicated that lower Raw toward the periphery of the lung
parenchyma is relatively lower in infants during the early postnatal
years than in adults. A later study in children has also confirmed
these findings.141
Tissue Viscoelastic Resistance

It has been assumed for a long time that the majority of the forces
necessary to overcome the total respiratory system resistance
during breathing were expended by airway (frictional) resistance.
The pressure needed to overcome tissue viscous resistance during
inspiration was estimated to be about 35% in adults and 28% in
children.19 However, studies since the mid-1980s on mechanical
ventilation, in both animals and humans, have indicated that
viscoelastic resistance, or the energy required to counter the lung
and chest wall tissues hysteresis or viscoelasticity, contributed a
significantly greater proportion of the total resistance than
previously assumed.142 Furthermore, flow and volume dependence
of viscoelastic resistance (Rvis or R) behaves very differently and
is opposite that of flow resistance. Raw increases with increasing
flow because of higher turbulence, whereas Raw decreases with
increasing lung volume because airway caliber also increases with
volume. The traditional view has been that the total resistance
Figure 9-14. A: Diagrammatic representation of the sequence of elements in the conductive, transitory, and respiratory zones
of the airways. AD = alveolar ducts; AS = alveolar sacs; BL = bronchioles; BR = bronchi; RBL = respiratory bronchioles; T = terminal generation; TBL = terminal bronchioles; z = order of generation of branching. B: Total airway cross-sectional area, A(z),
in each generation, z. A and B: From reference 138, with permission.
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Figure 9-15. Flow and volume dependence

of respiratory system resistance (Rrs) and its
subdivisions, resistive component (Rint or airway
resistance [Raw]) and viscoelastic component
(
Rrs) (Rrs = Rint + Rrs). IA: Average relationship of Rrs and Rint with increasing inspiratory
flow at a constant inspiratory volume (0.47 L)
in 16 anesthetized and paralyzed adult subjects.
IB: Similar relationship between Rrs with variable inspiratory flow. IIA: Average relationship
of Rrs and Rint with variable inspiratory volume
at a constant inspiratory flow (0.56 L/s1) in same
subjects as IA. IIB: Similar relationship in terms
of Rrs. Bars, 1 standard deviation (sd). Modified
from D'Angelo E, Calderini G, Torri F, et al.
Respiratory mechanics in anesthetized paralyzed
humans: effects of flow, volume, and time. J Appl
Physiol. 1989;67:255664.
followed the same direction of flow and volume dependence.

Paradoxically, Rvis decreases with increasing flow while the volume
is kept constant, and while the flow rate is kept constant, Rvis
increases with increasing lung volume143 (Figure 915). Furthermore, the direction of changes in total resistance followed that
of Rvis, but not Raw. A study in anesthetized and ventilated children
has shown the same flow and volume dependence of Rvis as in
adults; that is, opposite the direction of changes in Raw122,144 (Figure
916). This new evidence on the behavior of Rvis has important
clinical implications. Traditionally, the patient with airway
obstruction has been treated with large VTs and a slow respiratory
rate, to allow complete exhalation in order to avoid PEEPi and air
trapping. With the new understanding, it makes more sense to
breathe with smaller VT and higher respiratory rate in order to
minimize both Rvis and total respiratory system resistance and
decrease the work of breathing.145
markedly in patients breathing through an ET tube under general

anesthesia.
Time Constant of the Respiratory System
In awake adults, FRC is maintained with the rigid thorax and

sustained inspiratory muscle tone throughout the respiratory
cycle. Sustained inspiratory muscle tone is especially important in
infants because of the extremely compliant cartilaginous thoracic
cage with poorly developed thoracic muscles. Turning from the
upright to the supine position alone reduces FRC about 10% of
TLC (0.70.8 L in adults) even in awake individuals. Anesthesia
with or without muscle paralysis reduces FRC further by abolishing the inspiratory muscle tone (the diaphragm and intercostals). FRC under general anesthesia (called relaxation volume,
VR) is decreased 9 to 25% in healthy young adults, bringing FRC
closer to the level of RV in the awake state.127,128 In older patients,
the average reduction in FRC was reported to be greater (30%),
probably because of decreased elastic recoil of the lung and airway
closure.148
The effect of general anesthesia on FRC is more pronounced
in infants and young children because of their thorax is more
When the lung is allowed to empty passively from end-inspiration

to FRC, the speed of lung deflation is determined by the product
of respiratory system resistance and compliance (R C or R/E),
which is a unit of time (time constant, ). If the respiratory system
is considered as a single compartment with a constant resistance
and compliance within the VT range of breathing (which is a
reasonable assumption in healthy individuals):
= RC
Under these conditions, the volume-time profile can be
represented by an exponential decay and at 1 time constant (1 ),
VT is reduced by 63%. In healthy children and adults, is 0.4 to 0.5
s, whereas it is considerably shorter in neonates (0.20.3 s).19 In
patients with obstructive lung disease, such as bronchial asthma,
is increased because of an increase in Raw. It is also increased
Effects of Anesthesia on Respiratory Mechanics

General anesthesia significantly affects respiratory mechanics
and alters pulmonary gas exchange. The single most important
mechanism causing a cascade of changes in respiratory mechanics
in anesthetized infants and children appears to be the relaxation of
inspiratory muscles by anesthetics. This muscle relaxation, in turn,
results in a reduction in FRC, cephalad displacement of the
diaphragm, airway closure and atelectasis of dependent lung segments, ventilation-perfusion imbalance, and eventually, increases
in venous admixture.146,147
Anesthetic Effects on FRC
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Figure 9-16. Flow and volume dependence of respiratory system resistance (Rrs) and its subdivisions, resistive component (Rint or Raw) and viscoelastic component (
R or Rvisc) (Rrs = Rint + R), in eight healthy children (25 y of age). A: Average relationship of Rrs, Rint, and R with in.
creasing inspiratory flow (VI) at a constant inspiratory volume (VT, 12 mL/kg1). Rint tended to increase, whereas R and Rrs decreased significantly
with increasing flow. These changes
are similar to those in adults. B: Average relationship of Rrs, Rint, and R with increasing volume while inspira.
tory flow was kept constant (VI, 15 mL/s1/kg1) in the same subjects as A. As in adults, Rint decreased significantly with increasing volume, whereas
.
R increased significantly with increasing volume. Unlike in adults, the total resistance (Rrs ) did not change with volume. Bars, 1 sem; VI, inspiratory flow; Vr, relaxation volume (or FRC under anesthesia and paralysis). A and B: Data from reference 122.
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compliant and more vulnerable to collapse when general anesthesia decreases or abolishes thoracic inspiratory muscle tone. In
children (618 y of age), there was a 35% reduction in FRC under
general anesthesia and paralysis from awake controls. When
evaluating only those children who were 12 years of age or younger, the average reduction in FRC was 46%.149 Fletcher and associates reported a 35% decrease in respiratory system compliance
in children under general anesthesia,150 reflecting airway closure
or atelectasis.151,152 The reduction in FRC also occurs in children
breathing spontaneously under both inhaled and intravenous
anesthesia.151,152
In a classic study in healthy adults, general anesthesia (thiopental) was associated with a reduction of FRC by 25%.128 The
addition of muscle paralysis tended to decrease FRC further, but
the difference was not statistically significant.128 In a recent study
in infants and children receiving propofol anesthesia and
mechanical ventilation, the addition of a muscle relaxant decreased FRC even greater in infants 0 to 6 months of age compared
with children 2 to 6 years of age.153 FRC decreased from 21.3 to
12.2 mL/kg (43%) in infants versus from 25.6 to 23.0 mL/kg (
10%) in children.153
Anesthetic Effects on the

Position of the Diaphragm
Using cineradiography, Froese and Bryan were the first to report
the cephalad displacement of the diaphragm in the supine position in children under general anesthesia that contributes to the
reduction in FRC.110 The cephalad displacement was more
pronounced in the posterior, dependent portion of the diaphragm during either spontaneous breathing or paralysis with
mechanical ventilation. This finding was explained by the loss
of inspiratory muscle tone, which allowed the abdominal viscera
to push the diaphragm cephalad. Cyclic displacement of the
diaphragm by mechanical ventilation under muscle paralysis
was predominantly anterior and was far less in the posterior,
dependent portion of the diaphragm. The cephalad displacement of the diaphragm was far less when the patients were
not paralyzed.151
Anesthetic Effects on Airway

Closure and Atelectasis
The reduction of FRC to values at or below RV and CC makes the
airways vulnerable to premature closure during tidal exhalation
and increases venous admixture.152 CC is the volume at which
airways in the dependent portion of the lung start to collapse.
Using computed tomography (CT) scanning, increased density,
representing airway closure and/or atelectasis, has been reported
immediately following the induction of anesthesia and muscle
paralysis in adults154 as well as in infants and children155,156 (Figure
917). Atelectasis occurs in most patients and is localized to
the posterior, dependent portions of the lungs bilaterally. Serafini
and coworkers also reported that the addition of low PEEP
(5 cmH2O) prevented the development of increased density on
CT scans in children ventilated with an O2-N2O mixture.156 In
adults, although PEEP of 10 cmH2O consistently reopens portions
of collapsed lungs, the lung collapse returns immediately after
the removal of the PEEP.157 The rapid onset of airway closure or
atelectasis (as evidenced by increased density on the CT scan)
soon after induction of anesthesia or the removal of PEEP
Figure 9-17. Top: Transverse computed tomography (CT) scan of the

thorax during anesthesia (5 min after induction) without positive endexpiratory pressure (PEEP). Note the appearance of atelectasis in the
dependent regions of both lungs. Bottom: Transverse CT scan of the
thorax during anesthesia with a PEEP of 5 cmH2O, showing the disappearance of atelectasis in dependent regions of both lungs. From reference 156, with permission.
indicates that the likely cause of the observed density is compression of the lung (gravity-dependent atelectasis), rather than
resorption of the gas following the airway closure.147 Conversely,
atelectasis does not develop rapidly if the lungs are ventilated with
30 to 40% O2 in nitrogen, indicating that absorption of O2 from the
alveolar space is also an important factor for the development of
atelactasis.157 (The effect of anesthesia on FRC and the effect of
PEEP on FRC under general anesthesia are discussed more in
detail in the section on Effect of Anesthesia on Respiratory
Mechanics.)
Effect of PEEP on FRC Under General Anesthesia

The addition of PEEP is important and effective in preventing
anesthesia-induced reductions in FRC and resultant airway
closure and atelectasis.132 Thorsteinsson and colleagues have
shown that FRC, or more accurately, end-expiratory volume under
general anesthesia and paralysis (VR) is situated in the lower, flatter
portion of the pressure-volume curve and is much lower than
normal FRC in the steep midportion of the pressure-volume
curve.117 The mean PEEP that was needed to restore FRC to the
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Figure 9-18. Compliance of respiratory system (Crs) under general

anesthesia in infants and children
and the effect of positive endexpiratory pressure (PEEP). An
addition of PEEP (56 cmH2O)
improves (restores) Crs significantly in all age groups studied.
The beneficial effect of PEEP, however, was most dramatic in infants
younger than 8 months of age (see
text). From reference 132.
normal, midportion of the pressure-volume curve (with optimum

compliance) was 6 cmH2O in infants younger than 6 months of
age and 12 cmH2O in children. A more recent study in children
(26 y) under general anesthesia also showed that PEEP as high as
17 cmH2O was needed to raise FRC to the midpoint of the
inspiratory pressure-volume curve of the respiratory system without previous recruitment maneuvers.122 Clinically, a lower level
of PEEP (56 cmH2O), preceded by deep sighs (TLC maneuvers),
appears sufficient to maintain respiratory system compliance
without higher PEEP, which may have deleterious hemodynamic
effects. A study has shown that, in infants younger than 6 months
of age, the addition of PEEP (6 cmH2O), preceded by deep sighs
or recruitment (TLC) maneuvers, increased the CRS an average
of 75%, indicating a large volume of lung recruitment. By contrast,
in older infants and toddlers (9 mo2.5 y of age), the increase
in CRS with PEEP was 22%. The change in CRS with PEEP in
older children (2.56.0 y) was 9%, the level one would expect in
adults132 (Figure 918). Thus, physiologic PEEP is clinically important for infants and young children younger than 3 years
whereas PEEP is essential, if not mandatory, for infants younger
than 9 months undergoing general anesthesia with controlled
ventilation.
It has been a common practice in clinical anesthesia for many
years that, toward the end of inhalation anesthesia before
extubation, the patient be preoxygenated by turning off all the
inhaled anesthetics and turning up the flow of 100% O2 to wash
out the inhalational anesthetic agents from the lungs and circulation. This maneuver has also been suggested to fill the
lungs with pure O2 to ensure better oxygenation of the patient
during the immediate postoperative period. The patients trachea
is then extubated, when ready, with or without positive airway
pressure.158,159 Benoit and associates found significant areas of
atelectasis remaining in the lung with moderate O2 desaturation
(mean PaO2 < 80 mmHg) after preoxygenation with 100% O2 even
after proper recruitment (TLC or VC) maneuvers with deep
sighs.159 By contrast, in the same study, after the VC maneuvers
were performed with 40% O2 instead of 100% O2, atelectasis was
significantly reduced and PaO2 was significantly higher (~95
mmHg) than in those with preoxygenation with 100% O2. These
findings emphasize the importance of lung recruitment maneuvers using an inert gas (nitrogen) and PEEP to stent open the
terminal airways and prevent atelectasis.
Anesthetic Effects on Compliance

of the Respiratory System
It has been known that respiratory system compliance decreases
soon after the induction of general anesthesia. Westbrook and
associates found a 25% reduction in FRC shortly after the induction
of anesthesia along with a marked rightward shift and decrease in
the slope of the pressure-volume curve of the lung128 (Figure 919).
There was also a small reduction in CW. The mechanism and
the sequence of events leading to these changes were not well
understood at that time, although a reduction in muscle tone with
anesthesia and the resultant reduction in FRC were considered as
possible causes. This puzzle was solved by De Troyer and BastenierGeens in their study on healthy volunteers with partial muscle
paralysis, as described earlier in the section on the Anesthetic
effects on FRC.126 These authors postulated that, in the awake state,
inspiratory muscles (external intercostals and the diaphragm) have
intrinsic tone that maintains outward recoil and rigidity of the chest
wall. The sequence of events leading to reduced CL and CW are as
follows: anesthesia or paralysis abolishes inspiratory muscle tone,
thereby reducing the outward recoil and CW. This reduction in the
outward recoil of the chest wall, in turn, reduces FRC and finally
decreases CL with the shift in the position of the pressure-volume
curve with or without airway closure. As previously discussed in
the section on Elastic Properties, with more compliant chest walls,
infants and young children would be more vulnerable for decreases
in FRC and resultant airway closure and atelectasis.
Anesthetic Effects on Resistance

of the Respiratory System
Although studies on pressure-flow relationships during anesthesia
are relatively limited compared with the abundant information on
pressure-volume relationships, most available studies show
considerable increases in Raw and total respiratory system resistance even after the resistance to gas flow through the ET tube is
subtracted.127 Clinically, however, the presence of an ETl tube adds
the most significant frictional resistance, equaling or surpassing
the total Raw before intubation. These changes are related to the
smaller diameter of the ET tube compared with that of the upper
airway dimensions.147 In patients who are anesthetized and
breathing spontaneously without an ET tube, increased Raw results
from the relaxation of pharyngeal and laryngeal muscles and the
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Figure 9-19. AC: Pressure-volume curves

of the total respiratory system (left panel),
the lung (middle panel), and the chest wall
(right panel) awake and during anesthesia
without and with muscle paralysis. Note the
right shift and flatter slope of the curves of
the total system and of the lung (reduced
compliance) during anesthesia and the minor
effect of adding muscle paralysis. The
pressure-volume curve of the chest wall
remains much the same awake and anesthetized. Pao = airway opening (mouth)
pressure; Pes = esophageal pressure; Ptp =
transpulmonary (Pao Pes) pressure.
From reference 128, with permission.
resultant partial obstruction of the upper airways, as previously

discussed in the section on Upper Airway Resistance.
VENTILATION AND
PULMONARY CIRCULATION
Ventilation is achieved by the movement of air in and out of the
lung. The diaphragm is the most important muscle producing
normal breathing, whereas the intercostal and accessory respiratory muscles are mobilized when increased ventilation is needed.
Normally, exhalation is accomplished passively by the elastic recoil
of the lung and thorax. Exhalation by the neonate, however,
appears active even when resting or asleep. Similar active expiratory activities have been observed in healthy individuals under
general inhalation anesthesia.115 The mechanisms have not been
elucidated. Forced exhalation is accomplished with the contraction
of abdominal muscles together with the spinal flexors and internal
intercostal muscles.
.
Minute volume or ventilation (VE) is the amount of air breathed
in or out per minute and is the product of V T and respiratory
frequency (f), as follows:
.
VE = VT f
The respiratory rate or frequency (f) of quiet breathing is high
in young infants with frequencies up to 30 to 40 breaths/min.
Respiratory rate decreases with age down to 8 to 12 breaths/min
in the young adult. The exact basis for this change is not known,
but may be related to the work of breathing. It appears that, in
humans, respiratory rate and V T are adjusted to accomplish
breathing with the least amount of work. The relatively high rate
in neonates compared with that in adults is consistent with this
minimum work concept.160 Conversely, Mead has proposed that,
in the normal resting state, breathing is adjusted so that the
minimum average force of the respiratory muscles is needed.161
He further postulated that the principal site of the sensory end of
the control mechanism is in the lung.
Dead Space and Alveolar Ventilation

The part of minute volume that contributes
to pulmonary
.
gas exchange is alveolar ventilation (VA). The remainder of air
moves in and out of respiratory
dead space (VD) and does not
.
participate in gas exchange. VA can be expressed in terms of CO2
in arterial blood:
.
.
VA = (PB 47) x VCO2/PaCO2
.
where VCO2 is the CO2 production per minute, PaCO2 is arterial
CO2 tension, and (PB 47) is the barometric pressure minus
water vapor pressure at 37C. .Thus, assuming that the CO2
production remains constant, if VA is halved, PaCO2 will double
and vice versa.
In normal individuals, anatomic dead space (VDanat), the
amount of air in the respiratory system from the airway opening
to the terminal bronchioles proximal to the gas-exchanging
segments of the lung, can be estimated as 1 mL/lb or 2 mL/kg of
body weight.162 In children and young adults, a more accurate
estimate can be obtained based on body height.163 In reality, VD
varies significantly from VDanat and is dependent upon the
distribution of ventilation and pulmonary blood flow.
The
between minute volume and alveolar ventila. difference
.
tion VE or VA is the wasted or dead space ventilation due to
physiologic dead space (VDphys). The VDphys can be calculated from
the PCO2 between the arterial blood and the mixed expired gas
(PECO2) and is normally expressed as a fraction of the VT:
VD/ VT = (PaCO2 PECO2)/PaCO2
.
VA is considerably higher per unit of lung volume in normal
infants than in adults. This is because of the relatively higher
metabolic rate and O2 consumption of infants whose lung volume
is also relatively smaller than that of adults.
Distribution of Ventilation
Distribution of ventilation is affected by gravitational force. In the
upright position, the interpleural pressure surrounding the apex of
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the lung is more negative than at the base. Consequently, the
transmural distending pressure and the regional FRC at the apex
are greater than the regional distending pressure and the regional
FRC at the base (Figure 920A). With tidal inspiration, a greater
fraction of air is distributed to the base, where regional FRC is at
the steepest portion of the pressure-volume curve, as long as the
airways to this segment remain open (see Figure 920A, B).
Similarly, in the lateral decubitus position in adults, the lower lung
receives a larger share of VT than the upper lung.164
In infants, however, the opposite seems to be the case. In the
lateral decubitus position in infants with unilateral lung disease,
oxygenation improves when the healthy lung is up165 (Figure
921). Using a krypton-81m ventilation scan, Davies and coworkers have demonstrated that, in infants and young children up to
2 years of age with or without lung disease, tidal ventilation is
preferentially distributed to the uppermost part of the lung and
diminished in the dependent lung.166 This paradoxical distribution
of ventilation in young children under sedation may be explained
by premature airway closure in the dependent lung. Because the
infants chest wall is exceptionally compliant, the interpleural
pressure is near atmospheric. This condition resembles that of
adults breathing at extremely low lung volumes near RV (see
Figure 920B). Under these circumstances, airway closure occurs
and ventilation is preferentially shifted to the upper part of the
lung.167 In paralyzed and ventilated adults, tidal ventilation is

preferentially shifted to the uppermost part of the lung, presumably by a similar mechanism with decreased FRC and airway closure.
In infants and young children, with the use of CT imaging,
increased density (airway closure or atelectasis) has been consistently observed immediately after the induction of anesthesia.156
The addition of low PEEP cleared the density in the dependent
lung, preventing atelectasis. Similarly, in infants and young children, especially those younger than 8 months with an exceptionally
compliant chest wall, respiratory system compliance was reduced
markedly under general anesthesia and paralysis. The addition of
PEEP (56 cmH2O) restored the compliance and O2 saturation.132
These findings demonstrate the presence of airway closure and
maldistribution of ventilation under general anesthesia, particularly in young infants and children.
Distribution of Pulmonary Perfusion

As with regional ventilation, gravity affects pulmonary blood flow
and results in the uneven distribution of pulmonary perfusion.
West and colleagues divided the characteristics of upright lung
perfusion into three zones, which they later modified into four
zones.168,169 Perfusion of lung tissues depends on the interrelation
Figure 9-20. Effect of vertical gradient of pleural surface pressure on distribution of tidal ventilation. A: At the beginning of
lung inflation from functional residual capacity (FRC), the lower regions are operating on the steeper part of the compliance
curve of the lungs than the upper regions. Accordingly, during slow inspiration from FRC, ventilation is greater in the lower
lung regions (arrows). B: At residual volume (RV), the pleural surface pressure at the lung base is positive (+4.8 cmH2O) and
the lower airways are closed. Consequently, at the beginning of slow inspiration from RV, the lower lung regions are not ventilated and the uppermost part of the lung is preferentially ventilated (arrows). A and B: From Milic-Emili J. Pulmonary statics. In: Widdicomb JG, editor: Respiratory Physiology. MTP International Review of Science. Series 1, vol. 2, Borough Green
Kent, UK: Butterworth; 1974; and Baltimore: University Park Press; 1974. p. 105, with permission.
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Figure 9-21. Posterior krypton-81m ventilation lung scan in a healthy

31-year-old man and in a 2-month-old girl after repair of a right congenital diaphragmatic hernia. In the adult, ventilation is preferentially
distributed to the dependent lung; in the infant, the reverse is seen, with
ventilation greater in the uppermost lung. For all scans, the distribution
of ventilation to each lung is expressed as a percentage of the total to
both lungs. From reference 165, with permission.
among three pressures, namely, airway pressure (PA), pulmonary

arterial pressure (Pa), and pulmonary venous pressure (PV)
(Figure 922). Because normal pulmonary circulation is a lowpressure system, regional pulmonary perfusion pressure varies
from the top to the bottom of the lung, barely overcoming the
hydrostatic pressure to reach the apex of the upright lung,
especially in tall adults. Both pulmonary perfusion pressure and
flow are increased toward the base of the lung.169
In apical zone I, PA is higher than both Pa and PV. Alveolar
capillary blood flow is absent or occurs only intermittently with
peak pulsatile pressure and flow. Ventilation in zone I, therefore,

is mostly wasted for gas exchange. Excessive PEEP would widen
zone I and increase alveolar dead space; by contrast, increases in
pulmonary perfusion pressure as seen in exercise or hypoxemia
(high altitude) decreases or abolishes zone I. In zone II (also
known as the waterfall zone) below zone I, Pa becomes higher than
PA as the vertical distance above the right ventricle decreases,
whereas PV remains lower than PA. The driving pressure in zone
II is the difference between pulmonary arterial and airway
pressures (Pa PA), which determines regional pulmonary blood
flow independent of downstream venous pressure (waterfall
phenomenon). Regional blood flow increases toward the base
of the lung as the driving pressure increases, until Pv equals PA.
In zone III, both Pa and PV are higher than PA. Throughout this
zone, the driving pressure of the blood flow is the difference
between Pa and PV. However, the blood flow is greater toward the
base of the lung, presumably because both the Pa and PV are
greater and the pulmonary vessels are distended. The relationship
among the Pa, PV, and PA in these three zones can be summarized
as follows:
Zone I: PA > Pa > PV
Zone II: Pa > PA > PV
Zone III: Pa > PV > PA
In zone IV, pulmonary blood flow is progressively decreased
toward the base of the lung, presumably because of increased
interstitial pressure surrounding the extra-alveolar vessels. This
zone increases in size with reductions in lung volume toward RV
and with increasing interstitial fluid volume, such as interstitial
pulmonary edema.169
In the supine position, the vertical distance between the top
and the bottom of the lung is diminished and zone I disappears.
Zone II also decreases as PV increases throughout the lung. The
effect of gravity in infants and young children, who have a smaller
Figure 9-22. Four zones of lung perfusion. Zone

I has no flow because alveolar pressure exceeds
pulmonary arterial pressure, thereby collapsing
alveolar vessels. Zone II is present when pulmonary
arterial pressure exceeds alveolar pressure and both
are greater than pulmonary venous pressure. This is
termed the vascular waterfall, because flow is unaffected by downstream (pulmonary venous) pressure. Zone III is characterized by a constant driving
force, the difference between pulmonary arterial
and venous pressure. Both are greater than alveolar
pressure. Flow increases throughout zone III, even
though driving pressure is constant because the absolute pressures lower in the lung distend the vessels to a greater extent, thereby lowering resistance.
Zone IV has less flow per unit lung volume, probably because of the increased parenchymal pressure
surrounding pulmonary vessels. From reference
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hydrostatic gradient, especially in the supine position, would be
minimal. In addition, PA is elevated during the first months of life,
as the transition from the fetal to the extrauterine circulatory
pattern is being completed. This further diminishes the gravitational effect on pulmonary circulation.
VentilationPulmonary Perfusion Relations

In order to maintain normal gas exchange in the lung, it is essential
that regional distribution of ventilation and blood flow be well
balanced.
The overall ratio of ventilation and pulmonary perfusion
. .
. .
(VA/Q) is approximately 0.8. Because both components of VA/Q
are influenced by gravity, they are both affected by the individuals
body position. When the patient is in the upright posture,
both the ventilation and the pulmonary. blood
. flow are less in the
apex than in the base of the lung. The VA/Q ratio is highest at the
apex and decreases toward the base because the difference in
pulmonary blood flow between the apex and the base of the lung
is greater relative to the changes in ventilation170 (Figure 923). In
hypotensive and hypovolemic patients, gravitational effects may
be exaggerated with positive-pressure breathing. In the supine or
lateral decubitus position, similar gravitational effects exist but are
less pronounced. During exercise, both ventilation and pulmonary
blood flow are increased and more evenly distributed as the
gravitational effect is diminished. In awake infants and young
children, distribution of pulmonary perfusion is more even than
in adults because of relatively higher blood pressure and less
gravitational effect.
. .
In abnormal or diseased lungs, the VA/Q ratio may be increased or decreased as the result of uneven distribution of
ventilation,
pulmonary perfusion, or both. The most
. uneven
.
extreme VA/Q mismatches are seen in children with congenital
heart disease. In patients with decreased pulmonary blood flow
with right-to-left
. . intracardiac shunt, such as in the tetralogy of
Fallot, the VA/Q ratio is increased; whereas in those with increased
Figure 9-23. Effect of vertical height (expressed as

the level of the anterior ends of the ribs) on ventilation and pulmonary blood flow (left-hand ordinate)
and the ventilation-perfusion ratio (right-hand ordinate). From West JB: Ventilation/Blood Flow and
Gas Exchange. 2nd ed. Oxford: Blackwell Scientific;
. .
pulmonary flow due to left-to-right shunt, the VA/Q ratio is
decreased.
The lung
. has
. an intrinsic regulatory mechanism that preserves
a. normal
V
A
/Q
ratio. In the lung segment with a relatively high
.
VA/Q ratio, a low regional PCO2 constricts small airways and, at
the same
. . time, dilates pulmonary vasculature. In the area with a
low VA/Q ratio, in addition to the PCO2 effects as just discussed,
hypoxic pulmonary vasoconstriction
tends to decrease
. (HPV)
.
regional blood flow and steers the VA/Q ratio toward normalization. Administration of vasoactive agents, such as -adrenergic
agonists, theophylline, sodium nitroprusside, and nitroglycerin,
diminishes or abolishes HPV and increases venous admixture.171
In children with severe reactive airway disease, such as status
asthmaticus, administration of a -adrenergic agonist is often
associated with a substantial decrease in PaO2 concomitant
with significant decreases in RAW. Inhaled anesthetics decrease
HPV in vitro,172,173 but their effect on HPV in vivo has not been
conclusively demonstrated.174,175
O2 TRANSPORT
For the maintenance of body metabolism, O2 must be transported
continuously to all body tissues and CO2 must be eliminated.
Changes in metabolic demand are met by the integrated response
of three major components of the gas transport systems: alveolar
ventilation, cardiac output, and hemoglobin concentration and
characteristics. With acute increases in O2 demand, such as severe
exercise, high fever, or hypoxemia, O2 transport is increased
primarily by increases in cardiac output, together with increased
pulmonary ventilation for the maintenance of alveolar PO2 and
PCO2 levels. Chronic hypoxemia, as occurs in cardiopulmonary
disease or during a sojourn to a high altitude, results in increased
hemoglobin and erythrocyte mass, produced by increased
erythropoietin activities. This adaptation, however, is a relatively
slow process and takes several weeks to accomplish.176 Hemoglobin concentrations greater than the upper normal level of
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15 to 16 g/dL (and especially a hematocrit > 60%) increase

viscosity and interfere with microcirculation.
O2 is transported in blood in two ways: combined with
hemoglobin as oxyhemoglobin or dissolved in plasma. The
amount of O2 carried by the plasma depends on the PaO2 and its
solubility. Under most statues, this amount is small, approximately
0.31 mL/100 mmHg at 37C (Bunsen coefficient). Conversely,
each molecule of hemoglobin combines loosely with four
molecules of O2 (1.34 mL O2/g hemoglobin). In normal air
breathing, as much as 98% of O2 is carried by hemoglobin. The
amount of O2 dissolved in plasma, however, becomes clinically
important for O2 transport when the patients with severe anemia
or carbon monoxide poisoning are given 100% O2 to breathe or
when hyperbaric O2 treatment is administered. Because it is highly
lipid soluble, CO2 diffuses freely through cell membranes and is
transported more readily in the blood than O2. CO2 is primarily
transported in blood as bicarbonate ions (as much as 70%). A
smaller, but substantial, fraction (1530%) is combined with
hemoglobin (to form carbaminohemoglobin) whereas the rest is
dissolved in plasma and erythrocytes (10%).
O2 Dissociation Curve
The O2 dissociation curve of hemoglobin reflects the affinity of
hemoglobin for O2 (Figure 924). As mixed venous blood in the
pulmonary artery in healthy subjects circulates through the
pulmonary capillary network, PO2 increases from approximately
40 to 100 mm Hg in arterialized blood with hemoglobin in
pulmonary venous blood becoming saturated with O2 to about
97%. Because the dissociation curve is increasingly flat at the high

end of the curve, further increases in PO2 result in only a small
increase in saturation, reaching 100% saturation between 130 and
160 mmHg. As blood circulates through the tissues, O2 is taken
up from the capillaries and both the PO2 and the oxygen saturation
of hemoglobin (SaO2) decrease.
The blood of healthy adults has an SaO2 of 50% when the PO2
is approximately 27 mmHg at 37C and pH 7.4. The P50 (PO2 of
whole blood at 50% O2 saturation) is an indicator of the affinity of
hemoglobin for O2. An increase in blood pH (both respiratory
and metabolic alkalosis) increases the O2 affinity of hemoglobin
(Bohr effect) and decreases P50. Similarly, a decrease in temperature shifts the dissociation curve to the left with a decrease in
the P50. A decrease in pH or an increase in temperature has the
opposite effect.177
Effect of Organic Phosphates on

O2 Affinity of Hemoglobin
In addition to temperature and the Bohr effect, the O2 affinity
of hemoglobin is decreased by an addition of organic phosphates, particularly 2,3-diphosphoglycerate (2,3-DPG) and adenosine triphosphate (ATP), which bind to deoxyhemoglobin but
not to oxyhemoglobin.178 Human erythrocytes contain unusually
high concentrations of 2,3-DPG compared with ATP and other
organic phosphates.179 An increase in erythrocyte 2,3-DPG
decreases O2 affinity, shifts the O2 dissociation curve to the right,
and increases the unloading of O2 molecules at the tissue level.
The level of 2,3-DPG is increased in chronic hypoxemia, such as
seen in patients with cyanotic heart disease and those living at
high altitudes.
Developmental Changes in
O2 Affinity of Hemoglobin
Figure 9-24. Schematic representation of oxygen dissociation curve

and factors that affect blood oxygen affinity. Oxygen partial pressure
at 50% blood oxygen saturation (P50) is a convenient index of oxygen
affinity. P50 of adult blood (at 37C; pH, 7.40; PCO2, 40 mmHg) is
roughly 27 mmHg and is influenced by a number of factors. 2,3 DPG =
2,3-diphosphoglycerate; H+ = hydrogen ion concentration; PaO2 = arterial oxygen tension; SaO2 = arterial oxygen saturation; T = blood temperature (see text).
In the neonate, 70 to 80% of hemoglobin is fetal hemoglobin or

hemoglobin F that contains gamma polypeptide chains (22), as
opposed to beta chains in adult type hemoglobin A (22). Fetal
hemoglobin reacts poorly with 2,3-DPG. Consequently, red cell
O2 affinity is very high (P50 of 1820 mmHg) and O2 delivery at the
tissue level decreased despite an increased red cell mass and
hemoglobin levels (hemoglobin 18 g/dL). During early infancy,
the total hemoglobin level decreases rapidly as red cells containing
fetal hemoglobin diminish, reaching the lowest level (11 1 g/dL)
at 2 to 3 months of age (physiologic anemia of infancy). During the
same time period, the O2 affinity of hemoglobin decreases and P50
increases rapidly. By 3 to 6 months of age, P50 is increased to that
of the adult (27 mmHg) and continues to increase so that
at 9 months of age, O2 affinity reaches its highest value of 29 to
30 mmHg.180,181
In spite of a large swing in hemoglobin levels throughout
infancy and childhood, O2 unloading at the tissue level steadily
increases during this period (Table 91). The O2 affinity of
hemoglobin continues to be relatively low throughout childhood
(and most likely through adolescence) before it attains the adult
level. This high P50, associated with increased levels of ATP and
2,3-DPG, is probably related to the general growth and development of the body and the high plasma levels of inorganic
phosphate.182 It can be speculated that, with increased O2 unloading capacity, children do not require the higher levels of hemo-
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TABLE 9-1. Changes in P50, Hemoglobin, and Oxygen Unloading With Age
Age
1d
3 wk
69 wk
34 mo
6 mo
811 mo
58 y
912 y
Adult
P50, mmHg
Percent Saturation at Venous

Oxygen Tension of 40 mmHg
Hemoglobin, g/100 mL
Oxygen Unloaded,a
mL/100 mL
19.4
22.7
24.4
26.5
27.8
30.0
29.0b
27.9b
27.0
87
80
77
73
69
65
67
69
71
17.2
13.0
11.0
10.5
11.3
11.8
12.6
13.4
15.0
1.84
2.61
2.65
3.10
3.94
4.74
4.73
4.67
4.92
P50 = arterial oxygen pressure at 50% hemoglobin saturation.

a
Assume arterial oxygen saturation of 95%.
b
Derived from data of Card RT and Brain MC; remainder of P50 as previously reported.
From reference 180.
globin present in adults (physiologic anemia of childhood;

hemoglobin levels, 1112 g/dL).
These findings have important clinical implications for pediatric anesthesiologists. Until the 1980s, children with a hemoglobin level less than 10 g/dL were considered anemic and were not
acceptable for general anesthesia and surgery. This level of hemoglobin was used arbitrarily without the realization that the characteristics of O2 affinity of hemoglobin and tissue O2 unloading are
quite different in children, especially during the first year of life.
We can see from Table 92 that, for an infant older than 3 months
(P50 = 30 mmHg), a hemoglobin level of 8.2 g/dL is equivalent to
10 g/dL in adults (P50 = 27 mmHg), in terms of tissue O2 delivery.
Conversely, for a 2-month-old premature infant (P50 = 24 mmHg),
a hemoglobin level of 10 g/dL is equivalent to only 6.8 g/dL in
adults and less than 5.5 g/dL in older infants. This level is not
acceptable for anesthesia and surgery for sick infants with limited
lung function and cardiac output.39
A graphic comparison of O2 unloading at the tissue level among
neonates, older infants, and adults is illustrated in Figure 925.
Assuming that the SaO2 is 100% and the mixed venous PO2 is 40
mmHg, approximately 25% of O2 content in adult arterial blood
(P50 = 27 mmHg) is unloaded at the tissue level. In older infants
(P50 = 30 mmHg), O2 unloading is increased to approximately 35%
because of the low O2 affinity of hemoglobin. By contrast, in
newborn infants with a high O2 affinity (P50 = 20 mmHg), less than
15% of O2 content can be unloaded at the tissue level unless mixed
venous PO2 decreases or cardiac output and ventilation increase.39
With the spread of HIV in epidemic proportions in many
parts of the world, including the industrialized nations, and the
resultant anxiety among the medical profession and lay public
about blood transfusion, the criteria for transfusion have changed
dramatically since the early 1980s. Although this problem has
been discussed extensively for adult patients,183 useful guidelines
for infants and children have not yet emerged. A hemoglobin level
of 8.0 g/dL (hematocrit, 24%) may be adequate for an otherwise
healthy child for a simple surgical procedure. Conversely, postoperative hypoxemia is common even among healthy infants and
children undergoing simple elective procedures, such as inguinal
herniorrhaphy and myringotomies and ear tube insertions.184
Children with a borderline anemia should be given O2 by mask
during and after the transfer to the postoperative care unit and
their SaO2 monitored with pulse oximetry (SpO2). The lowest
acceptable level of hemoglobin for infants younger than 2 months
has not been established, although a hemoglobin level of 12 to 13
g/dL (equivalent to 89 g/dL in adults) or a hematocrit of 36 to 40%
is desirable for sick infants.
The availability and the routine use of pulse oximetry since the
late 1980s, as dictated by the American Society of Anesthesiologists and others, have dramatically improved the quality of
monitoring and safety of patients undergoing general anesthesia
and surgery by maintaining proper oxygenation of patients.185
In addition, in premature infants, the maintenance of a proper
range of oxygenation is especially important for the prevention
of hyperoxia and the resultant retinopathy of prematurity.186
In premature infants with a birthweight of less than 1300 g, the
incidence of retinopathy increases markedly with the exposure to
a PaO2 exceeding 80 mmHg for 12 hours or more.12 Thus, SaO2
must be maintained carefully so as to maintain PaO2 within the
normal rage of 60 to 80 mmHg. Because O2 affinity of red blood
cells is very high at birth and decreases rapidly during the first
6 months of age, the estimated PaO2 should be adjusted according
to age, as shown in Table 93. In the neonate with a P50 of 18 to 20
mmHg, the range of SaO2 required to maintain adequate PaO2
(6080 mmHg) is 97 to 98%, whereas in the adult (P50, 27 mmHg),
it is 91 to 96%. In the neonate, conversely, an SaO2 of 91%
corresponds to a PaO2 of only 41 mmHg. Although the values in
TABLE 9-2. Hemoglobin Requirement for Equivalent Tissue Oxygen Delivery

P50, mmHg
Adult
Infant > 3 mo
Neonate < 2 mo
27
30
24
Hb for Equivalent O2 Delivery, g/dL

7
5.7
10.3
8
6.5
11.7
Hb = hemoglobin; P50 = arterial oxygen pressure at 50% hemoglobin saturation.
9
7.3
13.2
10
8.2
14.7
11
9.0
16.1
12
9.8
17.6
13
10.6
19.1
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Figure 9-25. Schematic representation of oxygenhemoglobin dissociation curves with different oxygen affinities.
In infants older than 3 months of age with high P50 (nearly 30
mmHg vs 27 in adults), tissue oxygen delivery per gram of hemoglobin is increased. In neonates with a lower P50 (20 mmHg)
and a higher oxygen affinity, tissue oxygen unloading at the same
tissue PO2 is reduced.
Table 93 are estimated on the basis of Severinghaus nomogram

for the Bohr effect, published data comparing PaO2 and corresponding SaO2 seem to agree well with values in the nomogram.39
Another factor compounds the confusion that is clinically too
important to ignore. The accuracy of pulse oximeter readings
differs among manufacturers. Although a PaO2 above 130 to 160
mmHg is required to fully saturate hemoglobin thereby resulting

in an SaO2 reading of 100%, this value cannot be reached in room
air at sea level. The pulse oximeter by Nellcor, a brand widely used
in the United States, reads an SpO2 that is 2 to 3% higher than the
true SaO2 in the 90 to 100% range. The original unit by Ohmeda,
which was more commonly used in Europe, conversely, tended
TABLE 9-3. Estimated PO2 at Different P50 of Red Blood Cellsa

Age
P50, mmHgb
1D
2 Wk
19
22
SO2, %
99
98
97
96
95
94
93
92
91
90
88
86
84
82
80
78
76
74
72
70
69 Wk
24
6 Mo6 Y
29
Adult
27
Estimated PO2 (mm Hg) at neutral pH (7.40)

108
77
64
56
52
48
45
43
41
40
37
35
34
32
31
30
29
28
27
26
130
92
77
68
62
58
55
52
50
48
45
42
40
39
37
36
34
33
32
31
143
101
84
74
68
63
60
57
55
53
49
47
44
42
41
39
38
36
35
34
171
122
101
89
82
76
72
68
66
63
59
56
53
51
49
47
45
44
42
41
156
111
92
82
74
69
66
62
60
58
54
51
49
47
45
43
41
40
39
37
P50 = arterial oxygen pressure at 50% hermoglobin saturation; PO2 = oxygen pressure; SO2 = oxygen saturation.
a
Calculated from Severinghaus JW. Blood gas calculator. J Appl Physiol 1966;21:1108 assuming that the shift in oxygen
dissociation curve of hemoglobin due to changes in its oxygen affinity at neutral pH (7.40) is the same as the shift due
to the Bohr effect.
b
PO2 at which oxygen saturation of hemoglobin (SO2) is 50%.
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to read about 2% lower than actual SaO2.187,188 Unfortunately,

the newer and perhaps more advanced pulse oximeter manufactured by Masimo, which is being increasingly used in the
United States and elsewhere, had to add a similar fudge factor to
be comparable with the other pulse oximeter outputs (Motoyama,
EK, personal communication). In view of these findings, the range
of SpO2 of 93 to 95% (or even lowerw), often recommended as
the desirable maintenance level for neonates and premature
infants, corresponds only to a PaO2 of 40 to 50 mmHg, which
seems much too low for adequate tissue oxygenation, particularly
for sick infants. In addition, respiratory alkalosis, often resulting
from controlled mechanical ventilation, would shift the O2
dissociation curve further to the left (P50, even lower) and further
decrease PaO2 and tissue O2 delivery. In clinical practice, therefore,
SpO2 values of 95 to 97% (corresponding to a PaO2 of 50 to
70 mmHg in the neonate and 60 to 80 mmHg in infants 12 mo
old) should be considered for adequate oxygenation without
O2 toxicity.
SURFACE ACTIVITY AND

PULMONARY SURFACTANT
The surface of the alveoli and small airways are lined with a
specific phospholipid-protein complex that possesses a unique
surface activity and stabilizes the gas-liquid interface of small
air spaces. These materials are collectively called pulmonary
surfactant and are essential for pulmonary gas exchange and, thus,
for human survival.
Surfactant and Lung Mechanics

The relationship among pressure (P), surface tension (T), and
radius (r) of a small sphere, such as a soap bubble or pulmonary
alveolus, is expressed by the LaPlace equation:
P = n T/r
where n = 1 for a cylindrical airway, n = 2 in case of the
alveolus, and n = 4 for a soap bubble. It can be seen from this
equation that, if the surface tension is constant (as is the case with
most liquid substances, such as water or detergents) in multiple
spheres that are connected to a common tube, the sphere with the
smallest radius would have the highest pressure. Thus, the smaller
spheres would empty their gas content into the larger ones
and collapse. If this concept were applied to a lung, the lung unit
would be unstable, with most alveoli collapsing into several large
terminal air spaces, as seen in premature infants with IRDS or
HMD with insufficient or inadequate surfactant activity.39 Such
alveolar instability, fortunately, does not occur in normal lungs.
As Clements and associates initially demonstrated, saline extract
of minced normal lung tissues exhibits an extremely low surface
tension (05 dynes/cm compared with 72 dynes/cm with saline
alone) during dynamic compression of the surface area on a
Wilhelmy balance.189 When the surface area is expanded, surface
tension increases sharply (3050 dynes/cm). These findings
indicate that, in normal lungs, the surface tension decreases as the
alveolar radius decreases during expiration and vice versa. Thus,
the stability of small air spaces is maintained, regardless of the size
of each alveolus (Figure 926).
Surface tension plays an important role in normal lung
physiology and gas exchange beyond the stability of terminal air
Figure 9-26. Schematic drawing of stable alveoli of different sizes

(see text).
spaces afforded by the presence of pulmonary surfactant. Surface

tension accounts for more than 65% of elastic recoil pressure, even
in lungs with normal surfactant activity. Elastic recoil pressure is
essential to keep the small airways extended via the interdependence of airways and the lung parenchyma. Conversely, when
the alveolar surface area is not expanded periodically (sighs),
minimum surface tension would gradually rise and the alveoli
start to collapse, especially in the dependent portions of the lung
with lower regional lung volumes. These changes occur even in
normal lungs under general anesthesia, resulting in scattered
airway closures and microatelectasis. This condition can be
prevented by the addition of a moderate level of PEEP (57
cmH2O). Once the alveoli or small airways collapse, it will require
a high sustained airway pressure (3040 cmH2O, 1015 s) to
overcome surface tension and reopen the airspace.
Cell Biology and Biochemistry

of Pulmonary Surfactant
Pulmonary surfactant is produced in the cuboidal type 2 alveolar
pneumocytes, which are found on the alveolar surface, between
the flat type 1 pneumocytes that cover most of the alveolar surface
area. Surfactant is formed in the lamellar bodies within type 2
pneumocytes, which start to appear at approximately the 27th
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week of gestation. The contents of mature lamellar bodies are

expelled into the alveolar surface by exocytosis.190 The alveolar
lining layer harvested by lung lavage contains 80 to 90%
phospholipids and 10% lipoproteins. The largest fraction of
phospholipids (7080%) is lecithin or phosphatidylcholine (PC),
of which the majority is disaturated PC (DPPC) and is highly
surface-active. Another important surface-active phospholipid is
phosphatidylglycerol (PG), which accounts for 5 to 10% of the
phospholipids within the alveoli.191 Other phospholipid fractions
include phosphatidyl-ethanolamine (PE), phosphatidylserine (PS),
and sphingomyelin (S), which are also surface-active. In the fetal
lung, surfactant is secreted into alveolar or lung fluid that
eventually constitutes approximately one third of the amniotic
fluids. The quantity of PC increases rapidly toward the term. The
ratio of PC (lecithin) to sphingomyelin (L/S ratio) is correlated
with the degree of lung maturation in premature newborn
infants.192
Four surfactant-specific proteins have been isolated and
characterized with the locations of their genes in specific chromosomes identified. Surfactant protein A, B, C, and D (SP-A,
SP-B, SP-C, SP-D), named in the order of discovery, are primarily
produced in type 2 pneumocytes. Surfactant proteins, with the
exception of SP-C, are also produced in Clara cells in the respiratory bronchioles. These proteins play specific roles in surfactant
homeostasis and host defense.193 Surfactant proteins can be
classified into two distinct groups based on their characteristic
structure and function. SP-A and SP-D are relatively abundant
hydrophilic proteins that belong to the calcium-dependent lectin
family of proteins. They have relatively weak surface-active
qualities, but are able to bind complex carbohydrates on the
surface of microorganisms and likely play important roles in
host defense in the lung. By contrast, SP-B and SP-C are small,
hydrophobic proteins and play critical roles in enhancing the
stability of surfactant phospholipids on the alveolar lining.193
The synthesis of pulmonary surfactant is tightly regulated
during both fetal and postnatal development.194 Synthesis of both
surfactant phospholipids and proteins increases markedly during
late gestation and the levels of surfactant protein mRNA are
increased during the perinatal period in association with increased
surfactant production and secretion for neonatal respiratory
adaptation.
Pulmonary surfactant phospholipids and proteins are taken up
rapidly, mostly by type 2 alveolar penumocytes and are recycled
(Figure 927). In adult rabbits, approximately 10% of the alveolar
pool of PC (1015 mg/kg body weight) is recycled every hour.
In newborn rabbits, the turnover time of the alveolar PC is
10 hours.195 Although alveolar macrophages contribute 10 to 15%
of surfactant uptake, this pathway appears important in the control
of steady-state surfactant homeostasis.
Acceleration of Surfactant Biosynthesis

In the early 1970s, deLemos and coworkers12 and Motoyama and
colleagues13 demonstrated that surfactant biosynthesis in the fetal
lung is accelerated by glucocorticoids. Subsequently, a variety of
pharmacologic agents was also shown to enhance lung maturation
or surfactant secretion including thyroxine,14 heroin,196 cyclic
adenosine monophosphate (cAMP), epidermal growth factor
(EGF), tumor necrosis factor- (TNF-), and transforming
growth factor- (TGF-).193 In 1972, Liggins and Howie reported
accelerated human fetal lung maturation after the administration
of corticosteroids to pregnant women 24 to 48 hours before
Figure 9-27. Life cycle of pulmonary

surfactant. Surfactant protein A (SP-A),
SP-B, SP-C, and lipids are packaged in
lamellar bodies and secreted by type II
alveolar epithelial cells into the air
space. Lamellar bodies unfold into tubular myelin, which gives rise to the
lipid/protein film at the air-liquid interface. Used surfactant lipids are released
from the film as small vesicles, which
are taken up and recycled or degraded
by type II cells. Alveolar macrophages
also take up surfactant and degrade it.
From Whitsett JA, Horowitz AD: Surfactant and associated proteins. In:
Fishman AP, editor. Fishmans Pulmonary Diseases and Disorders. 3rd ed.
New York: McGraw-Hill; 1998. Chapter
7, p. 123.
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the delivery of premature babies.15 Prenatal steroid therapy has
been widely and successfully practiced ever since, with minimal
side effects.
Surfactant Replacement Therapy

The intratracheal instillation of bovine or synthetic surfactant in
premature infants born with surfactant deficiency, originally
described by Fujiwara and associates in 1980 has been established
as an important and essential form of treatment for surfactant
deficiency with the demonstration of marked improvements in
morbidity and mortality in infants born prematurely.197 Surfactant
replacement with preparations containing surfactant phospholipids and SP-B and SP-C rapidly increases lung volume and
compliance and decreases the requirement for positive-pressure
ventilation as well as O2 requirements. Synthetic surfactant without surfactant proteins is less effective and its efficacy is generally
delayed. More recently, surfactant replacement therapy has been
extended to treat other clinical conditions including neonates with
persistent pulmonary hypertension (PPHN), congenital diaphragmatic hernia, and meconium aspiration syndrome as well as
infants and children with acute lung injury or acute respiratory
distress syndrome (ARDS) in whom surfactant production by
type 2 pneumocytes is diminished or surfactant inactivated by
protein leakage into the alveolar spaces.198 Measurements of
surfactant activity and surfactant components in bronchoalveolar
lavage can be used for the diagnosis of surfactant deficiency in
patients with ARDS caused by a variety of etiologies including
neonates with homozygous SP-B deficiency.199,200 This latter
disorder is characterized by atelectasis and respiratory failure in
full-term neonates and is uniformly fatal within several months
of life unless treated with lung transplantation.
CONCLUSION
It is evident that an infant or a young child is not a small adult on
the basis of respiratory physiology and, consequently, should
not be treated as such for anesthetic management. Neonatal
adaptation seems to take approximately 1 month for a full-term
neonate or 44 weeks postconception for a premature infant. This
is particularly true in terms of respiratory control. Hypoxic
stimulation of breathing is not sustainable in the neonate, and the
incidence of postanesthetic apnea is not uncommon in the
prematurely born infant during this period. During the perinatal
and neonatal periods, the production of pulmonary surfactant is
markedly increased to accommodate the aeration and stabilization
of previously fluid-filled air spaces. Beyond the period of neonatal
adaptation, the development and growth of the lung continues at
an accelerated pace. The formation of the alveoli begins late in
gestation and is essentially completed by 18 months of age with
the number of alveoli increasing 10-fold in this short time period.
As lung parenchymal maturation and growth continue, elastic
fibers, which are nearly absent at birth, increase rapidly in the
lung. As a result, the elastic recoil pressure increases and lung
compliance decreases toward normal adult levels throughout the
first decade of life. Collagen fibers, in which development takes
longer than that of elastic fibers, add strength and stability to
pulmonary membranes, preventing damage from hyperdistention.
The chest wall is very compliant at birth and is incapable of
maintaining FRC against elastic recoil of the lung when general
anesthesia removes the normally present sustained inspiratory
muscle tone and abolishes other mechanisms that maintain

thoracic stability in the awake state. Consequently, anesthesia in
infants results in airway closure and atelectasis of dependent lung
segments. The loss of pharyngeal muscle tone results in partial
upper airway obstruction even when the child is breathing
spontaneously. Chest wall stability develops by 12 months of age,
although increases in the outward recoil of the chest wall and the
inward recoil of the lung continue for several more years. The
addition of moderate PEEP prevents the airways from premature closure and maintains ventilation/perfusion stability under
general anesthesia.
O2 affinity of hemoglobin changes dramatically during the first
months of life because of the characteristics of fetal hemoglobin
with a high O2 affinity (low P50) and a low tissue O2 unloading
capability. Consequently, the relationship between PaO2 and SaO2
in young infants is quite different from that of the adult. Beyond
this period, the P50 increases, because of increased 2,3-DPG, and
tissue O2 delivery of hemoglobin surpasses that of the adult. These
changes are important for the evaluation of anemia and criteria
for blood transfusion during anesthesia, surgery, and intensive
care of neonates and young infants.
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125. Colin AA, Wohl MEB, Mead J, et al. Transition from dynamically
maintained to relaxed end-respiratory volume in human infants.
126. De Troyer A, Bastenier-Geens J. Effects of neuromuscular blockade
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127. Rehder K, Marsh MH. Respiratory mechanics during anesthesia and
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128. Westbrook PR, Stubbs SE, Sessler AD, et al. Effects of anesthesia and
muscle paralysis on respiratory mechanics in normal man. J Appl
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129. Henderson-Smart DJ, Read DJC. Reduced lung volume during
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130. Dobbinson TL, Nisbet HIA, Pelton DA. Functional residual capacity
(FRC) and compliance in anaesthetized paralysed children. Part I.
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131. Fletcher M, Ewert M, Stark C, et al. Influence of tidal volume on
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132. Motoyama, EK. Effects of positive end-expiratory pressure (PEEP)
on respiratory mechanics and oxygen saturation (SpO 2) in infants
and children under general anesthesia. Anesthesiology. 1996;85:
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133. Sly PD, Hayden MJ. Applied clinical respiratory physiology. In
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134. Ferris BG, Mead J, Opie LH. Partitioning of respiratory flow
resistance in man. J Appl Physiol. 1964;19:653.
135. Stocks J, Godfrey S. Nasal resistance during infancy. Respir Physiol.
1978;34:233.
136. Sasaki CT. Development of laryngeal function. etiologic significance
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137. Stocks J. Effect of nasogastric tubes on nasal resistance during

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138. Weibel ER. Morphometry of the Human Lung. New York: Academic
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139. Macklem PT, Mead J. Resistance of central and peripheral airways
measured by a retrograde catheter. J Appl Physiol. 1967;22:395.
140. Hogg JC, Williams J, Richardson JB, et al. Age as a factor in the
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anatomy of obstructive lung disease. N Engl J Med. 1970;282:1283.
141. Taussig LM, Landau LI, Godfrey S, et al. Determinants of forced
expiratory flows in newborn infants. J Appl Physiol. 1982;53:1220.
142. Milic-Emili J, Robatto FM, Bates JH. Respiratory mechanics in
anaesthesia. Br J Anaesth. 1990;65:4.
143. D Angelo E, Calderini G, Torri FM, et al. Respiratory mechanics in
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144. Kaditis AG, Motoyama EK, Seki I, et al. Flow and volume dependence of respiratory mechanics in anesthetized children. Pediatr Res.
1999;46:419.
145. Kaditis AG, Venkataraman ST, Zin WA, et al. Partitioning of respiratory system resistance in children with respiratory insufficiency.
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146. Don H. The mechanical properties of the respiratory system during
anesthesia. Int Anesthesiol Clin. 1977;15:113.
147. Hedenstierna G. Effects of anaesthesia on respiratory mechanics.
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Respiratory Mechanics and Artificial Ventilation. Milan: SpringerVerlag; 1999. p. 223.
148. Bergman NA. Distribution of inspired gas during anesthesia and
artificial ventilation. J Appl Physiol. 1963;18:1085.
149. Dobbinson TL, Nisbet HIA, Pelton DA. Functional residual capacity
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150. Fletcher M, Ewert M, Stark C, et al. Influence of tidal volume on
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151. Reber A, Nylund U, Hedenstierna G. Position and shape of the
diaphragm. Implications for atelectasis formation. Anaesthesia.
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152. Dueck R Prutow RJ, Davies NJ, et al. The lung volume at which
shunting occurs with inhalation anesthesia. Anesthesiology. 1988;
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153. von Ungern-Sternberg BS, Hammer J. Schibler A et al. Decrease of
functional residual capacity and ventilation homogeneity after
neuromuscular blockade in anesthetized young infants and preschool children. Anesthesiology. 2007;105:670675.
154. Brismar B, Hedenstierna G, Lundquist H, et al. Pulmonary densities
during anesthesia with muscular relaxation. a proposal of atelectasis.
155. Damgaard Pedersen K, Qvist T. Pediatric pulmonary CT-scanning
anaesthesia-induced changes. Pediatr Radiol. 1980;9:145.
156. Serafini G, Cornara G, Cavalloro F, et al. Pulmonary atelectasis
during paediatric anaesthesia. CT scan evaluation and effect of positive end-expiratory pressure (PEEP). Paediatr Anaesth. 1999;9:225.
157. Rothen HU, Sporre B, Engberg G, et al. Prevention of atelectasis
during general anaesthesia. Lancet. 1995;345:1387.
158. Tusman G, Boehm SH, Tempra A, et al. Effects of recruitment
maneuvers on atelectasis in anesthetized children. Anesthesiology.
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159. Benoit Z, Wicky S, Fischer J-F, et al. The effect of increased FIO2
before tracheal extubtion on postoperative atelectasis. Anesth Analg.
2002;95:17771781.
160. Cook CD, Sutherland JM, Segal S, et al. Studies of respiratory
physiology in the newborn infant. III. Measurements of mechanics
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161. Mead J. Control of respiratory frequency. J Appl Physiol. 1960;
15:325.
162. Radford EP Jr, Ferris BJ Jr, Kriet BC. Clinical use of nomogram to
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163. Hart MC, Orzalesi MM, Cook CD. Relation between anatomic
respiratory dead space and body size and lung volume. J Appl
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164. Kaneko K, Milic-Emili J, Dolovich MB, et al. Regional distribution
of ventilation and perfusion as a function of body position. J Appl
Physiol. 1966;21:767.
165. Heaf DP, Helms P, Gordon I, et al. Postural effects on gas exchange
in infants. N Engl J Med. 1983;308:1505.
166. Davies H, Kitchman R, Gordon I, et al. Regional ventilation in
infancy. reversal of adult pattern. N Engl J Med. 1985;313:1626.
167. Milic-Emili J, Henderson JAM, Dolovich MB, et al. Regional
distribution of gas in the lung. J Appl Physiol. 1966;21:749.
168. Hughes JMB, Glazier JB, Maloney JE, et al. Effect of lung volume on
the distribution of pulmonary blood flow in man. Respir Physiol.
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172. Sykes MK, Loh L, Seed RF, et al. The effect of inhalational
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177. Comroe JH. Physiology of Respiration. 2nd ed. Chicago: Year Book
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180. Oski FA. Designation of anemia on a functional basis. J Pediatr.
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181. Oski FA. The unique fetal red cell and its function. Pediatrics.
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182. Card RT, Brain MC. The anemia of childhood: evidence for
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187. Jennis MS, Peabody JL. Pulse oximetry. An alternative method for
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189. Clements JA, Brown ES, Johnson RP. Pulmonary surface tension
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190. Kikkawa Y, Motoyama EK, Cook CD. Ultrastructure of lungs of
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191. Rooney SA, Canavan PM, Motoyama EK. The identification of
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Renal Function, Acid-Base,

and Electrolyte Homeostasis
10
John Chandler and Robert Plant
INTRODUCTION
Despite the efficiency with which the bodys various homeostatic
mechanisms work to maintain the internal milieu within tight
limits, the system has its limitations. Fluid, electrolytes, and acidbase disturbances are extremely common in the perioperative
period. Such disturbances are of particular concern to the
pediatric anesthesiologist because the corrective mechanisms in
children are more easily overwhelmed than those in adults.
Cardiovascular, neurologic, and neuromuscular function can be
significantly disturbed by major fluid and electrolyte disturbances.
The kidneys regulate the volume and composition of the bodys
fluids. Maintaining a physiologic pH is vital to the bodys
biochemical and enzymatic reactions. Changes in ventilation and
perfusion, common during anesthesia and surgery, can rapidly
alter acid-base balance. It is essential that the anesthesiologist be
familiar with the many disturbances of acid-base and fluidelectrolyte states that may affect the pediatric patient. This chapter
examines the important physiology of the kidney, with particular
attention to fluid and electrolyte handling and acid-base balance,
and provides a structured approach to the anticipation, diagnosis,
and perioperative management of the specific physiologic disturbances in these areas.
RENAL PHYSIOLOGY
The functional unit of the kidney is the nephron, with each kidney
containing over 1 million of them. They consist of a hollow, singlecellwalled, tortuous tube. The nephron can be conveniently
divided into six functional and anatomic divisions, a basic
understanding of which is crucial to a proper understanding
of acid-base balance and fluid and electrolyte handling. These
divisions are
1.
2.
3.
4.
5.
6.
The glomerular capillaries and Bowmans capsule.

The proximal convoluted tubule (PCT).
The loop of Henle (LOH).
The distal convoluted tubule.
The collecting tubule.
The juxtaglomerular apparatus.
Renal Blood Flow and Glomerular Filtration

The glomerulus is formed by a cluster of capillary loops projecting
into an invagination of the proximal end of the nephron lined by
a single layer of epithelial cells, commonly referred to as Bowmans
capsule. The barrier to filtration is formed by these two layers of
C H A P T E R
cells (capillary endothelium and Bowmans capsular epithelium),

which are tightly adherent to a common basement membrane.
There are relatively large fenestrations between the endothelial
cells. The epithelial cells interdigitate tightly, thereby providing a
filtration barrier to large molecules and blood components, but
not to water and small molecules.
The two main determinants of filterability (in descending order
of importance) are molecular size and charge. The cut-off size is
not absolute. Resistance to filtration begins at a molecular radius
of approximately 2 nm. Substances of molecular radius larger
than 4 nm are not filtered at all. The glomerular membranes are
negatively charged; consequently, positively charged molecules are
filtered at a greater molecular size than those negatively charged.1
Urine formation begins with the production of an ultrafiltrate of
plasma by the glomerulus. This activity is dependent upon a large
renal blood flow (RBF). The volume of ultrafiltrate produced per
minute is referred to as the glomerular filtration rate (GFR). RBF
and GFR share an interdependent relationship because GFR relies
on RBF for its preservation and GFR influences RBF via a feedback
mechanism.
Glomerular Filtration
Approximately 900 L of plasma pass through the adult kidneys
each day. Of this 900 L, the proportion that passes across the
glomeruli (the filtration fraction) is about 20%. This equates to
roughly 180 L/day or a GFR of 125 mL/min. Glomerular filtration
differs from transcapillary exchange, which occurs in other tissues,
by virtue of the much greater proportion of water and small solutes
that cross the capillary wall and by the near-complete exclusion
of plasma proteins from the ultrafiltrate. GFR is affected by
four factors:
1. Glomerular hydrostatic pressure (PG), which promotes
filtration, depends on the relative vascular tone of the afferent
and efferent arterioles and on RBF.
2. Bowmans capsular hydrostatic pressure (PB), which opposes
filtration, is generally a minor determinant of GFR; however, it
may increase significantly with obstructive process of the
urinary collecting system.
3. G, which opposes filtration, is primarily determined by plasma
albumin concentration.
4. B, which promotes filtration, is generally zero in the normal
state because of the lack of proteins in the glomerular filtrate.
Because B is considered to be zero because of the almost
complete lack of proteins in filtrate, the GFR can be expressed as
GFR = KF (PG PB G)
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where KF is the filtration constant. GFR is an excellent measure
of the excretory function of the kidney. It is the best estimate of
functioning renal mass in patients with chronic renal disease, and
decline in GFR is the principal indicator of ongoing progression of
disease.
Renal Blood Flow

Between 20 and 25% of cardiac output perfuses the kidneys. RBF
is determined by the following relationship:
RBF =
Renal artery pressure renal vein pressure

(renal perfusion pressure)
renal vascular resistance (RVR)
Renal perfusion pressure approximates mean arterial pressure,

whereas RVR is primarily determined by afferent and efferent
arteriolar tone. RBF is not distributed equally to all parts of the
kidney. Blood flow to the cortex greatly exceeds that to the medulla
(98% vs 2%). RBF is controlled by both intrinsic and extrinsic
mechanisms with short-lived changes in blood pressure being
counteracted by autoregulation. This autoregulation is capable of
preserving RBF and GFR over a range of mean arterial pressures
from approximately 75 to 150 mmHg. This is accomplished
through two processes including (1) a myogenic reflex, which
involves the contractile response of the afferent arteriolar smooth
muscle to increases in hydrostatic pressure, and (2) a tubuloglomerular feedback, which regulates afferent arteriolar resistance to
ensure constant sodium chloride (NaCl) delivery to the macula
densa of the juxtaglomerular apparatus (JGA).
The JGA is a specialized area of each nephron that consists of a
segment of the afferent arteriole, containing the juxtaglomerular
cells in its wall, and the end of the thick ascending cortical segment
of the LOH, the macula densa. Increased RBF and GFR increase
NaCl delivery to the distal tubule, stimulating the macula densa of
the JGA. This causes constriction of the afferent arteriole by a
paracrine effect and a consequent decrease in GFR and NaCl
delivery. A decrease in GFR or RBF causes diminished NaCl, a
consequent dilation of the afferent arteriole, renin release resulting
in an increased GFR, and NaCl delivery to the macula densa. Renin
released into the bloodstream acts on angiotensinogen to form
angiotensin I, which is converted in the lungs by angiotensinconverting enzyme (ACE) to angiotensin II. Angiotensin II is a
potent vasoconstrictor in the renal and systemic vasculature. Its
effect is to constrict the efferent arterioles preferentially resulting in
a decrease in RBF; however, there is a preservation of GFR because
of an increase in the filtration fraction. Although the effects of the
prostaglandins (PGE2 and PGI2) do not contribute greatly to the
regulation of RBF during the normal state, they oppose vasoconstrictive effects during times of stress or hypovolemia, thereby
maintaining RBF.
Extrinsic mechanisms of RBF control are classified as neural,
hormonal, and autacoidal. These influence the balance between
afferent and efferent arteriolar tone. Sympathetic fibers innervate
all parts of both the renal vasculature and the nephron. Direct
effects on RBF are mediated via vascular 1-adrenergic receptors
that trigger vasoconstriction of both the afferent and the efferent
arterioles and a decrease in RBF and GFR.2
Developmental aspects of RBF and GFR

Nephrogenesis is complete by 36 weeks of gestation. RBF and GFR
are both low in neonates and correlate with gestational age. GFR
Renal Function, Acid-Base, and Electrolyte Homeostasis 141
is 20 to 25% of adult levels at term. RBF and GFR both increase

rapidly in the postnatal period because of both an increase in
cardiac output and a decrease in renal vascular resistance, doubling
by 2 weeks and reaching adult levels (120 mL/min/70kg) by 2 years
of age.3
Both GFR and RBF can be measured using the clearance
concept. The renal clearance of a substance X (Cx) is the amount
of plasma from which all of the substance is removed and excreted
into the urine per unit time. It is described by the equation:
Cx = (Ux V)/Px
where Ux and Px are urine and plasma concentrations of X, and
V is the volume of urine generated per unit time.
Ideally, calculation of RBF would require a marker that is
completely cleared from plasma on its passage through the
kidneys. Para-aminohippuric acid (PAH) clearance is commonly
used to estimate RBF. The accuracy of this technique is good
(within 10% of the true value) in adults, but less (within 65% of the
true value) in infants under 3 to 5 months of age.4
The clearance of a substance that is freely filtered but neither
reabsorbed nor secreted by the tubules is used to calculate
GFR. Exogenous or endogenous markers may be used. The gold
standard of GFR measurement employs an inulin (a polysaccharide) infusion to achieve a steady-state plasma concentration. However, this assay is inconvenient to perform and assays
of plasma and urine inulin concentration are problematic. In
clinical practice, the concentration of creatinine, an endogenous
metabolite produced at a relatively constant rate and eliminated
mainly by filtration, is used to estimate GFR. This is achieved
using one of a number of equations calculated from large
observational studies. The Modification of Diet in Renal Disease
(MDRD) equation is used most often in adults5 and the Schwartz
equation6 is commonly utilized for children and adolescents.
There are two main problems with creatinine-based calculations.
First, with declining GFR (down to 60% of normal), tubular
secretion assists in creatinine elimination producing a creatinineblind range of reduced GFR. Second, there is a large variability in
creatinine production between individuals and at different times
in the same individual. Children have especially inconsistent
plasma creatinine concentrations and the Schwartz equation
underestimates GFR in muscular children and overestimates GFR
in anorexic or chronically ill children.7
Recent research has focused on a low molecular protein,
cystatin C. It is produced at a constant rate by all nucleated cells,
freely filtered by the glomerulus, and completely catabolized in,
and not secreted by, the tubular cells. Reference ranges in children
reach adult levels in the second year of life and are unaffected by
nutritional status or muscle mass. Cystatin C has been shown to be
elevated in the creatinine-blind range of GFR from 60 to 90
mL/min/70 kg. A recent meta-analysis examining calculation of
GFR from cystatin C concentrations showed improved diagnostic
accuracy compared with creatinine-based estimates.8
Tubular Function
Following filtration, glomerular filtrate travels through the
four main parts of the nephron: the proximal tubule, LOH, distal
tubule, and collecting duct.9 The filtrate is modified by reabsorption and secretion to arrive at the end of the nephron as urine.
These modifications are the processes whereby the body regulates
electrolyte and water balance and acid-base status and excretes
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unwanted metabolites and foreign substances. The three determinants of urine composition are glomerular filtration, tubular
reabsorption, and tubular secretion.
The two types of solute transfer across the membrane of tubular
cells are
1. Passive transport, which is subdivided into
a. Simple diffusion.
b. Facilitated diffusion.
2. Active transport, which may be described as
c. Primary.
d. Secondary.
e. Tertiary.
f. Pinocytosis.
Simple diffusion is the movement of solutes down an electrical
or a chemical gradient. Although facilitated diffusion also occurs
down a concentration gradient, it is dependent upon a specific
carrier protein. Conversely, active transport moves solute against
a concentration gradient and, as a result, consumes energy.
Primary active transport mechanisms use energy directly derived
from adenosine triphosphate (ATP) such as the Na+/K+-ATPase
pump. Secondary active transport mechanisms couple the
movement of sodium to the cotransport or exchange of another
molecule such as the Na+-K+-2Cl cotransporter. Tertiary active
transport systems are associated with secondary active transport
mechanisms such as the -ketoglutarate cotransporter. Na+/K+ATPase is a basolateral membrane transport protein that is critical
to the operation of all of the passive and most of the active
transport processes of the renal tubule. It accounts for the high
renal oxygen consumption (and energy necessary for normal renal
function). Approximately 70% of the oxygen consumption of the
kidney is used for the turnover of Na+/K+-ATPase. Three Na+ ions
are exchanged for two K+ ions for every ATP molecule that is
hydrolyzed. This has two consequences. First, it maintains a very
low concentration of Na+ intracellularly, and second, it maintains
an electrical gradient of (70mV across the cell membrane. These
gradients act to increase the reabsorptive force for sodium across
the luminal membrane. Na+/K+-ATPase activity is affected by
many factors. It is increased by norepinephrine via -adrenergic
receptors and angiotensin II, and it is decreased by dopamine,
atrial natriuretic factor, and endothelin. Because of the dependence of so many transport systems on sodium gradients, changes
in the activity of Na+/K+-ATPase affect the excretion of many
substances.
Proximal Tubule
In addition to its primary role of bulk reabsorption, the proximal
segment of the nephron has three other functions: secretion of
organic molecules (e.g., creatinine), hydroxylation of vitamin D,
and formation of ammonia to regulate acid-base balance.
Morphologically, the proximal tubular cells are well adapted to
their functions. To increase surface area, their luminal membranes
have an abundance of microvilli and the basolateral membranes
have many in-foldings. To provide the energy for transport,
tubular cells contain many mitochondria.
Proportionally, the PCT reabsorbs more than half of the filtered
sodium, potassium, chloride, calcium, urea, and water and almost
all of the filtered bicarbonate (HCO3), phosphate, glucose, amino
acids, and low-molecular-weight proteins. These processes are
largely dependent upon sodium gradients (Figure 101).
Figure 10-1. Major transport proteins in the proximal tubular cells.

ATP = adenosine triphosphate. Adapted from Johnson and Freehally (9)
Sodium is actively pumped across the basolateral membranes

generating the gradient from lumen to interstitium for sodium
reabsorption with water following passively. As a result, fluid
leaving the proximal tubule is iso-osmolar with plasma. At normal
plasma concentrations, glucose is almost completely reabsorbed
from the proximal tubular fluid with Na+ ions, via a cotransporter.
The glucose transport system is remarkably efficient up to the
tubular maximum, with little glucose excretion. Beyond this, the
transporters are overwhelmed and the excess glucose is excreted.
The plasma glucose concentration at which this occurs is the
threshold for glucose.
LOH
The LOH has two main functions: the reabsorption of water and
ions, and the establishment and maintenance of a hypertonic
medullary interstitium, which enables the distal segments of the
nephron to concentrate urine. The LOH contains three distinct
parts: two thin limbs (descending and ascending) that are
metabolically inactive and a thick ascending limb (TAL) that is
metabolically active. The descending limb passes from the cortex
into the medulla and is permeable to water but relatively
impermeable to sodium chloride. By contrast, the TAL passes back
to the cortex and is impermeable to water but permeable to NaCl.
These LOHs are accompanied by capillaries (vasa recta).
Between 20 and 30% of the filtered sodium, chloride, and
potassium is reabsorbed in the LOH accompanied by approximately 20% filtered water. The TAL is the primary site of ion
removal from the filtrate. A unique carrier protein, the Na+/K+/2Cl
cotransporter (NKCC) is responsible for most ion movement
across the luminal membrane. This is the site of action of loop
diuretics (Figure 102). In common with most other transport
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CHAPTER 10
Figure 10-2. Ion channels in the loop of Henle.
proteins in the nephron, it relies upon the sodium gradient created

by basolateral Na+/K+-ATPase. Because of the low concentration of
potassium in the tubular fluid, a recycling system pumps ions back
into the lumen to allow continued function of the NKCC. The
removal of two negative charges for each positive charge leaves the
luminal fluid with a positive charge relative to the interstitium.
This electrical gradient facilitates the movement of calcium and
magnesium via the intercellular pathways to the interstitium.
Countercurrent multiplication creates the hypertonic environment of the medullary interstitium and countercurrent exchange
helps maintain it. Countercurrent multiplication comprises two
elements. First, the TAL is impermeable to water, and therefore,
the tubular fluid becomes progressively hypotonic as NaCl is
pumped into the interstitium. The resulting increased interstitial
osmolarity equilibrates with the descending limb tubular fluid,
leaving it hypertonic. This hypertonic fluid then enters the TAL,
which again produces hypotonic tubular fluid by removing NaCl,
but a greater amount of salt needs to be removed than in the
previous circuit. This creates a more hypertonic interstitium,
which produces a still more hypertonic descending limb fluid and
so on until the maximum reabsorptive capacity of the TAL is
reached. The result of this multiplication leaves a maximum
interstitial osmolarity of approximately 1200 mOsm/L. The second
part of the countercurrent exchange is due to the capillary loops of
the vasa recta. In order to prevent the solutes in the interstitium
from being washed out by blood flow, ions and water are
exchanged in opposite directions between vessels traveling to and
from the medulla, thereby protecting the hyperosmolar interstitium created by countercurrent multiplication.
cortical collecting duct, and the medullary collecting duct. These

three segments are responsible for reabsorption of approximately
8% of filtered sodium, reabsorption of a variable amount of water
(8-17% of that filtered), and secretion of variable amounts of
K+ and H+ ions.
The first section of the distal tubule (early distal tubule), which
forms part of the JGA, is also functionally similar to the TAL of
the LOH. It continues the process of dilution of tubular fluid
by ion reabsorption although it is impermeable to water. A
thiazide diureticsensitive, luminal membrane sodium chloride
cotransporter powered by the basolateral Na+/K+-ATPase is the
major ion transporter. Parathyroid hormone (PTH)sensitive
calcium reabsorption also occurs in this section accompanied by
magnesium.
The late distal tubulecortical collecting duct is made up of two
types of cells: principal cells and intercalated cells. Principal cells are
primarily responsible for aldosterone-mediated sodium reabsorption and potassium secretion. These functions are predictably
reliant upon basolateral Na+/K+-ATPase to create a concentration
gradient down which sodium and potassium flow in opposite
directions via carrier proteins across the luminal membrane
(Figure 103). Aldosterone has two main effects on principal cells:
(1) it increases the number of Na+/K+-ATPase carriers in the
basolateral membrane and (2) it increases the number of carrier
proteins in the luminal membrane. The net effect of aldosterone is
to retain sodium and secrete potassium. Increased delivery of Na+
to this segment (i.e., the upstream effects of natriuretics such as
loop and thiazide diuretics) will enhance kaliuresis.
The two subtypes of intercalated cells (alpha and beta) are
responsible for secretion of H+ and HCO3 ions, respectively.
H+ ion secretion in a intercalated cells is partly under the control
of aldosterone. These cells are also important in potassium
Lumen
Cell
Interstitium
Ald
3Na
ATP
Na
2K
K+
K+
Distal Tubule and Collecting Duct

The distal tubule and collecting duct have three functionally
different segments: the early distal tubule, the late distal tubule
Figure 10-3. The principal cell of the distal tubule/collecting duct.

Ald = aldolase; ATP = adenosine triphosphate.
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reabsorption via a H+ ion transport system. These cells are

discussed further in the Acid-Base Balance section.
The cells of the medullary collecting duct are modified
principal cells. It is here that the final volume and osmolarity of
excreted urine are determined. The cells are permeable to sodium
via a luminal carrier that can be inhibited by atrial natriuretic
peptide. Water permeability of the medullary collecting duct cells
is determined by antidiuretic hormone (ADH). ADH is the
primary determinant of urine volume and osmolarity. It is secreted
by the posterior lobe of the pituitary gland in response to increased
plasma osmolarity and decreases in systemic blood pressure.
The basolateral membrane of these cells is permanently highly
permeable to water owing to fixed water-carrying proteins
called aquaporins (types 3 and 4). The luminal membrane is
impermeable to water in the absence of ADH. In the presence of
ADH, aquaporin (type 2)-containing vesicles are inserted into
the luminal membrane allowing water to enter the cell and then
move to the interstitium across the water-permeable basolateral
membrane10 (Figure 104). Water reabsorption in the medullary
collecting duct is therefore reliant upon two variables: (1) the
presence of ADH-induced luminal aquaporins to allow water to
cross epithelial cells and (2) the hypertonic interstitium created by
the LOH to provide a gradient down which water moves.11 This
results in a hypertonic urine and electrolyte-free water retention.
The difference between urine osmolarity in the presence and the
absence of ADH can be seen in Figure 105.
Developmental Aspects of Tubular Function

Differences between adult and neonatal tubular function can
be categorized into morphologic, functional, and regulatory
categories. The reabsorptive area offered by the PCT increases
greatly during the first 2 years of life. This results from an increase
in its length and the development of in-folding of both the luminal
and the basolateral membranes. The number and function of
the powerhouse of tubular reabsorption, the Na+/K+-ATPase
transporter, are reduced at birth. Na+/K+-ATPase activity increases
5- to 10-fold during the postnatal period. Because of the decreased
activity of Na+/K+-ATPase in early life, all transporters reliant on
the Na+ gradient, which it provides, are also reduced in function.
For example, PCTs maximum capacity for glucose reabsorption in
premature babies is 10 times less than that in adults. Aquaporin
Figure 10-5. The effect of antidiuretic hormone (ADH) on the

osmolarity and volume of tubular fluid. Adapted from Guyton A,
Hall J. The kidneys and body fluids. In: Textbook of Medical Physiology.
Philadelphia: Elsevier Saunders; 2006.
expression is similarly decreased at birth and develops to adult

levels during the first year of life.3
Hormone effects on the kidney in infants are somewhat
different than those in adults.12 The renin-angiotensin system in
the very young cannot be maximally inhibited, which decreases
the kidneys ability to deal with large NaCl loads. The implications
of these differences between adult and immature kidneys on
neonatal renal function are
1.
2.
3.
4.
Neonates are obligate salt losers.

Neonates cannot excrete a large salt load.
Neonates cannot concentrate urine effectively.
Processes linked to sodium gradients work inefficiently (e.g.,
glucose reabsorption, potassium secretion).
ACID-BASE BALANCE
Physiology
Acid-Base Chemistry
Figure 10-4. Effect of antidiuretic hormone (ADH) on the medullary

collecting duct cells.
The concentration of H+ ions in both the extracellular fluid (ECF)

and the intracellular fluid (ICF) is aggressively maintained by the
body. Almost all cellular and organ functions are sensitive to
changes in (H+) concentrations, and consequently, large deviations
are incompatible with life. Normal ECF (H+) concentrations are
very low, in the order of 40 nmol/L, which is 3 to 4 million times
less than that of sodium. In order to express these concentrations
more conveniently, the negative log (p) of (H+) or pH is used.
Thus, normal pH of the ECF is 7.4. Because this is a logarithmic
scale, an increase in one unit of the pH scale is equivalent to a 10fold increase in concentration.
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An acid is any substance that releases a proton (H+) in solution
and a base is any substance that accepts a proton (H+) in solution.
Strong acids are those that readily give up H+ ions, thereby
decreasing the pH of a solution. Conversely, strong bases are those
that avidly take up H+ ions and increase pH. In an acidic solution,
a weak acid (e.g., the phosphate group of a nucleic acid) will tend
to hold onto its H+ ion (i.e., remain largely unionized), whereas a
weak base will take up protons (i.e., ionize). The reverse is true for
a basic solution in which a weak acid will give up protons (and
ionize) and a weak base will remain un-ionized or only partially
ionized. A buffer is a mixture of a weak acid and its conjugate base
or a weak base and its conjugate acid. A buffer will resist change
in (H+) in a solution by readily accepting or donating H+.
The body at rest continuously produces two types of acid:
(1) volatile and (2) nonvolatile. Volatile acid is produced by tissue
respiration and excreted by the lungs as CO2. As a result, this
metabolically derived CO2 has no impact on acid-base balance.
Nonvolatile acids are independent of CO2 production. They
include either (1) organic acids produced by muscle, liver, and
adipose tissue (e.g., lactic acid, hydroxybutyric acid, and
acetoacetic acid) or (2) fixed acids produced by the metabolism
of sulfur-containing amino acids and organic phosphates
(e.g., sulfuric and phosphoric acids). These nonvolatile acids
accumulate at the rate of approximately 1 mEq/kg/day and are
excreted by the kidneys.13 The regulation of acid-base balance is of
particular importance during the provision of anesthetic care.
Anesthesia and surgery, through their effects on tissue perfusion
and ventilation, can alter acid-base balance. Conversely, altered
states of acid-base balance can alter the patients response to
anesthesia. The rates at which these effects occur are greater in
children than in adults.
Protection against (H+) Changes

Three levels of protection against (H+) changes are
1. Immediate chemical buffering.
2. Respiratory compensation.
3. Renal compensation.

that is,
( )
pH = pK log (HA)
(A)
This equation is known as the Henderson-Hasselbach equation, from which it is apparent that the pH of a solution is related
to the ratio of the dissociated anion to the undissociated acid.
Buffer system power is maximized under two conditions: (1) when
the concentrations of the conjugate pairs are equal: (A) = (HA),
that is, when pH = pK, and (2) when the absolute concentrations
of the conjugate pairs are high.
THE HCO3 BUFFER: The conjugate pairs of the HCO3 buffer sys-
tem is H2CO3 and HCO3 (i.e., H2CO3 HCO3 + H+). However,

CO2 can be substituted for H2CO3 because H2O + CO2 H2CO3.
Therefore, the result of adding acid to the HCO3 buffer is the production of CO2 and water, which are readily excreted by the lungs
and kidneys, respectively. If the solubility coefficient of CO2 (0.03
mmol/L) and the pKa (6.1) for HCO3 are substituted, the Henderson-Hasselbach equation applied to HCO3 can be written as
pH = 6.1 + log (HCO3)

0.03 PaCO2
From this equation, the pH of plasma can be calculated if the

arterial carbon dioxide pressure (PaCO2) and (HCO3) are known.
The fact that the pKa of 6.1 is not close to physiologic pH
suggests that HCO3 might not be an efficient buffer because at pH
of 7.4, (HCO3) greatly exceeds (H2CO3). The HCO3 buffer system
has two important advantages: (1) the concentrations of CO2 and
HCO3 can be altered by the lungs and the kidneys, respectively,
and (2) HCO3 is present in plasma in relatively large concentrations. The implication of the fact that the pKa for HCO3 is less
than normal plasma pH is that HCO3 buffers change more
effectively if they are tending to decrease pH than if they are
tending to increase pH.
THE PHOSPHATE BUFFER: This buffer system is important both
Chemical buffering is provided by various body fluid buffer

systems including (1) the main extracellular bufferHCO3;
(2) the two main urinary buffersphosphate and ammonia; and
(3) the three main intracellular buffersprotein, hemoglobin, and
phosphate. We present a brief overview of chemical buffer
function followed by a discussion of the individual buffers. Where
HA is a weak acid in solution, it will dissociate as follows: HA
H+ + A. HA can act as an acid by donating H+ and A can act as
a base by taking up H+. Therefore, A is the conjugate base of the
acid HA. The equivalent reaction for a base B is B + H+ BH+
where BH+ is the conjugate acid of the base B.
For the first reaction outlined previously, a dissociation
constant K can be defined:
K = H)(A
(HA)
and
(H+) = K(HA)
(A)
The negative log of this reaction is
log(H+) = pK log (HA)
(A)
( )
intracellularly and in renal tubules where its concentration reaches

useful levels. The conjugate pair is
HPO42 + H+ H2PO4 (pKa = 6.8)
This system is suited to working in the ICF and tubular fluid
for two reasons: (1) phosphate is concentrated in these fluids and
(2) the pH of these fluids is less than that of plasma and, thus,
closer to the pKa of the phosphate buffer system.
HEMOGLOBIN: Hemoglobin (Hb) is the principal nonbicarbonate

blood buffer. The Hb molecule has many buffering sites,
principally histidine moieties with a pK of 6.8. Unlike HCO3, Hb
can effectively buffer volatile (CO2) and nonvolatile acids by acting
as a weak acid and as a potassium salt:
H+ + KHb HHb + K+
CO2 + H2O + KHb HHb + HCO3 + K+
PROTEIN BUFFERS: Proteins are important in intracellular

buffering because, in addition to their high ICF concentrations,
many protein buffer pairs have a pKa at or near 7.4. Protein amino
acids have COOH groups that can release H+ and NH2 groups
that can accept H+ ions. Therefore, they act as weak acids or bases
depending on the pH of the solution.
RESPIRATORY COMPENSATION: Medullary chemoreceptors that
respond to changes in cerebrospinal fluid (CSF) pH modulate the
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respiratory response to changes in the acid-base state. The lungs

are responsible for eliminating the 15,000 mmol of CO2 produced
daily by metabolism and for compensation for metabolic variations. A decrease in pH stimulates the medullary chemoceptors,
causing increased ventilation and a prompt decrease in PaCO2,
restoring pH toward normal. An increase in pH inhibits the
medullary chemoceptors, causing a prompt increase in PaCO2,
which restores pH toward normal. Both of these corrections are
incomplete. The response to alkalosis is limited by progressive
hypoxia, secondary to hypoventilation. In general, PaCO2 does not
tend to increase to greater than 55 mmHg in response to metabolic
alkalosis
RENAL COMPENSATION: Under normal conditions, the kidneys

excrete the same amount of nonvolatile acid as are produced by
metabolism each day (1 mEq/kg/day). Compensation for acidbase changes entails four mechanisms:
1.
2.
3.
4.
Filtered HCO3 reabsorption.

H+ secretion.
HCO3 regeneration by titratable acid excretion.
HCO3 secretion.
Although all parts of the nephron contribute to HCO3

reabsorption, the proximal tubular cells perform 85% of this task.
For each mmol of HCO3 reabsorbed, 1 mmol of H+ is secreted into
the tubular fluid. This is achieved by the Na+/H+ secondary active
transport protein and is limited by the sodium gradient so that the
minimal tubular pH achievable is 6.7. The secreted H+ ions
combine with filtered HCO3 forming H2CO3 and ultimately H2O
and CO2. CO2 enters tubular cells and freely combines there with
water in a reaction catalyzed by carbonic anhydrase to form
carbonic acid. This in turn, dissociates into H+ and HCO3. The
HCO3 enters the bloodstream via the basolateral Na+/HCO3
cotransporter and the H+ is resecreted into the tubule (Figure
106). Thus, filtered HCO3 is neutralized with the concomitant
Figure 10-6. Cellular mechanisms for bicarbonate reabsorption in

the proximal tubule. ATP = adenosine triphosphate; CA = carbonic
anhydrase.
Figure 10-7. Active H+ secretion in the collecting tubule.

ATP = adenosine triphosphate; CA = carbonic anhydrase.
tubular generation of HCO3 into the blood. The net effect is Na+
reabsorption and HCO3 reabsorption. For every mole of HCO3
that is neutralized in the tubular fluid, a mole enters the blood,
although it is not the same mole.
Active secretion of H+ ions occurs in the alpha-intercalated cells
of the late distal and collecting tubules. This process is achieved by
primary active transport and allows a much greater gradient (900
times) across the luminal membrane to be achieved than in the
proximal tubule. A pH of 4.4 is the minimum possible for tubular
fluid. Carbonic anhydrase is the source of the H+ ions and the
HCO3 produced is cycled back to the interstitium via a basolateral
Cl/HCO3 exchanger (Figure 107).
The amount of H+ excreted in the urine is limited by the ability
of tubular cells to produce a concentration gradient across
the luminal membrane. As we have seen, this is limited at a
pH of approximately 4.4. At this pH, the (H+) is only 0.1 mEq/L.
Given the requirement to excrete 1 mEq/L/day of acid,
a mechanism of excreting much more H+ is necessary. To limit the
(H+) in the filtrate, two buffers (called titratable acids) bind H+,
limiting its concentration and thereby allowing much more to
be excreted. The first buffer is the phosphate system, which has
been previously mentioned. HPO42 is concentrated in the renal
tubules and accepts an H+, forming H2PO4. Once this phosphate
buffer has been exhausted and all filtered HCO3 reabsorbed,
ammonia becomes the most important buffer. Ammonia (NH3)
is produced in the tubular cells, largely from the deamination
of glutamine. It diffuses into the lumen where it combines
with H+ to form ammonium ions (NH4+). NH4+ and H2PO4 are
not reabsorbed, resulting in loss of H+ and, consequently,
generation of HCO3 from the disassociation of carbonic acid
(Figure 108).
In the presence of alkalosis, the amount of HCO3 that is filtered
normally allows the kidneys to excrete large quantities if necessary.
The beta-intercalated cells of the cortical collecting tubule are
capable of actively secreting HCO3 in response to an alkaline
load, but only if there is sufficient luminal Cl for exchange,
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CHAPTER 10
Developmental Aspects of Acid-Base Balance
Figure 10-8. Titratable acid excretion. ATP = adenosine triphosphate;

CA = carbonic anhydrase; DA = deamination.
because the luminal channel that allows HCO3 excretion is one

that exchanges it one-to-one for Cl. This fact is key to the understanding of metabolic alkalosis (Figure 109).
Figure 10-9. Bicarbonate secretion at the -intercalated cells of the

collecting tubule ATP = adenosine triphosphate; CA = carbonic
anhydrase.
In utero, the fetus maintains a mild respiratory acidosis, with a

similar plasma HCO3 concentration, but a greater PaCO2 than its
mother. Following birth, infants have a reduced plasma HCO3
concentration and PaCO2 than older children and adults. They
have a comparatively greater basal acid production and are less
able to respond to an acid load. Endogenous acid production in
small children is somewhat between 50 and 100% greater per
kilogram than in adults. This is primarily because of the deposition of Ca2+ in bone, a process that produces 0.5-1 mEq/L of
acid/day. HCO3 absorption from the gastrointestinal (GI) tract is
an important source of base to neutralize this nonvolatile acid and,
in part explains the tendency of infants to become profoundly
acidotic when suffering from gastroenteritis.
Both HCO3 reabsorption and acid excretion are poorly
developed in infants. The HCO3 tubular threshold (the plasma
level above which HCO3 appears in the urine) is less for two
reasons: (1) the immaturity of Na+/ K+-ATPase and its inability to
produce a sufficient sodium gradient and (2) decreased carbonic
anhydrase activity. Acid secretion is also impaired by two processes: (1) decreased H+-ATPase activity in the collecting ducts
impairs the ability of the kidney to produce an acid urine (minimal
pH, ~6.5) and (2) titratable acid excretion is less because of the
limited availability of tubular phosphate and ammonia. The net
result is that the infant or small child is living near its limit of acid
compensation and is, therefore, prone to develop acidosis during
the course of an acute illness or starvation.
Pathophysiology of Acid-Base Disturbances

Metabolic Acidosis
Although frequently used to describe a situation in which there is
a decrease in the pH, the term acidosis more correctly describes a
situation that, if unopposed, would tend to cause a fall in pH.
The term acidemia more accurately describes the situation in
which there has been an actual fall in pH. For example, a person
may have a chronic respiratory acidosis but, because of renal
compensation, may have a normal pH and, therefore, not in fact
be acidemic. Various pathologic conditions may result in acidosis
(Table 101).
The clinical manifestations of acid include a combination
of sympathoadrenal stimulation and direct depressant effects.
With a pH less than 7.2, the depressant effects predominate.
Cardiovascular effects include direct myocardial and smooth
muscle depression, which results in vasodilatation, leading to
progressive hypotension. There is also decreased response to
endogenous or exogenous catecholamines and an increased risk of
ventricular fibrillation (decreased fibrillation threshold). There is
a rightward shift in the oxyhemoglobin dissociation curve. Central
nervous system (CNS) depression occurs to a greater extent
during respiratory than during metabolic acidosis, because H+
ions do not readily cross the blood-brain barrier whereas CO2
does. Additional CNS effects include increased intracranial
pressure because of increased cerebral blood flow and intracellular
acidosis, which may be partially responsible for CO2 narcosis.
Progressive hyperkalemia may develop because of the exchange
of intracellular K+ for H+ (an ~0.6 mEq/L potassium increase per
0.1 decrease in pH).
The CNS and cardiovascular depressant effects of most
sedatives, volatile inhalational anesthetic agents, and intravenous
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TABLE 10-1. Causes of Acidosis

Causes of Metabolic
Acidosis
Causes of Respiratory
Acidosis
High Anion Gap

Increased production of acid
Inborn errors of metabolism
Lactic acidosis
Ketoacidosis
Failure to excrete acid
Renal failure
Ingestion of toxins/acid
Salicylate
Ethanol
Ethylene glycol/methanol
Alveolar Hypoventilation
CNS depression
Depressant drugs
CNS ischemia/trauma
Neuromuscular disorders
Myopathies
Neuropathies
Parenchymal lung disorders
Pneumonia
Pulmonary edema
Cystic fibrosis
Airway obstruction
Foreign body
Laryngospasm
Bronchospasm
Tumor
Chest wall/pleura
Kyphoscoliosis
Flail chest
Pneumothorax
Normal Anion Gap

GI tract bicarbonate wastage
Severe diarrhea
Enterocutaneous fistula
Ileostomy
Renal bicarbonate wastage
Proximal RTA
Impaired H+ excretion
Hypokalemic distal RTA
Hyperkalemic distal RTA
Dilutional
Increased CO2 Production

Malignant hyperthermia
Large carbohydrate load
(enteral or parenteral
carbohydrate load)
Shivering
Seizure
Thyrotoxicosis
Neuroleptic malignant
syndrome
CNS = central nervous system; GI = gastrointestinal; RTA = renal tubular acidosis.
anesthetic agents are enhanced by acidemia. In addition, any

anesthetic agent that inhibits sympathetic tone will allow unopposed cardiovascular depression. The arrhythmogenic effects of
halothane are greater in acidemia. If acidemia is present, the use of
suxamethonium may cause a dangerous increase in plasma potassium. Respiratory, but not metabolic, acidosis can prolong the effect
of nondepolarizing neuromuscular blocking agents. Most opioids
are weak bases, and therefore, acidosis increases the nonionized
drug fraction, increasing CNS penetration and drug effect.
Metabolic acidosis is, by definition, a primary reduction in
(HCO3) and can be caused by three processes:
1. HCO3 wastage.
2. Excessive acid load.
3. Rapid dilution of the ECF with HCO3 free fluid.
Occasionally, the cause of the metabolic acidosis is not obvious
(e.g., toxins, renal tubular acidosis [RTA], and inborn errors of
metabolism). Useful diagnostic information obtained from simple
tests includes the plasma anion gap. This is defined as the
difference between the major measured cations and the major
measured anions. The anion gap is calculated as
Anion gap = (Na+ + K+) (Cl + HCO3)
The normal anion gap is 8 to 16 mmol/L. In reality, a true anion

gap does not exist because all anions and cations maintain
electroneutrality. The anion gap represents the difference
between the unmeasured anions and the unmeasured cations,
defined as
Anion gap = (Unmeasured anions) (Unmeasured cations)
Unmeasured anions include phosphates, sulfates, and organic
anions, such as plasma proteins. Unmeasured cations include
Ca2+ and Mg2+. Any process involving increased (endogenous or
ingested) nonvolatile acid will result in a high anion gap acidosis.
Normal anion gap acidosis is typified by hyperchloremia.
Another quick and useful test in the evaluation of metabolic
acidosis is the urine pH. In the presence of a significant metabolic
acidosis, intact functioning of the distal tubule is evidenced by the
ability to generate a urinary pH less than 5.5 in all ages and less
than 5.0 in older children. In certain patients, it may be necessary
to render the patient more academic, using one of the acid load
protocols in order to obtain this diagnostic information.
The urine anion gap can also be calculated. It may provide
additional information in the case of hyperchloremic, normal
anion gap acidosis.
Urine anion gap = (Na+ + K+ + NH4+) (Cl + HCO3).
The capacity of the distal tubule to generate NH4+ in response
to acidosis is greater than its ability to generate free H+; thus,
measurement of (NH4+) would be a more sensitive indicator of
urinary acidification ability. However, NH4+ is not easily measured,
but it can be estimated from the urine anion gap as the difference
between (Na+) + (K+) and (Cl). In reality, (HCO3) can be
excluded from this calculation because it will not be present in a
metabolic acidosis and such the urine anion gap is calculated as
(Na+ + K+) Cl.
The result of this calculation is generally negative in a metabolic
acidosis, thereby confirming NH4+ formation. A positive result
suggests failure to acidify urine.
HIGH ANION GAP ACIDOSIS: High anion gap acidosis results

from increased endogenous or exogenous nonvolatile acid by
either:
1. Increased production of acid.
2. Failure to excrete acid.
3. Ingestion of toxins/acid.
Various pathologic conditions can result in increased
production of acid. Inborn errors of metabolism are a group of
inherited disorders that present in the newborn period or early
childhood. They may be disorders of amino acid metabolism (e.g.,
maple syrup urine disease) or organic acid metabolism (e.g.,
methylmalonic or propionic acidemia). Inherited disorders of
carbohydrate metabolism may also cause severe lactic acidosis
(e.g., glycogen storage disease type 1). Lactic acidosis is more
commonly a result of severe tissue hypoxia, as a result of
hypoxemia, hypoperfusion, or the inability to use oxygen as in
cyanide poisoning. Less commonly, decreased hepatic and renal
lactate utilization and metabolism can lead to accumulation.
Causes include hypoperfusion, hepatic disease, and alcoholism.
Accumulation of D-lactic acid, not recognized by routine assay,
can occur in the short bowel syndrome, causing acidosis.
Ketoacidosis, with accumulation of beta-hydroxybutyric acid and
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acetoacetic acid, can result from a relative or absolute lack of
insulin. It is also seen following starvation.
Failure to excrete the endogenous acid load can also result in
metabolic acidosis. Endogenously produced acids are normally
excreted by the kidneys in the urine. Renal failure typically causes
progressive metabolic acidosis from accumulation of these acids.
Finally, ingestions of toxins or acids may result in acidosis. The
presence of a severe metabolic acidosis in an otherwise healthy
child should suggest ingestion of drugs or toxins. Salicylate
ingestion is the classic example in childhood. Salicylates disrupt the Krebs cycle and oxidative phosphorylation, leading
to lactate accumulation and metabolic acidosis. The typical
concomitant respiratory alkalosis seen in adults with salicylate
overdose is much less evident in children. Ethanol inhibits hepatic
gluconeogenesis and causes hepatic underutilization of lactate,
leading to metabolic acidosis, which can be severe in children,
especially those with underlying liver disease. Ethylene glycol and
methyl alcohol breakdown products also precipitate lactic acidosis
because of interference with mitochondrial function by a direct
toxic effect.
NORMAL ANION GAP METABOLIC ACIDOSIS: Normal anion gap

acidosis is most commonly caused by HCO3 wastage through the
GI tract. GI HCO3 wastage can be profound when one considers
that small bowel, biliary, and pancreatic secretions contain
approximately five times as much HCO3 as plasma. Any condition
leading to severe diarrhea, artificial drainage, and/or fistulation
will rapidly lead to profound HCO3 wastage, with a compensatory
hyperchloremia maintaining a normal anion gap. With the
exception of congenital chloride diarrhea, which does not cause
HCO3 loss, acute diarrheal disease is the most common cause of
hyperchloremic acidosis. Urine in contact with the colon will
cause HCO3 wastage by exchange of HCO3 for chloride, a problem
that declined with the advent of direct cutaneous diversion of the
ureters. Recent use of bowel augmentation cystoplasty makes this
a more common phenomenon again, although significant acidbase disturbance is seen in only a minority of patients.
Renal wastage of HCO3 occurs in proximal (formerly type 2)
RTA. This condition is characterized by low renal HCO3 threshold
and impairment of proximal generation of HCO3. Distal mechanisms to excrete H+ remain intact; therefore, severe acidemia is
unusual. Although it may occur as an isolated defect, it is generally
part of a generalized tubular defect as in Fanconis syndrome with
additional urinary wastage of amino acids, glucose, phosphate,
and other organic and inorganic substances handled by the
proximal tubules.
Normal anion gap acidosis with a positive urine anion gap (i.e.,
distal tubules not producing NH4+) is suggestive of a renal inability
to acidify urine, typical of distal RTA. A variety of conditions have
as a common link an inability of the distal renal tubules to acidify
urine. These are grouped under the heading distal tubular acidoses
and can be usefully divided into hypo- and hyperkalemic types.
Hypokalemic distal RTA (formerly type 1) is characterized by an
inability to decrease urinary pH below 5.3 even in the presence of
severe acidemia. Although proximal re-absorption of HCO3 is
normal, the elevated urine pH causes a certain amount of filtered
HCO3 to escape re-absorption. Up to 50% of patients suffer from
nephrocalcinosis and urolithiasis, caused by a combination of
hypercalciuria and hypocitraturia. In children, distal RTA is
mainly caused by genetic defect in the H+ pump, whereas in adults,
it is usually multifactorial. Hyperkalemic distal RTA (formerly
type 4) is most frequently observed in children with hypoaldosteronism or pseudohypoaldosteronism (aldosterone resistance),
either occurring as an isolated problem or associated with chronic
renal parenchymal damage. Acidosis in these patients is only a
part of a spectrum of metabolic and biochemical abnormalities
caused by the impaired aldosterone effect. Hyperkalemia associated with the aldosterone defect impairs H+ excretion via a
number of mechanisms including the effect of increased ICF (K+)
in the principal cells of the collecting tubule causing lower
intracellular (H+). After an acid load, the urine can be acidified,
but the net acid excretion remains subnormal owing to low NH4+
production. There is no wastage of HCO3.
Dilutional acidosis will also produce a normal anion gap
acidosis. Rapid expansion of the extracellular space with nonbicarbonate-containing fluid, such as large volumes of normal
saline, commonly produces an acidosis. This has been explained
by the increase in the volume of distribution of existing HCO3
effecting a decrease in HCO3 concentration. In addition, volume
expansion may increase the filtrate volume and sodium load
passing the PCT and leading to reduced absorption of HCO3.
More recently, it has become apparent that dilutional acidosis is
more commonly a function of the chloride load and that it can
occur in the absence of plasma expansion. The use of buffered
solutions with a lower chloride concentration, such as Ringers
lactate, are associated with less chloride load and acidosis.14
The expanded theory of acid-base balance15 would explain such
acidosis on the basis of decreasing strong ion difference (SID). The
SID is the difference between strong cations (Na+, K+, Ca2+, Mg2+)
and strong anions (Cl, unidentified anions). To maintain electroneutrality, a decrease in SID must be balanced by an increase in the
balancing (H+).16 Dilutional acidosis is important to the anesthesiologist because confusion may arise over whether an intraoperative acidosis represents poor tissue perfusion or hypovolemia
that might trigger administration of normal saline.17 Obviously,
this would worsen the situation if the acidosis was in fact secondary to excess chloride load.
TREATMENT OF METABOLIC ACIDOSIS:
In treating a metabolic
acidosis, any respiratory component contributing to the acidosis
should be corrected. If HCO3 therapy is instituted, it may
transiently increase PaCO2 as HCO3 is consumed by acid,
emphasizing the need to control ventilation in severe acidemia.
Specific measures are dependent on treating the underlying cause
of the acidosis. In the case of the inborn errors of amino acid
metabolism discussed under High Anion Gap Acidosis, dietary
protein should be restricted and adequate calories provided by
lipid and carbohydrate until a definitive diagnosis is made by
plasma and urine organic acid analysis. The relevant metabolite
can then be removed if necessary by dialysis or rendered harmless
by intracellular transport using a dextrose/insulin infusion. Lactic
acidosis, caused by hypoxia or hypoperfusion, is treated primarily
by measures aimed at reversing the tissue oxygen deprivation. The
question of the use of HCO3 is discussed later in this section.
Specific therapy for diabetic ketoacidosis consists of fluid resuscitation, insulin, potassium, phosphate, and magnesium. Acidosis
related to renal failure is treated primarily by addressing the cause
of the renal failure and reversing it if possible. Alkalinization of
the urine with sodium HCO3 to a pH greater than 7.0 enhances the
elimination of salicylate following salicylate poisoning. For ethylene glycol or methanol intoxication, ethanol infusion is indicated. Ethanol competes with ethylene glycol or methanol for
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alcohol dehydrogenase and slows the formation of formic acid or

oxalic acid, respectively. More recently, specific pharmacologic
therapy with fomepizole, an agent that inhibit alcohol dehydrogenase, has largely replaced the need for ethanol infusions. When
significant acidosis or visual or mental disturbances are present,
consideration should be given to hemodialysis. With proximal
hypokalemic RTA, the most common clinical problems are failure
to thrive, vomiting, and stunted growth. The mainstay of treatment is correction as required of Na+, K+, and Ca2+ deficits and
possibly also vitamin D supplementation. Severe acidemia is
uncommon, and hence, the achievement of normal serum HCO3
concentration is neither necessary nor practicable (the low renal
threshold for HCO3 means massive doses would be necessary to
achieve this). Distal hypokalemic RTA requires sodium and
potassium citrate or HCO3 in the region of 1 to 2 mmol/kg/day to
restore normal thriving. However, in this condition, long-term
renal function is principally threatened by nephrocalcinosis. The
appropriate alkali supplementation should be titrated to achieve
normal HCO3 levels and normalization of renal calcium excretion.
Hyperkalemic distal RTA (hypo- or pseudohypoaldosteronism)
rarely requires treatment of acidosis; however, hyperkalemia may
be a problem that is best treated by an adequate urine output,
dietary sodium supplementation, and avoidance of medications
that further increase serum K+ values.
The primary goal of therapy in metabolic acidosis is correction
or reversal of the underlying cause. Empirical alkali therapy aimed
at preventing severe acidemia (pH < 7.2) is often recommended,
but is of questionable benefit. The most urgent concern associated
with acidosis is the risk of impaired myocardial contraction and
decreased myocardial and vascular response to endogenous or
exogenous catecholamines.
Various formulas exist for calculation of HCO3 dose:
HCO3 deficit (mEq) = 0.6 Wt (kg)
(desired (HCO3) measured (HCO3)
where 0.6 represents the apparent HCO3 space (a reflection of
total body buffering capacity), which is 60% of body weight in mild
to moderate acidosis (apparent HCO3 space varies from ~25%
at normal pH to 100% at a pH of 7.0) and where a (HCO3) of
15 mEq/L is considered adequate to maintain pH in a safe
range in the absence of any respiratory acidosis. An alternative
formula is
HCO3 deficit (mEq) = Base excess Wt (kg) 30%
For the latter formula, half of the estimated dose is given and
another blood gas measured subsequently.
In lactic acidosis, the restoration of tissue perfusion will result
in metabolism of lactate by the heart, liver, and kidneys and
regeneration of HCO3, which will return to normal levels. In this
situation, administration of HCO3 can give rise to an overshoot
alkalosis. This is by contrast to some other organic acidoses (e.g.,
diabetic ketoacidosis) in which a variety of organic acids with
different renal thresholds are produced. In some circumstances,
these acids may be excreted by the kidneys in the early stages of the
disorder. Although this is helpful as a homeostatic response in the
short term, it can result in depletion of HCO3 substrate and a
persistence of metabolic acidosis when the shock and metabolic
disturbance have been corrected. In this particular circumstance,
the administration of HCO3 may be appropriate. However, the
disadvantages of HCO3 therapy are its unproven benefits and the
associated risks. The negative inotropic effects of acidosis are offset
to a degree by the ability of acidosis to stimulate catecholamine

release. Acidosis causes vasodilatation, whereas correction with
HCO3 causes vasoconstriction. This may lead to persistence
of anaerobic metabolism in a critically ill patient. Also, acidosis
may have a role in protecting from cell death in clinical shock.
Sodium HCO3 solution has the potential to cause volume
overload, hyperosmolality, and hypernatremia. One of its principal
disadvantages is its ability to generate CO2. This can result in
intracellular hypercarbia and a paradoxical worsening of the
intracellular pH.
Respiratory Acidosis
Respiratory acidosis is defined as a primary increase in PaCO2.
This drives the equation H2O + CO2 H2CO3 H+ + HCO3 to
the right, leading to an increase in (H+) and a fall in pH. PaCO2
represents the balance between production of CO2 from
carbohydrate and fat metabolism and its elimination through
the lungs. Although increased muscle activity, body temperature,
and thyroid hormone can all increase CO2 production, in general,
production varies little under normal circumstances and respiratory acidosis is the result of alveolar hypoventilation. In a patient
with limited ability to increase alveolar ventilation, an increase in
CO2 production can precipitate respiratory acidosis.
The physiologic response to respiratory acidosis can be
divided into acute and chronic phases. The acute (612 h)
response to respiratory acidosis is limited. Buffering is primarily
by hemoglobin and the exchange of extracellular H+ for Na+ and
K+ from bone and intracellular fluid. The renal response acutely is
limited, such that plasma (HCO3) increases only about 1 mmol/L
for each 10 mmHg increase in PaCO2 above 40 mmHg. The
chronic response is characterized by renal compensation. This
is appreciable only after 12 to 24 hours and may be incomplete for
up to 3 to 5 days. During chronic respiratory acidosis, plasma
(HCO3) increases approximately 4 mmol/L for each 10 mmHg
increase in PaCO2 above 40 mmHg.
TREATMENT
OF RESPIRATORY ACIDOSIS: The treatment of

respiratory acidosis is to reverse the imbalance between production
of CO2 and alveolar ventilation. In specific instances, measures
to reduce CO2 production are appropriate (e.g., dantrolene in
malignant hyperthermia, antithyroid medication, or reduction in
carbohydrate intake). Temporizing measures aimed at improving
alveolar ventilation may include bronchodilation, reversal of
narcosis, or respiratory stimulant administration (doxapram,
caffeine). In a patient with moderate to severe acidosis (pH < 7.20),
CO2 narcosis, or respiratory fatigue, ventilatory support is
indicated. In a patient with chronic respiratory acidosis who is
accustomed to a higher than normal PaCO2, the aim should be to
return PaCO2 to the patients normal: level, because lowering it to
normal levels will result in a metabolic alkalosis.
Alkalosis
The word alkalosis is best used to describe a situation tending to
cause a rise in pH. An alkalemia is the correct term for a situation
in which there has actually been a rise in pH. Alkalosis has a
number of clinically important effects related to its biochemical
and vascular effects. Alkalosis
1. Increases peripheral vascular resistance and may precipitate
coronary vasospasm.
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2. Shifts the oxyhemoglobin curve to the left, increasing
hemoglobins affinity for oxygen and potentially reducing
oxygen delivery to the tissues.
3. Decreases cerebral blood flow.
4. Increases bronchial smooth muscle tone, but relaxes
pulmonary vascular resistance.
5. Results in hypokalemia caused by K+ movement into cells in
exchange for H+.
6. Decreases ionized (Ca2+) because alkalosis increases the
number of plasma protein binding sites for Ca2+.
Alkalosis has implications for anesthesia related both to its
direct effects and to the often concomitant hypokalemia. Alkalosis
may prolong opioid-induced respiratory depression owing to
enhanced protein binding. Augmentation of nondepolarizing
neuromuscular block is reported, and this may be an indirect
effect related to hypokalemia. Respiratory alkalosis can cause
decreased cerebral blood flow especially in the presence of
systemic hypotension. The combination of alkalemia and
hypokalemia is particularly arrhythmogenic and can produce
supraventricular and ventricular arrhythmias.
METABOLIC ALKALOSIS: Metabolic alkalosis is by definition a

primary elevation of plasma (HCO3) with a tendency to an
increase in pH. Metabolic alkalosis has the capacity to be selfsustaining after the inciting event resolves. This is attributable to
a chloride depletion, which impairs HCO3 excretion as explained
in the section on Metabolic Acidosis. It is precipitated by three
basic processes (Table 102):
1. Chloride depletion (chloride-sensitive alkalosis).
2. H+ loss with enhanced mineralocorticoid effect (chlorideresistant alkalosis).
3. Excessive intake of alkali.
TABLE 10-2. Causes of Alkalosis
Causes of Metabolic
Alkalosis
Causes of Respiratory
Alkalosis
Chloride-Sensitive
GI tract chloride loss
Vomiting
Nasogastric suction
Villous adenoma
Chloride diarrhea
Renal chloride loss
Diuretic therapy
Renal response to respiratory
acidosis
Sweat
Central Stimulation
Pain
Anxiety
Infection
Fever
Drugs (e.g., salicylates)
Chloride-Resistant
Enhanced mineralocorticoideffect
Primary hyperaldosteronism
Cushings syndrome
Congenital adrenal hypoplasia
Increased plasma renin activity
ECF depletion
Renal artery stenosis
Bartters syndrome
Excessive Alkali Intake
Milk-alkali syndrome
ECF = extracellular fluid; GI = gastrointestinal.
Peripheral Stimulation
Hypoxemia
High altitude
Severe anemia
Pulmonary disease
Iatrogenic
Overventilation
If the cause of a metabolic alkalosis is unclear, a random urine

chloride concentration can help identify possible sources. In
chloride-sensitive alkalosis, the urinary chloride is typically less
than 15 mmol/L, whereas in chloride resistant alkalosis, it is
typically greater than 20 mmol/L.
Chloride-sensitive alkalosis is caused by chloride depletion
resulting from loss by a number of routes including the GI tract,
the kidney, or the skin (sweat). The mechanism whereby metabolic
alkalosis develops is common to all. Normal tubular Na+ reabsorption is through the NKCC channel. This does not occur in
the absence of luminal Cl. Therefore, there is enhanced reabsorption of Na+ through exchange for K+ and H+ distally, leading
inexorably toward metabolic alkalosis (and often hypokalemia).
GI loss of Cl occurs through vomiting, nasogastric suction,
villous adenoma, and the rare chloride diarrhea. In the case of
pyloric stenosis, there is loss of H+, Na+, and K+ in addition to Cl
and ECF depletion. The kidney responds by avid absorption of
tubular Na+, which can be done only at an accelerated rate of
exchange with H+, and K+ in the distal tubule, leading inexorably
to metabolic hypokalemic alkalosis. Congenital chloride diarrhea
is a rare, autosomal recessive condition characterized by an
inability to transport chloride against an electrochemical gradient.
Thus, chloride in the gut is unabsorbed, leading to a severe
osmotic diarrhea. There is typically a history of polyhydramnios
and prematurity. Symptoms of abdominal distention and watery
diarrhea begin in the first 2 weeks of life. Renal loss of Na+, K+,
and Cl in response to diuretic therapy can precipitate a metabolic
alkalosis. In the initial stages, urinary chloride concentration will
be increased but subsequently decreased. If there is inadequate
dietary intake of chloride (e.g., an infant being fed formula
containing Na+ but no Cl), a metabolic alkalosis readily develops
because increased H+ or K+ secretion must accompany tubular
reabsorption of Na+. Children with cystic fibrosis lose excessive
amounts of Na+ and Cl in their sweat and can become Cl- and
volume-depleted in hot weather, leading to metabolic alkalosis.
Chloride-resistant metabolic alkalosis includes a number of
conditions in which there is increased renal excretion of H+ for
Na+ re-absorption as a primary event. Mineralocorticoid activity
enhances distal tubular Na+ absorption and K+ and H+ loss and,
thus, promotes urinary acidification. This can be a primary event
independent of plasma rennin, as is the case with primary
hyperaldosteronism, Cushings syndrome, and some types of
congenital adrenal hyperplasia. Alternatively, it may be due to
increased plasma renin activity because of ECF depletion, renal
artery stenosis, or Bartters syndrome. Bartters syndrome is an
autosomal recessive syndrome caused by disturbed tubular
chloride re-absorption. Except for severe hypokalemia and
Bartters syndrome, all of these are associated with ECF expansion
and hypertension. It is frequently observed that hypokalemia and
metabolic alkalosis occur together because many conditions
precipitate both (e.g., chronic vomiting).
Milk-alkali syndrome, with excess alkali ingestion leading to
metabolic alkalosis, occurs less commonly in children than in
adults. Healthy kidneys are generally well able to cope with excess
HCO3. When the renal threshold is exceeded, HCO3 leaks into the
urine and normal pH is restored (assuming the presence of
luminal Cl to allow for HCO3 excretion). Nonabsorbable anions
(e.g., carbenicillin) will cause continued HCO3 generation by the
tubular epithelial cells as they bind to the H+ secreted into the
luminal fluid, thus generating a metabolic alkalosis.
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TREATMENT OF METABOLIC ALKALOSIS: As with metabolic

acidosis, the primary aim in the treatment of metabolic alkalosis
is correction of the underlying cause. Severe metabolic alkalosis
with (HCO3) greater than 50 mmol/L is a rare occurrence, usually
seen only when there is prolonged loss of gastric juice, diuretic
therapy, or hyperadrenalism. In the case of chloride-sensitive
alkalosis, the treatment of choice is intravenous fluid replacement
with normal saline and potassium replacement with KCl. The
amount of saline required is often calculated on the basis of a
chloride deficit. In practice, the required amount of saline is that
volume that restores circulating volume and increases urinary
chloride excretion to greater than 20 mmol/L. KCl is not an
appropriate fluid for total Cl replacement because the rate of
administration is limited to 3 mmol/kg/day. Metabolic alkalosis
associated with primary increases in mineralocorticoid activity is
responsive to the aldosterone antagonist spironolactone or to
direct inhibition of the aldosterone-mediated renal tubular Na+
channel with amiloride.
RESPIRATORY ALKALOSIS: Respiratory alkalosis is by definition

a primary decrease in PaCO2. The mechanism is generally an
inappropriate increase in alveolar ventilation relative to CO2
production. The distinction between acute and chronic respiratory
alkalosis is less obvious because the change in (HCO3) is variable.
Plasma (HCO3) decreases 2 to 5 mmol/L for each 10 mmHg
decrease in PaCO2 below 40 mmHg. Causes of respiratory alkalosis
include (1) central stimulation due to pain, anxiety, infection, fever,
or drugs (salicylates); (2) peripheral stimulation of chemoreceptors
from hypoxemia, high altitude, severe anemia, or pulmonary
disease; and (3) iatrogenic from excessive mechanical ventilation.
TREATMENT OF RESPIRATORY ALKALOSIS:
The treatment of
respiratory alkalosis is essentially the treatment of the underlying
disorder. Severe alkalemia (pH > 7.6) has been treated with
intravenous hydrochloride or ammonium chloride.
FLUID AND ELECTROLYTES

Physiology
Despite large variations in daily intake of fluids and electrolytes,
the concentrations of these are maintained nearly constant by the
body. This fluid and electrolyte homeostasis is an essential
requirement for normal cellular and organ function. Fluid and
electrolyte disturbances are very common in the perioperative
period. Intravenous fluid therapy is often required to correct fluid
deficits and losses associated with surgery. The anesthesia provider
should be familiar with the physiology of fluid and electrolyte
homeostasis, along with the management of the common abnormalities. This is especially in the field of pediatric anesthesiology
where the physiologic capacity for coping with inappropriate fluid
and electrolyte therapy is more limited.
Definition of Compartments
The body is composed of 50 to 70% water by weight. The variation
depends on the proportion of adipose tissue, which contains only
10% water whereas muscle contains 75% water. Total body water
(TBW) varies inversely with age, and females have a lower TBW
than males. TBW is composed of ICF and ECF. The latter in turn
is composed of the interstitial space (ISS) and intravascular space
(IVS) fluid, separated by the capillary membrane. The age-related
changes in TBW and its distribution are shown in Table 103.
TABLE 10-3. Age-Related Changes in Total Body Water
TBW, % of wt
ECF, % of wt
ICF, % of wt
Preterm
Term
13 Y
Adult
85
55
30
80
45
35
65
25
40
65
25
40
ECF = extracellular fluid; ICF = intracellular fluid; TBW = total body water;
wt = weight.
From reference 16.
In the fetus during the first trimester, TBW accounts for more
than 90% of weight, the greatest portion of this being in the ECF.
At term, approximately 56% of TBW is in the ECF. With increasing
age, TBW decreases and the proportion of TBW as ECF decreases,
so that by 3 years of age adult proportions are reached. The
movement of water between these compartments is dependent on
the concentration of osmotically active particles in each. This
movement occurs by osmosis. Osmosis is the movement of water
across a semipermeable membrane because of a difference in the
concentrations of nondiffusible solutes on either side. The osmotic
pressure is the pressure that must be applied to the side with more
solute to prevent net movement of water. Osmotic pressure is
dependent only on the number and not the nature of the particles.
One mole of a substance is that amount that contains 6 1023
(Avogadros number) molecules of that substance. The weight of
1 mole of a substance in grams is that substances molecular
weight. One osmole is the amount that will release that number of
osmotically active particles in solution, which equals the
molecular weight divided by the number of active particles
produced, that is, 1 mole of NaCl produces 2 osmoles in solution.
A difference of 1 mOsm/L between two solutions will produce an
osmotic pressure of 19.3 mmHg across an intervening semipermeable membrane. The osmolarity of a solution is the number
of osmotically active particles per liter of solvent, whereas the
osmolality of the same solution is the number of osmotically active
particles per kilogram of solvent. In humans, the solvent is
essentially water with a density of 1 kg/L, which is why osmolality
and osmolarity are sometimes used interchangeably.
Regulation of Compartments
Diffusion between the ECF and the ICF takes place across the cell
membrane by one of three methods: (1) diffusion directly through
the lipid bilayer of the cell membrane (e.g., O2, CO2, H2O, and
lipid-soluble molecules); (2) movement through protein channels
(e.g., Na+, K+, and Ca2+); and (3) facilitated diffusion through
transmembrane carrier proteins (e.g., glucose and amino acids).
Fluid exchange between the ECF and the ICF is governed by the
osmotic forces generated by the differences in nondiffusible solute
concentrations between the compartments. A relative change in
osmolality will result in movement of water from the hypoosmolar to the hyperosmolar compartment. If serum osmolality
increases, as in diabetes insipidus, water will move from the ICF
to the ECF to equalize osmolalities. Similarly, if the ECF osmolality
decreases, as in the syndrome of inappropriate antidiuretic
hormone secretion (SIADH), water will move from the ECF to the
ICF. In this regard, potassium is the major determinant of ICF
osmolality and sodium is the major determinant of ECF
osmolality:
(K+)ICF = ~140 mmol/L and (Na+) = approximately 140 mmol/L
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Diffusion within the ECF, between the ISS and the IVS, takes
place across the capillary membrane. This can occur directly
through the endothelial cell, as is the case for O2, CO2, H2O, and
lipid-soluble molecules, or through the 6- to 7-nm-wide intercellular clefts, as is the case for low-molecular-weight molecules
such as Na+, K+, Cl, and glucose. Because proteins cross the
intercellular clefts poorly under normal circumstances, they are
the osmotically active solutes involved in osmotic movement
across the capillary membrane. By contrast to the situation across
the cell membrane, the movement of water between the ISS and
the IVS across the capillary membrane is governed by hydrostatic
in addition to osmotic forces. There is generally a hydrostatic force
tending to force water out of the IVS at the arterial side of a
capillary bed and the opposite at the venous side. The normal
functioning of this system is also dependant on the structural
integrity of the capillary membrane and the effective removal of
protein from the ISS by the lymphatic system.
Regulation of Osmolality and Fluid Balance

There is an intimate association between sodium and water
balance that is important in the understanding of ECF osmolality
and volume homeostasis. In essence, the body controls ECF
volume by controlling the excretion of its dominant cation
sodiumand controls osmolality (mainly (Na+)) by controlling
water intake and excretion. These two complementary mechanisms are summarized in Table 104 and dealt with in more
detail in the following sections.
OSMOREGULATION: Plasma osmolality is closely regulated by

specialized neurones in the supraoptic and paraventricular nuclei
of the hypothalamus. These osmoreceptors control the release of
ADH and the thirst mechanism. When the ECF osmolality
increases, these cells shrink and release ADH, which increases
water re-absorption at the renal collecting ducts, tending to reduce
ECF osmolality. At a plasma osmolality of 280 mOsm/kg water or
less, plasma ADH concentration is maximally suppressed to less
TABLE 10-4. Regulation of Fluid Balance (Volume)
and Osmolality
Purpose
Volume Regulation
Osmoregulation
Control ECF volume
Control ECF
osmolality
Vary water intake
Vary water excretion
Hypothalamic
osmoreceptors
Mechanism Vary renal Na+ excretion

Sensors
Effectors
Afferent renal arterioles

Carotid baroreceptors
Atrial stretch receptors
Renin-angiotensinaldosterone
Sympathetic nervous
system
Tuberoglomerular
balance
Renal pressure
natriuresis
Atrial natriuretic peptide
Antidiuretic hormone
ECF = extracellular fluid.

From reference 17.
Thirst
Antidiuretic hormone

TABLE 10-5. Factors Regulating the Secretion of
Antidiuretic Hormone
Stimulatory
Inhibitory
Narcotics
Nicotine
-Adrenergic agents
Anesthetic agents
Hypoxia
Hypercapnia
Vincristine
Cyclophosphamide
Clofibrate
Carbamazepine
Barbiturates
Phenytoin
Alcohol
Narcotic antagonists
-Adrenergic agents
Potentiate ADH Action
Chlorpropamide
Aspirin
ADH = antidiuretic hormone.

From reference 11.
than 1 pg/mL. At a plasma osmolality of 295 mOsm/kg water or

greater, the plasma ADH concentration is maximal at greater than
5 pg/mL. There are a variety of nonosmotic stimuli for ADH
secretion including
1. Hemodynamic causes such as hypovolemia and hypotension,
which are mediated through low-pressure atrial baroreceptors
and high-pressure carotid baroreceptors.
2. Perioperative causes such as nausea, pain, anxiety, and
administration of opiate drugs.
3. Drugs (Table 105).
4. Pulmonary stimuli including pneumonia, bronchiectasis, and
mechanical ventilation.
5. Febrile illnesses.
6. CNS disturbances including head injury and infections.
7. Endocrine disturbances (e.g., hypoaldosteronism, hypothyroidism).
Neurons in the lateral preoptic area of the hypothalamus are
also very sensitive to changes in ECF osmolality, and activation of
these neurons by increased osmolality causes thirst. Because it
is the only mechanism that increases water intake, thirst is the
main protective mechanism against hyperosmolality and hypernatremia. The thirst mechanism is operative only in those who are
able to increase their water intake, which is often not the case with
sick patients, especially in the pediatric age group.
ECF volume and sodium concentration are regulated by a
number of sensor and effector mechanisms. Although they are not
generally regarded as such, the principal volume receptors in the
body are in fact baroreceptors. Because blood pressure is the
product of cardiac output and systemic vascular resistance, significant changes of intravascular volume (preload) also transiently
affect blood pressure. Changes in pressure at the carotid baroreceptors, as mentioned previously in the section on Regulation of
Osmolality and Fluid Balance, modulate nonosmotic ADH release
and, in addition, sympathetic nervous activity. Changes at the
afferent renal arteriole and macula densa modulate the reninangiotensin-aldosterone system. Changes at the atrial stretch
receptors also modulate nonosmotic ADH release and atrial
natriuretic peptide release.
EFFECT OF ADH: In the face of disorders that threaten to cause
hyponatremia and cellular overhydration, the kidney will excrete
solute-free water and, conversely, will conserve solute-free water
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when hypernatremia is threatened. In the proximal tubule,

water is reabsorbed primarily with solute absorption through
aquaporin-1 water channels. Some re-absorption of solute-free
water takes place in the thin ascending limb of the LOH in
response to medullary hypertonicity. The TAL permits active
solute absorption through the NKCC cotransporter, but is
impermeable to water. This process is vital because it is the basis
for the diluting segment of the nephron, and in addition, the
transport of solute from the medullary thick ascending limb of the
loop of Henle (MTALH) generates the hypertonic medullary
interstitium. This creates the osmotic gradient for absorption of
solute-free water. The maintenance of the hypertonic medulla
is dependent on the delivery of Na+ and Cl to the MTALH
and, in addition, the delivery of sufficient urea to allow the
countercurrent multiplier to operate.
ADH acts on the collecting duct via the V2 receptor, leading to
insertion of the aquaporin-2 water channel across the membrane
of what is otherwise a water-impermeable section of the nephron.
Solute-free water re-absorption is thus permitted by the action of
ADH, driven by the medullary osmotic gradient.
Fluid Management
Basic Fluid Requirements
NEONATES: Fluid homeostasis in newborn babies differs from that
in older children and adults because both fluid requirements
and excretion are substantially different in neonates. Fluid
requirements in both term and premature babies are much greater
than those in older children owing to greater metabolism and
growth and greater insensible water loss (IWL). IWL is greater in
neonates because of the larger relative body surface area and as a
result of greater transepithelial water loss (TEWL) from the
immature skin, which is deficient in stratum corneum, and from
the immature respiratory tract. TEWL is increased by radiant
heaters and phototherapy units and decreased by adequate
humidification of incubators and inspired gases. Despite the
inability of the immature kidney to concentrate urine, healthy
infants are able to maintain an adequate water balance over a wide
range of intake once their insensible and obligatory urinary losses
are covered. As discussed earlier in the section on the Definition
of Compartments, neonates have relatively greater ECF and TBW
volumes. As a result, newborns undergo a diuresis and natruresis
in the first postnatal days.12 This is mediated by atrial natriuretic
peptide and is part of the normal physiologic response that results
in the contraction of the ECF volume. The result of this is a negative sodium balance during these immediate postnatal days.
A large number of complicated tables describe neonatal fluid
requirements as a function of weight and gestational age. Because
of the large number of variables that affect neonatal fluid balance,
a more physiologic approach seems sensible. The most useful
parameters to monitor fluid balance in newborn babies are
weight, serum sodium concentrations, and urine output. Weight
accurately reflects changes in water balance of neonates. Ideally,
weights should be monitored twice daily. Changes in serum
sodium concentrations during the first days of life are sensitive
markers of dehydration and overhydration, respectively. Urine
production should be monitored, with a target of 0.5 to 1 mL/kg/h.
Adequate humidification of incubators and inspired gases is
important. A reasonable approach to fluid administration in
infants would entail the administration of 40 mL/kg/day initially
and adjusting this value depending on clinical circumstances and

the variables mentioned previously in this section. Until the
postnatal diuresis occurs, administration of salt-free dextrose
solutions aiming to deliver 7 mg/kg/min of glucose to meet metabolic needs is recommended.12
INFANTS AND OLDER CHILDREN: Fluid therapy in children can be

categorized as: maintenance, deficit, and replacement of losses
(please refer to the section on Deficits and Losses later in this
chapter). The quantity and type of maintenence intravenous fluids
prescribed for children has been the subject of some controversy.1820 Traditionally, maintenance fluid requirements have
been calculated with reference to the energy expenditure of the
child. Heat loss is directly related to IWL and indirectly to the
requirement for excretion of waste products in urine. For healthy
children, Holliday and Segar calculated the relationships of calorie
expenditure to body weight and calorie expenditure to water
requirement.21 Their calculation rendered the following estimates
of energy expenditure: 100 cal/kg up to 10 kg; 50 cal/kg for each
kilogram between 10 and 20 kg; and 20 cal/kg for each kilogram
over 20 kg. Given that fluid requirement is roughly 100 mL/100 cal
expended, simple math leads approximately to the familiar 4:2:1:
or Oxford formula:
4 mL/kg/h for the first 10 kg
2 mL/kg/h for the next 10 kg
1 mL/kg/h for each subsequent kilogram
For example, a 15-kg child would require (4 mL 10 kg
24 h) + (2 mL 5 kg 24 h) = 1200 mL of fluid/day.
In addition to the fluid requirements, Holliday and Segar also
recommended electrolyte requirements based upon the electrolyte
constituents of cows and breast milk, arriving at a figure of 2 to
3 mEq/100 kcal/day of sodium and potassium, while acknowledging that much greater loads could be readily handled by the
kidney.21 Given these calculations, 0.18% saline in dextrose
became adopted as the maintenance fluid of choice for children
because using the 4:2:1 volumes, it delivers approximately the
recommended amount of sodium and enough glucose to prevent
ketosis. This approach works very well for healthy children. In sick
children, however, there are many nonosmotic stimuli of ADH
release, and especially so during the perioperative period. These
patients retain electrolyte free water at the expense of excreting a
concentrated urine with a large sodium content.22,23 This becomes
dangerous when these patients have a source of electrolyte-free
water continually added (80% of the volume of 0.18% is effectively
electrolyte-free water). In the presence of this inappropriate ADH,
ECF sodium concentration gradually declines. Children can
become profoundly hyponatremic and continue to produce
hypertonic urine and retain free water owing to nonosmotic ADH
secretion.24 This leads to our current recognition that the number
one cause of postoperative seizures is hyponatremia and the
number one cause of postoperative hyponatremia is the inappropriate administration of hypotonic fluids.
Hyponatremia principally affects the CNS because of
movement of water across the blood-brain barrier from the
plasma to brain neurons, glia, and interstitium, causing cerebral
edema. This is manifested clinically as a progression from confusion and agitation to a reduced level of consciousness, seizures,
coma, and ultimately, herniation of vital brain structures and death
as plasma sodium concentration decreases. Children are especially
at risk from hyponatremia because they have larger numbers of
brain cells per volume of cranium and they have proportionately
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less skeletal muscle mass (in which 50% of body water is
located) than adults (see Alternations in Serum Sodium Concentration, later).
Many case reports have described morbidity and mortality in
children related to maintenance fluid in the form of hypotonic
solutions at appropriate rates.19,25 Observational studies have
shown that as many as 10% of general pediatric hospital admissions develop in-hospital hyponatremia, with the majority of these
due to electrolyte-free water administration in the setting of
increased ADH.26 Administration of isotonic saline is associated
with a more rapid normalization of plasma ADH levels in sick
children than hypotonic fluids.27 Three randomized, controlled
trials have compared the administration of hypotonic and isotonic
fluids for maintenance in children.2729 Children undergoing
surgery tend to exhibit a decrease in serum sodium concentration
in the first 24 hours postoperatively. Those given hypotonic saline
decrease their serum sodium concentration substantially more (an
average 4.5 mmol/L) than children who received isotonic fluids. A
systematic review of six studies has demonstrated both the
tendency of hypotonic fluid administration to produce hyponatremia and the safety of isotonic saline in medical and surgical
pediatric populations.30 No cases of hypernatremia in children
treated with isotonic saline were reported, confirming the ability
of the pediatric kidney to maintain sodium homeostasis. As a
result of these articles, it has been suggested that hypotonic fluids
be abandoned in the acutely ill or perioperative pediatric patient
to be replaced by isotonic saline solutions with or without
glucose.19,31
It has been suggested that children at risk for nonosmotic
secretion of ADH should be prescribed intravenous fluids at
decreased infusion rates. In the presence of ADH, the kidneys
retain water, and hence, requirements are reduced. However,
when compared with traditional infusion regimens, this approach
does not appear to influence serum sodium concentration, and
therefore, such fluid restriction is not necessary, especially in the
postoperative setting.29
Further adjustments must be made to maintenance fluid
requirements in children according to the clinical context. For
example, an increase in free-water requirement is necessary in the
following circumstances:
1. Pyrexia, which increases requirements by 12% per degree
centigrade above 37.5C.
2. Sweating, which increases requirements by 10 to 25%.
3. Hypermetabolic states (e.g., hyperthyroidism, salicylism, and
burns) in which requirements increase by 25 to 75%.
4. Radiant heat or phototherapy, which increases requirements
increase by 25%.
A decrease in water requirements is necessary in the following
circumstances:
1. Hypothermia, in which requirements decrease 12% per degree
centigrade below 37.5 C.
2. Edematous and antidiuretic states.
Deficits
In addition to providing for maintenance requirements, perioperative fluid therapy needs to address any preexisting deficits
in water and electrolytes. The preoperative assessment must
include a history of the duration of fasting; presence and duration
of fever, vomiting, diarrhea, sweating; and the particular disease
state or surgical problem likely to affect fluid status (e.g., bowel

obstruction, peritonitis, dialysis). Preoperative fasting can cause
significant dehydration and even hypoglycemia in children.
Assuming that a healthy child is in fluid and electrolyte balance
at the onset of fasting, then the deficit incurred is that childs
calculated hourly requirement multiplied by the number of hours
fasting. This is generally replaced, along with hourly maintenance
fluid, as one half during the first hour and one half over the next
2 hours.
Data are conflicting about the need for glucose in the
perioperative period. Early work has shown that hypoglycemia
may occur in children younger than 4 years who are fasted for
6 hours.32 Others have failed to show hypoglycemia in children
fasted for 6 to 8 hours.33,34 Preterm infants, conversley, should be
monitored for hyperglycemia because their kidneys are less well
able to hyperfiltrate glucose in hyperglycemia.35,36
Children who are permitted to drink clear fluids until 2 to
3 hours before elective anesthesia have residual gastric volumes
and pH similar to those fasted for longer periods. The shorter
fasting periods are advantageous in that children are less thirsty,
have a better perioperative experience, and have improved
compliance.3638 Clinical practice has changed to incorporate
shorter pediatric fasting guidelines.39
Whereas the estimation of fluid deficit on the basis of fasting
time and hourly requirement may be sufficient in elective cases, an
assessment of hydration status is usually required in the case of
any disease process associated with increased fluid requirements
or losses (e.g., vomiting, diarrhea, pyrexia). Some of these may
also merit specific assessment of electrolyte status, which is dealt
with further in the section on Deficits.
Assessment of hydration is largely on the basis of clinical signs
with laboratory measurements as indicated in Table 106.
In children, it is important to note that the compensatory
response to hypovolemia is largely through increased heart
rate because the ability to increase stroke volume as a means to
increase cardiac output is a later development. Peripheral vasoconstriction generally maintains blood pressure within a normal range
except until severe hypovolemia is present. Hence, hypotension is
a late and ominous sign of hypovolemia, suggesting imminent
decompensation and requiring immediate treatment.
Losses
INTRAOPERATIVE THIRD SPACE LOSS: Intraoperative losses are
subdivided into third space loss and blood loss. Surgical trauma,
blunt trauma, infection, burns, and many of the surgical conditions that bring the pediatric patient to operation are associated
with the isotonic transfer of fluid from the ECF to a nonfunctional
interstitial compartment. This is called third space loss. If such
sequestration of fluid continues without replacement, the plasma
volume will become depleted. Third space loss is impossible to
measure, and therefore, it must be estimated by the extent of the
surgery and the clinical response to appropriate fluid replacement.
The magnitude of third space loss is usually highest in infants
undergoing intra-abdominal procedures and least in those undergoing superficial surgery or neurosurgery. Approximate ranges are
shown in Table 107. Because replacement of sequestered plasma
volume is the aim, Ringers lactate, normal saline, or some other
isotonic fluid is an appropriate replacement fluid. The clinical
response to appropriate replacement is a sustained and adequate
blood pressure and heart rate, adequate tissue perfusion, and a
urine output of 1 to 2 mL/kg/h.
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TABLE 10-6. Signs and Symptoms of Varying Degrees of Dehydration

Signs and Symptoms
Mild
Moderate
Severe
Weight loss, %
Deficit, mL/kg
Vital signs
Pulse
Blood pressure
Respiration
Appearance
5
50
10
100
15
150
Normal
Normal
Normal
Thirsty, restless, alert
Skin turgor
Anterior fontanelle
Mucous membranes
Urine
Flow (mL/kg/h)
Specific gravity
Normal
Normal
Moist
, Weak
Normal/low
Deep
Thirsty, restless, or lethargic but
rousable, pale
Sunken
Dry
, Feeble
Reduced, orthostatic
Deep and rapid
Drowsy to comatose, limp, cold sweaty,
gray/cyanosed
Markedly depressed
Very dry
<2
1.020
<1
1.02021.030
<0.5
>1.030
INTRAOPERATIVE BLOOD LOSS REPLACEMENT: Pediatric patients

undergoing major surgery including organ transplantation, cardiac
surgery, trauma surgery, or major burn surgery invariably require
blood volume replacement. The indications for when replacement
with blood components is necessary are not always clear or
well-defined. It is imperative that the anesthesia provider has a
preoperative plan regarding blood loss replacement, based on the
patients preoperative condition, preoperative hematocrit, and
nature of the surgery. The concept of an allowable blood loss (ABL)
is a useful approach to planning when blood products are indicated.
Blood loss is typically replaced with a nonglucose-containing
crystalloid such as Ringers lactate with 3 mL administered for every
1 mL of blood lost. This is done to achieve, in effect, normovolemic hemodilution to a predetermined hematocrit. The lowest
hematocrit that is acceptable has not been defined. It clearly varies
with the patients preoperative medical state and the anticipated
postoperative course. Generally, a hematocrit of 28 to 30% is
acceptable, although in the case of neonates, a value of 40% is more
appropriate and lower values down to a hematocrit of 18% may be
acceptable in some patients. In determining ABL, an estimate of
blood volume (EBV) must first be made (Table 108). Using EBV
and the patients original hematocrit (Ho), the ABL can be calculated
from the following formula:
ABL = Wt EBV (Ho Hl)/Ha.
where Hl is the lowest acceptable hematocrit and Ha is the
average of H1 and Ho ((Ho + Hl)/2).
Intraoperative blood loss is replaced with isotonic crystalloid
such as Hartmanns solution or Ringers lactate at a rate of 3 mL/1
mL blood loss, or a milliliter for milliliter volume of isotonic
colloid solution such as 5% albumin, until the ABL is exceeded or
TABLE 10-7. Estimation of Third Space Losses
in Pediatric Patients
Procedure
Intra-abdominal surgery
Intrathoracic surgery
Eye surgery/neurosurgery/
superficial surgery
Estimated Third Space

Loss, mL/kg/h
610
47
12
TABLE 10-8. Estimated Blood Volume in Pediatric Patients

Age
Premature neonate
Term neonate
3 mo1 y
36y
>6 y
EBV, mL/kg
90100
8090
7580
7075
6570
EBV = estimated blood volume.
about to be exceeded. Subsequently, ongoing losses in excess of

ABL must be appropriately replaced with blood to maintain the
desired hematocrit. Because the hematocrit of the red cell
concentrate (RCC) is approximately 60 to 75% depending on the
anticoagulant that is used, 0.5 mL/1 mL blood loss is generally
adequate. Concurrent crystalloid or colloid administration is
necessary to maintain intravascular volume. This may include
either colloid, 0.5 mL/mL RCC, or crystalloid, 1.5 mL/mL RCC.
As a rule of thumb, 1 mL/kg of RCC will raise the hematocrit by
approximately 1.5%. The management of major transfusion and
blood component therapy is dealt with in chapter 53 and 54.
Electrolyte and Fluid Disorders:

Pathophysiology and Management
Alterations in serum sodium concentration
As previously discussed in the section on Fluid and Electrolytes,
the regulation of plasma volume and plasma osmolality are linked
in such a way that it is generally more appropriate to view alterations of serum sodium as disorders of water balance rather than of
sodium balance. Disturbances of both water and sodium homeostasis are common in pediatric practice. Pure sodium deficiency is
rare, the occurrence in association with a water deficit being the
norm. With sodium deficiency, the ECF is invariably depleted with
appropriate signs and symptoms of same, as outlined in the section
on Regulation of Compartments.
HYPONATREMIA: Hypo-osmolality is usually associated with

hyponatremia, but in some situations, hyponatremia does not
necessarily reflect hypo-osmolality, which must be considered in
the approach to a patient with a low serum sodium (Figure 1010).
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Figure 10-10. Etiology and pathology

of plasma hypo-osmolality. ECF =
extracellular fluid; SIADH = syndrome
of inappropriate secretion of antidiuretic
hormone.
In the evaluation of the patient with hyponatremia, various false

causes of a low serum sodium must be ruled out. With factitious
hyponatremia, a fluid shift occurs between ICF and ECF as a result
of an increase in ECF osmolality by impermeate solutes such as
glucose or, mannitol or toxins such as alcohol, methanol, or
ethylene glycol. In factitious hyponatremia, the plasma osmolality
is high and is the difference between measured osmolality
and calculated osmolality (2 ([(Na+) + (Urea) + (Glucose)]) >
10 mOsm/kg) except in the setting of hyperglycemia.40
Pseudohyponatremia results from an increase in the nonaqueous portion of plasma. This may occur in hyperlipidemia,
hyperproteinemia, or glycine absorption in transurethral surgery.
In these cases, the sodium concentration expressed as millimoles
per liter of plasma (as opposed to millimoles per liter of plasma
water) will be low. In such pseudohyponatremias, the measured
osmolality is usually normal, but there is again a discrepancy
between the measured and the calculated osmolality of greater
than 10 mOsm/kg.40
In true hyponatremia, plasma osmolality will be low (<285
mOsm/kg), due to either a loss of salt in excess of water or a gain
in water in excess of salt. An assessment of ECF volume status will
differentiate the causal groups.
HYPONATREMIA WITH LOW TOTAL BODY SODIUM:
Progressive
loss of both salt and water will lead to symptoms and signs of ECF
depletion. As intravascular deficit reaches 5 to 10%, nonosmotic
ADH release is triggered and takes precedence over any
hyponatremia-induced suppression of ADH because preservation
of intravascular volume takes place at the expense of plasma
osmolality. In the case of extrarenal losses, the renal response is

production of a concentrated urine with low urinary (Na+).
Sources of extrarenal loss include (1) GI loss (diarrhea, vomiting,
fistulae, nasogastric aspirate, or ileostomy output; (2) third space
loss (ileus, ascites, burns, peritonitis); or (3) skin (excessive
sweating).
In the some salt-losing states, hypovolemia will develop but the
normal renal conservation of sodium will not occur, with urine
(Na+) remaining high. In addition, urine volume will be maintained for relatively longer, allowing the potential development of
profound salt and water deficit. These situations include diuretics,
mannitol, glucosuria, RTAs, salt-losing nephropathies, mineralocorticoid deficiency, postobstructive dieresis, and the diuretic
phase of acute tubular necrosis (ATN).
HYPONATREMIA WITH NORMAL TOTAL BODY SODIUM:
Hyponatremia without the features of either ECF depletion or excess is

seen in situations in which the primary disorder is mainly water
retention in the absence of sodium retention, with the excess water
being distributed equally between the ECF and the ICF. It may be
seen with glucocorticoid insufficiency, hypothyroidism, drug
therapy, reset osmostat, and the SIADH. SIADH is the most
common euvolemic hypotonic condition and is defined as the
presence of hyponatremia and hypo-osmolality in normotensive,
normovolemic, nonedematous patients without renal, hepatic,
adrenal, thyroid, or cardiac dysfunction. The levels of ADH
(arginine vasopressin) are inappropriately high for the osmolality
of the blood and are not suppressed by further hydration and
dilution of body fluids. The urine is not maximally dilute despite
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Increase in ADH
Positive balance of
solute-free water
Increase in TBW and

ECF
Reduced plasma
aldosterone
Increased GFR
Increased urinary
sodium excretion
plasma hypo-osmolality. A sequence of events for the mechanism

of SIADH is shown in Figure 1011.
Causes of SIADH in children may be divided into CNS, pulmonary, and malignant etiologies. CNS causes include infection
(encephalitis, meningitis, or intracranial abscess), hypoxia or
ischemia, cerebral vascular accidents, primary or secondary CNS
malignancy, Guillain-Barr syndrome, and cerebral malformations. Pulmonary causes include infection (abscess, pneumonia,
tuberculosis, aspergillosis), positive-pressure ventilation, atelectasis or pneumothorax in the newborn, hyaline membrane
disease, and cystic fibrosis. Malignant causes include Hodgkins
disease, lymphosarcoma, thymoma, GI tract carcinoma, leukemia,
and lung carcinoma.
Hyponatremia due to SIADH is uncommon in premature and
term infants younger than 6 weeks because of factors that limit
the urinary concentrating ability to less than 600 mOsm/kg. These
include low dietary sodium intake, low ADH levels, and reduced
tubular sensitivity to ADH.4143 Antidiuretic drugs can induce
hyponatremia by causing inappropriate ADH release, potentiating
its action, or by impairing solute-free water excretion independent
of ADH. For example chlorpropamide increases ADH release and
enhances its effect on the renal tubule; carbamazepine increases
ADH release without a direct tubular effect; and oxytocin mimics
ADH in its effect on the renal tubule.
Reset osmostat refers to a state of chronic asymptomatic
hyponatremia that may be seen in malnutrition or chronic illness.
In these states, the level of osmolality that triggers ADH release is
lowered below 285 mOsm/kg.44 Normal response to fluid or
sodium load is retained.
Compulsive water drinking with chronic water excess as a
cause of hyponatremia is rare in childhood, but may occur
in adolescents as part of a behavioral disorder or psychiatric
condition. It is similar to SIADH in that the water excess is
distributed between ECF and ICF so that signs of volume overload
are rarely seen.
HYPONATREMIA WITH INCREASED TOTAL BODY SODIUM:
Edematous disorders are characterized by an increase in TBW and
Relative increase
in urine osmolality
Hyponatraemia,
reduced plasma
osmolality, and
increased ICF
Reduced urea and

creatinine
Figure 10-11. Sequence of events of

the mechanism of the syndrome of
inappropriate antidiuretic hormone
secretion (SIADH). ADH = antidiuretic
hormone; ECF = extracellular fluid;
GFR = glomerular filtration rate;
ICF = intracellular fluid; TBW =
total body water.
total body sodium. When the increase in water is greater than that
of sodium, hyponatremia will result. In hypoproteinemic states,
such as the nephrotic syndrome or chronic malnutrition, the
reduced plasma oncotic pressure permits movement of fluid from
the IVS to the interstitial space ISS. This reduction in effective
circulating volume results in enhanced renal tubular re-absorption
of sodium and water in an attempt to correct the hypovolemia, but
because of the reduced oncotic pressure, the retained water and
sodium continue to expand the ISS. Cardiac insufficiency or
hepatic insufficiency with ascites will also create the situation of a
reduced effective circulating volume with retention of sodium and
water. All of these conditions produce hyponatremia by similar
mechanisms with decreased effective arterial volume leading to
decreased GFR with increased proximal tubular fluid absorption,
further enhanced by increased renal sympathetic tone. There is
decreased filtrate delivery to the MTALH-diluting segment. The
apparent decrease in effective arterial volume is also a potent
nonosmotic stimulant of ADH release. All of these derangements
impair the ability to excrete solute-free water. The renal response
will be to produce small volumes of concentrated urine with
urinary (Na+) less than 20 mmol/L.
In the case of acute or chronic renal failure, a hypo-osmolar
intake will result in hyponatremia. There will be expansion of the
ECF with edema and hypervolemia. Urine volume is usually
reduced with urinary (Na+) greater than 20 mmol/L. Urine and
plasma osmolality are similar, with plasma osmolality maintained
by increased urea despite hyponatremia.
CLINICAL MANIFESTATIONS OF HYPONATREMIA:
Apart from
symptoms relating to the volume disturbance associated with
some of the causes of hyponatremia just outlined, the symptoms
relating to the hyponatremia itself are largely confined to the CNS
and result from increased intracellular water. The severity of
symptoms is related to the severity of the hyponatremia and the
rapidity of the change in serum sodium. Children with mild to
moderate hyponatremia, (Na+) greater than 125 mmol/L, are frequently asymptomatic. Early symptoms are generally nonspecific
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including irritability, headache, anorexia, weakness, and depressed
tendon reflexes. Serious manifestations are associated with (Na+)
less than 120 mmol/L. These include progressive cerebral edema
leading to confusion, lethargy, seizures, coma, and death. Slowly
developing or chronic hyponatremia is generally less symptomatic,
because a progressive compensatory loss of intracellular solutes
(Na+, K+, and amino acids) restores cell volume to normal.
ANESTHETIC IMPLICATIONS OF HYPONATREMIA:
Hyponatremia
is often a manifestation of a serious underlying problem and, as
such, merits careful preoperative assessment. Levels of (Na+)
greater than 130mmol/L1 are generally considered safe for general
anesthesia; for elective procedures, the sodium level should be
corrected to at least this level. Lower levels may result in cerebral
edema that could manifest intraoperatively as a decrease in
minimum alveolar concentration (MAC) or postoperatively as
agitation, confusion, or drowsiness.
TREATMENT OF HYPONATREMIA: The management of
hyponatremia is dependent on the severity, rapidity of onset, and
duration of the hyponatremic state. Although a detailed diseasespecific description of therapies is beyond the scope of this
chapter, a summary of the basic approach to the correction of
hyponatremia relating to these disease categories follows.
In hyponatremia with reduced total body sodium, as in extrarenal losses of salt and water and renal or extrarenal salt-losing
states, an ECF volume deficit needs to be replaced and a sodium
deficit. The sodium deficit may be calculated as:
Na+ deficit (mmol) = TBW (Desired (Na+) Present (Na+)

If dehydration is significant, an initial resuscitation phase is
frequently required. Isotonic fluid such as normal saline is
appropriate, at rates of 5 to 10 mL/kg/3060 min until hemodynamic parameters indicate adequate resuscitation. More rapid
administration is indicated if there is end-organ evidence of
hypoperfusion. The fluid deficit should then be replaced with
normal saline, with appropriate maintenance fluids additionally,
aiming to correct the fluid and sodium deficit over a 24-h period.
Hyponatremia with excess total body sodium, as in the
edematous conditions just discussed, is treated primarily by salt
and water restriction with diuretic therapy. In hypoproteinemic
states, the infusion of a 25% albumin solution in addition to the
diuretic therapy may help preserve the intravascular volume,
increase intravascular colloid osmotic pressure, increase the
efficacy of the diuretic therapy, and hasten the resolution of the
edema.
In euvolemic hyponatremic states, the decision as to how to
correct the sodium level is based on the clinical symptoms and the
rapidity with which the disorder developed. It is desirable to
prevent symptoms by bringing the sodium concentration above
125 mmol/L. In general, hyponatremia with a serum sodium
concentration above 125 mmol/L should be corrected in the same
amount of time as it took to develop. In SIADH, the basis of
treatment is the creation of a negative water balance at the same
time as treating the underlying cause. Asymptomatic or mildly
symptomatic patients should be treated by water restriction to
between one half and two thirds of maintenance requirements. If
water restriction does not hasten the correction of hyponatremia,
intravenous loop diuretics may be added to increase free water
clearance. Urinary sodium and potassium losses should be
monitored and replaced. For severe symptoms of water
intoxication, 3% saline may be given at a rate of 6 mmol/kg/h
(12 mL/kg/h) until (Na+) is greater than 125 mmol/L, followed by

slower correction with normal saline over 24 to 48 hours.
Alternatively, a single bolus dose of 3% saline (3 mL/kg) can be
administered over 5 to 10 minutes for patients with symptomatic
hyponatremia (seizures). There is some concern that overrapid
correction of hyponatremia can lead to neurologic deterioration
through development of central pontine myelinolysis and
demyelination of extrapontine myelinated neurons, which is the
rationale for slower correction of hyponatremia once a level of a
serum sodium concentration above 125 mmol/L has been
achieved.
HYPERNATREMIA AND HYPEROSMOLALITY: Hypernatremia is by

definition a plasma (Na+) greater than 150 mmol/L. It reflects a
relative excess of salt relative to water but, importantly, does not
reflect total body sodium thath may be normal, high, or low.
Hypernatremia is nearly always the result of either loss of water
in excess of sodium or, less commonly, retention of sodium.
Generally, even when renal concentrating ability is impaired, the
thirst mechanism is highly effective in preventing hypernatremia,
but in the case of infants or debilitated children, this may not be
functional or the patients may not be able to gain access to water.
Hypernatremia will cause hyperosmolality of the ECF so that the
volume of this compartment is well maintained at the expense of
the ICF, which bears the brunt of the fluid deficit. Relative
preservation of the ECF volume will also, to some degree, mask
the classic signs of dehydration and hypovolemia.
Premature infants and neonates have an inability to excrete a
sodium load45,46 because of reduced GFR and a tubular inability
to increase fractional excretion of sodium (FENa). Although several
conditions cause hypernatremia, the two primary mechanisms are
either (1) loss of water in excess of sodium or (2) gain of sodium
in excess of water. The assessment of hypernatremia is shown
in Figure 1012. Loss of water in excess of sodium may occur
because of (1) extrarenal losses (diarrhea, vomiting, hyperventilation, or pyrexia); (2) inadequate intake; or (3) renal losses
(diabetes insipidus, hyperglycemia, or an osmotic diuresis).
EXTRARENAL WATER LOSS:
In pediatric practice, the most

common presentation of hypernatremia is as hypernatremic
dehydration, typically from viral gastroenteritis. Although the
water loss may be greater than isotonic or hypertonic losses, the
signs of dehydration may be less, as explained previously in the
section of Fluid and Electrolytes. The situation may be exacerbated
by concomitant poor free water intake and inappropriate highsolute feeding. Less commonly, the same situation may arise as a
result of insensible respiratory tract losses with respiratory tract
infection or insensible skin losses in pyrexia.
INADEQUATE INTAKE: The thirst mechanism is, under normal
circumstances, a potent line of defense against hypernatremia. In
infants who are unable to get water for themselves, comatose or
debilitated patients, or those with hypodypsia because of a lesion
affecting the thirst center, hypernatremic dehydration develops.
An appropriate renal response is seen, with small volumes of
concentrated urine.
RENAL WATER LOSS:
Increased loss of solute-free water due to

impaired urinary concentrating ability occurs in the setting of an
inadequate response to appropriate ADH levels or an inadequate
secretion of ADH. In both of these instances, there is an
inappropriately low urine osmolality in the face of increased
plasma osmolality and hypernatremia. Central diabetes insipidus
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Figure 10-12. Assessment of hypernatremia
encompasses a number of disorders in which there is decreased

central release of ADH (Table 109). Nephrogenic diabetes
insipidus includes a number of clinical situations characterized by
an impaired tubular response to ADH (see Table 109).
Polyuria is the hallmark of these disorders. In the older child,
polyuria may manifest as nocturia, nocturnal enuresis, thirst, or
polydipsia. However, in an infant, polyuria may go unnoticed.
These patients are at greater risk than older patients for hypernatremic dehydration. Typical presentation includes nonspecific
signs such as failure to thrive, developmental delay, irritability,
frequent feeding requirements, constipation, and unexplained
pyrexia.
When diabetes insipidus is suspected, normal renal function,
normal plasma calcium and potassium, and normal urinary tract
ultrasound should first be confirmed. The diagnosis is on the basis
TABLE 10-9. Etiology of Diabetes Insipidus
Central
Nephrogenic
Head trauma
Intracranial tumor
Intracranial hemorrhage
CNS infection
Idiopathic
Postneurosurgical procedure
Congenital
Hypocalcemia
Hypokalemia
Reflux nephropathy
Obstructive nephropathy
Fanconis syndrome
Sickle cell nephropathy
Polycystic nephropathy
Chronic renal failure
Drugs (lithium/rifampin)
CNS = central nervous system.
of response to exogenous ADH in the form of 1-deamino-(8-Darginine) vasopressin (DDAVP), and to water deprivation. A water
deprivation test is not without risk and is contraindicated in the
setting of hypernatremia. DDAVP in a dose of 2 g/m2
intravenously or 20 g/m2 intranasally should produce an increase
in urine osmolality to greater than 800 mOsm/L after 4 hours, if
the renal response to ADH is intact. In a normally hydrated
normonatremic patient, a water deprivation test may be performed. The aim is to measure urine and plasma osmolality during
6 to 8 hours of water deprivation or until 3% body weight loss is
lost. The test is abandoned if a normal urine osmolality response
of greater than 800 mOsm/L is found. If this does not occur,
DDAVP is administered at the end of the deprivation period. In
central diabetes insipidus, the urine osmolality will subsequently
rise to greater than 800 mOsm/L, whereas in nephrogenic diabetes
insipidus, the urine osmolality will remain unchanged.
Hyperglycemia associated with diabetic ketoacidosis or excessive glucose administration can cause hypotonic fluid loss by
osmotic diuresis. In diabetic ketoacidosis, there may be unrecognized hypernatremia contributing to the hyperosmolality
caused by hyperglycemia, because an increase in the blood glucose
of 5 mmol/L should lower the measured sodium concentration by
2.5 mmol/L owing to fluid shift into the ECF. Calculation of
corrected (Na+) is by the following formula47:
(Na+)corrected = (Na+)measured + (2.5 mmol/L
for each 5 mmol/L glucose over normal)
Hypernatremia in the absence of a fluid deficit is unusual. It
can be iatrogenic in the case of inappropriate intravenous fluid
therapy (hypertonic saline or sodium HCO3 or incorrect reconstitution of feed). Sea water ingestion can also cause hypernatremia.
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Disorders associated with mineralocorticoid excess such as
Cushings or Conns syndrome may result in hypernatremia
and edema.
Neurologic symptoms predominate in patients with hypernatremia, with any fluid deficit being less evident. Restlessness,
lethargy, and hyperreflexia can progress to seizures, coma, and
ultimately, death. Neurologic manifestations develop by two main
methods. First, symptoms are thought to relate to cellular
dehydration and the severity correlates more closely with the rate
of movement of water out of brain cells than with the absolute level
of sodium. Focal intracerebral hemorrhage or subarachnoid
hemorrhage may develop when the osmolar gradient develops
rapidly.48 Second, neurologic manifestations may be precipitated
by treatment. This is because of the development of idiogenic
osmoles, notably the amino acid taurine, during prolonged
hypernatremia. These idiogenic osmoles have a protective effect
and return brain water to normal.49 Thus, during rehydration of
chronic hypernatremic dehydration and the return of serum
sodium to normal values, there is a slower decline in the intracellular decline of these idiogenic osmoles and, therefore, a
marked brain avidity for water with the potential development of
cerebral edema. Other clinical features of hypernatremia include
hypocalcemia and hyperglycemia, the etiology of which is obscure.
In animal studies, hypernatremia increases the MAC for
volatile anesthetic agents, but in clinical practice, the associated
fluid deficits are more likely to be of significance. Any hypovolemia will accentuate the hypotensive effects of the vasodilation
or cardiac depression of anesthetic agents. Similarly, the volume of
distribution for intravenous drugs will be reduced, necessitating
dose reductions. Elective surgery should be postponed in patients
with (Na+) greater than 150mmol/L until a cause is established and
both isotonic and water deficits replaced.
The approach to the treatment of hyponatremia is based on
determining the etiology and addressing this as well as correcting
the fluid deficit. Regardless of the etiology, in the presence of a
circulatory deficit, initial management must be resuscitation with
isotonic saline to restore vital signs and urine output. Restoration
of normal hydration and sodium concentration should then take
place over at least 48 hours. This should be extended to 72 hours
with (Na+) greater than 170 mmol/L. Coexisting potassium deficit
or metabolic acidosis should also be addressed. During therapy,
plasma sodium levels should be closely monitored so that serum
sodium is not allowed to fall faster than 0.5 mmol/L/h. Oliguria on
the initial assessment, in the absence of circulatory impairment,
should prompt determination of urinary (Na+) to confirm that the
oliguria is purely volume related, in which case, the urine (Na+)
will be less than 20 mmol/L. Other features consistent with prerenal oliguria may also present. A fluid challenge is then appropriate in such patients to reverse intravascular dehydration.
Persistent oliguria is suggestive of possible renal vein thrombosis,
a complication of hypernatremia often associated with hematuria,
thrombocytopenia, and renal enlargement.
Central diabetes insipidus is treated by aerosolized DDAVP
administered nasally along with regulated water intake to prevent
hypernatremia. In patients with proven central diabetes insipidus,
administration of aerosolized DDAVP at a dose of approximately
20 g/m2 will correct the urinary concentration defect. Dose and
water intake need to be individualized to avoid hyponatremia. The
management of nephrogenic diabetes insipidus aims to prevent
dehydration and hypernatremia while reducing the fluid intake to
tolerable levels. Freely offered fluids as dictated by thirst, with
nocturnal nasogastric fluid for infants, are the first line of therapy.
Measures to reduce the daily urinary volumes include dietary
measures such as a low-sodium and -protein diet,and medications
such as hydrochlorthiazide and indomethacin.
Alterations in Serum Potassium Concentration

Potassium in the body plays a major role in the electrophysiology
of cell membranes as well as carbohydrate and protein synthesis.
The resting membrane potential of all cell membranes is dependent on the ratio of intracellular to extracellular potassium
concentration. Intracellular potassium concentration is approximately 140 mmol/L, whereas extracellular potassium is approximately 4 mmol/L. Changes in ECF (K+) can be mediated by
alterations in intake, loss of potassium, or changes in ECF/ICF
distribution. The intracellular/extracellular (K+) ratio is dependent
on the activity of the membrane Na+/K+-ATPase, which is affected
by H+ balance, plasma tonicity, plasma insulin, epinephrine, and
aldosterone concentrations. The kidney is the major excretory
organ for potassium. Urinary potassium is predominantly derived
from distal tubular secretion because over 90% of proximally
filtered K+ is re-absorbed. Secretion occurs in the principal cells of
the middle and late distal tubule and the cortical collecting duct.
Potassium secretion is enhanced by increased distal tubular
sodium delivery, reduced distal chloride delivery, mineralocorticoid activity, and alkalosis. A useful determination is the
urinary Na+/K+ ratio, which is normally between 1 and 4, the
higher figure being seen in premature infants. In pediatric practice, it is important to be aware of the age-related changes in
plasma (K+) (Table 1010).
HYPOKALEMIA: Hypokalemia is defined as a plasma (K+) less than

3.5 mmol/L. It is produced by either (1) total body potassium
deficiency (inadequate intake, extrarenal loss, renal loss) or
(2) redistribution (alkalosis, familial periodic paralysis, insulin
administration, drugs, toxins). Pseudohypokalemia is a situation that has been described when blood samples from leukemic patients with exceedingly high white blood cell counts
(=100,000/mm3) are not promptly separated into plasma and
cellular components before estimation of plasma (K+). In such
circumstances, the ongoing uptake of K+ by the white blood cells
when samples are left standing at room temperature gives a
spurious impression of hypokalemia.50
HYPOKALEMIA ASSOCIATED WITH TOTAL BODY POTASSIUM DEFICIENCY: Because of the kidneys ability to decrease urinary (K+)
to as low as 5 to 20 mmol/L and potassiums ubiquitous presence

in foods, a deficient diet alone seldom causes symptomatic
hypokalemia. However, inadequate intake in association with
obligatory physiologic renal and GI tract losses, accentuated by a
TABLE 10-10. Age-Related Changes in Potassium
Age
3032 wk
3335 wk
3638 wk
3941 wk
112 mo
220 y
From reference 16.
Plasma K+ concentration, mmol/L

6.5 0.5
5.6 0.2
5.3 0.3
5.1 0.2
5.0 0.5
4.3 0.4
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high sodium intake, may cause a relative deficit. Such a deficit may
be symptomatic in a patient maintained on potassium-free
intravenous fluid, in protein-calorie malnutrition, or in infants fed
inappropriate formulas.
In children and infants, the most common cause of hypokalemia is secondary to acute or chronic GI tract losses. Diarrheal
potassium losses may be marked, as may upper or lower GI
fistula/stoma losses and losses from ureterosigmoidostomies. In
the case of vomiting, hypokalemia does not result directly from
GI tract potassium loss, but rather from the kaliuretic effect of the
metabolic alkalosis on the renal tubules. Diarrhea results in direct
potassium loss and very often a metabolic acidosis. Volume depletion from any of these may cause secondary hyperaldosteronism
and enhance urinary potassium losses. Excessive sweating or
heatstroke may cause hypokalemia through a combination of
exocrine gland loss and secondary hyperaldosteronism due to ECF
contraction. This is a particular risk to cystic fibrosis patients.
Renal wastage of potassium occurs by five different mechanisms. Increased distal tubular Na+/K+ exchange will occur in
response to increased circulating mineralocorticoid concentrations, glucocorticoids, or foods and drugs that mimic/enhance
mineralocorticoid effects. Thus, Cushings syndrome, Conns
syndrome, nonsalt-losing congenital hyperplasia, and high-dose
corticosteroid therapy may be associated with hypokalemia.
Licorice contains glycyrrhizic acid, whose structure resembles the
cyclopentenophenanthrene steroid molecule and thereby behaves
like aldosterone. If ingested in excess, it can cause hypokalemia.
Increased delivery of Na+ to the distal tubule will result in
increased Na+/K+ exchange and potassium wastage. This occurs
with proximal tubulopathies such as proximal RTA and Fanconis
syndrome. Similarly, the use of thiazide and loop diuretics
enhances distal Na+ delivery and potassium wastage. This effect is
enhanced by concomitant chloride deficiency and contraction
alkalosis. The presence in the distal tubular lumen of a nonabsorbable anion increases the electronegativity of the luminal
fluid, thus enhancing K+ and H+ excretion. This is the basis for the
kaliuretic effect of carbenicillin and large doses of penicillins.
Congenital disorders associated with K+ wastage cause hypokalemia. The major example is Bartters syndrome, which involves
an inherited defect in either the NKCC cotransporter or the
inwardly rectifying potassium channel (ROMK) in the MTALH.
The resulting biochemical defect is a hypokalemic alkalosis with
hypercalciuria. Clinical symptoms include failure to thrive, rickets,
polyuria, polydipsia, hypotonia, and tetany. Lastly, direct renal
epithelial damage may precipitate kaliuresis and hypokalemia.
Renal toxins such as amphotericin B, polymixin, and aminoglycosides and interstitial nephritides such as pyelonephritis produce
hypokalemia by such a mechanism.
HYPOKALEMIA ASSOCIATED WITH POTASSIUM REDISTRIBUTION:
Although hypokalemia is usually associated with total body

potassium depletion, hypokalemia can be caused by intracellular
shifts in K+ without depletion. Alkalosis, of respiratory or metabolic origin, causes an intracellular shift of K+. This effect is more
marked for metabolic alkalosis with a decrease of plasma (K+) by
approximately 0.3 mmol/L for each 0.1 unit increase in pH as
opposed to about 0.25 mmol/L fall per 0.1 pH unit increase in
respiratory alkalosis. Insulin, by a direct effect on the membrane
Na+/K+-ATPase increases Na+ efflux and K+ influx, thereby
lowering plasma (K+). -Adrenergic agonists promote cellular
uptake of K+ by cyclic adenosine monophosphate (cAMP)
mediated activation of the Na+/K+-ATPase. This is mediated

through 2 receptors in most tissues except the heart in which 1
receptors mediate K+ uptake. Conversely, -adrenergic receptor
activation increases (K+) by reducing muscle uptake and promoting hepatic release. Toxicity from barium salts, theophylline,
and toluene also cause intracellular K+ shift with hypokalemia.
Hypokalemic periodic paralysis is a rare, autosomal dominant
disorder with episodic bouts of profound muscle weakness and
severe hypokalemia. It generally presents within the first or second
decade of life. High carbohydrate intake, low potassium intake,
exercise, infection, and alcohol are known precipitants of attacks.
A similar syndrome has been described in thyrotoxicosis, especially amongst Asian patients.
CLINICAL MANIFESTATION OF HYPOKALEMIA:
Hypokalemia
is generally asymptomatic until levels fall below 3.0 mmol/L.
Symptoms are the result of the effect of hypokalemia on skeletal,
cardiac, and smooth muscle, renal function, and hormonal and
metabolic effects. Skeletal manifestations are the earliest signs
with weakness, cramps, paralysis, and rhabdomyolysis. Cardiac
manifestations include electrocardiographic (ECG) abnormalities,
arrhythmias, decreased contractility, and labile blood pressure
owing to autonomic dysfunction. ECG changes are due to delayed
ventricular repolarization and include flattening and inversion
of the T-wave, an increasingly prominent U-wave, ST-segment
depression, and prolongation of the PR interval. Increased
myocardial automaticity and delayed repolarization promote both
atrial and ventricular arrhythmias. Paralytic ileus is the typical
smooth muscle response to hypokalemia. Renal dysfunction is
also common including both structural and functional changes.
Decreased RBF and GFR, renal hypertrophy, tubuloepithelial
dilation, vacuolization, and sclerosis may be caused by hypokalemia.51 Functional defects include impaired concentrating
ability (tubular ADH resistance), sodium retention, HCO3 reabsorption often resulting in alkalosis, and impaired urinary
acidification. Hormonal effects of hypokalemia include decreased
insulin, growth hormone, and aldosterone release. Altered protein
metabolism in chronic hypokalemia can result in a negative
nitrogen balance. Increased ammonia production secondary
to hypokalemia can precipitate encephalopathy in patients with
liver disease.
ANESTHETIC IMPLICATIONS OF HYPOKALEMIA:
Although mild
chronic hypokalemia (>3.0 mmol/L) does not appear to be a
significant risk for anesthesia, the anesthesiologist needs to
consider the rate at which the hypokalemia developed and the
likelihood of these causes being responsible, because these
conditions may in themselves be of more significance to the
planned anesthetic than the absolute value of the plasma (K+). In
addition, the anesthesiologist needs to be aware that the use of
glucose-containing solutions or hyperventilation may result in a
significant drop in the serum (K+). Digoxin toxicity is more likely
in the setting of hypokalemia. In patients receiving the drug, a
plasma (K+) above 4.0 mmol/L is preferable. The effects of
neuromuscular blocking agents may be enhanced by hypokalemia,
necessitating a reduction in dose and careful attention to nerve
stimulator testing of degree of paralysis and adequacy of reversal.
TREATMENT OF HYPOKALEMIA:
The treatment of hypokalemia

involves addressing the underlying cause as well as restoring
normal plasma (K+). Mild to moderate hypokalemia can be treated
with either supplementation of the diet with potassium-rich foods
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or oral potassium supplements. In patients with cardiac or neuromuscular manifestations of hypokalemia, intravenous replacement
is appropriate. The rate of cellular potassium uptake, even in a
depleted state, is limited, and therefore, slow replacement and
ECG monitoring is required when intravenous potassium is
administered. Intravenous potassium administration should be no
faster than 0.25 mmol/kg/h. Concentrations of up to 40 mmol/L
of potassium in the replacement fluid may be given peripherally,
but higher concentrations should be given via central access
because of the risk of thrombophlebitis. Concentrations of greater
than 60 mmol/L are not recommended. Administration of potassium supplementation may be required in redistributive hypokalemia, even though there is no total body deficit. However, there
is the potential for plasma (K+) to increase as the underlying cause
is treated.
HYPERKALEMIA: Hyperkalemia is defined as a plasma (K+) above

5.5 mmol/L. Because the kidneys capacity to excrete potassium is
tremendous, hyperkalemia is, with a few exceptions, usually
associated with impaired renal excretion. The causes of hyperkalemia can be grouped into three categories: (1) redistribution
hyperkalemia, (2) increased potassium intake, and (3) decreased
renal potassium excretion. Pseudohyperkalemia is an artifactual
elevation in the measured plasma (K+). Spurious elevations of
plasma (K+) measurement may occur when there is red cell
hemolysis (e.g., from prolonged application of a tourniquet while
obtaining a specimen). In vitro release of K+ from platelets or
white cells can elevate the measured plasma (K+) in the setting
of thrombocytosis or leukocytosis, respectively (platelet count
> 1000 109/L or white cell count > 70 109/L).
REDISTRIBUTION HYPERKALEMIA: A number of conditions cause
a shift in K+ from the ICF to the ECF, thereby elevating the plasma
(K+) without an increase in total body potassium. Acidosis causes
an extracellular shift of K+ as K+ and H+ are exchanged to buffer
the falling pH. As with hypokalemia, the effects of metabolic
acidosis are greater than those of respiratory acidosis. Metabolic
acidosis causes an increase of the plasma (K+) of approximately
0.6 mmol/L for every 0.1 unit decrease of the pH as opposed to a
0.1 mmol/L decrease in plasma (K+) for every 0.1 pH decrease in
respiratory acidosis. Hypertonicity, as occurs in hyperglycemia
with poorly controlled diabetes, causes extrusion of K+ from cells,
a situation compounded by the lack of insulin, which would have
the reverse effect. Conversely, hyperglycemia in a nondiabetic
patient will induce hypokalemia because of the increase in insulin
release that is stimulated by the hyperglycemia and the resultant
intracellular movement of K+. Tissue damage will cause direct
release of K+. This occurs in trauma, burns, rhabdomyolysis,
major hemolysis, tumor lysis with chemotherapy, and acute graft
rejection. Succinylcholine increases muscle cell K+ permeability
during depolarization, causing an acute rise in plasma (K+). This
effect is augmented in patients with renal failure, high body stores
of potassium, or when there are increased extrajunctional acetycholine receptors, as in the case of spinal cord injuries, lower
motor neuron lesions, certain myopathies such as Duchennes, and
following major trauma and burns. -Adrenergic blockade
accentuates the plasma (K+) increase that occurs with exercise. The
basis for the adrenergic effect on ECF/ICF K+ is detailed under
Hypokalemia, earlier. Digoxin, by blocking Na+/K+-ATPase, can
in overdose cause hyperkalemia. Hyperkalemic periodic paralysis
is a rare, autosomal dominant disorder because of a defect in
sodium channel deactivation. It presents with episodic paralysis

and hyperkalemia, lasting from minutes to hours.
INCREASED POTASSIUM INTAKE:
Increased intake of potassium

rarely causes hyperkalemia unless given rapidly and intravenously.
An intake of 50 mmol K+ (<2% normal daily intake) orally by
an adult can cause a transient rise in the serum (K+) of 0.5 to
1.0 mmol/Lr, which is dealt with by intracellular sequestration and
subsequent excretion over 15 to 30 minutes. Thus, with normal
renal function, large amounts of oral potassium are tolerated well.
The intravenous administration of K+ at greater than 0.5 mmol/
kg/h can rapidly cause dangerous hyperkalemia. Other sources of
a large intravenous load of K+ include the transfusion of old
banked blood (1530 mmol/L (K+]), irradiated blood, and
potassium penicillins.
DECREASED RENAL POTASSIUM EXCRETION:
Decreased GFR
inevitably leads to hyperkalemia. In chronic renal failure (CRF),
hyperkalemia is slow to develop in the absence of endogenous or
exogenous K+ loads. In CRF, there is increased fractional excretion
of potassium per surviving nephron, increased colonic potassium
excretion, and increased intracellular distribution. In acute renal
failure (ARF), there is obviously less time for these compensatory
mechanisms to develop and the resultant hyperkalemia may be of
more rapid onset and severe degree. In addition, associated
acidosis impairs the intracellular redistribution of the retained
potassium. The daily increase in serum (K+) averages 0.3 to
0.5 mmol/L in oliguric ARF under optimal conditions, but can
exceed 0.7 mmol/L/day when there is concomitant increased
catabolism or trauma.
Aldosterone promotes distal tubular Na+ absorption and K+
loss. Therefore, aldosterone deficiency, as in primary hypoaldosteronism and pseudohypoaldosteronism, causes hyperkalemia. In addition, adrenal insufficiency and Addisons disease
are characterized by salt wastage and hyperkalemia. Hyporeninemic hypoaldosteronism is a syndrome characterized by a degree
of hyperkalemia that is inappropriate to the degree of reduction of
GFR. It occurs in the setting of interstitial nephritis, obstructive
uropathy, and sickle cell disease. Drugs that interfere with the
renin-angiotensin-aldosterone system have the potential to cause
hyperkalemia, especially if there is any additional renal impairment. Non-steroidal anti-inflammatory drugs (NSAIDs) interfere
with prostaglandin-mediated renin release; ACE inhibitors
interfere with angiotensin-mediated aldosterone release; heparin
in large doses can interfere with aldosterone release; and spironolactone, the potassium-sparing diuretic, directly antagonizes
aldosterones distal tubular action.
CLINICAL FEATURES OF HYPERKALEMIA:
The most important

effects of hyperkalemia are on skeletal muscle and cardiac muscle.
The first signs are ECG changes, primarily because of delayed
depolarization, occurring when the plasma (K+) reaches 7.0
mmol/Lr with prolongation of the PR-interval and tenting of the
T-wave. Shortening of the QT-interval, QRS widening, and STsegment depression occur when the plasma (K+) is 8.0 mmol/Lr.
With a further increase in the plasma (K+), there is loss of the Pwave, loss of the R-wave, and progressive widening of the QRS
complex. This results in an electrocardiogram that resembles a
sine wave until ventricular fibrillation occurs at a plasma (K+) level
of 9.0 mmol/L or greater. These changes are augmented by hypoxia
and acidosis. Arrhythmias may occur at lower levels in these
contexts. Skeletal muscle weakness is not seen until plasma (K+) is
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above 8.0 mmol/L. The weakness is due to sustained spontaneous

depolarization and inactivation of muscle membrane Na+
channels, resulting in an ascending paralysis.
ANESTHETIC IMPLICATIONS OF HYPERKALEMIA: Hyperkalemia is
a medical emergency whose management takes precedence over

elective surgery. The management of the hyperkalemic emergency
surgical patient is directed at both lowering the plasma potassium
and avoiding further increases. The use of succinylcholine is
contraindicated in hyperkalemia, as are any potassium-containing
intravenous fluids including lactated Ringers. Avoidance of respiratory or metabolic acidosis is essential to avoid further increases
in the plasma (K+). Therefore, ventilation should be controlled
under general anesthesia; mild hyperventilation may even be
desirable. Neuromuscular function must be closely monitored
because hyperkalemia can exaggerate the effects of nondepolarizing neuromuscular blocking agents.
TREATMENT OF HYPERKALEMIA:
Because of its lethal potential,

hyperkalemia greater than 6.0 mmol/L should receive emergency
treatment with cardiac monitoring and resuscitation facilities
readily to hand. The treatment of hyperkalemia can be thought of
as having four components: (1) reducing the potassium load;
(2) reversing the membrane effects of hyperkalemia; (3) increasing
intracellular K+ shift; and (4) removing potassium. Reducing the
potassium load can be accomplished by decreasing dietary potassium, discontinuing K+-containing fluids, prescribing medications, and removing the conditions that favor hyperkalemia such
as acidosis or sodium restriction. These measures may be sufficient in mild hyperkalemia, but more rapid measures are required
when ECG changes or neuromuscular signs are evident. Antagonizing the membrane effects of hyperkalemia with calcium is the
fastest means of reversing cardiotoxicity. Intravenous calcium
gluconate at 100 to 200 mg/kg/dose is an effective measure, even
in the absence of hypocalcemia. Calcium decreases the threshold
potential of excitable tissue, thus stabilizing the myocardial cell
membrane. The intracellular shift of potassium is stimulated by
insulin, alkalosis, and -adrenergic stimulation. Dextrose (0.5 g/
kg) as a 10% solution, with insulin added at a ratio of 1 unit/5 g of
dextrose will rapidly reduce the plasma (K+) within minutes.
Equally effective is sodium HCO3 (12 mmol/kg/dose) intravenously. These are effective irrespective of acid-base or insulin status.
An inhaled -adrenergic agonist, such as salbutamol (albuterol),
will also reduce the plasma (K+) by a further 0.1 to 0.3 mmol/L.
Hyperventilation (and, thus, respiratory alkalosis) increases
intracellular shift to a lesser extent, but also increases urinary
excretion of K+ for up to 24 hours. Removal of potassium from the
body may be accomplished by polystyrene sulfonate resins, which
act as ion exchangers in the GI tract. However, the onset of action
is slow. Loop diuretics (furosemide) may be used to increase
urinary K+ losses. If hyperkalemia remains severe, especially with
more severe ECG changes and renal impairment, dialysis therapy
is necessary.
Disorders of Calcium Homeostasis

CALCIUM METABOLISM
AND REGULATION: Regulation of

calcium, phosphorus, and magnesium within narrow limits is
dependent on the action of PTH, calcitonin, and 1,25 dihydroxycholecalciferol (vitamin D) on the GI tract, bone, and renal
tubules. Additional influences include acid-base status and ECF
volume status.
Calcium is vital to the body because of its obvious importance

in bone metabolism and also for the stability it provides to
excitable cell membranes, regulation of neuromuscular function,
blood coagulation, cellular transport, secretory function, and as
an intracellular second messenger. Normal plasma calcium
concentration is 2.1 to 2.6 mmol/L. Forty percent is proteinbound, 50% is in the free ionized form, and 10% is bound to
anions such as citrate and amino acids. The free ionized calcium
concentration (Ca2+) is physiologically most important. It is
normally 1.1 to 1.25 mmol/L or 2.2 to 2.5 mEq/L. Changes in
plasma albumin concentration will affect the total, but not the
ionized calcium concentration. An approximate correction for
plasma calcium is to add (or subtract) 0.02 mmol/L for each gram
by which the plasma albumin lies below (or above) a standard
figure, normally 40 g/L. Changes in pH directly affect the degree
of protein binding and, thus, the ionized (Ca2+). Ionized (Ca2+)
increases approximately 0.03 mmol/L for each decrease of 0.1 unit
in pH and decreases by the same amount for a similar pH increase.
Calcium enters the ECF by either absorption from the GI tract
or resorption from bone and leaves the ECF by deposition into
bone, urinary excretion, secretion into the GI tract, and sweat
formation. Three hormones (PTH, vitamin D, and calcitonin)
regulate ECF (Ca2+), acting primarily on bone, small bowel, and
the distal tubules of the kidney. GI tract absorption of calcium is
by vitamin Ddependent, saturable, energy-dependent absorption
and by vitamin Ddependent, nonsaturable, passive absorption.
Calcium absorption is enhanced by dietary sugars (e.g., lactose)
in the absence of vitamin D, which may explain higher calcium
levels in infants. Up to 80% of the total daily intake is lost in the
feces. The kidneys are responsible for calcium excretion. Normally,
90% of filtered calcium is absorbed. Proximal tubular absorption
parallels sodium absorption. In the MTALH, calcium and
magnesium absorption takes place through a paracellular route as
a result of the electropositive gradient. Therefore, loop diuretics,
which interfere with the generation of this gradient, increase
urinary excretion. In the distal convoluted tubule/collecting
segment, calcium reabsorption is accomplished by an apical
calcium channel, a basolateral sodium-calcium exchanger, and
calcium ATPase pump and is regulated by PTH. Therefore,
thiazide diuretics, which decrease intracellular (Na+) and therefore
increase basolateral Na+/Ca2+ exchange, will increase Ca2+ reabsorption. PTH is the most important regulator of ECF (Ca2+).
Decreases in (Ca2+) stimulate PTH secretion, and increases inhibit
PTH secretion. The calcemic effect of PTH is due to mobilization
of Ca2+ from bone, indirect increased small bowel absorption via
enhanced vitamin D formation, and enhanced renal tubular
reabsorption.
Vitamin D is the product of the conversion of cholecalciferol
first by the liver to 25-cholecalciferol and then by the kidneys to
1,25-dihydroxycholecalciferol. The latter process is enhanced by
PTH and hypophosphatemia. Vitamin D augments intestinal
calcium absorption, facilitates the action of PTH on bone, and
augments the renal tubular effect of PTH. Calcitonin is a
polypeptide hormone secreted by the parafollicular cells of the
thyroid, in response to hypocalcemia. Calcitonin secretion is
inhibited by hypercalcemia. The effects of calcitonin include the
inhibition of bone re-absorption and the augmentation of urinary
calcium excretion.
HYPOCALCEMIA: Hypocalcemia should be diagnosed only on the

basis of a plasma ionized (Ca2+). If not available, the plasma (Ca2+)
should be corrected for albumin concentration. A plasma (Ca2+)
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TABLE 10-11. Etiology of Hypocalcemia
1. Failure of appropriate PTH secretion:
Neonatal hypocalcemia:
Early hypocalcemia-calcitonin-PTH imbalance
Delayed postfeeding hypocalcemia (transient physiologic
hypoparathyroidism)
Congenital hypoplasia of the parathyroid glands:
Aplasia or hypoplasia
Pseudoidiopathic hypoparathyroidism
Acquired hypoparathyroidism:
Idiopathic hypoparathyroidism
Genetic autoimmune hypoparathyroidism
Surgical hypoparathyroidism
2. Inadequate responsiveness of tissues to PTH
Vitamin D deficiency:
Primary deficiency
Defect in production of active 1,25dihydroxycholecalciferol
Pseudohypoparathyroidism type 1 and 2
Magnesium deficiency
Hypernatremia, hypokalemia, infections.
3. Hyperphosphatemia
4. Precipitation of calcium
Pancreatitis
Rhabdomyolysis
Fat embolism
5. Chelation of calcium
Multiple transfusions
Rapid infusion of large amount of albumin
PTH = parathyroid hormone.
less than 1.0 mmol/L or a corrected total calcium concentration

less than 2.0 mmol/L is indicative of true hypocalcemia. The
potential causes of hypocalcemia in the pediatric-aged patient are
outlined in Table 1011.52
Early neonatal hypocalcemia develops within 48 hours after
birth in about 33% of premature neonates, born at 37 weeks of
gestation or less, 50% of infants of insulin-dependent diabetics,
and 30% of infants with birth asphyxia. Elevated calcitonin levels,
as opposed to lowered PTH levels, are suggested as the cause.53,54
Delayed hypocalcemia occurring 5 to 7 days after birth, is often
associated with cows milk ingestion. Maternal vitamin D levels
may play a role in late neonatal hypocalcemia.55 CRF causes hypocalcemia by a number of mechanisms including (1) hyperphosphatemia leading to soft tissue calcification; (2) increased sulfate
and phosphate complex formation; (3) defective 1,25-dihydroxycholecalciferol synthesis with impaired calcium absorption; and
(4) PTH resistance. In pancreatitis, precipitation of calcium with
fats (soaps) occurs following the release of lipolytic enzymes and
fat necrosis. A similar mechanism is likely in fat embolism. Largevolume transfusion may produce calcium chelation with the
citrate ions in the blood preservative. A transient reduction
in plasma (Ca2+) may follow large-volume rapid infusions of
albumin.
CLINICAL FEATURES OF HYPOCALCEMIA:
Increased neuromuscular excitability forms the basis for the typical symptoms of
hypocalcemia. Central features include irritability, anxiety, jitteriness, twitching, and seizures. There may be perioral, finger, and
toe paraesthesias, masseter spasm (Chvosteks sign), and carpo-
pedal spasm (Trousseaus sign). Cardiac manifestations include a

prolonged QT-interval, decreased cardiac contractility, dysrhythmias, and decreased responsiveness to digitalis and -adrenergic
agonists. Laryngospasm, bronchospasm, and a high-pitched cry
are seen in older infants.
ANESTHETIC IMPLICATIONS OF HYPOCALCEMIA:
Hypocalcemia
should be corrected preoperatively and efforts made to avoid
further decreases in ionized calcium concentration including
avoidance of alkalosis and frequent monitoring of plasma ionized
(Ca2+) during transfusion or albumin infusion. In hypocalcemia,
the potentiation of the negative inotropic effects of anesthetic
agents should be expected, whereas the response to neuromuscular blocker agents may be enhanced.
TREATMENT OF HYPOCALCEMIA:
Symptomatic hypocalcemia is
a medical emergency requiring administration of intravenous
calcium. Calcium is available as a chloride, gluconate, or gluceptate
solution. Of the commonly used solutions of either calcium
chloride (10%) or calcium gluconate (10%), calcium chloride
provides three times the elemental calcium of calcium gluconate
on a milligram-for-milligram basis (27.2 mg/mL of elemental
calcium in calcium chloride vs 9 mg/mL of elemental calcium in
calcium gluconate). Calcium chloride is most commonly used in
critically ill children.56,57 If calcium gluconate is used, three times
as much is required to result in a similar increase in the plasma
ionized (Ca2+) when compared with calcium chloride. The recommended dose of 5 to 7 mg/kg of elemental calcium can be given as
0.2 to 0.25 mL/kg of calcium chloride 10% infused over 10 minutes
and repeated once if required.58 The danger of cardiac dysfunction
with too-rapid infusion and soft tissue necrosis with extravasation
must be recognized. The potential for concurrent hypomagnesemia must be considered and treated simultaneously, as
outlined in the section on Hypomagnesemia later in this chapter.
HYPERCALCEMIA: Hypercalcemia may occur by a number of

mechanisms listed in Table 1012, but because its features are
nonspecific, it is less easy to diagnose. Primary hyperparathyTABLE 10-12. Etiology of Hypercalemia
1. Hyperparathyroidism
Primary
Tertiary
2. Malignancy
Bony destruction
PTH-like mediator release
Neoplastic vitamin D production
3. Increased intestinal calcium absorption
Hypervitaminosis D
Granulomatous disease (sarcoidosis/Ttuberculosis)
Milk-alkali syndrome
4. Increased bony reabsorption
Chronic immobilization
Pagets disease
5. Thyrotoxicosis
6. Drug-induced
Thiazide diuretics
Lithium
7. Familial hypocalciuric hypercalcemia
Idiopathic infantile hypercalcemia (Williams syndrome)
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roidism is rare in childhood, occurring as part of the multiple

endocrine adenoma syndrome with hypercalcemia, hypercalciuria, and nephrolithiasis. Infantile hyperparathyroidism is a
life-threatening surgical emergency, characterized by plasma
(Ca2+) of 3.7 to 7.2 mmol/L, unexplained anemia, hepatosplenomegaly, skeletal demineralization, and nephrocalcinosis. Secondary hyperparathyroidism is the elevation of PTH levels secondary
to chronic hypocalcemia. Tertiary hyperparathyroidism occurs
when prolonged secondary hyperparathyroidism gives rise to
autonomous PTH secretion leading to hypercalcemia. Neoplasia
can give rise to hypercalcemia even without bony metastases
through the release of PTH-like mediators or neoplastic production of 1,25-dihydroxy vitamin D. Increased intestinal absorption
of calcium is seen in hypervitaminosis D and in granulomatous
disease in which there is enhanced sensitivity to vitamin D.
CLINICAL FEATURES OF HYPERCALCEMIA: The symptoms of
hypercalcemia are relatively nonspecific with typical features
including anorexia, nausea, vomiting, weakness, drowsiness, confusion, and ultimately, coma. Typical ECG changes are a shortened
QT-interval and ST-segment. Hypertension is often seen before
hypovolemia develops. The renal effects of hypercalcemia include
polyuria due to a nephrogenic diabetes insipidus (insensitivity to
the tubular effect of ADH), decreased GFR, nephrolithiasis, and
nephrocalcinosis. Pancreatitis, peptic ulceration, and renal failure
may complicate hypercalcemia.
ANESTHETIC IMPLICATIONS OF HYPERCALCEMIA: Hypercalcemia
is a medical emergency that should, if possible, be corrected

before any general anesthetic is administered. Saline diuresis,
as explained below in Treatment of Hypercalcemia, should be
continued intraoperatively, taking care to avoid hypovolemia,
hypokalemia, or hypomagnesemia. Acidosis should be avoided to
prevent an increase in the plasma ionized (Ca2+).
TREATMENT OF HYPERCALCEMIA:
The most effective treatment

of hypercalcemia is establishment of a brisk diuresis. This is done
by a saline infusion at 20 mL/kg/h for 4 hours and furosemide
(1 mg/kg/dose), which augments urinary calcium excretion.
During saline diuresis, hypokalemia or hypomagnesemia may
develop. Frequent monitoring of plasma levels is required with
replacement when necessary. For plasma ionized (Ca2+) greater
than 3.7 mmol/L, mithramycin, administered intravenously in a
dose of 25 g/kg over 4 to 8 hours, will produce a fall in plasma
ionized (Ca2+) within 1 day. Calcitonin, 4 IU/kg subcutaneously
every 12 hours, will produce a more moderate fall in plasma
ionized (Ca2+) that is usually not sustained. In the presence of renal
or cardiac failure, emergency dialysis may be required.
Disorders of Phosphorous Homeostasis

PHOSPHOROUS METABOLISM AND REGULATION: Phosphorus is
an important intracellular constituent, required for the synthesis
of phospholipids and phosphoproteins in cell membranes and
intracellular organelles as well as phosphonucleotides involved in
protein synthesis and reproduction. In addition, it is a key
constituent of ATP used for the storage of energy. Approximately
0.1% of total body phosphorus is in ECF, 85% is in bone, and 15%
is intracellular. Fifty to 60% of dietary phosphorus is absorbed in
the small intestine. Vitamin D increases intestinal absorption. The
kidneys are the major route for phosphorus excretion and are
responsible for regulating total body phosphorus. Urinary phos-
phorus excretion depends on both intake and plasma level. PTH

inhibits proximal tubular re-absorption of filtered phosphorus,
enhancing urinary phosphorus excretion. In the absence of PTH,
the re-absorption of phosphorus is complete.
Plasma phosphorus exists in both organic and inorganic forms.
Organic phosphorus is in the form of phospholipids. Inorganic
phosphorus exists as H2PO4 and HPO42 in a ratio of 1:4. Of
inorganic phosphorus, 80% is filterable in the kidney and
20% is protein bound. Normal plasma level is 2.5 to 4.5 mg/dL
(0.8-1.5 mmol/L) in adults and up to 6 mg/dL in children.
Hypophosphatemia increases vitamin D production, whereas
hyperphosphatemia decreases it.
HYPOPHOSPHATEMIA: Causes of hypophosphatemia include

those associated with a total body depletion of phosphorus and/or
an intracellular shift of ECF phosphorus (Table 1013).11
CLINICAL MANIFESTATIONS OF HYPOPHOSPHATEMIA:
Mild to
moderate hypophosphatemia (1.52.5 mg/dL) is generally asymptomatic. By contrast, severe hypophosphatemia (<1.0 mg/dL) is
associated with widespread organ dysfunction. The features of
severe hypophosphatemia are largely neuromuscular and hematologic. Neurologic and neuromuscular features include encephalopathy, coma, and seizures as well as skeletal myopathy and
rhabdomyolysis. Hematologic features include impaired oxygen
delivery (decreased 2,3,-diphosphoglycerate [2,3-DPG] levels),
hemolysis (because of reduced intracellular ATP), impaired leukocyte function, and platelet dysfunction. Cardiomyopathy, respiratory failure, skeletal demineralization, and hepatic dysfunction
may occur with severe hypophosphatemia.
ANESTHETIC IMPLICATIONS OF HYPOPHOSPHATEMIA: Anesthetic
management of the hypophosphatemic patient requires familiarity

with the potential complications outlined in the clinical manifestation of hypophosphatemia above, along with avoidance of measures likely to further decrease plasma phosphorus concentration,
TABLE 10-13. Etiology of Hypophosphatemia
Gastrointestinal
Inadequate intake (e.g., during enteral nutrition)
Refeeding syndrome
Chronic antacid administration (intraluminal binding of
phosphorus)
Vitamin D deficiency
Renal
Fanconis syndrome
Recovery phase of acute tubular necrosis
Postrenal transplant dysfunction
Postobstructive diuresis
Vitamin Dresistant rickets
Idiopathic hypocalciuria
Excess PTH
Diuretic therapy
Hypomagnesemia
Hyperglycemia
Salicylate poisoning
Intracellular shift
Respiratory alkalosis (effect greater than metabolic alkalosis)
Carbohydrate ingestion
Insulin ingestion
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such as hyperglycemia and respiratory alkalosis. Neuromuscular
function should be closely monitored and severe hypophosphatemia may make postoperative ventilatory support necessary.
TREATMENT OF HYPOPHOSPHATEMIA: Oral phosphorus is
generally preferable to intravenous phosphorus administration,
which may result in hypocalcemia and metastatic calcification. In
severe, symptomatic hypophosphatemia, intravenous phosphorus
can be given over 6 to 12 hours in a dose of 2 to 5 mg/kg of
elemental phosphorus as the potassium or sodium phosphate.
When potassium phosphate is used, the potential clinical impact
of the potassium dose must also be considered.
HYPERPHOSPHATEMIA: Hyperphosphatemia is seen with increased

intake, decreased excretion, or cellular release of phosphorus.
Increased intake may occur with phosphate enemas and laxatives
or high-phosphorus diets (e.g., cows milk in infants). Decreased
excretion may result from renal failure, hypoparathyroidism, and
pseudohypoparathyroidism. The cellular release of potassium
occurs with hemolysis, rhabdomyolysis, and tumor lysis (e.g., post
chemotherapy for lymphoma/leukemia).
CLINICAL MANIFESTATIONS OF HYPERPHOSPHATEMIA:
The
clinical manifestations of hyperphosphatemia are largely as a
result of its effect of decreasing plasma ionized (Ca2+). Thus, the
symptoms of hyperphosphatemia are those of hypocalcemia
(see Hypocalcemia). In addition, hyperphosphatemia may contribute to the genesis of ARF in rhabdomyolysis, tumor lysis
syndrome, and hemolysis. Hyperphosphatemia may lead to
calcium-phosphorus precipitation and deposition in brain, lungs,
kidneys, pancreas, corneas, and blood vessels.
ANESTHETIC IMPLICATIONS OF HYPERPHOSPHATEMIA:
The
anesthetic implications of hyperphosphatemia relate primarily to
the associated hypocalcemia (see Hypocalcemia).
TREATMENT OF HYPERPHOSPHATEMIA:
The treatment of
hyperphosphatemia is through the decrease of dietary intake of
phosphorus and the use of phosphate-binding antacids such as
aluminum hydroxide or carbonate. In severe cases, hemodialysis
may be necessary.
Disorders of Magnesium Homeostasis

MAGNESIUM METABOLISM AND REGULATION: Magnesium is an
important intracellular cation that functions as a cofactor in many
enzyme pathways. Approximately 1 to 2% is in the ECF, 67% is in
bone, and 31% is intracellular. Dietary absorption occurs primarily
in the distal small bowel, and renal excretion is the primary route
of elimination. Re-absorption of 95% of the filtered load occurs
primarily in the LOH and less so in the proximal and distal
tubules. Re-absorption occurs by a paracellular route down
an electrochemical gradient. Factors known to increase renal
magnesium re-absorption include hypomagnesemia, PTH,
hypocalcemia, ECF depletion, and metabolic alkalosis. Factors
known to decrease renal magnesium re-absorption include
hypermagnesemia, acute volume expansion, hyperaldosteronism,
hypercalcemia, ketoacidosis, diuretics, phosphate depletion, and
alcohol consumption. Plasma magnesium levels are closely
maintained between 1.5 and 2.1 mEq/L (0.71.0 mmol/L or 1.7
2.4 mg/dL). The exact mechanisms are unclear but involve the
interaction of the GI tract absorption, bone storage, and renal
excretion.
HYPOMAGNESEMIA: Hypomagnesemia is a common and often

overlooked problem, especially in the critically ill. It is frequently
associated with other electrolyte abnormalities such as hypocalcemia or hypokalemia. Hypomagnesemia is generally the result
of either inadequate intake or absorption or increased renal
excretion. Inadequate intake may result from prolonged fasting or
inadequate supplementation during enteral or parenteral feeding.
Inadequate absorption may result from several different types of
pathology in the GI tract including malabsorption syndromes,
small bowel or biliary fistulas, prolonged nasogastric suctioning,
severe diarrhea, and short gut syndrome. Increased losses may
occur through the kidney because of increased sodium load,
hyperglycemia, the use of diuretics (loop or osmotic), hypercalciuria, hyperparathyroidism, hyperaldosteronism, damage
to the renal tubules related to various medications (cisplatin,
aminoglycoside antibiotics, amphotericin B, and alcohol), or
during the postobstructive phase of ATN or GI obstruction.
CLINICAL MANIFESTATIONS OF HYPOMAGNESEMIA: Many patients
with hypomagnesemia are asymptomatic, but cardiovascular,
neurologic, and neuromuscular manifestations may be seen.
Cardiovascular effects include electrical irritability and potentiation of digitalis toxicity, both of which are exaggerated by
concomitant hypokalemia. ECG changes include prolongation of
the PR- and QT-intervals, often reflecting concomitant hypocalcemia. Anorexia, weakness, fasciculations, paraesthesia, confusion,
ataxia, and seizures may also be seen.
ANESTHETIC IMPLICATIONS OF HYPOMAGNESEMIA:
Isolated
hypomagnesemia should be corrected before elective procedures
because of its potential to cause arrhythmias. In addition, coexistent electrolyte disorders involving calcium, potassium, and
phosphorus should be sought and corrected as appropriate.
TREATMENT OF HYPOMAGNESEMIA: Asymptomatic hypomagnesemia should be treated with oral supplementation or intramuscular magnesium. Serious manifestations such as seizures should
be treated with intravenous magnesium sulfate. The intravenous
dose is 25 to 50 mg/kg every 4 to 6 hours.52 Intravenous magnesium should be administered over 20 or 30 minutes and repeated
plasma magnesium levels checked to avoid overtreatment and the
adverse effects of hypermagnesemia (see Hypermagnesemia).
HYPERMAGNESEMIA: Increases in plasma magnesium are almost

always due to excessive intake, renal impairment, or a combination
of the two (e.g., the use of magnesium-containing antacids or
laxatives in the setting of renal failure). Iatrogenic hypermagnesemia may also occur in the newborn fetus of a mother treated
with magnesium for preeclampsia. Less common causes include
adrenal insufficiency, hypothyroidism, rhabdomyolysis, and
lithium administration.
CLINICAL MANIFESTATIONS OF HYPERMAGNESEMIA:
Features
of hypermagnesemia include neurologic, neuromuscular, and
cardiac effects. Signs of hypermagnesemia appear at plasma levels
of 4 mmol/L or greater. Initial signs are ECG changes with prolongation of the PR-interval and QRS-complex widening.
Hyporeflexia, weakness, and sedation are characteristic. Magnesium impairs the release of acetylcholine and decreases endplate
sensitivity to acetylcholine at the neuromuscular junction. At
levels of 10 mmol/L or greater, vasodilation, bradycardia, heart
block, and myocardial depression can lead to hypotension.
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ANESTHETIC IMPLICATIONS OF HYPERMAGNESEMIA: Hypermagnesemia necessitates close monitoring of the electrocardiogram, blood pressure, and neuromuscular function. Potentiation
of the vasodilating and negative inotropic effects of anesthetic
agents is to be expected. The effect of nondepolarizing neuromuscular blocking agents may be enhanced.
TREATMENT OF HYPERMAGNESEMIA:
The effects of hypermagnesemia mentioned earlier in the section on Clinical Manifestations

of Hypermagnesemia can largely all be reversed transiently, but
rapidly, by the administration of intravenous calcium. Further therapy includes cessation of exogenous administration and potentiation of renal excretion. A loop diuretic along with infusion of normal
saline enhances urinary magnesium excretion. Use of a normal
saline diuresis may also result in hypocalcemia, which will further
accentuate the effects of hypermagnesemia. If there is renal impairment and hypermagnesemia, emergency dialysis may be required.
CONCLUSION
Although no review of this length could claim to be exhaustive,
the information presented here should provide an overview of the
common and important perioperative disturbances of fluid and
electrolyte homeostasis likely to be encountered by the pediatric
anesthesiologist. Fluid, electrolytes, and acid-base disturbances
are extremely common in the perioperative period. Such disturbances are of particular concern to the pediatric anesthesiologist because the corrective mechanisms in children are more
easily overwhelmed than in adults. Given the role that the kidneys
play in these homeostatic processes, a fundamental knowledge of
renal physiology is mandatory for the provision of anesthesia in
infants and children.
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55. Cockburn F, Belton NR, Purvis RJ, et al. Maternal vitamin D intake
and mineral metabolism in mothers and their newborn infants.
Br Med J. 1980;281:1114.
56. Broner CW, Stidham GL, Westenkirchner DF, et al. A prospective,
randomized, double-blind comparison of calcium chloride and
calcium gluconate therapies for hypocalcemia in critically ill children.
J Pediatr. 1990;117:986989.
57. White RD, Goldsmith RS, Rodriguez R, et al. Plasma ionic calcium
levels following injection of chloride, gluconate, and gluceptate salts
of calcium. J Thorac Cardiovasc Surg. 1976;71:609613.
58. 2005 American Heart Association (AHA) guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiovascular care
(ECC) of pediatric and neonatal patients: pediatric advanced life
support. Pediatrics. 2006;117:e1005e1028.
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Digestive System, Metabolic

Functions, and Nutrition
Bndicte Ringuier, Jean-Louis Ginis, and Jean-Claude Granry
INTRODUCTION
Throughout the course of the intrauterine life, a parallelism exists
between the development of intestinal structures and digestive
functions. The presence of the sucrase-isomaltase complex is
contemporary to the formation of the brush border. However, a
number of functions, in particular pancreatic enzymes, the
secretion of gastric acid, and the synthesis of bile acids are not
mature at birth. This is likely to affect the capacity of the digestion
and the absorption of nutrients in the newborn and, particularly,
the premature infant. This chapter discusses the development of
the intrauterine digestive, gastric, intestinal, pancreatic, and biliary
functions and their consequences on the intestinal digestive
capacities and the absorption of the nutrients.
The metabolic status of the patient helps to determine the proper nutritional support. It must be adapted to improve physiologic
stability, which can improve the outcome of hospitalized children.1,2 This challenge is significant because a quarter of the
children admitted to the intensive care unit are malnourished.
This malnutrition has a tendency to worsen the course of hospitalization.3 In this context, malnutrition is associated with an
increased risk of infection, a prolongation of the duration of
assisted ventilation, and a delay of healing.2,4,5 It has been demonstrated that a Pediatric Risk of Mortality (PRISM) score greater
than 10, a C-reactive protein (CRP) greater than 50 mg/L, and
fluid restriction are independent factors responsible for the delay
in providing proper caloric support.6 Overnutrition is also
deleterious, leading to a risk of hepatic steatosis (fatty liver) and a
prolongation of the need for assisted ventilation and hospitalization.4,5 Because of the consequences of these nutritional issues,
The American Society of Parenteral and Enteral Nutrition has
made the following recommendations among children hospitalized in the intensive care unit7 :
1. Assess the nutritional status.
2. Evaluate the energy expenditure (EE) by indirect calorimetry
or the use of standardized equations to avoid overnutrition.
3. Encourage the use of enteral nutrition (EN) rather than
parenteral nutrition (PN).
GAASTROINTESTINAL TRACT
SECRETORY FUNCTION
Acid Production
The parietal gastric cells, which produce hydrochloric acid and the
intrinsic factor, are individualized as early as the 11th week of
gestation. The principal cells, which produce pepsin and gastric
11
C H A P T E R
lipase as well as gastrin, are present as early as the 14th week of

gestation.13 The production of gastric acid is in the order of
1 mL/kg/h for the newborn at term as well as the premature infant,
aged 32 weeks. Acid secretion exists in the premature infant
evidenced by the finding of a pH less than 4 from the first day of
life.48 When expressed as mEq/kg/h, acid secretion is minimal in
the premature infant (32 wk old), on the order of 0.01 mEq/kg/h.
For the newborn at term, acid secretion on the first day of life is
approximately 0.02 mEq/kg/h. The maximum H+ ion secretion,
especially in response to a stimulation triggered by histamine or
pentagastrin, is not different from the basal secretion until 2 to 3
months of age. At that time, it is half of the value of the adult (0.2
0.4 mEq/kg/h). Adult values for acid secretion are achieved at 1 year
of life.4,9 This very weak response of parietal cells to stimulation is
even more paradoxical because the plasma levels of gastrin are very
high at birth, even higher in premature infants than in newborns at
term. This neonatal hypergastrinemia demonstrates a lesser
sensitivity of the parietal cells to gastrin in the neonatal period.4,9
Intrinsic Factor Secretion

The maturation of the secretion of the intrinsic factor comes from
the same cells producing the hydrochloric acid and is carried out
much more quickly. It is present in the newborn at term and can
be measured even in the premature infants at birth. By the age of
3 months, it is already equal to half of what is normally observed
in the adult. Therefore, the newborn is able to absorb a dose of
vitamin B12 immediately after birth and as effectively as the adult.6,9
Pepsin and Lipase Secretion

Already measurable at the 15th week of gestation, the secretion of
pepsin increases starting at the 28th week of gestation.7 Nevertheless, it remains very low at birth until 3 months of age. By
18 months of age, it achieves values comparable with those of the
adult.10,11 In addition, because of the lack of acid secretion, the
gastric pH exceeds the optimum pH of pepsin, which results,
particularly among premature infants, in a lack of gastric digestion
of proteins during the first weeks of life. That could promote the
transfer in the neonatal period of intact proteins into the
circulation. This consideration is also important for consideration
of the fasting guidelines in this age group.
Similar maturation of lipase production and secretion occur
during in the fetus and neonate. Present from the 11th week of
gestation, lipase secretion at birth is half that of the adult. Levels
observed in the adult population are achieved by 3 months of
age.7,10,12
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Digestive System, Metabolic Functions, and Nutrition 171
INTESTINAL MORPHOGENESIS
AND MATURATION OF THE
BRUSH BORDER
Intestinal Morphogenesis
The anatomic structures and functions of the intestine develop
early during gestation and, for all practical purposes, are completed by the sixth month of gestation. The intestine lengthens a
thousand times from the fifth week of gestation until birth. This
grow is linear until the second week of gestation and then
progresses more quickly with intestinal length doubling during
the last weeks of gestation. The small intestine measures approximately 100 cm after the 20th week, 170 cm by the 31st week, and
200 to 250 cm in the term newborn. During the same period, the
length of the colon increases from 25 to 50 cm.13 The volume
involved in the rapid development of the intestinal structure
combined with that of the liver results in the primitive intestinal
herniating into the umbilical cord as early as the sixth week of
gestation. The primitive gastrointestinal (GI) tract is, therefore,
transiently in a sac communicating freely with the abdominal
cavity before it returns to the abdominal cavity by the 10th week.
The differentiation of the GI tract begins during that period. It
proceeds from the proximal end to the caudal end. The villi appear
at the level of the duodenum during the eighth week, the jejunum
by the 10th week, and the distal ileum at the 14th week of gestation. The epithelium is multistratified until the eighth week, at
which time it becomes monostratified, allowing the development
of the villi. At 12 weeks of gestation, the mucosa of the GI tract is
no longer constituted by a single layer of cells, but gradually
develops into mature cylindrical cells with microvillus membrane
of normal length (Figure 111).14
Hydrolytic Enzymes
Hydrolytic enzymes include three different protein complexes:
1. The sucrase-isomaltase complex.
2. The lactase-maltase complex.
3. The peptidase and enterokinase complex.
Figure 11-2. Development of the sucrase activity during fetal life and
the neonatal period in human. Modified from reference 52.
organization of the brush border (from the seventh to the eighth

week at the level of the proximal intestine). It increases until the
14th week of gestation, at which time it is similar in function to
that of the adult system15,16 (Figure 112).
The emergence of the neutral -galactosidase (lactase) system,
responsible for the digestion of both lactose and the thermoresistant maltases, occurs much later.15,17 It appears after the sucraseisomaltase complex is developed and occurs toward the ninth
week of gestation (Figure 113). However, its activity remains very
low until the 12th week, after which time it increases significantly
to reach adult values after the 35th week of gestation.16,17 The
peptidases involved in the terminal peptides digestion appear at
the same time as the individualization of the brush border.18
The emergence of the sucrase-isomaltase complex, which

covers the totality of the saccharase-dextrokinase activity and
three quarters of the maltase activity, is contemporary to the
Figure 11-1. Jejunal enterocyte maturation sequence during human

fetal life.
Figure 11-3. Development of the lactase activity during the fetal life
and the neonatal period in human. Modified from reference 52.
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Transfer Systems
The development of transmembrane transport systems also occurs
very early in the development of the intestinal structures. Glucose
uptake, measured by a technique of inversed concentration bags
and increased transmural potentials, can be identified at the level
of the jejunum as early as the 19th week.19 These findings imply
that the carrier of glucose facilitating its cellular entry coupled
with sodium in the intestinal cell is well developed. The active
transportation system of sodium (the Na-K-ATPasedependent),
which allows the accumulation of glucose against a transmural
difference in concentration, is already functional at this stage. At
the level of the ileum, we must wait until the 15th week of gestation
for glucose to demonstrate an increase in transmural potentials
difference. At this stage, glucose uptake is four to five times higher
in the jejunum than it is by the age of 11 or 12 weeks. At 21 weeks
of gestation, the values are substantially equal to the level
measured in the jejunum and the ileum, but they still are three
fifths and at birth two thirds of those observed in the adult.20
Pancreatic Functions
The development of the anatomic structures of the pancreas
occurs later than those of the intestine. The first acinar cells appear
during the 12th week of intrauterine life, and the first pancreatic
lobules begin to form in the course of the 14th week of gestation.21
The lobular and lobar architecture of the pancreas, the acini, and
the channels of the gland are well individualized in the embryo by
the age of 16 weeks. However, the pancreatic functions are not
mature at birth. The activity of the -amylase is usually absent
until birth. It remains extremely low during the first weeks of life.
Its concentration is, at the age of 6 months, three to four times
lower than that of older children and does not reach adult values
until 2 to 3 years of age.22,23 It is the only enzyme whose concentration in pancreatic secretions increases significantly in the years
following birth.24
Trypsin appears earlier than amylase. At 7 months of gestation,
its concentration is half of what it will be at birth.22,23 However,
trypsin concentration is still low at birth. Even after stimulation,
it is only 10% of that which occurs in children older than 1 year.
The values are even lower in premature infants, particularly in the
days immediately following birth. The trypsin activity reaches,
within the first month of life, approximately those values observed
in a 2- to 6-year-old child24,25 and its ability to digest casein is not
very different in infants than in adults (1.6 g/kg/h). Finally, a lipase
activity begins after the fifth month of gestation. At birth, it is only
25% of the values observed among children older than 1 year.22,23
Its activity is even lower among premature infants, but it grows
rapidly.
Bile Salt Synthesis and Function

Bile is present in the fetal gallbladder as early as the 22nd week of
intrauterine life, but the total bile salts concentration in the
vesicular bile is still three times lower among infants younger than
1 year than that observed among children older than 1 year.26 In
the term newborn, a biliary secretion inadequacy is present during
the initial 2 to 3 weeks of life.27 This deficiency is linked to low
synthesis, which is two times less in the newborn at term and six
times lower in the premature infant when compared with the
levels observed in the adult.
NEWBORN AND PREMATURE

INFANT DIGESTION AND
INTESTINAL ABSORPTION
The capacity of digestion and intestinal absorption of food and
nutrients in the newborn at term are associated with the development of the intestinal structures, the production of the digestive
enzymes, and the functionality of the transfer systems. It is also
dependent on the nature of carbohydrates, proteins, and fats
presented to the infant.
Digestion and Absorption of Carbohydrates

The newborn and the premature infant are sufficiently mature at
birth to digest and absorb carbohydrates. This requires hydrolysis
at the level of the microvillus membrane (trace and disaccharides)
or direct transfer into the circulation (monosaccharides). Lactose
provided by the mothers milk is responsible for 40% of the energy
and is one of the main nutrients that the intestine of the newborn
must digest and absorb immediately after birth. The activity of
lactase is the limiting factor in the absorption of lactose. It reaches
its maximum values near term. The digestive tolerance of lactose
has often been questioned in the neonatal period and in the
premature infant. It may indeed be insufficient in the premature
infant during the first week of life, leading to malabsorption and
fermentation by the colon.28 Nevertheless, the ability to digest
lactose appears to be satisfactory within a few days after birth in
the most newborn and premature infants.17,29,30
In spite of the very low activity of pancreatic amylase, the infant
is perfectly capable of digesting a quantity of starch as high as 100
g/m2 as early as 1 month of age.31 The significant activity of pancreatic amylase at birth, which is comparable with that of adults, is
more than 10 times higher than what is required to hydrolyze the
quantity of starch that is normally ingested. The intestinal glucoamylase complex contributes in part to these digestive capabilities in
term and premature infants.32,33 However, the -amylase present in
the mothers milk and the salivary glands -amylase also play an
essential role in the digestion of these nutrients. The concentration
of -amylase found in the mothers milk is identical to the amylase activity present in the salivary glands. Its activity is maximum in the colostrum and tends to decrease during lactation.34,35
Digestion and Absorption of Proteins

The secretion of the proteolytic enzymes by the pancreas, although
incompletely developed until 2 to 3 years of age, is generally
sufficient from birth. No significant difference in the digestion of
proteins between premature and term infants or between young
infants and older children has been identified.36,37 A 5-month-old
infant can digest in 1 hour the quantity of protein contained in
250 mL of cows milk.38 It is clear that the capacity of digestion and
absorption of protein is functionally sufficient in the newborn.
However, the amount of proteins that can be given to a neonate is
limited because of the immaturity of renal function and not
because of the digestive apparatus.
Digestion and Absorption of Fats

(Breast Milk vs Cows Milk)
Digestion and absorption of triglycerides, which constitutes 98%
of fat ingested by the infant, depend on many factors including
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1. Total lipase activity, primarily pancreatic, but also that of gastric origin whose activity is present at birth.
2. The intraluminal concentration of bile salts, which are indispensable to the micelle solubilization of products of lipolysis,
3. The structure of triglycerides present in the milk ingested.
For the newborn at term, the absorption coefficient of fats is
90 to 95% during the first weeks of life and at least 96% at 11/2
months of age. The absorption of the fat present in the mothers
milk if it is pasteurized or lyophilized is less optimal. It has been
measured at 80% during the first days of life, increasing to 93%
between 1 and 2 months of age. It is more than 95% only after
2 months of age.37,39 This better absorption of the fat present in
fresh breast milk emphasizes the physiologic importance of the
gastric lipase. This lipase is produced in a stable quantity all
through the lactation period. This lipase resists gastric acidity and
pancreatic proteolysis because of the bile salts. Its function is
complementary to the pancreatic lipase at an age at which the
activity of the latter is still low. Its role during the newborn period
is, therefore, important. It is responsible for a significant part, up
to 50%, of the hydrolysis of the triglycerides in the milk.40 Its
importance in the neonatal period is illustrated by the fact that the
absorption coefficient of fats in premature infants fed by stomach
tube decreases when intragastric lipolysis is bypassed by the use of
a nasojujenal tube.41 By contrast, its role appears negligible in the
infant after a few months of life.42
The malabsorption of the fat included in cows milk is much
greater than the 1% of breast milk because the newborn at term
has an absorption coefficient of cows milk fats estimated at 60%
during the first week of life, 80% at 15 days, and 85% between
2 and 3 months of age.43 In the premature infant, malabsorption of
fats is even more significant (Figure 114).41 It affects approxi-
mately half of lipids without significant variation after the seventh

and ninth months of gestation. When compared with the fat
present in breast milk, the malabsorption of cows milk fat is the
consequence of the inadequacy of biliary secretion during the
neonatal period. Among newborns prematurely fed on cows milk
or industrial formula, there is a close correlation between the
degree of the fat malabsorption and the intraluminal bile salts
concentration. This correlation is not found when the child is fed
breast milk.43,44 The chemical structure of the triglycerides present
in the mothers milk (i.e., less stearic acid on the external position
and palmitic acid, especially in the internal position on the
glycerol molecule) is indeed much more favorable to the micelle
solubilization than that of the triglycerides in the cows milk,
which contains a higher concentration of stearic and palmitic
acids, especially in the external position on the glycerol molecule.
In addition, the high concentration of calcium in the cows milk,
approximately three times higher than that of breast milk, leads
to the development of insoluble and nonabsorbable calcium stearate, which is the result of a reaction between the calcium and the
stearic acid released by pancreatic lipase. Because this malabsorption results in a loss of 15 to 20% of energy produced by the
calories consumed, formulations containing medium-chain triglycerides, whose absorption is independent of bile salts, have been
developed for the feeding of premature infants.45
METABOLIC FUNCTIONS,
ENERGETICS, AND
NUTRITIONAL STATUS
Assessment of the Nutritional Status
Nutritional assessment is based on the acquisition of data evaluating the anthropometric and biologic conditions. The developmental information is summarized in Table 111. The analysis of
the growth is based on static and dynamic parameters.
Static Parameters
Static parameters include weight, size, and head circumference,
which are collected and compared with average values provided by
tables or growth curves used as reference. These tables and charts
can express the variations using the Z-score (i.e., deviation from
the median). The ratios of weight-to-age (weighttoideal weight
TABLE 11-1. Information About Nutritional Evaluation
Personal and Family History
Associated pathologies
Previous therapies
Family, psychological, and social context
Weight and size of the parents
Food Custom Investigation
Quantity of food rations
Quality of the alimentation:
Figure 11-4. Distribution of fat absorption coefficients in 18 premature

infants fed with milk obtained from a woman or from a cow. Modified
from reference 82.
Deficit or excess of nutrients

Eccentric or monotonous regime
Quality of the appetite

Presence of vomiting or diarrhea
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TABLE 11-2. Classification of Malnutritiona

Normal Minor
Moderate
Severe
Report Malnutrition Malnutrition Malnutrition
Size/
age, %
Weight/
age, %
95
9095
8590
85
90
8090
7080
70
a
The decrease in the ratio size-to-age suggests a chronic malnutrition (stunting)
whereas the ratio weight-to-age defines an acute malnutrition (wasting).
From reference 46.
for age) and size-to-age (sizetoideal size for age) suggest the
acute (wasting) or chronic (stunting) nature of malnutrition and
assess its severity according to the criteria defined by Waterlow46
(Table 112).
The ratio of weight-to-size (weighttoideal weight for the size)
serves as a diagnostic criterion of malnutrition when it is less than
90% (undernutrition is severe if the ratio < 80%). Two indices are
used:
1. The body mass index (weight/size2) or BMI.
2. The ratio of waist size/size (waist-to-height ratio).47
The curve of references of the BMI for children of 5 to 19 years
of age revised in 2006 by the World Health Organization (WHO)
and a recent editorial by Greer are recommended for additional
reading.48,49 These curves help to define: overweight above +1
standard deviation (sd), obesity above +2 sd, paucity (thinness)
below 2 sd, and severe paucity (severe thinness) below 3 sd.
Dynamic Parameters
The curves developed to assess the speed of growth were established in 1991.50 They enable the practitioner to date the
beginning of nutritional impact of a pathologic condition and to
verify the effectiveness of nutritional intervention.
TABLE 11-3. Calculation of the Total Fat Mass and the Lean
Body Mass Obtained from the Measurement of Skin Folds
1. Determine the weight (kg) and the age (y) of the patient.
2. Obtain the thickness (ply of cutaneous tissue in millimeters)
from four areas; bicipital, tricipital, subscapular, and suprailiac.
3. Calculate the sum of all plies obtained from the four areas
(millimeters).
4. Apply the following equations according to the age and sex
and calculate the body density (D):
Brooks equation (111 y)15:
D (boys) = 1.1690 0.0788 log sum of the 4 plies (mm)
D (girls) = 1.2063 0.0999 log sum of the 4 plies (mm)
Durnin and Rahamans equation (1216 y)16:
D (boys) = 1.1533 0.0643 log sum of the 4 plies (mm)
D (girls) = 1.1369 0.0598 log sum of the 4 plies (mm)
1. Calculate the fat mass = body weight (kg) 4.95/D 4.5
2. Calculate the lean body mass = body weight (kg) fat mass (kg)
From references 51 and 52.
is less than 3.2 mg/dL. The utility of its assay is limited by the
prolonged half-life (20 d), which explains why it cannot be used in
the early screening of malnutrition. Furthermore, it has a lack of
specificity for nutritional status because decreases of albumin
plasma concentration may be seen in other pathologic states such
as hepatocellular failure, excessive digestive losses, or hemodilution. In addition, it has been demonstrated that, for 50% of
TABLE 11-4. Nutritional Protein: Normal Plasma Level
and Variation Factors
Protein
Normal
Plasma Level
Albumin
3645 g/L
Anthropometry
Anthropometry corresponds to the study of the body compartments. It provides information on the state of energy reserves or
fat mass and the lean body mass. The fat mass can be evaluated
using the measurement of skin folds, whereas the lean body mass
is calculated from the fat mass (Table 113).51,52 In children with
edema or ascites, the study of the fat mass and of the lean body
mass allows one to quantify the malnutrition status, even though
the weight is falsely increased, thereby negating the value of the
classic ratios. During renutrition, the use of anthropometry measurements help to provide information on the changes to the compartments. It has been demonstrated that malnourished children
reconstituted preferentially their lean body mass by proliferation
of their active cell mass.53
Thyroxin0.320.35 g/L
binding
prealbumin
Retinolbinding
protein
4476 mg/L
Transferrin
24 g/L
Biologic Evaluation of the Nutritional Status

The concentrations of certain plasma proteins reflect the synthetic
functions of the body and are regarded as markers of the nutritional status.54 None of these proteins is a specific marker of
malnutrition, and their sensitivities vary according to their halflives (Table 114). Serum albumin is a classic marker of protein
status and, therefore, malnutrition. The pathologic threshold value
Variation Factors
Malnutrition
Insuffisance hepato cellulaire:
hepatocellular insufficiency
Pertes digestives, urinaires ou
cutanes: Digestives, urinary
and cutaneous losses
Hepatic disorders
Infections prolonges:
Prolonged infections
Malnutrition
Hepatic disorders
Hyperthyroidism
Inflammation
Malnutrition
Inflammation
Vitamin A deficiency, zinc
deficiency
Hepatic disorders
Glomerular nephropathy
Glomerular nephropathy
Enteropathy
Hepatic disorders
Inflammation
Iron deficiency
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children with hypoalbuminemia at admission, there was no correlation between this anomaly and the clinical outcome (e.g.,
duration of assisted ventilation and hospitalization).55
The interest of the assay of thyroxin-binding prealbumin is
based on its short half-life (2 ds), which makes it an interesting
early and sensitive marker of malnutrition. It shows a rapid and
measurable increase within 5 days following renutrition. It is an
effective marker that can be used as a parameter to monitor the
therapy. However, two potential limits to its specificity should be
noted. An increase in the serum concentration can be observed
in the case of chronic renal failure or hyperthyroidism and a
decrease occurs in the presence of a zinc or retinol deficiency.
Transferrin, with an intermediate half-life (8 d), is a very
sensitive marker of malnutrition, but its specificity is poor. Variations in plasma concentration may occur related to liver function,
the presence of an inflammatory syndrome, or anemia. Retinolbinding protein (RBP) has a short half-life (12 h), but also lacks
specificity. Insulin-like growth factor-1 (IGF-1) has a plasma concentration that varies according to the age and the pubertal stage
of the patient, but its rapid normalization occurs after a few days
of renutrition, which makes it an efficient marker of nutrition.
Table 114 outlines the plasma concentrations of the proteins
used as markers of nutritional status and their modifications in
the event of an inflammatory syndrome. Some authors have
proposed different scores that integrate the values of nutritional
protein weighted by the values of proteins during inflammation.
The prognostic inflammatory and nutritional index (PINI) was
established in 1985.56 The PINI is a simple scoring system of the
overall health that integrates blood markers of inflammation and
nutritional status (albumin and transthyretin). The formula is
PINI = orosomucoid (mg/L) CRP (mg/L)/
albumin (g/L) complement (mg/L)
It is a reliable indicator of nutritional status and a prognostic
indicator in the case of trauma, burns. or infectious syndromes
(i.e., with high risk of comorbidity if the PINI > 21). It has been
modified in pediatric resuscitation to57
PINI modified = fibrinogen (mg/dL) CRP (mg/dL)/
transferrin (mg/dL) prealbumin(mg/dl).
It has been reported that, in 71 intubated and ventilated
children, the PINI correlated best with the amount of protein
provided. The score decreased after 5 days of EN.
ESTIMATION OF ENERGY
METABOLISM AND
NUTRITIONAL NEEDS
In the accurate assessment of the energy metabolism of the child,
it is important to adapt the energy inputs to expenditures, to avoid
under- or overnutrition, and to allow normal growth. The total
EE is the sum of EE related to basal metabolism (basal metabolic
rate), to the metabolism of growth, to the physical activity, and to
the diet-induced thermogenesis. The EE can be measured by
direct or indirect calorimetry or estimated by means of equations
predictive of the nutritional status and established by population
norms. The pediatric resuscitation guidelines advocate the estimation of the daily energy needs by using the weight of the patient
or by referring to weighted predictive equations or measures of
EEs.58 In Europe, 83% of pediatric resuscitation teams estimate the
EE using the weight, 92% use the age, and 30% use the predictive
equations, whereas only 17% use indirect calorimetry.58
Estimation of EE by the Use

of Predictive Equations
The three predictive equations used most commonly are outlined
in Table 115.5862 The equations of Harris and Benedict published
in 1919 were established from basal metabolic measurements
obtained among 239 subjects, ranging in age from 15 to 73 years.60
For healthy children, two other equations have been developed
TABLE 11-5. Equations for Calculating Resting Energy
Expenditure and Basal Metabolic Rate
A. Infants (03 Y)
WHO
Schofield (W)
Schofield
(W and H)
Male
Female
Male
Female
Male
Female
HarrisBenedict
Male
Female
REE = 60.9 W 54
REE = 61 W 51
BMR = 59.48 W 30.33
BMR = 58.29 W 31.05
BMR = 0.167 W + 1517.4 H
617.6
BMR = 16.25 W + 1023.2 H
413.5
REE = 66.47 + 13.75 W + 5 H
6.76 A
REE = 655.10 + 9.56 W + 1.85 H
4.68 A
B. Children (310 Y)
WHO
Schofield (W)
Schofield (W
and H)
HarrisBenedict
Male
Female
Male
Female
Male
Female
Male
Female
REE = 22.7 W + 495

REE = 22.4 W + 499
BMR = 22.7 W + 505
BMR = 20.3 W + 486
BMR = 19.6 W + 130.3 H + 414.9
BMR = 16.97 W + 161.8 H +371.2
REE = 66.47 + 13.75 W + 5 H
6.76 A
REE = 655.10 + 9.56 W + 1.85 H
4.68 A
C. Teenagers (1018 Y)
WHO
Schofield (W)
Schofield (W
and H)
HarrisBenedict
Male
Female
Male
Female
Male
Female
Male
Female
REE = 12.2 W + 746

REE = 17.5 W + 651
BMR = 13.4 W + 693
BMR = 17.7 W + 659
BMR = 16.25 W + 137.2 H + 515.5
BMR = 8.365 W + 465 H + 200
REE = 66.47 + 13.75 W + 5 H
6.76 A
REE = 655.10 + 9.56 W + 1.85 H
4.68 A
D. Whites Equation for Critically Ill Children

EE = (17 (A, mo) + 48 (W) + 292
(body temperature, C) 9677) 0.239
A = age, y; BMR = basal metabolic rate, kcal/day; EE = energy expenditure;
H = height, m; REE = resting energy expenditure; W = weight, kg; WHO =
World Health Organization.
Data from references 5963.
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since 1985. The accuracy of these equations for patients undergoing critical care resuscitation are controversial, with conflicting
data in regards to under- or overevaluation of the EE.6366 Three
studies have suggested that the estimation of the EEs provided by
the equation of Schofield were not significantly different from
direct measurements.6568
In order to limit the inaccuracies that are present in critically ill
children, White and coworkers have proposed an equation
predictive of the EE at rest for children ventilated in the critical
care unit (see Table 115).63 This equation includes the temperature of the body based on the observation made by Joosten and
colleagues, who reported that any variation of a mere 1C increased the EE by an average of 6%.69 Unfortunately, the accuracy
of the equation developed by White and coworker has not been
validated.68 In order to take into account the hypermetabolic
response to stress, it is classically recommended to multiply the
estimated values obtained in healthy children by various factors:
1.1 in postoperative patients, 1.4 in patients with congenital heart
disease or severe sepsis, and 2.1 in case of burns or severe
trauma.62,70,71 A recent study demonstrated that the hypermetabolic response (defined as > 110% of the estimated value) in
resuscitation occurs in only 15 to 35% of children and that 22 to
42% of children are hypometabolic (EE measured at < 90% of the
calculated EE).68 Faced with all these inaccuracies, Skillman and
Wischmeyer have proposed in 2008 to estimate the EE by
averaging the results of two different equations.66
Measurement of EE by Calorimetry
The oxidation of nutrients allows the production of energy, and
the energy produced corresponds to the EE. There is a link
between heat released, oxygen consumption (VO2), and carbon
dioxide produced (VCO2). Equation 1 shows that the oxidation of
a molecule of glucose produces 673 kcal:
Equation 1: C6H12O6 + 6 O2 6 CO2 + 6 H2O 673 kcal
The lower respiratory quotient of this reaction is equal to 1
because VO2 is equal to VCO2. In application of this equation, the
energy released by the oxidation of a known quantity of glucose
can be obtained by
1. Direct calorimetry: estimated directly if the amount of heat
produced is measured.
2. Indirect calorimetry: estimated by the measurement of VO2
and VCO2.
Similar equations are available for other nutrients: palmitate
(Equation 2) and amino acid (Equation 3):
Equation 2: C16H32O2 + 23 O2 16 CO2 + 16 H2O 239
kcal RQ = 0.7
Equation 3: 1 AA + 5.1 O2 4.1 CO2 + 0.7 urea + 2.8 H2O 475
kcal RQ = 0.8
where AA is amino acid and RQ is
Direct calorimetry consists of placing a subject in an insulated
and thermally isolated room and measuring the heat generated. It
is a very accurate, but complex, method to implement. Use of this
technique is generally limited to research or validation of the other
methods. Indirect calorimetry is feasible at the bedside, even in
children hospitalized in the critical care unit.6373 In ventilated
children, the total daily measurement of the EE can be assessed
precisely by one or two measures of EE using indirect calorimetry

as long as the leak around the endotracheal tube is less than 10%
of the expired volume and that the fractional concentration of
oxygen in inspired gas (FIO2) is less than 0.6.66,69,70 The respiratory
quotient can also be used as a marker of adequate feeding. A
respiratory quotient greater than 0.85 eliminates the possibility of
undernutrition (specificity, 89%; negative predictive value, 90%),
whereas a respiratory quotient greater than 1 indicates overnutrition (specificity, 97%; positive predictive value, 93%).72
NUTRITION OF THE CHILD

IN CRITICAL CARE
Nutritional support should be considered for all patients who may
not resume normal enteral feeding (full oral diet) within 3 days.62,66,73
Enteral Nutrition
The superiority of the enteral approach in comparison to the
parenteral access has been well demonstrated in the adult population. However, the pediatric literature lacks formal proof for this
commonly accepted practice. It is generally accepted that the
enteral approach is preferred among all children, with the
exception of those whose digestive tract must remain unusable for
a prolonged period of time.66,74 The early use of EN promotes the
preservation of the mechanical and immunologic functions of
the digestive system, which stimulates the trophic activity of the
intestine and reduces the risk of bacterial translocation, thereby
reducing the incidence of sepsis and multivisceral failures.75,76
In adults, the early use of enteral nutrition (in the first 2448 h)
is recommended by the European Conference Consensus as grade
C evidence.73 The most recent recommendations also suggest the
same approach for children.66,77 In pediatric resuscitation, the
advantages of EN begin within the first 12 hours and include
1. An immediate improvement in the nutritional status, which
can be assessed by the concentrations of complement and
transferrin.57
2. Rapid calorie intake in conformation to the estimated EE,
which has been demonstrated to improve intensive care unit
outcome.57
3. A significant reduction in the number of digestive complications, such as abdominal distention, diarrhea, necrotizing
enterocolitis, and hemorrhage.78,79
Although EN may be administered by a nasogastric tube, in
critically ill children, alterations in GI motility including gastroparesis may lead to intolerance of nasogastric nutrition. The
recovery of satisfactory peristalsis occurs earlier in the duodenum
and jejunum than in the stomach. Also, the protective role of the
pylorus favors the use of postpyloric EN because it may be safer
and lower the risk of regurgitation and pneumonitis. However,
these potential risks remain controversial in the literature.66,74,80,81
The placement of a feeding tube throughout the pylorus may be
difficult, especially in critically ill infants and children. Several
techniques have been described to facilitate this procedure. The
intragastric insufflation of air (10 mL/kg) or the administration
of an intravenous prokinetic agent such as erythromycin (3 mg/kg)
or metoclopramide (0.15 mg/kg) have been suggested. However,
the efficacy of these methods has been received with varying
results.78,81
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EN should be initiated at rates of 0.5 to 1 mL/kg/h with an increase of 0.5 to 1 mL/kg/h every 3 to 4 hours if the gastric residues
are lower than 25% of the volume administered within the previous
3 to 4 hours and there is no abdominal distention. The objective is
to obtain normal caloric intake for the patient within 36 to
48 hours. Although generally well tolerated, the literature suggests
that patients with certain comorbid diseases may be somewhat
intolerant of enteral feedings. In children with acute renal failure,
the use of duodenal EN is possible in 90% of the cases but is
associated with an increased rate of digestive complications.82 In
critically ill children, for instance, those with shock, although the
enteral route may provide better caloric intake, there may be a
significant increase in digestive complications (30.7% vs 9.1%).80
Several studies have reported significant interest in the potential
impact of the administration of immunonutrition, especially in
patients in the critical care setting. Immunonutrition consists of a
mixture of arginine, glutamine, omega-3 polyunsaturated fatty
acid, antioxidants, beta-carotene, vitamin E, zinc, selenium, and
copper. In children with septic shock, immunonutrition modifies
the production of cytokine without affecting its regulation. Furthermore, it does not have a significant impact on the incidence of
complications.83,84 In children with serious traumatic brain injury,
the use of immunonutrition reduces the rate of interleukin-8 (IL8) production and the degree of gastric colonization on the fifth
day without influencing the number of nosocomial infections, the
duration of assisted ventilation or hospitalization time, and the
survival rate.85 The outcome of critically ill adults hospitalized is
improved by supplementation of glutamine. In children, the
available data are rare, but the most recent recommendations propose the use of supplementation for children with serious conditions, especially if they are victims of thermal injury or severe
trauma.66 The catabolism and oxidation of the arginine are increased in the case of burns or severe sepsis in children, but the
data are insufficient to recommend supplementation.66
The positive effects of probiotics on the immune system and
the prevention of diarrhea after antibiotic therapy have been
established in children. However, in the critical care situation, a
randomized probiotic study (Lactobacillus rhamnosus) versus
placebo had to be interrupted because of an increased number of
nosocomial infections in the probiotic group.86
Complications and Disadvantages

of Enteral Nutrition
The median energy intake can be significantly lower with EN than
with PN or combined techniques. Interruptions are much more
frequent than with PN. These may occur during invasive procedures or examinations, because of the need for free water
restriction, and the occurrence of digestive intolerance.87 Digestive
intolerance occurs in up to 50% of cases including significant
residuals (2631%), vomiting (350%), abdominal distention (3.5
15%), diarrhea (2.420%), enterocolitis (0.43.7%), duodenal
perforation (1.51.9%), and hemorrhage (0.3%).78,80,82,85,87 However,
intolerance rarely requires the total suspension of EN (1.1% of the
children in the critical care unit), except when there is a state of
shock in which interruption is needed in almost 19% of cases.78,80
Parenteral Nutrition
PN should be started within 3 to 5 days if the use of EN is not
possible, or if it is poorly tolerated.62,66 The main recommendations
TABLE 11-6. Amino Acids, Lipids, and Fluid and

Electrolytes Requirement During Parenteral Nutrition
1st mo of life
1st mo3 y
35 y
Amino acids
(g/kg/d)
612 y
Adolescent
Infants with
linoleic acid
Children with
linoleic acid
Infants
Children
Infants
Children
Infants
12 y
35 y
612 y
1318 y
Lipids
(g/kg/d)
Na+
(mmol/kg/d)
K+
(mmol/kg/d)
Fluid
(mL/kg/d)
1.53
12.5
12 (3 for critically ill
patients)
12 (3 for critically ill
patients)
12
34 (0.130.17 g/kg/h)
0.1
23 (0.080.13 g/kg/h)
0.1
23
13
13
13
120150 (maximum, 180)
80120 (maximum, 150)
80100
6080
5070
Modified from reference 62.
are outlined in Tables 116 and 117.62 Three elements must be

taken into account when PN is begun:
1. PN must allow a gain in weight consistent with the reference
curves.
2. The nutrients administered (carbohydrates, amino acids, and
lipids) must be in accordance with the recommendations in
terms of quantity and distribution.
3. The tolerance of the PN must be monitored for hyperglycemia,
elevated triglyceride values, and cholestasis.
Lipids (see Table 116) can provide a significant intake of
calories in a small volume (2.0 kcal/mL for 20% emulsions) with
a low osmolarity. They contain the essential fatty acids and should
represent 25- to 40% of the nonprotein calories in the case of
exclusive PN. Classically, although the lipid intake is increased
gradually, no benefit of this practice has been demonstrated.62,66
Carbohydrates (see Table 117) should contribute 60 to 75% of
the nonprotein calories. The contribution of essential amino acids
(histidine, isoleucine, leucine, lysine, methionine, phenylalanine,
threonine, tryptophan, and valine) is vital because they cannot be
synthesized by the body. As with lipids, the advantage of a gradual
increase in intake is not demonstrated.66 Even in premature
TABLE 11-7. Carbohydrates Requirement in Parenteral
Nutrition, g/kg/d
Weight, kg
<3
310
1015
1520
2030
>30
Day 1
Day 2
Day 3
Day 4
10
8
6
4
4
3
14
12
8
6
6
5
16
14
10
8
8
8
18
1618
1214
1012
12
10
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infants, the immediate administration of essential amino acids according to the recommended doses has been shown to be effective
and well tolerated.88 To ensure that the use of the amino acids by
the body is optimal, although not for the purpose of energy
support, the ratio of calorie-to-nitrogen should be maintained at
30 to 40 kcal/g of amino acid.62
Monitoring and Complications

Monitoring of the tolerance to the lipid administration requires
the daily determination of the triglyceride level. It has been
demonstrated that hypertriglyceridemia in children is associated
with an increase of the duration of mechanical ventilation and
hospitalization.55 The intake should be reduced if the plasma
concentration of triglycerides exceeds 250 mg/dL in infants and
400 mg/dL in children.62 Close surveillance of patients with sepsis,
newborns with hyperbilirubinemia, and patients with thrombocytopenia or coagulation disturbances is mandatory because high
triglyceride levels may exacerbate these conditions. Hepatic
enzymes should be regularly determined and lipid intake decreased or interrupted in the presence of cholestasis. Supplementation with omega-3 polyunsaturated fatty acids may hasten
the regression of cholestasis induced by PN in infants.89 The
tolerance to carbohydrate intake is assessed by monitoring plasma
levels of glucose and glycosuria. Various potentially detrimental
effects of hyperglycemia have been reported in the literature, and
its presence may be correlated with an increased risk of morbidity
and even mortality, especially in patients with traumatic brain
injury. It is associated with an increased in duration of stay,
increased duration of assisted ventilation, and increased risk of
death in postoperative cardiac surgery patients.90,91 The mechanisms to explain this hyperglycemia and its consequences vary. In
case of systemic infection, van Waardenburg and associates have
reported that hyperglycemia was secondary to insulin resistance in
children without shock and to a low plasma concentration of
insulin in the case of septic shock.92 In the adult population, strict
control of the glucose level improves the clinical prognosis and
outcome.93 Although definitive data are lacking in the pediatric
population, pending further data, it appears reasonable to suggest
maintaining the plasma glucose concentration between 140 and
180 mg/dL.66 However, if insulin administration is started to
maintain normoglycemia, frequent monitoring of blood glucose is
mandatory, given the devastating consequences of hypoglycemia
in infants and children. Excessive glucose intake may also be
responsible for the emergence of liver steatosis often accompanied
by the increased production of hepatic very low density lipoprotein (VLDL) caused by the diversion of substrates to lipogenesis.62
CONCLUSION
The maturation of the digestive functions and intestinal absorption
in humans is remarkable, especially considering its developmental
precocity during intrauterine and neonatal life. Immediately after
birth, the newborns GI function is such that it is capable of absorbing all the necessary nutrients for growth and development. These
include secretion of lipase and amylase by the pancreas and bile
salts from the liver. Although bile salts are present at birth, they are
least developed. Therefore, breast milk is essential for the neonates
nutrition because of its enzymatic components and also because of
the triglyceride structure, which is better adapted to this degree of
intestinal immaturity. The intake of breast milk allows the newborn
to have normal digestive capabilities of fats and carbohydrates.

Regardless of the scenario, if nutrition is adapted to the metabolic
condition of the child, it can significantly improve the prognosis
of critically ill patients. It is essential to incorporate this goal in the
management of children, especially those confronted with dysfunctional metabolic and nutritional status caused by critical medical or
surgical conditions. Although the pediatric literature still lacks
evidence for many of the specific recommendations on this subject,
it is clear that the basic principles in the management of these
patients must be maintained. Clinical research in this field must
be encouraged in order to answer many additional questions in this
field.
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76. Heyland D, Cook DJ, Winder B, et al. Enteral nutrition in the critically ill patients: a prospective survey. Crit Care Med. 1995;23:
10551060.
77. Hulst JM, Joosten KF, Tibboel D, et al. Causes and consequences of
inadequate substrate supply to pediatric ICU patients. Curr Opin Clin
Nutr Metab Care. 2006;9:297303.
78. Sanchez C, Lopez-Herce J, Carrillo A, et al. Early transpyloric enteral
nutrition in critically ill children. Nutrition. 2007;23:1622.
79. Gottschlich MM. The 2002 Clinical Research Award: an evaluation of
the safety of early vs delayed enteral support and effects on clinical,
nutritional, and endocrine outcomes after severe burns. J Burn Care
Rehabil. 2002;23:401415.
80. Lpez-Herce J, Menca S, Snchez C, et al. Postpyloric enteral nutrition in the critically ill child with shock: a prospective observational
study. Nutr J. 2008;7:6.
81. Phipps LM, Weber MD, Ginder BR, et al. A randomized controlled
trial comparing three different techniques of nasojejunal feeding tube
placement in critically ill children. JPEN J Parenter Enteral Nutr.
2005;29:420424.
82. Lopez-Herce J, Sanchez C, Carrillo A, et al. Transpyloric enteral

nutrition in the critically ill child with renal failure. Intensive Care
Med. 2006;32:15991605.
83. Briassoulis G, Filippou O, Hatzi E, et al. Early enteral administration of immunonutrition in critically ill children: results of a
blinded randomized controlled clinical trial. Nutrition. 2005;21:
799807.
84. Briassoulis G, Filippou O, Kanariou M, et al. Comparative effects of
early randomized immune- or nonimmune-enhancing enteral
nutrition on cytokine production in children with septic shock.
85. Briassoulis G, Filippou O, Kanariou M, et al. Temporal nutritional
and inflammatory changes in children with severe head injury fed a
regular or an immune-enhancing diet: A randomized, controlled
trial. Pediatr Crit Care Med. 2006;7:5662
86. Honeycutt TC, El Khashab M, Wardrop RM 3rd, et al. Probiotic
administration and the incidence of nosocomial infection in pediatric
intensive care: a randomized placebo-controlled trial. Pediatr Crit
Care Med. 2007;8:452458
87. Rogers EJ, Gilbertson HR, Heine RG, et al. Barriers to adequate
nutrition in critically ill children. Nutrition. 2003;19:865868.
88. Thureen PJ, Melara D, Fennessey PV, et al. Effect of low versus high
intravenous amino acid intake on very low birth weight infants in the
early neonatal period. Pediatr Res. 2003;53:2432.
89. Gura KM, Lee S, Valim C, et al. Safety and efficacy of a fish-oilbased
fat emulsion in the treatment of parenteral nutrition-associated liver
disease. Pediatrics. 2008;121:e67886.
90. Klein GW, Hojsak JM, Rapaport R, et al. Hyperglycemia in the
pediatric intensive care unit. Curr Opin Clin Nutr Metab Care. 2007;
10:187192.
91. Yates AR, Dyke PC II, Taeed R, et al. Hyperglycemia is a marker for
poor outcome in the postoperative pediatric cardiac patients. Pediatr
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92. van Waardenburg DA, Jansen TC, Vos GD, et al. Hyperglycemia in
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between plasma levels of insulin and inflammatory mediators. J Clin
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93. Van den Berghe G, Wilmer A, Hermans G, et al. Intensive insulin
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12
Endocrine System
Carlos Hervs Puyal, Manuel Garca Grriz, and Rosario Nuo Sanz
INTRODUCTION
Growth and development are genetically determined and are
modulated by a number of factors that either facilitate or hinder
the expression of that genetic code and may in turn be subdivided
into regulating, permissive, and effecting factors. The regulating
factors, which are responsible for the transcription of gene-coded
instructions into the adult individual phenotype, will be highlighted. Their mechanism of action involves the induction of
enzyme, hormone, and structural protein synthesis. At the initial
stages of embryonic development, this regulation depends exclusively on an autocrine or a paracrine mechanism. Later during
fetal life, some tissues differentiate into endocrine glands and
secrete several hormones with specific metabolic actions that will
become the main regulators of postnatal growth.
BASIC CONCEPTS IN
ENDOCRINOLOGY
Concept of the Neuroendocrine System
Multicellular organisms require mechanisms by which the individual cells can intercommunicate. In humans, this intercommunication is achieved by means of the endocrine, nervous, and
immune systems.12 These systems regulate growth, development,
reproduction, homeostasis, and the response to environmental
stimuli. These interactions lead to the concept of the neuroendocrine system, which integrates and coordinates the metabolic
activities of the organism.34 The central regulator of this system is
the hypothalamus. The hypothalamus receives and modulates a
large number of signals that arrive from the higher brain centers.
In turn, it transmits this information in the form of hormonal
stimuli, which regulate the activity of the cells in the anterior
pituitary.
Classification and Mode

of Action of Hormone
Endocrinology is the discipline that studies the internal secretory
glands and their products, termed hormones. Hormones can be
classified according to their chemical structure (peptide, steroid,
and amine) and their mechanism of action through either intracellular receptors (group 1) or cell membrane receptors (group 2).
Hormone synthesis takes place mainly in the endocrine glands,
although there is some activity in other tissues (e.g., brain, digestive tract). The majority of protein hormones are synthesized in
C H A P T E R
the form of prohormones, which must be modified after synthesis

to give rise to biologically active hormones. The steroid hormones
are synthesized from cholesterol. The body does not usually
contain significant deposits of hormones because synthesis is
generally followed by a quick metabolic turnover. Hormones can
be stored within secretory granules, bound to the cell membrane
in the case of protein hormonesecreting cells or in the precursor
form (cholesterol) in cells that secrete steroid hormones. Because
of their limited storage capacity, the majority of hormones are
released into the plasma at a rhythm that reflects their rate of
synthesis. Diurnal rhythm, sleep, development, and nervous
system factors can influence the release of some hormones.
Hormones are generally transported by the blood. The majority
of the peptide hormones circulate freely, with the exception of
insulin-like growth factors (IGFs) and growth hormone (GH).
Hormones that are not soluble in water require the presence of
carrier proteins. Albumin and prealbumin are the general carrier
proteins, but some are hormone-specific such as thyroglobulin
(Tg) and sex hormonebinding globulin (SHBG). These binding
proteins act as reservoirs in such a way that the protein carrier
bound hormone is in a dynamic equilibrium with the free fraction
in the plasma. Hormones must bind to specific sites on the target
cells, receptors, to perform their function. Hormone-receptor
binding is noncovalent and reversible. Hormonal function is
centered on various physiologic processes including reproduction;
growth; development; maintenance of homeostasis; regulation of
cardiovascular function; and production, use, and storage of
energy. The principal regulating mechanism that controls hormone synthesis and secretion is a humoral process by which the
hormone concentration itself determines the need to increase or
decrease production. This regulation is carried out through
various feedback circuits, which can be altered by nonhormonal
factors.
HYPOTHALAMICADENOHYPOPHYSEAL SYSTEM
Overview
The hypothalamus and the hypophysis (pituitary gland) constitute
a functional unit that controls several important functions in the
organism.5 The specific actions of this unit are exerted by means
of its hormonal secretions. Hypothalamic regulation of the hypophysis is carried out by a neural route in the posterior hypophysis
(neurohypophysis) and through a vascular transport system in the
anterior hypophysis (adenohypophysis).4 The neuroendocrine
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The neurons of the hypothalamic nuclei receive the innervation of
fibers proceeding from neurons that synthesize monoamines.
These are extensively distributed through the mesencephalon and
lower brainstem. The biologic amines (dopamine, adrenaline,
noradrenaline, and serotonin) play an important role in the neuroendocrine regulation of the adenohypophysis.
Regulation of Adenohypophyseal Secretion
Figure 12-1. Feedback loops.
cells of the hypothalamus synthesize and release neurosecretory

substances. These substances are deposited in the posterior lobe of
the hypophysis or used to control the synthesis and release of the
adenohypophyseal hormones (hypophysiotropic hypothalamic
hormones), reaching the anterior hypophysis by means of the hypophyseal portal system. Hormone secretion in the hypothalamichypophyseal axis is regulated by two systems that maintain
hormone levels within narrow margins. The first is based on the
secretion of each of the hormones according to an intrinsic, specific rhythm, and the second is a feedback control mechanism.
This last system acts in both the hypothalamus and the hypophysis
and is divided into three types (Figure 121):
The regulation of adenohypophyseal function is carried out by

coordinated neuronal and humoral mechanisms. The hypophysiotropic hypothalamic neurons are, in themselves, able to sustain
a certain autonomic function.3,5 However, to achieve complete
function, other stimulating and inhibiting impulses from various
brain regions or the hypothalamus itself are needed. Several
important brain structures, such as the septum, hippocampus, and
amygdale, contribute information to the hypothalamus through an
interaction of afferent and efferent pathways. The hypothalamus
contains specialized neurons that possess receptors sensitive to
changes in hormone levels, temperature, glucose levels, and
osmolality. This information has an influence on the activity of the
hypophysiotropic and neurophysiotropic hypothalamic neurons.
The hypothalamic peptidergic neurons are, in turn, controlled by
neurotransmitter-synthesizing neurons and other substances.6
The hypothalamic peptidergic neurons are, in turn, controlled
by neurotransmitter-synthesizing neurons and other substances.
An example of these is a series of small peptides found within the
central nervous system (CNS) neurons that function as neurotransmitters, acting directly on the hypothalamic neurons or the
adenohypophysis (Figure 122). The primitive hypothalamicpituitary complex differentiates and synthesizes hypothalamic
hypohysiotropic factors and pituitary hormones early in gestation,
whereas the maturation of neuroendocrine control of hormonal
secretion by the fetal pituitary gland does not occur until late
1. Long loop: Peripheral concentrations of the hormone inhibit

or stimulate the synthesis or secretion of its corresponding
hypophyseal hormone through the hypothalamus.
2. Short loop: The hypophyseal hormones act upon the hypothalamus.
3. Ultrashort loop: The hypothalamic and hypophyseal hormones
can modulate their own secretion.
Anatomic Data
The hypothalamus is located at the base of the brain, superior
to the pituitary gland and superior and posterior to the optic
chiasma, at the floor of the third ventricle. It is posteriorly related
to the mammillary tubercula. Its lower part, the tuber cinereum,
has a central projection that forms the base of the third ventricle,
the median eminence. This eminence is surrounded by the pars
tuberalis of the adenohypophysis. The anterior portion extends to
a frontal plane that includes the anterior commissure and the optic
tract. It is in dorsal relation with the cerebral thalamus. The
median eminence is a specialized region of the floor of the third
ventricle, which gives rise to the pituitary stalk. It has an important
vital function, being the area of contact between the tuberoinfundibular nerve terminals and the capillaries of the hypophyseal
portal circulation, by which the stimulating and inhibiting hypothalamic factors that regulate hypophyseal function are transferred. It is a highly vascularized area with considerable blood flow.
Figure 12-2. Hypothalamic-hypophyseal functional unit.
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CHAPTER 12
gestation or during the postnatal period. The growth and development of the target tissues are affected in utero by the relative
deficient secretion of adrenocorticotropic hormone (ACTH),
thyroid-stimulating hormone (TSH), follicle-stimulating hormone
(FSH), luteinizing hormone (LH), and growth factors.78 Vascular
connection between the brain and the hypophysis is not established until midgestation.9 Thereafter, hypothalamic neurotransmitters and peptidergic hormones directly enter the pituitary to
regulate the synthesis and release of the hormonal products.9
Dysfunction of the hypothalamic-hypophyseal system leads to
a deficient output of hypophysiotropic hormones or, less frequently, to an excess in their secretion. The most common cause
of panhypopituitarism in childhood is compression of the hypophyseal gland by a craniopharyngioma. Less frequent causes are
hypothalamic tumors, tuberculosis, sarcoidosis, toxoplasmosis,
and some aneurysms. Treatment consists of specific hormone
replacement, which includes gonadotropins, cortisol, and thyroxin. In those patients scheduled for surgery, preoperative assessment should be performed, taking into account the presence of
any endocrine dysfunction as well as the possibility of intracranial
hypertension or decreased compliance associated with tumors. In
those patients undergoing operations on the hypothalamic-hypophyseal system, the potential occurrence of diabetes insipidus,
hormonal deficiencies, reduced insulin requirements in the presence of diabetes mellitus, hyperpyrexia, and cerebrospinal fluid
losses should be considered. The effects on hypothalamic hormonal release induced by the different anesthetic agents are largely
hypothetical. Opiate receptor occupation by morphine derivatives
develops a negative-feedback control on endorphin secretion by
their precursors. This effect remains throughout the entire surgical
procedure whenever strongly active morphine-like agents (fentanyl) are used at high doses and it disappears upon awakening.
Halogenated anesthetic agents and neuroleptic agents induce an
increase in plasma GH, whereas morphine-like agents increase
prolactin (PRL) levels. Droperidol antagonizes actions of dopamine on hypophyseal D2 receptors.
Hypophysiotropic-Hypothalamic Hormones
Synthesis of the adenohypophyseal hormones is regulated by
neurosecretions originating in the peptidergic neurons of the
hypothalamic nuclei (Table 121).
Thyrotropin-Releasing Hormone
Thyrotropin-releasing hormone (TRH) can be detected in the fetal
hypothalamus by midgestation.10 The precise profile of the
ontogeny of TRH secretion and function in the fetus is undefined
at this time. During the early phase of development, the thyroid
gland will develop in the absence of TRH and TSH. The fetus
progresses from a state of both primary (thyroid) and tertiary
(hypothalamic) hypothyroidism in midgestation through a state of
mild tertiary hypothyroidism during the final weeks of pregnancy
to fully matured thyroid function in the perinatal period.10 Thyroid
hormones affect important developmental processes including
growth, thermogenesis, and development. Early treatment of
congenital hypothyroidism in the neonate prevents mental retardation, suggesting that the period of thyroid dependency of the
human brain begins in the postnatal period. Norepinephrine
directly stimulates TRH secretion in the paraventricular nucleus
neurons, whereas dopamine inhibits its secretion at the level of the
Endocrine System
183
TABLE 12-1. Anterior Pituitary, Hypophysiotropic

Hormones, and Their Target Organs
Hypophysiotropic Pituitary Target
Hormones
Hormones Organ
TRH
LH-RH
TSH
LH
FSH
GH-RH
Somatostatin
CRH
ADH
Dopamine
GH
GH
ACTH
ACTH
Prolactin
Hormone
Thyroid
Gonads
Gonads
T3 and T4
E2 and testosterone
Inhibin, E2,
testosterone
Multiple
IGF-1
Multiple
IGF-1
Suprarenal Cortisol
Suprarenal Cortisol
Breast
?
ACTH = adrenocorticotropic hormone; ADH = antidiuretic hormone; CRH =

corticotrophin-releasing hormone; E2 = estradiol; FSH = follicle-stimulating
hormone; GH = growth hormone; GH-RH = growth hormonereleasing
hormone; IGF-1 = insulin-like growth factor-1; LH = luteinizing hormone; LHRH = luteinizing hormonereleasing hormone; T3 = triiodothyronine; T4 =
thyroxine; TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating
hormone.
median eminence. TRH reaches the hypophysis from the median

eminence through the hypophyseal portal system and acts on the
thyrotrope cells. Prostaglandins and calcium seem to be implicated
in the release of TSH by TRH. The intravenous administration of
TRH produces a rapid dose-dependent release of hypophyseal TSH
that reaches a peak concentration at 20 minutes. In addition to
stimulating TSH release, a second phase provokes an increase in
TSH synthesis and increases thyroidal cell growth. Somatostatin
and high doses of glucocorticoids reduce the response of TSH to
TRH. The main hypothalamic control over TSH is stimulatory. The
thyroid hormones exercise a negative-feedback regulation. Small
increases in T3 (triiodothyronine) and T4 (thyroxine) levels decrease the release of TSH in response to TRH. Inversely, small
decreases in circulating thyroid hormone levels increase TSH
release in response to TRH. The hypothalamus modulates the
sensitivity of the thyroidal cells to the negative-feedback mechanism of the thyroid hormones. TRH also stimulates the release of
PRL, and in certain pathologic conditions (acromegaly, renal
failure, hepatic failure, anorexia), it induces the release of GH.
Finally, TRH has a series of nonendocrine effects. As a neurotransmitter, it tends to produce excitatory consequences including
increased motor activity, trembling, and peripheral neural
sympathetic activity with shivering, hypertension, tachycardia,
diaphoresis, and nausea. An abnormality anywhere in the
hypothalamic-pituitary-thyroid axis can result in deficient thyroid
hormone secretion and hypothyroidism. It is classified as tertiary
when the defect is one of hypothalamic function, secondary for
abnormalities of TSH synthesis and release, and primary for
diseases that impair thyroid hormone secretion or action. The
anesthetic care of the symptomatic patient requires caution when
any depressant medications are given. Prolonged effects may result
from decreased drug metabolism. Invasive monitoring may be
indicated when significant blood loss or fluid shifts are expected to
occur. Care should be taken to minimize heat loss intraoperatively.
Luteinizing HormoneReleasing Hormone

Development of the neuroendocrine system responsible for the
regulation of gonadotropin secretion, including FSH and LH,
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begins during the final half of gestation.3 Luteinizing hormone

releasing hormone (LH-RH) content increases until midgestation
and then decrease steadily throughout the last half of gestation.10
The prepubertal reproductive system is characterized by FSH and
LH secretion with a high ratio of FSH to LH and an enhanced
sensitivity to the negative-feedback effects of sex steroids. The
release of LH-RH is pulsatile in nature. LH-RH pulse frequency is
lower in prepubertal children than during early puberty. LH-RH
stimulates the release of LH and FSH. Epinephrine and norepinephrine stimulate the secretion of LH-RH while modulating other
factors (opioid peptides and gamma-aminobutyric acid [GABA])
modulate gonadotropin secretion. The biologic activity of LH-RH
depends on the form of administration. Pulsatile administration
results in the ongoing release of gonadotropins, whereas continuous administration produces transitory stimulation followed by
desensitization and inhibition of secretion. Cell function can be
modified by changes in the receptor density. The number of receptors increases with estrogens and decreases with the androgens.
The intravenous administration of LH-RH to a normal adult
produces a dose-dependent release of LH and FSH, the former
being more pronounced. Complex interactions, important for
control of LH and FSH release, are established between the steroid
sex hormones and LH-RH. The differences in the secretion of LH
and FSH seem to be due to variations in the sensitivity to LH-RH
and to the effects of steroid and peptide hormone feedback. FSH
is more sensitive than LH to the inhibitory effects of the estrogens.
Supraphysiologic doses of testosterone suppress basal gonadotropin levels and decrease their response to LH-RH. Regulation of
gonadotropin secretion is complex, with simulating and inhibiting effects at different levels of the hypothalamic-hypophysealgonadal system, and interactions among several feedback effects.
Growth Hormone ReleaseInhibiting

Factor or Somatostatin
Somatostatin is a tetradecapeptide found within the body of the
neuron and in the nerve terminals. It is widely distributed
throughout the CNS and is considered to be a neurohormone both
in the hypothalamus and in the hypophysis. In the pancreatic
islets, somatostatin can be located in the D and A cells. It may act
as a local regulator of function in the islets of Langerhans, with
the peptide being released to the intercellular space and acting
directly on the endocrine cells of the pancreas. Somatostatin seems
to interfere with the release of various hormones but does not
affect their synthesis. Its exact mechanism of action is still
unknown. Somatostatins effects on the pituitary include blockade
of GH release in response to exercise, insulin-induced hypoglycemia, arginine, L-dopa and inhibition of the secretory waves of GH
produced during sleep and in situations of stress. Basal secretion
continues despite suppression of the GH response. Endovenous
perfusion of this peptide inhibits TSH release by TRH and
suppresses the nocturnal increase of basal TSH levels. It does not
alter ACTH secretion in normal individuals, but it is inhibitory in
cases of ACTH hypersecretion. Extrahypophyseal actions include
inhibition of the release of insulin, glucagon, and other peptide
hormones from the gastroenterohepatic system. Somatostatin
controls secretion of insulin and glucagon in the islets of Langerhans, either through a paracrine effect, by direct membrane contact, or through a local vascular system. An elevated blood glucose
stimulates the release of glucagon, provoking somatostatin secretion, which in turn exerts an inhibitory control on glucagon.
Somatostatin reduces splanchnic blood flow by 30% and inhibits

gastric and duodenal motility. Finally, it inhibits galactose and
lactose absorption in the small intestine, gluconeogenesis stimulated by glucagon, and hepatic glycogenolysis.
Growth HormoneReleasing Factor

Growth hormonereleasing factor (GH-RF) secretion is regulated
by the action of dopamine upon the hypothalamic factors and by
complex interactions among many neurotransmitters and peptides. Secretion is pulsatile, and prolonged administration does
not seem to provoke desensitization of its hypophyseal effects.
GH-RF stimulates the synthesis and release of GH in a time- and
dose-dependent manner, without affecting the secretion of other
hypophyseal hormones. The response of GH to GH-RF is greater
in young individuals and decreases after the fourth decade of life.
The capacity of the hypophysis to respond to GH-RF is exhausted
by repeated administration of the peptide.
Corticotropin-Releasing Factor
Corticotropin-releasing factor (CRF) secretion is controlled by at
least two types of stimuli including stress and the biologic clock
responsible for the circadian rhythm of the hypophyseal-adrenal
axis. The circadian rhythm is independent of plasma cortisol
levels. The secretory neurons receive multiple stimuli from different parts of the brain, regulating their function. It stimulates
the hypophyseal release of ACTH and beta-lipoprotein from proopiomelanocortin. CRF plays an important role in regulation of
the autonomous nervous system, stimulating the sympathetic and
inhibiting the parasympathetic nervous system. It influences
behavior and learning capacity and stimulates the production of
somatostatin by the cortical and hypothalamic cells.
Hypothalamic ProlactinInhibiting Factor

PRL is secreted under inhibitory tonic control. A break in the
hypothalamic-adenohypophyseal connection by pituitary stalk
section or destructive hypothalamic lesions results in PRL hypersecretion. The hormone that inhibits PRL has not as yet been
conclusively identified. According to some authors, dopamine
is implicated, whereas others have proposed neuropeptides as
well. High concentrations of dopamine are found in the median
eminence. Concentrations in portal blood are high enough to
inhibit PRL release.
Hypothalamic ProlactinReleasing Factor

The structure of prolactin-releasing factor (PRF) is not known; it
may correspond to that of TRH. It is believed that the vasoactive
intestinal polypeptide present in the hypothalamus and in pituitary stalk blood can act as a physiologic stimulator of PRL
secretion. GABA and prostaglandins (PG2) may also have a role.
Some studies have demonstrated a release of PRL by serotonin and
an inhibition by antiserotoninergic agents.
Other Substances Isolated

From the Hypothalamus
Substance P
Substance P is an 11-amino acid peptide. In the hypothalamus, it
has been isolated from the neuron bodies of the dorsomedial and
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ventromedial nuclei and in the anterior hypothalamic nucleus, but
not in the external layer of the median eminence.11 Substance P
has also been found in various structures outside the hypothalamus. It acts mainly upon the smooth muscle. At the vascular level,
it produces vasodilation and hypotension, whereas in the intestine,
it causes contraction of the smooth muscle of the intestinal wall.
It stimulates salivary secretion and has analgesic effects that are
antagonized by naloxone. Substance P plays an important role in
the dorsal horn of the spinal cord where it modulates sensitivity to
pain by activating the neurokinin-1 (NK-1) receptor.11 The distribution of nerve endings with a high content in substance P is
closely related to the distribution of enkephalin and opiate receptors within the CNS. Substance P seems to act as both a neurotransmitter and a neuromodulator, causing either hyperalgesia or
analgesia, depending on its site of action.11 It has interactions with
other neurochemical substances including opioids, resulting in
enhancement or blunting of their effects. It seems to behave as a
neurotransmitter of the exciting type.
Neurotensin
Neurotensin is a tridecapeptide with a single amino acid sequence.
It is distributed throughout the CNS, with highest concentrations
in the hypothalamus. It is also found in the intestine. Endovenous
administration produces hypotension, a painful sensation, and
hyperglycemia. Neurotensin increases PRL, ACTH, GH, LH, and
FSH production. Intraventricular administration increases the
effects of barbiturates, produces hypothermia, and results in
analgesic effects.
Vasoactive Intestinal Peptide

Vasoactive intestinal peptide (VIP) is a polypeptide with a short
half-life. At the level of the CNS, it is distributed in the hypothalamus, median eminence, and the hypophyseal portal blood. It is
concentrated within the vesicles of the synaptic terminals of the
nerves, together with other neurotransmitters such as dopamine
and noradrenaline. The peripheral effects of VIP include vasodilation, stimulation of cardiac contractility, bronchodilation, glycogenolysis, lipolysis, insulin secretion, gastric inhibition, and
pancreatic secretion flow. It also stimulates activation of the
adenylate cyclase system of the suprarenal cortex cells, resulting in
steroidogenesis among other effects. VIP is believed to act as a
paracrine secretion or local hormone at the peripheral level,
whereas in the CNS, it functions as a neurotransmitter or neuromodulator.
Other Functions of the Hypothalamus

The endocrine-metabolic aspects of hypothalamic function can
be classified into
1. Regulation of energy metabolism and control of sleep, body
temperature, weight, and appetite.
a. Sleep rhythms are regulated by the centers located within
the lateral hypothalamus.
b. Body temperature is maintained constant by the activity of
the thermoregulating centers located in the tuber cinereum.
These centers control both heat loss and production.
c. Appetite and body weight are thought to be regulated
by the lateral areas (feeding) and the ventromedial areas
(regulating centers). Stimuli from the regulating centers are
Endocrine System
185
believed to inhibit the feeding centers. Thus, when inhibition fails because of destruction of the ventromedial
area, hyperpyrexia and obesity often appear.
2. Regulation of body water metabolism.
3. Regulation of the secretion of several adenohypophyseal hormones.
HYPOPHYSIS
Anatomic Data
The hypophysis (pituitary) is a gland located in the sella turca of
the sphenoid bone and is covered with a layer of dura mater, called
the sellar diaphragm, which is traversed by the pituitary stalk. It is
connected to the tuber cinereum region through the pituitary stalk
below the base of the brain. The lateral walls of the sella turca are
in contact with the cavernous sinus, which contains the internal
carotid artery and cranial nerves III, IV, V, and VI. Its size is variable, increasing during pregnancy and decreasing with age. The
hypophysis can be divided into two morphologically and functionally different units: the neurohypophysis and the adenohypophysis. The adenohypophysis does not possess direct innervation,
except for a small number of sympathetic fibers that penetrate the
anterior lobe next to the blood vessels. These nerve fibers can
modify blood flow but not hormone secretion. The hypothalamus
has a neurohumoral regulating function. The cells of the adenohypophysis group to form nests or acinus-like structures surrounded by a network of sinusoidal capillaries. Different cell types
exist for each hormone synthesized (Table 122). The adenohypophyseal cytology changes in parallel to the functional alterations
of the gland.
Adenohypophyseal Hormones
Overview and Assessment
The anterior hypophysis can regulate several organs by the integration of specific signals from the brain and by the intermittent
production of releasing factors that stimulate the selective release
of hormones from a specific gland (Table 123). All of the adenohypophyseal hormones are governed by pulsatile secretion. The
adenohypophyseal hormones are classified into three families
according to their structure and activity: (1) corticotropin hormone family and related peptide hormones. Within this group are
included ACTH, beta-lipoprotein, and the opioid peptides
(encephalins, endorphins) as well as the hormone that stimulates
the melanocytes of the intermediate lobe of certain animals. All
of these are derived from a large-molecule common precursor; (2)
glycoprotein hormone family, which includes FSH, LH, chorionic
TABLE 12-2. Classification of Anterior Pituitary Cell Types
Cell Type
Hormone
Somatotropic
Lactotropic
Thyrotropic
Gonadotropic
GH
PRL
Thyrotropin
LH
FSH
ACTH
Corticotropic
ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone;

GH = growth hormone; LH = luteinizing hormone; PRL = prolactin.
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TABLE 12-3. Adrenohypophyseal Hormones

Pituitary Hormone
Target Organ
Hormone
TSH
LH
Thyroid
Gonads
FSH
Gonads
ACTH
GH
PRL
Adrenal gland
T4, T3
Estradiol
Testosterone
Inhibin
Activin
Follistatin
Cortisol androgens
IGF-1
?
Breast, gonads
ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone;

GH = growth hormone; LH = luteinizing hormone; PRL = prolactin; TSH =
thyroid-stimulating hormone;
gonadotropin, and TSH. With a 15 to 30% carbohydrate content

and proceeding from a primitive common molecule, they are all
composed of two amino acid chains, called alpha and beta. The
structure of the alpha chain is very similar or identical in all of
them, whereas their biologic specificity resides in the beta chains;
and (3) somatotropin family, which includes GH, PRL, and
placental lactogen. The structure of the hormones in this group is
very similar.
Growth Hormone
GH is a nonglycosylated protein, with a single polypeptide chain,
secreted by the adenohypophyseal somatotrope cells. The
secretion of GH is pulsatile; its plasma concentrations are widely
variable, indicating the great number of factors involved in its
secretion. GH is regulated by at least two hypothalamic hormones,
one stimulating and one inhibiting. The physiologic stimuli that
influence its secretion to the greatest degree include exercise,
stress, and certain metabolic states, such as fasting and food
ingestion. GH inhibits its own secretion through a short-loop
mechanism. In like manner, its secretion is modified by various
hormones and neurotransmitters. GH-containing adenohypophyseal cells are detected from the sixth week of intrauterine life. The
levels of GH increase gradually with gestational age. Although
changes can barely be seen during the first year of life, there is an
almost 10-fold increase during puberty. The levels of circulating
GH at the moment of birth, which approach those that may occur
with acromegaly, are significantly higher than those of the mother.
These levels decrease until, at 3 months after birth, they reach
concentrations similar to those of prepubertal subjects.
The principal action of GH is to favor growth. This activity is
not carried out directly, but instead through the induction of
certain plasma components called somatomedins. The structure of
these components is very similar to that of proinsulin, and for this
reason, they are also called insulin-like growth factors (IGF) and
include IGF-1 or somatomedin C and IGF-2. IGF-1 and -2 can be
synthesized by various tissues, but the liver synthesizes the
majority of them together with their carrier proteins and releases
them to the circulation. The agents stimulate protein synthesis.
Somatomedin C does not show appreciable daily variations, but it
does show changes with age. Before 6 years of age, levels are very
low; they increase significantly with puberty and then decrease
once again to adult levels. Somatomedin C levels are very low in
cases of GH deficit, fasting states, caloric and protein malnutrition,
and hepatic diseases. In acromegaly and gigantism, the levels are
extremely high. GH stimulates the metabolism of nucleic acids

and proteins mainly in the liver (production of IGF-1), adipose
tissue (lipolysis), and the muscles (insulin antagonism). Its action
can be described as anabolic, lipolytic, and diabetogenic. GH
administration in children produces a positive nitrogen balance,
decreases in urea production, a redistribution of body fat, and a
reduction in the use of carbohydrates. Although prolonged administration produces insulin resistance and the appearance of
hyperglycemia, it has no effect on the development of diabetes
mellitus. GH and GH-RF levels increase during puberty, a
phenomenon modulated by the amplitude and not the frequency
of the secretory episodes. Significant increases in plasma IGF-1
and growth factortransporting protein levels are produced at this
time. The increases in circulating IGF-1 explain the rapid growth
seen during puberty.
Adrenocorticotropic Hormone
ACTH is synthesized from a large precursor molecule, proopiomelanocortin (POMC). POMC is cleaved in the hypophysis,
giving rise to ACTH, beta-lipoprotein, and an N-terminal precursor. ACTH receptors are located not only in the hypophysis but
also in the mononuclear leukocytes and in the cells of the spleen.
The most important biologic action of ACTH is maintenance of
adrenal function. In addition to its trophic effect on this gland,
ACTH stimulates the synthesis of corticosteroids, mineralocorticoids, and androgens from the adrenal gland. Its main action is
related to control of cortisol secretion; it has a weak action on the
mineralocorticoids and a principal control on the renin-angiotensin system. It also stimulates the melanocytes, probably by the
action of alpha- or beta-lipoprotein, which structurally have
sequences similar to those of melanocyte-stimulating hormone
(MSH). ACTH acts as a powerful steroidogenic stimulus on the
adrenal glands of the human fetus and can have relevant functions
in adrenal gland growth over the fetal life. The fetal levels of
ACTH seem to originate in the fetus; there is no correlation between maternal levels and fetal levels at birth, and the transmission
of maternal ACTH seems very limited. Three mechanisms of
ACTH secretion are recognized: circadian rhythm related to the
phases of sleep and activity, inhibition of ACTH secretion by
circulating glucocorticoids, and quick release in response to stress.
ACTH itself can inhibit corticotropin-releasing hormone (CRH)
secretion by a short-loop, negative-feedback mechanism. ACTH
secretion is episodic. The number and duration of the episodes
are greatest 3 or 4 hours before getting up in the morning and
gradually decrease during the day, with little activity in the final
hours of the night. These changes, initiated by pulsatile release of
hypothalamic CRF, produce the classic circadian rhythm of ACTH
and cortisol. The rhythm disappears in Cushings disease patients,
in patients with altered consciousness, and in subjects who receive
exogenous corticosteroids (chronic administration suppresses the
hypothalamic-hypophyseal-adrenal system). Cortisol and the
glucocorticoids inhibit ACTH secretion through a negativefeedback system that acts on the hypothalamus (inhibits CRF
release) and on the hypophysis (reduces hypophyseal response).
This negative-feedback mechanism has two components: an
immediate component that initiates its effect minutes after increases in plasma glucocorticoid concentrations and a delayed
component that appears much later when glucocorticoid concentrations are high, decreasing, or low.
Hormonal responses after surgery are characterized by increased hypothalamic-pituitary-adrenal (HPA) axis hormones.
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Stress produces ACTH release, and the common mediator in all
cases is hypothalamic CRF. Other stimuli such as cold, insulin hypoglycemia, hemorrhage, and serious infections are also ACTHreleasing factors. Norepinephrine increases plasma ACTH
concentrations, whereas propanolol increases the ACTH response
to the hypoglycemic stimulus. Serotonin stimulates ACTH release.
Stressful circumstances, as can be generated by a surgical or an
anesthetic procedure, stimulate ACTH release, partly because of
an increase in CRF. However, ACTH secretion is greater than that
obtained with maximal stimulation by CRF. The immunologic
system bears a close relationship with the HPA axis. Glucocorticoids inhibit the immune response, and some immunologic
mediators are strong stimulators of ACTH secretion. These mediators may account, to some extent, for the connection between
stress and activation of the HPA axis, with the resulting increased
cortisol levels modulating the immune response. Most of the
inhaled anesthetic agents elicit an increase in plasma cortisol levels
(two- to threefold of its initial values within 2 h of their administration) except for isoflurane, which has a lesser effect.
Thyroid-Stimulating Hormone
TSH is a glycoprotein hormone formed by an alpha subunit
common to LH and FSH and a beta subunit that gives it specificity.
Its main biologic action is regulation of the synthesis, storage, and
release of the thyroid hormones and determination of the size of
the thyroid gland. TSH possesses extrathyroidal actions, such as
stimulation of lipolysis in the adipocytes and an action favoring
production of exophthalmos in certain experimental animals.
TSH appears in the fetus at 10 days of gestation. In 10% of normal
individuals, its concentration in plasma may be undetectable (0.5
5.0 mU/L). TSH secretion is pulsatile and presents a circadian
variation with maximum secretion between 4:00 AM and 6:00 AM
with minimum secretion at 3:00 PM. TRH is the most important
hypothalamic factor for TSH secretion. It has also been observed
at the extrahypophyseal level. The thyroid hormones, T3 and T4,
inhibit TSH production by a direct hypophyseal mechanism. The
affinity of T3 for the hypophyseal receptors is much greater than
that of T4, whereas exogenous administration of T4 inhibits TSH
release to a greater degree than T3. Half of intrahypophyseal T3
results from a conversion of T4. In humans, the effect of T3 and T4
on the hypothalamus is not known. Somatostatin inhibits basal
TSH release, the response of TSH to TRH, and the nocturnal TSH
peak. Dopamine and glucocorticoids reduce TSH concentrations
and the response of TSH to TRH. TSH concentrations can be
interpreted correctly only when serum levels of the thyroid
hormones are known. The latter are increased in hyperthyroidism,
inhibiting TSH release with associated TSH suppression and abolition of the TSH response to TRH. TSH-induced hyperthyroidism
is rare. Plasma concentrations of TSH remain constant throughout
life except in the newborn period in which there are increases in
the first 24 hours after birth. As a consequence of surgical trauma,
there is a decrease in T3 and T4 levels with normal TSH. Thiopental has an antithyroid action because it diminishes hormonal
synthesis. This effect is immediate and goes on for several days.
Halothane promotes TSH secretion and T4 release.
Gonadotropins (LH and FSH)

LH and FSH are glycoprotein substances formed by two peptide
chains, alpha and beta. Structurally, they are similar to hypophyseal TSH and to human chorionic gonadotropin (hCG). LH acts
Endocrine System
187
on the Leydig or interstitial cells in men, stimulating testosterone

synthesis, and on the interstitial cells in women, stimulating steroidogenesis and favoring development of the luteal body. The
gonadotropins bind to membrane receptors and induce cyclic
adenosine monophosphate (cAMP) synthesis. In men, FSH acts
upon the Sertol cells, stimulating the development of the seminiferous tubules and promoting spermatogenesis. Moreover, FSH
increases the number of LH receptors and stimulates aromatization of the androgens to estradiol. In women, it acts by binding to
the granular cells of the follicles and stimulates growth and
maturation of the follicles, acting synergistically with the estrogens
and LH. Changes in sensitivity to the feedback mechanisms are
related not only to gender but also to age. Gonadotropin secretion
is pulsatile, with rapidly appearing waves or peaks that are
superimposed on a continuous basal secretion. The hypothalamus
controls the synthesis and release of LH and FSH through LH-RH.
The gonadal steroid hormones establish a system of negative
feedback with the gonadotropins and the hypothalamic hormones.
From the beginning of puberty to the end of maturity, there is an
increase in gonadotropin secretion, first of FSH and later of FSH
and LH, because of a decrease in sensitivity of the negativefeedback mechanisms. With puberty, a characteristic nocturnal
pulsatile release that is minimal during the day appears. At the end
of puberty, secretion is pulsatile over 24 hours. The pulsatile
secretion is controlled by cyclic neuronal centers that act through
LH-RH. The action of the sex steroids (estrogens, androgens, and
gestagens) on FSH secretion is carried out by the hypophysis,
which would probably stimulate secretion, whereas testicular and
ovarian inhibin would suppress secretion. The androgens appear
to suppress LH synthesis and release at the level of the hypophysis
and the hypothalamus. The estrogens would have a stimulating
effect on the hypophysis, which would partially explain the
increase in sensitivity to LH-RH with the ovulatory peak, showing
greater LH and FSH response. By contrast, they would have an
inhibitory effect in the hypothalamus.
Prolactin
PRL is a polypeptide hormone whose single demonstrated activity
consists of stimulation and maintenance of lactation. Some of the
actions attributed to PRL are produced in synergism with the
gonadal and suprarenal steroid hormones. The increase in
estrogen production during pregnancy stimulates growth and
replication of the hypophyseal lactotrope cells. The hypophysis
doubles in size during pregnancy and returns to normal after the
infants birth. PRL-containing cells can be detected in the fetal
hypophysis after the 10th week of gestation. Circulating PRL levels
follow a similar process, showing a great increase during the third
trimester and a gradual decrease after birth. PRL acts through
specific receptors in several tissues (e.g., mammary, testicular, and
ovarian) and the liver. PRL initiates and maintains the process of
lactation. It is inhibited during gestation by the estrogen and
progesterone concentrations. PRL concentrations increase from
the beginning of pregnancy. This is a gradual process and is
probably due to increases in the estrogens. Suckling at the nipple
produces an immediate PRL release reflex. Other factors, such as
stress situations, surgery, anesthesia, insulin hypoglycemia, and
arginine, produce PRL release. PRL release with stress is blocked
by opioid antagonism and is probably mediated by endogenous
opioids. The hypothalamus exerts an inhibitory tonic control over
PRL secretion through a still-unidentified factor. TRH stimulates
PRL secretion. Dopamine inhibits PRL secretion, whereas serotonin stimulates it through hypothalamic PRF.
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Neurohypophyseal Hormones
Antidiuretic Hormone or Vasopressin
A part of the antidiuretic hormone (ADH) produced is released to
the CSF and a part enters the anterior hypophysis through the
portal system. ADH acts in the tissues through binding to specific
receptors coupled with protein G. There are two types of receptors:
activation of V1 stimulates hydrolysis of phosphatidylinositol and
mobilization of intracellular calcium. Two subunits, V1a and V1b,
have been described. V1a, found in the liver and kidney, has a
potent vasoconstricting effect, whereas stimulation of V1b located
in the anterior hypophysis, triggers corticotropin secretion. V 2
activation produces the antidiuretic and vasodilatory effects of
ADH, as well as its ability to increase the release of coagulation
Factor VIII. ADH does not cross the placental barrier and is
present in the neurohypophysis after the 11th week of gestation.12
One of its functions during fetal life may be to contribute to
circulatory adjustment, facilitating the movement of water across
the placenta from the mother to the fetus.12
ADH conserves water, increasing urinary concentration. At the
collecting tubule, it enhances the hydro-osmotic flow of water
from the tubule lumen to the medullary interstitium and contributes to maintaining constant the osmolality and volume of the
body fluids. Occupation of 2.5% of the V2 receptors by ADH produces a complete antidiuretic effect. The release of ADH depends
on several stimuli. The hypothalamus, the neurohypophysis, and
the kidneys form an interrelated system that is in charge of body
fluid homeostasis. The angiotensin-renin axis, which regulates
sodium balance, is also connected with the hypothalamic-ADHkidney system. The thirst center regulates the intake of water,
whereas the kidney regulates water excretion. The effective osmolality of the intracellular liquid is the main regulator of thirst
and of ADH release.
Effective osmolality = mean osmolality (urea + glucose 7.5)
The osmoreceptor cells, located in the anterior hypothalamus,
change their volume through the flow of water across their cell
membrane in response to changes in osmolality. In this way, there
is stimulation of the neurons that transmit nerve impulses to the
supraoptic and paraventricular nuclei, provoking ADH release, and
to the cortex to detect the sensation of thirst. The blood pressure
and volume of the blood are secondary determinants of ADH
secretion and of thirst. The receptors related to volume are located
in the carotid sinus and the aortic arch (high-pressure baroreceptors) and in the left auricle and lung (low-pressure receptors).
Decreases in plasma volume stimulate ADH release by reducing
the tonic inhibitory impulses sent by the vagus and glossopharygeal
cranial nerves (after multiple synapses in the brainstem) from the
left atrium toward the hypothalamus. This process is a consequence
of the effect on the distention receptors of this structure and the
pulmonary veins. Positive-pressure ventilation, quiet standing, and
vasodilatation also act upon this mechanism, which permits
restoration of plasma volume, even, at times, surpassing osmotic
inhibition. Sensitivity is lower than that of the osmoreceptors
because a decrease of 10 to 15% of circulation volume is required
to produce a significant release of ADH. Once this point is reached,
ADH concentrations can increase up to 10-fold the values induced
by hypertonicity. Increased plasma volume inhibits ADH release.
Activation of the carotid and aortic baroreceptors by hypotension
produces a release of ADH. High concentrations of ADH may
cause an intense vasoconstriction. Hypothalamic neurotransmitters and neuropeptides intervene in the regulation and modulation
of ADH release. Catecholamines influence endogenous ADH
release by activation of the alpha and beta receptors. Angiotensin
II is a potent stimulator of ADH release in situations of hypovolemia. Acetylcholine stimulates ADH release by its nicotinic effect
on the supraoptic neurons. Although the importance of these
neurotransmitters and peptides has not been completely defined,
the antidiuretic action produced by stress, vomiting, and pain
indicates that there could be an influence of the higher neural
centers on ADH release. The pharmacologic agents that stimulate
ADH secretion are nicotine, morphine, barbiturates, vincristine,
cyclophosphamide, clofibrate, chlorpropamide, and some tricyclic
anticonvulsants and antidepressants. Ethanol inhibits neurohypophyseal function under several conditions. Some narcotic antagonists also inhibit ADH release. The hormones of the suprarenal
cortex and the posterior hypophysis possess an antagonistic effect
on water excretion. Cortisol elevates the osmotic threshold for
ADH release. It also acts directly on the renal tubules, decreasing
the permeability to water and increasing the free water in the
absence of ADH.
Oxytocin
Oxytocin is a nonapeptide, synthesized in the paraventricular and
supraoptic nuclei of the hypothalamus. It is transported in
neurosecretory granules via neuronal axons to the neurohypophysis, where it is stored together with an oxytocin-specific
neurophysin. The release of oxytocin is stimulated by nerve
impulses originating in the hypothalamus, which cause depolarization of the neurosecretory terminals of the posterior lobe of the
hypophysis. The subsequent release of oxytocin is a calciumdependent process. The estrogens stimulate the release of oxytocin
and neurophysin. Oxytocin acts on the membranes of myoepithelial and myometrial cells, increasing their force of contraction.
The sensitivity of the myometrium to oxytocin increases during
pregnancy. Hypophyseal concentrations of oxytocin similar to
those in women are also found in men, though their function
is not known. Oxytocin is metabolized in the liver and kidney. The
uterus and mammary gland also contribute to its elimination. It
is used clinically to induce labor, to control hemorrhage after
incomplete abortion, and to treat altered milk flow. Its antidiuretic
action is maximum after the administration of 40 to 50 mU/min.
PINEAL GLAND OR EPIPHYSIS

The pineal gland or epiphysis is a single, pinecone-shaped organ
located on the roof of the third ventricle, close to the choroid
plexuses and in front of the anterior quadrigeminal tubercles. It is
innervated exclusively by postganglionar sympathetic fibers
proceeding from the superior cervical ganglia. The pineal is
derived from the ependymal cells of the third ventricle and is
formed of parenchymatous cells (pinealocytes), sustained by a
network of neuroglia. The pinealocytes have -adrenergic receptors acted upon by norepinephrine, which is released by the
sympathetic nerve terminals and controls melatonin synthesis
from serotonin. It also receives fibers from the CNS system
through the pineal stalk. The neurotransmitters of the pineal gland
are peptides or acetylcholine whose neuronal bodies are localized
in several brain nuclei.
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The physiologic significance of the pineal gland is not known,
although it is recognized that the pinealocytes have neurosecretory
ability. A wide range of biogenic amines are found within the
pineal gland including serotonin, norepinephrine, histamine,
dopamine, melatonin, GABA, and vasotocin. It also contains
hypothalamic peptides such as TRH and GH-inhibiting factor or
somatostatin. Melatonin is a pineal gland hormone synthesized
from tryptophan and serotonin. One of the most important factors
that regulate melatonin secretion is the light-dark cycle. Stimulation by light inhibits secretion and prolonged darkness increases
it. Nocturnal levels are 10-fold higher than diurnal levels. The light
information reaches the pineal gland by means of a multisynaptic
nervous pathway connected with the retina. Increases in sympathetic activity, intense hypoglycemia, stress, and l-dopa administration stimulate its secretion. The -adrenergic inhibitors
decrease its synthesis and secretion. Melatonin inhibits gonadal
function by decreasing gonadotropin secretion. This effect seems
to take place in the hypophyseal-hypothalamic system and,
perhaps, directly in the gland itself. The function of melatonin in
the brain is the induction of sleep.
THYROID GLAND
The thyroid hormones, T4 and T3 exert important actions during
fetal development participating in the growth, differentiation, and
maturation of the CNS. After birth and throughout life, the
thyroid hormones participate in the regulation of several basic
metabolic processes, such as oxygen consumption and the metabolism of the energy substrates and proteins. All organ systems
require minimum levels of these hormones for normal functioning.
Anatomy
The thyroid is the first gland to appear during embryonic development and can be identified at 16 to 17 days of gestation. Of
endodermal origin, the thyroid arises from a proliferation of the
pharyngeal epithelium, migrating caudally at 40 to 50 days of
gestation to attain its definitive position.13 It remains joined to its
primitive origin by the thyroglossal duct, which later disappears.
The distal part of this duct persists in the adult and can undergo
hyperplasia, giving rise to a contiguous structure called the
pyramidal lobe. The ability of the thyroid to concentrate iodine
appears in the second embryonic trimester and hormone production begins at 20 to 24 weeks of gestation. The thyroid is an
unpaired gland located in the anterior region of the neck in front
of the cricoid cartilages. It has two symmetrical lobes on either
side of the trachea and larynx. These lobes are joined by a part of
the glandular structure located above the trachea, called the
isthmus. If the pyramidal lobe is present, it is attached to the
isthmus. The thyroid is large, weighing 1 to 3 g in the newborn
and 20 g in an adult. It is richly vascularized by the superior
thyroid arteries, arising from the external carotids, and by the
inferior thyroid arteries, which arise from the subclavian artery.
The amount of blood that reaches this gland (46 mL/min/g) is
greater than the flow to a highly vascular organ such as the kidney
(3 mL/min/g). With increases in size and hyperfunctioning of the
gland, vascularization increases accordingly, at times surpassing
1 L/min, giving rise to a thrill and a thyroid murmur. The thyroid
is innervated by adrenergic and cholinergic systems, with branches
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189
arising from the cervical ganglia and the vagus nerve, respectively.
This innervation regulates the vasomotor system and, thus, the
blood flow of the gland. A fine network of adrenergic fibers
terminates at the thyroid cells, connecting with them through
specific receptors, thereby demonstrating a direct function of this
system in the regulation of thyroid function.
The anatomic relation of the thyroid to the recurrent nerves
and to the parathyroid glands is important. The recurrent
laryngeal nerves arise from the vagus nerve on both sides. The
right recurrent laryngeal nerve originates where the vagus nerve
crosses the first portion of the subclavian artery. It passes behind
this artery and descends 1 to 2 cm from the trachea next to the
thyroid where it penetrates the posterior larynx at the cricothyroid
articulation. The left recurrent arises from the vagus where it
crosses the aortic arch, passes behind the arch, and ascends next
to the thyroid within 1 to 2 cm of the trachea until it reaches the
laryngeal muscles. Although their exact location varies, the two
pairs of parathyroid glands usually lie on the posterior surface of
the thyroid lobes. The thyroid gland has a unique histologic
structure within the endocrine system, being formed by groups of
follicles of varying size (15500 mm in diameter). The follicle is
formed by a layer of cylindrical epithelial cells filled with a mainly
colloidal substance and is the functional unit of the gland.
Physiology
Iodine is an essential trace element for all vertebrates, being required for the biosynthesis of the thyroid hormones. The body
obtains iodine by ingestion, and the requirements for this
substance increase with age. The range in children is 90 g/kg/d
in the breast-fed infant to 120 g/kg/d in children 10 years old.
Adult requirements are approximately 150 g/kg/d.14 During
pregnancy and lactation, it increases to up to 200 g/kg/d. Iodine
is absorbed in the proximal small intestine in both the organic and
the inorganic forms. The inorganic form makes for the majority,
after hydrolysis of the organic compounds produced in the
gastrointestinal tract. The release of iodide after enzymatic
hydrolysis is later completed in the liver and kidney. In this way,
iodide forms part of the extracellular fluid iodide pool, which in
iodine-rich conditions, reaches concentrations of 1 to 1.5 mg/
dL/min. As it passes through the circulation, this iodide is taken
up by the kidneys, thyroid gland, gastric parietal cells, and salivary
glands. Iodide uptake by the parietal cells and the salivary glands
is re-absorbed and recovered by the iodide pool; thus, there is
competition only between the kidney and the thyroid. Renal
iodide clearance is 30 to 40 mL/min and is not related to humoral
factors or iodide concentrations. For this reason, the thyroid is
subjected to a degree of competition unrelated to its necessities.
Thyroid iodide clearance varies according to the functional state
of the gland. The intrathyroid iodine pool is, by far, the largest in
the organism. When the availability of iodine is abundant, this
pool reaches 8000 mg, the majority in the form of iodinated amino
acids. Iodine elimination is carried out mainly by the kidneys.
With a daily ingestion of 500 mg, for example, 488 mg is excreted
mainly by the kidney as iodide, and the remaining 12 mg is
eliminated in the feces, essentially in the form of organic iodine.
The main function of the thyroid gland is to generate and
release the thyroid hormones, T4 and T3, produced in the thyroid
follicles.15,16 The complex process of thyroid hormone biosynthesis
can be summarized as follows: (1) uptake of plasma iodine by
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means of the iodine pump in the thyroid cell, resulting in an iodine

concentration 40 times greater than plasma levels; (2) organization
of iodine by the peroxidases; (3) iodination of the tyrosyl
components of thyroglobulin (glycoprotein previously formed by
the thyroid cell and principal component of follicular colloid) for
the elaboration of monoiodotyrosine (MIT) and diiodotyrosine
(DIT); (4) coupling of the iodotyrosines by means of peroxidase
action to form T3 and tetraiodothyronine or T4; and (4) thyroid
cell uptake of colloid droplets by pinocytosis or endocytosis, and
after proteolytic cleavage of the thyroglobulinthyroid hormone
bonds, release of the hormone to the circulation.
The thyroid gland forms a part of the hypothalamicadenohypophysealdependent endocrine system. Its principal
mechanism of functional regulation is TSH negative feedback. The
thyroid is also governed by a system of autoregulation, separate
from TSH secretion, and closely related to the amount of iodine in
the organism.17 The more iodine there is in the diet, the less is
taken up by the thyroid and vice versa. The rapid administration
of considerable amounts of iodine notably reduces the organification of iodide, a phenomenon known as the Wolff-Chaikoff
effect. The effect is transitory; if the supply continues, the gland
adapts to the situation, and escape occurs, in which thyroid
function may even rise above normal. Nearly the total amount of
circulating T4 is strongly bound to various proteins, mainly a
globulin, thyroxine-binding globulin (TBG); a prealbumin,
thyroxine-binding prealbumin; and albumin, which carry 70 to
75%, 15 to 29%, and 5 to 10% of the transporting function, respectively. T3 transport is carried out by TBG and, to a small degree,
by albumin. Only the free fraction is responsible for biologic
actions in the peripheral tissues. Only 0.03% of the total amount
of T4circulates freely. The percentage of free T3 is much greater,
reaching 0.3% of the total hormone. Thus, although the total
concentrations of the two hormones are very different, the levels
of biologically active free fractions are more similar. Normal
serum concentrations of the thyroid hormones in pediatric patient
are listed in Table 124. The daily secretion of T4 is approximately
80 mg. Approximately 35% of this production is converted in the
periphery into T3, constituting 80% of the circulating T3. Likewise,
35% of the T4 produced is transformed into reverse T3 (rT3), which
has no known metabolic effects.
The effect of the thyroid hormones extends to all the organs
and tissues. These hormones participate in morphogenesis,
growth differentiation, and development by regulating numerous
metabolic processes such as oxygen consumption, thermogenesis,
mineral balance, and the synthesis and breakdown of proteins,
carbohydrates, and lipids. Deficiencies of the thyroid hormones
produce several effects depending on age. During fetal and neona-
tal development, serious alterations of the CNS are produced and

when a deficit occurs before growth is complete. The mechanism
of action of the thyroid hormones in the peripheral tissues (Figure
123) has not yet been clearly defined. They exert their action after
they are introduced in the cell, but by contrast to the steroid
hormones, they do not require binding to cytosolic receptors to
penetrate the cell nucleus. The nuclear receptors of the thyroid
hormones have been recognized for some time, but recently, two
types of receptors (TRa and TRb) have been identified and cloned.
The binding of T3 to these nuclear receptors gives rise to the T3-TR
complex, which in turn functions by binding to specific DNA
sequences or response elements (TRE, thyroid hormone response
element) found in the regulating regions of the genes that respond
to thyroid hormones. There are different types of TREs because
T3 controls the expression of numerous genes. This is the main
mechanism of action of the thyroid hormones through which the
synthesis of various proteins is regulated. Besides this central
mechanism, the thyroid hormones activate mitochondria, through
the action of a specific mitochondrial protein and also a primary
effect on the cytoplasmic membrane regulating the transcellular
flow of substrates and cations. Through these highly complex
mechanisms, the thyroid hormones activate energy metabolism
by increasing calorie consumption and regulate the growth and
maturation of tissues and the turnover of numerous substrates,
vitamins, and hormones in the body. The biologic activity of T3 is
several times greater than that of T4 and its metabolic effects are
more rapid. T3 metabolism is also faster, with a turnover three or
four times greater than that of T4. These data demonstrate the
importance of T3 in determining the metabolic state of the person
and cast doubt on the intrinsic activity of T4. It may be that all the
actions of T4 are produced after its peripheral transformation into
T3. This metabolic process constitutes a significant extraglandular
regulation mechanism of thyroid function. Various clinical situations are characterized by decreased peripheral conversion of T4
into T3, which is almost always accompanied by increases in rT3.
Thyroid gland dysfunction, with overproduction or underproduction of T3 or T4, may result in adverse patient responses during
the perioperative period. The overproduction of thyroid hormones results in an exaggerated response to surgical stimulation
and potentiates the administration of medications that stimulate
the sympathetic nervous system. Modified drug metabolism can
produce organ toxicity under anesthesia (hepatic toxicity with
volatile anesthetic drugs and nephrotoxicity with enflurane).18,19
Controlled studies in hyperthyroid patients have not demonstrated an increased requirement for anesthetic agents, despite the
clinical impression to the contrary, but the elevations in body
temperature in these patients can alter drug metabolism as well as
TABLE 12-4. Normal Serum Concentrations in Pediatric Patient (mean 2 de)

Age
T4, mg/dL
T3, ng/dL
Umbilical cord
13 d
24 wk
412 mo
15 y
510 y
1015 y
10.2 (7.413)
17.2 (11.822.6)
11 (715)
11 (7.816.5)
10.5 (7.315)
9.3 (6.413.3)
8.1 (5.611.7)
45 (1575)
124 (32216)
190 (160240)
176 (110280)
168 (105269)
150 (94241)
113 (83213)
TBG, mg/dL
TSH, mU/mL
5.6
5.0
4.4
4.2
3.8
3.3
9 (<2.517.4)
8 (<2.513.3)
4 (0.610)
2.1 (0.66.3)
2 (0.66.3)
2 (0.66.3)
1.9 (0.66.3)
de = dose equivalent; T3 = triiodothyronine; T4 = thyroxine; TBG = thyroxine-binding globulin; TSH = thyroid-stimulating hormone.
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191
Physiology of Calcium
and Phosphorus Metabolism
Figure 12-3. Mechanism of action of the thyroid hormones.
hemodynamic and ventilatory needs. Neuromuscular blocking

agents need to be carefully selected with avoidance of agents such
as pancuronium which may induce tachycardia, and those that
may result in histamine release. In the reversal of nondepolarizing
neuromuscular blockade, glycopyrrolate is a logical choice because
it has less chronotropic effect than atropine. The underproduction
of thyroid hormones cause a hypodynamic cardiovascular state
with bradycardia, decreased cardiac output and stroke volume, as
well as exaggerated sensitivity to depressant drugs, decreased
intravascular volume with increased systemic vascular resistance,
and unresponsive baroreceptor reflexes. There may be reduced
metabolism of anesthetic drugs, particularly opioids. Reduced
adrenal cortical function often accompanies hypothyroidism.
PARATHYROID GLANDS
Anatomy
The parathyroid glands are paired organs that originate in the
endodermis of the third (inferior parathyroids) and fourth
(superior parathyroids) branchial pouches. There are normally
four parathyroids in humans, although in 2 to 5.5% of the
population, six to eight are present. The parathyroids are small,
weighing 30 to 50 mg each (somewhat more in women). They
migrate with the thyroid isthmus, a fact that determines a variable
ectopic localization, anywhere from the angle of the mandible to
the pericardium. The parathyroids may be located in the thyroid
gland capsule or embedded in the thyroid tissue but are always
individualized by a capsule of conjunctive tissue, through which
vascular and nervous elements penetrate to the interior. The
parathyroid glands are composed of three main cell types: chief,
oxyphil, and clear cells. The chief cells are the most abundant and
are responsible for secretion of parathyroid hormone (PTH) and
a carrier protein (SP-I) whose function has not been clearly
defined.20 During fetal life, these cells produce PTH-related
peptide (PTHrP), which is involved in fetal bone metabolism and
transplacental transport of calcium.21 The oxyphilic cells comprise
less than 5% of the cells of the parathyroid gland. They are dispersed among the chief cells and their function is unknown. The
clear cells are larger cells that do not seem to have secretory function. They are prominent in some cases of glandular hyperplasia.
PTH, together with 1,25-(OH)2-D3 (active metabolite of vitamin

D) and calcitonin, forms a complex endocrine system that controls
the metabolism of calcium and phosphorus in all vertebrates.
Other factors (diet, physical agents), hormones (GH, thyroxine,
gonadal hormones, cortisol, somatomedins), and some incompletely characterized substances also play roles in various aspects
of the regulation and modulation of effector organ response to
these hormones. Calcium, a bivalent metal, is the most abundant
cation of the organism accounting for 2.24% of lean body weight
in adults. It is found in the musculoskeletal system and participates
in numerous biologic processes that require a constant, precise
level of calcium. It is essential for enzymatic system function,
blood coagulation, hormonal action, nerve and muscle excitability,
and muscle contractility. Ninety-nine percent is found in the bone,
forming insoluble and relatively inaccessible hydroxyapatite crystals. The remainder is found mainly in muscle and the extracellular fluid. From 0.5 to 1% of the bodys calcium is rapidly
exchangeable with plasma. The normal serum calcium concentration is 8.5 to 10.5 mg/dL. Regulation is precise and variations do not exceed 1.5 mg/dL. Total serum calcium is composed
of three fractions. The ionized fraction (47%) is biologically active
and directly regulated by the hormones. The ionized fraction
together with the complex fraction (6%), which is bound to
phosphates, citrates, and bicarbonate, constitutes the diffusible
fraction. The protein-bound fraction (47%) is nondiffusible. Four
fifths of the total circulating protein-bound calcium is bound to
albumin and the remainder to globulin.
Under normal conditions, 30 to 40% of dietary calcium (600
1000 mg) is absorbed in the small intestine. The nonabsorbed
calcium plus the content of the secreted digestive juices (200 mg/d)
make up the fecal excretion. This process is influenced by the
calcium content in the diet and other components of the diet with
various factors increasing absorption (lactose, fatty acids) or
decreasing absorption (phosphates, phytates). The net calcium
absorption is generally equivalent to urinary excretion. Calcium
excretion to the intestinal lumen is a nonregulated constant
process, whereas net absorption is regulated by 1,25-(OH)2-D3.
Daily adult calcium requirements are 500 to 600 mg/d, but given
the variability of the daily dietary ingestion, 800 mg/d is recommended.22 An additional 200 mg is required during growth, lactation, and pregnancy and in persons older than 60 years. The
calcium requirement in children aged 1 to 10 years is at least 800
mg/d.22
Calcium is absorbed in the intestine by two processes, passive
diffusion and active transport by carrier proteins, whose synthesis
is induced by 1,25-(OH)2-D3. Passive diffusion is produced when
calcium concentrations in the lumen are very high, generating a
positive concentration gradient. The bone is the main reservoir of
calcium, but exchange between bone and plasma is low. The
mobilization of calcium from the bone is subject to cell control
and contragradient transport. Calcitonin decreases the mobilization of calcium and PTH increases it. Calcium is filtered by the
renal glomeruli. There is 99% tubular re-absorption of the filtrate,
of which only 10% is regulated by PTH and 1,25-(OH)2-D3 in the
distal tubule. The capacity of the kidneys to eliminate calcium
is limited. Thus, in conditions of increased bone resorption or
greater intestinal absorption, the excretory function can be
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overwhelmed, producing hypercalcemia. Likewise, in hypocalcemia, the kidneys capacity to decrease calcium excretion (~100
mg/d) is clearly limited. The physiologic response to calcium
overload includes by a fast mechanism that inhibits PTH secretion
and its effects in bone and kidney and a slow mechanism that
decreases 1,25-(OH)2-D3 synthesis and its intestinal effects.
The phosphorus content in the body is approximately 700 g, of
which 85% is in the skeleton and 15% in soft tissue and body fluid.
Osseous phosphorus is intimately associated with calcium, forming crystals of hydroxyapatite (amorphous calcium phosphate).
Extraosseous phosphorus is essentially intracellular. Very little is
inorganic, because the majority is bound to carbohydrates, lipids,
and proteins. Phosphorus is necessary for cell function and
organic metabolic processes because it regulates a number of
enzymes. It plays an important role in providing oxygen to the
tissues as well as regulating the levels of 2,3-diphosphoglycerate
and adenosine monophosphate (ATP) in the red blood cells. It
forms a part of the urine and plasma buffer systems and is involved
in the energy-storing processes of the organism. An adult ingests
approximately 1400 mg/d of phosphorus, 60% of which is
absorbed by passive diffusion and active transport (similar to that
of calcium) mediated by an 1,25-(OH)2-D3-stimulated carrier
protein. Intestinal absorption is concentrated in the duodenum
and ileum. There is a linear relationship between net absorption
and dietary phosphorus intake. Under normal conditions, the
amount of phosphorus excreted in the urine is equal to the net
digestive absorption. Normal plasma phosphorus varies from 2.2
to 4.4 mg/dL in adults. Although levels are higher in children, they
decrease after puberty to reach normal adult levels. Ninety percent
of inorganic phosphorus circulates in a free form or bound to
monovalent and divalent anions and 10% is bound to proteins. Of
the 7000 mg of phosphorus that is filtered daily by the kidneys,
6100 mg is re-absorbed in the proximal tubule by a sodiumdependent, saturable process (maximum tubular transport) and
900 mg is excreted in urine. PTH is the main regulator, inhibiting
renal re-absorption of phosphorus, whereas calcitonin and 1,25(OH)2-D3 are less important. Phosphorus regulation in hyperphosphatemic and hypophosphatemic states involves both
immediate and delayed mechanisms. Decreases in serum phosphorus produce initial stimulation of 1,25-(OH)2-D3 synthesis in
the kidney, greater mobilization of calcium and bone phosphorus,
and efficient adaptation of renal tubule re-absorptive capacity. The
1,25-(OH)2-D3 stimulates intestinal absorption of calcium and
phosphorus and enhances mobilization of these ions from the
bone. This cascade of events inhibits release of PTH, which in turn
increases renal phosphorus re-absorption with a tendency to
restore normal phosphorus levels. In hyperphosphatemia, there is
a decrease in ionized calcium which stimulates PTH release, thus
provoking phosphaturia and restoring serum phosphorus to
normal. The delayed defense mechanism of the organism to
prolonged variations in phosphorus levels depends mainly on the
re-absorptive capacity of the renal tubule, which increases or
decreases according to phosphorus secretion. This mechanism is
largely PTH-independent, and an interval of more than 48 hours
is required to reach the maximum effect.
Parathyroid Hormone or Parathormone

Pro-PTH, a 90-amino acid fragment, is obtained from preproPTH, a 115-amino acid precursor, in the smooth endoplasmic
reticulum. Cleavage of another hexapeptide results in conversion
to PTH, a single-chain polypeptide containing 84 amino acids.

PTH is found within the free chief cells or stored in secretory
granules for later release. The intact hormone goes through at least
one more cleavage in the secretory granules to generate inactive
carboxy-terminal fragments that can be released with the intact
hormone to the circulation. The precursors (prepro-PTH and proPTH) do not have known biologic activity and are not detected in
the circulation. The main regulator of PTH secretion and storage
is plasma ionized calcium through a negative-feedback mechanism. When plasma ionized calcium reaches high levels, a PTH
breakdown pathway is quickly activated within the chief cells,
provoking PTH proteolysis without affecting the hormonal
precursors. Low levels of calcium ion inhibit this process. A
nonsuppressible basal PTH secretion in proportion to the mass of
chief cells in the gland is independent of extracellular calcium. The
extracellular magnesium concentration also participates in regulation of PTH secretion. Thus, important deficits of magnesium
would produce decreases in hormone production with resistance
to its effects in the peripheral target cells.
PTH metabolism occurs in the liver, kidney, and to a lesser
degree, bone. In the liver and kidney, intact PTH is cleaved to form
inactive carboxy-terminal and active amino-terminal fragments.
The carboxy-terminal fragments, together with a small proportion
of the amino-terminal fragments and intact PTH, are eliminated
mainly by glomerular filtration. Re-uptake of the amino-terminal
fragments occurs in the tubules. In parathyroid gland venous
blood, intact PTH makes up 80% of secretion and the fragments
20%, whereas at the peripheral level, the contribution of carboxyterminal fragments is 80% and PTH is reduced to 10%. The
amino-terminals are biologically active, but have a short circulating half-life, similar to that of intact PTH (~20 min), whereas the
carboxy-terminals are inactive and have a longer half-life (40 min).
PTH plays a pivotal role in the homeostasis of extracellular
calcium and is essential for protecting the organism against
hypocalcemia by regulating mineral mobilization from the bone,
kidney, and intestine (Figure 124). In the kidney, PTH produces
a rapid and dramatic increase in urinary phosphate excretion,
independent of changes in glomerular filtration. This is carried
out by decreases in proximal tubule re-absorption of this ion. PTH
induces increased tubular re-absorption of calcium and magnesium and urinary excretion of bicarbonate by inhibiting its proximal tubule re-absorption. Hypercalciuria can predominate in
situations of chronic hypercalcemia despite elevated PTH levels.
This is explained by the fact that PTH in the distal tubule affects
only 10% of the calcium that is re-absorbed. Ninety percent of the
filtered load of calcium is re-absorbed by a nonsaturable PTHindependent process and is linked to sodium transport in the
proximal tubule and Henles loop. cAMP is involved in the PTHinduced phosphaturia mechanism. PTH is bound to a receptor on
the basal tubular cell, activating the adenyl cyclase system and
increasing cAMP in the target cells.23 In the skeleton, PTH initially
stimulates osteocyte osteolysis and bone resorption by preexisting
osteoclasts, generates new osteoclasts, and depresses osteoblast
function. The final effect of these processes is increased calcium
and phosphate release to the blood. In the long term, PTH
stimulates generation of coupling factors for bone remodeling and
can even override direct inhibition of the osteoblasts and provoke
differentiation of cells with osteoblast function and formation of
new bone.24 Because the osteoblasts, but not the osteoclasts, have
PTH receptors, it is possible that a part of the effects of this
hormone on the osteoclasts is mediated by the former. It has been
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193
Figure 12-4. Biologic activity of parathormone (PTH).
demonstrated that PTH is less effective in promoting bone

resorption in the absence of 1,25-(OH)2-D3. PTH induces renal
synthesis of 1,25-(OH)2-D3, which stimulates intestinal absorption
of calcium and phosphorus.
Vitamin D
Vitamin D and its metabolites form a group of steroid compounds
that also play an active role in the regulation of calcium and
phosphorus metabolism. Vitamin D3 (cholecalciferol) and vitamin
D2 (ergocalciferol) are absorbed from food by passive diffusion in
the presence of biliary salts in the gastrointestinal tract. These
compounds, bound to chylomicrons, pass through the lymphatic
system to the general circulation, where they circulate bound to a
carrier protein (alpha globulin). Under normal conditions,
vitamin D is mainly produced in the skin (granular stratum of the
epidermal cells). Here, the ultraviolet rays of the sun transform
the provitamin 7-dehyrocholesterol into previtamin D3 by nonenzymatic photochemical conversion (Figure 125).25 Previtamin
D3 then slowly converts to vitamin D3 at body temperature. It
circulates bound to alpha globulin, a carrier protein common to all
the vitamin D metabolites, but with an affinity 200 times greater
than for vitamin D3. This protein is no more than 3% bound with
vitamin D3 in physiologic conditions, and thus, it is a large
potential reservoir. Endogenous levels of vitamin D3 are tightly
controlled because, despite prolonged exposure to sunlight,
increases are minimum. This control is probably through the
regulation of vitamin D release in the skin and not by inhibition
of hepatic 25-hydroxylase. The adipose and muscle tissues contain
the largest deposits of vitamin D in the organism.
Synthesis of the active form of vitamin D is carried out by
successive hydroxylations. The first hydroxylation results in 25(OH)-D3 production and takes place primarily in the liver, with
90% occurring in the microsomal system. This initial hydroxylation also occurs in the kidney and intestine. Although there is no
retroactive inhibition of 25-(OH)-D3 on 25-hydroxylase, regula-
Figure 12-5. Vitamin D, metabolism, and biologic activity.
tion seems to be influenced by the concentration of substrate

(vitamin D3). Calcium, phosphorus, and PTH have no influence
on the activity of this enzyme, although 1,25-(OH)2-D3 and
anticonvulsant medications depress it by incompletely defined
mechanisms. The 25-(OH)-D3 is the most abundant vitamin D
metabolite in the blood and is 100 times less powerful in
stimulating intestinal calcium absorption than 1,25-(OH)2-D3. In
the mitochondria of the proximal tubules of the kidney, 25-(OH)D3 is hydroxylized in position 1 to produce 1,25-(OH)2-D3 the
most active and biologically potent metabolite of vitamin D for
inducing bone resorption and intestinal absorption of calcium and
phosphorus. It circulates at very low concentrations (~30 pg/mL)
and has a half-life of 2 to 4 hours. A second hydroxylation takes
place in the kidney and, through 24R-hydroxylase, gives rise to
24,25-(OH)2-D3. With a half-life of 6 hours, this compound is
present in higher quantities in plasma (15 ng/mL) and has a
regulation contrary to that of 1,25-(OH)2-D3. It has little biologic
activity, similar to that of 25-(OH)-D3.
PTH secretion is stimulated in hypocalcemia and this, in
turn, stimulates renal 1-hydroxylase, which results in greater
synthesis of 1,25-(OH)2-D3. This process tends to restore normal
calcium concentrations and at the same time suppresses 24hydroxylation. The gradual increases in calcium produces a
reduction in 1,25-(OH)2-D3 synthesis and parathyroid gland
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activity. Type 1-hydroxylase activity is also present in the bone,

intestine, and platelets, and type 24-hydroxylase activity is present
in the intestine, cartilage, and bone. Hypophosphatemia increases
1,25-(OH)2-D3 levels and decreases production of 24,25-(OH)2D3. Similar to the effects of calcium, increased serum phosphorus
inhibits the production of 1,25-(OH)2-D3 and stimulates synthesis
of 24,25-(OH)2-D3. There are approximately 20 metabolites of
vitamin D, with biologically inert calcitroic acid being the main
metabolite of 1,25-(OH)2-D3. Excretion of vitamin D metabolites
takes place mainly through the bile, and there is evidence of
enterohepatic circulation for 25-(OH)-D3 and 1,25-(OH)2-D3.
Vitamin D regulates the intestinal absorption of calcium and
phosphorus. Ionized calcium is absorbed by the intestinal tract by
an active transport process (65% in the ileum and 17% in the
jejunum) and by passive diffusion (only 15%). The active transport
is vitamin Ddependent and is characterized by the entrance of
calcium through the microvilli of the intestinal cells against the
concentration gradient and by active expulsion of the ion into the
blood through the lateral basement membrane. Neither calcitonin
nor PTH directly affects this absorption. The process is regulated
by 1,25-(OH)2-D3, which traverses the basolateral border of the
intestinal mucosa cell and interacts with a specific receptor. The
1,25-(OH)2-D3 receptor complex enters the nucleus, inducing the
production of calcium and phosphorus carrier protein mRNAs.
Two other enzymes related to intestinal calcium absorption,
alkaline phosphatase and calcium-dependent ATPase, have been
isolated. After migrating from the luminal pole to the basolateral
border of the intestinal cell, calcium passes into the blood together
with phosphorus. This process requires a high sodium gradient.
The role of vitamin D in regulation of the passive diffusion process
is not known. In the bone, 1,25-(OH)2-D3 promotes bone
resorption, which in conjunction with its stimulating action on
the net calcium absorption in the intestine favors a mineral-rich
environment in the areas of bone remodeling, making possible
mineralization of new bone matrix. It has been provend that 1,25(OH)2-D3 stimulates differentiation of the osteoclast progenitors to
mature cells, an effect that is enhanced by PTH. In the kidney,
1,25-(OH)2-D3 increases tubular re-absorption of calcium and
phosphorus.
Calcitonin
Calcitonin is a hormonal, 32-amino acid polypeptide that is
secreted by the parafollicular C cells of the thyroid gland in
response to hypercalcemia. Its primary physiologic effect is the
inhibition of bone resorption. The C cells originate in the fetal
neural crest, migrate caudally, and subsequently localize in the last
brachial pouch. They later reach their definitive site in the thyroid
gland and, to a lesser degree, in the thymus and parathyroid
glands. They are mainly found in the internal and medial part of
the thyroid lobes. The gene responsible for calcitonins complex
biosynthesis is located on chromosome 11. The hormone is
formed from a precursor molecule, preprocalcitonin, which
cleaves to become procalcitonin. This large polypeptide gives rise
to calcitonin at its median region and to 21-amino acid katacalcin
from its extreme amino-terminal. Katacalcin has effects that serve
to lower serum calcium values. It is secreted simultaneously with
calcitonin in pathologic states including medullary carcinoma of
the thyroid.
The calcitonin gene codifies a protein, calcitonin generelated
peptide (CGRP), which has a weak action of lowering serum
calcium, although its main effect is vasodilatation. This peptide is

also produced by certain tumors and, thus, can be used as a tumor
marker. In patients with medullary carcinoma of the thyroids and
other neoplasms (bronchial carcinoma), 32-amino acid calcitonin
can coexist with circulating forms of high-molecular-weight
immunoreactive calcitonin. The sequences of calcitonin have been
deciphered in different species (human, pig, sheep, cattle, salmon,
and rat) and have shown to have in common nine amino acids and
a carboxy-terminal proline amide. All are active in humans,
although their potencies are different. Salmon calcitonin is 10
times more powerful than human calcitonin, being more resistant
to breakdown and having a higher affinity for receptors in the
bone and kidney.26
Calcitonin is secreted in response to increases in plasma
calcium concentrations. When calcium concentrations exceed
9 mg/dL, there is a positive correlation between serum calcium
concentration and calcitonin levels. There is also an unidentified
relationship between calcitonin production and gastrointestinal
hormones (gastrin, cholecystokinin, glucagon), -adrenergic
catecholamines, estrogens, and vitamin D. Calcitonin intervenes in
calcium metabolism at different levels, particularly in bone, where
it inhibits osteoclast bone resorption and the activity of certain
enzymes that increase with PTH (Figure 126). This effect in the
bone is greater in situations of increased in bone remodeling (e.g.,
growth, Pagets disease) or with previous vitamin D or PTH
stimulation. With prolonged administration, its physiologic effects
decrease (escape). The hormonal action requires the activation
and participation of adenyl cyclase. The inhibitory action on bone
resorption does not accompany changes in serum calcium in
normal conditions. In the intestine, calcitonin facilitates calcium
absorption, and in the presence of calcium in the intestine, various
gastrointestinal hormones that stimulate calcitonin secretion
(gastrin, cholecystokinin) are produced. Calcitonin administration
transiently increases urinary excretion of calcium, phosphorus,
sodium, potassium, and magnesium. The phosphaturic effects are
not mediated by PTH. Calcitonin binds to specific renal receptors
with adenyl cyclase activation. In Pagets disease, calcitonin
administration has analgesic effects, which seem to be mediated
through a beta endorphin. This fact, together with the presence
of calcitonin-like peptides in the CNS, indicates its possible role as
a central neurotransmitter or modulator. The physiologic function
Figure 12-6. Calcitonin, physiologic effects.
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and importance of calcitonin are still not well established because
calcitonin deficiency does not produce a defined clinical process.
Anesthetic Implications
of Calcium Disorders
The evaluation of disturbances in calcium homeostasis must be
made by measurement of ionized calcium concentrations because
this is the physiologically active form of calcium. The ionized
calcium plasma concentration is dependent on the arterial pH
(increased by acidosis and decreased by alkalosis).
Hypercalcemia
Potential causes of hypercalcemia in the pediatric population include primary hyperparathyroidism, vitamin A and D intoxication, immobilization, malignancies, sarcoidosis, and milk-alkali
syndrome. The perioperative management is based on the maintenance of hydration and urine output to facilitate calcium excretion, avoidance of nephrotoxic medications, recognition of the
physical signs and symptoms of hypercalcemia, and continuous
monitoring of the electrocardiogram. However, there is evidence
that QT intervals may not be reliable indices of changes in plasma
calcium levels. There is no evidence that specific anesthetic techniques or medications are better in such patients. The response to
neuromuscular blocking agents may be unpredictable, and
therefore, use of short-acting agents, reduction of the initial dose,
and monitoring with a peripheral nerve stimulator are suggested.27
Hypocalcemia
A low plasma albumin concentration remains the most common
cause of a low total serum calcium concentration; however, the
ionized calcium may be normal. In infants and children, common
causes of a low ionized calcium concentration include hypoparathyroidism, acute pancreatitis, vitamin D deficiencies, hyperphosphatemia, and renal failure. The rapid infusion of calcium
chelators (edetate and citrate in same radiographic contrast media
or citrate in blood-stored transfusion), or their slow metabolism
or elimination owing to hypothermia or hepatic/renal dysfunction, can also reduce plasma calcium concentrations. Alkalosis
caused by hyperventilation or the intravenous administration of
sodium bicarbonate can alter calcium binding to proteins and
result in low ionized calcium concentrations.28 During the
perioperative period, the prompt recognition of hypocalcemia is
necessary because of the potential deleterious physiologic effects
on the cardiovascular system. Typical electrocardiographic changes (prolonged QT) or, more frequently, exaggerated hypotension,
secondary to anesthetic drug administration, are signs of the
decreased plasma ionized calcium concentration. The monitoring
of the electrocardiogram, arterial blood gases, arterial pH, plasma
albumin, and plasma ionized calcium concentrations should be
part of the intraoperative management. The effect of nondepolarizing neuromuscular blocking agents may be potentiated by
hypocalcemia. Preterm neonates, neonates of diabetic mothers,
and neonates with birth asphyxia are particularly prone to
neonatal hypocalcemia.29 In the preterm neonates, the immaturity
of the renal system results in the decreased renal excretion of
phosphate and a resulting high plasma concentration that inhibits
calcium resorption. In addition, the kidney shows a relatively
refractory response to PTH, and there is a relative and transient
Endocrine System
195
hypoparathyroid state further predisposing these patients to

hypocalcemia.30 In rare circumstances, DiGeorges syndrome,
characterized by hypoplasia or aplasia of the parathyroid and
thymus gland, congenital heart disease, and abnormalities of
chromosome 22, may present as neonatal hypocalcemia. These
patients also have associated defects in cellular immunity.31
SUPRARENAL GLANDS
The suprarenal (adrenal) glands are paired structures located
at the upper pole of the kidney. They perform the functions of
two distinct and well-differentiated endocrine glands. The cortex
of the suprarenal glands is of mesodermal origin. It synthesizes steroid hormones, which are classified according to their
predominant biologic effects into glucocorticoids, mineralocorticoids, and androgens. The suprarenal medulla, located in the
interior of the gland, is of ectodermal origin and forms a part of
the sympathetic-adrenal system, which belongs to the autonomic
or visceral system. The medulla synthesizes, stores, and secretes
catecholamines.
Suprarenal Cortex and Steroid Hormones

The suprarenal glands are small, weighing 4 to 5 g at birth, reduced
to less than 1 g in normal infants aged 1 year, and have an adult
weight of 4 to 6 g. The cortex contains 90% of their mass. They
are highly vascularized glands. Arterial blood enters by the
capsular plexus through branches of the inferior diaphragmatic
arteries, aorta, and renal branches. Venous blood drains through
a central vein to the renal vein on the left side and the inferior cava
on the right. Three zones having different cell types are recognized
in the suprarenal cortex, including the zona glomerulosa consisting of small cells; the zona fasiculata, the largest zone, formed of
clear cells with lipid inclusions; and the internal zona reticularis,
formed of eosinophilic and lipofuscin granules. The suprarenal
cortex forms in the sixth week of gestation by condensation of
mesodermal tissues adjacent to the coelomic epithelium. In this
phase, the internal fetal zone, where dehydroepiandrosterone
sulfate (DHEA-S) synthesis predominates over cortisol, and the
external definitive zone, which gives rise to the definitive cortex,
can be distinguished. After birth, the fetal zone progressively
disappears and is substituted by the definitive zone at 6 months.
Ten percent of premature and newborn babies have accessory
suprarenal glands consisting only of cortical cells. The majority of
these disappear during childhood.
The steroid hormones are derived from a common precursor,
cholesterol, which is obtained from dietary ingestion or synthesized in the cell. Eighty percent of the cholesterol used for
steroidogenesis in the suprarenal cortex cells comes from plasma
low-density lipoproteins (LDL). These are taken up by membrane
receptors and internalized. Cholesterol esters are hydrolyzed in
the lysosomes by cholesterol esterases and cholesterol is released.
The remaining 20% is synthesized by the cells from acetate and
coenzyme A (acetyl CoA). ACTH increases the number of LDL
receptors and cholesterol sterase activity, increasing the amount
of free intracellular cholesterol. In the structure of all the steroid
hormones, there is a common cyclopentanoperhydrophenanthrene nucleus. The 18-carbon atom derivatives (C-18) are known
as estranes, the C-19 derivatives as androstanes, and the C-21
as pregnanes. Conversion of cholesterol into the various steroids
is carried out by the action of an enzyme system containing
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cytochrome P450, which requires NADPH (nicotinamide adenine

dinucleotide phosphate, reduced form) and molecular oxygen,
located in the mitochondria or the endoplasmic reticulum
(microsomes).
Conversion of cholesterol to pregnenolone occurs in the mitochondria and is regulated by ACTH, angiotensin II, and potassium. In the smooth endoplasmic reticulum, under the action of
steroid 3--dehydrogenase, pregnenolone undergoes various
transformations. Pregnenolone is transformed to progesterone in
the zona glomerulosa. In the zona fasiculata and zona reticularis,
conversion of pregnenolone to 17--hydroxypregnenolone predominates. In the zona glomerulosa, progesterone follows the
pathway of aldosterone synthesis and 17--hydroxyprogesterone
follows that of cortisol. By means of hydroxylations in position 21
and the action of a P450-specific cytochrome, deoxycorticosterone
and 11-deoxycortisol, respectively, are formed. These steroids pass
to the mitochondria, where an 11--hydroxylation-specific P450
cytochrome catalyzes their transformation into corticosterone and
cortisol. All three zones of the suprarenal cortex are active. There
is a functional compartmentation because of the distribution of
the enzymes involved in steroidogenesis. Thus, aldosterone is
produced only in the zona glomerulosa, the most external part,
whereas cortisol and the androgens are synthesized exclusively in
the zona fasiculata and the zona reticularis.32 The suprarenal
glands also synthesize androgens, 19-carbon atom steroids,
which result from the removal of the lateral C-17 chain of 17-hydroxypregnenolone. Secretion of androgens with weak
androgenic activity, dihydroepiandrosterone (DHEA), DHEA-S,
and androstenedione predominates. In the peripheral tissues,
these are transformed into potent androgens. The suprarenals also
secrete small quantities of testosterone and estradiol. The
biosynthesis of steroid hormone is summarized in Figure 127.
Secretion of glucocorticoids and androgens is mainly regulated by
hypothalamic and hypophyseal factors. Aldosterone production
is controlled by a multifactorial system whose most important
components are the renin-angiotensin system and the extracellular
concentration of potassium. Suprarenal cortisol secretion is
Figure 12-7. Steroid hormone biosynthesis.
regulated by a hypothalamic-hypophyseal system through a

CRF-ACTH-cortisol negative-feedback mechanism. ACTH is a
hypophyseal peptide that acts by binding to specific receptors and
acting through the cAMP system in the presence of calcium.
ACTH has immediate effects on steroidogenesis. Within minutes,
it increases the transformation of cholesterol into pregnenolone
by activation of the enzyme required for this conversion. Chronic
ACTH secretion increases protein and DNA synthesis in the suprarenal cortex cells, provoking their hypertrophy and hyperplasia.
The glucocorticoids inhibit the secretion and synthesis of CRF,
ACTH, and arginine-vasopressin.33
The principal regulator of aldosterone production, angiotensin
II, acts by binding to high-affinity membrane receptors associated
with guanosine diphosphate (GTP)dependent proteins. Angiotensin II is produced under the proteolytic action of renin on
circulating plasma angiotensinogen (globulin of hepatic origin) to
form the decapeptide angiotensin I, which has a weak vasoconstrictor effect. Angiotensin I passes into the circulation and, by the
action of angiotensin-converting enzyme (ACE), which is present
in numerous tissues (particularly the lung), is converted into
angiotensin II. Besides inhibiting renin release, this octapeptide
has a potent direct vasoconstrictor effect and is the suprarenal
stimulant of aldosterone synthesis. Angiotensin II has a short halflife (12 min) and is converted into other peptides by the action
of an aminopeptidase. One of these peptides, angiotensin III, a
7-amino acid peptide, is also biologically active in the suprarenal
glands, although it is less potent than angiotensin II.
Renin is an enzyme synthesized by the cells of the renal
juxtaglomerular apparatus, which is located in the walls of the
afferent arterioles near the macula densa of the distal tubule.
Secretion of renin is regulated by a system of baroreceptors in the
arteries adjacent to the juxtaglomerular cells. Increases in circulating aldosterone cause augmented sodium and water retention
and an increase in blood pressure, which inhibit renin production. A decrease in the sodium concentration stimulates its release.
The sympathetic nervous system augments renin release through
the effects of norepinephrine via the -adrenergic system.
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ACE
Figure 12-8. Renin-angiotensin-aldosterone system.
A diagrammatic representation of the renin-angiotensinaldosterone system is presented in Figure 128. An acute increase
in the plasma potassium concentration causes a reduction in the
release of renin and directly stimulates aldosterone production by
the zona glomerulosa. A chronically elevated potassium concentration exerts a trophic effect on this area. The mechanism of
action of this process is the depolarization of the cell membrane
with activation of the calcium channels and a resultant increase in
intracellular calcium. There is also a small increase in cAMP.34
Other factors that intervene in the regulation of aldosterone
synthesis are ACTH, which stimulates aldosterone release, and
atrial natriuretic factor, which blocks it. Reductions in sodium
concentration increase the release of renin and, consequently, of
aldosterone. Dopaminergic agents can inhibit aldosterone release.
Secretion of DHEA and androstenodione is controlled by ACTH.
The gonadotropins do not appear to have any control in the
process. In addition, there seems to be an ACTH-independent
regulation that is dependent on a proposed hypophyseal factor
that controls androgen secretion, particularly during puberty
(adrenarche).
Many pharmacologic agents inhibit steroid biosynthesis.
Metyrapone is an inhibitor of 11-hydroxylation, but also 17-, 18-,
and 21-hydroxylation, reducing cortisol production. Aminoglutethimide inhibits the conversion of cholesterol to pregnenolone,
blocking the production of cortisol and aldosterone. Mitotane
affects suprarenal synthesis by blockade of the mitochondrial and
extrasuprarenal cortisol metabolism. It also produces intense
atrophy of the zona fasiculata and reticularis and, to a lesser degree,
the zona glomerulosa by cytolysis. Trilostane inhibits 3-dehydrogenase-isomerase hydroxysteroid. Ketoconazole inhibits the
P450 cytochrome enzymes, 11-hydroxylase, and 17,20-lyase among
others. Another substitute imidazole derivative, etomidate, used as
an anesthetic induction agent, inhibits 11-hydroxylase and desmolase and reduces cortisol synthesis in a dose-dependent manner.
Cortisol is the main circulating glucocorticoid, with 95%
bound to plasma proteins. Seventy percent is bound to a highaffinity, low-capacity globulin, transcortin or cortisol-binding
globulin (CBG), 10 to 15% is bound to a low-affinity, highcapacity protein, albumin, and less than 5% is bound to other
proteins or circulates in free form. To a lesser degree, CBG, a
Endocrine System
197
glycoprotein of hepatic origin, also transports corticosterone, progesterone, deoxycorticosterone (DOCA), prednisolone, and other
synthesized corticosteroids. Free cortisol is the physiologically
active fraction, and with changes in the fixed cortisol concentration, the free fraction is maintained constant. Cortisol has a halflife of 60 to 80 minutes. As occurs with all the steroids, its
metabolism is mainly hepatic with the production of hydrocortisol
and tetrahydrocortisone. Ninety percent is eliminated by the
kidneys in the urine, and the remainder is eliminated in the bile.
The majority of circulating aldosterone, the principal plasma
mineralocorticoid, is bound to albumin (5060%). Binding with
CBG is only 10% that of cortisol. Free aldosterone concentrations
in plasma are greater than those of DOCA, 90% of which is
protein-bound. Aldosterone has a half-life of 45 minutes and is
metabolized in the liver. The suprarenal androgens, androstendione and DHEA, have a higher affinity to the carrier protein, SHBG, than to CBG, but their affinity is lower than that of the
peripheral androgens, testosterone and dehydrotestosterone. They
are partially metabolized by the liver, but there is substantial
peripheral metabolism in the gonads, skin, and adipose tissue,
where they are interconverted into various sex steroids.
All of the steroid hormones have a common mechanism of
action. The steroid separates from its carrier protein and diffuses
through the membrane, binding to specific intracellular protein
receptors. There are two types of receptors: type I receptors are
found in low concentrations and have a high affinity for both
mineralocorticoids and glucocorticoids and type II receptors,
which are more abundant, have a decreased affinity to mineralocorticoids, acting mainly as glucocorticoid receptors. It is possible
that the specificity of the hormonal action in the mineralocorticoid target tissues depends on the presence of the enzyme, P450C11, which converts cortisol to cortisone. Cortisone has a low
affinity for type I receptors. In tissues in which this enzyme is
absent, the glucocorticoids bind to the type I receptor to exert their
biologic actions.35 The activated steroid receptor complex acquires
the capacity to bind to DNA at the level of specific regulating
sequences called, in the case of glucocorticoids, the glucocorticoid
response element (GRE). The interaction with DNA increases or
inhibits the capacity to stimulate gene expression and transcription of new mRNA.
The predominant actions of the glucocorticoids are on intermediary metabolism. They influence electrolyte and water metabolism and affect almost all organs and tissues of the organism.
In carbohydrate metabolism, cortisol is a contraregulating hormone with anti-insulin activity, decreasing insulin-receptor
binding and blunting tissue glucose uptake except in the liver,
heart, brain, and red blood cells. In the liver, it induces glucose
synthesis by stimulating gluconeogenesis and increasing glycogen
deposits, and it indirectly stimulates gluconeogenesis by inducing
the release of glucagon. In addition to inhibiting amino acid
uptake and protein synthesis, it stimulates their mobilization by
catabolism of muscle and bone. It also mobilizes fatty acids,
facilitating the activation of cellular lipase by the catecholamines
and the hypophyseal peptides. By itself, cortisol inhibits lipolysis
and blocks lipogenesis. The glucocorticoids are released mainly in
situations of stress and subsequently act to block the production
and release of many hormones and neurotransmitters including
catecholamines, prostaglandins, and kinins. In the absence of this
control, these products can lead to shock. Cortisol maintains the
arterial smooth muscle capacity to respond to the vasopressor
stimuli and participates in the maintenance of arterial blood
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pressure, cardiac output, and renal blood flow. The glucocorticoids

have a great influence on the distribution and excretion of body
water. Cortisol affects renal water excretion by decreasing secretion of ADH while augmenting the rate of glomerular secretion
and the permeability of the tubular cells, thereby enhancing free
water clearance. High concentrations of cortisol decrease intestinal
calcium absorption and increase its renal excretion, contributing
to the development of osteopenia. It also induces the production
of a factor that is essential for the maturation of the fetal lung. The
absence of this factor in premature neonates contributes to the
development of the infantile respiratory distress syndrome due to
surfactant deficiency.
In the digestive tract, the glucocorticoids inhibit DNA synthesis
and increase stomach secretion, an effect that can favor the formation of gastroduodenal ulcers. High glucocorticoid concentrations can have an anti-inflammatory activity. They modify cell
immunity and can inhibit the formation of antibodies at high
doses. They also have complex effects in the brain. Pharmacologic
doses of these hormones tend to produce euphoria. Depressive
states are common in Cushings syndrome and have also been
described, although less often, in patients with suprarenal insufficiency. Glucocorticoids suppress ACTH secretion, tend to decrease ADH release, and augment insulin and PTH.
Painful stimuli results in an immediate physiologic, humoral,
and inmune response. The stress response is a catabolic reaction
with a significant increase of cortisol, catecholamines, aldosterone,
glucagons, and other steroid hormones.36 This pituitary-adrenal
response is present in the neonate and can be prolonged in preterm neonates.37 Several studies have demonstrated a correlation
between an increase of serum cortisol concentration after surgery
and the degree of arousal and distress during the operation.38 The
harmful effects of the surgical stimuli can be reduced by a suitable
perioperative analgesia.37 Following major surgical procedures,
neonates receiving potent analgesic and anesthesia agents have
been shown to have decreased morbidity and also decreased
mortality.36
The mineralocorticoids regulate electrolyte transport across the
various epithelial tissues. Aldosterone is the principal endogenous
hormone in this group, whereas corticosterone and desoxycorticosterone are secreted in small amounts. Aldosterone acts
primarily upon the kidney, but also on the intestine, the salivary
glands, and the sweat glands, increasing sodium uptake and
potassium excretion. Aldosterone also increases the secretion of
hydrogen ions in the medullary collecting tubules of the kidneys.
Their secretion and synthesis are regulated by the renin-angiotensin system and plasma concentrations of potassium. Primary
mineralocorticoidrelated diseases are rare in children. Hyperaldosteronism may occur in association with various forms of
congenital adrenal hyperplasia. Secondary hyperaldosteronism
with low total body sodium and accumulation of potassium is
present in congestive heart failure, cirrhosis of the liver, and
nephrotic syndrome. The excess of mineralocorticoids results in
increased sodium retention with hypertension (typically with high
diastolic blood pressures) and hypocalemia with metabolic
alkalosis, hypocalemic nephropathy, and possible tetany with
normal serum calcium.
Suprarenal Medulla
The suprarenal medulla is embryologically and functionally a part
of the sympathetic nervous system. It is considered to be a group
of postganglionic sympathetic neurons without axons that produce, store, and release catecholamines. The predominant catecholamine is epinephrine. Catecholamines are released directly to
the blood, as with the endocrine organs.
SEX DIFFERENTIATION
Human beings are differentiated into two sexes, male and female,
through a process that has different phases throughout life.
Genetic sex, gonadal sex, and genital sex are determined during
the fetal period. Phenotypic sex and psychosocial sex are
determined during infancy and, particularly, in puberty and
adulthood.39 Sex differentiation during the fetal period requires a
series of steps that are established and regulated, in part, by genetic
and endocrine factors (Figure 129). Genetic sex is determined at
the moment the ovum is fertilized by the sperm. According to the
X or Y sex chromosome contained in the fertilizing sperm,
feminine (46 XX) or masculine (46 XY) genetic sex is established.
Gonadal sex is determined early in the life of the embryo and
depends on genetic sex. Starting from the blueprint of the undifferentiated primitive gonads, ovarian differentiation in females
takes place during the eighth week of gestation and testicular
differentiation in males occurs during the seventh week. This
process terminates in the 28th week of fetal life. In the absence of
the Y chromosome, the primitive gonad differentiates into the
ovary. However, for complete differentiation of the ovary, as well
as its maintenance, a double X chromosome is required. Differentiation of the primitive gonad into the testes depends on the
presence of a testes-determining factor (TDF) coded by a gene on
the short limb of the Y chromosome, corresponding to the gene
known as the sex-determining region, Y chromz (SRY). Other
genes, both autosomal and X-linked, are also required for the
complete differentiation of the testes.
To determine masculine genital sex, the fetal testes must
produce hormonal products including mllerian ductinhibiting
factor (MIF) in the Sertoli cells and testosterone in the Leydig
cells. Secretion of MIF is initiated during the eighth week
of gestation. Its stimulation depends on hypophyseal FSH,
being greatest around the middle of gestation, chronologically
parallel to the disappearance of the mllerian ducts. The
development and maintenance of the wolffian ducts is regulated
by testosterone. Maturation of the testosterone-producing Leydig
cells is initially induced by hCG, although in the first trimester of
fetal life, hypophyseal LH also plays a role. The action of
testosterone on the wolffian ducts is regulated through specific
receptors. In the absence of MIF, the mllerian ducts develop to
form the uterus, Fallopian tubes, and the upper two thirds of the
vagina. In the absence of testosterone, the blueprint of the
wolffian ducts does not develop. Finally, the absence of
testosterone and its metabolites, which act upon the tubercles and
the urogenital sinus, allows differentiation of the external
feminine genital sex (lower third of the vagina, labia major, and
clitoris).
Psychosocial sex refers to a complex and progressive differentiation that leads to different types of identity. Several
basic mechanisms, such as learning and education, are implicated in this differentiation, reinforced by correct pubertal
development. Studies investigating the presence of anatomic or
functional differentiating factors in the CNS are under way.
Additional efforts are focused on determining whether the sex
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199
Figure 12-9. Genetic, gonadal, and genital sex differentiation in the human fetus.
hormones (androgens) have a role in the differentiation of certain

attitudes.40
physical and psychic changes, with rapid growth and important

developmental phenomena, coinciding with sexual maturity.
GROWTH
Growth Regulation
Growth is a complex biologic process by which living beings

progressively increase in mass, mature morphologically, and reach
full functional capacity. It is a continuous process that is initiated
with fertilization of the ovum and terminates at the end of adolescence. Growth is determined genetically and is modulated by a
variety of extragenetic factors. The interaction of these elements
produces the growth pattern. Growth after the embryonic stages
in humans is controlled and regulated by an intricate system in
which systemic and endocrine mechanisms intervene together
with local factors.41
Growth is determined genetically and environmental factors can

facilitate or obstruct expression of the genetic pattern. Genetic
control is carried out through a polygenic mechanism, in which
the various genes show their maximum expression in different
periods of life. Among the environmental factors, nutrition is of
capital importance, but others such as climate, psychosocial
elements, and family also play a part.4244 Growth is regulated
mainly by local mechanisms and systemic or hormonal
mechanisms (Figure 1210). The hormones directly implicated in
the growth process include hypophyseal GH, thyroid hormones,
cortisol, suprarenal androgens, testosterone, active metabolites
of vitamin D, and insulin. GH is the main regulator of extrauterine
growth and, together with the somatomedins or IGFs, it forms
an efficient system for adaptation of growth to the environmental
and metabolic situation. The thyroid hormones, essentially T3,
regulate maturation of the CNS and GH production, without affecting cell proliferation. The androgens participate in
sexual differentiation and maturation, stimulating GH production
and cell maturation at puberty. At low doses, the estrogens have
an action similar to that of the androgens, but at high doses,
they limit growth by accelerating epiphyseal closure. Because
of its role in cell metabolism, insulin is almost a fundamental
factor in prenatal growth. Physiologic doses of glucocorticoids
facilitate GH secretion and collagen synthesis. Vitamin D and
PTH regulate bone growth. Local growth factors are produced
in a variety of tissues, acting upon the cells that produce them or
the surrounding cells by intracrine, autocrine, and paracrine
mechanisms.45
Growth Pattern
The human species has a growth curve characterized by two
periods of rapid development separated by a period of stable
growth.42 The first period of rapid growth corresponds to the fetal
period and the first months of life, and the second occurs during
puberty. Between these phases, there is an interval of uniform
growth with slight acceleration around 7 to 10 years of age coinciding with the adrenarche. In utero, growth is regulated by autocrine and paracrine mechanisms during which the transplacental
passage of nutrients is crucial for modulating insulin secretion,
stimulating synthesis of both IGF-1 and IGF-2, as well as modulating their activity. In the postnatal period, the rapid growth
decelerates, and at 6 months of age, endocrine regulation is
initiated by GH. From 3 years of age to the pubertal growth spurt,
there is a period of slow uniform growth with a small transitory
acceleration at 7 to 10 years of age. Puberty is a period of great
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TABLE 12-5. Basal and Peak Serum Concentrations of
Luteinizing Hormone and Follicle-Stimulating Hormone
in Normal Pediatric Populationsa
Males
AGE, Y
13
49
1013
1115
1318
Adult
FSH
LH
Basal
Peak
Basal
Peak
1.0
0.8
1.1
1.5
2.0
2.3
4.3
3.0
3.1
3.0
3.5
5.2
0.9
0.8
0.7
1.0
1.3
2.0
3.6
2.6
3.4
6.9
10
15
Females
AGE, Y
Figure 12-10. Main factors in growth regulation.
PUBERTY
Puberty can be considered a critical stage in the process of development in which the child becomes an adult. It is characterized by
a phase of intense changes regulated by substantial hormonal modifications and the fundamental reactivation of the hypothalamic-hypophyseal gonadal axis. This activation coincides with
activation of growth (hypothalamic-hypophyseal-somatomedin
axis) and is preceded by maturation of the suprarenal and thyroid
glands. These endocrine glands affect the gonads and secondary
sex characteristics, resulting in the acquisition of reproductive
capacity, the phenotype resulting in a rapid growth phase, the end
of growth, and acquisition of sex phenotype, and the psychological
maturity of the person. However, the neuroendocrine mechanisms
responsible for puberty begin much earlier, in four recognized
phases. The first phase begins during fetal life and extends to
infancy. In this phase, the reproductive system is very active with
gonadal hormone levels similar to those found at the beginning
of puberty and with elevated gonadotropin levels. Maturation of
the CNS limits LH-RH secretion by an unknown intrinsic
mechanism independent of the gonadal steroids and decreases
gonadotropin production. The second or prepubertal phase extends from early infancy to the end of the first decade of life and
is characterized by decreased gonadotropin secretion (particularly
LH) with a high FSH/LH ratio, low LH response to LH-RH
administration, low gonadotropin levels, and a hypothalamichypophyseal system that is highly sensitive to the negative
feedback of the gonadal steroids. In this phase, LH-RH and the
gonadotropins exhibit a very short pulsatile release with slight
nocturnal increases. The third stage or pubertal phase begins at
the end of the first decade of life and is characterized by a sharp
amplification of pulsatile nocturnal LH secretion, which is dependent on episodic LH-RH release. The rhythmicity and duration of
the LH-RH release are critical to attaining normal sexual maturity.
As pubertal maturation follows its course, gonadal hormone
secretion increases and the differences between diurnal and
nocturnal LH secretions become progressively smaller until the
fourth stage or sexual maturity is reached, in which they disappear.
Basal and peak serum concentrations of LH and FSH in normal
13
49
1013
1115
1318
Adult
Menstruating
Follicular phase
Luteal phase
FSH
LH
Basal
Peak
Basal
Peak
1.5
1.2
1.7
2.0
31
14
8.3
6.4
6.6
7.0
0.7
0.9
0.9
1.0
1.8
4.0
2.7
2.9
5.0
13
3.3
3.8
2.0
6.6
7.6
5.0
2.4
2.5
1.4
18
13
17
FSH = follicle-stimulating hormone; LH = luteinizing hormone.

aMedium values in U/L.
From reference 46.
pediatric population (medium values in units per liter) are displayed in Table 125.46
Two key events take place over the course of puberty. The
intrinsic inhibiting CNS mechanism over gonadotropin secretion is
progressively reduced, and the sensitivity of the hypothalamichypophyseal system to the negative feedback of the gonadal hormones also decreases progressively.47 A new mechanism of positive
feedback between estrogens and gonadotropins, responsible for the
secretory peak of LH and FSH preceding ovulation, appears in girls.
In this phase, gonadal hormones similar to those in an adult are
reached, and LH-RH administration produces a definitive release of
LH and smaller release of FSH. The capacity to secrete LH-RH at
correct frequency and amplitude is acquired during this phase and
is absolutely necessary to attain normal reproductive function.
During puberty, the concentration of IGF increases in parallel to
the increases in sex steroids. Concentrations above adult values can
persist for months or years after having reached the peak of pubertal
development. The values later decrease and reach normal adult
values. The initial increase of suprarenal androgens (adrenarche)
has a fundamental role in the physiology of puberty in both sexes.
This increase is related to body weight and is responsible for growth
acceleration and bone development as well as changes in the
hypothalamic-hypophyseal system. The first signs of sexual maturity are the appearance of the mammary buds in girls and enlargement of the scrotum/testes in boys.48 The development of the sex
characteristics culminates with maturation of reproductive capacity
with menarche in women and formation of mature spermatozoids
with fertilizing capacity in men.
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CONCLUSION
The endocrine system is necessary for the bodys homeostatic
regulation, growth and development, and the physiologic response
to stress. An understanding of endocrine physiology and pathophysiology is essential for the anesthetic management of pediatric
patients. Although pediatric endocrine diseases are a relatively
uncommon indication for a surgical procedure, abnormalities of
endocrine function may be present in any surgical pediatric
patient. Alterations in any of the endocrine systems may occur
with either the over- or the underproduction of the hormonal
components of these glands. These pathologic processes may be
related to destructive processes of the endocrine glands, enzymatic
deficiencies in the synthesis of the endocrine products (congenital
adrenal hyperplasia), autoimmune diseases, or paraneoplastic
syndromes. More importantly, the exogenous administration of
pharmacologic doses of corticosteroids may be required in the
treatment of various nonendocrine disorders and may secondarily
result in suppression of the HPA axis with the need for perioperative supplementation.
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28. Zaloga GP, Chernow B. Hypocalcemia in critical illness. JAMA.
1986;256:19241929.
29. David L, Anast C. Calcium metabolism in newborn infants. J Clin
Invest. 1974;54:187189.
30. Tsang RC, Chen IW, Friedman MA, et al. Parathyroid function in
infants of diabetic mothers. J Pediatr. 1975;86:399441.
31. Flashburg MH, Dunbar BS, August G, Watson D. Anesthesia for
surgery in an infant with DiGeorge syndrome. Anesthesiology.
1983;58:479481.
32. Fraser R. Biosynthesis of adrenocortical steroids. In: James VHT, editor. The Adrenal Gland. New York: Raven Press; 1992. pp. 117130.
33. Saffran M, Schally AV. Release of corticotrophin by anterior pituitary
tissue in vitro. Can J Biochem Physiol. 1955;33:408415.
34. Quinn 53, Williams OH. Regulation of aldosterone secretion. Annu
Rev Physiol. 1988;50:409426.
35. Barrihat K, Mellon PL. The orphan nuclear receptor, steroidogenic
factor-1, regulates the glycoprotein hormone-subunit gene in
pituitary gonadotropes. Mol Endocrinol. 1994;8:878885.
36. Anand KJS, Hickey PR. Pain and its effects in the human neonate and
fetus. N Engl J Med. 1987;317:1321.
37. Anand KJS, Aynley-Green A. Metabolic and endocrine effects of
surgical ligation of PDA in the human preterm infant: are there
implications for further improvement of postoperative outcome? Mod
Probl Pediatr. 1985;23:143.
38. Gunnar MR, Fisch RO, Korsvik S, Donhowe JM. The effects of circumcision on serum cortisol and behavior. Psychoneuroendocrinology. 1981;6:269.
39. Bergad C, Coco R, Chemes H. Assymetric Gonadal Differentiation.
In: Martinez Mora J, (ed). Intersexual States. Disorders of Sex Differentiation. Barcelona, Spain: Doyma; 1994; p. 2839.
40. Breedlove SM. Sexual differentiation of the human nervous system.
Annu Rev Psychol. 1994;45:389418.
41. Blizzard RM. Control of growth: a review of the physiology and
interrelationships of growth hormone (GH), OH-releasing hormone
(OHRH), insulin-like growth factor (IOF-Y), estrogens and androgens. In: Taner JM, editor. Auxology 88. Perspectives in the Science of
Growth and Development. London: Srnith-Oordon; 1989. p. 283.
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42. Tanner JM, (ed). Fetus into Man. Physical Growth From Conception
to Maturity. 2nd ed. Cambridge, Mass: Harvard University Press;
1989. p. 271.
43. Waterlow JC, (ed). Linear Growth Retardation in Less Developed
Countries. New York: Raven Press; 1988. p. 295.
44. Bizzar RM. Psychosocial short stature. In: Lifshitz F, editor. Pediatric
Endocrinology. New York: Marcel Dekker; 1990. p. 77.
45. Underwood LE, Van Wyk JJ. Normal and aberrant growth. In: Wilson
JD, Foster DW, editors. Williams Textbook of Endocrinology. 8th ed.
46. Roger M, Lahlou N, Lidner D, Chaussain JL, Exploracin de la

hormona liberadora de gonadotropinas en pediatra. In: Ranke MB,
editor. Diagnstico Endocrinolgico Funcional en Nios y Adolescentes.
Madrid : Diaz de Santos; 1993. pp. 259278.
47. Cuttler L, Rosenfield RL, Ehrmann DA, et al. Maturation of gonadotropin and sex steroid responses to gonadotropin releasing hormone agonist in males. J Clin Endocrinol Metab. 1993;76:2631.
48. Rosenfield RL. Normal and almost normal precocious variations in
pubertal development, premature pubarche and premature thelarche
revisited. Horm Res. 1994;41(Suppl 2):713.
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Principles of Hematopoiesis,
Immunity, and Coagulation
Chaim Kaplinsky, Raz Somech, and Gili Kenet
INTRODUCTION
The anesthesiologist is facing an ever-increasing amount of
complex information that has risen beyond the empirical and
descriptive era and now requires an understanding of processes at
the molecular level. This chapter presents a review of the anatomy
and physiology of normal coagulation, hematopoiesis, and
immune system from the neonatal period through childhood to
adolescence. The developmental aspects of these systems as well as
the consequences of deranged differentiation and maturation
leading to hematologic and immunologic abnormalities are briefly
described. Unfortunately, it is not possible, within the confines of
a chapter, to provide a comprehensive and detailed review of the
total knowledge concerning hematopoiesis, blood components,
and the immune system. The chapter focuses on clinically relevant
aspects, aiming at turning theoretical knowledge into practice and
translating this information from the bench to the bedside.
HEMATOPOIESIS
Overview
The marrow cavity can be visualized as a maze composed of a
network of vascular channels, arterial vessels, small arterioles, and
capillaries that drain into sinusoids through veins. It is held
together by reticular fibroblastoid cells, energy-rich fat cells, and
macrophages. The sinusoidal wall consists of a single layer of
endothelial cells and is devoid of supporting cells. The lack of a
regular vessel wall in the sinusoids results in a high level of
permeability. The hematopoietic cells are found between the
interlacing network of vascular sinuses. The stromal cells support
attachment and subsequent growth, which is enhanced by specific
chemokines. The concept of the hematopoietic stem cell (HSC)
was first proposed by Schofield in 1978, who suggested that stem
cells are fixed tissue cells that are prevented from differentiation
and continue to proliferate within the functionally and spatially
characterized niche.1 Within this niche, the microenvironment
supports and instructs these stem cells.1 It has been shown that
HSCs and hematopoietic precursors are not randomly distributed
in the bone marrow, but rather are localized close to the endosteum of the bone and around blood vessels within the endosteal
zone, which provides the appropriate environment for the HSCs to
perform their role in hematopoiesis. The centrally located vascular
niche serves as the location that allows differentiation and,
ultimately, mobilization of the cellular elements of the blood to
the peripheral circulation.2 The interaction of HSCs with their
13
C H A P T E R
particular microenvironment (niche) is critical for hematopoiesis.

Several studies have demonstrated that osteoblasts are also crucial
regulatory cellular elements of the HSC microenvironment. Their
function and fate are controlled by ligand-mediated signaling
pathways.3,4 In addition to soluble factors, matrix components and
the extracellular matrix contribute to the in vivo microenvironment of HSCs.
The colonization of the hematopoietic organs is a multistep
process that begins with primitive cells emerging from the aortagonad-mesonephros region. These primitive cells travel to the fetal
liver where they proliferate before their movement to their final
sites in the bone marrow and spleen. These processes are under
the control of stromal cellderived factors (SDF) such as SDF-1.5
All blood cells are derived from embryonic connective tissue. They
can be first detected by the 14th day of gestation. The first blood
cells produced by the embryo are red cells that have megaloblastic
features. By the ninth to 10th week of gestation, they acquire a
normoblastic appearance. By the fifth to sixth week of gestation,
the fetal liver is the major site for erythropoiesis and remains the
principal organ of hemopoiesis until the sixth fetal month.
Myelopoiesis begins at the fourth to fifth fetal month. At birth,
most of the hematopoietic activity is in the bone marrow, with
only minor residual activity in the liver and spleen. The amount of
the marrow continues to grow and expand following birth by
increased and rapid turnover of cells.
The clonal nature of hematopoiesis and the concept that a
single pluripotent stem cell exhibits the capacity to repopulate the
entire hematopoietic system was first demonstrated by Till and
McCulloch.6 The fact that a stem cell can differentiate to form
progenitor cells for all lineages of the cellular components of the
blood was demonstrated in disease states like chronic myeloid
leukemia7 and polycythema vera8 in which clonality of each of the
abnormal erythroid, granulocytic, and megakaryocytic precursor
was evident. Moore and Metcalf demonstrated the presence of
HSCs in the yolk sac and the murine fetal liver,9 and Micklem and
Ross showed that these HSCs have a proliferative capacity of six
generations when serially transplanted into the spleen of an
irradiated recipient.10 Murine models, particularly short- and
long-term transplant studies, have provided a number of insights
into the biology of HSCs and their progenitors. The results of these
studies have demonstrated that HSCs are able to generate every
lineage found in the hematopoietic system including red blood
cells, platelets, and a variety of lymphoid and myeloid cells.11,12
HSCs are rare, constituting only 1/10,000 to 1/1,000,000 of the
cells in the bone marrow depending on the species, age, and
technical aspects of the model. Although HSCs are primarily
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found in the bone marrow, they are present in a variety of other

tissues including the peripheral and umbilical cord blood. They
are also found, albeit in lower numbers, in the liver, spleen, and
several other solid organs. These HSCs may have somewhat
different properties than those found in the bone marrow, but they
retain the ability to generate all of the different blood lineages in
large numbers for a prolonged period of time. A single pluripotent
stem cell is capable of giving rise to many committed progenitor
cells, which are destined to form differentiated recognizable
precursors of the specific cellular components of the blood.13
However, any cell at any specific stage of development has only
one differentiation option and can produce only one specified pair
of daughter cells.14
Currently, the specific phenotype of human HSCs and progenitors has not been completely defined. Most studies suggest that
human HSCs and progenitors are small quiescent cells that express
the surface glycoprotein CD34.15,16 In addition, the cells express high
levels of multidrug resistant (MDR) activity, lack expression of
lineage commitment markers, and express low levels of thymus cell
antigen-1 (Thy-1). Human CD34+ cells that express high levels of
CD34 with low or absent levels of a variety of other cell surface
markers including CD33, CD38, thy-1, and CD71 appear to be
enriched for primitive progenitor and HSC activity, whereas more
mature progenitors express one or more of these markers.
These cells are parents to precursor cells known as colonyforming units (CFUs). When cultured in semisolid media, cells
supplemented with appropriate growth factors are capable of
yielding progeny of granulocyte-macrophagecolony forming
units (CFU-GMs), erythroid colonyforming units (CFU-Es), and
megakaryocyte colonyforming units (CFU-Megs), or combinations of multilineage colonies (CFU-GEMM). A coordinated
hierarchy of growth factors that are elaborated by marrow stromal
cells, fibroblasts, and endothelium govern the proliferation of
hematopoietic cells in vivo.17,18
Hematopoiesis is a complex process of interplay between
several components including HSCs, progenitors, and the bone
marrow microenvironment, as well as a balance between maturation, proliferation, and programmed cell death. It involves stimulation and regulation by cytokines,19 chemokines, extracellular
matrix components,2022 and a number of intrinsic genes including
the Rb family, the E2Fs, cyclins, SCL, and Hox that regulate
proliferation and self-renewal of early hematopoietic cells.23 The
classic model for hematopoiesis is that committed HSCs give rise
to two lineages: (1) a common lymphoid progenitor capable of
producing lymphocytes and (2) a common myeloid progenitor
with developmental potential restricted to myeloid, macrophage,
eosinophil, erythroid, and megakaryocyte lineages. Erythroid and
megakaryocyte lineages arise from a common megakaryocyteerythroid progenitor (MEP) derived from the common myeloid
progenitor. However, progenitors that have surface markers
similar to those of HSCs, but have become Flt3-positive, after
further differentiation into lymphoid and myeloid lineages, do
not produce megakaryocytes or erythrocytes in vitro or in vivo
(Figure 131).23
Erythropoiesis
The regulation of erythroid differentiation, proliferation, and
maturation results from the coordinated and sequential interplay
of three essential cytokines: erythropoietin (EPO), stem cell factor
(c-kit ligand), and insulin-like growth factor (IGF-1). EPO

expression is up-regulated in response to hypoxia, which results in
the production of a surplus of CFU-Es and a large fraction of EPOdependent progenitors remaining on call in the marrow sinuses.
Within 12 hours, the rate of erythropoiesis increases by as much
as threefold as a wave of pluripotent stem cells is stimulated into
active cell cycles. EPO is essential for the terminal maturation of
erythroid cells.24 The erythroid progenitor cells undergo timed
morphologic changes manifested by gradual loss of nuclear
material (denucleation). The end product of erythropoiesis, the
enucleated red cell, is a transport cell that functions as a carrier of
oxygen to and from the tissues.
Myelopoiesis, Granulocytes,
and Neutrophil Function
Neutrophil precursors are first detected in the yolk sac and then in
the liver, spleen, and bone marrow. Mature neutrophils are first
detected by the 14th to 16th weeks of gestation. Up until the 22nd
to 24th weeks of gestation, neutrophils constitute less than 10%
of circulating leucocytes, increasing to 50 to 60% at term.25 The
ability of the human neonate to increase neutrophil production in
response to infection is limited. The most clearly defined deficits
in neonatal neutrophil function are adherence and migration in
response to chemotactic stimuli. Monocytes from term neonates
are normal in number and as competent as adult monocytes in
phagocytic and microbicidal activity.26,27 Neutrophils, eosinophils,
and basophils are formed in the marrow from a unipotential CFU,
following synchronized stimulation by interleukin-3 (IL-3) and
specific colony-stimulating factors.28 These cells arise through
similar cytokinetic patterns of proliferation, differentiation, and
maturation. Volume and nuclear changes accompany maturation
and division of proliferating myeloid cells.
By morphologic criteria, six stages of myeloid maturation are
conventionally recognized including three early stages, including
myeloblasts, promyelocytes, and myelocytes, and the three later
myeloid stages, including metamyelocytes, band forms, and
segmented neutrophils.29 The production of neutrophils is highly
compartmentalized into the circulating granulocyte pool and the
marginating granulocyte pool. The transit times within each
compartment are relatively long, lasting up to 14 days from the
stem cell compartment to release into the circulating granulocyte
pool. In certain disease states, these transit times shorten in order
to increase the production and supply of granulocytes. Once
released into the blood stream, neutrophils have a half-life of 6 to
10 hours. However, once in the tissues, they may live another day
or two before disintegrating by apoptosis.30 Neutrophils are the
infantry of the host defenses because their primary function is to
move rapidly into tissue sites to destroy invading microbes and
clear inflammatory debris.
During infections, activated macrophages release cytokines
such as IL-2, IL-6, and tumor necrosis factor, which activate
stromal cells and T lymphocytes to produce more colonystimulating factors and increase myeloid cell production. To
respond to inflammatory stimuli, the neutrophil is equipped with
an array of cell surface receptors for adhesive ligands, chemoattractants, and cytokines. Neutrophils are attracted to inflammatory sites by plasma chemotactic factors generated by the
interaction of immunoglobulins and complement with antigens
or pathogens. This process is commonly known as chemotaxis.
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205
Figure 13-1. Hierarchy of hematopoiesis from the earliest hematopoietic stem cell (HSC). CLP =
common lymphoid progenitor; CMP = common myeloid progenitor; GMP = granulocyte monocyte progenitor; LT-HSC = long-term HSC; MEP = megakaryocyte-erythroid progenitor; ST-HSC =
short-term HSC.
Through this process, neutrophils are recruited from the flowing
blood within the vascular system and adhere to vascular endothelium. Neutrophils are capable of locomotion, phagocytosis, and
secretory functions. Circulating hematopoietic progenitors must
exit blood vessels near specific areas of injury, inflammation, or
tissue repair. The vessel wall at these sites displays a specific
combination of signals in the form of adhesion molecules and
chemotactic cytokines that operate in sequence to recruit only the

specific circulating subsets with the appropriate receptors for these
signals (Figure 132).
Mature eosinophils make up 0.3% of the nucleated bone
marrow cells and 5 to 10% of peripheral granulocytes. They arise
from a progenitor CFU-Eos (eosinophil colony-forming unit),
committed to terminal differentiation into eosinophils. The
Figure 13-2. Current view on the possible role of shear in integrin outside-in
signaling promoting transendothelial migration. The leading edge of leukocytes
positioned at endothelial junctions rearranges under shear forces to trigger protusions
and gap formation between underlying endothelial cells. Reproduced with permission
of Prof. Ronen Alon, The Linda Jacobs Chair in Immune and Stem Cell Research,
Weizmann Institute, Rehovot, Israel.
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Figure 13-3. Selectins, chemoattractants (chemokines), and integrins coordinate in capturing a

circulating leukocyte to the vessel wall at specific sites. Further leukocyte exposure to apical endothelial
chemokines and shear flow triggers their potential to undergo transendothelial migration without
disrupting the integrity of the endothelial barrier. Reproduced with permission from Prof. Ronen Alon,
The Linda Jacobs Chair in Immune and Stem Cell Research, Weizmann Institute, Rehovot, Israel.
majority of mature eosinophils reside in tissues. The number of
circulating eosinophils has a circadian nature, being highest at
night. The granules of the eosinophils contain major basic protein
(dense core), peroxidase, eosinophil-derived neurotoxin, argininerich cationic proteins, acid phosphatase, and other hydrolytic
enzymes. Eosinophils are armed with receptors for the epitopes
of the Fc region of immunoglobulins of the IgG and IgE classes as
well as receptors for complement. The functions of eosinophils
include anaphylactic reactions, IgG production, bacterial killing,
and early antigen recognition. The two major functions of
eosinophils are defense against helminths and modulation of the
immediate hypersensitivity response. The first of these functions
is carried out by binding of the eosinophils to the helminth
followed by peroxidation of the larval surface with damage from
the release of major basic proteins and hydrolytic enzymes
(Figure133). The capacity of eosinophils to restrain the selfdestructive hypersensitivity and inflammatory reactions is
mediated by amino-oxidases and histaminase that neutralize
histamine. Prostaglandins E1 (PGE1) and E2 (PGE2) also serve a
role because they inhibit degranulation of mast cells and basophils.
Megakaryocyte Biology
Although erythroid and megakaryocyte lineages are believed
to share a common MEP, the signals that regulate the final separation of these lineages are not well understood. Erythroid and
megakaryocytic precursors express both common and unique
hematopoietic transcription factors. The first cells fully committed
to the megakaryocyte lineage, termed CFU-Meg, are characterized
by a unique cell surface phenotype and form a small cluster of
pure megakaryocytes in culture.31 CFU-Meg cells give rise to 2N
megakaryocytes, which, in turn, undergo endomitosis and
cytoplasmic differentiation, resulting in a pool of mature megakaryocytes recognized by their large size and characteristic morphology.32 The hallmark of megakaryocyte development is the
formation of a large cell (50100 m in diameter) containing a
single, large, multilobulated, polyploid nucleus. Eventually, each

megakaryocyte releases approximately 104 platelets. Unlike other
cells, megakaryocytes undergo an endomitotic cell cycle during
which they replicate DNA, but do not undergo anaphase (mitosis)
or cytokinesis. As a result, they acquire a DNA content of up to
256N/cell.
Megakaryopoiesis is first noted in the embryonic yolk sac,
although studies of animals with severe quantitative and qualitative platelet deficiencies, such as NF-E2/ mice, have demonstrated that platelets are not critical for prenatal survival.33
Megakaryopoiesis is regulated by multiple transcription factors
that control the survival and proliferation of increasingly
committed progenitors including the GATA-1/FOG-1 complex,
Fli-1 and TEL, NF-E2, RUNX1. Chemokines involved in these
processes include thrombopoietin (TPO) (Mpl), IL-3, IL-6; IL-11,
IL-12, granulocyte macrophage colonystimulating factor (GMCSF), SDF1/CXCR4, and PF4 (Figure 134). Mpl ligand or TPO,
a more potent and relatively specific megakaryocyte/platelet
cytokine, has been shown to markedly stimulate megakaryocyte production. The TPO:Mpl axis appears to be important for
hematopoiesis in general and megakaryopoiesis specifically.34,35
THE IMMUNE SYSTEM

Overview and General Mechanism Involved
The two components of the immune system, namely, innate
immunity and adaptive immunity, interact synergistically to
provide protection against microbials and infectious agents while
maintaining tolerance to self-antigens. The primary host response
is mediated by the innate immunity (natural immunity) through
natural physical and chemical barriers, phagocytic cells, and
various blood proteins or excreted cytokines. The immune
response carried out by these mediators is rapid, is nonspecific,
and confers short-lasting protective immunity to the host.36 By
contrast, the adaptive immune system is characterized by a late
response, specificity, an ability to mount a memory response, and
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Figure 13-4. Regulation of megakaryopoiesis by cytokines, chemokines, and transcription factors. BFU-EM = burst-forming
unitserythrocyte, megakaryocyte; CFU-EM = colony-forming unitserythrocyte, megakaryocyte; CFU-GEMM = colonyforming unitsgranulocyte, erythrocyte, macrophage, megakaryocyte; CFU-Meg = colony-forming unitsmegakaryocyte;
HSC = hematopoietic stem cell. Modified from reference 31.
an ability to discriminate between self and nonself. This highly
evolved system is constructed mainly of lymphocytes and includes
two major arms: (1) humoral immunity mediated by soluble
proteins (antibodies) and (2) cellular immunity mediated by
circulating cells. Antibodies produced by B lymphocytes are the
primary component of and responsible for the humoral system.
These antibodies recognize specific antigens of microbial
pathogens and provide a principal response in defense against
encapsulated microbial organisms and microbial toxins through
neutralization, opsonization, and activation of the complement
pathway. Five different types of antibodies are involved in humoral
immunity: IgM, IgD, IgG, IgE, and IgA. Each antibody has an
antigen-binding site, a hinge region, and a region that determines
its class or subclass. Cellular immunity is mediated by the T cell
receptor (TCR) complex. Two major types of T cells are involved
including CD4+ (helper) and CD8+ (cytotoxic) T cells. These two
subsets of T cells comprise approximately 60 to 65% and 30 to 35%
of circulating T cells, respectively. By contrast to the recognition of
whole antigens by B cells, most T cells cannot bind free antigen.
They recognize antigens only when they are bound to and
presented by major histocompatibility complex (MHC) molecules.
The adaptive immune system eliminates pathogenic challenges
through clonal selection, which ensures diversity and an unlimited
repertoire of both cell types.37 A third subset of lympocytes in
addition to the T and B cells is the natural killer (NK) cells. These
cells are considered cytotoxic lymphocytes and are a component
of innate immunity. They play a major role in the rejection of
tumors and virus-infected cells in a manner unrestricted by MHC
antigens because they do not require antigenic presentation. The
NK cells kill by releasing small cytoplasmic granules of proteins
called perforin and granzyme that cause the target cell to die by
programmed cell death.38 Inherited defects in one or more components of the immune system result in primary immunodeficiencies. These diseases provide valuable insight into the immune
system, notably in vivo immune responses to microorganisms as
based on the variable vulnerability to pathogens and opportunistic
agents in these patient populations.39
Embryogenesis of the Immune System

The ontogeny of the host defense system begins during the first
month of gestation with hematopoietic stem cells located within
the blood islands of the yolk sac. These pluripotential stem cells
will further differentiate into all of the cellular components
of blood including granulocytes, monocytes, and lymphocytes,
megakaryocytes, and erythrocytes. Hematopoiesis occurs
predominantly in the liver during the first 3 months of fetal life
until the skeletal elements are formed, after which time they
become the major site of hematopoiesis. T, B, and NK lymphocytes
are derived from lymphoid stem cells. Precursors of T and B
lymphocytes can be detected by 7 to 8 weeks of gestation.
Lymphocytes destined to become T cells emerge from the bone
marrow and travel to the developing thymus for further maturation. The maturation of B lymphocytes occurs in the bone
marrow under the influence of the stromal reticular cells. The
basic cellular elements of the immune system such as the
TCR/CD3 complex can be found in peripheral lymphoid organs at
13 to 15 weeks of gestation, whereas the ability to respond to
polyclonal stimuli such as PHA (phytohemagglutinin) is detected
at 15 to 16 weeks of gestation. Nevertheless, the system is
functionally immature at birth and requires antigen selection to
achieve full maturation during infancy.40
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The Development of the T Cell Lineage

The thymus, which is the main organ for T cell development and
maturation, develops from the third and fourth pharyngeal
pouches. This multilobed organ is composed of cortical and
medullary areas surrounded by a capsule. It contains MHCexpressing thymic epithelial cells, dendritic cells, and macrophages. Progenitor T cells migrate from the circulation into the
thymus following the expression and elaboration of specific chemokine receptors, chemokines, and adhesion molecules. Thymic
education occurs during the movement of progenitor cells from
the cortex toward the medulla (Figure 135). It is a mandatory
process for the selection of T cells that have the ability to respond
to several exogenous antigens presented in the context of selfMHC molecules. TCRs that are expressed on the surface of T cells
are composed mostly of heterodimeric proteins composed of
either alpha/beta (>95%) or gamma/delta chains. These protein
chains have variable (V), diverse (D), joining (J), and constant (C)
segments (beta and delta chains) or V, J, and C regions (alpha and
gamma chains) encoded by noncontinuous gene segments. Pre-T
cells first attempt to undergo rearrangement of their TCR genes
while expressing the CD3 complex (Figure 136). At that time,
they do not express either CD4 or CD8 and are therefore called
double-negative T cells. An accurate machinery involving recombination, activating, DNA recognition, damage, and subsequent
Figure 13-5. Development of T and B lymphocytes
repair genes is critical for the development of different TCR

through rearrangement of the VDJ segments. Those cells with
nonproductive TCR rearrangements are destined for programmed
cell death. Successful rearrangement of the beta chain of the TCR
stimulates expression of CD4 and CD8 and rearrangement of
the alpha chain. At this step, cells are called double-positive T cells
(expressing both CD4 and CD8). Subsequently, interaction of
MHC molecules on thymic epithelial cells through a process
termed negative and positive selection further commits and
differentiates the surviving T cells. By negative selection, clones
bearing TCRs that have a phigh affinity for self-MHC or selfantigens are deleted (self-antigen means peptides from selfproteins bound to MHC molecules). Positive selection is unique to
T cells. It appears that cells are selected for a moderate affinity for
self-MHCpeptide complexes. Only about 2% of all doublepositive T cells survive the dual positive and negative selection
processes. Interaction with MHC class II molecules generates
CD3+/CD4+/CD8 T cells, whereas interaction with MHC class
I molecules generates CD3+/CD8+/CD4 T cells. These singlepositive (either for CD4 or for CD8) functional T cells are released
from the thymus to the peripheral blood41 (see Figure 135).
During the rearrangement process in the thymus, unused and
excised DNA segments form the TCR excision from circular
complexes (TRECs). The presence of these extrachromosomal
DNA circles, which are not replicated during peripheral T cell
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Figure 13-6. Gene structure of immunoglobulin chains and T cell receptor chains
division, serve to identify newly thymus-derived T cells.
Quantifying TRECs has recently emerged as another tool to assess
thymic activity. Indeed, a reduced number of TREC copies has
been found in patients with severe combined immunodeficiency
(SCID) and HIV and was proposed as a potential tool to follow T
cell reconstitution after stem cell transplantation (Figure 137).
A profound defect in either T cell differentiation or function
may cause SCIDs. Typically, patients have T cell lymphopenia, lack
of cellular and humoral immunity, and in some cases, decreased B

and NK cell number and function. Deleterious mutations in more
than 10 different genes including components of cytokine
receptors (IL-2RG, Jak3, and IL-7R), components essential for
antigen receptor gene rearrangement (RAG1, RAG2, and Artemis),
components of the T cell antigen receptor (CD3, CD3e, CD3z),
toxic accumulations of metabolites that affect immune stem cells
(adenosine deaminase [ADA] deficiency), and a deficiency of
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Figure 13-7. Development of T cell

receptor excision circles (TRECs). A:
The alpha and delta loci. B: Deletion
of the delta locus. C: Complete
recombination of the alpha locus.
CD45, a key protein involved in pre-TCR and/or TCR signaling at
the positive selection stage may cause human SCID. These
genotypes result in near absence of circulating mature CD3+ T
cells and variable degree of absent of B or NK cells.42
In the periphery, CD4+ helper T cells may be classified into
Th1, Th2, or Th3 (regulatory cells) subsets based on the predominant patterns of cytokine secretion and functional attributes.
A Th1 response is important for cell-mediated immunity and
interferon (INF)-. IL-2, and tumor necrosis (TNF)- are the
predominant cytokines produced. A Th2 response is critical in
humoral immunity and hypersensitivity. IL-4, IL-5, and IL-13 are
the main cytokines released. Th3 cytokines are transforming growth factor (TGF)- and IL-10, which are important in
regulating the Th1/Th2 balance. In order to explain the increasing
prevalence of allergy noted in many Westernized populations, a
shift from Th1 to Th2 response or inability to suppress Th2
response during infancy has been suggested (hygiene hypothesis).43 A recent modification of the hygiene theory suggests
induction of Th3 cytokines that controls both Th1 and Th2
responses (Figure 138).
The Development of the B Cell Lineage

Antibody-mediated immune responses play a critical role in the
defense against extracellular pathogens and many viruses. The
primary development of the B cell lineage occurs in the fetal
liver and in the bone marrow (see Figure 135). This is a
T lymphocyte and antigen-independent process that results in

the expression of membrane IgM and IgD molecules and a specific
antigen-binding site of the B cell receptor. The B cell receptor is
composed of one heavy chain and one light chain (kappa or
lambda chains). During B cell development, a progenitor cell
(pro-B cell), carrying Ig gene segments is assembled by DNA
rearrangements involving the joining of V, D, and J (heavy-chain)
and V and J (light-chains) elements into a contiguous sequence
upstream of the IgM (and IgD) constant region (see Figure 136).
The first identifiable cell within the B cell lineage is the pro-B cell
that expresses precursor proteins that allow the recombination of
gene segments at the heavy-chain locus and the expression of a
surrogate light chain. Expression of this pre-B cell is essential for
allelic exclusion of a nonused heavy-chain locus. Interactions of
the developing B cells with bone marrow stromal cells and several
cytokines such as IL-2 and IL-7 result in the maturation of the preB cell into a mature B cell with the replacement of the surrogate
light chain by a fully rearranged light chain. A mature B cell has
the ability to respond to antigen; however, these IgM (IgD is
spliced) antibodies are of low avidity. Shaping of the secondary
antibody repertoire is generated by two modifications. Classswitch recombination (CSR) replaces IgM with other isotypes
(IgG, IgE, IgA), thus allowing a change in antibody effector
function. The second modification is somatic hypermutation
(SHM), which allows production of high-affinity antibodies by
introduction of point mutations at a high rate in the V regions of
the Ig genes, allowing the selection of high-affinity antigen-
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211
Figure 13-8. Hygiene hypothesis. A link

between the Th1/Th2 paradigm, Th3 cytokines
response, and the risk of developing allergic
diseases in Westernized countries. Th = helper
T cell.
specific antibodies. These secondary antibody repertoire processes
are generated in the peripheral lymphoid organs and are antigendependent and T celldependent. The main cross-talk between
T and B cells is through the interaction between CD40L (CD154)
expressed by activated T cells and CD40 expressed by B cells. Both
CSR and SHM require transcription through target switch and
V regions on V(D)J exons and DNA editing, which requires two
crucial enzymes expressed by germinal center B cells, AID, and
UNG.44 A defect of CSR or SHM is associated with hyper-IgM
syndrome. The study of these patients has allowed us to recognize
that both T and B cell interactions (resulting in CD40-mediated
signaling) and intrinsic B cell mechanisms involving AID and
UNG genes are important for CSR and SHM.
Inherited defects in several genes are known to cause reduced
or absent immunoglobulin levels. Common variable immunodeficiency (CVID) is the most frequent symptomatic primary
immune deficiency. CVID is characterized by the sequelae of an
antibody deficiency syndrome with impaired terminal B cell
differentiation, hypogammaglobulinemia, and susceptibility to
recurrent infections.45 By contrast, defects in early B cell development can result in agammaglobulinemia. Approximately 85% of
patients with defects in early B cell development have X-linked
agammaglobulinemia, a disorder caused by mutations in the cytoplasmic Brutons tyrosine kinase (BTK). This kinase is the most
critical signal transduction pathway initiated by the pre-B cell and
B cell antigen receptor complex. An additional 5 to 7% of patients
with defects in early B cell development have mutations in the
components of the pre-B cell and B cell antigen receptor complex.46
Chronology of Immune Defense

Mechanisms in Infants and Children
In order to survive after transition from a sterile intrauterine
environment to a nonsterile ex utero environment, which is rich
in foreign antigens, the newborn needs a complex set of immunologic functions involving both innate and adaptive immunity.
The neonate should be able to maintain and control protection
against infection and primary colonization of the skin and intestinal tract as well as to avoid potentially harmful proinflammatory/
T helper responses that can induce alloimmune reactions between
mother and fetus. However, several important differences between
the neonatal and the adult immune systems remain. Some components function less well in neonates compared with adults,
giving rise to the concept of an immunodeficiency of immaturity. One particularly clear example that shows the weakness of
the neonatal immune system is infection with HIV. In the absence
of retroviral therapy, there is a more rapid progression from initial
infection to disease presentation in pediatric patients than in
adults after the primary infection. In addition, the neonate may
be at risk for graft-versus-host disease following the administration of allogeneic blood even in the absence of a specific
immunodeficiency state. Differences between neonatal and adult
immune systems include a reduction in the available bone marrow
reserve of granulocyte precursors, the decreased production
of proinflammatory cytokines from the components of innate
immunity, a reduction in serum complement activity, decreased
ability to produce antibodies against bacterial polysaccharide
antigens, and increased percentage of T lymphocytes bearing
an antigenically nave cell surface phenotype. Although T cell
immunity is relatively intact at birth, the ability to respond with
antibody production to specific antigens develops chronologically.
The neonate receives passive protection through the placental
transfer of maternal IgG during the third trimester of pregnancy.
Ig concentrations similar to or higher than maternal concentrations are achieved after 34 weeks of gestation. The maternal IgG
disappears by the age of 9 months, by which time endogenous
synthesis of IgG is well established. The IgM and IgA of the
neonate are entirely endogenously synthesized because maternal
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IgM and IgA do not cross the placenta. Human milk contains
bacterial and viral antibodies, including relatively high concentration of secreted IgA antibodies, that are passively transferred to
the neonate. This passive transfer of antibodies serves to augment
the immune system. The limited capacity of naive neonatal T cells
to produce certain lymphokines with immature humoral immunity may contribute to the poor response to polysaccharide
vaccines (which is a T cellindependent response) and to
encapsulated bacteria such as group B streptococci. In addition,
neonatal B cells require a competent signal by an activating T cell
and a higher concentration of IL-2, IL-4, and IL-6 than do adult
B cells. Neonatal T cells produce sufficient IL-2 to drive T cell
proliferation but not enough for optimal B cell differentiation.
By contrast, the neonatal response to protein antigens appears relatively intact because this immune response is T cell
dependent, and a mature T cell immunity ensures an adequate
response. Limitations in isotype expression by B cells after
immunization with T celldependent antigens appear primarily
to reflect limitations in T cell help rather an intrinsic limitation
of B cells.40,47
The MHC
Antibodies and TCRs are highly specific in their ability to
recognize a foreign antigen and display tolerance to self-antigens.
The specificity of the receptor is mainly carried out by a set of
molecules known as MHC, displayed on the cell surface. MHC
molecules provide the basis for discriminatory self from nonself,
the ability to elicit graft rejection, and the governing of the
intrathymic selection of T cells. The MHC is encoded by several
genes located on human chromosome 6 (Figure 139). They are
inherited in haplotypic fashion from each parent and are
codominantly expressed. Class I molecules are encoded by the
BCA region and are therefore called human leukocyte antigen
(HLA)-A, HLA-B, and HLA-C, whereas class II molecules are
encoded by the D region and are therefore called HLA-DR,
HLA-DQ, and HLA-DP. A region between these two areas on
chromosome 6 encodes class III molecules including some
components of the complement system. The major role of class II
MHC molecules is in antigen presentation to T cells and in graft
rejection. Therefore, providing a graft that is highly matched
to the recipient in the HLA-A, HLA-B, HLA-C, HLA-DR, and
HLA-DQ molecules is important to ensure success after a
transplantation procedure.48 Absence of constitutive and inducible

expression of MHC class I or II determinants on immune cells
result in the bare lymphocyte syndrome. MHC class II deficiency
is characterized by an SCID phenotype.49
The variability in HLA phenotypes is of considerable interest
given its association with susceptibility to certain human diseases.
A few examples of this include autoimmune diseases, infectious
diseases, primary immunodeficiencies, and malignancies. The
strongest linkage for the association of an HLA phenotype and a
specific disease is for ankylosing spondylitis and the B27 phenotype, with a relative risk of disease estimated at 90%. Examples for
other associations between HLA markers and various autoimmune diseases include Goodpastures syndrome and DR2,
rheumatoid arthritis and DR4, diabetes mellitus type 1 and HLADR3, and myasthenia gravis and HLA-DQ.
Immune Tolerance
Tolerance is the term used to describe the process that eliminates
or neutralizes autoreactive cells. Knowing the mechanism of
tolerance is important in understanding the pathophysiology of
autoimmune diseases. Both central and peripheral mechanisms
are involved in the establishment and maintenance of immune
tolerance. Deletion of self-reactive T cells in the thymus through
negative and positive selection (of clones with high or moderate
MHC/T cell affinity, respectively) is the central mechanism
for tolerance. Peripheral T cell tolerance is achieved through
ignorance (expression of low level of antigen or physical barriers),
anergy (absence of costimulation signals), and peripheral deletion
(activation of apoptotic pathway) and regulation. The latter is
carried out through CD4+ T cells specializing in suppression of
the immune response. These regulatory T cells (TREG) express
CD4 and CD25 and actively suppress pathologic and physiologic
immune responses, contributing to the maintenance of immunologic self-tolerance and immune homeostasis mainly by secretion of TGF- and IL-10 (Figure 1310). The discovery of FOXP3
as an essential transcription factor not only for differentiation and
function of TREG cells but also for the regulation of intracellular
molecules related to effector T cell responses has provided new
insights into the pathogenesis of immune-mediated diseases.50
Indeed, a rare X-linked disorder known as immune dysregulation,
polyendocrinopathy, enteropathy, X-linked (IPEX) caused by
mutations of the FOXP3 gene, has provided important new
insights into the essential role of TREGs in maintaining tolerance
Figure 13-9. Scheme of the human leukocyte antigen (HLA) locus on chromosome 6.
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213
Figure 13-10. Development of naturally occurring and

adaptive T regulatory cells (TREG) in the thymus and in
peripheral blood.
to self-antigens.51 B -cell tolerance is achieved e by elimination of
ither immature B cells or autoreactive clones in the bone marrow
or in the T cell zones of the spleen or lymph nodes. It is predominantly dependent on interactions with T cells.
COAGULATION
Hemostasis is the complex and dynamic process leading to clot
formation and cessation of hemorrhage at the site of vascular
injury. It involves the interplay of endothelial cells, platelets,
coagulation factors, and the fibrinolytic system, which ensures the
sealing of injured blood vessels as well as maintenance of their
patency once clots have been created. The following section deals
with some of the more commonly encountered congenital and
acquired bleeding disorders as well as thrombotic disorders
affecting children.
Physiology of the Coagulation Process

The endothelium of the intact vessel wall serves as a barrier
between the blood components and the thrombogenic subendothelium. It synthesizes endothelin, prostacyclin (PGI2) and
NO, which control vessel vasoconstriction and vasodilatation.
The endothelium also inhibits surface clot formation by the
secretion of thrombomodulin and heparan sulfate and modulates
fibrinolysis via synthesis of tissue plasminogen activator (TPA)
and plasminogen activator inhibitors (PAIs).5255
The initial event in hemostasis is platelet adhesion to exposed
vascular subendothelium after injury, which is mediated by the
binding of von Willebrands factor (vWf) to platelet integrin or
glycoprotein Ib (GPIb). Following adhesion, the platelets are activated, change shape, degranulate, and release active mediators
from storage granules. The next step is platelet aggregation
mediated by binding of fibrinogen to the platelet GpIIb-IIIa
complex. Coincident with this binding, platelets enable the tenase
(Xase) complex (Factors IXa, VIIIa, and X) and the prothrombinase complex (Factors Xa, Va, and prothrombin) to assemble on
the surface, resulting in thrombin formation (Figures 1311 and
1312). Thrombin is essential for clot formation as well as for
clot inhibition. Once thrombin is formed, it is inhibited by the
fibrinolytic enzyme, antithrombin (AT). Thrombin also binds
to thrombomodulin and activates proteins C and S to slow
down the active process of coagulation by proteolysis of Factors

Va and VIIIa.
Coincident with platelet aggregation is the formation of
thrombin via the intrinsic and extrinsic coagulation cascades.
Thrombin formation is the final step of the common coagulation
pathway (see Figure 1312). Thrombin then results in the
formation of fibrin strands from fibrinogen. Further assembly and
polymerization of fibrin occurs in the presence of Factor XIII or
fibrin-stabilizing factor, which cross-links the fibrin strands.5658
As clot is formed, the fibrinolytic system is activated to control the
coagulation system and maintain patency of the blood vessel. 59
The delicate equilibrium between coagulation and fibrinolysis is
further maintained by the presence of circulating coagulation
inhibitors. Thrombi are composed of fibrin and blood cells;
the relative proportion of these influence the types of thrombi.
White thrombi, composed mainly of platelets and fibrins strands,
form under high-shear/-flow conditions at sites of rupture or
atherosclerotic plaques of the arterial wall. Mural thrombi may
give rise to emboli, causing distal ischemia. Venous thrombi
forming in areas of slow flow are the classic red thrombi,
composed of red blood cells with fibrin and relatively fewer
Figure 13-11. General overview of the coagulation process.
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Neonatal Hemostasis: Developmental

Aspects and Laboratory Evaluation
Figure 13-12. The coagulation cascade.

platelets. In areas of moderate blood flow, thrombi are a mixture
of platelets, fibrin, and red cells.6063
Bleeding Tendency
An increased bleeding tendency may result from alterations of
blood vessel integrity and its collagen-fibril structure, changes in
platelet number or function, and altered levels of the coagulation
factors. A careful history (including family history) can provide a
valuable screening measure for the detection of a bleeding
tendency. In addition, the following symptoms may indicate the
presence of a bleeding disorder and lead to its perinatal diagnosis:
bleeding into the scalp forming cephalohematomas, injury-related
bleeding following relatively minor invasive procedures (e.g.,
circumcision), hematoma formation following intramuscular
injections, and bleeding into the skin at sites of peripheral
venipunctures. Facial purpura following birth is usually associated
with severe platelet dysfunction or thrombocytopenia. Oral
mucous membrane bleeding is common in thrombocytopenic
infants; however, gum bleeding and epistaxis are rarely present in
neonates. Joint hemarthroses, typical for severe hemophilia, rarely
occur before the onset of ambulation. Persistent oozing from the
umbilical stump is typical for infants with defective fibrinogen
production or function and Factor XIII deficiency. Bleeding
isolated to a single organ is more likely to occur because of a
local cause (trauma) rather than a hemostatic abnormality. Hemoptysis, hematemesis, gastrointestinal tract bleeding, or hematuria
is rarely the presenting symptom of a bleeding disorder.
By contrast, hematuria in neonates may be the presenting symptom of renal vein thrombosis. A small proportion of infants
with severe coagulation factor deficiencies present with intracranial hemorrhage (ICH) as the first manifestation of their
bleeding tendency.64 Nevertheless, hemostatic abnormalities such
as disseminated intravascular coagulation (DIC), liver failure, or
vitamin K deficiency may exacerbate those symptoms in critically
ill infants and children. Although vitamin K deficiency has
become exceedingly rare with the routine perinatal administration
of vitamin K, disastrous consequences may occur when vitamin
K is omitted for any reason. In such cases, a careful history
regarding the administration of vitamin K is paramount in making
the appropriate diagnosis.
Hemostasis is a dynamic process that begins in utero. Coagulation

factors are synthesized starting at 10 weeks of gestational age.
Their concentrations gradually increase, being physiologically
lower in premature infants than in full-term infants or healthy
children.6568 The absolute values of reference ranges for coagulation assays in neonates and children vary with analyzer and
reagent systems. All laboratory measures confirm the concept of
developmental hemostasis by showing that physiologic concentrations of coagulation proteins gradually increase and are lower
in premature infants than in full-term infants or healthy
children.6569 A study of 125 premature infants suggested a correlation between coagulation Factors II, V, VII, and X with gestational
age and also with perinatal events. Extreme prematurity, perinatal
asphyxia, and lower birthweight were associated with poorer
coagulation status and potentially higher susceptibility to perinatal
hemorrhagic complications.70
The activation of platelets71,72 and coagulation proteins73 and
release of TPA74 usually occur during the birth process and
probably represent a developmental, nonpathologic phenomenon.
Nevertheless, any complications of delivery, resulting in birth
asphyxia, may play an important role in the pathogenesis of
consumptive coagulopathy and promote the risk for significant
bleeding. In the neonate, plasma concentrations of vitamin
Kdependent coagulation factors (II, VII, IX, X) and contact
factors (XI, XII, prekallikrien, and high-molecular-weight
kininogen) are at about 50% of adult values.68 The postnatal gain
in coagulation factor concentrations in infancy is greatest among
premature infants with the lowest gestational age at birth.75
The capacity of newborns to generate thrombin, which is
directly dependent on plasma concentrations of procoagulants,
is reduced.76,77 Thrombin generation shows age dependency with
endogenous thrombin potential at 30 to 60% in cord plasma
compared with adult plasma. However, newborn plasma shows
more rapid thrombin formation and enhanced sensitivity to
activated protein C (APC) and a lower concentration of tissue
factor.7880 After activation with low-dose tissue factor, higher
amounts of anticoagulants are required to suppress cord plasma
thrombin generation compared with adult plasma.81 This may
stem from the fact that the theoretically increased risk of bleeding
is balanced by the protective effects of physiologic deficiencies of
the inhibitors of coagulation as well as by the decreased capacity
of the fibrinolytic system in infants.68,82,83
Laboratory Screening Tests for

Bleeding Neonates
Diagnostic problems of special concern are the need to adapt all
coagulation assays for small amounts of blood and the age-related
interpretation required for test results. The initial set of laboratory
tests, which may provide important information regarding the
possible etiologies of hemorrhagic disorders, include a platelet
count, a prothrombin time (PT) and an activated thromboplastin
time (aPTT). Fibrinogen levels, thrombin clotting time (TCT),
and bleeding time (BT) may be added in some cases, followed by
specific factor assays, as required.
The normally prolonged aPTT in neonates reflects decreased plasma concentrations of the contact factors, whereas
the prolonged PT reflects decreased plasma levels of vitamin
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Kdependent factors.6668 The interpretation of coagulation factor
assay results should consider the fact that, in neonates and infants,
the lower normal boundary for the assays of Factors II, X, and XI
may overlap with values typically seen in adults who are
heterozygous for factor deficiencies.6669 The levels of other factors
including VIII, V, and XIII correlate well with the normal values
seen in the adult population, and therefore, the diagnoses of
hemophilia A, Factor V, and Factor XIII deficiencies can be
established. Plasma concentrations of fibrinogen may be skewed
upward, despite the fact that TCT may be prolonged, because
of the normal and expected presence of fetal fibrinogen.84 BT,
the test that measures platelets and vessel wall interaction and
function, is shorter in healthy neonates than in adults. This
phenomenon probably is the result of a higher hematocrit and the
presence of large red cells as well as increased concentrations and
enhanced function of vWf and large vWf multimers.6669,85 It has
also been shown that premature infants exhibit lower levels of
vWF-cleaving protease (ADAMTS13) than term infants, potentially promoting the risk for intravascular platelet aggregation and
focal cerebral ischemia in these neonates.86
In general, if the initial laboratory test results reveal abnormalities when compared with age-related values, a stepwise
diagnostic approach should follow to characterize specific defects.
This may include specific factor assays to pinpoint the acquired
or congenital bleeding diathesis. In the bleeding neonate that has
no laboratory abnormality, Factor XIII activity should be assessed
by direct measurement or using a simple test, based on dissolving
a fibrin clot in 5-molar urea. In addition, when primary hemostatic defects are suspected, platelet function should be evaluated.
Platelet Disorders: Clinical and

Laboratory Diagnosis
By far, the most common hemostatic abnormality in neonates and
children is thrombocytopenia.87,88 The etiology of thrombocytopenia is variable and caused by increased destruction, decreased
production, dilution from massive blood transfusion, or sequestration in the spleen (Table 131). Conditions associated with
215
nonimmune thrombocytopenia in neonates and infants include

asphyxia, perinatal aspiration, necrotizing enterocolitis, hemangiomas, respiratory distress syndrome, and DIC. In the neonatal
period, septicemia and DIC, both of which are associated with
increased consumption, are the most common causes of thrombocytopenia.89 In older children, DIC, giant hemangiomas, indwelling catheters, hypersplenism, and hypothermia are more
common. Congenital and hereditary thrombocytopenia, because
of impaired or ineffective production, are uncommon and
generally do not manifest early in life. Bone marrow replacement
disorders such as congenital leukemia, neuroblastoma, histocytosis, and osteopetrosis are likewise relatively uncommon during
the neonatal period but should always be kept in the differential
diagnosis when more common causes are excluded. The qualitative abnormalities associated with either platelet structurefunction relationships or congenital metabolic defects are very
rare. A severe form of the various types of thrombasthenia may
manifest itself in the neonatal period (see the slide presentation
for demonstration of a typical platelet aggregation test in a patient
with Glanzmanns thrombasthenia, a quality platelet defect).
Review of the peripheral blood smear and a bone marrow aspirate
may provide diagnostic information enabling detection of some
platelet disorders. Evaluation of thrombocytopenia when other
screening tests are normal may be simplified and based on the
mean platelet volume (Figure 1313).
Evaluation of qualitative platelet function disorders, especially
in neonates, is troublesome and requires a significant amount of
blood drawn in order to obtain platelet-rich plasma for classic
testing of aggregation with specific agonists. Some studies have
reported that neonatal platelets are normally hyporeactive. This
may result from decreased receptor numbers, deficient thromboxane synthesis, and impaired signal transduction,71,72,90,91 as well
as from perinatal platelet activation.74 Some studies have also
revealed increased platelet deposition on subendothelial surfaces
in neonates, probably because of the higher concentration of vWf
and its large multimers that are present in neonatal plasma.92
Whole blood shear and flow-based platelet assays have demonstrated that the platelet function of neonates correlates with
TABLE 13-1. Diagnostic Approach to the Bleeding Child

Conditions
Differential Diagnosis
Tests
Plt
PT
PTT
Plt normal
PT
PTT
Plt normal
PT normal
PTT
Plt normal
PT
PTT normal
All screening tests normal
DIC
Thrombin time. FSP.

Factor V assay.
Red cell fragmentation.
Factor II, V, VII, X assays.
Liver function tests.
Response to vitamin K.
Factor VIII, IX, XII assay.
Vitamin K deficiency.
Hepatocellular damage. Excessive heparin.
Congenital factor VIII, IX, XI deficiency.
vWD.
Heparin administration.
Congenital factor VII deficiency.
Factor VII assay.

Platelet dysfunction
(vWD).
Factor XIII deficiency.
Platelet aggregation tests.

Thrombin time.
Factor XIII assay
DIC = disseminated intravascular coagulation; FSP = fibrin split products; Plt = platelet; PT = prothrombin time; PTT = partial thromboplastin time; vWD = von
Willebrands disease;
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Figure 13-13. Evaluation of thrombocytopenia with normal

screening tests.
gestational age.93 However, apart from conditions with severe
congenital platelet dysfunction, the clinical correlation and the
predictive value of platelet function testing in neonates under
various conditions remains to be elucidated.
Congenital Factor Deficiencies:

Symptoms and Diagnosis
The clinical presentation of a severe factor deficiency is
spontaneous bleeding or excessive bleeding following minor
trauma in otherwise healthy infants. ICH may be the presenting
symptom.64 The majority of newborns with congenital coagulation
factor deficiencies do not bleed in the perinatal period unless
traumatized or when a hemostatic challenge is present. The
correct diagnostic assays and appropriate management vary
according to the underlying basic disorder. Patients with Factors
VIII and IX deficiencies (hemophilia A and B) generally have
limited problems during the first year of life if they are not
traumatized during or immediately after delivery. Excessive
bruising may be noted, but bleeding into the joints is uncommon.
During the toddler years when the child is learning to walk and
frequently falling, bleeding episodes are more common and acute
hemorrhages, spontaneous or post-traumatic, usually occur.
Although von Willebrands disease (vWD) is the most common
congenital bleeding disorder, patients rarely present during the
neonatal period. The most common variant, type I vWD, accounts
for about 70% of patients and is associated with mild bleeding.
However, type 3 vWD, which is associated with low or
undetectable levels of vWf, manifests as a severe bleeding disorder,
often similar to severe hemophilia.94,95
Acquired Coagulation Disorders and

Associated Abnormalities
The most common of the acquired coagulation disorders are
liver disease, vitamin K deficiency, anticoagulant therapy, and DIC
with consumption of coagulation factors. The liver is the site of
synthesis of the majority of the coagulation factors. It is also
involved in the clearance from the circulation of activated
coagulation factors and activators of fibrinolysis. Hepatocellular
damage is frequently associated with excessive bleeding owing to
subnormal or deficient levels of coagulating factors. The hemostatic abnormalities in liver disease may be similar to those found
in DIC. DIC should not be considered a disease in itself, but rather
a process occurring secondary to a variety of underlying

insults.96,97 In the neonatal period, sepsis, asphyxia, preeclampsia
and maternal toxemia, respiratory distress syndrome, necrotizing
enterocolitis, and hypothermia may initiate DIC. In infants and
children, bacterial sepsis, leukemia, and severe intracranial
injuries are the more common causes of DIC. The diagnosis of
DIC is based on the presence of thrombocytopenia, prolonged PT,
aPPT, decreased fibrinogen levels, elevated fibrinogen split
products, and the presence of microangiopathic hemolytic
anemia. Recently, more sensitive markers for endogenous thrombin and plasmin generation have become available and may soon
have some clinical utility in securing the diagnosis. In practice,
no single laboratory test can be used exclusively to confirm or
exclude DIC. The cornerstone of the management of DIC is
treatment of the underlying disorder while supportive therapy is
applied to correct the hemostatic abnormalities. The practical
approach for diagnosis of the bleeding pediatric patient is
summarized in Table 131.
Therapy of Bleeding Disorders

in Neonates and Children
Therapeutic options for treatment of the various bleeding disorders include routine vitamin K for neonatal prophylaxis to avoid
vitamin K deficiency bleeding (VKDB) and fresh frozen plasma
(FFP) or specific factor concentrates for the treatment of VKDB or
specific factor deficiencies. Such therapy may include recombinant
or plasma-derived Factor VIII or Factor IX to treat hemophilia A
or B; prothrombin complex concentrates or fibrogamin for Factor
XIII deficiency; recombinant activated Factor VII for hemophilia
patients with inhibitors, Factor VII deficiency, or Glanzmanns
thrombasthenia; cryoprecipitate for hemophilia A, vWD, and
fibrinogen disorders; platelet transfusions for platelet function
disorders; and adjunct antifibrinolytic therapy for all infants with
bleeding disorders during acute bleeding episodes or surgical
procedures.98 For diseases such as hemophilia, the progress of gene
therapy trials may yield the best therapeutic answer within a few
years. Prenatal diagnosis of most congenital severe factor deficiencies is currently possible in families with a history of inherited
coagulation factor deficiency.64
Thrombotic Disorders
Thrombosis occurs when the usual balance between protective
mechanisms and thrombogenic factors is disrupted. This may be
caused by exposure of the subendothelium following vascular
injury, activation of platelets and coagulation factors without
sufficient neutralization by coagulation inhibitors, stasis or impaired fibrinolysis of blood clots. In cases of acute severe arterial
or venous thromboembolism, thrombolytic therapy can be
considered. Within the pediatric population, such therapy is more
often recommended in neonates and premature babies, given their
low capacity for spontaneous fibrinolysis.
The incidence of thromboembolic events among children is
much lower than among adults.99101 Among children, neonates
exhibit the highest risk with a reported incidence of 0.24 to 0.51
per 10,000 births for venous thrombosis.101103 The pathogenesis
of any vascular thrombosis stems from acquired as well as
inherited causes, the latter defined as inherited thrombophilia.104
The most common genetic thrombophilias include the substitution of arginine by glutamine at amino acid residue 506 in
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coagulation Factor V (Factor V Leyden) 105 and a guanine to
arginine transition at position 20210 of the 3 untranslated region
of the Factor II gene (FIIG20210A) otherwise known as the
prothrombin mutation.106 These changes make these molecules
resistant to the endogenous fibrinolytic cascade. In addition, the
homozygous state with amino acid alterations in the enzyme
methyl-tetrahydrofolate reductase may be associated with vascular
disease, possibly because of increased plasma homocysteine
levels.107 Genetic prothrombotic risk factors play an important role
in the pathogenesis of infantile thrombosis.99103 As already
mentioned in the section on Neonatal Hemostatis: Development
aspects and laboratory evaluation, plasma concentrations of
coagulation inhibitors differ among newborns and adults. The
values of protein C, protein S, AT-III, and heparin cofactor II are
low at birth. Protein C levels reach adult values in early childhood.
Plasminogen levels are also low in neonates, reaching normal
adults levels at 6 months of age. The etiologies of classic thrombophilia are mostly caused by decreased or absent inhibitors of
coagulation. Homozygous patients with prothrombotic disorders
such as protein C and protein S deficiencies rarely present during
the neonatal period or infancy. All of the reported cases have presented with life-threatening or lethal conditions, such as purpura
fulminans, large vessel thrombosis, hemorrhagic necrosis of the
skin, and secondary DIC. The homozygous state for AT-III deficiency is incompatible with life. Patients who are heterozygous for
prothrombotic disorders rarely have thromboembolic events in
infancy. Problems generally arise when there is an additional insult
such as immobilization, infection, or surgery that unmasks the
basic problem. A prothrombotic state may also be associated with
acquired thrombophilic risk factors such as the presence of antiphospholipid antibodies.108 In these patients, thrombosis is also
often triggered by additional predisposing factors such as sepsis,
cancer, or the presence of central lines.109111
217
Anesthesia and Coagulation Disorders

The evaluation of a pediatric patient before surgery varies from
that of the adult in many aspects including coagulation problems.
Routine preoperative evaluation is not necessary unless there is
enough concern to suggest congenital or familial problems such as
bleeding disorders, hypercoagulable states, and anemias or a
history of drug exposure (anticoagulants). These are generally
identified during the taking of the preoperative history. Specific
hematologic and oncologic conditions that may affect the anesthetic plan are outlined in Table 132. Significant coagulation
abnormalities may be encountered during obstetric interventions,
cardiac surgery with cardiopulmonary bypass, and liver transplantation, in which both the coagulation and the fibrinolytic
systems have been triggered and vigorously activated. Continuous
monitoring of coagulation studies and subsequent replacement
therapy with appropriate clotting factors or anticoagulants may be
indicated. DIC is the most dreaded outcome of serious medical
conditions such as sepsis, acidosis, shock, electric shock, and many
other situations may also trigger its appearance. Therapy should be
started promptly, but the outcome depends on the successful
treatment of the primary disease.
Replacement of blood products and correction of coagulation
function may be necessary before surgery. Patients with factor
deficiencies should have their PT/PTT (partial thrombolasin time)
corrected before surgery by either specific factor concentrates
(VIII or IX) or FFP. Additional therapy may include the use
of topical agents such as fibrin adhesives or the perioperative
administration of antifibrinolytic agents such as aminocaproic
acid or tranexamic acid. Patients who require chronic anticoagulation because of previous thromboembolism or valve replacement should stop their warfarin treatment 3 to 5 days before
surgery, if possible, with a switch to heparin or low-molecularweight heparin (LMWH) therapy. LMWH should be stopped
TABLE 13-2. Preoperative Hematologic Considerations

Conditions
Definition
Comments
Anemia
Hemoglobin <
710 g/dL
Thrombocytopenia
Platelet count <

50,000/mm3
No specific transfusion triggerbased on patients comorbid conditions.

RBC transfusion (1015 mL/kg).
For elective surgery, erythropoietin may be considered to avoid
transfusions.
Platelet replacement (one unit of random donor platelets/10 kg or 1015
mL/kg of pheresed platelets). If no increment in previous transfusion,
use single donor or HLA-matched.
Premedication if previous allergic or anaphylactic reaction.
Withhold for 5 d before surgery.
Restart immediately postoperatively.
If intraoperative bleeding occurs, platelet transfusion.
Withhold for 35 d preoperatively with parallel heparin or LMWH
replacement. If 1.8 < INR < 2.5, institute therapy for 1 d
and restart postoperatively.
In emergency situation, intravenous vitamin K.
If overt bleeding: FFP or off-label use of rFVIIa.
Stop 46 h preoperatively.
Restart 624 h postoperatively.
Withhold one dose at night and one at morning preoperatively.
Restart that same evening.
Antiaggregants: aspirin
Anticoagulation: Coumadin
INR > 1.8
Heparin
Maintenance
LMWH
Maintenance
HLA = human leukocyte antigen; INR = International Normalized Ratio; LMWH = low-molecular-weight heparin; RBC = red blood cell; rFVIIa = recombinant
activated factor VII.
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12 to 24 hours before surgery and heparin should be stopped 4 to

6 hours before surgery. In emergency situations, vitamin K and
FFP should be given to allow the procedure to proceed. Once
the bleeding risk has subsided, preoperative anticoagulation
medications should be resumed with the intention of achieving
therapeutic levels of PTT and the International Normalized
Ratio (INR).
22.
23.
24.
CONCLUSION
It has been long conceptualized that a child is not a miniature
reflection of an adult. The abnormalities encountered in neonates,
infants, and later, in children and adolescents, are age-, development-, and maturation-dependent. Anatomic malformations,
genetic aberrations, and exogenous factors may all contribute to
the disruption of the normal hematopoietic process, formation
of cellular and humoral blood components, and function of
the immune system. These factors may affect not only on the
intraoperative care of the patients but also the entire continuum
of their perioperative care.
25.
26.
27.
28.
29.
30.
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Temperature Regulation:
Physiology and Pharmacology
Igor Luginbuehl
INTRODUCTION
Maintaining central body temperature within narrow limits is a
prerequisite for the survival of homeothermic organisms and
requires a complex feedback system. Despite changes in the
ambient temperature, a homeothermic organism has the ability to
maintain central or core body temperature constant. In humans,
core body temperature refers to the temperature of the vessel-rich
group organs (i.e., brain, heart, lungs, liver, and kidneys). Under
normal conditions, this temperature is maintained within 0.2C
of its normal value of 37.0C. This so-called interthreshold range
represents the minimal deviation tolerated by the body under
normal circumstances. Within this range, no thermoregulatory
effector responses are triggered and the human organism behaves
poikilothermic. Not many other physiologic parameters are as
tightly and effectively controlled as central body temperature.
Measuring body temperature in almost 25,000 patients and
acquiring a total of more than 1 million measurements at the
University Hospital of Leipzig, the German physician, Karl
Reinhold August Wunderlich (18151877), was the first to
systematically measure axillary body temperature under various
conditions, to widely use thermometers in clinical practice, and
to define the normal body temperature of 37.0C with a range of
36.2 to 37.5C.1 He also realized that body temperature oscillates
not only in sick but also in healthy subjects. Given the fact that
thermometers at that time were rather bulky and slow and that
computers were not available for data analysis, even by todays
standards, Wunderlichs work should be regarded as a most
impressive achievement. However, the calibration and accuracy of
the thermometers that he used are not known and the same
applies to his statistical methods for data analysis. A systematic
review of the literature defined the normal for axillary temperature
in adult men and women as ranging between 35.5 and 37.0C (the
oral, rectal, and tympanic temperature ranges were 33.238.2C,
34.437.8C, and 35.437.8C, respectively). The authors concluded that the range of normal body temperature, particularly its
lower limit, needs to be adjusted.2
TEMPERATURE MONITORING
Temperature is one of the seven base quantities in the International System of Units (SI) and its unit is Kelvin (symbol K). By
definition, 1 Kelvin is the fraction 1/273.15 of the thermodynamic
temperature of the triple point of Vienna Standard Mean Ocean
Water (i.e., despite the name, the reference is pure water). However, in medicine (and daily life), temperature has traditionally
14
C H A P T E R
been measured in degrees Celsius or Fahrenheit. A temperature

of zero Kelvin equals approximately 273.15C or approximately
459.67F. A body temperature of 37.0C is equal to 98.6F; the
following formulas allow for easy conversion among Celsius,
Fahrenheit, and Kelvin:
Celsius = (Fahrenheit 32) 0.56
Fahrenheit = (1.8 Celsius) + 32
Kelvin = Celsius + 273.15
In order to detect perioperative changes in temperature,
appropriate measures to assess temperature need to be in place.
Guidelines of the American Society of Anesthesiologists and
numerous other national anesthesia societies require or at least
recommend that one method for measuring body temperature
during anesthesia be available.37 Although standard for clinical
purposes in earlier times, mercury-in-glass thermometers have
now been mostly replaced by thermocouples and thermistors.
A thermocouple consists of two different metals, commonly
copper and constantan (a copper-nickel-manganese-iron alloy).
The principle is based on the Seebeck effect, named after the
Estonian physicist Thomas Johann Seebeck (17701831) who, in
1821, discovered the temperature-measuring properties of this
setup. The Seebeck effect states that a small electrical potential
is produced at any junction between two different metals from
the thermoelectric series. The magnitude of this current is
temperature-dependent and can, therefore, be used to measure
temperature.
The American inventor, Samuel Ruben (19001988), discovered in 1930 that electrical resistance changes exponentially
with temperature. This formed the basic principle of the thermistor type of thermometer, a semiconductor resistor that consists
of a tiny blob of metal (copper, cobalt, nickel, or manganese). The
change in resistance is used to measure temperature, which is also
reflected in the name thermistor, a combination of the words
thermal and resistor. Both thermocouples and thermistors
are fairly inexpensive, are easily available, and have a reasonably
fast response time. For clinical purposes, both are considered
sufficiently accurate, although thermistors in general are more
precise (up to 0.1C).
Temperature-sensitive liquid crystals have been used to measure skin temperature. Although safe, easy, convenient to handle,
and with a theoretical accuracy in the range of 0.5C, these
devices generally do not meet the accuracy criteria required for
clinical use because the measurement can easily be influenced by
changes other than body temperature and skin blood flow.8,9 To
compensate for this error, it has been suggested to simply add a
correction factor to an arbitrary skin temperature measurement,
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but this does not provide a reliable estimate of central temperature

and is, therefore, neither recommended nor widely used in
anesthesia practice.8,10 However, at least one study has reported
that forehead temperature assessed by liquid crystal thermometry
correlates better with esophageal temperature than axillary or
rectal temperature during rapid rewarming after cardiopulmonary
bypass (CPB) surgery.11
Although less suitable for continuous temperature monitoring
under anesthesia, infrared thermometers (thermopiles) are widely
used in clinical practice (e.g., in postanesthesia care units). Their
function is based on the fact that any object with a temperature
above absolute zero (i.e., ~273.15C) emits blackbody radiation
with a characteristic temperature-dependent wavelength. These
probes consist of a small lens that allows the infrared radiation
from an object to be focused onto a detector that then converts
the infrared energy into an electrical signal with a corresponding
temperature readout. The two main advantages of this type of
thermometer are that they have a quick response time (typically
< 1 s) and that they do not need to be in direct contact with the
object to be measured, which makes them theoretically ideal for
tympanic (and, to a lesser degree, skin) temperature assessment.
However, the medical literature is, at best, inconclusive about the
clinical benefits and accuracy of these thermometers.1226
Handheld infrared scanners (noninvasive temporal artery
thermometers) have recently been developed to assess central
temperature via skin temperature measurement. By contrast to
liquid crystal thermometers, these devices theoretically detect the
highest temperature in the temporal or forehead region, which
normally is the skin area in closest proximity to the temporal
artery. Unlike liquid crystal thermometers, the device compensates
for ambient temperature with a built-in proprietary algorithm.
However, in both adult and pediatric patients, the accuracy of
the device has not been considered sufficient to meet clinical
purposes.2629
Sites for Temperature Monitoring

Within the body, temperature is neither constant nor uniform and
its regulation involves several organs and systems. Because of the
high perfusion rate, core tissues maintain their temperature
relatively constant and tightly regulated within the superimposed
circadian changes in central temperature. By contrast, peripheral
tissues demonstrate a much wider and far less uniform temperature range, which may differ by several degrees within a short
distance from each other.30 This is explained by the fact that
the peripheral compartment acts as a highly dynamic buffer
between the central and the shell compartment. Depending on the
requirements and the environment, it acts as a source of heat gain
or heat loss.
Body temperature can be monitored at basically any anatomic
site. However, the accuracy of measurements depends on the
chosen site, with each site having its advantages and disadvantages.31,32 The ideal site of temperature monitoring should reflect
core temperature and be associated with no (or only negligible)
morbidity. Because core temperature is the key player in thermoregulation, it has attracted the most clinical attention. Core
temperature measuring sites available for clinical use include the
tympanic membrane, nasopharynx, distal esophagus, pulmonary
artery, and with some limitations, bladder and rectum. Under ideal
conditions, all of these sites provide similar readings in awake as
well as in anesthetized humans undergoing noncardiac surgery.31
However, most monitoring sites have specific limitations, which

may result in different temperature readings, and it is useful to
know the physiologic and clinical significance of such differences.
Because of its wide variability depending on the site of
monitoring, skin temperature is not an acceptable site for the
estimation of core temperature.32,33 Several investigators have
suggested that skin monitoring can be used with the monitoring
of 4 to 15 cutaneous sites and the use of both weighted and unweighted formulas to accurately describe mean skin temperature30,3436 However, to be of clinical value, skin temperature would
have to accurately reflect central temperature in the perioperative
period and during hypothermia or malignant hyperthermia.
For example, it is unlikely that skin temperature closely correlates
with central temperature during the early stages of malignant
hyperthermia, because skin perfusion will be significantly altered
by circulating catecholamine levels that are up to 20 times higher
than normal.37
No physiologic evidence exists that hypothalamic temperature
precisely represents central temperature. Benzinger, nevertheless,
suggested that central temperature is the temperature of the
hypothalamus and that tympanic membrane temperature probes
reliably reflect central temperature.38 A pulmonary artery catheter
with a distal-tip thermistor is the gold standard for assessing
central body temperature, providing the reference temperature
against which all other sites are compared. However, because of
its invasive nature, its use is limited to special situations, namely,
critically ill children.
Tympanic membrane temperature has been suggested to be
the most ideal temperature-monitoring site to determine core
body temperature. However, the accuracy of infrared tympanic
thermometers is controversial. In order to accurately reflect
tympanic temperature, even noninfrared temperature probes are
not required to be in direct contact with the tympanic membrane
as long as the probe seals the external auditory canal, allowing the
air column trapped between the probe and the tympanic membrane to reach a steady state. However, it has been demonstrated
that tympanic temperature does not correlate well with brain
temperature in the initial postoperative period in infants and
children after cardiac surgery and, therefore, does not provide an
accurate estimate of central body temperature.39,40 Mainly because
of the difficulty related to obtaining appropriate-sized thermistors,
but also because of concerns regarding tympanic membrane
perforation, their clinical use has been discouraged.41,42
Nasopharyngeal temperature probes can accurately reflect core
temperature if properly positioned, that is, placing the tip of the
probe in the posterior nasopharynx in close proximity to the
soft palate. This provides a good estimate of the hypothalamic
temperature. However, an uncuffed endotracheal tube with a
moderate to large air leak may create enough leak flow to result
in falsely low temperature readings. Further limitations include
slight, but usually self-limiting, bleeding from the nose or
nasopharynx (particularly in children with large adenoids) and
impracticality during mask anesthesia. Nevertheless, in clinical
practice, this site is an often used, is easy accessible, and remains
a fairly reliable site for temperature measurement. Oral temperature has been reported to reliably reflect central temperature
in orally intubated adult patients in the critical care unit.18,43
Limitations include impracticality and potential inaccuracy with
mask anesthesia because a moderate to large leak around the
endotracheal tube or an open mouth during anesthesia can result
in falsely low readings.
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Esophageal temperature probes are often combined with
an esophageal stethoscope, which makes this site particularly
attractive for the pediatric population. However, in infants and
children as well as in cachetic patients, the thermal insulation is
minimal between the tracheobronchial tree and the esophagus.
The inspiratory gas flow may, therefore, depending on its temperature, result in erroneous temperature readings, particularly
when minute ventilation is high and the gas temperature is significantly different from body temperature.32 Central temperature
is measured only if the tip of the probe is positioned in the distal
third of the esophagus at the point at which the heart sounds are
the loudest.32,44 However, in patients with endotracheal intubation,
esophageal temperature is more reliable than rectal temperature
and more practical than tympanic temperature. The optimal depth
of a nasally inserted esophageal temperature probe in adults has
been determined as:45
Insertion depth [cm] =
body height (cm)

4
4 cm
Malpositioning of the axillary temperature probe is the most

common reason for its notoriously low reliability in reflecting
central temperature. Nevertheless, it is the most commonly used
and convenient site for temperature monitoring during the
administration of general anesthesia. Axillary temperature has
been reported to be as accurate in measuring central temperature
as tympanic membrane, esophageal, and rectal temperature sites,
but this requires the tip of the thermometer to be carefully placed
over the axillary artery and the arm to be closely adducted.32 In
small children, high flow rates of intravenous solutions at less than
body temperature on the arm of the thermometer may result in
falsely low temperature reading, which explains why the axillary
temperature probe should not be placed on the same side as the
infusion.
The accuracy of rectal temperature monitoring can be affected
by problems of probe insulation by feces, cooler blood returning
from the legs, the influence of an open abdominal cavity for surgery, or irrigation of the abdomen or bladder with fluids of a
temperature different from the rectal temperature. A significant
lag in the response time may occur in situations with rapid
changes in central temperature (e.g., cooling and rewarming on
CPB).4648 With these limitations in mind, the rectal site usually
provides an easy and fairly reliable way to monitor central temperature and is associated with minimal morbidity.32 If possible,
rectal temperature should not be used in patients with inflammatory bowel disease (risk of perforation), bleeding disorders,
thrombocytopenia or neutropenia, perirectal disease such as
hemorrhoids (risk of bleeding), or in patients whose abdomen,
bowel, or bladder is to be irrigated (inaccurate reading). Bladder
temperature is also considered an appropriate site for core temperature measuring.49,50 In adults, it has been demonstrated that
as long as urinary output is maintained at approximately 250 mL/
h, bladder temperature closely reflects pulmonary artery temperature.49,51 However, when urinary output is normal or decreased,
this site becomes a less accurate representation of central temperature.
The choice of the temperature monitoring site is often influenced by the operative procedure. In patients undergoing cardiac
surgery, temperatures from different body sites convey useful
information explaining why temperature is usually measured
Temperature Regulation: Physiology and Pharmacology
223
simultaneously at multiple sites (e.g., rectum, bladder, esophagus,

nasopharynx, tympanic membrane). For nonintubated pediatric
patients undergoing a short operative or diagnostic procedure, the
author uses either a rectal or, with its limitations in mind, an
axillary temperature probe. If the childs trachea is intubated, other
preferred sites include the distal esophagus (combined with
esophageal stethoscope) or the nasopharynx.
THERMOREGULATION
The French obstetricians, Etienne Stphane Tarnier (18281897),
and his student, Pierre Constant Budin (18461907), both now
considered fathers of modern perinatology, were the first to
detect that, although the survival rate of neonates with a rectal
temperature between 32.5 and 33.5C was a shocking and dismal
10%, it could be dramatically increased to 77% when the infants
were warmed to a rectal temperature of 36 to 37C.52 No other
medical intervention can claim an equally profound impact on
neonatal survival rates. In addition, this is a great example to
highlight the power and limits of thermoregulation.
Tarnier was also the inventor of the first incubator for
premature and smallforgestational age neonates. The idea for
an incubator occurred to him while visiting the Paris zoo in 1880,
where he saw eggs of exotic birds being hatched in a couveuse
(incubator). He immediately recognized the potential of such a
device and had one custom built for his hospital. In 1881, this
resulted in the first closed incubator used in a hospital.53 The
incubator had space for four babies and used an oil flame to heat
a large tank of water underneath the bed. Other investigators later
confirmed Tarnier and Budins findings regarding the importance
of thermal stability for neonatal adaptation and further elucidated the mechanisms by which infants and children behave as
homeotherms.5457
In terms of thermoregulation, the body can be treated as a
three-compartment model with central, peripheral, and shell compartments (Figure 141). The vessel-rich group organs represent
the majority of the central compartment; the musculoskeletal
system makes up the greater part of the peripheral compartment
and acts as a dynamic buffer in the thermoregulatory system
between the core and the shell, which is represented by the skin
and functions as a barrier to the environment.
Circadian rhythms ensure optimal function of a biologic
system, maximizing its performance and efficiency while
maintaining an appropriate comfort level.58 It appears that the
circadian changes in core body temperature are generated by
a rhythmic input from the central pacemaker located in the
suprachiasmatic nuclei (hypothalamus) acting upon impulses
from neighboring hypothalamic thermoregulatory centers, which
may not only alter the thresholds for thermoregulatory effectors
(e.g., cutaneous vasodilatation or sweating) but also modulate the
set point of body temperature.59,60
Despite the fact that the central body temperature is under very
tight control, it shows circadian variations. The circadian rhythm
of body temperature is generally closely related to the sleep-wake
cycle. However, under specific circumstances, it may also occur
independently of it, dependent on pineal melatonin secretion and
the circadian pacemakers response to light.6163 In the evening,
when ambient light and physical activity usually decrease, the
secretion of melatonin increases, which results in cutaneous
vasodilatation and eventually a drop in body temperature and
the induction of sleep (heat loss mode).64 Because of supine
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Figure 14-1. Central and peripheral compartment during anesthesia. Depiction of the anesthesia-induced changes in the
sizes of the central and peripheral compartments. A: In the awake child, the core and peripheral compartment show a normal
relationship. B: Following 1 hour of anesthesia, internal redistribution of heat from expansion of the core and shrinkage of the
peripheral compartment results in a rapid decrease in core temperature associated with an increase in peripheral compartment
and skin temperature. C: After approximately 2 hours of anesthesia, thermoregulatory vasoconstriction becomes effective and
the central compartment shrinks again in favor of the peripheral compartment. This pronounced peripheral vasoconstriction
leads to a marked decrease in skin temperature. AC: Adapted from reference 505.
positioning in bed, sympathetic tone and stress on the cardiovascular system are reduced, further supporting the decrease in
body temperature. The observed changes in the evening are
reversed in the morning, when the internal clock and brighter
ambient light reduce melatonin secretion, which in turn causes
increased physical activity and distal cutaneous vasoconstriction
that reduce heat loss and result in higher central, but lower
peripheral, temperature signaling the organism to wake up (heat
gain mode).6567 In an individual with a constant daily routine,
the phasic changes in central body temperature cause a plateau
between 2:00 PM and 10:00 PM, with a maximum at 5:00 PM and a
minimum at around 5:00 AM.58
These circadian changes in body temperature are agedependent and, when compared with young adults, are less
developed in neonates and older people.68 Circadian swings in
body temperature rhythms are already present in the first days of
life, although the phase variability is increased and the amplitude
diminished.61,69,70 In approximately 50% of preterm infants (28
34 wk of gestational age), the circadian pattern in body temperature can even be detected.71 Other circadian rhythms that
control body temperature may still be absent or weak (e.g.,
changes between rest and activity), although the suprachiasmatic
nuclei (the location of the central pacemaker) and its melatonin
receptors are developed by 18 weeks of gestation. This most likely
implies that the functional pacemaker does not have a mature
effector system at this point of development.72
Body temperature also follows a monthly rhythm in fertile
women (owing to a higher set-point temperature in the luteal
phase of the menstrual cycle).73 A delicate and sophisticated

control system is responsible for effectively balancing heat
production and heat loss to maintain body temperature within
its tight limits. Despite this powerful regulatory system with the
ability of the body to dissipate or generate heat by regulating
skin blood flow, sweat production, minute ventilation, and metabolism, it can easily be overwhelmed by external factors. Anesthesia
and surgery may have a significant impact on thermoregulation,
and minor changes in body temperature may result in cellular and
tissue dysfunction. This explains the need not only for a tight
regulation system but also for perioperative temperature monitoring and management. Without appropriate prevention, inadvertent hypothermia is an almost certain occurrence in patients
of any age undergoing anesthesia and surgery. Unfortunately, this
fact has led to a widespread acceptance of hypothermia as an
inevitable consequence of anesthesia, leading Pickering half a
century ago to his famous statement: The practical difficulty in
cooling men is to break through the defenses of the body; the most
effective means is to give an anesthetic, which has been shown
to interrupt at some point or points the reflex arcs which protect
against cooling, particularly by shivering.74
Physiology of Thermal Regulation

Survival from a body temperature as low as 13.7C has been
reported,75 whereas death, resulting most likely from protein
denaturation, occurs within 7C from normothermia at approximately 44C and irreversible neuronal changes may occur at core
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temperatures around 40C.76,77 This demonstrates that the
tolerance to cold is more than three times higher than to heat,
which explains why the system to dissipate heat has to be much
more effective than the cold defense system. Similar to other
regulatory systems in the body, temperature is controlled by a
sophisticated network of sensors (afferent input), a central
controller (hypothalamus), and effectors (efferent output). The
thermoregulatory system uses negative-feedback mechanisms
to keep variations from normal values as minimal as possible.78
The most important center for integration of afferent thermal
information and triggering of autonomic thermoeffector responses is the preoptic anterior part of the hypothalamus (POAH).
This is where afferent signals from temperature-sensitive cells
from various tissues converge, including other parts of the brain
(e.g., pons, medulla oblongata, midbrain), spinal cord, vessel-rich
group organs, respiratory and gastrointestinal tract, and the skin
surface. The processing of thermoregulatory information occurs
in three stages: (1) afferent thermal sensing, (2) central integration
and regulation, and (3) efferent response.
Afferent Thermal Sensing

In the periphery of the body, anatomically distinct warm and
cold receptors sense the ambient temperature. The skin contains approximately 10 times more cold than warm receptors,
underlining the important function of the skin in detecting
cold.79 These cold receptors are located in the epidermis and the
subcutaneous tissue and convey their information by thin, myelinated A-delta fibers. Unmyelinated C fibers transfer information
collected by warm receptors, which are located in the deeper layers
of the skin. However, the speed of transmission depends more on
the intensity of the stimulus than on the type of nerve fiber. In
addition, the rate of a skin temperature change affects its impact
on central thermoregulation. A rapid change contributes about
five times as much as the same change made slowly,80 although
it seems that only CPB is capable of inducing temperature
changes fast enough to substantially alter the provoked regulatory
response. Afferent thermal signals from cold and warm receptors
potent enough to trigger a thermoregulatory response converge
at the level of lamina I neurons, from which they reach the brain
via a spinoreticulohypothalamic pathway and project to the
reticular formation.81 This form of convergence may occur at
several levels along the signal pathway and enables the body to
collect thermal information from a larger body area.82 Finally, the
tertiary neurons of this afferent pathway terminate in the
hypothalamus (mainly the POAH area). Peripheral, deep body
thermosensitive receptors measure core temperature and are
found in close proximity to the great vessels, the viscera, the abdominal wall, and the spinal cord.83 These primary thermosensitive
receptors are bipolar neurons whose cell bodies are located in the
dorsal root ganglia, from which their central axon projects to the
lamina I of the spinal dorsal horn. From there, lamina I neurons
transmit their information via a spinothalamocortical pathway
to the insular cortex either with a relay in the posterior part of
the ventromedial nucleus of the thalamus or with two relays in the
parabrachial nucleus and the basal ventromedial nucleus of the
thalamus. However, the significance of this pathway lies more in
the thermoregulatory interaction, behavior, and decision-making
related to the environment than in actual thermoregulation
itself.84,85 There are indications that some peripheral thermoreceptors have the option to convey their information through a
225
more direct connection from the spinal cord to the brain via
spinohypothalamic pathways.8688 Thermosensitivity of peripheral
thermosensors most likely is associated with changes in the
resting membrane potential. Their activity increases significantly
during temperature changes but normalizes quickly again once
the temperature has stabilized.83 Peripheral thermoreceptors,
including skin warm and cold sensors, express several different
types of transient receptor potential (TRP) channels, which are
part of a mammalian TRP superfamily consisting of approximately
30 different channel types divided into six subfamilies.83 Each of
these channels is sensitive to a narrow temperature range only, but
combined, they cover a wide temperature range.89 The so-called
thermo-TRP channels consist of the heat-sensitive channels
TRPV1V4, M2, M4, and M5, whereas TRPM8 and A1 channels
are cold-sensitive.90,91 Activation of these channels at the peripheral
terminals of cutaneous or visceral warm fibers triggers a cation
influx with subsequent depolarization of neurons in the dorsal
root ganglion projecting to thermosensitive neurons in lamina I of
the dorsal horn.92 From here, their axons decussate to ascend
within the spinothalamic tract and to send off collateral branches
to the parabrachial nucleus in the pons, where projections to the
POAH then activate warm-sensitive neurons and/or inhibit coldsensitive neurons.89 The vagal nerve may also convey afferent
thermal information and be involved in the induction of fever and
nutritional and/or metabolic information signaled to the brain,
which may influence metabolism and body temperature. However,
its role in thermoregulation is still largely unknown.93
Central Regulation
The primary thermosensitive area and most important center in
the control of autonomic thermoeffector responses in the central
nervous system is located in the POAH. However, other parts of
the brain, such as the dorsomedial hypothalamus, periaqueductal
gray matter, and nucleus raphe pallidus in the medulla oblongata,
also play a crucial role in thermoregulation. These centers are
responsible not only for the integration of afferent thermal information but also for the reception and processing of nonthermic
afferent information, which is important in controlling adaptive
mechanisms and thermoregulatory behavior.94 The threshold
in this system represents the central temperature at which a
particular regulatory effect is initiated, whereas the gain quantifies
the intensity of the response. Approximately 70% of the POAH
neurons are temperature-insensitive, although slightly more
than 20% are warm-sensitive.95 Using chemical and/or thermal
stimulation in the POAH, it can be demonstrated that both heat
loss and heat generation are mainly controlled by these warmsensitive neurons.96,97 Increased activity on their part owing to
increased input from warm-sensitive thermoreceptors triggers
heat loss (i.e., cutaneous vasodilatation and sweating) and, at the
same time, inhibits heat generation by tonic inhibition of coldsensitive neurons in the hypothalamus and brainstem. By contrast,
decreased activity of the warm-sensitive POAH neurons initiates
heat gain mechanisms (i.e., cutaneous vasoconstriction and shivering and nonshivering thermogenesis) and inhibits heat loss
mechanisms.83,92,98 Because these warm-sensitive neurons in the
POAH show spontaneous membrane depolarizations (owing to
inhibition of a transient outward hyperpolarizing potassium
current), they are considered to be pacemakers with warming
significantly accelerating their depolarization rate.91,98,99 Accordingly (and unlike peripheral thermoreceptors), the cellular
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mechanism responsible for neuronal warm sensitivity lies in the

thermosensitive elements of the depolarizing current. Warminsensitive neurons use mainly inhibitory (and, less commonly,
excitatory) postsynaptic potentials to modulate the activation and
sensitivity of warm-sensitive neurons.98 Electrophysiologic studies
have demonstrated that some midbrain reticulospinal neurons (for
shivering) and premotor neurons in the medulla oblongata (for
skin vasomotor control) have direct projections to the spinal cord
level to elicit thermoregulatory effector control.93
The difference between the lowest temperature triggering warm
responses and the highest temperature triggering cold responses
defines the thermal sensitivity of the system. The concept of
thermoregulation described in the section on Thermoregulation
forms the basis of the set-point model originally described by
Hammel, in which the body defends a certain temperature (or,
more precisely, a temperature range, normally 37.0 0.2 C) set
by the organism.100 A central temperature above and below this
range triggers heat loss and heat gain mechanisms, respectively. It
should be emphasized that this set-point model has more recently
been reviewed, questioned, criticized, and defended.98,101104 The
set-point theory in thermoregulation has been borrowed from
engineering models to serve as a convenient analogy and to
provide a method to improve our understanding of how body
temperature is regulated through the control of heat production
and heat loss. This model uses the assumption that the body
compares its core temperature against a set reference temperature
in a unified control system to create an error signal that then
triggers a correcting effector response. Although such a model may
be ideal for teaching purposes, it may not accurately reflect the true
concept of thermoregulation. There is no question that peripheral
temperature sensors, as well as afferent and efferent pathways, exist
in the body; however, the correlate for the reference signal and how
it is established in the thermoregulatory system has not been
determined yet.105
The critical review of the set-point model originated when
Kobayashi proposed a new and different approach to thermoregulation.106 In short, he proposed that peripheral and central
thermoreceptors synapse via several neurons to a thermoregulatory effector cell. Once the temperature reaches the range for
which the sensory neuron is sensitive, this neuron significantly
increases its firing rate and hence triggers, independent of a central
controller, a response in the effector cell. If a sufficient number of
neurons in the same sensitivity range fire simultaneously, a
thermoeffector response will be elicited. In this model, no central
network for integration of afferent information is required;
thermoregulation happens almost automatically by the temperature discriminating sensory neurons. The thermoregulatory effectors work by adjusting their own threshold and gain
according to the physiologic needs. They do so by selecting the
order of responses and by regulating the intensities. In terms of
set point, with Kobayashis model, which is increasingly, but not
unanimously, favored among physiologists, there is no single
controller and no unified temperature to which the body tries to
adhere. The central body temperature is the averaged result of all
these individual and independent thermoeffector loops. Despite
these limitations and perhaps inaccuracies, the set-point model
has a long tradition in thermoregulation, has made the concept of
thermoregulation easier to understand, and even if proved to be
incorrect at some point in the future, will most likely be difficult
to eliminate for quite some time.
Efferent Responses
The importance of skin temperature in thermoregulation lies in
its ability to trigger behavioral changes such as seeking shade in
hot weather or bundling up in cold weather. However, in regards
to the autonomic thermoregulatory response, it accounts for only
about 20% of the effector response.107109 The main determinant
of the autonomic thermoregulatory response depends on afferent
thermal information from central core tissues, which include the
brain (areas other than the POAH), the spinal cord, and deep
thoracic and abdominal tissues, with each of them contributing
approximately 20% to the central thermoregulatory control.110113
Although highly sophisticated and efficient, our thermoregulatory
system is easily overwhelmed by environmental challenges outside
the thermoneutral temperature range (i.e., ~28C for an unclothed
adult). Behavioral responses are, therefore, paramount and the
most important thermoregulatory effector in humans. When
appropriate, they easily surpass the efficiency of all the autonomic
responses combined.
Digital skin blood flow can be divided into nutritional
(capillaries) and thermoregulatory (arteriovenous shunts) components. Thermoregulatory cutaneous vasoconstriction is the first
and most consistent thermoregulatory response to hypothermia.
Cold-mediated decreases in cutaneous blood flow are most
pronounced in arteriovenous shunts of the hands, feet, ears, lips,
and nose. Thermoregulatory vasoconstriction can decrease the
blood flow in these locations by up to 99% of the flow at neutral
temperature.114 These thermoregulatory arteriovenous shunts
typically have a diameter of approximately 100 m, which means
that one can divert 10,000 times as much blood as a capillary
with a 10-m diameter under otherwise unchanged conditions
(given pressure gradient, length and blood viscosity remain
constant).115 A combination of neural mechanisms and local,
direct temperature effects on the skin vessels lead to thermoregulatory cutaneous vasodilatation during heat and vasoconstriction during cold exposure. However, in terms of neuronal
regulation of cutaneous arteriovenous shunts, one has to
distinguish between nonglabrous (hairy) and glabrous (nonhairy)
skin areas (i.e., palms, soles, lips). In glabrous skin, blood flow is
controlled solely by vasoconstrictive impulses mediated by
norepinephrine binding to peripheral, postsynaptic 1- and
2-receptors. In nonglabrous skin regions, blood flow is controlled
by dual sympathetic opposing mechanisms, which include both
noradrenergic-mediated vasoconstriction and cholinergicmediated vasodilatation. It is unknown whether this cholinergic
vasodilatation is triggered by the same nerves that trigger sweating. However, two observations would support this assumption:
(1) sweating and active thermoregulatory vasodilatation usually
begin simultaneously and (2) patients suffering from anhidrotic
ectodermal dysplasia (an inherited disease with congenital lack
of sweat glands) are unable not only to sweat but also to actively
vasodilate their cutaneous arterioles in response to heat.116120
It has also been demonstrated that nitric oxide contributes up
to 30% of this heat stressrelated active vasodilatation, which
may also require the release of histamine (H1 receptor action),
vasoactive intestinal peptide (VIP), and additional, as yet
unknown, neurotransmitter(s) for complete vasodilatation.121125
Vasoconstriction in response to local cooling is triggered by
local activation of adrenergic nerves and is independent of central
nervous system input.126 In the case of localized heat exposure,
cutaneous vasodilatation occurs in response to local capsaicin
release, which activates TRPV1 channels in afferent C fibers,
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triggering antidromic calcitonin generelated peptide (CGRP),
neurokinin A, and substance P,127 although TRP channels are
thermosensitive themselves.
Skin blood flow at rest during normothermia accounts for
approximately 5% (or 250 mL/min) of cardiac output, which
translates to approximately 80 to 100 W of heat dissipation
per hour in an adult. This roughly equals the metabolic heat
production at rest. During extreme heat stress with maximal
vasodilatation, up to 60% (or 68 L/min) of the cardiac output can
be directed to the skin.118,128 This results in a drastically increased
heat transfer from the core to the periphery of the body, from
which the heat dissipates by means of convection and radiation.
Most likely, sweating is also profuse in this scenario, which further
increases heat loss and at the same time provides cooling of the
blood, which upon return to the core, also helps cooling the
body.128130 By contrast, profound vasoconstriction during marked
hypothermia drops skin blood flow to almost zero, thereby
reducing heat loss to the environment and, in case of shivering,
allows the generated heat from the muscles to be transported to
the core instead of being dissipated through the skin. Such
profound changes in the distribution of cardiac output need to
be regulated carefully, which explains why both sympathetic
cutaneous vasoconstriction and vasodilatation participate in
arterial blood pressure regulation via the baroreflex.116,131134 The
decrease in cutaneous perfusion secondary to thermoregulatory
vasoconstriction results in an impressive heat loss reduction from
hands and feet by 50%, but by only 17% from the trunk, which
reduces overall heat loss by approximately 25%.135
The ability of the body to dissipate heat from heat stress or
metabolic processes is vital to the human body, but the potential
of active vasodilatation of skin vessels for heat loss is limited and,
therefore, sweating is required. The latent heat of vaporization of
sweat, which is 2.5 106 J/kg, defines the energy required for the
evaporation of 1 kg of sweat. This demonstrates the extraordinary
power of sweating as a means of heat loss, particularly when
considered that an extremely athletic adult can produce 2 to 3 L of
sweat per hour, although these rates cannot be maintained for a
prolonged period of time.136,137 The human body has apocrine
and eccrine sweat glands, but only the latter are involved in
sweat production. Sweating is primarily controlled by core body
temperature, but is secondarily affected by skin temperature,
which has the power to influence the rate of sweating through
central mechanisms. In addition, localized warming of sweat
glands directly activates sweating, whereas cooling inhibits
sweating.138,139 Sweating is the only effective mechanism for heat
loss in an environment with air temperatures equal to or above
skin temperature. Under these circumstances, anything that limits
evaporation, such as impermeable or tight clothes or high ambient
humidity, restricts the efficiency of sweating and may lead to
hyperthermia or heat stroke with potentially fatal outcome.
Sweat gland development starts from the epidermal ridge as an
epithelial cell cord at about 14 to 16 weeks of gestation. It begins
first on the palms and soles, then in the axillae at approximately
20 weeks of gestation, and finally on the remainder of the skin
3 to 4 weeks later.140,141 Although the lumen of the sweat glands
starts to develop as early as 16 weeks of gestation, it widens only
in the last 8 weeks of gestation and the myoepithelial cells become
identifiable no earlier than the last weeks of pregnancy. At birth,
the sweat glands on the palms and soles are functional and
morphologically identical to those in adults. Sweat production on
the palms and soles is already functional on day 1 of life, which
227
means as early as the 36th or 37th week of gestation. Because sweating on the palms and soles occurs independently of thermal
sweating, it is known as emotional or mental sweating because it is
triggered independent of temperature by stress and other
emotions.142 By contrast, thermoregulatory sweating depends
more on the postnatal age in a way that almost every neonate,
independent of the gestational age, is able to sweat in response to
high ambient temperatures after 2 weeks of life.143 Babies born at
36 weeks or older are even capable of thermoregulatory sweating
from day 1 of life. Thermoregulatory sweating in neonates occurs
first and most pronounced on the forehead.143 However, the
intensity and extent of the sweat response depend on gestational
age. Although the extent of the sweat response increases rapidly
with postnatal age, sweat intensity increases only slowly and the
ambient temperature required to induce sweating are higher in
immature babies. Despite the ability of thermoregulatory sweating,
its efficiency is initially is very limited.143 Full-term neonates begin
to sweat when the rectal temperature reaches 37.5 to 37.9C and
ambient temperature exceeds 35C. The onset of sweat production
in infants who are small for gestational age is slower than in fullterm infants, but their maximal sweating rates are comparable.144
Premature infants with a gestational age of less than 30 weeks show
no response because their sweat glands are not yet fully developed.
The total number of sweat glands varies between 2.5 and
5 million. The density is approximately 10 times higher on the
palms and soles than on the back (~600 vs 60 glands/cm2). The
amount of sweat produced is regulated through a combination of
the number of activated sweat cells (responsible for the initial
increase in sweat rate) and the amount of sweat production per
gland (responsible for a further rise in sweat rate).145,146 The
absolute number of sweat glands recruited increases in a linear
manner with rising rectal temperature during exercise, with sweat
gland recruitment on the limbs being proportionally greater than
on the trunk.147
Children have a smaller body surface area, but already
the complete number of sweat glands. This means that their
sweat gland density is up to six times higher than in adults.148
Nevertheless, because of a lower sweat production per gland, the
overall sweating rate in children is lower than in adults, which is
explained by the smaller sweat gland size (which is directly related
to sweating rate and to cholinergic and adrenergic sensitivity
of the sweat gland), a lower sensitivity of the sweating mechanism
to thermal stimuli, and possibly, a lower sweat gland metabolic
capacity.149151 During exercise in the heat, adults started to
sweat after a rise in rectal temperature of 0.2C, whereas children
required a rise of 0.7C to reach the sweating threshold. Furthermore, the sweat production per degree temperature increase in
children was lower than in adults.152 With their larger body surface
areatomass ratio, children have an advantage over adults in
a thermoneutral or warm environment when metabolic heat
dissipation can depend on convection, radiation, and conduction
only. This same large body surface areatomass ratio is the factor
responsible for increased heat loss in the cold as well as increased
heat absorption in a hot climate.
Sweat is initially secreted as an isotonic precursor fluid into
the secretory coil. As it is transported out through the glandular
duct in the direction of the skin surface, sodium, chloride,
and bicarbonate are re-absorbed leaving sweat hypotonic in
comparison with plasma and slightly acidic. However, at high
sweating rates, the re-absorptive mechanism can be overwhelmed
by the high flow rates and electrolyte losses may increase,
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explaining the fact that sodium concentration of sweat depends

on the sweating rate.149 Increased sweating occurs through a
combination of an increased number of activated sweat glands
and increased amount of sweat released per gland.145 The exact
neurologic pathways responsible for sweating are only partially
known. It is known from animal studies that efferent fibers from
the POAH traveling via the pons and the medullary raphe regions
project to the intermediolateral cell column of the spinal cord and
on through the white ramus communicans to synapse in the
sympathetic ganglia. Postganglionic, nonmyelinated C fibers then
join peripheral nerves to reach the sweat glands153,154 Cholinergic
innervation clearly outnumbers adrenergic terminals. Sympathetic
cholinergic nerve endings mainly surround the secretory coil
of the sweat gland, but a few projections also extend to the
sweat duct.149 Binding of acetylcholine to muscarinic sweat gland
receptors increases the intracellular calcium concentration,
resulting in increased permeability for potassium and chloride
ions, which then triggers the secretion of sweat from the secretory
cells.155 By contrast, adrenergicmediated sweat secretion relies
exclusively on activation of a cyclic adenosine monophosphate
(cAMP)dependent cystic fibrosis transmembrane conductance
regulator (CFTR, the ion channel defective in cystic fibrosis),
leading to increased chloride, but not potassium, ion conductance.
Compared with cholinergic secretion, adrenergic secretory
response is smaller.156,157
The CFTR mutation in cystic fibrosis results in reduced sodium
re-absorption from the isotonic sweat precursor fluid from the
glandular duct and, hence, sweat with higher concentration of
sodium and chloride. Acetylcholine is also involved in the
contraction of myoepithelial cells located in the basal membrane
of the sweat gland duct. It had been suggested that the highfrequency, pulsatile secretion of sweat (at 1221 Hz) is caused by
pulsatile myoepithelial contraction158; however, a later study failed
to confirm these findings.159 The main function of the myoepithelial cells lies most likely in the provision of structural support
for the secretory epithelium, so that it can easily develop and
withstand high intraluminal hydrostatic pressures to overcome
difficulties in transporting sweat onto the skin surface under
conditions such as sweat pore occlusion.159 This could potentially
occur when the skin becomes wet (e.g., during sweating) and skin
cells swell enough to partially obstruct sweat secretion. This
and the fact that sweating is a vital process may explain why
intraluminal pressure in the sweat gland has been reported to be
as high as 500 mmHg.160
Skin temperature varies considerably throughout the body.
Mean skin temperature refers to a physiologically weighted,
averaged skin temperature. Several different formulas exist to
calculate it and they can be divided into four categories: areaweighted formulas, derived regression formulas, physiologic
formulas, and modifications.3436,161 For anesthetized children
younger than 10 years, mean skin temperature can be calculated
as follows:
Tskin mean = 0.5 Tchest + 0.2
Tupper arm + 0.1 Tthigh + 0.2 Tleg.36
Similarly, mean body temperature describes a physiologically
weighted, averaged body temperature, which was created in
an attempt to accurately reflect the thermoregulatory importance
of various tissues, in particular the central compartment. Mean
body temperature is now often used instead of or together
with the core temperature to define the thresholds for sweating.
The formula for mean body temperature was originally designed

in 1935162:
Tmean body = 0.65 Tcore + 0.35 Tskin mean
where Tskin mean refers to mean skin temperature calculated
from the skin temperatures of trunk, lower leg, and forearm.
Although its accuracy has been confirmed by some investigators,162,163 other studies found it to be unreliable and suggested
that a more sophisticated approach was needed.164,165
The thermoregulatory responses and their corresponding
threshold temperatures in the awake state and under anesthesia
in adults, children, and infants are depicted in Figure 142.
Heat Loss Mechanisms

In order to be homeothermic (maintain a constant core temperature independent of the ambient temperature), the organism
must be capable of both regulated and active heat dissipation and
heat generation. Controlled heat dissipation is fundamental to
homeotherms and accomplished in two steps, both of which are
mediated by radiation, convection, conduction, and evaporation
and governed by the physical laws described in the second law of
thermodynamics. The latter states that spontaneous heat flow can
occur only from an object of higher temperature (higher energy)
to an object of lower temperature (lower energy).
In the first step of heat loss during anesthesia (see Figure
141), heat is transferred from the core to the peripheral compartment and the skin surface, referred to as internal redistribution of
heat. As the name implies, this process does not, despite the now
lower core temperature, result in significant heat loss. In the
second step, heat is now dissipated from the skin surface to the
environment and physiologic adaptations of regional blood flow
(thermoregulatory vasodilatation) as well as changes in the thermal conductance properties of the insulation tissue can influence
the degree of heat loss. A study in naked adult men in an ambient
temperature of 27C quantified the relative contributions of
radiation, convection, and evaporation to total heat loss as 58%,
15%, and 27%, respectively.166 A similar study in newborns kept in
a thermoneutral environment determined the contribution of
radiation, convection, evaporation, and conduction to total heat
loss to be 39%, 34%, 24%, and 3%, respectively.167 However, any
change in ambient temperature, air draft, or relative humidity can
change not only the overall magnitude of heat loss but also the
relative contribution of each of these four physical components.
Simply changing the ambient temperature to 22C changed the
contribution of radiant, evaporative, and convective heat loss in
healthy women to over 70%, 15%, and 10 to 15% of total heat loss,
respectively.168
Although not often viewed as a major priority during intraoperative care, the maintenance of normothermia can have
significant effects during both the intraoperative and the
postoperative periods. Although generally counterproductive
during anesthesia, the ongoing heat loss serves an important
purpose in the unanesthetized person. Without any heat loss to
the environment, the body temperature would increase by
approximately 1C/h at rest. The importance of heat loss becomes
even more obvious considering that in athletes, metabolic heat
generation can increase 20-fold during strenuous exercise.169
The resulting increase in body temperature has been calculated
by the formula:
HSR = m dTB/dt
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229
Figure 14-2. Threshold temperatures. Graphic depiction of the expansion of the interthreshold range under
general anesthesia compared with the awake state. The temperature indicated on the thermometer represents
the body temperature at which the corresponding thermoregulatory mechanism is triggered. The range between
the first cold response (thermoregulatory vasoconstriction) and the first warm response (thermoregulatory
vasodilatation) defines the interthreshold range and is an indicator of the sensitivity of the thermoregulatory
system. Adapted from reference 504.
where HSR = heat storage rate (W); m = the body mass (kg);
= the specific heat coefficient of the human body (3.5.103 J/kg
C)162; dTB = the change in body temperature (C); and dt = the
time interval (s). For clinical purposes, metabolic heat production
at rest is estimated to be approximately 4.2 kJ/kg/h (or 1 kcal/
kg/h).
Conduction
Conduction refers to heat transfer from a warmer to a cooler object
when they are in direct physical contact with each other (Figure
143). In humans, the amount of heat transferred by conduction
(C) depends on the temperature gradient (T1 T2) between the
skin and the object with which it is in direct contact, the skin
surface area in direct contact with the object (A), and the
conductive heat transfer coefficients (hk) of the two materials.
Conductive heat transfer can be calculated using the formula:
C = hk A (T1 T2).
The conductive heat transfer coefficient, hk, is a property of
the material or interface between the two objects and determines
the rate of heat transferred per unit area and unit temperature
difference (W/m2 C). Ideally, the patient should be well shielded
from cold objects (bolsters and/or unwarmed blankets in the case
of the operating room table) or, even better, lying on a warming
blanket or a forced-air warming device. These simple steps should
keep conductive heat losses to a minimum during surgery.
However, large amounts of cold intravenous or irrigation fluids
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Figure 14-3. Heat loss mechanisms. The four major heat loss mechanisms are illustrated in the top predator of Antarctica, the leopard seal,
who, like most animals, is a true expert in thermoregulation. Lying on
the ice results in conductive heat loss, the wet fur leads to evaporation,
the warm body temperature in comparison with the cold ambient air
favors convective heat loss, whereas on the one hand, radiation warms
the body (sun), and on the other hand, the warm body loses thermal
energy, heating up the environment by radiation.
can quickly result in significant conductive heat losses and should

be avoided.
Radiation
Radiation heat transfer describes heat exchange by electromagnetic
waves between two objects of different temperatures not in direct
contact with each other (see Figure 143). Radiation does not
require a medium for heat transfer between the two objects. It can
be transmitted through a vacuum (e.g., the sun warms the earth by
radiation). Obeying the second law of thermodynamics, radiation
causes the warmer object to cool and the cooler object to warm.
This heat transfer occurs predominantly in the infrared light
spectrum at a wavelength in the range of 0.75 to 1000 mm.
Radiation heat transfer depends upon the difference of the fourth
power of the absolute temperatures of the two objects and the
surface area available for radiation but also on factors like
emissivity (a number between 0 and 1, with 1 meaning that a body
emits all of its thermal radiation and absorbs all the thermal
radiation striking it), surface reflectivity, and other variables
describing the objects surface characteristics:
of 4.1 to 5.8 N m/s m2 C.170 Thus, heat transfer by radiation

depends primarily on the temperature and the surface area of the
two surfaces concerned. As previously stated, newborns and
infants have a large surface areatovolume ratio; thus, radiant
heat loss is proportionally greater the smaller the infant. Radiation
is the major heat loss mechanism in the awake and the anesthetized infant under normal conditions. Radiant heat loss in the
operating room is caused by a temperature gradient between the
patient and the surrounding objects (e.g., operating room walls,
anesthesia cart and machine). As long as such a gradient exists,
the patient (warmer object ) will continue to transfer heat to the
cooler objects around him or her, thus losing energy to the
environment. Because heat loss by radiation is directly related to
the temperature gradient, warming up the operating room before
the arrival of the patient reduces this temperature gradient and,
thus, radiation heat loss. However, this must be done a sufficient
time before the patient arrives to allow for warming of the walls
and other objects in the environment. A thin, single covering layer
(e.g., a hospital gown providing minimal insulation) can help to
significantly reduce heat losses by convection and radiation and,
thus, to increase thermal comfort.
Convection
The transfer of heat to moving molecules (e.g., air or liquid)
is called convection (see Figure 143). The rate and direction
of convective heat loss in a human exposed to air depend on
the velocity of the air draft, the size of the skin surface area
exposed, and the temperature difference between the surface
of the skin or other membrane and the surrounding fluid (i.e.,
gas or liquid). Changes in lung minute ventilation and body
posture may affect convective heat loss, but under normal
circumstances, the contribution of convection to total heat loss is
minor. The following formula can be used to calculate convective
heat loss:
Q = hc A (Tsk Ta)
where Q = heat exchange by convection (W); A = surface area
exposed (m2); hc = convective heat transfer coefficient (W/m2
C); Tsk = mean skin temperature (C); and Ta = ambient
temperature (C). The convective heat exchange coefficient
depends on the physical properties of the medium (i.e., gas or
fluid), air draft (or fluid current) velocity, and body shape. Its value
for the human body when immersed in still water at neutral
temperature and in cold water is approximately 43 and 53 W/m2
C, respectively.171 The wind chill factor is probably the bestknown example of convective heat loss.
R = e s A (Tsk4 Tr4)
where R = heat transfer by radiation (W); e = emissivity; s = Stefan
Boltzmann constant (5.67 108 J/s m2 K4); A = surface area
of the object (m2); Tsk = skin temperature; and Tr = temperature
of the second object (both in K). The exact calculation of radiation
heat transfer is rather complicated. Because of the small differences, it has been accepted for clinical purposes to use the
simple difference between the two temperatures. Emissivity and
the Stefan Boltzmann constant can be integrated into the radiation
coefficient hr (N m/s m2 C), simplifying the formula to R
= hr A (Tsk Tr). The value of the radiation coefficient (hr)
depends on the temperatures of the two surfaces, emissivity, and
several other factors. For a clothed human, its value is in the range
Evaporation
Evaporation describes the transition of molecules from the liquid
(sweat) into the gaseous state (sweat vapor) (see Figure 143). In
order to reach the gaseous phase, the molecules must obtain a
certain kinetic energy to overcome the intermolecular forces of
the liquid phase. This is an energy-dependent process, energy is
drained from the body in the form of heat. Under conditions of
thermal neutrality, evaporation accounts for 15 to 25% of total heat
loss. Physical determinants of evaporative heat loss include relative
humidity of the ambient air, air draft velocity, and lung minute
ventilation. The driving force for evaporation is the vapor pressure
difference between the body surface and the environment. The
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higher the ambient humidity the less effective sweating will be.
Evaporative heat loss in the operating room consists of three
components: (1) sweat (sensible water loss), (2) (nonthermoregulatory) water loss from the skin, respiratory tract, and open
surgical wounds (insensible water loss), and (3) evaporation of
liquids applied to the skin such as antimicrobial solutions for skin
disinfection. The energy required to evaporate 1 kg of a certain
fluid is known as the latent heat of vaporization (2.5 106 J/kg
for sweat). Evaporative heat loss can be calculated with the following formula:
E = he Awet (Psk Pa)
where E = evaporative heat loss (W); he = evaporative heat transfer
coefficient (W/m2 kPa); Awet = wet skin area (m2); Psk = water
vapor pressure on the skin surface; and Pa = ambient water vapor
pressure (both in kPa). The coefficient for evaporative heat
transfer (he) integrates the latent heat of vaporization of water and
the essential effect of air draft on evaporation. For clinical
purposes, he can be calculated using the formula:
he = 124 V0.5 (W/m2 kPa)
where V denotes air draft velocity (m/s). Humidification of dry
inspired respiratory gases causes a small amount of heat loss by
evaporation of water from the tracheobronchial epithelium.
Respiratory losses in adults during anesthesia account for only 5
to 10% of total heat loss.172 Alveolar ventilation on a per-kilogram
basis is significantly higher in infants and children than in adults,
which explains why respiratory losses can account for up to one
third of total heat loss in that age group. Breathing cool and dry air
(by contrast to warm and humidified air) increases evaporative
and convective heat loss from the respiratory tract.32,173 Heat loss
from evaporation inside a large surgical incision may equal
all other sources of intraoperative heat loss combined.174
Evaporation of fluids from the exposed (and unprotected)
bowel may eventually result in a bowel temperature that is well
below the temperature of the rest of the body. Returning this cold
bowel back into the abdominal cavity can precipitate a brisk
drop in body temperature owing to conductive heat loss.174 This
can be avoided by either covering the exposed bowel in a plastic
envelope or irrigating the abdominal cavity with warm saline
solution immediately after the bowel has been returned into the
abdomen.
Heat Production
Except for evaporation, the other three physical mechanisms that
are usually responsible for heat loss (i.e., radiation, conduction,
and convection) can, depending solely on the temperature
gradient, also be used to transfer heat to the patient. Beside these
passive ways of increasing the body heat content, homeothermic
organisms have the ability to actively increase their metabolic rate,
which increases not only oxygen consumption but also heat
production and represents an important and efficient part of
thermoregulation. In addition to the heat generated from basic
metabolism, the body can actively increase metabolic heat
production in four different ways:
1.
2.
3.
4.
Voluntary muscle activity.

Involuntary muscle activity (shivering thermogenesis).
Nonshivering thermogenesis.
Dietary thermogenesis.
231
Voluntary Muscle Activity

The mechanical efficiency of muscle contractionsthe ratio
between power output and the sum of the caloric equivalent
of oxygen consumption and power outputcan initially reach
up to 50% for short exercises (seconds), but quickly decreases
to levels in the range of 25 to 35% for sustained, steady-state
exercise (e.g., cycling).175,176 This forms the basis of heat generation
by voluntary muscle activity, because most of the difference
between energy input and mechanical energy output is converted into heat. However, during anesthesia, this form of heat
generation is, similar to thermoregulatory behavioral changes,
either absent or only minimal and does not significantly contribute to thermoregulation.
Shivering Thermogenesis
Shivering refers to involuntary, irregular muscular activity
triggered by hypothermia (although strong emotions like fear or
pain can also act as triggers) that commonly begins in the muscles
of the upper body (e.g., masseter). Before the onset of overt shivering, tonic motor neuron activity increases resulting in elevated
muscle tone throughout the body with a concomitant rise in
metabolic heat generation.177 Only when this tone has risen above
a certain threshold level does shivering become visible. Mild
shivering can be voluntarily suppressed to some extent with
breath-holding or distraction techniques.178 The shivering intensity is higher in central muscles where it can reach up to about
16% of maximal voluntary muscle contraction, whereas this is
limited to about 4% in peripheral muscles.179 In awake, young, and
healthy adults, shivering can increase the metabolic rate by almost
500% for very short periods of time.180186 This number is often
cited to sensitize anesthesiologists to the adverse effects of shivering, but fortunately, the incidence and intensity of shivering,
particularly when sustained and in older patients, are reduced in
the postoperative period, mainly because of appropriate analgesic
therapy, slower spontaneous rewarming, and a less active thermoregulatory response.187190 The average increase in oxygen
consumption in the elderly, who have the highest risk for adverse
perioperative cardiac events, was found to be only 38% higher in
shivering than in nonshivering patients,190 although other studies
reported postoperative increases in oxygen consumption of up to
130%.180 For an otherwise healthy patient, the increased oxygen
consumption associated with shivering is compensated by an
increase in cardiac output without adverse effects. However, for
patients with already limited cardiac or pulmonary reserves, the
increased oxygen requirements could potentially result in
decreased tissue oxygenation and a potential risk for ischemia,
although shivering per se was not associated with a higher risk
of myocardial infarction.180,187 Shivering can lead to increased
intraocular and intracranial pressure, wound dehiscence, and
damage to the teeth.191,192 Along with nausea and vomiting and dry
mouth, postanesthetic shivering is one of the leading causes of
discomfort in patients recovering from general anesthesia.193 An
inverse correlation between intraoperative temperature and
postoperative oxygen consumption has been demonstrated.194
Despite the incidence of postoperative shivering being inversely
related to core temperature, shivering also occurred in patients
kept strictly normothermic during anesthesia with isoflurane or
desflurane, indicating that a significant component of postoperative shivering is nonthermoregulatory, with pain being a
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potential trigger.195,196 One study in more than 1500 children

undergoing general anesthesia found a surprisingly low shivering incidence of 3.5%.197 Risk factors for postoperative shivering
in this study included the use of intravenous induction agents
(thiopental vs sevoflurane), patient older than 6 years, and prolonged duration of surgery (over 40 min). A smaller study
reported a higher incidence of 14.4% shivering in children and, in
addition, found atropine administration and lower intraoperative
temperature to be risk factors.198 A large study in adults reported
a shivering incidence of 6.3%, and risk factors identified included
male gender, orthopedic surgery, anticholinergic premedication,
and use of neuromuscular blocking agents, whereas intraoperative
use of alfentanil or morphine seemed to have a protective effect.199
Two different electromyographic (EMG) patterns can be identified
during shivering including a basal, continuous low-intensity
shivering with a rate of 4 to 8 Hz associated with a low shivering
threshold and type I muscle fibers or superimposed bursts of highintensity shivering at a much lower frequency of 0.1 to 0.2 Hz
associated with a high-shivering threshold and type II muscle
fibers, creating the typical waxing and waning picture in the
EMG pattern.200,201 The shivering intensity depends on the
duration of cold exposure, the ambient temperature, and anatomic
characteristics (e.g., fat content and surface area of the body).186
The time course and the relationship between shivering and
nonshivering thermogenesis in infants have been examined,
but the exact time sequence and factors involved in the transition from nonshivering thermogenesis to shivering thermogenesis remain to be elucidated. Although the importance of
nonshivering thermogenesis rapidly decreases after the first
year of life, shivering thermogenesis assumes a more important
role in thermoregulation. However, it has been demonstrated that
shivering occurs only when all the other mechanisms such as
behavioral responses, nonshivering thermogenesis (both of which
are ineffective under anesthesia), and maximal thermoregulatory
vasoconstriction have failed to maintain body temperature within
the interthreshold range.202
It is generally accepted that newborns and small infants are not
able to shiver, presumably because of a combination of general
immaturity of the musculoskeletal system and limited muscle
mass, which renders muscle activity rather ineffective in terms of
heat production. However, a few case reports and occasional
observations exist describing shivering in neonates, which
occurred in some cases at a rectal temperature between 35.0 and
35.3C.203,204 It is debatable, if this was indeed thermoregulatory
shivering or if other factors (e.g., drugs) were involved, because
reported temperatures were not always extremely low. With
respect to thermoregulation, it is generally safe to assume that
neonates and small infants are not able to shiver, and even if they
were, the effect on temperature would be negligible.
Although carbohydrates account for only 1% of energy stores
(lipids 95% and proteins 4%) in healthy adults, carbohydrate
oxidation may provide up to 60% of the total heat generated
during cold exposure.205 In the presence of artificially elevated
carbohydrate storages (carbohydrate-rich diet) this percentage
may increase to 65 to 80%. Conversely, if glycogen reserves are
depleted, the body utilizes lipid and (to a lesser extent) protein
oxidation as a source of energy.206 Glycogen depletion does not,
therefore, compromise heat production from shivering. The rate
of glycogen oxidation is independent of plasma glucose levels. Fuel
selection for shivering (between carbohydrates, lipids, and
proteins) can be modified in three ways207:
1. Recruitment of different metabolic pathways within the same

muscle fiber.
2. Recruitment of specific subpopulations of muscle fibers within
the same muscle.
3. Recruitment of muscles varying in fiber composition.
Changing the type of muscle fibers (type I or II) activated also
changes the fuel mixture. However, in humans, the fiber
composition varies significantly not only between muscles but
also between individuals.208 In adults, hypoglycemia below approximately 2.5 mmol/L can result in limitation or complete
inhibition of shivering, an effect that, first, seems to be related to
inhibition of hypothalamic neurons rather than a general lack of
substrate and, second, is easily and almost immediately reversible
by administration of intravenous dextrose.209
Animal research indicates that the motor center for shivering
is located in the dorsomedial part of the posterior hypothalamus
adjacent to the wall of the third ventricle, but neurons from the
rostral raphe pallidus may also be involved.210212 Impulses from
peripheral cold receptors and from the spinal cord itself ascend
through the lateral spinothalamic tract and relay in the medulla
(nucleus raphe magnus) and the pons (locus subcoeruleus) before
they impinge at the POAH. Electrostimulation or cold stimulation
of the posterior hypothalamus triggers shivering.212215 In the
absence of cold sensation or hypothermia, it is assumed that this
center is inhibited by impulses from the heat-sensitive area (i.e.,
the center that triggers heat loss) in the POAH.
The efferent impulses leave the dorsomedial region of the
posterior hypothalamus and descend through the midbrain area,
dorsolaterally to the red nucleus, and then on through pons and
medulla oblongata to the lateral columns of the spinal cord. In
addition, selective stimulation and inhibition of reticulospinal
neurons, located in the reticular formation dorsolateral to the red
nucleus, demonstrated that in fact their signals control shivering.82
However, it is not known whether these neurons receive synaptic
input from the preoptic or posterior hypothalamus.93 Shivering
can also be induced at the spinal level by local cooling, which
means that the basic mechanisms for shivering are located in the
spinal cord and that the higher centers may act more to control
rather than to initiate the response. The recruitment of motor
neurons and their associated muscles form the final pathway for
shivering. Motor neurons seem to be recruited in the order of their
size, with the smaller ones being activated first, followed by the
small tonic, and finally the larger, phasic motor neurons.216
Various treatment options exist for shivering. Prevention of
hypothermia is certainly a good start to avoid the development of
shivering, however as mentioned in the section on Voluntary
Muscle Activity, not all shivering is thermoregulatory in nature.
Facial warming has been shown to reduce shivering in actively
cooled, unanesthetized, healthy adult volunteers almost completely and within seconds.217 Pharmaceutical treatment options
for shivering have included meperidine (pethidine), clonidine,
dexmedetomidine, ondansetron, and physostigmine.218220 Meperidine is probably the drug most commonly used in the treatment
of shivering. Inhibition of shivering with meperidine significantly
amplifies and prolongs core temperature afterdrop and the rewarming rate in unanesthetized, actively cooled volunteers.221
Nonshivering Thermogenesis
Nonshivering thermogenesis refers to an increase in metabolic heat
production in excess of the basal metabolism that is not associated
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with muscle activity. Heat produced by basal metabolism is
also known as obligatory thermogenesis, whereas nonshivering
thermogenesis is part of the adaptive thermogenesis that also
includes shivering thermogenesis and voluntary muscle activity.
This heat generation originates mainly from metabolism of brown
adipose tissue (BAT), but to a lesser degree also from skeletal
muscle, liver, brain, and white fat. Nonshivering thermogenesis is
the main source of thermoregulatory heat generation in newborns
and small infants, whereas in adults, shivering is the most important source of heat production.
Differentiation of BAT begins between 20 and 30 weeks of
gestation in the human fetus.222 It accounts for approximately
1 to 6% of the total body weight (depending on nutrition and
activation status) and can be detected in six main locations. This
includes large deposits between the scapulae and in the axillae; in
medium-size deposits in the mediastinum, around the internal
mammary vessels, the aorta, and the kidneys or adrenal glands;
and in smaller amounts around the blood vessels of the neck.
A significant percentage of venous vessels exiting from the interscapular BAT drain into the spinal canal surrounding the spinal
cord like a heat exchanger.223 Because functional mitochondria can
absorb99m Technetium-tetrofosmin, the use of gamma-camera
imaging with this radioactive tracer in infants and children allows
the visualization of the interscapular BAT. Activity has been shown
to be higher in winter than in summer with peak activity detected
in infants younger than 2 years of age.224
Brown fat is a highly specialized tissue whose brown color is
due to the abundance of large mitochondria in the cytoplasm of
these multiloculated, triglyceride-containing fat cells. The mitochondria are densely packed with cristae and have an increased
content of respiratory chain components and uncoupling protein1 (UCP-1 or thermogenin) located on the inner mitochondrial
membrane.225,226 Because of UPC-1, these mitochondria have the
unique ability to uncouple oxidative phosphorylation resulting in
heat production instead of generating adenosine triphosphate
(ATP). The proton motive force across the inner mitochondrial
membrane is normally used by ATP synthase for the generation of
ATP from adenosine diphosphate (ADP). Activation of UCP-1
increases proton leakage across the inner mitochondrial membrane in brown adipocytes and allows the proton motive force to
be dissipated as heat instead of being used for ATP synthesis.227
Besides UPC-1, glucocorticoids, leptin (an adipocyte-derived
hormone that acts on the ventromedial nucleus of the hypothalamus to signal satiety and regulate body weight), and thyroid
hormones have the potential to significantly modulate BAT
thermogenesis.228231 In fact, one of the deiodinases (type II or
brown adipose tissue iodothyronine 5monodeiodinase) is present
in BAT, and it has been estimated that BAT is responsible for about
50% of total systemic conversion of thyroxine (T4) to triiodothyronine (T3).232,233 Cold acclimation may lead to a 10-fold
increase in the release of T3 from BAT, whereas starvation inhibits
it.234 The lack of this deiodinase has profound, negative effects on
BAT function.235
Despite their name, the homologous proteins UCP-2, UCP-3,
UPC-4, and UPC-5 do not have the ability to uncouple oxidative phosphorylation, although their exact role remains to be
determined.236,237
Brown fat tissue has a very high density of blood vessels and
sympathetic nerve endings. Cold exposure activates the sympathetic nervous system, and the release of norepinephrine not only
results in the activation of -receptormediated uncoupling of
233
oxidative phosphorylation, but it also induces BAT cell proliferation, lipase activity in the BAT cells, mitochondriogenesis, and
increased expression and activation of UCP-1.227,238 Precursor cells
of BAT express 1-adrenergic receptors, which are important for
BAT cell proliferation, whereas 3-receptors are involved in BAT
cell differentiation.239 Mature brown adipocytes mainly express
1- and 3-receptors, with the latter being the most important in
terms of nonshivering thermogenesis.227
The majority of the heat produced by nonshivering thermogenesis is mainly a byproduct of fatty acid metabolism, but a
minor part can also originate from glucose metabolism. The
activation of nonshivering thermogenesis results in an increased
proportion of cardiac output being diverted through the brown
fat, which may reach up to 25% of the cardiac output, thus
facilitating the direct warming of the blood. Nonshivering
thermogenesis can be inhibited pharmacologically with ganglionic
and adrenergic receptor blockade,240 inhalational anesthetic
agents,241243 and surgically by sympathectomy.244 In vitro, halothane has been shown to inhibit nonshivering thermogenesis
in BAT cells from hamsters within 5 minutes of the onset of
exposure. Within 15 minutes after discontinuation of halothane,
nonshivering thermogenesis recovers to approximately 50%.241
Similar findings have also been reported from in vivo animal
studies.243 Nonshivering thermogenesis has also been shown to be
inhibited in infants younger than 9 months of age anesthetized
with fentanyl and propofol.245 However, an in vitro study on BAT
cells from hamsters concluded that inhibition of nonshivering
thermogenesis is caused by volatile anesthetic agents (halothane
was the only vapor tested that is still clinically used), but not with
nonvolatile anesthetic agents including pentobarbital, propofol,
or ketamine. Therefore, a distinction between thermogenesis
inhibitors and thermogenesis noninhibitors has been suggested.246
Analysis of oxygen consumption and plasma concentrations of
free fatty acids and glycerol in newborns between 6 and 30 hours
of age with a gestational age of 32 to 40 weeks demonstrated that,
within 20 minutes of cold exposure (ambient temperature of 25
26C), oxygen consumption doubled and the plasma concentration of glycerol significantly increased.247 The authors also
noted that the nape of the neck was the warmest skin area (i.e., in
close proximity to interscapular BAT) on the babies exposed to
cold. This study further demonstrates that term and preterm
neonates are capable of nonshivering thermogenesis shortly after
birth. Premature infants, full-term neonates, and infants are easily
able to double their metabolic heat production during cold
exposure.247249 Clinically significant nonshivering thermogenesis
is possible within minutes after birth and may persist up to the
age of 2 years.250 Although powerful and efficient, it should be kept
in mind that the effect of nonshivering thermogenesis is limited
and cannot compensate for the increased risk of hypothermia in
neonates and infants.
Nonshivering thermogenesis appears not to be functional
or clinically significant in adults.251 This is supported by the fact
that oxygen consumption does not increase significantly when
patients are vasoconstricted.247,248 However, there seems to be a
wide interindividual variability that depends on gender, body
composition, age, cold acclimation, and most likely, genetic
factors.251 In addition, under certain pathologic conditions,
humans have the potential to regenerate BAT, for example, in the
presence of a pheochromocytoma (caused by high and sustained
sympathetic stimulation),252,253 Chagas disease,254 or a hibernoma
(a rare, benign brown fat tumor originating from BAT remnants).
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Marked cold acclimation enables winter swimmers to survive

significantly greater temperature gradients between body and
environment than noncold-adapted subjects, which has been in
part attributed to increased nonshivering thermogenesis.255
However, there is no proof that the nonshivering thermogenesis
in these swimmers originates from BAT. In adults, alternative
mechanisms of metabolic heat generation exist, and it has been
demonstrated that the (noncontractile) contribution of skeletal
muscles can account for approximately 40% of thermogenesis
induced by local epinephrine infusion.256 Hydrolysis of ATP by
Ca2+-ATPase of the skeletal muscle sarcoplasmic reticulum may
represent another important source of heat.251 Further study in
cold-acclimated adults has demonstrated increased nonshivering
thermogenesis that can be inhibited by propranolol.257
Dietary Thermogenesis
Total daily energy expenditure consists of three primary components including resting metabolic rate, activity thermogenesis, and
diet-induced thermogenesis.258 The thermogenic response to the
ingestion or infusion of certain nutrients (e.g., amino acids and
proteins) has been described as dietary thermogenesis and is
commonly measured as the increase in energy expenditure above
the basal metabolic rate. It consists of two separate components: an
obligatory and a regulatory component. The former is due to the
energy requirements for digestion, absorption, and conversion
of the nutrients into their respective storage forms, whereas the
latter describes a mechanism for energy dissipation.259 In healthy
individuals, a diet high in protein and carbohydrate content
induces a greater thermogenic response than a high-fat diet.260
Except for a difference in time course, the thermogenic effects of
intravenous amino acid administration and oral protein intake are
basically identical. An intraoperative infusion of small amounts
of amino acids in adults can increase their heat generation by up
to 500% during general anesthesia when compared with the awake
state.261 The clinical effect of this phenomenon is demonstrated by
a study showing that adults patients receiving pre- and intraoperative amino acid infusions maintained their core temperature
at 36.5 0.1 C, whereas the temperature in the control group was
35.7 0.1C.262 A similar thermogenic response can also be
elicited during spinal anesthesia.263 The synthesis and breakdown
of proteins in extrasplanchnic tissues and stimulation of cellular
amino acid oxidation seem to play a crucial role in dietary
thermogenesis, although the exact physiology remains to be
elucidated. Approximately half of the heat generated from the
oxidation of infused amino acids originates from the splanchnic
region and results in an overall increase in cardiac output of almost
20% with significantly increased blood flow to extrasplanchnic,
but not splanchnic, tissues.264 In the same study, splanchnic oxygen
uptake during the first postprandial hour increased by 50%,
accounting for almost two thirds of the increase in whole-body
oxygen consumption. In the second postprandial hour, oxygen
uptake increased in extrasplanchnic tissues, but no further in
splanchnic tissues. During general anesthesia, thermoregulation
is attenuated and, therefore, amino acid triggered thermogenesis
potentially exaggerated. However, dietary thermogenesis can be
powerful enough to cause hyperthermia even in the awake patient
with intact thermoregulation or in a cold environment with ample
potential for heat dissipation.265 Leading to a synchronous increase
in the autonomic thermoregulatory defense thresholds, amino
acids seem to increase core temperature, at least in part, by

increasing the set-point temperature.266
Thermal Regulation in the Newborn

Premature and infants small for gestational age but also full-term
neonates have a significantly higher skin surface areatobody
mass ratio than that in adults. The normal ratio in a term neonate
is approximately 0.07 (0.2 m2/3.0 kg) vs 0.023 in an adult (1.72
m2/75 kg), which leaves the neonate with a ratio almost three times
higher than the adult. Compared with adults, children, therefore,
lose proportionally more heat in a cold environment but, at the
same time, also absorb more heat when it is hot. As such, the
neonatal thermoregulatory system may be compromised and
easily overwhelmed by external factors. This fact is amplified, on
the one hand, by increased thermal conductance in children
secondary to a thinner layer of subcutaneous fat and, on the other
hand, by increased evaporative heat loss owing to a lower keratin
content in the infants skin.267,268 Infants and children, therefore,
not only cool faster but also rewarm two to three times faster than
adults after hypothermia.269
In his 1961 classical paper, Brck demonstrated that neonates
are able to actively regulate and defend their body temperature.56
Until then, most clinicians considered neonates too immature
to respond to differences in ambient temperature. Even more
surprising is the fact that many clinicians, despite Budins work
half a century earlier,52 believed that it was safe to keep the rectal
temperature of preterm neonates in the range of 33 to 35C during
the first week of life and some even used medications to achieve
this state of hibernation.270,271 This practice derived from the idea
that lower body temperature should equal lower oxygen consumption (vant Hoff-Arrhenius effect, see explanation below in
this section). However, because core temperature is maintained
mainly by metabolic heat generation (nonshivering thermogenesis), at that age with lower body temperatures, oxygen consumption is actually significantly higher.272 The neonate, even when
born prematurely, is capable of active thermoregulation. When
subjected to a cool environment, the metabolic rate increases in
an attempt to compensate for increased heat loss. Conversely, in a
hot environment, the baby becomes restless, vasodilates the skin
vessels, and sweats to increase heat loss. The narrow temperature
range in between these thresholds for ambient temperature is
known as the thermoneutral zone.
Neutral temperature, or more accurately the thermoneutral
zone, is defined as the ambient temperature range in which the
oxygen demand (as a reflection of metabolic heat production) is
minimal and temperature regulation is achieved by nonevaporative physical processes alone such as cutaneous vasodilation
or vasoconstriction.273 The lower limit of the thermoneutral zone
defines the lower critical temperature and refers to the ambient
temperature below which the rate of metabolic heat production of
a resting thermoregulating organism increases by shivering and/or
nonshivering thermogenic processes to maintain thermal balance.
The upper critical temperature refers to the upper limit of the
thermoneutral zone and describes the ambient temperature above
which evaporative heat losses are triggered to maintain body
temperature within the normal range.273
The thermal environment depends on ambient air temperature,
air flow velocity, relative humidity, and radiant heat exchange. All
of these factors can be conveniently controlled or eliminated in an
incubator (isolette). The mean temperature required to provide
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thermal neutrality to a healthy baby nursed naked in a draft-free
environment with uniform temperature and moderate humidity
depends on the babys birthweight. For a birthweight of 1.0 kg,
1.5 kg, 2.0 kg, and more than 2.5 kg, these temperatures are 35C
(for the first 10 days of life), 34C (for the first 10 days of life),
34C (for the first 2 days of life), and 33C (for the first 2 days of
life), respectively.270 In comparison, the neutral temperature for an
unclothed adult is about 28C. Clothing the babies and putting
them in an incubator obviously allows the use of slightly reduced
temperatures. Metabolic heat production increases in both term
and preterm infants in response to cold exposure, but the metabolic rise is greater among term babies during the first 10 days of
life.56 The lower temperature limit of thermal regulationthat is.,
the lowest ambient temperature in which thermal balance can
be maintained for a limited time period and at which metabolic
rate reaches its peakis 0C in adults compared with 22C in
newborns.273 Maintaining core temperature in a cool environment
results in increased oxygen consumption and may lead to
metabolic acidosis. Neonatal cold exposure can lead to a vicious
circle starting with a drop in body temperature that triggers
nonshivering thermogenesis. If the cold exposure persists,
depletion of the BAT will ensue and eventually result in failing
heat generation and, thus, a further drop in body temperature with
lethargy and finally death.274
A normal rectal temperature in a neonate does not necessarily
indicate minimal oxygen consumption, because the baby may
use all of its defense mechanisms to maintain normothermia
and, thus, have a high oxygen consumption. It has been demonstrated that neonatal oxygen consumption is directly related to
the temperature gradient between the skin surface and the
environment. It can easily double and, in some cases, even triple
even during the first hours of life in response to cold stress.203 Of
particular concern regarding thermoregulation in the newborn
and small infants is the head, which accounts for approximately
20% of the total skin surface area at that age and which also has the
highest regional heat flux ability.275,276 In neonates and infants, the
head is the site for the production and loss of up to 40% and 85%
of body heat, respectively. This phenomenon results to the thin
skull bones and the frequently sparse scalp hair.277 Although this
setup is beneficial in a clothed or covered baby with intact
thermoregulation to avoid hyperthermia, it is less advantageous
in anesthetized infants who are at high risk of hypothermia. In
addition, cold exposure of the face significantly increases the
metabolic rate in term and preterm neonates with oxygen
requirements increasing by as much as 23% and 36%, respectively.274 These factors emphasize the need for protecting the babys
head from heat loss during surgery.248
Thermoregulatory vasoconstriction and vasodilatation are
generally present on the first day of life and can occur in both the
premature and the full-term infant.56,198 The even greater increased
skin surface areatobody mass ratio and thermal transfer
coefficients put the premature and smallforgestational age
newborn at the highest risk for accidental hypothermia with the
narrowest temperature range in which thermoregulatory stability
can be maintained. The slightly lower skin surface areatobody
mass ratio and increased motor tone in smallforgestational-age
infants offer a slight advantage in the protection against hypothermia when compared with the premature infant in terms of heat
loss or transfer. In addition to these physical limitations, surgery
further increases heat loss and fluid requirements by expos-
235
ing visceral surfaces (e.g., abdomen and thorax), resulting in

significant evaporative heat losses. Many premature babies require
phototherapy, which increases not only skin blood flow but also
evaporative heat loss.278,279
Despite the risks of hypothermia, maintaining a core
temperature at or above 37.8C in infants weighing less than 2 kg
is associated with a higher mortality.280 In part, this may be
explained by the vant Hoff-Arrhenius law (or Q10 effect), which
basically states that for every 10C increase in temperature, the
rate of a chemical reaction increases on average by a factor of 1.5
to 2.5. This in turn can increase the neonates metabolic heat
production to a point at which their heat loss mechanisms become
overwhelmed. Despite the higher risk for hypothermia of neonates
and small babies because of physical circumstances (e.g., size,
cold environment), this age group may react to an infection with
hypothermia instead of fever.
Thermoregulation and Anesthesia

All anesthetic agents, inhalational or intravenous, inhibit
thermoregulation at the peripheral and central level to variable
degrees in a linear or nonlinear and often dose-dependent
fashion.44,281,282 The interthreshold range for thermoregulation in
an awake, healthy adult is controlled within the set point of
37C by 0.4C in either direction. The shift of the threshold
temperatures for triggering a thermoregulatory response under
anesthesia may result in an expansion of the interthreshold range
by a factor of more than 10. This expansion is significantly greater
on the hypothermic than on the hyperthermic side (~2.5C vs
1.3C, respectively).283,284 The mechanism by which the body
determines the absolute threshold temperatures is not known, but
it appears that the thresholds are influenced by multiple factors
such as sodium, calcium, thyroid hormones, tryptophan, general
anesthetic agents and other medications, circadian rhythms,
exercise, pyrogens, food intake, as well as cold and warm acclimation. The anesthesia-induced changes result in a wider temperature range over which active thermoregulatory responses are
absent or diminished and the body behaves in a poikilothermic
manner with passive temperature changes proportional to the
difference between heat gained from metabolic production and
heat lost to the environment. General anesthesia eliminates
not only the behavioral aspect of thermoregulation but also
shivering thermogenesis, because most patients are paralyzed
or immobilized. Nonshivering thermogenesis and peripheral
vasoconstriction (although both occurring at lower temperatures only) are, therefore, the only defense mechanisms against
hypothermia that are active in anesthetized neonates and small
infants. Older children and adults are left only with peripheral
vasoconstriction.
Unfortunately, the definition of hypothermia is not unanimous,
but the subdivisions into mild (core temperature 34.035.9C),
moderate (32.033.9C), and severe hypothermia (<32.0C)
appear reasonable for clinical purposes.285 Patients with mild
intraoperative hypothermia demonstrate profound peripheral
vasoconstriction that can easily be measured using skin surface
temperature gradients (e.g., forearm vs finger tip skin temperature), laser Doppler blood flow measurements, volume plethysmography, or other techniques.201,283,284 Although the maximal
intensity of peripheral vasoconstriction and its gain (i.e., the
incremental increase in its intensity with progressing core
hypothermia) are preserved under anesthesia, there is a significant
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shift of its threshold temperature toward hypothermia when

compared with awake, unanesthetized patients. The one exception
seems to be desflurane, which not only lowers the threshold temperature but also decreases the gain of peripheral arteriovenous
shunt vasoconstriction.286 The threshold temperatures at which
vasoconstriction and nonshivering thermogenesis occur define
the corresponding lower thermoregulatory threshold for an
anesthetic agent at any given concentration.
Thermoregulation and Inhalational

Anesthetic Agents
The decrease in thermoregulatory threshold temperature for
vasoconstriction in adults under isoflurane anesthesia is inversely
correlated to the isoflurane concentration with the threshold
temperature dropping by approximately 3C for every 1% increase
in end-tidal isoflurane concentration.44 The same group of
investigators later found that isoflurane reduces the threshold
temperature disproportionately more at higher anesthetic concentrations, revealing a nonlinear dose-response relationship.282,287
In adults anesthetized with 0.7% isoflurane, the shivering temperature threshold and the peak intensity of shivering were
decreased. However, isoflurane produces a clonic muscular
activity that is different from normal shivering and superimposed
on normal thermoregulatory shivering. During progressive
hypothermia, these marked changes in the shivering pattern from
a linear increase to an unusual sawtooth pattern may help to
increase the gain of shivering.288
The rapid heat loss to the environment in small infants and
children is favored by their high surface areatomass ratio, but
is partially offset by their increased metabolic rate and welldeveloped thermoregulatory vasoconstriction, which under
isoflurane anesthesia showed basically the same changes as
those reported in adults. Central temperature thresholds under
isoflurane anesthesia do not, therefore, appear to be a function of
weight or age.289 However, because of the physical characteristics of
infants and children, the speed of cooling is higher than in adults.
Halothane administered to adults in a concentration of
0.86 to 1.01% decreased the threshold for thermoregulatory
vasoconstriction to 34.4 0.2C.284 Halothane in a concentration
of 0.6% combined with a caudal epidural block with bupivacaine
lowered the threshold temperature for vasoconstriction in infants
and children to 35.7C.290 The higher halothane concentration
used for adults may explain the lower threshold temperature
in that group. Neither the omission of the caudal block nor a
higher end-tidal halothane concentration (0.9%) resulted in a
significantly altered threshold temperature when compared with
the children receiving the lower halothane concentration in
combination with a caudal block.290 However, despite thermoregulatory vasoconstriction, central temperature in children
weighing more than 30 kg continued to drop, whereas the temperature reached a plateau in patients weighing less than 30 kg.
The exact reasons for this finding are unknown, but nonshivering
thermogenesis may play a role. It appears that thermoregulatory
defense mechanisms in small, anesthetized children are more
effective than in the older age group including adults. Comparing
halothane, enflurane, and isoflurane at an end-tidal concentration
of 1.0 minimum alveolar concentration (MAC) in combination
with a caudal epidural block in children confirmed the previous
findings for isoflurane and halothane. However, all but one child
in the enflurane group failed to vasoconstrict despite their core
temperature reaching 33.6 0.4C. The reason for this profound

inhibition of thermoregulation in children anesthetized with
enflurane is unknown, but it was concluded that the risk of
hypothermia in this age group with enflurane is significantly
higher when compared with isoflurane or halothane.291 Of note,
because there are no studies done determining the MAC equivalent of enflurane in children, end-tidal gas concentrations may
not have been equipotent. By contrast, enflurane administered to
healthy adult volunteers at an end-tidal concentration of 1.3%
(0.77 MAC) triggered thermoregulatory vasoconstriction at
35.1 0.6C in the absence of painful stimuli. The addition of
painful electrical stimulation raised the threshold temperature
to 35.5 0.8C, demonstrating a mild, although clinically insignificant, effect of nociception on anesthesia-induced thermoregulatory inhibition.292 In a concentration of 1 MAC in adult
women, enflurane increased the sweating threshold only slightly
more than previously reported for isoflurane, although the gain
and maximum intensity of the sweating response were well
preserved.293
In healthy adults immersed in cold water, the administration of
10 to 25% nitrous oxide in a normoxic mixture reduced shivering
thermogenesis in a dose-independent manner.107 Similar results
were reported for 30% nitrous oxide in oxygen,294,295 whereas the
sweating threshold was unaffected.295 When compared with
sevoflurane or isoflurane anesthesia at 1 MAC, the mixture of
0.5 MAC nitrous oxide and 0.5 MAC sevoflurane or isoflurane
resulted in a significantly higher threshold temperature for
thermoregulatory vasoconstriction.296 In adults undergoing
orthopedic or open abdominal surgery, anesthesia with either
sevoflurane or isoflurane in 70% nitrous oxide resulted in a similar
decrease in the threshold temperature for vasoconstriction;
however, the decrease in body temperature was significantly
slower in the sevoflurane group (0.5 0.2C/h vs 1.0 0.3C/h
with isoflurane).297 Studies using various 1 MAC combinations
of xenon, nitrous oxide, and isoflurane demonstrated that the
calculated reduction of the vasoconstriction threshold temperature was most pronounced with xenon (34.6 0.8C),
intermediate with isoflurane (35.1 0.6C), and lowest with
nitrous oxide (35.7 0.6C).298
Desflurane significantly increases the sweating threshold
temperature in adults in a dose-dependent and linear fashion.
However, the threshold temperatures for vasoconstriction and
shivering are reduced nonlinearly. Although the decrease in the
threshold temperatures for vasoconstriction and shivering at 0.8
MAC seem to be in a similar range compared with other inhalational anesthetic agents, the vasoconstriction threshold was higher
than expected at 0.5 MAC, thereby supporting the assumption
that desflurane may trigger a nonlinear concentration-response
relationship with regards to thermoregulatory vasoconstriction.299
As mentioned earlier in this section on Thermoregulation and
Anesthetic Agents, by contrast to other inhalational anesthetic
medications, the gain of thermoregulatory vasoconstriction with
desflurane in adults is markedly decreased even at relatively low
desflurane concentrations (0.4 MAC).
Hypothermia affects not only the physical characteristics of
inhalational anesthetic agents but also the pharmacokinetics and
pharmacodynamics of intravenous agents. In the temperature
range of 28 to 32C, the decrease in MAC with lower temperatures
parallels the increase in lipid solubility of the anesthetic gas.300304
For isoflurane, there is a linear reduction in the MAC of 5.1%/C
temperature decrease.302 Thus, for any inspired concentration of
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an inhalational anesthetic agent in a hypothermic patient, an
increased amount of anesthetic agent will be delivered to the
tissues at a time when the anesthetic requirements are decreased.
The mechanism by which hypothermia reduces the MAC is
unknown. According to the Meyer-Overton rule, the MAC of a
volatile anesthetic agent is inversely proportional to its lipid
solubility (i.e., its oil-to-gas partition coefficient) whereas the
product of anesthetic gas partial pressure (i.e., MAC) and its lipid
solubility is constant. Because hypothermia increases the lipid
solubility of the volatile anesthetic agents, the MAC has to be lower
to keep the product constant. However, it seems that the increased
solubility of the inhaled anesthetic agents in the lipid phase of the
central nervous system does not fully explain the MAC reduction
associated with hypothermia.
Thermoregulation and Intravenous

Anesthetic Agents
Opioids are a large and variable group of drugs in respect to both
their opioid receptor affinity and their chemistry. Therefore, not
unexpectedly, their effects on thermoregulation are not uniform.
Both -receptor and combined and receptor agonists impair
thermoregulation. In the clinically relevant plasma concentration
range, the pure receptor agonist alfentanil leads to a mild, dosedependent and linear increase in the sweating threshold and a
marked, but also linear and dose-dependent decrease in the
thresholds for vasoconstriction and shivering. Similar to general
anesthesia, the vasoconstriction-to-shivering range remains
normal.305 The combined and receptor agonist meperidine
(pethidine) also results in a slight increase in the threshold
temperature for sweating and a reduction in the threshold
temperature for vasoconstriction. However, the meperidineinduced reduction of the shivering threshold is twice as great as
the one for vasoconstriction. This significant increase in the
vasoconstriction-to-shivering range with meperidine is, at least in
part, due to its receptor activity and clinically used to effectively
treat shivering.305 However, neither alfentanil nor meperidine
reduce the maximum intensity or the gain of shivering.
When given to awake, healthy adults, tramadol, which has
a weak affinity for receptors and monoaminergic actions
(serotonin and noradrenaline re-uptake inhibition), results in a
linear and concentration-dependent decrease in the threshold
temperature for sweating (approximately 1.03 0.67C), whereas
the decrease in the threshold temperatures for vasoconstriction and
shivering are more pronounced (3.0 4.0C and 4.2 4.0C,
respectively). Because the vasoconstriction threshold temperature
decreases more than the one for sweating, the interthreshold range
doubles, which, in regards to thermoregulatory inhibition, is
considered mild. The effects of tramadol are thought to reduce the
thermoregulatory set point rather than generally impair thermoregulation.306 Tramadol has also been used successfully to stop
postanesthetic shivering.307 The pharmacokinetics of barbiturates
and opioids are also affected by hypothermia, which may further
affect their thermoregulatory effects.308,309 Surprisingly little
research has been done regarding the thermoregulatory effects of
sufentanil, fentanyl, and morphine when given as the sole drug to
humans. Sufentanil linearly reduces the shivering threshold
temperature and has been used successfully in the treatment of
postoperative shivering.310 Sufentanyl in combination with 70%
nitrous oxide in oxygen lowers the threshold for thermoregulatory
vasoconstriction by approximately 2.5C to 34.2 0.5C, which
237
is similar to the reduction seen during halothane anesthesia

(34.4 0.2C).283 When propofol was administered to healthy adult
volunteers, who also had a lumbar epidural anesthesia, there was
a slight increase in the threshold temperature for sweating with a
significant and linear decrease in the threshold temperatures for
vasoconstriction and shivering.311 Furthermore, the vasoconstrictionto-shivering range increased only slightly during propofol anesthesia.109
Small infants (<1 y of age), undergoing abdominal surgery
and anesthetized with propofol and fentanyl, demonstrated
vasoconstricted by the time core temperature reached 36C.
However, reducing core temperature further to 34.0 to 34.5C
did not result in increased oxygen consumption. Instead, oxygen
consumption decreased linearly and hypothermia failed to
increase plasma catecholamine concentrations. Even when lowering the core temperature approximately 2C below the vasoconstriction threshold, no evidence of nonshivering thermogenesis
could be identified. Infants thus appear similar to adults in their
inability to increase their metabolic rate in response to mild
intraoperative hypothermia.245 When comparing general anesthesia in adults induced with a single intravenous dose of propofol (2.5 mg/kg) followed by maintenance anesthesia with
sevoflurane in 60% nitrous oxide and oxygen versus induction
with sevoflurane followed by the same maintenance, core temperature in the propofol group was significantly lower than in the
sevoflurane group (35.5 0.3C vs 36.2 0.2C).312 The brief
propofol-induced vasodilation is thought to be responsible for
facilitating core-to-peripheral redistribution of body heat leading
to nonrecoverable heat loss to the environment and hypothermia
persisting throughout surgery.
Midazolam produces only a slight decrease in the threshold
temperature for sweating, with a more profound reduction in the
threshold temperature for vasoconstriction. This results in a
threefold expansion of the interthreshold range, which is similar
to the findings with central neuraxial nerve blockade (see Section
on Thermoregulation and Regional Anesthesia), but contrasts
with the effects of inhaled anesthetic agents, propofol, or opioids,
in which the interthreshold range can expand by a factor of more
than 10.313 Intramuscular premedication in healthy adults with
midazolam produces a dose-dependent temperature decrease after
30 minutes because of impaired thermoregulatory vasoconstriction, which allows heat to be redistributed from the core to the
peripheral compartment.314 This hypothermic effect of midazolam
can be neutralized by simultaneous administration of atropine.315
In adults, core hypothermia during the first hour of anesthesia
is less after induction of anesthesia with ketamine than with
propofol, even when anesthesia was maintained with sevoflurane
and 60% nitrous oxide in oxygen in both groups. The finding is
postulated to be caused by the preserved arteriovenous shunt
vasoconstriction during induction of anesthesia with ketamine
versus propofol, which reduces the extent of redistribution hypothermia.316 In a prospective, randomized trial, children younger
than 8 years of age undergoing anesthesia for herniorrhaphy
received either ketamine or halothane/nitrous oxide in oxygen
after intramuscular premedication with scopolamine.317 Children
in the halothane group had a greater decrease in temperature than
children in the ketamine group. In children older than 24 months
of age, body temperature in the ketamine group increased slightly
after the induction of anesthesia. However, independent of the
anesthetic technique used, hypothermia during general anesthesia
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was greatest in children with the highest surface areatobody

weight ratio.317
In healthy adult volunteers, dexmedetomidine reduces the
threshold temperatures for vasoconstriction and shivering in a
linear and dose-dependent manner and, thus, expands the
interthreshold range despite the fact that the sweating threshold
remains unchanged.318 The co-administration of meperidine has
an additive effect on the reduction of the shivering threshold,
making this combination an effective treatment option for
postoperative shivering.319 Premedication with 150 g of oral
clonidine in adults neither affects redistribution hypothermia nor
worsens hypothermia during general anesthesia.320 Clonidine
given as a bolus dose (either 2 or 4 g/kg) followed by an infusion
of either 2 or 4 g/kg/h resulted in a dose-independent increase in
the threshold temperature for sweating, but its gain remained
unchanged.321 By contrast to other sedatives and anesthetic agents,
clonidine seems to reach an early ceiling effect beyond which the
administration of additional doses fails to further enhance its
effects on thermoregulation, suggesting that the thermoregulatory inhibition of clonidine is limited. The thermoregulatory changes induced by clonidine resemble those of volatile
anesthetic agents, opioids, and propofol. The antishivering effect
of clonidine appears to result from central thermoregulatory
inhibition rather than a specific peripheral action on thermogenic
muscular activity.321
Atropine blocks sympathetic, cholinergic-mediated sweating,
increases the threshold temperatures for sweating, and may
therefore lead to hyperthermia in children.322 Systemic administration of atropine leads to marked (regional) cutaneous vasodilation at the same core temperature with the skin temperature
following passively. The effect of systemic atropine in stimulating
cutaneous vasodilation has been suggested to be the result of
a combination of central and local responses, which may be
mediated by the release of vasoactive substances.323
Thermoregulation and Regional Anesthesia

The central integration of afferent and efferent thermal impulses
remains fully functional during regional anesthesia and protects
against either hypothermia or hyperthermia. However, the
problem with regional anesthesia in terms of thermoregulation is
the blockade of afferent and efferent signals from and to the
anesthetized body part. Intraoperative hypothermia secondary to
regional anesthesia is caused by a combination of lost regional
thermal sensation, inhibition of thermoregulatory vasoconstriction and shivering, and increased internal redistribution
of heat to the anesthetized body part with increased heat loss to
the environment. The factors responsible for intraoperative
hypothermia during general anesthesia principally also apply for
central neuraxial anesthesia. In the first 30 minutes after the
induction of neuraxial anesthesia, the central core temperature in
healthy adult volunteers decreased by approximately 0.5 to 1.5C,
accounting for 81% of the core temperature decrease in the first
hour of anesthesia. Decreased metabolic heat generation and
increased heat loss to the environment were responsible for the
residual part in temperature drop. The impact of redistribution
of heat on the temperature drop decreased to 43% during
the second and third hour of anesthesia. This redistribution
accounted for a total of 65% of temperature reduction during the
first 3 hours of anesthesia, making it the major cause of hypothermia.324 Accordingly, the administration of a vasoconstrictor
(e.g., phenylephrine infusion) can limit the size of the peripheral

compartment and, hence, the magnitude of hypothermia caused
by redistribution.325
During lumbar epidural anesthesia in adult volunteers, internal
redistribution contributed 89% to the initial temperature decrease
in the first hour. During the subsequent 2 hours of epidural
anesthesia, redistribution still accounted for 62% of core
temperature reduction. In the first 3 hours of epidural anesthesia,
redistribution was responsible for 80% of the overall temperature drop, and even after 3 hours of anesthesia, redistribution
remained the main culprit of core hypothermia. Despite the
greater fractional contribution of redistribution during epidural
anesthesia, core temperature decreased only half as much as
during general anesthesia because the metabolic heat generation
could be maintained and thermoregulatory vasoconstriction in
the upper (nonanesthetized) body part was unaffected.326 The
degree of core hypothermia during central neuraxial anesthesia
depends on the amount of internal heat redistribution because of
a lack of thermoregulatory vasoconstriction in the anesthetized
body part and, thus, is directly related to the number of dermatomes blocked rather than to a centrally mediated inhibition
of thermoregulation.327,328 Similar to general anesthesia, advanced
age is also associated with more severe hypothermia during spinal
anesthesia.328 Epidural and spinal anesthesia commonly affect a
major part of the body mass, and therefore, hypothermia can be
quite pronounced. Regional anesthesia affects metabolic heat
generation only minimally.329 However, by contrast with general
anesthesia, central neuraxial anesthesia abolishes thermoregulatory peripheral vasoconstriction in the anesthetized body parts,
and hence, patients may fail to reach a steady state between heat
loss and heat generation. Despite maximal vasoconstriction in
the body part not affected by regional anesthesia, progressive
and serious hypothermia may not be preventable because the
nonanesthetized body mass is usually comparably small. At a
normal leg skin temperature of approximately 33C, the cutaneous
cold sensors are more active than the warm sensors. Blocking
these afferent pathways by central neuraxial anesthesia techniques
could potentially be interpreted as relative leg warming by the
hypothalamus. In addition, this blockade seems to be responsible
for the low intensity of shivering, and in some individuals its
delayed onset, further increasing the risk for hypothermia.329331
Mainly because of the failure of the upper body muscles to
compensate for lower body paralysis, the gain of shivering during
epidural anesthesia is reduced by more than 60%.332 When comparing epidural with general anesthesia in adults undergoing
radical prostatectomy, intraoperative and postoperative core
temperature profiles were virtually identical in the two groups.
Epidural anesthesia was associated with less intraoperative upper
body thermoregulatory impairment but greater and persistent
postoperative lower body impairment. Although the age-related
differences were minimal in the general anesthesia group, younger
patients appeared to maintain thermoregulation better than older
patients with neuraxial anesthesia.190 Inhibition of thermoregulation during regional anesthesia is reflected as significant
expansion of the interthreshold range. Comparable changes in
the threshold temperatures for sweating, vasoconstriction, and
shivering during epidural and spinal anesthesia with a doubling of the interthreshold range suggest that thermoregulatory
processing is similarly affected during both types of regional
anesthesia.331 The thermoregulatory inhibition described for
regional anesthesia is unlikely the result of the systemic absorption
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CHAPTER 14
of local anesthetic agents because similar local anesthetic agent
plasma concentrations without regional anesthesia fail to
reproduce these thermoregulatory changes.333 Regional anesthesia
for large surgical incisions may be associated with profound and
even more severe hypothermia than with general anesthesia, and
the recovery time to normal body temperature may be prolonged.
By contrast, regional anesthesia reduces the risk of hypothermia
when the incision is small and the patient is kept well insulated.334
The combination of general anesthesia with isoflurane and
epidural anesthesia in adults further reduces the threshold temperature for thermoregulatory vasoconstriction thereby significantly
exacerbating hypothermia when compared with general anesthesia alone.335 During combined enflurane (1 MAC) and epidural
anesthesia in healthy female volunteers, the sweating threshold
was 1.4 0.7C higher than during epidural anesthesia alone.293
Diabetic patients with autonomic neuropathy receiving a general
anesthesia had delayed thermoregulatory vasoconstriction resulting in lower core temperatures after 2 hours of anesthesia than
diabetic patients without autonomic dysfunction.336
By contrast, the combination of halothane anesthesia with a
caudal epidural block in children undergoing hypospadias repair
failed to significantly alter the threshold temperature for vasoconstriction when compared with children receiving halothane
anesthesia and a penile block (35.9C with caudal block vs 35.7C
with penile block).290 Although these data would demonstrate
that temperature monitoring during regional anesthesia is
239
equally important as it is during general anesthesia, only a third of

clinicians monitor temperature during regional anesthesia and less
than 15% use reliable core temperature monitoring techniques.337
It is likely that significant hypothermia, although common, goes
undetected and, therefore, untreated in these patients.
Anesthesia and Hypothermia

General anesthesia leads to an expansion of the interthreshold
range, both by increasing the threshold temperature for sweating
and by decreasing the threshold temperature for vasoconstriction
and shivering. As a result, hypothermia is common, although most
often mild ( 34C). Its etiology remains multifactorial including
1. Anesthesia-induced inhibition of central thermoregulation.338
2. Internal redistribution of heat from the central to the peripheral compartment.329
3. Linear reduction in metabolic heat production as a function of
mean and core body temperatures (48%/C).339
4. Increased exposure to the environment (up to 90% of heat loss
occurs via skin mainly by radiation and convection).
Anesthesia-induced hypothermia has a typical temperature
profile and develops in three distinct phases (Figure 144):
1. Internal redistribution of heat.
2. Thermal imbalance.
3. Thermal steady state (plateau or rewarming).
Figure 14-4. Intraoperative course of changes in body temperature. Graphic representation of the
three typical phases of intraoperative hypothermia in relation to the duration of anesthesia. The first
phase relates to internal redistribution with a drop in core temperature secondary to the expansion
of the central core volume induced by peripheral vasodilatation (the same heat content is now distributed in a larger volume). The second phase is characterized by actual heat loss to the environment resulting in further reduction in body temperature until the threshold temperatures of defense
mechanisms are reached. The third phase, thermal steady state in adults and rewarming phase in infants and children, is due to the active thermoregulatory defense mechanisms including peripheral
vasoconstriction, shivering, and nonshivering thermogenesis becoming effective. Adapted from reference 504.
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INTERNAL REDISTRIBUTION OF HEAT: In order to understand the

concept of internal redistribution of heat, it is helpful to remember
the thermoregulatory division of the body into central, peripheral,
and skin (or shell ) compartments. The core temperature describes the temperature of the central compartment, which in an
awake adult at rest, accounts for approximately 66% of the body
mass. This increases to about 71% during general anesthesia.340
The central compartment contains the vessel-rich group organs
that make up approximately 10% of the total body weight in adults
and 22% in neonates, but receive 75% of the total cardiac output.
The peripheral compartment makes up the remainder of the body
mass and acts as a dynamic buffer with a capacity in the adult of
more than 600 kJ between the core and the shell compartment,
thereby allowing the body by means of vasodilation or vasoconstriction to maintain core temperature constant with a minimal
amount of energy expenditure for thermoregulation despite
absorption or dissipation of significant amounts of heat. The shell
(or skin) compartment is almost virtual and defines the barrier
between the body and the environment.
Shortly after the induction of general anesthesia, peripheral
vasodilation increases the size of the central compartment,
resulting in the distribution of its heat content to a larger volume.
At the same time, the anesthesia-induced reduction in metabolic
heat generation makes it almost impossible for the body to
compensate for the expansion of the central compartment. As the
name implies, heat is mainly redistributed, with only a fraction
being lost, to the peripheral compartment, resulting in a decreased
core temperature and increased peripheral and skin compartment
temperature. This can be demonstrated by a forearm-fingertip or
calf-toe temperature gradient that may exceed 8C and is caused
by a more than fourfold increase in the perfusion of forearms and
legs after the induction of anesthesia.324
THERMAL IMBALANCE: The second phase of anesthesiainduced hypothermia, also known as thermal imbalance, results
from a combination of decreased metabolic heat generation
and increased heat loss to the environment. This phase lasts
approximately 2 to 3 hours and causes a linear decrease in mean
body temperature of typically 0.5 to 1.0C/h. Heat generation
during anesthesia is reduced not only by inhibition of metabolism
but also by very limited or absent muscular activity (e.g., absent or
reduced work of breathing).44,292 All of the heat loss mechanisms
(i.e., radiation, convection, evaporation, and conduction) contribute in variable degrees to heat loss from the patient to the
environment during anesthesia and surgery. Heat loss mainly
becomes a function of the temperature difference between the
patients body surface and the environment. Therefore, heat loss
decreases passively as the body temperature decreases toward
room temperature (i.e, the temperature gradient shrinks).
THERMAL STEADY STATE (PLATEAU OR REWARMING PHASE):

In the third stage of the response to anesthesia-induced hypothermia, the body almost reaches an equilibrium between internal
heat production and heat dissipation to the environment, resulting
in a core temperature that reaches a plateau and, hence, remains
fairly constant. This temperature plateau usually occurs between
34.5 and 35.5C and is also termed the thermal steady-state phase.
In order to achieve this steady state, the patient must increase
metabolic heat production and/or reduce heat loss. In adult
volunteers anesthetized with isoflurane at an end-tidal concentration of 1%, thermoregulatory vasoconstriction occurred at a
core temperature of 34.6 0.4C and resulted in a maximal
reduction in heat loss of 26%, which was deemed rather small

when compared with the reduction in metabolic heat production during anesthesia and the amount of heat lost by
evaporation from a large surgical incision.341 The limited effect
of thermoregulatory vasoconstriction may be related to the fact
that overall heat loss from the skin is determined predominantly
by capillary blood flow in large skin areas covering the limbs and
the trunk. However, these capillaries are unable to vasoconstrict to
the same degree as the arteriovenous shunts and also markedly
outnumber them. Despite these limitations, it seems possible
that limiting the size of the peripheral compartment in relation
to the central compartment by peripheral vasoconstriction
reduces the amount of heat dissipated and thereby contributes
to establishing the thermal plateau.339 Even more important in the
achievement of the thermal plateau is the evolving constraint of
the metabolic heat generated for a core that is now becoming
smaller again, approaching its original awake size. This is basically
a reversal of the internal redistribution.339 This concept is
supported by the finding that the use of unilateral or bilateral
leg tourniquets in small children anesthetized with halothane in
nitrous oxide and oxygen resulted in core hyperthermia, which
was more pronounced with bilateral tourniquets.342 Similar results
have also been demonstrated in adults.343 Most likely, hyperthermia induced with a tourniquet results from the limited
expansion of the central compartment, thereby containing the
metabolic heat within a smaller central compartment. This is
further supported by the fact that deflation of the tourniquet(s)
leads to a drop in central temperature.343345 Despite reaching
a thermal plateau, mean body temperature and body heat content
continue to decrease, although at a much slower rate (i.e.,
0.2C/h). That is, vasoconstriction reestablishes the normal core
toperipheral temperature gradient by preventing metabolic heat,
which is largely generated in the core, from escaping to peripheral
tissues.339
The assessment of the contribution of nonshivering thermogenesis in adult volunteers under anesthesia has demonstrated that
it has little effect on the thermal plateau.346 Even in small children
anesthetized with propofol and fentanyl, there is a failure to trigger
nonshivering thermogenesis at core temperatures approximately
2C below the vasoconstriction threshold. Similar to adults,
infants and children are unable to increase their metabolic rate in
response to anesthesia-induced hypothermia.245 However, by
contrast to adults, the third stage of the response to anesthesiainduced hypothermia in infants and children is a rewarming
rather than just a plateau phase. With muscular activity and
nonshivering thermogenesis inhibited and metabolic heat
production reduced during anesthesia, the only possible explanation for this rewarming phase is peripheral vasconstriction,
which seems to be more efficient in this age group than in adults.
A clinical study in children undergoing general anesthesia for
surgery found a twofold increase in oxygen consumption during
mild hypothermia, which was attributed to a higher metabolic
heat generation.347,348 This increased oxygen demand to maintain
normal core temperature may create or exacerbate pre-existing
cardiopulmonary insufficiency intraoperatively and even more so
in the postoperative period. Norepinephrine released to trigger
vasoconstriction may contribute to the development of acidosis,
tissue hypoxia, and increased right-to-left pulmonary shunting.349
Sustained pulmonary artery hypertension and right-to-left
pulmonary shunting may lead to the formation of a vicious circle
with ongoing pulmonary hypertension and vasopasm.
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Anesthesia and Hyperthermia

Similar to hypothermia using thresholds and gain, hyperthermia
triggers important physiologic thermoregulatory responses. The
defense mechanisms to fight core hyperthermia are preserved
during general anesthesia; however, the thresholds triggering them
are shifted toward higher temperatures. Volatile anesthetic agents
significantly expand the interthreshold range but change the gain
and maximum intensity of the response only minimally.293 The
interthreshold range expansion during anesthesia is not symmetrical and differs for hypothermia and hyperthermia. Although
the reduction in the threshold temperature (thermoregulatory
vasoconstriction) for hypothermia in an anesthetized patient may
be as great as 3.5C, the increase in the threshold temperature for
thermoregulatory vasodilatation may be as little as 1.0C.293
This observation suggests that the human body is significantly
more sensitive to hyperthermia than to hypothermia. Therefore,
it may be that hyperthermia represents a more dangerous threat to
the organism than a similar degree of hypothermia.293
The efferent responses to hyperthermia are limited to active
vasodilatation and sweating. Thermoregulatory vasodilatation
triggered by warm stress is not simply the absence of vasoconstriction, but rather an active peripheral vasodilatation resulting in
increased dissipation of heat.118,120,145,149,350 In fact, it has been
demonstrated in adult volunteers that -adrenergic vasoconstriction induced by high intravenous doses of norepinephrine
during local (forearm) or whole-body warming cannot fully ablate
the heat-induced vasodilatation.351 During normothermia, skin
blood flow is controlled by tonic adrenergic stimulation. With
increasing core temperature, skin blood flow initially increases by
reducing the tonic vasoconstriction. For glabrous or nonhaircontaining skin (palmar and plantar surfaces and lips), aside from
the direct vasodilating effects of heat itself, this mechanism is the
only way to adjust local blood flow. However, once the threshold
temperature has been reached in nonglabrous skin areas (haircontaining skin), active cutaneous vasodilatation is initiated by a
combination of sympathetic cholinergic impulses and release of
vasoactive substances including histamine, VIP, nitric oxide, and
perhaps other neurotransmitter(s).121124
It has also been demonstrated that men sweat more than
women. Compared with men, heat loss in women depends more
on cutaneous vasodilatation than on sweating, irrespective of
the phase of the menstrual cycle. However, the menstrual cycle
modifies the threshold temperature for vasodilatation and
sweating in women. The differences are more pronounced during
the luteal than during the follicular phase.352 The threshold
temperatures in women for hyperthermia defense are significantly
higher than in men. However, the later onset of sweating in
women does not result in a significant increase in rectal temperature, which is probably caused by a complex interaction
between sweating, increased skin blood flow, and reduced
metabolic rate.353
ADVERSE EFFECTS
OF HYPOTHERMIA: In both adults and

children, hypothermia during anesthesia is common. In infants
and children, it is usually more pronounced, mainly because of
their anatomic disadvantages in terms of thermoregulation, which
have been previously discussed in the section on Physiology of
Thermal Regulation. The exposure of open body cavities to low
humidity and operating room temperatures, infusion of large
amounts of cold fluids, and ventilation with cold and dry gases all
increase risk of hypothermia. Although we cannot change the
241
anatomic and physiologic characteristics of an infant or child, we

can control many of these other factors. Several preventive and
effective measures exist so that hypothermia must no longer be
viewed as an accepted and inevitable sequelae of anesthesia and
surgery. Although hypothermia has been shown in several studies
to be beneficial, mainly for patients with any type of ischemia or
traumatic brain injury,354,355 the vast majority of patients undergoing anesthesia do not suffer from these comorbid processes, and
therefore, the adverse effects of hypothermia generally outweigh
the benefits. Studies providing evidence for the adverse effects
of intraoperative and postoperative hypothermia have been
performed only the adult population. However, there are no
reasons to believe that these findings do not apply to infants and
children.
Hypothermia inhibits chemotaxis and phagocytosis of granulocytes, natural killer cell cytotoxicity, macrophage migration,
and T cellmediated antibody production.356360 Intraoperative
production of reactive oxygen species (i.e., hydroxyl ions, active
aldehydes, hypohalites, and lipid peroxides) by polymorphonuclear leukocytes has been shown to be linearly related to core
temperature in patients undergoing colorectal surgery.356 In a
randomized, double-blind study in 200 adult patients undergoing
open colorectal surgery, patients were assigned either to routine
warming measures (hypothermic group with a temperature of
34.7 0.6 C at the end of surgery) or to additional warming
measures (normothermic group with a core temperature of 36.6
0.5 C at the end of surgery).361 The incidence of surgical wound
infections was three times higher in the hypothermia group and
the time to suture removal and hospital discharge was prolonged
by 1 and 2.6 days, respectively. It has been hypothesized by these
and other investigators that the increased rate of wound infections
and delayed wound healing may be a direct consequence of
hypothermia-induced vasoconstriction, which results in diminished tissue oxygen partial pressures.361,362 The induction of
thermogenesis with an amino acid infusion during general
anesthesia has been shown not only to prevent postoperative hypothermia and shivering but also to result in a shorter
hospital stay.262
Normally, coagulation tests are performed at 37C, which results
in the effects of hypothermia being masked.363,364 However, if the
tests are done at the actual body temperature of the patient, it has
been shown that the enzymatic reactions of the coagulation cascade
are inhibited by hypothermia, which is reflected by a prolongation
of partial thromboplastin and prothrombin time, although the
clinical significance of these findings remain debatable.365367
In vitro experiments during moderate to profound hypothermia
(33 and 22C) reveal an increase in platelet -granule release, in
platelet binding of PAC-1 and P-selectin antibodies, and in platelet
aggregation and binding to fibrinogen (via activation of glycoprotein [GP] IIb/IIIa receptors). Upon rewarming, the aggregation
response of previously cooled platelets fully normalizes.368 The
authors concluded that, because hypothermia appears to result in
platelet activation, hypothermia-induced coagulopathy is unlikely
to be caused by an intrinsic defect in platelet function. A study in
mice confirmed these results.369 However, these findings are in stark
contrast to other reports. Coagulation and platelet function were
analyzed in 16 otherwise healthy adult patients scheduled for
elective intracranial surgery at a core temperature of 32C.367 Both
prothrombin time and platelet count decreased slightly during
hypothermia. Thrombelastography showed normal clot strength
in temperature-adjusted measurements; however, clot formation
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was delayed. No changes were detectable if the test was performed

at 37C. This was interpreted as an indicator for reduced plasmatic
coagulation and platelet reactivity during hypothermia. The comparison of results obtained from thrombelastography performed
at 37C and at the actual body temperature of the patient demonstrated prolonged reaction and coagulation time as well as a
reduced clot formation rate in the presence of hypothermia.370
Increased bleeding during hypothermia in humans has been shown
to be the result of a platelet adhesion defect and not reduced
enzyme activity or platelet activation. Reduced platelet function
and enzyme activity likely contributed to coagulopathy at temperatures below 33C.371 By contrast, moderate hypothermia to a
mean body temperature of 32.5 0.4C accomplished in the first
hour after induction of anesthesia and maintained during surgery
for subarachnoid aneurysms in 359 adult patients appeared to be
safe and not associated with a higher rate of perioperative complications such as hemodynamic instability, coagulation abnormalities, or infections.372
Although these conflicting results demonstrate that not all of
the effects of hypothermia on coagulation and platelet function
have been fully elucidated, from a clinical point of view, it seems
reasonable to assume that, independent of the exact pathophysiologic causes, blood loss is increased during hypothermia.
This has been confirmed in a recent meta-analysis of 24 studies
demonstrating that even mild hypothermia (a decrease of 1C)
significantly increased surgical blood loss by approximately 16%
as well as the relative risk for transfusion by approximately 22%.373
Similar findings were reported from an adult study that included
patients undergoing unilateral total hip arthroplasty in which
intraoperative and postoperative blood loss were significantly
greater in the group with mild hypothermia (35 0.5C).374 Thirty
minutes of prewarming before induction of anesthesia in adults
scheduled for major abdominal surgery resulted not only in
less hypothermia but also in a reduction of blood loss, length of
hospital stay, and total anesthetic costs.375 Decreased platelet
function with prolonged bleeding time during hypothermia has
also demonstrated in adult volunteers and appears to be secondary
to changes in platelet surface proteins with diminished platelet
aggregation and thromboxane B2 (the stable metabolite of thromboxane A2) generation.376
Myocardial infarction is one of the main determinants
of perioperative morbidity and mortality in adults. In adults
scheduled for vascular reconstruction of the lower extremities,
electrocardiographic signs and symptoms (angina) of myocardial
ischemia in the first 24 hours after surgery were significantly
more frequent in the hypothermic (<35.0C) than in the normothermic group (>35.0C).377 After subgroup and multivariate
analyses, body temperature remained an independent predictor
of myocardial ischemia. In addition, the incidence of arterial
oxygen pressure (PaO2) values below 80 mmHg was greater in the
hypothermic than in the normothermic group. The need for
prolonged mechanical ventilation, increased length of stay in the
intensive care unit, a higher rate of red blood cell transfusions, and
increased postoperative mortality in hypothermic group patients
were noted in a retrospective study in 5701 patients after <X>
coronary artery bypass grafting (CABG) surgery with CPB.378 A
decreased incidence of ischemia and myocardial injury, assessed
with serum troponin I levels, has been noted in patients who were
kept normothermic throughout the non-CPB phases of CABG
surgery.379
Although oxygen consumption in the postoperative period is

often increased, particularly in the presence of shivering, studies
examining the effects of shivering have concluded that shivering
itself is not a significant risk factor for perioperative myocardial
ischemia.180,187 Instead, the hypothermia-induced sympathetic
nervous system activation results in higher norepinephrine (by
251%) and epinephrine (by 120%) plasma concentrations, a
greater degree of peripheral vasoconstriction, higher arterial blood
pressure, and a risk of ventricular arrhythmias in the early
postoperative period.380382 The sympathetic activation is associated with increased cardiac work that can be inhibited by
adrenoreceptor blockers.382 In addition, general anesthesia
combined with hypothermia (33.9 0.5C) in healthy volunteers
resulted in significantly greater suppression of the baroreceptor
reflexmediated heart rate control, both intraoperatively and
postoperatively.383 High-risk cardiovascular patients undergoing
major surgery have been shown to have a threefold increased
risk of perioperative cardiac complications (i.e., unstable angina/
ischemia, cardiac arrest, myocardial infarction, or ventricular
tachycardia) in the presence of postoperative hypothermia (35.4
0.1C) when compared with normothermic patients (36.7
0.1C). Again, hypothermia was found to be an independent risk
factor, and maintaining normothermia resulted in a 55% risk
reduction for adverse cardiac events.384
Hypothermia increases the cardiac action potential duration
and refractory period significantly even at temperature changes
of as little as 1 to 2C. This is explained by delayed repolarization,
which is reflected by prolongation of the QT interval in the
electrocardiogram, thereby increasing the risk of arrhythmias.
Furthermore, nonuniform cooling or rewarming of the heart may
cause significant dispersion of conduction, action potential
duration, and refractoriness in the myocardium. This dispersion
may cause a unidirectional block and create a substrate for reentry
atrial and ventricular arrhythmias.385
Hypothermia inhibits drug metabolism and may lead to
prolonged drug activity. Intraoperative hypothermia in adults has
been shown to result in delayed recovery from anesthesia.386,387
However, in a study of 87 children, there was no difference in
recovery between normothermic and hypothermic patients.388 The
effects of hypothermia on neuromuscular blocking agents includes
a reduction of the requirements caused by increased sensitivity
of the neuromuscular junction as well as diminished hepatic
clearance because of reduced affinity of the drug substrate for
microsomal enzymes and decreased renal drug elimination.386,389
392
In the case of vecuronium, mild hypothermia (core temperature
34.5C) resulted in a more than twofold increase in the duration
of the spontaneous train-of-four (TOF) ratio recovery to 10% and
from 75% when compared with normothermic individuals (core
temperature > 36.5C). However, the neostigmine-induced TOF
ratio recovery time was not significantly different in the two
groups.386 Another volunteer study confirmed these findings and
determined that the vecuronium plasma clearance diminishes
by approximately 11%/C temperature reduction and that a
decreased rate constant for drug equilibration between plasma
and effect site increases the slope of the concentration-response
relationship.393 In healthy volunteers anesthetized with a propofol
infusion and paralyzed with a single bolus dose of atracurium, the
time required for spontaneous TOF ratio recovery to 10% was
prolonged by more than 50% in the hypothermia group, whereas
the time required for the TOF ratio recovery from 25 to 75% was
similar in the hypothermia and the normothermia groups.394
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In addition, propofol blood concentrations at hypothermia were
approximately 28% higher than in normothermia. By contrast,
hypothermia in adult neurosurgical patients did not affect the time
to respond to commands after propofol anesthesia, and it was
concluded that propofol dosing does not require adjustment
during mild hypothermia.395 Decreased clearance of other
pharmacologic agents including verapamil and propanolol have
been demonstrated in the presence of hypothermia.396
Unfortunately, most of these adverse effects of hypothermia are
derived from adult studies. However, until similar studies exist
specifically for the pediatric population, it seems reasonable to
assume that the same negative consequences related to hypothermia will also occur in children. Avoiding hypothermia
therefore is crucial not only in the adult patient but also (or
most likely even more so) in the pediatric patient. Applying our
knowledge from thermal physiology and thermoregulation
combined with meticulous and proactive anesthetic care will
provide a means for maintaining normothermia in the vast
majority of our patients. One should keep in mind that it is easier
to keep patients warm from the start of anesthesia than to rewarm
them later on. The vicious circle of hypothermia and its main
adverse effects are presented in Figures 145 and 146, respectively.
PREVENTING HYPOTHERMIA: OPERATING ROOM TEMPERATURE:

The main mechanisms of heat loss during anesthesia are radiation and convection. As mentioned in the section on Heat Loss
Mechanisms, radiant heat loss is a function of the temperature
difference between the patient and the surrounding objects.
Warming the operating room reduces the temperature gradient
between the patient and the environment, thereby decreasing heat
loss via radiation. The efficiency of higher operating room temperatures to control the body temperature of newborns during
surgery was demonstrated many years ago.397 Ideally, operating
room temperatures should be kept at a minimum of 27C for full-
243
term and 29C for premature neonates.397 For adults, 21C has
been determined to be the critical ambient temperature in order
to maintain normothermia.398400 As a rule of thumb, an increase
in the operating room temperature of 1C results in a heat loss
reduction of approximately 10%.
Convective heat loss is best controlled by keeping the patient
covered, because the air flow produced by the air conditioning
system in the operating room has to adhere to certain hygienic
standards (i.e., the air exchange rate should equal ~15 times the
operating room volume/h for systems solely using outdoor air and
25 times for systems relying on recirculated air).401 These
requirements result in a mandatory constant air draft responsible
for the convective heat losses.
Evaporative heat loss occurs from the respiratory tract and
accounts for only 5 to 10% of total heat loss during anesthesia.
Evaporation also results from surgical field preparation and
thereafter from skin incision and open wounds, particularly from
large open body cavities (i.e., chest and abdomen) from which heat
loss can be significant. Relative operating room humidity should
be kept in a range of 40 and 60%. Conductive heat loss should be
minimal during surgery because the patient should not come in
direct contact with cold objects. Maintaining the operating room
temperature at a higher level is, therefore, a crucial step in the
prevention of hypothermia, particularly when the type of surgery
requires the majority of the body surface to be exposed.
PREWARMING: Intensive skin-surface warming before the
induction of anesthesia with a forced-air warming device will
induce peripheral vasodilatation and equilibrate peripheral and
central compartment temperatures. This minimizes redistribution
hypothermia and is an effective strategy to maintain intraoperative normothermia.402406 Although an effective and otherwise
affordable technique to avoid hypothermia, in most cases, this
technique will require additional logistic organization and
Figure 14-5. Adverse effects of hypothermia in neonates. Hypothermia in neonates triggers norepinephrine secretion that results in
pulmonary and peripheral vasoconstriction, but also in activation of brown adipose tissue (BAT) for the generation of metabolic heat.
This cascade eventually results in a vicious circle that, if left untreated, may result in mortality in the infant.
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Figure 14-6. Adverse effects of hypothermia. The cascade of events triggered by hypothermia that eventually may lead to an
increased rate of wound infections and delayed wound healing. Adapted from reference 506.
operating room personnel. An adult volunteer study found that

neither sweating nor thermal discomfort limited heat transfer
during the first hour of prewarming and that half an hour of
forced-air warming enhanced peripheral tissue heat content (i.e.,
in arms and legs) by more than the amount of heat normally
redistributed during the first hour of anesthesia.405 However,
although shivering may double the heat production, sweating may
dissipate more than 10 times the amount of normal basal heat
production. Therefore, if the patient is sweaty after prewarming
and her or his body surface is exposed to ambient air, significant
evaporative heat losses may occur and eliminate the benefits of
prewarming. The prewarming technique could prove beneficial
for certain peripheral plastic reconstructive surgeries because
forearm capillary blood flow doubled or even tripled, depending
on the settings on the forced-air warming device. In addition,
thermoregulatory vasodilatation on the lower extremities resulted
in significantly increased capillary blood flow in the calf and
toes.405 Despite the active transfer of heat through the patients skin
via convection and radiation, central temperature remained
relatively constant or even slightly decreased in these patients.402
406
This can be explained by the fact that these volunteers were
awake (i.e., nonanesthetized), young, and healthy with fully
functional thermoregulation.
RADIANT HEATERS:
Radiant heaters are most commonly used

during the induction of anesthesia when insertion of central
venous lines, arterial cannulae, and/or regional anesthesia
catheters is planned. Extreme differences in radiant warmer
performances and energy transfer to the mattress surface can be
found, which depend on heater-element composition, reflector
design, and heater-to-mattress distance.407 Insensible water losses
in premature babies can increase significantly (up to 150%) when

nursed under the radiant heater, although this should rarely be
relevant in the anesthetic setting, in which the time exposed to the
radiant heater is generally limited.408,409 In order to avoid skin
burns, the manufacturer recommended that minimal distance
from the patients skin must be respected.
REFLECTIVE BLANKETS: The effect of reflective blankets (i.e., an
aluminized plastic foil designed to reflect ~80% of body heat) has
produced conflicting results in adults, whereas data in the
pediatric population are limited. However, it has been reported
that normothermia can be maintained with reflective blankets if
60% or more of the patients body surface area is covered.410 This
device may have a place in the out-of-hospital trauma setting
(particularly in combination with other warming measures), but
once in the hospital, other significantly more effective treatment
options are available to achieve or maintain normothermia.411414
Drawbacks, mainly in the context of out-of-hospital care, included
the fact that a clothed body radiates only a small amount of heat
and the impermeability of the plastic foil to both water and water
vapor allows condensation to be formed on the blankets interior
within less than 20 minutes (especially when the ambient
temperature is low). This condensation can potentially lead to wet
clothing with rapid conduction of heat away from the body. Once
the clothes are wet enough, the aluminum component becomes
effective and conducts heat about 10,000 times better than air
(thermal conductivity 250 W/m K for aluminum vs 0.024 W/m
K for air).415
In infants and children, nonevaporative cutaneous heat loss
can be reduced by almost 30% by simply covering the body
with disposable surgical drapes.275 Therefore, the significance of
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hypothermia prevention by covering the body should not be
underestimated. In general, the percentage of skin surface area
covered is more important than the choice of insulating material
or the skin region covered.416 Even one layer of plastic over
otherwise exposed body areas helps to limit radiant, conductive,
and evaporative heat losses.417 Covering very low birthweight
infants with a thin plastic layer reduces the requirement for
radiant heat, oxygen consumption, and insensible water loss.418
By contrast, facial cooling has been shown to increase oxygen
requirements by 23% and 36% in term and premature newborns,
respectively.274 The particular importance of the head in regards to
thermoregulation in small infants has been discussed earlier in the
section on Thermal Regulation in the Newborn and is highlighted
by the fact that the head accounts for approximately 20% of the
total skin surface area in neonates and represents the area with the
highest regional heat flux.275
SKIN-WARMING DEVICES:
A wide selection of passive and active

skin-surface warmers is available including circulating hot water
blankets, infrared radiant heaters, convective forced-air heaters,
and water-warming garments (WWGs). The forced-air warmers
use a disposable under- and/or overbody blanket blowing warm
air toward or over the patients skin, thereby raising the effective
ambient temperature immediately surrounding the patient.402
Newer versions using the same principle offer customizable,
whole-body suits instead of blankets to maximize skin surface
coverage. A different approach has been adopted for WWGs,
which are based on the liquid-cooled space suits used by
astronauts.419 With this system, the body is covered by a special
garment designed to allow maximal body surface coverage without impinging on the surgical field. Underneath this garment,
warm water is circulated adjacent to the skin surface. The system
is computer-controlled using temperature probes for afferent
feedback algorithms to achieve a preset body temperature. This
seems to be the most efficient system and its safety has also been
demonstrated in children.420422 The main advantage of the WWG
over a forced-air warming device seems to derive from the fact
that the WWG allows a larger body surface area to be covered and
warmed (i.e., the part of the body the patient is lying on).422
However, it seems that so far the favorable cost-efficiency ratio
and the ease of use of forced-air warming devices has limited the
widespread use of WWGs. In most cases, both these devices allow
not only the maintenance of normothermia but also an effective
means of rewarming a hypothermic patient.402,423425 Although
the potential heat transfer rate is higher for circulating water
mattresses, they are less effective than forced-air warmers because
significant heat loss still occurs from the anterior body surface.402
They are an ideal supplement to a forced-air warming blanket, but
used alone for long and major procedures, they often fail to
maintain normothermia. The author most often uses forced-air
underbody blankets. To get the maximal benefit, one has to make
sure before skin incision that air is freely circulating in the blanket
and that no body parts are in close proximity to the warm air inlet
to avoid skin burns (particularly in infants and neonates).426428
In patients with low cardiac output, peripheral vascular artery
disease, or otherwise compromised vascular circulation (e.g.,
cross-clamping of the aorta for coarctation repair or vasoconstrictor therapy), the device must be used only with extreme
caution and the high temperature setting should not be used for
a prolonged period of time. Another problem can be pooling of
fluids from the surgical field between the patient and the blanket
245
resulting in significant heat loss. This can best be avoided by using

self-adhesive plastic foils to cover the surgical field and the
surrounding drapes. That way, fluids are directed away from the
patient and the patient stays dry.
WARMING OF FLUIDS: It is well established that the rapid infusion
of large amounts of cold fluids can be used to induce hypothermia.

The peripheral infusion of 2 L of normal saline solution at 4C
over 20 to 30 minutes in cardiac arrest survivors assigned to the
hypothermia treatment group resulted in a quick and reliable core
temperature drop of 1.4C.429 Central venous infusion of 40 mL/kg
of normal saline at 4C over 30 minutes to anesthetized and
paralyzed volunteers resulted in a temperature drop of 2.5C, and
the researchers concluded that central venous infusion is more
effective than peripheral injection.430 Similar results have been
reported from a cardiac arrest survivor study for whom the
administration of 30 mL/kg of lactated Ringers solution at 4C
was used to induce a rapid fall in temperature of 1.7C.431
Therefore, it is apparent that in order to maintain normothermia,
all intravenous fluids (including blood products) must be warmed,
at least when infused rapidly and in large amounts.
Various devices are available to prewarm infusions to the
desired degree including specialized warmers combining fluid
warming with a rapid infusion pump system that is able to manage
very high flow rates in excess of 1000 mL/min. However, to take
full advantage of the warming capabilities of these devices, heated
or short extension tubing should be used because otherwise
significant heat loss of the infusate during transit from the warming device to the intravenous cannula may occur.432,433 At an ambient temperature of 20C and warming of the intravenous fluid to
37C, flow rates of at least 750 mL/h were required to keep the infusate temperature above 32C more than 25 cm from the warmer.
At lower and more appropriate infusion rates for pediatric patients,
heat exchange with the environment is further aggravated.433
A study in patients aged 1 to 3 years demonstrated that conservative fluid management (keeping the patients slightly hypovolemic preoperatively and intraoperatively) for minor surgical
procedures could avoid core hypothermia (core temperature
37.1C vs 36.4C in patients who received more aggressive fluid
therapy. In both groups, the fluid infusion temperature was
37C.434 However, despite this slight temperature advantage, this
should not preclude pediatric patients from appropriate fluid
resuscitation because other and more effective measures to
maintain normothermia are usually easily available.
Both the chest and the abdomen make up a large, well-perfused
surface area and, therefore, allow for significant heat exchange
during intraoperative lavage of these cavities. To avoid profound
and precipitous hypothermia, all irrigation fluids should be
warmed to body temperature before use.
HUMIDIFYING AND HEATING AIRWAY GASES:
High-efficiency
particulate air filters (HEPA) commonly are made from glass
fibers suspended in a rigid frame and pleated to increase the
surface area and hence efficiency without significantly increasing
the resistance to air flow. Larger particles (>0.3 m) are filtered by
inertial impaction and interception, whereas smaller particles are
captured by brownian diffusion.435 Particles with a diameter of
0.3 m (the typical diameter of bacteria) are the most likely to
be deposited in the lungs if inhaled and are also the most difficult
size to eliminate by filtration because at this size the effects of
inertial impaction, interception, and brownian motion are least
effective.435
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Heat and moisture exchangers (HMEs) usually contain a

hydrophilic material (e.g., cellulose) and HME filters (HME with
an antimicrobial filter [HMEF]) also contain a single pleated sheet
of hydrophobic resin-bonded and electrostatically charged
ceramic filaments to eliminate microorganisms.436 In clinical
practice, the terms HME and HMEF are often used interchangeably. The HMEs/HMEFs are designed to retain moisture exhaled
by the patient, but they can contribute to airway humidification
only if they are placed in the circuit in a way that bidirectional gas
flow occurs (i.e., at the Y piece or distal to it). Otherwise, the
HMEs/HMEFs may even facilitate drying of the absorber and
thereby increase the risk of carbon monoxide poisoning.
In spontaneously breathing patients, the tracheobronchial tree
acts as a natural heat and moist exchanger, ensuring that the air
reaching the alveoli is fully saturated with water vapor and has
body temperature. The warming of the air and its humidification
in adults results in a heat loss reduction of approximately 5 to
10 W/h, which is rather small in perspective to the overall heat
loss under anesthesia of about 70 to 80 W/h.437 Endotracheal
intubation significantly reduces the surface area of the respiratory
tract available for heat and moisture exchange and renders
the system insufficient. Artificial heating and humidification
of inspiratory gases is therefore required to minimize these
convective (warming the air from ambient to body temperature)
and evaporative (humidification of the air) heat losses from the
respiratory tract and provide airway humidification at the same
time.438 Humidity of an air-water mixture can be described as
absolute humidity (the mass of vaporized water in 1 m3 of air,
usually expressed in grams per cubic meter [g/m3]) or relative
humidity (defined as the percentage of the partial pressure of
water vapor in the air-water mixture compared with the saturated
vapor pressure of water at a specific temperature). The exothermic
reaction of carbon dioxide with the absorber in anesthesia circuits
results in the condensation of water in the air exiting the absorber
canister. However, the addition of dry, fresh gases quickly
decreases the humidity of the inspired air, explaining the need for
other means of humidification, particularly when using a fresh gas
flow that exceeds the upper flow limit for prevention drying of the
CO2 absorber (i.e., ~0.51.0 L/min).439441 For HMEs/HMEFs to
maintain a humidity of greater than 20 mg/L, the fresh gas flow
has to be below 2 to 3 L/min.442,443
Humidification can be either active (i.e., a heated device filled
with water is used to create vaporized or nebulized water) or
passive (i.e., with a so-called HMEF, or artificial nose ). An
interesting hybrid device has been described based on an HME
with computer-controlled addition of water to the filter resulting
in 100% relative humidity444; however, the combination of active
humidification and HME may result in filter obstruction.445,446
Producing water vapor by directing air over (pass-over humidifier)
or through (bubble-through humidifier) heated water are the
physical principles behind vaporizers, whereas nebulizers produce
tiny droplets of water either by ultrasound (droplet diameter
110 mm) or by a high-velocity gas jet through water entrained
with the Bernoulli effect (droplet diameter 530 mm). The size
of the water droplets determines how deep they will penetrate into
the airway. Droplets between 1 and 3 mm in diameter are small
enough to reach the bronchioles and are considered an ideal
size.447 Active humidifiers require proper care and sterilization to
avoid infections. In general, the active humidifiers achieve better
humidification than HMEs,173,448 although the differences are not
always clinically significant.449 Several studies have confirmed the
advantages of these devices on the humidification and temperature of inspired gases,173,450454 but other studies have failed to
demonstrate significant benefits in terms of maintaining body
temperature, especially when high fresh gas flow rates were
used.455457 In order to avoid thermal injury to the tracheobronchial
mucosa, active humidifiers should heat inspiratory gases to
normal body temperature only. It has been known for decades that
dry inspiratory gases cause a significant reduction in mucociliary
clearance and, hence, tracheal mucus flow and, therefore, may
result in tracheobronchial injury.458461 Humidification not only
prevents these adverse effects461,462 but also reduces respiratory
heat losses.438,463 The in vivo performance of different HMEs/
HMEFs is variable and often does not correspond to the in vitro
specifications declared by the manufacturers.464,465
Fully saturated air at 37C contains 43 to 44 g of water vapor/m3
air.466 Evidence demonstrates that a relative humidity of at least
50% is required to maintain normal mucociliary function and
prevent bronchospasm and tracheobronchial injury.461,462,467 This
latter value is easily achieved with heat- and moisture-exchanging
filters. Although it would seem reasonable to strive to achieve the
same values as a spontaneously breathing person does (i.e.,
inspiratory gas temperature of 37C with 100% relative humidity),
recommendations for anesthesia fail to provide an evidence-based
minimal absolute humidity with values varying from 14 to
44 g/m3.468470 Other sources suggest a relative humidity above
50%, but more recent research advocates for values closer to 75 to
100% with a temperature above 34C for inspired gases to avoid
mucociliary dysfunction and/or tracheobronchial injury.471 This
level of humidification and temperature is currently not achieved
by HMEs/HMEFs, especially not with high fresh gas flows. Using
a low fresh gas flow of 0.6 L/min increased the absolute humidity
of inspired gases more than fourfold (22.8 2.4 g/m3 vs 5.6 3.4
g/m3) when compared with a high fresh gas flow of 6 L/min,
whereas the changes in body and inspired gas temperature were
not significantly different between the two groups.472 In adults, the
heating and humidification of inspiratory gases to 37C and 100%
relative humidity not only maintained normothermia but also
reversed hypothermia during general surgery.
The higher minute ventilation per kilogram body weight in the
pediatric population makes humidification and warming of
inspiratory gases not only more important but also more effective
than in adults.173,473 Heat loss in newborns during general anesthesia is reduced significantly when heated, humidified gases
are used instead of dry anesthetic gases.474 By design, all HMEs/
HMEFs increase apparatus deadspace (although neonatal humidifiers [HMEs] are now available with a deadspace of < 2 mL,
whereas for HMEFs with an antimicrobial filter are available
with a deadspace of 1215 mL). These may result in the underestimation of arterial CO2 partial pressure when relying on endtidal CO2 measurement, particularly in small children breathing
spontaneously. They may also require an increase in the ventilation parameters settings.475477 A typical HME/HMEF creates an
additional pressure gradient of approximately 1.0 to 2.0 cmH2O
at a fresh gas flow of 30 to 60 L/min leading to a slight increase in
airway resistance, which is less of an issue during mechanical
ventilation, but becomes more important with spontaneous ventilation such as may occur when weaning infants from mechanical
ventilation or during the emergence from anesthesia.478480 With a
Mapleson F system, this resistance increase may result in up to
50% of the fresh gas flow being forced into the expiratory limb
thereby prolonging inhalational induction.481,482
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Despite the overall better efficiency of active humidifiers,
HMEs/HMEFs have replaced them in the majority of hospitals
mainly because of their simplicity in handling, acceptable effectiveness, active bacterial filtration capabilities, and reduced
workload and costs.461,483,484 Additional advantages of HMEs/
HMFEs include eliminating the risks of airway burns and
overhumidification with overhydration.485,486 However, despite
their simplicity, HMEs/HMEFs are not without adverse effects and
risks. The addition of a HME/HMEF introduces more connection
sites in the breathing circuit and, therefore, poses the increased
risk for disconnection. The connection between the endotracheal
tube and the HME/HMEF seems to be a common site of disconnection, which has resulted in a number of incidents, some of
them fatal.487,488 As mentioned in the section on Humidifying and
Heating Airway Gases, if positioned in the expiratory limb of the
circuit, HMEs/HMEFs may facilitate drying of the CO2-absorber
resulting in increased carbon monoxide generation and delayed
inhalational induction, because it has been demonstrated that a
dry absorber increases not only the absorption of inhalational
anesthetics but also the amount of their degradation that may
result in an overall reduced concentration of volatile agent
delivered to the patient.489,490
A HME with an antimicrobial filter (i.e., a HMEF) has the
potential to block the passage of microorganisms and its efficiency
is described by the percentage of particles being able to penetrate
the filter and potentially reach the patients airway (some
manufacturers give separate numbers for viral and bacterial
particles). In other words, an efficiency of 99.9997% translates into
three particles out of a million being able to pass beyond the filter.
Although this represents an impressive barrier, it seems not to be
enough to protect the circuit from contamination, and most groups
advocate to changing the circuit and HMEF after each patient.491,492
Other investigators consider HMEFs to be efficient enough that the
circuit can be reused at least twice.493,494 Beside their antimicrobial
characteristics, HMEs/HMEFs also efficiently filter latex particles.495
Severe or complete obstruction of HMEs/HMEFs with difficulties or even the inability to ventilate can result from copious
secretions in patients with chronic obstructive pulmonary disease
or mucoviscidosis, pulmonary edema, the use of nebulized
medications (e.g., albuterol), simultaneous administration of
humidified air (e.g., by an active humidifier), or HME/HMEF
manufacturing problems (e.g., retained foreign body in
HME).445,446,488,496501 In at least two cases, a blocked HME/HMEF
caused bilateral pneumothoraces.502,503 It has, therefore, been
recommended that HMEs/HMEFs should not be used in
combination with active humidifiers and only with extreme
caution in patients with one of these conditions. In addition, it is
recommended that easy access and visibility of the HME/HMEF
be ensured throughout the procedure.435
PATIENT TRANSPORT: Although we have focused on the intraoperative care of patients, measures to prevent hypothermia are
equally important during patient transport. Patients should be
appropriately covered during any transport. For older children
and adults, a warm blanket may be sufficient; however, neonates
and particularly premature babies should, whenever possible,
be transported in a prewarmed incubator. If an incubator is
not available, chemical heating pads can be used to maintain
normothermia or even rewarm a small patient. Even a short inhospital transport may be all it takes to ruin all of the successful
intraoperative efforts to maintain normothermia.
247
SUMMARY
In order to maintain central body temperature within its narrow
normal range of 37.0 0.2C, a highly sophisticated and efficient
regulation system is in place. It utilizes peripheral vasoconstriction
and shivering and nonshivering thermogenesis to preserve and/
or generate body heat, whereas peripheral vasodilatation and
sweating are triggered to result in heat loss. Except for shivering
thermogenesis, all these mechanisms are already functional in
neonates. However, because of anatomic differences, small infants
and children are at a higher risk for temperature disturbances than
older patients both in and out of the operating room. Anesthesia
alters thermoregulation and results in significant widening of the
interthreshold range (the temperature range within which no
compensatory thermoregulatory actions are triggered). Without
preventive measures, heat loss during anesthesia exceeds metabolic heat generation, which may result in hypothermia and
the myriad of potential adverse effects associated with it. In
modern anesthesia practice, several options compensate for the
increased thermal losses in order to maintain perioperative
normothermia. This chapter has reviewed the physiology and
pathophysiology of thermoregulation, heat loss mechanisms, and
options to avoid or reduce them. Furthermore, the specific effects
of anesthetic agents on thermoregulation in relation to the patients
age as well as the adverse effects of temperature disturbances have
been presented.
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Development and Evaluation

of Pain and the Stress Response
R. Blaine Easley, Kenneth M. Brady, Andrew R. Wolf,
Kanwaljeet J. S. Anand, and Joseph D. Tobias
INTRODUCTION
Although withholding analgesia during surgical stimulus is cruel
for patients of any age, providing anesthesia and analgesia to
neonates undergoing surgery is a relatively new practice. Our
understanding of the neonatal experience of pain and the effects
of nociception has root in this practice revolution. Today, it is
accepted without question that neonates require the treatment of
pain and that the provision of general anesthesia is mandatory for
any surgical procedure. With these beliefs supported by the
literature, surgical practice without neonatal analgesia will be a
distant memory. However, the erroneous assumptions that created
the aversion to pain control in the neonate and the methods used
to refute those assumptions are instructive.
The neonates responses to pain includes decorticate reflexes,
and early descriptions of these responses led to the conclusion that
the lack of localization indicated a lack of conscious perception of
the stimuli.1 This counterintuitive concept was supported with
anatomic descriptions of the fetal brain showing a lack of
myelination2 and the apparent inability of the human infant to
retain memory.3 Pain was also strictly defined as an emotional
experience, and infants lacked the ability to communicate their
emotional experience. Therefore, demonstrating the need for
neonatal analgesia to a skeptical audience required a shift in focus
from pain to nociception and from memory to neuroplasticity.
Landmark studies that came from this effort demonstrated a
profound stress response with deleterious effects on outcome
caused by untreated nociception in the preterm infant4 as well as
evidence for long-term hyperalgesia as a neuroplastic consequence
of untreated neonatal pain.5 Data from these and similar studies
forced a change in the practice of neonatal medicine and created
the culture of pediatric and neonatal anesthesia that we now
presuppose. In this chapter, we review, from a developmental
perspective, the anatomy and physiology of nociception in
developing infants and children. Further, we describe the impact
of the physiologic stress response on both the biochemical and the
behavioral acute pain response. Finally, we review commonly used
pediatric pain assessment tools and how they are utilized to
recognize perioperative pain in the nonverbal infant and child.
NEUROANATOMY
Nociceptive systems develop during the second and third
trimesters of gestation, with further maturational changes
occurring during the first 2 years of life. Part of the reluctance to
aggressively treat pain during the neonatal period and infancy was
rooted in the belief that the pain system was not yet fully
15
C H A P T E R
developed.6 Given the nonverbal nature of neonates and infants,

they are incapable of reporting and describing the subjective
phenomenon of pain. Therefore, it was concluded that these age
groups were also incapable of nociception.
Nociception begins with the sensation of the stimulus at the
level of the peripheral nervous system.7 Unlike the specific
sensations of touch, pressure, heat, or cold, there are no specific
pain sensors. Rather, pain is sensed by free nerve endings. Rapidly
adapting pressure receptors are the first to appear during fetal life,
followed by the development of slowly adapting pressure receptors,
and then rapidly adapting mechanoceptors. The depolarization
responses of these receptors to mechanical injury, chemical
irritants, and inflammatory mediators are similar to those of adult
receptors.8 Cutaneous sensory receptors appear in the perioral area
at 7 weeks postconceptual age (PCA), spread to the hands and feet
by 11 weeks PCA, and are present at all cutaneous and mucous
surfaces by 20 weeks PCA. Fetal sensory receptors are located
on or close to the skin surface soon after development and, with
the development of the stratum corneum, gradually become
subepidermal. Reflexes to cutaneous sensory stimulation from the
perioral area of the human fetus occur as early as 7 weeks PCA;
from the rest of the face, the palms of the hands, and the soles of
the feet by 11 weeks PCA; from the trunk and proximal parts of
the arms and legs by 15 weeks PCA; and from all cutaneous and
mucosal surfaces by 20 weeks PCA.9,10 The development of these
sensory reflexes is preceded by synaptogenesis between afferent
fibers and sensory neurons in the dorsal horn of the spinal cord.
The sensation of pain is mediated via free nerve endings of A-delta
and C fibers. These fibers do not demonstrate fatigue; rather,
repeated or continuous stimulation increases the ease of transmission of the impulse. Histologic studies show that the density
of nociceptive nerve endings in the newborn skin is similar to that
of adult skin.11 More importantly, the neurophysiologic properties
of the earliest nociceptors are also similar to those of adults.
Myelinated fibers are the first to grow into the developing spinal
cord and form connections with deeper layers of the dorsal horn,
with collaterals to neurons in the substantia gelatinosa. With the
ingrowth of C fibers (unmyelinated fibers) and synaptogenesis
with superficial dorsal horn neurons, these collaterals undergo
developmental degeneration. Nociceptive stimuli in fetal life (and
in the extremely premature neonate) are transmitted by myelinated A fibers until the maturation of C fiber connections.12
The first-order neuron, whose cell body lies in the paravertebral ganglion, carries the nociceptive input into the dorsal horn
of the spinal cord. The first-order neuron synapses with a secondorder neuron in the dorsal horn of the spinal cord. The secondorder neuron then crosses the midline and ascends in various
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Figure 15-1. A: Pain perception pathway: The spinothalamic tract. first-order and second-order neurons, spinal interneuron, and
descending inhibitory neurons. Later in development, a noxious stimulus will result in (1) activation of the peripheral nerve that will
synapse to a second-order neuron, (2) the second-order neuron (spinothalamic tract) will transmit the response up the spinal cord
to the thalamus, (3) From the thalamus, thalamocortical connections to cortical and subcortical regions result in pain perception.
B: Development of neurotransmitters. At 8 to 10 weeks postconcetpual age, first-order neurons develop to the periphery and this
correlates with the presence of neurotransmitters substance P, calcium generelated protein (CGRP), and somatostatin. At 12 to
16 weeks postconceptual age, additional transmitters and receptors become available in both the peripheral nerves (glutamate,
vasoactive intestinal peptide, and neuropeptide Y) and the spinal interneurons (met-enkephalin) of the fetus. At 34 to 38 weeks
postconceptual age, descending inhibitory pathways become active and demonstrate increased dopamine and norepinepherine
neurotransmitter activity with serotonin becoming active following birth.
pathways, including the spinothalamic tract, synapsing in the
thalamus with a third-order neuron, which projects to the sensory
cortex.13 In the dorsal horn of the spinal cord, nociceptive input is
modified (amplified and inhibited) by descending fibers from the
central nervous system and interneurons within the dorsal horn.
This modulation is mediated via various chemical compounds
(substance P, adrenergic agents, serotonin, and endogenous
opioids), which bind to the first- or second-order neuron via
specific receptor systems (Figure 151A).
In the first trimester of pregnancy, development of the spinal
cord and central nervous system begins with the closure of the
neural canal. At this time, the dorsal horn begins to appear.
Electron microscopic and immunochemical studies demonstrate
that the development of the various neuronal cell types in the
dorsal horn with their laminar arrangement, interneuronal
connections, and the expression of their specific neurotransmitters
and receptors begins before 13 weeks of gestation and is completed
by 30 to 32 weeks PCA. Initially, the receptive fields of dorsal horn
neurons are very large, with an extensive overlap between the
receptive fields of adjacent neurons. As maturation occurs, the
receptive fields of individual dorsal horn cells progressively
decrease and can be more precisely defined.14 On a cellular level,
the transmission of nociceptive impulses through the dorsal horn
of the spinal cord is mediated and modulated via the release of
excitatory neurotransmitters (see Figure 151B), such as substance
P, glutamate, calcitonin generelated peptide, vasoactive intestinal
polypeptide (VIP), neuropeptide Y, and somatostatin. Modulation
of this nociceptive transmission occurs by the release of metenkephalin from local interneurons and norepinephrine, dopamine, and serotonin from descending inhibitory axons. These
descending inhibitory axons originate in supraspinal centers and
terminate at all levels of the spinal cord and brainstem. During the
first and second trimesters up until the latter half of the third
trimester, an imbalance exists between the mechanisms that
facilitate and inhibit nociceptive input, with the former being
favored. Of the nociceptive neurotransmitters, substance P,
calcitonin generelated peptide, and somatostatin are expressed
in the dorsal horn by 8 to 10 weeks PCA. Glutamate, VIP, and
neuropeptide Y appear at 12 to 16 weeks PCA. Modulation of
incoming noxious stimuli in extremely premature infants may
occur through the local release of met-enkephalin, which is first
expressed at 12 to 16 weeks PCA. However, this mechanism is
unlikely to be effective in diminishing the transmission of
intensive painful stimuli. In the latter half of the third trimester,
with the maturation of the descending inhibitory pathways from
supraspinal centers, inhibition of incoming sensory stimuli can
occur with the release of dopamine and norepinephrine in the
dorsal horn of the spinal cord. These neurotransmitters are first
expressed at 34 to 38 weeks of human gestation, followed by
serotonin, which develops during the postneonatal period.15,16
Conduction of nociceptive impulses to the supraspinal centers
occurs via the spinothalamic, spinoreticular, and spinomesencephalic tracts located primarily in the anterolateral and lateral white
matter tracts of the spinal cord. Lack of, or decreased, myelination
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CHAPTER 15
in these tracts was previously proposed as an index of immaturity

of the neonatal central nervous system and was used to support
the argument that neonates cannot feel pain or do not react to
it in the same manner as adults. This argument was widely
supported despite the common knowledge that incomplete
myelination does not imply lack of function but merely imposes a
slower conduction velocity in the central nerve tracts of neonates.
In addition, any slowing in the central conduction velocity would
be completely offset by the shorter interneuronal distances that
must be traveled by the impulse when comparing an infant with
the much larger (and longer) adult.17 The nociceptive tracts to the
brainstem and thalamus are completely myelinated by 30 weeks
of human gestation, and the thalamocortical pain fibers are fully
myelinated by 37 weeks. The timing of the thalamocortical
connection is of crucial importance for cortical perception,
because most sensory pathways to the neocortex have synapses in
the thalamus. In the primate fetus, thalamic neurons produce
axons that arrive in the cerebrum before midgestation. These
fibers remain just below the neocortex until migration and
dendritic arborization of cortical neurons are complete and finally
establish synaptic connections at 20 to 24 weeks PCA.17
The functional maturity of the cerebral cortex is suggested
by the presence of fetal and neonatal electroencephalographic
(EEG) patterns and by the behavioral development of neonates.
Intermittent EEG bursts in both cerebral hemispheres, first seen at
20 weeks PCA, become sustained at 22 weeks and are bilaterally
synchronous at 26 to 27 weeks PCA. By 30 weeks, the distinction
between wakefulness and sleep can be made on the basis of EEG
patterns.18,19 Cortical components of somatosensory-, auditory-,
and visual-evoked potentials have been recorded in preterm babies
before 26 weeks PCA.20 Several forms of behavior imply cortical
function during fetal life. Well-defined periods of quiet sleep,
active sleep, and wakefulness occur even in utero, beginning at
28 weeks PCA. In addition to specific behavioral responses to
pain, neonates have various cognitive, coordinative, and associative capabilities in response to visual and auditory stimuli, attesting
to the presence of cortical function and intact processing of
nociceptive input. Several lines of evidence suggest that the
complete nervous system is active during prenatal development
and that detrimental or developmental changes in any part can
affect the entire system.13
NEUROPHYSIOLOGY
OF NOCICEPTION
Development of the Response
to Pain Stimulation
The human fetus is capable of spontaneous movements and
complex responses early in gestation. Reflex movement in
response to direct stimulation begins at 7.5 weeks PCA, initially
localized to the head and neck region.21 Sensitivity develops in
a craniocaudal direction, with the lower limbs responding by
14 weeks PCA. Data from the immature rat and other animals
show that responses to stimulation are initially inconsistent,
nonspecific, and poorly localized.22 However, if a response is
achieved, it can be extremely exaggerated and long-lasting.23 These
observations tie in well with neurophysiologic data in animals and
clinical work with preterm human infants. Single-cell studies from
the dorsal root ganglion of the rat show that cutaneous receptive
fields are present in the hindlimb as soon as innervation to the
skin has occurred.24 The firing rates and durations are lower than
Development and Evaluation of Pain and the Stress Response 261

those in the adult, but even at this stage, different classes of afferent
responses to noxious stimuli can be demonstrated. Initially,
stimulation of cutaneous afferents fail to produce suprathreshold
excitation in dorsal horn cells, but by birth, depolarization can be
produced from light touch alone.22 However, whereas the synaptic
linkage remains weak at birth, suprathreshold stimulation provokes a long-lasting hyperexcitable state in the dorsal horn cells.24
Polymodal nociceptors, which pass to the dorsal horn via
C fibers, show fully mature responses to pinch, heat, and chemical
stimulation by birth.25 However, despite their observed anatomic
connections, these C fiber afferents fail to evoke activity in the
dorsal horn cells until a week after birth. Thus, whereas the C fiber
connections remain immature at birth and fail to directly transmit
their nociceptive input, they may greatly increase the response to
other noxious (A fibers) and non-noxious inputs. This, together
with the large receptive fields observed in dorsal root ganglion
cells, may increase the likelihood of a central response from the
relatively immature nervous system. The lack of functional descending inhibitory pathways from higher centers also contributes
to the potentially excitable and poorly damped responses to
afferent inputs.
Central Integration of Afferent Inputs

In the human, complex central integration of afferent sensory and
nociceptive input is present at 30 weeks of gestation. Visual- and
auditory-evoked potentials are present,18 and a complex EEG
pattern reactive to external influences is seen at this time.19 Klimach
and Cooke have demonstrated the presence of somatosensoryevoked responses (SERs) in the preterm neonate.20 In fact, SERs
have been measured in infants as young as 28 weeks of gestation.
These investigators also demonstrated that the velocity of both
peripheral nerve conduction and central conduction increased
with gestational age. However, they observed considerable variability in peripheral velocity and central processing in younger
infants, suggesting that large individual differences exist in
maturation rates. SERs continue to mature during infancy.26
Subarachnoid injections of lidocaine in the expremature infant
cause rapid loss of the SERs that correspond to the onset of motor
and sensory blockade. The offset of the block can be monitored
with the return of SERs and shortening of the latency back to the
baseline.27 Positron-emission tomography scans in the infant have
shown that glucose utilization is maximal in the sensory areas of
the cerebral cortex, implying a high level of activity.28
Recent evidence also suggests that cortical activation occurs
after painful stimuli in preterm neonates.29 Bartocci and coworkers, using near-infrared spectroscopy in preterm infants at 28 to
36 weeks PCA, demonstrated increased blood flow in the somatosensory cortex but not in the occipital cortex after venipuncture.30 In a similar study, Slater and colleagues recorded cortical
activation after heel sticks in 18 infants between 25 and 45 weeks
PCA.31 No cortical response was noted after tactile stimulation,
even when this stimulation was accompanied by reflex limb
withdrawal. Taken together, these studies provide additional
evidence that the conscious sensory perception of painful stimuli
is present even in preterm newborns.
Interneuronal Connections
Given the data presented in the section on Development of the
Response to Pain Stimulation, it is now well established that even
premature human newborns have the functional components of a
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pain system and are capable of pain perception. In fact, the

development of a pain system suggests that the pain threshold may
be decreased in preterm neonates compared with term neonates or
older infants. The cutaneous flexor reflex has a lower threshold in
preterm neonates than in term neonates or adults.32 Thresholds
for the flexor withdrawal reflex are decreased (sensitized) after
repeated stimulation or local tissue injury in preterm neonates.
This prolonged hypersensitivity is abolished if topical analgesia is
applied before the injury.33 Sensitization of this reflex may result
from immature segmental or descending inhibition in the spinal
cord, the immaturity of other spinal or supraspinal mechanisms,
or factors associated with the intensive care environment and
critical illness (e.g., noise).
Human studies are necessarily less invasive than animal work,
but developments in minimally invasive monitoring and studies
that compare nociceptive reflexes with animal models provide
additional valuable information. The cutaneous withdrawal reflex,
previously termed the nociceptive flexor reflex, occurs when the
limb withdraws in response to a stimulus of sufficient intensity. In
adult humans, it is elicited by a specific nociceptive stimulus to
the limb, with a threshold similar to the pain threshold, whereas
in neonates, it can be elicited simply by touching the limb34; hence,
the change in terminology. The reflex is observed even in the most
premature infants, but the responses change considerably with
maturation.34 Fitzgerald used von Frey hairs to give a graded
intensity of stimulus and obtained a control threshold for
withdrawal of the foot.33 The cutaneous withdrawal reflex was
compared between infants whose feet had received regular heel
lancing with or without application of a topical anesthetic cream.
Heel lancing caused hypersensitivity or wind-up of the reflex but
only in the heel-lanced foot. The application of a topical anesthetic
cream could prevent development of the hypersensitivity.
Contralateral stimulation of the other foot at the time of testing
suppressed the withdrawal response, a centrally mediated phenomena seen in adult humans and the rat pup. A more detailed study
followed that confirmed that the youngest infants had the lowest
threshold for the response and that the threshold for the reflex
increased with postconceptual age.35 The receptive field for the
reflex was also much larger in preterm infants and could be elicited
not only from the foot but also from the leg (Figure 152).
The impression that emerges is that even the very preterm
infant has complex interneuronal connections capable of integrated responses to tactile or nociceptive input. These infants also
show inconsistent responses to external stimuli, which may reflect
the late functional connections of sensory afferents (particularly C
fibers) within the spinal cord. However, the combination of larger
receptive fields, recruitment of non-nociceptive afferents, and
reduced inhibitory controls results in underdampened responses
(long-lasting, exaggerated, and poorly localized) once afferent
stimuli have achieved central activation above a threshold level.
Inconsistency of response to more complex noxious stimuli may
also reflect the profound effects that conscious state36 and other
external responses37 have on behavior.
CYTOCHEMISTRY
Receptors Involved in Pain Perception
Studies of developmental cytochemistry in animal models have
focused on substance P, opioid peptides and receptors, N-methylD-aspartic acid (NMDA) receptors, and the expression of the C-fos
gene. Although transmitters can be demonstrated to be present
Figure 15-2. The effect of increasing postconceptional age

(PCA) and site of stimulus on cutaneous withdrawal threshold
in the neonate. Below 30 weeks PCA, the thresholds within the
receptive field are uniform at all sites tested (sole, ankle, leg).
After 30 weeks, a gradient of thresholds is observed, increasing
progressively from the sole of the foot toward the knee. A and
B: Adapted from reference 34.
early in gestation, their concentrations are usually very low, and
they may not always be found at sites that suggest a functional
role.38 By contrast, receptors are often seen in higher densities and
have a more widespread distribution than in adult life, which may
facilitate responses at a time when only low levels of transmitter
are available.7 The transient appearance of receptor populations
that have ceased to be expressed by birth39 remains puzzling and
demonstrates the large gap that exists between what we know of in
vitro cytochemical findings and our observations and understanding of in vivo nociception. Opioid receptors change both in
numbers and in receptor type during development. Pasternak and
associates demonstrated that, in newborn rats, high-affinity
binding sites for a triated encephalin ligand increased by up to
threefold in the first 2 weeks of life, whereas during this period, a
large rise in analgesic response to morphine occurred.40 The level
of high-affinity binding correlated with the median effective dose
(ED50) values for morphine analgesia. By contrast, the effects of
morphine on ventilatory drive during this period (214 d after
birth) were constant. Other studies have confirmed the increase in
the number of opioid receptors and changes in their binding
affinities during development.41 Opioid receptor expression is
dynamic even during intrauterine development.42
Gene and Protein Expression

During normal brain development, whether animal or human,
significant expansion and growth of specific neurons and synapses
occur, known as synaptogenesis. Most important, this crucial
period of neuronal expansion is guided by targeted deletion of
other cells (apoptosis). These processes are under the control of
genetic, environmental, cellular, hormonal, and other factors (such
as stressful stimuli and anesthetic agents). Depending upon the
age and brain region, as many as half of the synaptic connections
made in the first year of life will be gone a few years later. The
nociceptive response to stress and pain becomes important to the
dynamic molecular and cellular processes that simultaneously
signal the death, or pruning, of certain neurons and the
reinforcement and growth of others.43
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The ability to evaluate and analyze gene and protein expression

on cellular and tissue levels has led to a more systems-based
approach to the adaptation to nociceptive triggers, resulting in
new insights into the physiologic responses to painful stimulus.
The implication of such varied responses in rodent models allows
us to assess the earliest alterations in gene expression within
peripheral nerves, the spinal cord, and brain in both acute and
chronic pain response models.44
Analysis of the brain, spine, and peripheral nerves using
genomic microarray techniques in mature and fetal animal models
of nociception has informed our understanding of the dynamic,
diverse, and variable molecular responses of neural pathways to
pain. Because these integrative techniques are rapidly evolving,
high-throughput techniques combined with bioinformatics have
enabled the first system-wide gene-expression analysis, termed
genomics. These approaches have been applied to protein analysis,
termed proteomics, and have resulted in the identification of
previously unrecognized alterations in actual transcribed and
activated proteins from within a specific cell line and/or specific
tissues.15,45
Neurotransmitters mentioned in the section on Neuroanatomy
provide excellent examples of the utility of these techniques. First,
studies have localized the expression of early inducible genes
(EIGs) with the Fos protein in the specific areas of the dorsal horn
associated with primary afferent termination.46 In this rodent
model, precursor C-fos gene and protein expression can be
demonstrated after formalin or capsaicin injection, but it does not
occur after application of mustard oil, which is a specific stimulus
for C fiber afferents.47 This observation correlates well with the
neurophysiologic data on the later development of central C fiber
connections.25 These integrative techniques have also resulted in
the identification of genetic variations in the opioid receptor.
Following the studies of Pasternak and associates,40 these techniques have identified within animal and human populations
gene-splice variants and single-nucleotide polymorphisms that
can better explain the clinical variability in analgesia seen between
drugs that bind to altered opioid receptors differently.48 Future
directions in molecular pain research will develop molecular
signatures of neuronal and receptor responses that correlate with
our phenotypic definitions of acute and chronic nociception and
will lead to more personalized pain treatments based on these
molecular characterizations (pharmacogenomics).49
Substance P and Opioid Peptides

In the human fetus, substance P appears in the dorsal horn at 8 to
10 weeks PCA50 followed by enkephalin at 12 to 14 weeks.51
Endorphinergic cells appear early in fetal life in the anterior lobes
of the pituitary gland and, by 20 weeks PCA, are responding to
stimulation by corticotrophin-releasing factor.52 Human data
confirm the changing profile of opioid receptors with development. A study that compared opioid binding sites in the human
cerebellum reported more opioid-specific binding sites in the
developing cerebellum than in the mature cerebellum, and the
ontogenic profile of opioid receptor subtypes differed in that
increased and receptors were found in infant tissue at birth
compared with the adult, whereas mu receptorbinding affinity
and capacity fell dramatically in neonatal life.53 Again, this
provides a potential explanation for the variable responses to
different opioid drugs and the development of extreme tolerance
observed in some critically ill infants and children.54,55
NOCICEPTION AND PAIN

PERCEPTION IN THE INFANT,
CHILD, AND ADOLESCENT
General Considerations
Based on the previous review of the anatomy, physiology, and
molecular mechanisms of nociception, it is clear that nociception
and, perhaps, pain perception are present during gestation. In
addition, the systems are dynamic, changing during both the
intrauterine and the extrauterine periods. Having discussed the
sensory (afferent) mechanisms, we now examine the effects
(efferent responses) that painful stimuli have on the developing
infant and child. The International Association for the Study of
Pain (IASP) has defined pain as an unpleasant sensory and
emotional experience associated with actual or potential tissue
damage, or described in terms of such damage. Pain is always
subjective; each individual learns the application of the word
through experiences related to injury in early life.56 The sensory
experience of pain serves to alert the individual to potential or
actual bodily damage and puts in place protective responses
that may vary from withdrawing the threatened limb (noxious
external stimulus) to immobilizing the limb to prevent further
pain (bone fracture). The emotional experience of pain leads to
an expression of pain as a behavioral language that has some
instinctive properties (e.g., crying) and other learned responses
that are modulated by experience, social development, and other
factors. Clearly, the neonatal nociceptive responses are initially
purely instinctive and serve to protect the infant, but does this
imply that the noxious stimulus does not induce emotional
distress? Although the IASP definition implies that pain is learned
through experience, others have maintained that pain is an
inherent quality of life itself and that the neonate does not require
previous experience to sense emotional distress.57
As the infant develops, behavioral responses to painful stimuli
change because of maturation of nociceptive pathways and their
integration at higher centers as well as the development of
cognitive and emotional skills. Older infants develop anticipatory
responses to pain by 6 months of age, and distraction can be used
in this age group to reduce the duration and magnitude of
responses to painful stimuli.58 The neonate responds to a heelstick
with a facial response of pure pain, but it has been suggested that
by 18 months of age the facial expression has changed to pain
mixed with anger. Groaning, flinching, muscle rigidity, and
resistance to handling develop later as a learned response in the
older infant and child.59,60 Fewer data are available on age-related
changes in nociception in the older child and adolescent. Pain
thresholds appear to increase with age, and adolescents rate lower
levels of pain on both behavioral and self-reporting scales for
similar noxious stimuli than do younger children.61 It is unclear
as to whether these changes represent improved self-control and
learned coping strategies or that pain perception itself changes
with age. Even within similar age groups, differences in behavioral
responses to pain occur, representing both intrinsic personality
differences in pain response and other learned cultural responses.
Infants who are judged to have a better general mood in everyday
life have shorter pain responses to blood-sampling procedures
than infants with more unhappy dispositions.62 Boys respond
more quickly to painful stimuli than do girls, and responses to
noxious stimuli are dependent on pre-existing medical conditions
and the state of arousal at the time of the stimulus.4,63
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Effects of Nociception
The initial effects of nociception can be categorized under
physiologic responses, behavioral responses, and stress responses,
and these have been used either individually or together to form
the basis of measurement of the severity of the noxious stimulus.
These responses can be elicited by noxious stimuli from the
preterm neonate onward, but age-related differences do exist.
Physiologic Responses
Hemodynamic responses to fetal surgery occur at as early as 18
weeks PCA (Table 151).64 Middle cerebral artery pulsatility index
(MCA PI) was measured in fetuses undergoing therapeutic
procedures that involved puncture of the fetal trunk, and results
were compared with a matched group that had umbilical cord
puncture. MCA PI fell significantly in the fetuses undergoing
invasive procedures, indicating a significant fall in cerebrovascular
resistance during the noxious input. Heart rate and blood pressure
have both been extensively studied as potential indicators of infant
pain. A rise in heart rate occurs from activity, sepsis, pyrexia,
drugs, and both noxious and non-noxious stimulation, making it
a relatively poor measure of nociception. The average increase of
heart rate during heelstick in a group of neonates has been
reported to be 49 27.5 beats/min, indicating the large interindividual variation in response.65 Surprisingly, circumcision,
which represents a much greater noxious stimulus, does not
produce a larger rise in heart rate,66 although others have reported
that heart rate changes in the neonate are related to the magnitude
and duration of the stimulus.67 These same studies have observed
that the postcircumcision heart rate returns to baseline within 10
minutes of the procedure despite the painful nature of the wound.
Systemic blood pressure may be a better measurement of
nociception than heart rate. It varies according to state of arousal,
drugs, and other external factors but is much less sensitive than
heart rate to these effects. Blood pressure and intracranial pressure
responses to heelstick, surgery, and endotracheal intubation can be
extreme. Neonates undergoing awake nasotracheal intubation
were reported to have a rise in mean arterial pressure of 57% and
a similar rise in intracranial pressure during the procedure.68 It is
now unusual to observe such large rises in blood pressure during
invasive procedures because of the more appropriate use of
anesthesia and analgesia. Age-related differences in cardiovascular
responses to noxious stimuli have been reported.69 In a study on
lumbar puncture in preterm infants, infants younger than 32
weeks PCA showed the greatest rise in blood pressure during the
TABLE 15-1. Main Physiologic Responses to Pain
Function
Effect of Pain Stimulation
Middle cerebral artery

pulsatility index
Intracranial pressure
Systemic blood pressure
Heart rate
Transcutaneous oxygen
tension
Vagal tone (amplitude of
sinus arrhythmia)
Palmar sweating
Cerebral oximetry
Decrease
Increase
Increase
Increase (inconstant in neonates)
Decrease
Decrease
Increase
Decrease
handling phase rather than during the actual procedure. This was
in contrast to the older infants, who displayed maximum response
during the procedure itself. Measurement of ventilatory frequency
and RR interval on the electrocardiogram has shown that vagal
tone is significantly reduced during painful procedures in the
neonate and that the reduction is related to the intensity of the
surgical stimulus.70
Other physiologic responses that have been investigated in the
context of nociception are transcutaneous oxygen tension,
ventilatory patterns, and sweating. Large variations in oxygen
saturation have been described as a response to surgical stimulation,71 but the changes are inconsistent. Neonates undergoing
circumcision or heelstick can respond with a fall in transcutaneous
oxygen tension.72 However, some neonates have no changes73 or
even an increase in response to a noxious stimulus.74 Noxious
stimulation usually produces a rise in ventilatory rate; however,
breath-holding and apnea can occur and result in a fall in oxygen
saturation. Ventilated preterm neonates frequently fight the
ventilator when subjected to surgical procedures with inadequate
analgesia, producing significant changes in oxygen saturation and
raised intrathoracic pressure that can precipitate pneumothorax.
Water loss from the palm increases 200% to 300% after a
heelstick.75 The effect is dramatic, taking only a minute to develop
and returning to the baseline within 5 minutes. The response is
graded according to the intensity of painful stimulus but is also
affected by crying and level of arousal.76
Fluctuations in arterial oxygen content and blood pressure may
have particularly important consequences for clinical and subclinical neurologic compromise in the preterm infant. Alterations
in cerebral blood flow related to nursery care and procedures have
been demonstrated,77,78 Noninvasive measurements of cerebral
oxygenation using near-infrared spectroscopy have demonstrated
decrements of 20 to 50% in cerebral oxygenation, lasting up to 60
seconds during routine nursery care.79 Further, Slater and colleagues demonstrated a relative increase in ipsilateral cortical blood
volume compared with the contralateral side during a painful
stimulus in the infant.31 Volpe reported that normal arterial blood
pressure can shift close to the upper autoregulatory limit, rendering the infant at risk of hemorrhage during nociceptive stimulation.80 Decrements in cerebral blood flow may preferentially affect
cerebral white matter. Immature autoregulation of cerebral blood
flow in the preterm infant may render these infants vulnerable to
various neurologic events (such as intraventricular hemorrhage) as
well as a wide range of subclinical brain alterations that may be
associated with less severe, but pervasive, learning and behavior
problems associated with the long-term neurologic impairments
associated with prematurity.81
Behavioral Responses
From laboratory evidence, we know that the central nociceptive
connections remain immature in the preterm neonate (Table 15
2). However, the larger receptive fields, the immaturity of the
descending inhibitory pathways, and the ability of non-C fibers to
transmit nociceptive inputs into the dorsal horn facilitated by
subthreshold C fiber effects result in an underdamped, poorly
discriminative system with a potential for very exaggerated
responses. This model is borne out in Andrews and Fitzgeralds
observations on the cutaneous withdrawal reflex34 and other
studies that have shown that newborn reactions to painful stimuli
can be diffuse, unlocalized, or sometimes completely absent.82 This
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CHAPTER 15
TABLE 15-2. Nonverbal Behaviors Associated With Pain

Facial expression
Vocalizations
Body movements
Social interaction
Clenched teeth
Wrinkled forehead
Biting lips
Scowling
Closing eyes tightly
Widely opened eyes or mouth
Crying
Moaning
Gasping
Groaning
Grunting
Restlessness
Protective body movement
Muscle tension
Immobility
Pacing
Rhythmic movements
Silence
Withdrawn
Reduced attention span
Avoidance of painful
situations
Focus on pain relief
measures
failure to respond consistently to a standard noxious stimulus

such as circumcision can confound any attempt to quantify pain
using behavioral measurement. By contrast, careful studies on
behavioral responses to heelstick have shown that specific
expressions such as eye squeezing, brow contraction, nasolabial
furrowing, taut tongue, and mouth opening are specific for this
type of painful stimuli.36 Other studies of heelstick have shown
that, in addition to facial movements, other body movements can
be specific and graded according to the stimulus.83,.84
Spectrographic analysis of the sounds made by a crying infant
in response to a noxious stimulus suggests that they are distinct
from those resulting from other causes such as hunger or fear.85
Moreover, the latency and duration of the first cry can be correlated with the intensity of the stimulus.86 However, cry
characteristics do not appear to be entirely specific for pain. They
appear to indicate a more general level of distress that is modified
by the interaction between the infant and the observer. Therefore,
with the exception of immediate responses to point pain
(heelstick), the quality of an infants cry is not a reliable measure
for pain intensity. However, the presence of a cry and the ability to
modify this behavior by comfort or distraction have been used
effectively as part of a multidimensional approach in the evaluation of postoperative pain.87,88
Painful stimuli have profound effects on infant sleeping
patterns. Normally, the newborn spends approximately 50% of its
sleeping time in rapid eye movement (REM) sleep.89 Painful
stimuli result in disruption of the normal sleep pattern with the
selective loss of REM sleep for up to a day after surgery.90 Less is
known about long-term effects of disturbance of the sleep-wake
cycle caused by repeated painful stimuli, but data on behavioral
outcome in preterm neonates are worrisome, given that
preservation of REM sleep is essential for the ability to cope with
stress and the maintenance of psychological well-being.91 Not only
do painful stimuli alter sleep patterns, but sleep patterns also alter
responses to painful stimuli. Studies on behavioral responses to
heel lancing show that the facial response and cry varied with the
alertness of the infant at the time of the stimulus.36
Stress Response
Trauma to the body induces local changes (the inflammatory
response) and systemic hormonal and metabolic changes (the
stress response). Stress responses can be elicited by noxious
stimuli, even during fetal development. Giannakoulopoulos and

coworkers have studied changes in cortisol and beta-endorphin
concentrations in response to intrauterine needling.92 Fetal blood
samples taken from the intra-abdominal portion of the umbilical
vein via the fetal abdominal wall were associated with a timedependent increase in cortisol and beta-endorphin concentrations, whereas samples obtained from the placental cord were
not associated with similar increases in these hormones. The
neonatal stress responses to surgical trauma are present from birth
and appear to be greater in magnitude93 and to cause significantly
greater postoperative catabolic changes when compared with older
children.94
Given the fragility of neonatal homeostasis and the reduced
metabolic and cardiovascular reserves in this age group, an
excessive stress response is potentially more harmful. Although it
is unclear whether more complete suppression of the stress
response results in improved postoperative recovery for most
children and adults undergoing elective surgery,95 the sick patient
at the limits of survival may be an exception. Adult and pediatric
clinical studies both suggest that critically ill patients may benefit
from techniques that reduce the stress response. Anand and
colleagues have further demonstrated this observation in a series
of studies evaluating anesthetic management and the stress
response of the neonate93,96perhaps best illustrated in their study
of very preterm infants undergoing patent ductus arteriosus
(PDA) ligation, in which neonates with inadequate analgesia had
large rises in catecholamines, glucagon, glucocorticoid hormones,
glucose, and gluconeogenic substrates.4 The metabolic stress
response was mitigated in neonates receiving 10 g/kg of fentanyl
before surgery. Further clinical studies from the same investigators
have suggested that control of the stress response in infants
undergoing cardiac surgery decreases circulatory, ventilatory, and
metabolic complications. The stress responses and outcomes were
evaluated in neonates undergoing cardiac surgery under deep
anesthesia with high doses of sufentanil and were compared with
those receiving a halothane-based anesthetic. The authors
reported no deaths out of 30 patients in the sufentanil group
compared with 4 out of 15 in the control group. A reduced
incidence of sepsis, metabolic acidosis, and disseminated
intravascular coagulation was also seen in the high-dose opioid
group.97 The findings of these studies suggest an important
correlation between reduction in the stress response and reduced
postoperative morbidity and mortality.
These studies provide evidence that the release of catabolic
stress hormones leads to a breakdown of fats, proteins and
carbohydrate stores at any age. The latter may be particularly
detrimental in neonates, who have limited stores. Further, stress
hormone interference with immune function may delay wound
healing and increases the risk of sepsis. Studies regarding the
long-term effects of these neurohumoral responses suggest that
the developing infant is vulnerable and that these changes may
result in increased neurologic morbidity.98 High concentrations
of glucocorticoids in animals are associated with hippocampal
damage and exacerbation of hypoxic-ischemic neuronal
damage.99,100 Similar effects of hippocampal volume loss have been
observed in adult humans with Cushings syndrome,101 and a
higher incidence of cerebral atrophy and dementia has been noted
in victims subjected to torture.102
By contrast, complete elimination of the stress response may
also be undesirable. Suppression of the pituitary adrenocortical
system in critically ill patients has been reported to have
lethal consequences,103 and high-dose opioids can adversely affect
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cardiovascular and ventilatory function to the point that hemodynamic (inotropic and chronotrophic) and ventilatory support
may be required. Opioids have also been shown to have a
dose-dependent and time-dependent effect on cell-mediated
immunity,104 which is disturbing in the context of a critically ill
patient in an intensive care unit. Therefore, a technique that
reduces the stress response should not be necessarily regarded as
better based solely on a measurable biochemical difference105 but
should be considered within an individualized context. Infant data
suggest that doses of opioids much lower than previously recommended can be used to adequately suppress responses to major
surgery.106 Fentanyl doses of 25 g/kg appear quite adequate
without causing significant cardiovascular depression. Regional
anesthetic techniques with either epidural or spinal analgesia can
been used to provide analgesia and stress reduction without
ventilatory depression.16,107
Markers commonly used to measure the stress response
include catecholamines, cortisol, adrenocorticotropic hormone
(ACTH), beta-endorphin, and serum glucose concentration.
Catecholamines have very short half-lives and reflect an instantaneous picture, with wide variations in plasma levels from minute
to minute. Measurement cannot be taken at the bedside. By
contrast, whole blood glucose can be measured immediately and
accurately. Blood glucose concentrations are tightly controlled in
patients who are not receiving intravenous glucose and who are
not stressed. A rise in blood glucose may be used to give an
accurate picture of stress responses in both the pituitary-adrenal
and the pituitary-cortical axes and can be measured in real time,
even in infants.108
The harmful effects of the stress response are evident, and
various agents are effective at achieving adequate anesthesia and
analgesia. However, increasing evidence in developing animal
models suggests that many routine anesthetic agents may be
harmful to the developing brain (see Chapter 3). The possibility,
as suggested by animal models, of anesthesia-induced neuronal
cell loss during an otherwise uneventful procedure has sparked
vigorous discussions among anesthesiologists about the safety of
various anesthetic practices in human newborns and infants.
Interestingly, the most commonly used anesthetics that have been
investigated for their neurodegenerative properties (e.g., benzodiazepines, ketamine, propofol, nitrous oxide, and isoflurane)
have indeed been shown to exacerbate neuronal cell death or
apoptosis.109,110 Whether this is acceleration of the normal apoptotic process or pathologic cell death remains unclear.111
Regardless, the anesthesiologist caring for a newborn is faced with
the conundrum that no analgesia is harmful and yet the very
anesthetics administered to the developing brain may also cause
long-term harm. Contrary to the growing literature that anesthetics cause harm to the developing rodent brain, a recent study
in an infant rat model found that neurodegenerative effects and
behavioral impairment after repetitive painful stimulation were
ameliorated by a low-dose of ketamine (5 mg/kg).112 Notably, this
study differed from the others in both the modest dose of
anesthetic given (ketamine at 5 mg/kg vs 20 mg/kg), and the
presence of a painful stimuli. This finding offers an alternative
argument that nociceptive stimulation during surgical anesthesia
may protect the brain from anesthesia-induced neurodegeneration, whereas anesthetics administered during noxious surgical
stimulation protect the brain from the deleterious effects of
unopposed painful insults.113 At this time, no evidence exists that
either opioids or 2 agonists contribute to apoptotic processes
within the developing brain.
SECONDARY EFFECTS
OF NOCICEPTION
Although newborn infants often have short-lived behavioral and
stress responses to noxious stimuli, evidence suggests that surgical
trauma or injury at this age can have long-term consequences for
sensory and pain behavior in infancy. Studies of neonates exposed
to repeated noxious stimuli have demonstrated the development
of hypersensitivity to further stimulation.33 Circumcision without adequate analgesia can cause behavioral changes such as
irritability, reduced attentiveness, and poor orientation that may
continue for several days, long after the expected duration of
pain.114 More recently, it has been shown that awake circumcision
can have behavioral effects that can last for months after the
procedure.5 During a study on infant pain responses to routine
inoculations, Taddio and associates observed that male patients
had a greater response than females and that males circumcised at
birth appeared to have a greater response to the vaccination
injection at 4 to 6 months of age than uncircumcised patients.115
This interesting observation was followed up by a prospective trial
of 87 males who had either no circumcision, neonatal circumcision with topical EMLA (eutectic mixture of local anesthetics)
cream, or circumcision without any analgesia.5 Patients were
videotaped during their vaccination procedure at 4 months and
analyzed for pain response and duration of cry. The results
confirmed that patients undergoing neonatal circumcision
without analgesia had altered behavioral response to pain even
6 months later and that the application of topical EMLA cream
at circumcision could partially prevent this hypersensitivity
(Figure 153).
Early pain experience may also alter a childs perception of
a noxious stimulus,116 and long-term postoperative behavioral
differences during normal activity have been suggested from twin
studies.117 Alleviation of pain and distress are, therefore, especially
important in this age group. Comforting strategies that reduce
the stress of interventional procedures in preterm infants are
associated with improved developmental and clinical outcomes.118
By contrast, opioids need to be used with caution in the management of pain in neonates. Administering opioids to animals during
the perinatal period increases their pain sensitivity into adult
life.119 Human data have suggested that previous opioid exposure
may increase subsequent pain sensitivity120 and may be associated
with increased self-destructive behavior in adolescence.121
Certainly expremature infants that have been previously subjected to opioid infusions can be difficult to manage in the
pediatric intensive care unit even years later owing to an apparent
sensitivity to noxious stimuli that does not appear to be well
controlled with usual doses of opioids.
EVALUATION OF PAIN
Factors Affecting the Evaluation of Pain
The evaluation of pain in children cannot be reduced to a
standardized reproducible variable because of the highly
individual and diverse nature of the experience. The older child
has the ability to communicate directly with an assessor through
speech, but the infant (from the Latin infans meaning incapable of
speech) does not. Moreover, pain evaluation is a broader term than
pain measurement, because it encompasses cognitive, physiologic,
sensory, behavioral, affective, sociocultural, and environmental
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CHAPTER 15
Figure 15-3. Infant pain responses to vaccination after neonatal

circumcision (circle), neonatal circumcision with additional
local anaesthetic (square), and uncircumcised males (triangle)
in terms of facial action score, duration of cry, and visual analogue scale (VAS). Assessments were conducted by blinded
observers. Patients in the circumcised group had significantly
greater responses than the uncircumcised group. The use of
local anesthesia at the time of neonatal circumcision appeared
to have a modifying effect on the subsequent response at
infant vaccination. *Values are shown as mean (95% confidence
interval [CI]). From reference 5, with permission.

factors.122 Such issues must clearly be taken into account when
interpreting the score obtained from a pain measurement. Most
currently used pain assessment tools concentrate on behavioral,
physiologic, and sensory aspects of pain to provide quantitative
measurements. However, the modulating influence of cognitive,
affective, sociocultural, and environmental factors in the quantitative measurement of pain can be significant, particularly in the
adolescent. Well-motivated young adults who have been raised in
a sociocultural group that is not given to expansive expressions of
distress are likely to provide lower pain scores for the same
stimulus than are others. Even in the newborn, general disposition
and mood can affect behavioral aspects of pain,62 resulting in
a varied pain response that must be regarded as inherent to
the individual. Children with cognitive difficulties represent a
special problem, because their responses are not equivalent
to those of other children of comparable age. Pain assessment
must be highly individualized for these children in close cooperation with their parents, because conventional tools may be of
limited value.
Assessing pain based on physiologic measurements is problematic, because variables such as blood pressure, heart rate,
and oxygen saturation change in response to many events other
than pain. Even behavioral responses can be modified considerably by pacifying measures, state of arousal, and distraction.
One of the most interesting phenomena to be described is the
effect of oral sucrose in modifying neonatal pain responses. Oral
sucrose given to an infant immediately before heelstick can reduce
overall crying time and heart rate in a dose-dependent fashion.123
The effect has been postulated to result from the release of
endogenous opioids during non-nutritive sucking. Further
evidence for this mechanism is that the effect has been reported to
be eliminated by the administration of opioid antagonists such as
naloxone. Although it has been claimed that this phenomenon
represents true analgesia, other studies have shown that oral
pacifiers do not alter cardiovascular or stress responses to circumcision pain.124 However, many of these studies did not include the
use of sucrose solutions, which seem to play a key role in the
provision of this type of analgesia. It has, therefore, been suggested
that nonpharmacologic techniques such as massage, auditory and
tactile stimuli, and oral sucrose must be regarded as important
coping strategies that can modulate pain experience and pain
measurement, but should not be regarded as an analgesic.125
As with any type of treatment or therapy, a method of assessing
response is the first step in achieving success. Such is also the case
with pain management in infants and children, because a means
of assessing pain helps to determine both the severity of pain and
the childs response to therapy. These tools range from simple,
bedside checklists with four or five components that require only
5 to 10 seconds to complete to lengthy, involved surveys that are
cumbersome and time-consuming in a busy office practice or
hospital setting. Early tools to assess pain in adult patients, which
relied on self-reporting, were difficult if not impossible to apply
to preverbal patients such as neonates and infants as well as to
cognitively impaired children and adolescents. Although tools
have been developed to assess pain in these populations,126128 in
most clinical scenarios, the routine and standardized assessment
of pain in pediatric patients remains inconsistent at best. The use
of pain scales and compliance with these processes are aided by
the mandate of various hospital credentialing boards and auditing
agencies, which frequently evaluate pain management protocols
as benchmark criteria.
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Suitable Criteria and Tools

Efforts to develop valid tools for the measurement of pain in
infants and children are made more difficult by the rapid
maturation of behavioral pain responses in infancy and childhood.
Most of the early studies on infant pain measurement were based
on a single painful stimulus such as a heelstick, which is a useful
model because it provides a relatively consistent stimulus from
which to identify and grade responses. However, the applicability
of these data to postoperative pain in infants is limited because
longer-lasting pain in this age group does not produce the easily
identifiable and gross responses associated with an immediate,
self-limited nociceptive stimulus such as a pinprick.129 The variety
of pain assessment tools available to the clinician reflect the childs
increasing ability to communicate with the trained pain assessor
who can integrate these measurements with the myriad of confounding factors described previously. Techniques to measure
postoperative pain require assessment tools that are specific to
patient age and the nature of the pain. Further, the pain measurement tool must be validated for both interobserver agreement and
social validation (determining whether a measurement of
behavior is measuring the construct for which it is intended).
Much emphasis has been placed on evaluations repeated at regular
intervals that can identify changes in quality of analgesia over time
rather than relying on a single measurement.130
Pain assessment tools can be categorized into five broad categories, including self-report, observational (or behavioral), physiologic, neurophysiologic, and hormonal-metabolic (changes in
stress hormones such as epinephrine, norepinephrine, or cortisol).
Pain assessment in the verbal child most commonly relies on a
self-reported visual analogue score (VAS), as is routinely done in
the adult population. These scales ask the patient to identify where
their pain falls on a straight line from 0 (no pain) to 10 (worst
imaginable pain) and rely on the patients ability to assess and
report their own pain. Various scales have been designed to be
more user-friendly and applicable in younger children (down to
57 y of age); they include poker chips, a ladder, colored crayons,
or pictures of children in varying degrees of distress. With the
poker chip scale, the child expresses pain as a certain number
of red poker chips (14). Mild pain would be one poker chip,
whereas four chips are the most hurt the child could have. The
pain ladder is a picture of a ladder with nine steps or rungs.131 At
the bottom of the ladder is no hurt, and at the top of the ladder
is hurt as bad as it could be. The child is then asked to point at
the appropriate place on the ladder to indicate the amount of pain
that she or he is experiencing. The severity of pain can also be
expressed by selecting a colored crayon, with red indicating severe
pain and blue indicating little or no pain. However, reporting
accuracy when using colors to express pain may have some
variability, because the association of blue with calm or no pain
and red with pain does not cross all ethnic groups. Self-reporting
scores correlate well with behavioral responses and adult ratings
but tend to have less reliability until 5 years of age. Children
younger than 5 years tend to chose extremes from the scales and
are confused by the meaning of the scale, choosing the painful
faces to express their unhappiness rather than their lack of
analgesia. Children older than 7 years can generally use VAS or
color analogue scales, and in this age group, the memory for pain
is quite accurate over time. This population can accurately recall
pain intensities a week later, independent of their anxiety and
general memory abilities.132 However, it is recommended that
complex verbal descriptors such as mild, moderate, severe, or

excruciating should not be used in children younger than 13
years.133 Pain in older children carries a strong affective component with anxiety, anger, or depression, and these need to be
taken into account in the assessment of longer-term pain. In this
age group, sociocultural, environmental, and affective factors exert
a very large and variable effect on an individuals experience and
external expression of pain. Pain may become a symptom to avoid
situations or to gain advantage. All factors pertaining to the
individuals pain experience must be considered holistically to
allow an appropriate analgesic plan to be formed in cooperation
with the individual.
Observational tools rely on an observers assessment of stereotypic patterns of behavior that may suggest pain, including the
patients facial features, body positioning, and the presence or
absence of crying. Younger children are best managed with both
self-reporting and observational pain tools. By 3 years of age,
children may be able to self-report the intensity of pain using
modified visual analogue scales such as FACES127 or OUCHER134
scales or other tests that let a child quantitatively describe his
or her level of pain, such as with the poker chip tool.135 One
advantage of the FACES scale is that it can be used with various
ethnic groups and across language barriers between providers and
patients. Although the FACES scale was designed as a self-report
scoring system, some centers have modified its use into an
observational tool. In this circumstance, the health care provider
assesses the child and selects the facial expression (and hence the
degree of pain) that she or he believes the patient is manifesting.
In the pediatric population, acute illnesses, cognitive states, or
age may preclude the use of self-report scales. Observational
assessment tools have been described and validated for various
patient populations, including neonates,115,136 preterm infants,137
140
and patients with cognitive impairment. The latter group of
patients represents a growing subpopulation of the pediatric-aged
patient and, therefore has received significant attention since the
early 2000s. For patients with cognitive impairment, different
assessment tools may be helpful in the assessment of their
pain. The Non-Communicating Childrens Pain Checklist
Postoperative Version (NCCPC-PV) was developed specifically
for use in this population.141 It includes the grading of several
specific behaviors, such as vocalization, socialization, facial
expression, activity, body and limb positioning, and physiologic
signs that have been shown to be indicative of pain in children
with cognitive impairment. Alternatively, scales such as the Face,
Legs, Activity, Cry, and Consolability (FLACC) scoring system,
which is used for preverbal children, can be modified for cognitively impaired children by the addition of specific descriptors
and parent-identified behaviors for each individual patient.139
Recently, the clinical utility of these scales was studied, and a
comparison of their application found the revised FLACC to have
distinct advantages that may allow a more effective adaptation to
clinical practice.142 These tools have been shown to have excellent
interobserver reliability and are quick and easy to use, even in a
busy clinical practice (Table 153).
Physiologic parameters used in pain scales may include heart
rate, blood pressure, respiratory rate, oxygen saturation, palmar
sweating, alterations in heart rate variability, or changes in
pupillary size. However, factors other than pain may alter these
physiologic parameters or alter responses to the painful stimulus.
A frequent scenario is the critically ill infant or child in an
intensive care unit whose blood pressure is low because of a
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TABLE 15-3. Characteristics of Observational Pain Assessment Tools in Nonverbal Children

Tool
Categories
Items Scored
Score Range/Interpretation
Age Range, y
Revised FLACC
Facial expression
Leg position
Activity
Cry/vocalization
Consolability
Vocal
Social
Facial
Activity
Body and limbs
Physiologic
5 items, each with a score

of 02
Range: 010; >3 = moderate

to severe pain
419
27 items, each with a score

of 03
Range: 081; >10 = moderate

to severe pain
318
NCCPC-PV
FLACC = Face, Leg Position, Activity, Cry, Consolability; NCCPC-PV = Non-Communicating Childrens Pain ChecklistPostoperative Version.
comorbid disease process, thereby negating the ability to use an

elevated blood pressure as an indicator of pain.
Neonatal pain assessments use observational scoring (facial
expression, body position, crying, and movements) often combined with physiologic measurement such as blood pressure or
oxygen saturation. Studies in this age group demonstrate that
single behaviors are unreliable in the assessment of pain and that
the interobserver correlation and specificity can be improved by a
multidimensional approach that may also include physiologic
measurements.129 Tools commonly used include the Objective
Pain Scale (OPS),88 Childrens Hospital of Eastern Ontario Pain
Score (CHEOPS),128 crying, requires oxygenation, increased vital
signs, expression and sleepless (CRIES),136 and alertness, calmness/
agitation, respiratory response, physical movement, blood
pressure, heart rate, muscle tone, facial tension (COMFORT)
scales.143 The descriptors for these pain scales are compared in
Table 154. Although facial expression alone has proved useful in
the evaluation of the instantaneous pain associated with heelstick,
suctioning, or other invasive procedures, these pain assessment
tools attempt to quantify pain with different multidimensional
approaches. None of these individual tools can be regarded as the
ideal. The OPS score has a physiologic measurement (blood
pressure) as well as behavioral assessments, but most of the other
descriptors overlap, so that pain scores tend to be either very low
(no pain) or very high (major pain), with little gradation. However,
this scoring system is one of the simplest and practical to use and
has been modified for different age groups.87 The CRIES score is
a simple neonatal tool that uses both physiologic and behavioral
measurement. However, the use of oxygen saturation is questionable in that pain is not always associated with reduction in oxygen
saturation.144 The COMFORT score has no less than eight variables, including separate scoring for blood pressure and heart rate.
This tool suffers from the extensive crossover in scoring of the
separate components (i.e., agitation and alertness, blood pressure,
and heart rate).143
Another pediatric pain assessment tool that combines
observational and physiologic data is the CHEOPS developed by
McGrath and colleagues.128 This scale assigns a score of 0 to 2 for
six categories, including cry, facial expression, verbal complaints
of pain, position of the torso, whether the child is touching the
wound, and position of the legs. The CHEOPS pain assessment
tool was one of the first to be validated. It describes each criterion
in subtle detail, which may make it more discriminatory at the
expense of making it cumbersome for everyday clinical practice.
The final pain assessment tools use neurophysiologic and
hormonal-metabolic changes. Both are generally restricted to
research protocols and have limited applicability for the everyday practice of pediatric pain management. Neurophysiologic
monitoring is the least well known and least well studied of the
pain assessment tools. Potential tools include EEG monitoring and
waveform analysis, pupillary responses, brainstem-evoked responses, galvanic skin changes, and perhaps even changes in the
TABLE 15-4. Comparison of Commonly Used Infant Pain Assessment Tools

OPS
Heart rate/BP
Cry
Facial expression
Verbal expression
Position (torso)/movement
Position (legs)/movement
Position (hands)/movement
Agitation/calmness
Oxygen saturation
Ventilatory responses
Alertness
Total criteria
X
X
X
XX for posture + movement
CHEOPS
CRIES
X
X
X
X
X
X
X
X
X
X
X
COMFORT
XX for BP + heart rate
XX for muscle tone + movement
X
X
8
BP = blood pressure; CHEOPS = Childrens Hospital Eastern Ontario Pain Scale; COMFORT = alertness, calmness/agitation, respiratory response, physical movement,
blood pressure, heart rate, muscle tone, facial tension; CRIES = crying, requires oxygenation, increased vital signs, expression and sleepless; OPS = Objective Pain Scale.
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subcortical areas of the brain and brainstem. Hormonal-metabolic

changes such as alterations in plasma levels of stress hormones,
including epinephrine and cortisol, have been used to study pain
management regimens for patients with acute illnesses or those
undergoing major surgical procedures.32,145,146 To date, these tools
are limited to the research arena and tend to be too cumbersome,
too expensive, or unvalidated, thereby limiting their application
to our current clinical practice.
CONCLUSIONS
Pain is a complex phenomenon, representing a neurophysiologic nociceptive response combined with a psychobehavioral
component that is present throughout life. During the in utero
course of neurobehavioral development of the fetus to the mature
infant, it remains unclear at what stage pain pathway transmission
becomes pain sensation. This issue will continue to be debated
emotionally and philosophically. Nevertheless, it is important to be
aware of the consequences of noxious stimuli and bodily injury,
including hemodynamic, inflammatory, and stress responses.
Ongoing evidence continues to demonstrate the deleterious
physiologic effects of pain in children and the beneficial results of
effective postoperative analgesia. This growing body of clinical
knowledge has coincided with the growing public awareness of
the importance of effective pain management to the well-being of
infants and children. Although the long-term effects are unclear,
the use of analgesic drugs in all pediatric patients (from preterm
infants to adolescents) remains a necessity. The effects of these
medications and their pharmacokinetics and dynamics need to
be carefully studied to ensure that the drugs themselves do not
cause additional problems. In older infants and children, several
validated pain assessment tools can help to identify pain in infants
and children. Each practitioner must work to integrate these
tools and develop hospital-wide systems for the application of
appropriate pain monitoring and treatment techniques. Pain, like
hunger, is a non-negotiable experience for children. Either they
are free of pain and are well or they have pain and are suffering.
The latter requires our immediate attention. The recognition and
treatment of both medical and surgical pain in children has
improved but continues to lag behind adult pain management.
Further work is essential to refine and develop techniques to
promptly identify the onset of pain in pediatric patients and to
develop and implement more effective pediatric pain treatments.
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Chronic and Recurrent Pain

in the Pediatric Patient
Stephen C. Brown and Patricia A. McGrath
INTRODUCTION
Pain control is an integral component of pediatric clinical care.
Children may experience many different types of pain related to
invasive procedures, the cumulative effects of toxic therapies,
progressive disease, or psychological factors. The pain is often
complex with multiple sources, composed of nociceptive and
neuropathic components. In addition, several situational factors
usually contribute to childrens pain, distress, and disability. Thus,
to adequately treat pain in children, we must evaluate the primary
pain sources and ascertain which situational factors are relevant
for which children and families. Treatment emphasis should shift
accordingly from an exclusive disease-centered framework to a
more child-centered focus.
In this chapter, we describe a child-centered framework for
understanding and controlling pain in children. Pain control
should include regular pain assessments, appropriate analgesics
administered at regular dosing intervals, adjunctive drug therapy
for symptom and side effects control, and nondrug interventions
to modify the situational factors that can exacerbate pain and
suffering. Basic information on the pathophysiology, pharmacology, and physical interventions will not be repeated in this
chapter because they are presented elsewhere in this textbook.
This chapter provides a complementary focus to these other
contributions by describing the unique nature of childrens pain
including the primary factors that affect their pain and quality of
life, presenting guidelines for selecting and administering drug
therapy in accordance with the nociceptive and neuropathic
components, and recommending practical nondrug therapies for
integration within a home or hospital setting.
THE NATURE OF CHILDRENS PAIN

Since the early 2000s, we have gained an increasing appreciation
for the plasticity and complexity of childrens pain. As with adults,
childrens pain is often initiated by tissue damage caused by
noxious stimulation, but the consequent pain is neither simply
nor directly related to the amount of tissue damage. Perhaps even
more than in adults, differing pain responses to the same tissue
damage are noted. The eventual pain evoked by a relatively
constant noxious stimulus can be different depending on childrens
expectations, perceived control, or the significance that they attach
to the pain.1 Children do not sustain tissue damage in an isolated
manner, devoid of a particular context, but actively interpret the
strength and quality of any pain sensation, determine the
relevance of any hurting, and learn how to interpret the pain by
observing the general environment, especially the behavior of
16
C H A P T E R
other people. Childrens perceptions of pain are defined by their

age and cognitive level; their previous pain experiences against
which they evaluate each new pain; the relevance of the pain or
disease causing pain; their expectations for obtaining eventual
recovery and pain relief; and their ability to control the pain
themselves. Although plasticity and complexity are critical features
for all pain perception, plasticity seems an even more important
feature for controlling childrens pain.
Much research has been conducted to identify the critical
factors responsible for the plasticity of pain perception.2 Animal
behavior studies, in which the physiologic responses activated by
a noxious stimulus are directly recorded, have demonstrated that
certain factors such as the primates attention, the predictability of
a painful stimulus, and the relevance of the stimulus can directly
modify the intensity of the physiologic responses evoked by a
constant noxious stimulus. Parallel psychophysical studies, in
which adults rate the painfulness of constant noxious stimuli in
different contexts, have demonstrated that these same factors can
modify the perceived intensity and unpleasantness of the
consequent pain sensations. Psychologically mediated modulation
of pain can occur at the earliest levels of pain processing as well as
at its highest levels. Both positron emission tomography (PET)
and functional magnetic resonance imaging (MRI) studies have
demonstrated that painful stimulation activates different cortical
regions, depending on an individuals expectations and attention.3
Human studies evaluating the impact of environmental and
psychological factors on the perception of experimentally induced
pain have been conducted primarily in adults. However, results
from laboratory studies conducted with children are consistent
with those from adult studies.4,5 In addition, significant amount
of compelling evidence about the powerful mediating role of
psychological factors in childrens pain has been derived from
clinical studies of acute, recurrent, and chronic pain. These studies
highlight the need to recognize and evaluate the mediating impact
of these factors in order to optimally control childrens pain.
The model illustrated in Figure 161 provides a framework for
assessing these factors, based on our knowledge of the plasticity
and complexity of childrens pain. Some factors, such as gender,
temperament, and cultural background, are relatively stable for a
child, whereas other factors, such as age, cognitive level, previous
pain experience, and family learning, change progressively (listed
in the open box in the figure). These child characteristics shape
how children generally interpret and experience the various
sensations caused by tissue damage. By contrast, the cognitive,
behavioral, and emotional factors (listed in the shaded boxes) are
not stable. They represent a unique interaction between the child
and the situation in which the pain is experienced.1,6 These
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Figure 16-1. A model depicting the situational factors that modify childrens pain perception.
situational factors can vary dynamically throughout the course of

a childs illness, depending on the specific circumstances in which
children experience pain. For example, a child receiving treatment
for cancer will have repeated injections, central venous catheter
access attempts, and lumbar punctures, all of which may cause
some pain depending on the analgesics, anesthetics, or sedatives
that are used. Even though the tissue damage from these procedures is the same each time, the particular set of situational
factors for each treatment is unique for a child, depending on a
childs (and parents) expectations, a childs (and parents and
staff s) behaviors, and on a childs (and familys) emotional state.
Although the causal relationship between an injury and a consequent pain seems direct and obvious, what children understand,
what they do, and how they feel all affect their pain. Certain factors
can intensify pain, exacerbate suffering, or adversely affect a childs
quality of life.4 Although parents and health care providers may
be unable to change the more stable child characteristics, they
can modify situational factors and dramatically improve childrens
pain and lives.
THE IMPACT OF SITUATIONAL

FACTORS ON CHILDRENS PAIN
Cognitive factors include childrens understanding about the pain
source, their ability to control what will happen, their expectations
regarding the quality and strength of pain sensations that they will
experience, their primary focus of attention (i.e., distracted away
from or focused primarily on the pain), and their knowledge of
pain control strategies. In general, childrens pain can be lessened
by providing accurate age-appropriate information about pain, for
example, emphasizing the specific sensations that children will
experience (such as the stinging quality of an injection, rather than
the general hurting aspects), by increasing their control and
choices, by explaining the rationale for what can be done to reduce
pain, and by teaching them some independent pain-reducing
strategies.1,7,8 For children with chronic and recurrent pain, key
cognitive factors also include the relevance or meaning of their
illness, particularly if there is a life-threatening potential, and their
understanding of the significance of their lives.
Behavioral factors refer to the specific behaviors of children,
parents, and staff when children experience pain and also
encompass parents and childrens wider behaviors in response to

a chronic or recurrent pain problem or progressive illness.
Common behavioral factors include childrens distress or coping
reactions (e.g., crying, using a pain control strategy) and parents
and health staff s subsequent reactions to them (e.g., displaying
frustration, calmly providing encouragement for children to use
pain control strategies, engaging them in conversation and
activities).4 They also include the extent to which children
are physically restrained during invasive or aversive treatments
and the broader physical and social restrictions on childrens and
familys lives if children become sicker. Distress behaviors and
some altered behavioral patterns may initiate, exacerbate, or
maintain childrens pain. In general, as childrens mental or
physical activity increases, as children use coping and pain control
methods, as their distress and disability behaviors decrease, and
as staff and parental responses become more consistent in
encouraging the child to use pain control methods, their pain
should lessen. Children seem to report less pain, feel less distressed
by pain, and have a higher quality of life when families and
staff encourage them to remain engaged in life and live as fully
as possible.
Emotional factors include parents and childrens feelings in
response to pain, to the daily effects of the underlying illness or
condition, and to the subsequent impact of the childrens disease
on the family. Childrens emotions affect their ability to understand what is happening, their ability to cope positively, their
behaviors, and ultimately, their pain. Childrens immediate
emotional reactions to pain may vary from a relatively neutral
acceptance to annoyance, anxiety, fear, frustration, anger, or
sadness. The specific emotions depend on the nature of the pain
including its type, cause, intensity, and duration as well as its
impact on their lives. In general, the more emotionally distressed
children are, the stronger or more unpleasant their pain. When
children do not understand what is happening, when they lack
control and do not know independent pain control strategies, their
emotional distress increases and their pain intensifies. Similarly,
when childrens behaviors are restricted, when they are physically
restrained during medical procedures, or when their usual daily
activities and social interactions are disrupted, their emotional
distress and pain can intensify. Children with life-threatening
conditions may not understand what they are feeling or may be
unable to verbalize their fears and anxieties. Even very subtle
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CHAPTER 16
behavioral cues can still evoke fear, uncertainty, apprehension, or
depression depending on childrens ages and what they understand
about their disease and separation. Thus, an essential component
of pain control should be evaluating whether these emotions are
exacerbating childrens pain and distress and impairing the quality
of their lives.
SITUATIONAL FACTORS IN
CHRONIC AND RECURRENT PAIN
Cognitive and emotional factors are the most salient situational
factors that affect pain in children. Children sometimes have
already endured a prolonged period of intermittent pain, physical
disability, and multiple aversive treatments. Children undergoing
active and often changing therapies are more focused on the future
consequences of their disease. Their thoughts, behaviors, and
feelings change as their condition begins to improve or deteriorate.
Naturally, the type of support, information, and guidance children
require also changes. Although the impact is profound for all
children and families, each child and family is unique with respect
to their specific psychological, medical, social, and spiritual needs.
All families experience anguish and grief, but they may also
experience denial, anxiety, anger, guilt, frustration, and depression.
It is essential that health professionals listen attentively and
observe carefully not only to ensure that all the needs of both the
child and the family are met but also to resolve the myriad factors
that can exacerbate childrens pain and suffering. The primary
situational factors for chronic and recurrent pain are listed in Table
161. To many of our patients and families, we often summarize
these factors as the three Ps including pharmacologic, psychological, and physical factors. This summary has evolved from our
treatment of children referred to our pain clinic. Child and family
factors are listed in italics; the factors that are relevant for health
staff as well as families are listed in roman type.
The care of children with chronic and recurrent pain may at
times involve the care of children for palliative care. The shift in
care from curative to palliative therapies may signify to some
children and families that health professionals are giving up on
the child. Children and families must understand that stopping
ineffective therapies is not giving up, but represents a rational
decision based on childrens best interests. Pain control is also an
essential component of palliative care.915 Children and parents
should not fear that health professionals have given up on
controlling pain and aversive symptoms. As with chronic and
recurrent pain, all symptoms must be treated aggressively from
the dual perspective of targeting the primary source of tissue
damage and modifying the secondary contributing factors.
Although most families receive accurate information about their
disease and required treatments, few children or their parents
receive concrete information about their pain, the factors that can
attenuate or exacerbate it, a rationale for the interventions they
receive, and training in effective nondrug pain control methods.
The latter may be particularly important for children in palliative
care, who have diminishing control in their lives. Children and
their parents often do not understand that pain control therapies
may vary in efficacy because of changing disease, the effects of
other drugs, and situational factors. Thus, their confidence in
certain pain control therapies can decrease, even though these
therapies would effectively alleviate pain at another time. The fear
of inadequate pain control places an enormous emotional burden
Chronic and Recurrent Pain in the Pediatric Patient
275
TABLE 16-1. Situational Factors in Pediatric Palliative Care

Cognitive Factors
Meaning of life
Inaccurate understanding of:
?Impact of situational factors on pain and quality of life
?Course of disease
?Goals of therapy
Little independent control over pain
Limited choices
Expectation for continuing pain and suffering
Misunderstanding of drug therapy:
?Narcotics, non-narcotics, adjuvant analgesics
?Dosing and administration
?Criteria for evaluating effectiveness
Behavioral Factors
Social withdrawal
Physical inactivity, physical therapy
Passive approach to pain control
Secondary gains:
?Stress reduction
?Emotional denial
?Parent or staff attention
Inappropriate drug management:
?Choice or mode of drug administration
?Failure to aggressively treat medication side effects
Failure to evaluate pain sources and document pain level
Failure to use effective nondrug therapies
Emotional
Anxiety about:
?Pain
?Suffering
?Meaning of life
Fear of:
?Separation
?Inadequate pain control
?Increasing adverse symptoms
?Impact on family
Anger
Sadness or depression
Distancing by staff and friends
on an already distressed child and family and can create a situation

in which childrens pain and disability intensifies. The reader is
referred to references 13 and 16 through 21 for a comprehensive
care of the dying child.
Childrens physical activity can be progressively restricted
because of the disability caused by their condition. Parents who
encourage children to adopt passive patient roles, to behave
differently from other children, and to depend primarily on others
for pain control will undoubtedly create a situation in which
childrens pain is maximized. It is possible to create some normal
environment in which children can participate and actively
involve themselves. One cannot overemphasize the importance of
one of the three 3Ps, that being physical activity.
Children who experienced adverse physical effects from
medication, such as weight gain, may have become acutely selfconscious about their appearance. As a result, these children may
have progressively withdrawn from social interactions with their
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peers because they anticipated negative reactions. Children

become more distant from the people and activities that they
had enjoyed. Moreover, many children may lose the opportunity
to be regarded as unique individuals by the friends and classmates
they value. Instead, they are regarded increasingly as sick or
different. Their peers and their daily accomplishments (social,
academic, or athletic) provide special meaning about a childs
unique value in the world. Although families emphasize childrens
value to them and to the world, children often lose the objective
feedback they had routinely received. The increased withdrawal
and social isolation can exacerbate their pain and emotional
distress. Although important for children and families, the
exclusive focus on the family increases a childs social isolation and
may cause more anxiety for some children. Inadvertently, the
family may prevent children from interacting both with peers,
who can lessen their anxiety through play and conversation,
and with health professionals, who can help them to resolve
their anxiety. As can be often quoted from consultations in our
clinic, A child not in school is a child whose pain is far more
difficult to treat.
Children fear separation and abandonment; some children
may fear that their illness is a punishment. Children may feel
frightened, isolated, and guilty unless they are able to openly
express and resolve their concerns. It is essential to acknowledge
and resolve their fears. Children should receive accurate information, consistent with their beliefs, presented in a calm,
reassuring manner. Unresolved emotions add anguish and may
intensify their pain.
OPTIMAL PAIN CONTROL

FOR CHILDREN
Pain control is an intrinsic component of pediatric care. Because
children may experience complex pains because of myriad
physical and psychological factors, pain control must be childcentered rather than disease-centered. Health care providers must
carefully evaluate the varied causes and contributing factors to
select the most effective therapies for each childs pain. Onset,
location, intensity, quality, duration (or frequency, if recurring),
spatial extent, temporal pattern, and accompanying physical
symptoms are the key pain characteristics for assessment (Table
162). All of these characteristics should be evaluated as part of
the initial clinical examination with pain intensity and any other
characteristics that are clinically relevant for children monitored
regularly. Childrens descriptions about the nature of their pain
(when self-report is available) complete the information obtained
through radiologic and laboratory investigations. Because several
situational factors usually contribute to childrens pain, distress,
and disability, health care providers should evaluate the extent to
which these may be relevant for a child, building on their
knowledge of the childs and familys previous experiences
throughout the childs life and their observations of the current
situation.
The differential diagnosis of a childs pain is a dynamic process
that guides our clinical management. We should select specific
therapies to target the responsible central and peripheral mechanisms and to mitigate the pain-exacerbating impact of situational
factors, recognizing that the multiple causes and contributing
factors will vary over time. Drug therapies (analgesics, analgesicadjuvants, and anesthetics) are essential for pain control, but
TABLE 16-2. Primary Components of Pain Assessment

Sensory Characteristics
Onset
Location
Intensity
Quality
Duration
Spread to other sites (consistent with neurologic pattern)
Radiation
Temporal pattern
Accompanying symptoms
Medical/Surgical
Investigations conducted
Radiologic and laboratory results
Consult results
Analgesic and adjuvant medications (type, dose, frequency,
route, length of medication trial)
Clinical Factors
Environmental features
Roles of medical and associated health professionals
Nature of interventions
Complementary and alternative therapy
Documentation of pain
Criteria for determining analgesic effectiveness
Cognitive Factors
Understanding of pain source
Understanding of diagnosis, treatment, and prognosis
Expectations
Perceived control
Relevance of disease or painful treatments
Knowledge of pain control
Behavioral Factors
General coping style
Learned pain behaviors
Overt distress level
Parents behaviors
Physical activities and limitations
Social activities and limitations
Emotional Factors
Frustration
Anxiety
Fear
Denial
Sadness
Anger
Depression
nondrug therapies (cognitive, physical, and behavioral techniques)
are equally essential. As we monitor the childs improvement in
response to the therapies initiated, we refine our pain diagnosis
and treatment plan accordingly. Pain control is practically
achieved by adjusting both drug and nondrug therapies in a
rational child-centered manner based on the assessment process
as outlined by the treatment algorithm in Figure 162. (The
different therapies are described later in the chapter.) Controlling
childrens pain requires an integrated approach because many
factors are responsible, no matter how seemingly clear-cut the
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277
Misconceptions About the Risk of Addiction

Some health care providers and parents believe that opioid analgesics should be administered only as a last resort, to avoid drug
addiction. They have not understood that Tolerance + Physical
Dependence = Addiction. As a result, children have not always
received the potent analgesics required to relieve severe pain.
Moreover, they may not understand that opioid-related side effects
should be treated aggressively so that the potential efficacy of these
drugs for controlling pain is not compromised by adverse side
effects.
Misconceptions About the Efficacy

of Nondrug Therapies
Many health professionals do not realize that relatively simple
nondrug strategies can lessen childrens pain. As a result, they have
not taught children or their parents how to use practical cognitive,
physical, and behavioral strategies that are effective for reducing
pain, distress, and pain-related disability. Similarly, they have not
taught parents the importance of evaluating and modifying
situational and familial factors to lessen childrens pain.
Misconceptions About Comprehensive Pain Control
Figure 16-2. A treatment algorithm for controlling childrens pain.
etiology. Adequate analgesic prescriptions, administered at regular

dosing intervals, must be complemented by a practical cognitivebehavioral approach to ensure optimal pain relief.
Misconceptions Regarding
Pain Control in Children
Several misconceptions have led to inadequate pain control
in children (revised from reference 1).
Misconceptions About Childrens Pain Systems

Many health care providers continue to treat childrens pain from
an erroneous disease model perspective wherein pain is always
proportional to the extent and severity of tissue damage. As a
result of misconceptions about the plasticity and complexity of
childrens nociceptive systems, they focus on the primary source of
noxious stimulation, but not on all the causative and contributing
factors that affect nociceptive processing. As a result of misconceptions about nociceptive and neuropathic components of
pain, they fail to use the wide range of analgesic and analgesicadjuvants available to control pain.
Misconceptions About the Pharmacodynamics

and Pharmacokinetics of Opioid Analgesica
As a result of misconceptions about the pharmacodynamics and
pharmacokinetics of opioid analgesics, health professionals do not
always select the most appropriate drugs, doses, dosing intervals,
or administration routes.
Many health care providers believe that drug therapies are both
necessary and sufficient to control childrens pain. They have not
prescribed nondrug therapies to supplement or complement
analgesics, even when situational factors are impeding analgesic
efficacy.
Misconceptions About Pain Assessment

Many health care providers do not know how to routinely assess
childrens pain levels or the factors that intensify their pain and
distress. As a result, it may be difficult to evaluate the effectiveness
of changes in drug therapy, complementary therapies, and
situational factors.
Misconceptions About Who Is

in Charge of Pain Control
One individual should assume primary responsibility for ensuring
that a childs pain is controlled adequately. Diffusion of responsibility among various health care providers leads to gaps in
recognizing a childs pain and treating pain appropriately.
Misconceptions About the Importance

of Consistent Pain Control
The medical specialties, which provide care to children throughout their illness, do not always adopt a consistent approach to pain
assessment and pain control, similar to their consistent approach
to disease diagnosis and medical treatment. The failure to regard
pain control as important throughout a childs treatment can lead
to difficulties for children, especially if previous experiences with
inadequate pain management create undue stress and anxiety for
them and their parents.
GUIDELINES FOR PAIN ASSESSMENT

Pain assessment is an integral component in the diagnosis and
treatment of childrens pain. A thorough medical history, physical
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examination, and assessment of pain characteristics and contributing factors are necessary to establish a correct clinical diagnosis. Subsequent assessments of pain intensity enable us to
determine when treatments are effective and to identify those
children for whom they are most effective. Health care providers
need pain measures that are convenient to administer and whose
resulting pain scores provide meaningful information about
childrens pain experiences. An extensive array of pain measures
have been developed and validated for use with infants, children,
and adolescents.2224
Like adult pain measures, childrens pain measures are classified
as physiologic, behavioral, and psychological, depending on what
is monitored, physical parameters (e.g., heart rate, sweat index,
blood pressure, cortisol level), distress behaviors (e.g., grimaces,
cries, protective guarding gestures), or childrens own descriptions
of what they are experiencing (e.g., words, drawings, numerical
ratings). Physiologic and behavioral measures provide indirect
estimates of pain because health care providers must infer the
location and strength of a childs pain solely from his or her responses. By contrast, psychological measures can provide direct information about the location, strength, quality, duration, and affect.
The criteria for an accurate pain measure are similar to those
required for any measuring instrument. A pain measure must be
valid in that it measures a specific aspect of pain so that changes
in pain ratings reflect meaningful differences in a childs pain
experience. The measure must be reliable in that it provides
consistent and trustworthy pain ratings regardless of the time of
testing, the clinical setting, or who is administering the measure.
The measure must be relatively free from bias in that children
should be able to use it similarly, regardless of differences in how
they may wish to please adults. The pain measure should be
practical and versatile for assessing different types of pain (e.g.,
disease-related, procedural pain) in many different children
(according to age, cognitive level, cultural background), and it
should be applicable in diverse clinical and home settings.
Although physiologic parameters can provide valuable information about a childs distress state, more research is required to
develop a sensitive system for interpreting how these parameters reflect pain strength. At present, there are no valid
physiologic pain scales for children. Most behavioral pain scales
are checklists of the different distress behaviors that children
exhibit when they experience a certain type of pain.22,25,26 To
develop these scales, trained health care providers carefully observe
children when they are in pain (e.g., after surgery) and document
behaviors that seem to be caused by the pain. They then list these
presumed pain behaviors (e.g., crying, facial expression, limb
rigidity) on an itemized checklist. Parents complete the pain scale
by checking which of the listed behaviors they see when children
are ill. On many scales, parents also rate the intensity of the
behaviors. The intensity scores for each of the observed behaviors
are summed to produce a composite pain score. Although most
behavioral scales measure acute pain reliably in most patients,
there remains a need to develop more sensitive measures for
children who are cognitively or physically impaired.27 The
complexity of a childs disease or health condition, concomitant
drug therapy, and the other distress sources in the health care
environment may limit childrens ability to behave, thereby making
the behavioral pain score unreliable. Their pain behaviors may be
very different from those of the children studied to develop the
original scales. Moreover, the most salient pain behavior may be
very child-dependent and vary widely among different children or
change throughout the course of their illness. At present, health

care providers must use their content expertise and consult with
parents to carefully consider which behavior or behaviors are the
most relevant indices of pain for a particular child. They can chart
the presence and intensity of these behaviors (it is likely that these
will be more subtle indices than on current standardized scales)
and interpret them as an indirect measure of pain.
Psychological or self-report pain scales directly capture an
individuals subjective experience of pain. Interviews, questionnaires, adjective checklists, and numerous pain intensity scales
are available for children, each with some evidence of validity and
reliability.22,28 Clinical interviews are ideally suited for learning
about the sensory characteristics of pain, the aversive component,
and contributing cognitive, behavioral, and emotional factors.
Interviews should also include a simple rating scale to document
pain strength. Children choose a level on the scale that best
matches the strength of their own pain (i.e., a level on a number
or thermometer scale, a number of objects, a mark on a visual
analogue scale, a face from a series of faces varying in emotional
expression, or a particular word from adjective lists). Pain intensity
scales are easy to administer, requiring only a few seconds once
children understand how to use them. Many of these scales yield
pain scores on a 0 to 10 scale. Visual and colored analogue scales
are versatile for use with acute, chronic, and recurrent pain and
provide a convenient and flexible pain measure for use in hospital,
office, and at home.
Health care providers must consider the age and cognitive
ability of a child when selecting a pain scale. Most toddlers (~2 y
of age) can communicate the presence of pain using words learned
from their parents to describe the sensations they feel when they
hurt themselves. They use concrete analogies to describe their
perceptions. Gradually children learn to differentiate and describe
three levels of pain intensity: a little, some or medium, and a
lot. By the age of 5, most children can differentiate a wider range
of pain intensities and many can use simple pain intensity scales.
Childrens understanding and descriptions of pain naturally
depend on their age, cognitive level, and previous pain experience.
Children begin to understand pain through their own hurting
experiences; they learn to describe the different characteristics of
their pains (intensity, quality, duration, and location) in the same
way that they learn specific words to describe different sounds,
tastes, smells, and colors. Most children can communicate
meaningful information about their pain. Gradually, they develop
an increasing ability to describe specific pain features such as the
quality (aching, burning, pounding, sharp), intensity (mild to
severe), duration and frequency (a few seconds to years), location
(from a diffuse location on their skin to more precise internal localization), and unpleasantness (mild annoyance to an
intolerable discomfort). Childrens understanding of pain and the
language that they use to describe pain come from the words and
expressions used by their families and peers and from characters
depicted in books, television, videos, and movies. For a more
extensive review of developmental factors in childrens pain, the
reader is referred to references 1, 6, and 29 through 33. Physicians
should always ask children directly about their pain. Pain onset,
location, frequency (if recurring), quality, intensity, accompanying
physical symptoms, and pain-related disability should be assessed
as part of childrens clinical examination. Health care providers
should also assess relevant situational factors in order to modify
their pain-exacerbating impact, especially the factors listed in
Table 161.
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ANALGESIC SELECTION
AND ADMINISTRATION
Pain control should include regular pain assessments, appropriate
analgesics with adjuvant analgesics administered at regular dosing
intervals, adjunctive drug therapy for symptom and side effect
control, and nondrug therapies to modify the situational factors
that can exacerbate pain and suffering. Analgesics include acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), and
opioids. Adjuvant analgesics include a variety of drugs with
analgesic properties, such as anticonvulsants and antidepressants,
that were initially developed to treat other health problems. The
use of adjuvant analgesics has become a cornerstone of pain control in pediatric care. They are especially crucial when pain has a
neuropathic component.
The guiding principles of analgesic administration are by the
ladder, by the clock, by the child,, and by the mouth. By the
ladder refers to a three-step approach for selecting drugs
according to their analgesic potency based on the childs pain level:
acetaminophen to control mild pain, codeine to control moderate
pain, and morphine for strong pain.34 The ladder approach was
based on our scientific understanding of how analgesics affect pain
of nociceptive origins. If pain persists despite starting with the
appropriate drug, recommended doses, and dosing schedule,
move up the ladder and administer the next more potent analgesic.
Even when children require opioid analgesics, they should
continue to receive acetaminophen (and NSAIDs, if appropriate)
as supplemental analgesics. The analgesic ladder approach is based
on the premise that acetaminophen, codeine, and morphine
should be available in all countries and that doctors and health
care providers can relieve pain in the majority of children with a
few drugs. The World Health Organization (WHO) model of (1)
appropriate policies, (2) adequate drug availability, (3) education
of the health care workers, policymakers and the public, and (4)
implementation has been shown to provide an effective strategy to
establish pediatric pain control.35,36 Oral morphine in either
immediate-release or sustained-release form remains the analgesic
of choice for moderate or severe pain.37,38 The accelerated use of
narcotics and sedatives (when required) takes place when end of
life care (EOLC) discussions have been implemented.39
Increasing attention is focusing on thinking beyond the
ladder in accordance with our improved understanding of pain
of neuropathic origins.40,41 Children should receive adjuvant
analgesics to more specifically target neuropathic mechanisms.
Regrettably, two of the main classes of adjuvant analgesics,
antidepressants and anticonvulsants, have unfortunate names.
Proper education of health care providers, parents, and children
should lead to a wider acceptance and use of these medications
for pain management. For example, amitriptyline may require 4 to
6 weeks to affect depression, but often requires only 1 to 2 weeks
to affect pain. The newer classes of antidepressants, the selective
serotonin re-uptake inhibitors (SSRIs), may be beneficial to treat
depression in a child with pain, but have not been shown to be
beneficial for pain management. The other main class of adjuvant
analgesics is the anticonvulsants. The two principal medications
used for this purpose in pediatric patients are carbamazepine and
gabapentin. With gabapentin, the main dose-limiting side effect is
sedation so that a slow titration to maximal dose is required.
Because of its greater number of significant side effects, the use of
carbamazepine has decreased and the use of gabapentin has
increased. Although some reports support the use of gabapentin
279
in children,4244 we still await published studies to support this

wider use in children, both in general and specifically in palliative
care.45 Similar pediatric studies are also required for the recently
proposed indications for the use of pregabalin, a pharmacologic
analogue of gabapentin, in chronic pain conditions.
NSAIDs are similar in potency to aspirin. NSAIDs are used
primarily to treat inflammatory disorders and to lessen mild to
moderate acute pain. They should be used with caution in patients
with hepatic or renal impairment, compromised cardiac function,
hypertension (because they may cause fluid retention), and those
with a history of gastrointestinal bleeding or ulcers. NSAIDs may
also inhibit platelet aggregation and, thus, must be monitored
closely in patients with prolonged bleeding times. Although
acetaminophen should be considered the routine nonopioid
analgesic for children, NSAIDs are often more effective for
patients with bony lesions causing chronic and recurrent pain.
Tramadol was launched in the area of pain practice in the late
1970s in Germany. It has more recently been released in Canada
in a long-acting oral preparation (Zytram XL) and as a combination drug with acetaminophen (Tramacet). Its use has been
welcomed as an additional analgesic in our drug armamentarium
with a potency compatible with level two agents of the WHO
analgesic ladder. Tramadol is a synthetic, 4-phenyl-piperidine
analogue of codeine that is marketed as a racemic mixture of (+)
and () enantiomers. The opioid activity of tramadol results from
low-affinity binding of the (+) enantiomer to opioid receptors.
The (+) enantiomer inhibits serotonin uptake and has a direct
serotonin-releasing action, whereas the () enantiomer is a more
effective inhibitor of norepinephrine uptake.46 The analgesic
potency of tramadol is considered to be medium, having one tenth
the potency of morphine. Its advantages over opioids are mainly
the lower incidence of side- effects such as respiratory depression,
nausea, vomiting, constipation, sedation and a low potential for
dependence or abuse. Rose and coworkers reported that, in 113
children, aged 7 to 16 years, oral tramadol at 1 mg/kg every 4 to 6
hours for various painful conditions provided effective analgesia
and was well tolerated.47 Tramadol may prove particularly useful in
patients with poor cardiopulmonary, renal, or hepatic function and
in those whom NSAIDs are not recommended or need to be used
with caution.48 A growing number of studies and case reports have
demonstrated the safety and efficacy of tramadol in the pediatric
population.49,50 Although it continues to be prescribed routinely in
Europe and North America, its clinical use is not recommended
in the pediatric population in some countries because of limited
prospective studies in patients younger than 18 years.
Although the specific drugs and doses are determined by the
needs of each child, general guidelines for drug therapies to
control pain for children with chronic and recurrent pain are few.
Guidelines have been developed through a Consensus Conference
on the Management of Pain in Childhood Cancer, published as a
supplement to Pediatrics51; in a monograph from the WHO
entitled, Cancer Pain Relief and Palliative Care for Children15;
and in clinical practice guidelines.5254 The drugs listed in this
chapter are based primarily on these sources, from the abundance
of literature on pain management for children with cancer or those
receiving palliative care, and from guidelines from our institution.55 Recommended starting doses for analgesic medications
to control childrens disease-related pain are listed in Tables 163
and 164. Starting doses for adjuvant analgesic medications to
control pain, drug-related side effects, and other symptoms
are listed in Table 165. For further review of analgesics and
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TABLE 16-3. Nonopioid Medications for Relieving Pain in Children

Drug
Dosage
Comments
Acetaminophen
1015 mg/kg p.o., q46h
Ibuprofen
510 mg/kg p.o., q68h
Naproxen
1020 mg/kg/d p.o., divided q12h
Diclofenac
1 mg/kg p.o., q8-12h
Lacks gastrointestinal and hematologic side effects; lacks antiinflammatory effects; may mask infection-associated fever. Dose
limit of 65 mg/kg/d or 4 g/d, whichever is less.
Anti-inflammatory activity. Use with caution in patients with
hepatic or renal impairment, compromised cardiac function or
hypertension (may cause fluid retention or edema), history of GI
bleeding or ulcers. Inhibits platelet aggregation. Dose limit of 40
mg/kg/d (maximum dose 2400 mg/d).
Anti-inflammatory activity. Use with caution and monitor closely
in patients with impaired renal function. Avoid in patients with
severe renal impairment. Dose limit of 1 g/d.
Anti-inflammatory activity. Similar GI, renal, and hepatic
precautions as noted for ibuprofen and naproxen. Dose limit of
50 mg/dose.
GI = gastrointestinal.
Note: Increasing the dose of nonopioids beyond the recommended therapeutic level produces a ceiling effect in that there is no additional analgesia, but there are
major increases in toxicity and side effects.
adjuvant analgesics in children, the reader is referred to references

41 and 56 through 63.
Principles of Opioid Administration

1. If pain relief is inadequate and there is no toxicity at peak onset
of opioid action, increase the dose in 50% increments.
2. Avoid intramuscular administration.
3. Whenever using continuous infusion, plan for hourly rescue
doses with short-onset opioids if needed. The rescue dose is
usually 50 to 200% of the continuous hourly dose. If greater
than six rescues are necessary in a 24-hour period, increase the
daily infusion total by the total amount of rescue doses for
the previous 24 hours. An alternative is to increase infusion
by 50%.
4. If changing between opioids with a short duration of action,
start the new opioid at 50% of the equianalgesic dose. Titrate to
effect. If changing between opioids from short to long duration
of action (i.e., morphine to methadone), start at 25% of the
equianalgesic dose and titrate to effect. These adjustments are
needed because of incomplete cross-tolerance between opioids.
5. To taper opioids (anyone on opioids over 1 wk must be tapered
to avoid withdrawal): taper by 50% for 2 days, and then
decrease by 25% every 2 days. When the dose is equianalgesic
to an oral morphine dose of 0.6 mg/kg/d, the dose may be
stopped. Some patients on opioids for prolonged periods may
require much slower weaning.
Children should receive analgesics at regular times, by the
clock, to provide consistent pain relief and prevent breakthrough
pain. The specific drug schedule (every 4 or 6 h) is based on the
drugs duration of action and the childs pain severity. Although
breakthrough pain episodes have been recognized as a problem
in adult pain control, they may represent an even more serious
problem for children. Unlike adults, who generally realize that
they can demand more potent analgesic medications or more
frequent dosing intervals, children have little control, little
awareness of alternatives, and fear that their pain cannot be
controlled. They may become progressively frightened, upset, and
preoccupied with their symptoms. Thus, it is essential to establish

and maintain a therapeutic window of pain relief for children.
Analgesic doses should be adjusted by the child. No one dose
will be appropriate for all children with pain. The goal is to select
a dose that prevents children from experiencing pain before they
receive the next dose. It is essential to monitor the childs pain
regularly and adjust analgesic doses as necessary to control the
pain. The effective opioid dose to relieve pain varies widely among
different children or even at different times in the same child.
Some children require massive opioid doses at frequent intervals
to control their pain. If such large doses are necessary for effective
pain control, and the side effects can be managed by adjunctive
medication so that children are comfortable, the doses are
appropriate. Children receiving opioids may develop altered sleep
patterns so that they are awake at night, fearful and complaining
about pain, and then sleep intermittently throughout the day. They
should receive adequate analgesics at night with antidepressants or
hypnotics as necessary to enable them to sleep throughout the
night. To relieve severe ongoing pain, opioid doses should be
increased steadily until comfort is achieved, unless the child
experiences unacceptable side effects such as somnolence or
respiratory depression (Table 166).
Medications should be administered to children by the simplest
and most effective route, usually by mouth. Because children are
afraid of painful injections, they may deny that they have pain or
they may not request medications. When possible, children should
receive medications through routes that do not cause additional
pain. Although optimal analgesic administration for children
requires flexibility in selecting routes according to childrens needs,
parenteral administration is often the most efficient route for
providing direct and rapid pain relief. Because intravenous,
intramuscular, and subcutaneous routes cause additional pain for
children, serious efforts have been expended on developing more
pain-free modes of administration that still provide relatively
direct and rapid analgesia. Attention has focused on improving
the effectiveness of oral routes. As an example, oral transmucosal
fentanyl citrate (OTFC) has previously been shown to provide the
rapid onset of analgesia via a pleasant route for children
undergoing painful medical procedures. OTFC produces effective
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TABLE 16-4. Opioid Medications: Usual Starting Doses for Analgesia in Pediatric Patients
Drug
Equianalgesic Dose
(parenteral)
Morphine
10 mg
Hydromorphone
Codeine
1.5 mg
120 mg
Bolus dose: 0.050.1 mg/kg

q24 h; Continuous
infusion: 0.010.04
mg/kg/h
0.0150.02 mg/kg q4h
Not recommended
Oxycodone
Meperidinea
510 mg
75 mg
Not recommended
0.51.0 mg/kg q34h
Fentanylb
100 g
Bolus dose: 12 g/kg;

continuous infusion:
12 g/kg/h
Controlled-release
morphinec,d
Controlled-release
hydromorphoned
Controlledrelease codeined
Controlled-release
oxycodoned
Methadone
Tramadol
0.6 mg/kg q8h or

0.9 mg/kg q12h
0.18 mg/kg q12h
Starting Dose IV
IV:p.o.
Ratio
Starting Dose
p.o./Transdermal
Duration of
Action
1:3
0.150.3 mg/kg/dose q4h
34 h
1:5
0.06 mg/kg q34h

1.0 mg/kg q4h
(maximum 1.5
mg/kg/dose)
0.10.2 mg/kg q34h
1.02.0 mg/kg q34h
(dose limit 150 mg)
25 g transdermal patch
24 h
34 h
0.2 mg/kg q48 h

1 mg/kg
q4-6h (dose limit
400 mg/d)
1250 h
46 h
1:4
34 h
13 h
1520 min
(IV); 72 h
(patch)
3 mg/kg q12h
0.6 mg/kg q12h
10 mg
100 mg
0.1 mg/kg q48h

2.0 mg/kg q46h
1: 2
Note: Doses are for opioid-naive patients. For infants younger than 6 mo, start at one quarter to one third the suggested dose and titrate to effect.
a
Avoid use in renal impairment as metabolite may cause seizures.
b
Potentially highly toxic. Not for use in acute pain control.
c
Use may be hampered by childs difficulty in swallowing large tablets.
d
The widely equianalgesic doses in adults are used as guidelines in pediatric practice, but have not been substantiated in children.
plasma concentrations within 15 to 20 minutes.64 Children aged 2

to 14 years have shown good cooperation and sedation when given
OTFC as a premedication prior to anesthetic induction.65,66 OTFC
produced safe and effective analgesia for outpatient wound care
in children and the taste was preferred to oral oxycodone.67
Many hospitals have restricted the use of intramuscular
injections because they are painful and drug absorption is not
reliable. They advocate the use of the intravenous route so that
medications can be administered directly without causing further
pain. Topical anesthetic creams should also be applied prior to the
insertion of intravenous lines in children. The use of Port-Aa-Cath
or some type of chronic indwelling central venous access has
become the gold standard in pediatrics, particularly for children
who require the administration of multiple drugs at frequent
intervals. A continuous infusion has several advantages over
intermittent subcutaneous, intramuscular, or intravenous administration. This method circumvents repetitive injections, prevents
delays in analgesic drug administration, and provides continuous
levels of pain control while avoiding adverse effects that occur with
peak levels and pain breakthroughs at trough levels. Continuous
infusion should be considered when children have pain for which
oral and intermittent parenteral opioids do not provide satisfactory pain control or when intractable vomiting prevents oral
medications. Children receiving a continuous infusion should
continue to receive rescue doses to control breakthrough pain,

as necessary. As outlined in Table 164, the rescue doses should
be 50 to 200% of the continuous hourly infusion dose. If children
experience repeated breakthrough pain, the basal rate can be
increased by 50% or by the total amount of opioid administered
through the rescue doses over a 24-hour period (divided by
24 h).
Patient-controlled analgesia (PCA) enables children to
administer analgesic doses according to their pain level. PCA
provides children with a continuum of analgesia that is prompt,
economical, not nurse-dependent, and results in a lower overall
use of opioids.6873 PCA has a high degree of safety, allows for wide
variability between patients, and avoids delays in analgesic
administration. The reader is referred to reference 49 for a full
review of PCA. It can now be regarded as a standard for the
delivery of analgesia in children older than 5 years of age.74
However, there are opposing views about the use of background
infusions with PCA. Although they may improve efficacy, they
may increase the occurrence of adverse effects such as nausea,
vomiting, sedation, and respiratory depression. In a comparison of
PCA with and without a background infusion for children having
lower extremity surgery, the total morphine requirements were
reduced in the PCA-only group and the background infusion
offered no advantage.75 In another study comparing background
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TABLE 16-5. Adjuvant Analgesic Drugs

Drug Category
Drug, Dosage
Indications
Comments
Antidepressants
Amitryptyline:
0.20.5 mg/kg p.o. Titrate upward by 0.25
mg/kg q23d. Maintenance dose: 0.23.0
mg/kg. Alternatives: nortriptyline,
doxepin, imipramine, venlafaxine.
Neuropathic pain (i.e.,

vincristine-induced,
radiation plexopathy,
tumour invasion,
CRPS-1).
Anticonvulsants
Carbamazepine: Initial dose of 10 mg/kg/d

p.o. divided OD or BID. Maintenance
dose: up to 2030 mg/kg/d p.o. divided
q8h. Increase dose gradually over 24 wk.
Alternatives: phenytoin, clonazepam.
Gabapentin: 5 mg/kg/d p.o. Titrate up
over 37 d. Maintenance dose: 1550
mg/kg/d p.o. divided TID
Neuropathic pain,
especially pain with
shooting or stabbing
qualities.
Usually results in improved sleep

and pain relief within 35 d.
May result in insomnia.
Anticholinergic side effects are
dose-limiting. Use with caution
for children with increased risk
for cardiac dysfunction.
Monitor for hematologic,
hepatic, and allergic reactions.
Side effects may include
gastrointestinal upset, ataxia,
dizziness, disorientation,
somnolence.
Sedatives, hypnotics,
anxiolytics
Diazepam: 0.0250.2 mg/kg p.o. q6h.
Acute anxiety or muscle

spasms.
Lorazepam: 0.05 mg/kg/dose SL.

Midazolam: 0.5 mg/kg/dose p.o. administered 1530 min prior to procedure;
0.05 mg/kg/dose IV for sedation.
Hydroxyzine: 0.5 mg/kg p.o. q6h.
Diphenhydramine: 0.51.0 mg/kg p.o./IV
q6h.
Dextroamphetamine or methylphenidate: 0.10.2 mg/kg BID. Escalate to 0.3
0.5 mg/kg as needed
Prednisone, prednisolone, and
dexamethasone: dose depends on clinical
situation. Dexamethasone: initial dose of
0.2 mg/kg IV to a maximum of 10 mg.
Subsequent dose of 0.3 mg/kg/d IV
divided q6h.
Premedication for
painful procedures.
Antihistamines
Psychostimulants
Corticosteroids
Sedative effect may limit opioid

use. Other side effects include
depression and dependence
with prolonged use.
Sedative side effects maybe

helpful.
Opioid-induced pruritus, Side effects include agitation,
anxiety, nausea.
sleep disturbance, and
anorexia. Administer second
Opioid-induced somnodose in afternoon to avoid
lence. Potentiation of
sleep disturbances.
opioid analgesia.
Headache from increased Side effects include edema,
intracranial pressure,
dyspeptic symptoms, and
spinal, or nerve comoccasional gastrointestinal
pression; widespread
bleeding. Burning and pain
metastatic disease.
with peripheral IV
administration.
CRPS-1 = complex regional pain syndrome type 1; SL = sublingual.
infusion and PCA, children between 9 and 15 years of age

achieved better pain relief with PCA, whereas children between
5 and 8 years of age showed no difference.76 Our current standard
is to add a background infusion to the PCA if the pain is not
controlled adequately with PCA alone (bolus-only mode). The
selection of opioid used in PCA is perhaps less critical than the
appropriate selection of parameters such as bolus dose, lockout,
and background infusion rate. The opioid choice may be based on
adverse effect profile rather than efficacy. Clearly, PCA offers
special advantages to children who have little control and who are
extremely frightened about uncontrolled pain. PCA is as it states,
patient-controlled analgesia. When special circumstances require
that alternate people administer the medication, we do allow both
nurse- and parent-controlled analgesia. Under these circumstances, parents require our nurse educators to fully educate them
on the use of PCA.
Alternatives to the intravenous for pain management are still
being investigated, especially in the pediatric population. Fentanyl
is a potent synthetic opioid, which like morphine binds to

receptors. However, fentanyl is 75 to 100 times more potent than
morphine. The intravenous preparation of fentanyl has been used
extensively in children. A transdermal preparation of fentanyl was
introduced in 1991 for use with chronic pain. This route provides
a noninvasive but continuously controlled delivery system.
Although limited data are available regarding transdermal fentanyl
(TF) in children, its use is increasing for children with stable and
chronic pain. Noyes and Irving demonstrated that TF was well
tolerated, provided effective pain relief in 11 of 13 children, and
suggested that it was the ideal approach for children in whom
compliance with oral analgesics was problematic.77 In the palliative
care setting, children were converted from oral morphine to TF.78
The investigators noted diminished side effects and improved
convenience with TF. The majority of parents and investigators
considered TF to be better than previous treatment. No serious
adverse events were attributed to fentanyl, suggesting that TF was
both effective and acceptable for children and their families.
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TABLE 16-6. Opioid-Related Adverse Effects

Side Effect
Management Strategy
Respiratory depression
Reduce opioid dose by 50%, gradual dose titration to maintain pain relief without
respiratory depression.
Control of airway, breathing and circulation as needed. Naloxone, titrated to effect with
0.01 mg/kg/dose IV/ETT repeated as needed. Even smaller frequent doses of diluted
naloxone or naloxone drip are preferable for patients on chronic opioid therapy to
avoid severe, painful withdrawal syndrome. Repeated doses often required until
opioid side effect subsides given short half-life of naloxone.
Frequently subsides after a few days without dosage reduction. Methylphenidate or
dextroamphetamine (0.1 mg/kg administered BID in the morning and midday so as
not to interfere with nighttime sleep). The dose can be escalated in increments of
0.050.1 mg/kg to a maximum of 10 mg/dose for dextroamphetamine and 20
mg/dose for methylphenidate.
Increased fluids and bulk, prophylactic laxatives as indicated.
Administer an antiemetic (e.g., ondansetron, 0.10.15 mg/kg IV/p.o./transmucosal q8h.
Antihistamines (e.g., dimenhydrinate 0.5 mg/kg/dose 46 h IV/p.o.) may also be
used. Prechemotherapy, nabilone 0.51.0 mg p.o. and then q12h may also be used.
Reassurance only with mild symptoms. A reduced dose of opioid or a change to a
different opioid. Addition of a neuroleptic agent (e.g., haloperidol 0.1 mg/kg p.o./IV
q8h to a maximum of 30 mg/d).
Generally occur only during extremely high-dose therapy. Reduction in opioid dose
indicated if possible. Addition of a benzodiazepine (e.g., clonazepam 0.05 mg/kg/d
divided BID or TID increasing by 0.05 mg/kg/d q3d as needed up to 0.2 mg/kg/d to a
maximum of 20 mg/d).
Rule out bladder outlet obstruction, neurogenic bladder, and other precipitating
medications (e.g., tricyclic antidepressant). Particularly common with epidural
opioids. Change of opioid, route of administration, and dose may relieve symptom.
Bethanechol or catheter may be required.
Respiratory arrest
Drowsiness and sedation
Constipation
Nausea and vomiting
Confusion, nightmares, hallucinations
Multifocal myoclonus, seizures
Urinary retention
ETT = endotracheal tube.
Similarly, no adverse effects were noted in a study of TF for

children with pain caused by sickle cell crisis.79 This study showed
a significant relationship between TF dose and fentanyl concentration. Pain control with TF was improved in 7 of 10 patients
in comparison with PCA alone. In a multicenter crossover study
in adults, TF resulted in significantly less constipation and less
daytime drowsiness than morphine, but a greater incidence of
sleep disturbance and shorter sleep duration.80 Of those patients
able to express a preference, significantly more preferred TF. As
with all opioids, fatal adult complications have been noted
with the use of multiple transdermal patches.81 Zernikow and
colleagues provide a thorough summary in a recently published
review of TF in childhood and adolescence.82
The use of regional techniques (epidural and spinal) for the
administration of local anesthetic agents and analgesics for children continues to be an integral part of pain control.83 Experience
from many centers suggests that these techniques can be extremely
useful for children with advanced disease with resulting pain that
may be difficult to control by more conventional means. It is also
feasible for children to receive epidural and spinal infusions at
home on an extended basis.
When one undertakes the administration of potent analgesics
and anesthetics, whether by intravenous or a regional anaesthetic
technique such as an epidural or spinal approach, appropriate
monitoring remains paramount to ensuring the safety of our
patients. This involves the education and training of staff, the
immediate availability of resuscitative drugs and equipment, and
an accurate and timely pain record consisting of vital signs, pain
scores, and sedation scores. A complete set of intravenous and

epidural monitoring guidelines have been included in Table 167.
Dosing Considerations for

Neonates and Infants
Research on controlling pain in neonates has led to improved and
rational therapeutic regimens to provide safe and effective
analgesia while minimizing adverse effects.8491 Neonates and
infants require the same three categories of analgesic drugs as
older children. However, the differences in pharmacokinetics and
pharmacodynamics among neonates, preterm infants, and fullterm infants warrant special dosing considerations for infants and
close monitoring when they receive opioids. Acetaminophen can
be safely administered to neonates and infants with limited
concern for hepatotoxicity, when given for short courses at the
recommended dose (1015 mg/kg p.o.). The rate of absorption is
slower in neonates and the plasma half-life is prolonged. Peak
serum concentrations are reached at approximately 60 minutes
after an oral dose and subsequent doses may be required at 6rather than 4-hour intervals. Acetaminophen does not cause
respiratory depression and does not produce tolerance.
Opioid analgesics are the mainstay of treatment for controlling
severe pain in neonates. When compared as in Table 164, the
starting doses for opioid analgesics in infants younger than 6
months of age are one quarter to one third the recommended
doses for older patients. As with children, the dosage and mode of
administration of opioids need to be titrated to achieve the degree
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TABLE 16-7. Analgesia Monitoring Guidelines

Baseline Assessment
Obtain RR, HR, BP, O2 saturation, sedation score, and pain score
before administering a single or intermittent dose or initiating
continuous infusion.
Intermittent Intravenous Administration
RR, HR, BP, and sedation score q5min 4, then q30min 2,
and then as per childs condition/pre-existing orders.
Pain score q2030 min.
Continuously monitor O2 saturation only for children whose
underlying condition predisposes them to respiratory
depression.
Intravenous additive (to run over 1520 min)
RR, HR, BP, and sedation score q10min 2, then every 30 min
2, and then as per childs condition.
Pain score at completion of the flush, then q30min 2, and then
as per childs condition or pre-existing orders.
Continuously monitor O2 saturation only for children whose
underlying condition predisposes them to respiratory
depression.
Continuous IV Infusion/PCA
RR, HR, BP, pain score, and sedation score q1h 4, then RR and
sedation score q1h, and then HR, BP, and pain score q4h.
Continuously monitor O2 saturation and document reading q1h.
Intermittent Epidural Administration
RR, HR, and BP q5min for the first 20 min following a bolus
dose, and then RR and sedation score q1h.
HR, BP, pain score, and motor block score q4h.
Continuously monitor only for children whose underlying
condition predisposes them to respiratory depression.
Continuous Epidural infusiona,b
RR, HR, BP, sedation score, pain score, and motor block score
q1h 4 h, then RR and sedation score q1h, and HR, BP, pain
score, and motor block score with sensory level q4h.
Continuously monitor O2 saturation and document reading q1h.
BP = blood pressure; ECG = electrocardiographic; HR = heart rate; PCA =
patient-controlled analgesia; RR = respiratory rate.
a
Opioids used with bupivacaine.
b
After any change in drug dose, infusion rate or if transferred between patient
care areas, return to assessments q1h for 4 h. Continuous RR or apnea
monitoring may provide additional benefits for certain children who are
receiving continuous opioid infusions by alerting the nurse to a decreasing RR.
RR monitoring is not a substitute for frequent patient observation and vital sign
monitoring. ECG monitoring is not routinely required, but may be ordered if the
childs underlying condition predisposes them to ECG abnormalities.
Adapted from 20012002 Drug Formulary, The Hospital for Sick Children,
Toronto.
of analgesia required and a reasonable level of sedation. The drug

clearance and the analgesic effects of morphine, fentanyl,
sufentanil, and methadone for infants older than 6 months and
children are similar to those for young adults. Thus, the general
clinical impression is that morphine and other opioids have a
reasonable margin of safety and excellent efficacy for most
children older than 6 months of age. However, premature and
term newborns show reduced clearance of most opioids. The
widely observed sensitivity of newborns to morphine is probably
because of pharmacokinetic factors including a smaller volume of
distribution and diminished clearance as well as physiologic
factors including immaturity of the blood-brain barrier and

increased sensitivity owing to the immaturity of ventilatory
responses to hypoxemia and hypercarbia. Therefore, opioids
should be used more cautiously in infants younger than 6 months
of age and only with appropriate monitoring or cardiovascular and
respiratory function. Proper dosing and careful monitoring will
help minimize adverse effects. Tolerance has significance only as
a signal of receptor function or a potential indicator of withdrawal
when therapy is discontinued.
Neonates who have pain severe enough to require opioids
usually have an intravenous line in place. If a limited number of
doses are needed and if intravenous access is not available,
intramuscular or subcutaneous routes are still used occasionally in
full-term neonates. However, these routes are painful and not
suitable for preterm neonates because of their sparse muscle mass
and delicate skin. They are also not suitable for long-term pain
management in term neonates because plasma levels and clinical
effects are less controlled and difficult to titrate, especially with
intramuscular administrations. Intravenous bolus dosing may
produce high peak concentrations resulting in depressed mental
status and respiratory depression followed by a rapid decline in
plasma levels causing alternating periods of pain and analgesia.
Thus, a continuous intravenous infusion of opioids, producing
constant blood levels and minimal fluctuations in analgesia, is the
most effective route. The use of peripherally inserted central
catheters (PICCs) has become standard practice for the neonate
with difficult venous access or for the patient that may require
access for a prolonged period. For morphine dosing, Anand and
associates have recommended an initial loading dose of 50 g/kg
followed by a continuous infusion at 10 to 20 g/kg/h.85 Further
increases in the infusion rate may be required to titrate to clinical
effect or with the development of tolerance. However, infants must
be monitored carefully because most opioids have a prolonged
duration of action in neonates, so that continuous infusions can
result in slow accumulation of the drug over time with high blood
levels that may not be detected immediately.
The principal and potentially life-threatening side effect of all
opioid drugs is the dose-dependent respiratory depression leading
to apnea, which may be observed in infants and neonates at
relatively low doses. This may be advantageous in ventilated
patients, but obviously poses considerable challenges when using
opioids in spontaneously breathing newborns. Opioid-induced
respiratory depression can be reversed with naloxone, but the
effect of the drug diminishes within 30 minutes so that repeated
naloxone dosing may be required. If apnea does occur, stimulation
of the baby will usually elicit some respiratory effort temporarily
while emergency arrangements are made to provide respiratory
support and administer naloxone. Naloxone should be titrated to
effect in increments of 10 g/kg until the desired effect is obtained
or up to a total dose of 100 g/kg. High doses of naloxone may
produce a massive stress response from sudden nociception and
withdrawal or may result in undesirable fluid shifts. Following an
effective dose of naloxone, the neonate should be monitored
closely for at least 24 hours. In fact, because plasma concentrations
of morphine can increase in some neonates even after an opioid
infusion is discontinued, neonates require close monitoring for at
least 24 hours after morphine administration is discontinued.
Young infants, especially premature babies or those who have
neurologic abnormalities or pulmonary disease, are more susceptible to apnea and respiratory depression when systemic
opioids are used. An infants metabolism is altered because of the
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immaturity of the hepatic microsomal enzymes so that the
elimination half-life of opioids is longer and there may be
increased entry of the opioid into the brain owing to immaturity
of the blood-brain barrier. Both factors result in young infants
having a higher concentration of opioids in the brain for a given
dose than mature infants or adults. Thus, nonventilated infants
who are younger than 1 year of age should be monitored closely
when they receive opioids because extreme sedation and
decreased respiratory effort may be difficult to assess. Institutions
in which neonates and infants are treated should train personnel
in the safe and effective administration of analgesia and provide
appropriate technologies for monitoring. Monitoring should
include respiratory rate, heart rate, blood pressure, sedation score,
and pain score at regular intervals, as outlined in Table 167.
Epidural analgesia is now widely used for infants with
postoperative pain. The hemodynamic effects of major regional
analgesia in infants with postoperative pain appear minimal. For
pediatric epidural infusions, the standard local anesthetic that we
use is bupivacaine at an infusion rate of 0.2 to 0.4 mg/kg/h.
Epidural infusions that exceed the recommended rate may lead to
convulsions. In addition even at constant infusion rates, bupivacaine levels may continue to increase after 48 hours. Epidural
opioids such as morphine and fentanyl have been used successfully, even for very young infants. The proper use of infusions or
intermittent doses of epidural opioids or local anesthetics requires
expertise and appropriate monitoring, as outlined in Table 167.
PHYSICAL DEPENDENCE,
TOLERANCE, AND ADDICTION
Physical dependence is defined as a state of adaptation that often
includes tolerance and is manifested by a drug classspecific
withdrawal syndrome that can be produced by abrupt cessation,
rapid dose reduction, decrease in the blood level of the drug, or the
administration of an antagonist. Tolerance is a state of adaptation
in which exposure to a drug induces changes that result in a
diminution of one or more of the drugs effects over time.
Addiction is a primary, chronic, neurobiologic disease, with
genetic, psychosocial, and environmental factors influencing its
development and manifestations. It is characterized by behaviors
that include one or more of the following four Cs: impaired control
over drug use, compulsive use, continued use despite harm
(consequences), and craving.92 The fear of opioid addiction in
children has been greatly exaggerated. Although physical dependence is common, gradual tapering protocols can control the
withdrawal syndromes caused by an abrupt cessation of the
medication. Physical dependence may develop in as short a period
as 5 to 7 days. Tolerance is also an expected change to be seen and
should be anticipated in children. There is no empirical evidence
that children receiving opioid analgesics for pain control are at
risk for addiction. By contrast, children who do not receive
appropriate analgesic medications are probably more at risk for
pseudoaddiction by becoming excessively concerned about
receiving their next medication dose in the hope that they might
eventually relieve their suffering.
Parents, and occasionally staff, may have misconceptions about
the use of potent opioids. Although the sensory characteristics of
childrens pain should be consistent with the known pattern from
the presumed source of tissue injury, the source is not easily
identified for all children. This is particularly true for children
285
who have complex health care difficulties because there may be

multiple sources of noxious stimulation caused by disease and the
effects of prescribed therapies. Yet, childrens pain must be
controlled, even when the specific etiology has not yet been
determined. Otherwise, children become increasingly anxious,
fearful, and distressed, thereby beginning a cycle of increasing pain
that will be more difficult to alleviate.
Parents are often anxious about opioids for their children,
particularly when children require increased dose increments.
Staff must educate parents that physical dependence and tolerance
are very different from addiction. Parents will then understand
that physical dependence and tolerance are normal drug effects;
they do not mean that their children with pain have become
addicted. Physical drug dependence is well recognized. When
opioids are suddenly withdrawn, infants and children may
suffer from irritability, anxiety, insomnia, diaphoresis, rhinorrhea,
nausea, vomiting, abdominal cramps, and diarrhea. These
withdrawal symptoms can be prevented by the gradual tapering
of an opioid. Even though children with severe pain require
progressively higher and more frequent opioid doses because of
drug tolerance, they should receive the doses they need to relieve
their pain. However, children who require increased opioids to
relieve previously controlled pain should be assessed carefully to
determine whether the disease has progressed because pain may
be the first sign of advancing disease.
Therapists can use familiar analogies to explain dependence, tolerance, and addiction. For example, parents are often
accustomed to drinking coffee in the morning. They know that
they will experience some noticeable effects without their usual
caffeine intake, but they also know that they can withdraw from
coffee by gradually lowering their daily consumption. The fact that
their body is used to a certain amount of caffeine at certain times
of the day means that they are dependent. Similarly, many people
become accustomed to a certain level of salt for a food to taste
salty. After a while, they may need to increase their salt intake if
they want foods to taste the same, because their bodies have
adjusted to or now tolerate the previous amount of salt so that it
no longer has the same effect. In the same way, their children can
become tolerant to a morphine dose so that they require a slightly
higher dose to achieve the same pain reduction. These benign
examples of a bodys normal responses to substances often help
parents understand that when opioids are prescribed for their
children, the effects of those drugs are well known, are well
understood, and will not lead to adverse effects including
addiction.
Opioid-Related Adverse Effects

The safe, rational use of opioid analgesics requires an understanding of their clinical pharmacology. The potent opioids that
we use to treat children for pain control have no fixed upper dose
limit. The dose can be increased as necessary to maximize pain
control, as long as children do not experience dose-limiting side
effects (i.e., vomiting, respiratory depression). The goal should be
titrating medication either up or down for maximum clinical
effect. Side effects must be anticipated and treated aggressively.
Because opioids produce physical dependence and tolerance,
doses must be increased over time to control pain. Doses must be
adjusted according to the childs need depending on pain severity,
prior analgesic medication use, and the bioavailability and drug
distribution of the medication.
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All opioids have a similar spectrum of side effects. These wellknown problems should be anticipated and treated whenever
opioids are administered, so that children can receive pain control
without suffering untoward effects. Children may not report all
side effects (e.g., constipation, dysphoria) voluntarily, so they
should be asked specifically about these problems. Some side
effects may resolve within the first 1 or 2 weeks of initiating therapy
as the child develops tolerance to them (e.g., nausea, vomiting, and
drowsiness). The clinician must educate the patient about these
problems and encourage them to give the medication an adequate
trial. Slow titration may minimize this problem. Other side effects
may require aggressive treatment. If they persist despite appropriate
interventions, conversion to an alternate opioid may be indicated.
There is generally incomplete cross-tolerance between opioids, so
that a general guideline for converting from one opioid to another
is to begin the new opioid at the lower dosing range and titrate
upward. When used in therapeutic doses, opioids have not been
demonstrated to cause long-term permanent organ toxicity. This
makes them a safe choice for use in infants and children. There is
evidence that untreated severe chronic pain may cause cognitive
impairment, which is improved with opioid therapy. The treatment
of opioid side effects is summarized in Table 166.
Nondrug Therapies
Cognitive and Behavioral Approaches
An extensive array of nondrug therapies are available to treat
childrens pain, including counseling, guided imagery, hypnosis,
biofeedback, behavior management, acupuncture, massage, homeopathic remedies, naturopathic approaches, and herbal medicines.
Nondrug therapies are generally regarded as safe with few
contraindications to their use in otherwise healthy children. However, almost no pediatric research has been conducted on many
of the therapies regarded as complementary to traditional medical
approaches. Thus, the efficacy of complementary therapies
for treating childrens pain is unknown, even though children
are increasingly using complementary therapies.93 By contrast,
the evidence base supporting the efficacy of cognitive and
behavioral approaches is strong.4,5,15,94105 These methods can
mitigate some of the factors that intensify pain, distress, and
disability for children.
The primary cognitive and behavioral therapies are listed in
Table 168. Cognitive therapies are directed at a childs beliefs,
expectations, and coping abilities. They encompass a wide range
of approaches from basic patient education to formal psychotherapy. Most children and families benefit from supportive
counseling. Accurate information about what will happen and
what children may feel should improve childrens understanding,
increase their control, lessen their distress, and reduce their pain.
TABLE 16-8. Cognitive and Behavioral Therapies
Cognitive
Behavioral
Information
Choices and control
Counseling
Stress management
Attention and distraction
Guided imagery
Hypnosis
Simple exercise
Participation in activities
Desensitization training
Relaxation training
Biofeedback
Behavioral modification
In addition, health care providers can teach children how to

use a few pain control methods to lessen pain and guide families
to recognize the particular circumstances that exacerbate pain and
distress. These methods provide children with some independent
strategies, either to relieve mild pain or to complement the
medication needed to relieve strong pain. Children should begin
by learning a few basic methods. As they acquire confidence in
using these methods, they seem to naturally adapt them to fit their
personality or invent new equally effective methods. A therapist
guides them throughout this process. Children should be
interested and motivated in learning some independent pain
control methods. They seem more adept than adults at using
nondrug therapies, presumably because they are usually less
biased than adults about their potential efficacy.
Distraction is a simple and effective pain control method.
When children intently attend to something other than their pain,
they can lessen its intensity and unpleasantness. Distraction is
often incorrectly perceived as a simple diversionary tactic with
the implication is that the pain is still there, but the child is
momentarily focused elsewhere. However, when childrens
attention is fully absorbed in some engaging topic or activity,
distraction is a very active process that can reduce the neuronal
responses to a noxious stimulus. Children do not simply ignore
their pain, but are actually reducing it. The essential feature for
achieving pain relief is a childs ability to attend fully to and
concentrate on something else besides the pain. Therefore, the
choice of a distraction is crucial and varies according to childrens
age and interests. Young children usually need to be actively
involved with their parents or peers, whereas older children and
adolescents can distract themselves more independently. Children
should work with their parents or a therapist to choose distracting
activities that can be practically incorporated into their lives.
Guided imagery is a specific method of distraction and attention.
A health care provider guides children to concentrate fully on the
image of an experience or situation. Children recall and vividly
describe what they experienced including the colors, sounds,
tastes, and feel of the situation. Children are guided to become as
immersed in their image as if it were occurring in the present
situation.
There is considerable overlap among the interventions of
attention/distraction, guided imagery, and hypnosis. Hypnosis
usually begins with an induction procedure in which a childs full
attention is focused gradually on the therapist and their
suggestions. The therapist guides the child into a very relaxed
physical and mental state, an altered level of consciousness, which
is distinct from an alert or sleep state. The induction procedure
typically includes guided imagery for children and progressive
muscle relaxation for adolescents. The induction can be very
simple for young children. They can be guided into a hypnotic
state as they vividly imagine their favorite television shows,
movies, books, or cartoon characters.106108 As they imagine an
activity, scene, or character, they gradually receive suggestions for
relaxation, reduced anxiety, increased control, and pain reduction.
The therapist provides consistent positive suggestions, rather than
authoritative commands. The emphasis is on the childs own
natural abilities, as in Notice that your back, legs (painful body
areas) feel lighter, the heaviness and pain are starting to lessen. It
seems as if your back doesnt hurt as much as before. You are doing
well at turning down the pain switch. During a hypnotic state,
individuals become extremely susceptible to suggestions including
suggestions for pain relief. Children become so involved in
thoughts or ideas that they dissociate from a reality orien-
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tation.107 Hypnosis enables children to redirect attention from the
painful sensation or to reinterpret the sensation as something
more pleasant, less aversive, or less bothersome.108 Like adults,
children differ in their ability to be hypnotized. Childrens ability
to use their imagination is the key component in determining their
hypnotic susceptibility.
Behavior therapy is often used in combination with cognitive
therapy. The goals are to lessen the specific behaviors amongst the
child, family, and staff that may increase pain, distress, or disability
while concomitantly increasing healthy behaviors that engage
children in living as fully as possible. Relaxation training is a
common method used for children with chronic pain. Therapists
train children how to achieve a state of mental and physical
relaxation so that children can eventually relax independently
when they experience pain or feel stressed and fearful about their
condition. Therapists may use guided imagery, hypnosis, deep
breathing, or progressive relaxation exercises to train children.
Biofeedback is a useful tool for teaching children to recognize
when their bodies are relaxed. Surface electrodes, attached to the
skin or specific muscle groups, transform the electrical activity of
the body into easily observable signals.
Pain Control Methods

Health professionals and parents can relieve childrens pain, not
only by administering analgesic drugs but also by increasing their
understanding and control, decreasing their emotional distress,
and teaching them some simple methods to reduce their pain and
anxiety. In addition to providing support and reassurance, parents
can help children to understand what will happen, make choices,
gain whatever control is possible within the setting, and independently use pain-reducing methods. Thus, the family as well as
health professionals share a fundamental role in managing the
childrens pain. The key concept underlying the use of all analgesic
and nonanalgesic therapies for children is by the child.
Specific pain control methods that require the child to
concentrate and focus attention should always be used for children
with pain. Beales noted critical differences between adults and
children in their perceptions of pain.109 Childrens pain seemed
even less positively correlated with pathology than adults pain.
Beales suggested that some of the psychological mechanisms
involved in pain perception may be manipulated more easily in
children than in adults, consistent with our clinical observations
that childrens pain is more plastic than that of adults.1,102 Children
seem to possess an enhanced ability to absorb themselves completely in a task, game, or imagined event and, thus, might be more
able than adults to trigger endogenous pain-inhibitory mechanisms. Even very young children can easily learn to use a variety
of practical pain control methods. The goals of therapy are to
enable children to understand what is happening and to have
something that they can actively do to lessen their anxiety, distress,
and pain.
The specific methods selected depend on the age of the child,
the type of pain experienced, and the resources available. Simple
methods such as deep breathing, blowing bubbles, alternately
tightening and relaxing their fists, squeezing their mothers hand,
listening to stories or music, and imagining that they are in a
pleasant setting can be very effective for reducing procedurerelated pain, when used with appropriate analgesics. When
possible, children should learn a few basic methods to reduce their
pain and distress. They should not be encouraged to develop a
false reliance on the magical benefits of any one method. Instead,
287
they should understand that these practical methods relieve pain

because they change the factors that usually increase pain and they
help to restore normal sensory input.
All children should learn that pain from some procedures is
generally less when they are able to choose the site and rub the
area before and after the injection or fingerstick. They should learn
that pain is less when they are very relaxed. Progressive muscle
relaxation uses simple exercises in which they tense and relax their
body limbs, whereas using biofeedback can help to show them that
any type of pain can be intensified if the muscles are always
tightened. Children should learn that fear and anxiety can make
them tense and increase pain. They need practical tools to alleviate
their fear or their anxiety toward necessary treatments. Children
and families must learn that what they think, how they behave,
and how they feel affect their childrens pain. Then they can begin
to work independently and with staff to create additional nondrug
pain control methods based on the childs interest, the cultural
setting, and the availability of resources. Specific interventions
should be selected and administered to children as part of a
comprehensive pain program, in the same manner as the most
appropriate analgesics are selected and administered in adequate
doses, at regular dosing intervals, through the most efficient
routes.
SUMMARY
Optimal pain control for children with chronic and recurrent pain
requires an integrated treatment plan with both drug and nondrug
therapies. However, the specific interventions must be selected
after determination of the primary and secondary sources of
noxious stimulation and after a thorough assessment of the unique
situational, behavioral, emotional, and familial factors that affect
a childs pain. It is impossible to adequately relieve childrens pain
from a unidimensional perspective, in which pain is considered
as synonymous with the nature and extent of tissue damage.
Childhood pain must be viewed from a multidimensional
perspective because multiple sensory, environmental, and
emotional factors are responsible for the pain, no matter how
seemingly clear-cut the etiology may be. Treatment begins with a
thorough assessment of these multiple factors using structured
interviews and standardized measures. Pharmacologic, physical,
and psychological strategies must be incorporated into a flexible
intervention program for children, in which parents and siblings
form an essential component of treatment.
Like adults, childrens pain affects the entire family and must
be viewed within a broader context. Effective pain control is
possible when the goals are to reduce or block nociceptive activity
by attenuating responses in peripheral afferents and central
pathways, activate endogenous pain inhibitory systems, and
modify situational factors that exacerbate pain. Thus, the choice
for pain control is not merely drug versus nondrug therapy, but
rather a therapy that mitigates both the causative and the
contributing factors for pain. Pain management is a continuous
dynamic process, because the disease state and factors that
influence pain are not static. Different combinations of drug and
nondrug therapies will be required at different times. Thus, health
professionals must continually assume as much responsibility for
monitoring and relieving childrens pain as for medically
managing their diseases. Children should not suffer. We have the
knowledge to ensure that children receive adequate pain control.
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73. Webb C, Paarlberg J, Sussman M. The use of a PCA device by parents
or nurses for postoperative pain in children with cerebral palsy. J Pain
Symptom Manage. 1991;6:160.
74. McDonald AJ, Cooper MG. Patient-controlled analgesia: an appropriate
method of pain control in children. Paediatr Drugs. 2001;3:273284.
75. McNeely JK, Trentadue NC. Comparison of patient-controlled
analgesia with and without nighttime morphine infusion following
lower extremity surgery in children. J Pain Symptom Manage. 1997;
13:268273.
76. Bray RJ, Woodhams AM, Vallis CJ, et al. A double-blind comparison
of morphine infusion and patient controlled analgesia in children.
77. Noyes M, Irving H. The use of transdermal fentanyl in pediatric
oncology palliative care. Am J Hosp Palliat Care. 2001;18:411416.
78. Hunt A, Goldman A, Devine T, et al. Transdermal fentanyl for pain relief
in a paediatric palliative care population. Palliat Med. 2001;15:405412.
79. Christensen ML, Wang WC, Harris S, et al. Transdermal fentanyl
administration in children and adolescents with sickle cell pain crisis.
J Pediatr Hematol Oncol. 1996;18:372376.
80. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained-release
oral morphine in cancer pain: preference, efficacy, and quality of life.
The TTS-Fentanyl Comparative Trial Group. J Pain Symptom Manage.
1997;13:254261.
81. Edinboro LE, Poklis A, Trautman D, et al. Fatal fentanyl intoxication
following excessive transdermal application. J Forensic Sci. 1997;42:
741743.
82. Zernikow B, Michel E, Anderson B. Transdermal fentanyl in childhood and adolescence: a comprehensive literature review. J Pain.
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83. Wilder RT. Regional anesthetic techniques for chronic pain
management in children. In: Schechter NL, Berde CB, Yaster M, editors.
Pain in Infants, Children, and Adolescents. 2nd ed. Philadelphia:
Lippincott Williams & Wilkins; 2003. pp. 396416.
84. Stevens BJ, Johnston CC, Gibbins S. Pain assessment in neonates. In:
Anand K, Stevens B, McGrath P, (Eds). Pain in neonates. Amsterdam:
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85. Anand K, Shapiro B, Berde CB. Pharmacotherapy with systemic
analgesics. In: Anand K, McGrath P, editors. Pain in Neonates. New
York: Elsevier; 1993. pp. 155198.
86. Fitzgerald M, Howard R. The neurobiological basis of pediatric pain.
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87. Franck L, Gregory G. Clinical evaluation and treatment of infant pain
in the neonatal intensive care unit. In: Schechter NL, Berde CB, Yaster
M, editors. Pain in Infants, Children, and Adolescents. Baltimore:
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89. Koren G, Butt G, Chinyanga H, et al. Postoperative morphine
infusion in newborn infants: assessment of disposition characteristics
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90. Collins C, Koren G, Crean P, et al. Fentanyl pharmacokinetics and
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93. Spigelblatt L, Lan-Ammara G, Pless IB, et al. The use of alternative
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94. Dahlquist LM, Gil KM, Armstrong FD, et al. Behavioral management
of childrens distress during chemotherapy. J Behav Ther Exp
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95. Dash J. Hypnosis for symptom amelioration. In: Kellerman J, editor.
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96. Hartman GA. Hypnosis as an adjuvant in the treatment of childhood
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97. Hilgard JR, LeBaron S. Relief of anxiety and pain in children and
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98. Hilgard JR, Frankel FH, LeBaron S, (eds). Hypnotherapy of Pain in
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99. Jay SM, Ozolins L, Elliott CH, et al. Behavioral management of
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100. Katz ER, Kellerman J, Ellenberg L. Hypnosis in the reduction of

acute pain and distress in children with cancer. J Pediatr Psychol.
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101. LaBaw W, Holton C, Tewell K, et al. The use of self-hypnosis by
children with cancer. Am J Clin Hypn. 1975;17:233238.
102. McGrath PA, HL. A practical cognitive-behavioral approach for
controlling childrens pain. In: Gatchel R, Turk DC, editors.
Psychological Approaches to Pain Management. A Practitioners
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103. Olness K. Imagery (self-hypnosis) as adjunct therapy in childhood
cancer: clinical experience with 25 patients. Am J Pediatr Hematol
Oncol. 1981;3:313321.
104. Olness K. Hypnosis in pediatric practice. Curr Probl Pediatr.
1981;12:147.
105. Zeltzer L, LeBaron S. Hypnosis and nonhypnotic techniques for
reduction of pain and anxiety during painful procedures in children
and adolescents with cancer. J Pediatr. 1982;101:10321035.
106. Hall H. Hypnosis and pediatrics. In: Tennes R, editor. Medical
Hypnosis: An Introduction and Clinical Guide. New York: Churchill
Livingstone; 1999. pp. 7993.
107. LeBaron S, Zeltzer L. Children in pain. In: Barber J, editor. Hypnosis
and Suggestion in the Treatment of Pain: A Clinical Guide. New York:
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108. Olness K, Kohen DP, editors. Hypnosis and Hypnotherapy with
Children. 3rd ed. New York: Guilford Press; 1996. pp. xiv, 457.
109. Beales J. Pain in children with cancer. In: Bonica J, Ventafridda V,
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II
P A R T
17
C H A P T E R
An Introduction to the Intricacies

of Pharmacology in Pediatrics
Brian J. Anderson
INTRODUCTION
Children have been labeled therapeutic orphans in the past.1 They
were involved in all of the major therapeutic catastrophes that have
shaped modern drug development,2,3 and as a consequence,
pharmacokinetic (PK) and pharmacodynamic (PD) studies were
not performed in children for many years because it was considered
unethical. Unmonitored off-label use of medicines in children,
extrapolated from adult data, has resulted in significant morbidity
that could have been avoided or minimized by appropriate testing
in children.47 This morbidity extended to the practice of pediatric
anesthesia; neonates and infants given continuous-infusion epidural analgesia suffered seizures attributable to high serum bupivacaine concentrations, and these high concentrations were a direct
consequence of a failure to appreciate reduced clearance in the
neonatal age group.5 Licensing laws that encourage pediatric
studies,8,9 improvements in drug assay techniques that allow smallvolume samples, and population modeling have dramatically
altered the scene for pediatric pharmacologic studies.
PEDIATRIC DIFFERENCES
Subsequent chapters detail current knowledge of pediatric
anesthetic pharmacology. A recurring theme is the impact growth
and development has on PK and PD in children. Disease type,
presentation, and progression are different from those in adults.
Pediatric anesthesiologists have always sought detailed insight of
the drugs they use and have been at the forefront of such research
in order to best serve their patients. The effect of some of these
differences is highlighted in this chapter.
Pharmacokinetic Considerations
Absorption
The majority of drugs used in anesthesia are administered either
intravenously or through the lungs. Pulmonary absorption is
generally more rapid in infants and children than in adults.10 The

greater fraction of the cardiac output distributed to the vessel-rich
tissue group (i.e., a clearance factor) and the lower tissue/blood
solubility (i.e., a volume factor) also affect the more rapid wash-in
of inhalational anesthetics in the younger age group.11 Solubility
determines volume of distribution. An inhalational agent with
a greater volume of distribution will take longer to reach a steadystate concentration when delivered at a constant rate. The
solubilities in blood of halothane, isoflurane, enflurane, and
methoxyflurane are 18% less in neonates than in adults.12 Infants,
with their decreased solubility, would be expected to have a shorter
time to reach a predetermined FE/FI (fraction of expired gasto
fraction of inspired gas) ratio because of a smaller volume of
distribution. Decreased solubility (i.e., smaller volume of distribution) and size factors (i.e., faster physiologic processes)
increase speed of onset. The increased minimum alveolar concentration (MAC; i.e., a pharmacodynamic difference) and a ratedependent cardiac output set the scene for a relative overdose with
halothane. A lack of awareness of what constitutes bradycardia in
neonates and infants completes the recipe. Age has little effect on
the solubility of the less-soluble agents nitrous oxide and sevoflurane.13 Reduced solubility and the reduced cardiac effects of
sevoflurane guaranteed its superiority over halothane for many
indications.
The rate at which most drugs are absorbed when given by the
oral route is slower in neonates and young infants than in older
children because gastric emptying is delayed; normal adult rates
may not be reached until 6 to 8 months.1417 The larger relative
skin surface area, increased cutaneous perfusion, and thinner
stratum corneum in neonates increase absorption and exposure
of topically applied drugs (corticosteroids, local anesthetic creams,
antiseptics). Neonates have a tendency to form methemoglobin
because they have reduced levels of methemoglobin reductase and
fetal hemoglobin is more readily oxidized than adult hemoglobin.
This, combined with increased absorption through the neonatal
epidermis, resulted in reluctance to use lidocaine-prilocaine cream
for repeat use in this age group.18,19
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Distribution
HEPATIC ELIMINATION: The mixed function oxidases (phase I)
BODY COMPOSITION: Total body water and extracellular fluid
are reduced. Some appear to be switched on by birth, whereas in

others, birth is necessary but not sufficient for the onset of expression.23,24 Cytochrome P (CYP) 2E1 activity surges after birth,25
CYP2D6 becomes detectable soon thereafter, the CYP3A4 and
CYP2C families appear during the first week, whereas CYP1A2 is
the last to appear.26 Neonates are dependent on the immature
CYP3A4 for levobupivacaine clearance and CYP1A2 for ropivacaine clearance, dictating reduced epidural infusion rates in this
age group.5,27,28
If a drug has a high extraction ratio, then intrinsic clearance
may be very much greater than liver blood flow, and in these
situations, hepatic clearance is primarily determined by liver blood
flow characteristics. Fentanyl clearance (CYP3A4) is 70 to 80% of
adult values in term neonates and, standardized to a 70-kg person,
reaches adult values within the first few weeks of life. Omphalocoele repair may be associated with raised intra-abdominal pressure (a covariate effect), resulting in reduced fentanyl clearance
attributable to both decreased hepatic blood flow and reduced
hepatic function (decreased fentanyl extraction).
Some phase II pathways are mature in term neonates at
birth (sulfate conjugation), whereas others are not (acetylation,
glycination, glucuronidation).29 Covariate effects contribute to
clearance variability. Maturation of clearance (UGT2B7) occurs
more quickly in infants undergoing noncardiac surgery than in
those receiving morphine after cardiac surgery.30 Similarly,
clearance of propofol (UGT, CYP2B6, CYP2C9, CYP2A6) was
reduced after cardiac surgery in children admitted to a pediatric
intensive care unit.31
(ECF)20 decrease dramatically in the first year of life. Polar drugs

such as aminoglycosides and nondepolarizing neuromuscular
blocking drugs (NMBDs) distribute rapidly into the ECF, but enter
cells more slowly. The initial dose of such drugs is consequently
higher in the infant than in older children and adults. The 90%
effective dose (ED90) of succinylcholine (mg/kg) is greater in
infants than in children and adults.
Body fat, protein mass, and relative body proportions change
dramatically over the first few years of life and similarly affect
volumes of distribution of drugs. These volumes will affect initial
dose estimates. Reduction of propofol concentrations after induction is attributable to redistribution. Neonates have low body fat
and muscle content and, therefore, less propofol is apportioned to
these tissues. Delayed awakening occurs because central nervous
system concentration remains higher than that observed in older
children as a consequence of reduced redistribution and reduced
clearance.
PLASMA PROTEINS: Albumen and 1-acid glycoprotein (AAG)
concentrations are reduced in neonates but are similar to those in

adults by 6 months. Other endogenous compounds (e.g., bilirubin) also compete with drugs for binding sites. AAG is an acutephase reactant that increases after surgical stress. This causes an
increase in total plasma concentrations for low to intermediate
extraction drugs such as bupivacaine.21 The unbound concentration, however, will not change because clearance of the unbound
drug is affected only by the intrinsic metabolizing capacity of the
liver. Any increase in unbound concentrations observed during
long-term epidural administration is attributable to reduced
clearance rather than AAG concentration.22
Total bupivacaine concentrations increase in the first 24 hours
after surgery in neonates given analgesia by continuous epidural
infusion. This increase is attributable to an increase of AAG, which
is an acute-phase reactant. This increase, combined with reports
of seizures in infants given epidural bupivacaine infusion, has led
to recommendations to stop epidural infusion at 24 hours.
However, it is the unbound bupivacaine that is responsible for the
effect and this unbound concentration may not change, implying
that the infusion could be run for a longer duration. Clearance is
the key parameter. Unfortunately, clearance is associated with a
large between-subject variability, meaning that unbound bupivacaine concentrations may continue to rise in those individuals
with very low clearance. Infusion rates for continuous amide local
anesthetic regional blockade may be safely predicted based on
clearance and its variability estimates and these infusions may be
run for longer than 24 hours.
Drug Metabolism
The main routes by which drugs and their metabolites leave the
body are the hepatobiliary system, the kidneys, and the lungs. The
liver is the primary organ for clearance of most drugs. Nonpolar,
lipid-soluble drugs are converted to more-polar and water-soluble
compounds. Water-soluble drugs are excreted unchanged in the
kidneys by glomerular filtration and/or renal tubular secretion.
Many of these processes are immature in the neonate and mature
within the first year of life.
RENAL ELIMINATION: Drugs and their metabolites are excreted

by the kidneys by two processesglomerular filtration and
tubular secretion. Glomerular filtration rate (GFR) is only 10%
that of mature value at 25 weeks, 35% at term, and 90% of the adult
GFR at 1 year of age.32 Aminoglycosides are almost exclusively
cleared by renal elimination, and the maintenance dose is
predicted by postmenstrual age because it predicts the time course
of development of renal function.33
Immaturity of clearance pathways can be used to our advantage
when managing apnea after anesthesia in the premature nursery
graduate. N7-Methylation of theophylline in the newborn to
produce caffeine is well developed, whereas oxidative demethylation (CYP1A2) responsible for caffeine metabolism is deficient
and develops over the ensuing months. Theophylline is effective
for the management of postoperative apnea in the premature
neonate, partly because it is a prodrug of caffeine, which is effective in controlling apnea, in this age group and caffeine can be only
slowly cleared by the immature kidney.
EXTRAHEPATIC ELIMINATION: Many drugs are metabolized at

extrahepatic sites. Remifentanil (and atracurium to some extent)
are rapidly broken down by nonspecific esterase in tissue and
erythrocytes. Clearance (L/h/kg) is increased in the younger
children,3438 but this may be attributable to size. The half-life of
formation of paracetamol by plasma esterase hydrolysis has been
investigated.39 Hydrolysis half-life was the same in all age groups
when standardized for size using allometry.
Metabolites
Many drugs have active metabolites that contribute to effect. Examples include norketamine from ketamine,40 4-hydroxydiclofenac
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An Introduction to the Intricacies of Pharmacology in Pediatrics 293
from diclofenac,41 O-demethyl tramadol from tramadol,42 and

morphine 6-glucuronide (M6G) from morphine.43
Contributions to both the desired effect (analgesia) and the
undesired effects (nausea, respiratory depression) of M6G are the
subject of clinical controversy.44 M6G PD has been explored in
adults using pupil size as a measure of central opioid effect, but
results are confusing. Effect compartment modeling suggested that
M6G was apparently 22 times less potent than morphine.45,46
Contrarily, other authors have suggested that M6G was four times
more potent than morphine in producing meiosis,47 half as potent
as an analgesic,48 and with reduced respiratory depressive effects.49
Stereoisomerism
Some drugs commonly used in anesthetic practice are racemic
compounds, and activity may reside in only one isomer. There is
increasing interest in these isomers (e.g., levobupivacaine, S(+)
ketamine) because they may have a greater potency or safety
profile.50,51 Interpretation of the pharmacokinetics of racemic
compounds may not be straightforward because clearance of one
enantiomer may be greater than that of the other, whereas therapeutic activity resides only in one enantiomer (e.g., ibuprofen).52
Enantiomeric PK differences are best explained by stereoselective
plasma protein binding and metabolism.53
Pharmacogenomics
Pharmacogenomics (PG) is the investigation of variations of DNA
and RNA characteristics as related to drug response that incorporates both PK and PD. There is large between-individual PK
variability that is contributed to by polymorphisms of the genes
encoding for metabolic enzymes.54 Genetic variability influencing
plasma cholinesterase activity and its influence on succinylcholine
is a well-known example. Another example is the CYP2D6 single
nuclear polymorphism (SNP) that is inherited as an autosomal
recessive trait. Homozygous individuals are deficient in the metabolism of a variety of important groups of drugs adrenoreceptor blocking agents, antidepressants, neurolept agents, and opioids.
Poor metabolizers have reduced morphine production from
codeine.55,56 Tramadol is also metabolized by O-demethylation in
the liver (CYP2D6) to O-desmethyl tramadol (M1) and the M1
metabolite has a -opioid affinity approximately 200 times greater
than that of tramadol.
A SNP is important only if it contributes greater than 50%
metabolism and has an active metabolite, a steep dose-response
relationship, and a narrow therapeutic index. These polymorphisms may have little impact during the neonatal period when
metabolism is developmentally limited.42,5759
PG differences also have an impact on PD. Candidate genes
involved in pain perception, pain processing, and pain management like opioid receptors, transporters, and other targets of pharmacotherapy are under investigation. These genetic differences
(G118 allele) may explain why some patients need higher opioid
doses and the adverse effects profile may be modified by these
mutations.60 Some genes (e.g., fetal hemoglobin) are expressed
much more in early life than in adults, and gene switching may
mean a drug is effective at one age and not another.
In adults, gene testing may prove invaluable for reducing
adverse drug effects.61,62 However, most drug responses involve
a large number of proteins regulated by multiple genes. Genotype
does not equate with phenotype; environment, concomitant
therapy, and disease have impact, and allele prevalence varies

among ethnic groups. The situation in children is more complex.
Allelic variants may remain unchanged throughout life, but transcriptomonic, proteomic, and metobonomic data in children are
continuously changing throughout development.
Pharmacodynamic Considerations
Childrens responses to drugs have much in common with the
responses in adults.63 The perception that drug effects differ in
children arises because the drugs have not been adequately studied
in pediatric populations who have size- and age-related effects as
well as different diseases.
There are, however, situations in which age-related PD changes
have been described. Classic examples are MAC age-related
changes of anesthetic inhalation agents and NMBD effects. Calcium is an effective inotrope in neonates because cardiac calcium
stores in the endoplasmic reticulum are reduced. Amide local
anesthetic agents induce shorter block duration and require a larger
weight-scaled dose to achieve similar dermatomal levels when
given by subarachnoid block to infants. This may be caused, in part,
by myelination, spacing of nodes of Ranvier, and length of nerve
exposed as well as size factors. Inhibitory gamma-aminobutyric
acid (GABA) receptors, which may not reach maturity until 10
years of age, influence the response seen after benzodiazepines in
children. The coagulation cascade is immature at birth, influencing
anticoagulant effect. There is an age-dependent expression of intestinal motilin receptors and the modulation of antral contractions in
neonates. Prokinetic agents may not be useful in very preterm
infants, partially useful in older preterm infants, and useful in fullterm infants. Catecholamine release and response to vasoactive
drugs vary with age.
STATE OF THE ART

Improving the Pharmacopoeia
The introduction of a new drug onto the market is extremely
costly for the pharmaceutical industry. Despite this cost, drugs of
value to pediatric anesthesia continue to materialize. Improved
licensing regulations in both Europe and the United States ensure
that these compounds are investigated in children. Our management of the neuromuscular junction, for example, will improve
with the introduction of sugammadex.
The benefits of pure compounds are recognized. The S(+)
isomer of ketamine is now widely used and single-isomer nonsteroidal anti-inflammatory drugs (NSAIDs) are appearing for the
treatment of acute pain that may have fewer adverse effects than
traditional NSAIDs. Nitroxyparacetamol (nitroacetaminophen) is
a new nitric oxidereleasing version of paracetamol with analgesic
and anti-inflammatory properties. Potency is enhanced, and animal models suggest reduced liver damage in overdose situations.
Xenon continues to be investigated as an anesthetic agent.
Dexmedetomidine, licensed only for adult sedation in the intensive care unit, has found a niche with pediatric sedation. Investigations in children by clinical anesthesiologists may result in
broadening of the original narrow indication. Old therapies have
found new roles. Intralipid is now used for the management of
local anesthetic toxicity. Exploration of the PK and PD of old drugs
such as ketamine should refine clinical use. Drug combinations
often improve the effect seen from one drug alone.
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Defining the Required Effect

This target concentration strategy is a powerful tool for determining clinical dose.64 Anesthesia lends itself to this strategy in
which we have clearly defined target effects and monitoring of
adverse effects. The key to this approach be able to measure such
effects. We excel in the fields of neuromuscular, evoked potentials,
anesthesia depth, and cardiovascular monitoring. These tools
continue to be refined and adapted for even the premature neonate. Measurement of target concentration in which effect is more
crudely measured is routine for inhalational agents. Anesthesia
has advanced from observing Guedels stages65 and a finger on the
pulse. The assessment and measurement of pain and its many
subtleties, however, continue to be a barrier to effective analgesia,
although advances are progressive.66
Population Modeling
Pediatric anesthetists have embraced the population approach for
investigating PK and PD. This approach is achieved through
nonlinear mixed effects models. They provide a means to study
variability in drug responses among individuals representative of
those in whom the drug will be used clinically. Traditional
approaches to interpretation of time-concentration profiles (e.g.,
naive and standard two-stage approaches) relied on rich data
from a small group of subjects. By contrast, mixed effects models
can be used to analyse sparse (two or three samples) data from
a large number of subjects. Sampling times are not crucial for
population methods and can be fitted around clinical procedures
or outpatient appointments. However, optimal sampling schedules
can be determined through previous information and the Fisher
Information Matrix.6769 Sampling time bands rather than exact
times are equally effective70 and allow flexibility in children.
Mixed effects models are mixed because they describe the
data using a mixture of fixed and random effects. Fixed effects
predict the average influence of a covariate such as weight as an
explanation of part of the between-subject variability in a parameter like clearance. Random effects describe the remaining
variability between subjects that is not predictable from the fixed
effect average. Explanatory covariates (e.g., age, size, renal
function, sex, temperature) can be introduced that explain the
predictable part of the between-individual variability. Nonlinear
regression is performed by an iterative process to find the curve of
best fit by maximizing the likelihood.71,72
Interpretation of truncated individual sets of data or missing
data is also possible with this type of analysis, rendering it useful
for pediatric studies. The appropriate number of patients for a
population study is difficult to determine and will depend on the
number of covariates under examination.73 Population modeling
also allows pooling of data across studies to provide a single robust
PK analysis rather than comparing separate smaller studies that
are complicated by different methods and analyses.
FUTURE DIRECTIONS
It is not possible to predict the future. The Bell telephone was once
considered such an advance that every town would eventually have
one. Missiles were thought to be the future method of mail
delivery and the US Postal Service sent 3,000 letters via missile
from Virginia to Florida in 1959. Lessons from the past suggest
that the forces driving innovation and change are not always
predictable. The most popular analgesics in children, paracetamol
and the NSAIDs, were derived almost by accident. Although
salicylic acid was used by ancient Egyptians, attempts to revive its
use in the 18th century failed. Marketing by Bayer took off only
because of surreptitious use by local dentists after aspirin characterization. Paracetamol and indomethacin were byproducts of coal
tar, the substrate that supported the German dye industry, established Prussian economic power, and caused the loss of Great
Britains jewel in the crown, India.74
Future anesthetic benefits for children will come from incentives for drug development and investigation (regulatory climate),
PKPD understanding,75 target concentration approaches,76 stereoisomer and circadian rhythm investigations,5052,77 and understanding of metabolites. Investigation of covariate effects influencing
PK (e.g., pharmacogenetics78) and PD (e.g., disease processes,
maturation) will reduce variability and allow tailoring of drugs to
individual need. Refinement of current or future effect measures
will allow greater delivery finesse and reduce complication rates.
Improvements in delivery systems with feedback systems must go
hand in hand with effect measure improvements. Education
remains a major barrier, and it is hoped that subsequent chapters
will overcome a part of that barrier.
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32. Rhodin MM, Anderson BJ, Peters AM, et al. Human renal function
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38. Egan TD. Pharmacokinetics and pharmacodynamics of remifentanil: an
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metabolite in children and the implications for analgesia. Paediatr
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42. Allegaert K, Anderson BJ, Verbesselt R, et al. Tramadol disposition in the
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43. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NH. Developmental
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53. Kauffman RE, Lieh-Lai MW, Uy HG, Aravind MK. Enantiomer-selective
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55. Williams DG, Hatch DJ, Howard RF. Codeine phosphate in paediatric
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Using Pharmacokinetics and

Pharmacodynamic Models to
Prevent Adverse Events in
Neonates, Infants, and Children
18
C H A P T E R
Brian J. Anderson
INTRODUCTION
Models describe systems in simple terms, although some models
may be quite sophisticated. They are used to describe, predict, and
explain observations. Pharmacokinetics (PK) and pharmacodynamics (PD) models are used to improve pediatric anesthetic management. They quantify the exposure-response relationship, often
providing clarity and insight into complex systems as well as a
mechanistic understanding of the drug effect. Dose selection can
be rationalized. Models may enable extrapolation beyond observed data. Modeling is a knowledge management tool; it captures
and integrates data from all studies. Models can also be used for
hypothesis testing and can drive decision-making during drug
development.
This chapter explores common models used in pediatric pharmacology and demonstrates their usefulness to determine the
appropriate dose for neonates, infants, and children, with consequent reduction of adverse effects.
THE TARGET CONCENTRATION

APPROACH
The goal of treatment is the target effect (TE). A PD model is used
to predict the target concentration (TC) given a TE. Population
estimates for the PD model parameters and covariate information
are used to predict typical PD values in a specific patient. Population estimates of PK model parameter estimates and covariate
information are then used to predict typical PK values in a specific
patient. This TC strategy is a powerful tool for determining clinical
dose.1 Monitoring of serum drug concentrations and bayesian
forecasting may be used to improve dosing in individual patients.
Defining theTE also requires knowledge of adverse event
relationships. The best TC in Figure 181 may not be the higher
concentration of 7 mg/L if adverse effects are troublesome. Further, an effect measure of 8 may offer little advantage over an effect
measure of 6, achieved with the lower concentration of 2.5 mg/L.
Other factors may also enter into decision-making. For example,
age, weight, concomitant disease pharmacogenetics, or other
drugs may alter the shape of the concentration-response curve.
This approach to dose selection is quite different from that commonly taken in double-blind, randomized, placebo-controlled
trials. Such trials often use a homogeneous population. The maximum safe dose is chosen to show clear difference from placebo;
smaller doses would require greater patient numbers and exhibit
more noise. A sense of the dose- or concentration-response is not
achieved for either TE or adverse effects, and further comparative
dose studies are required to define a minimum effective dose.
This TE approacho is intrinsic to pediatric anesthetists using
target-controlled infusion systems. These devices target a specific
plasma concentration in a typical individual, and this concentration is assumed to have a typical TE. The TC is one that achieves
target therapeutic effect (e.g., anesthesia) without excessive adverse effects (e.g., hypotension). Effect monitoring (e.g., bispectral
[BIS] index) can be used to refine the TE.
PK MODELS
Compartment Models
Noncompartment methods (moment analysis) represent the
gold standard for parameter estimation, but compartment models
dominate anesthetic literature. Compartment models may comprise one, two, or more compartments. Drug is administered into
and eliminated from a central compartment. This central compartment may be connected to peripheral compartments.
Figure 18-1. The higher target concentration (TC) of 7 mg/L

achieves a better effect, but at the expense of increased adverse
effects. The lower concentration of 2.5 mg/L may be satisfactory
and have fewer adverse effects.
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A single compartment is often insufficient to characterize the

time-concentration profile and further compartments are required
(mammillary models). Drug is administered into a central compartment (V1) and redistributes to peripheral compartments (e.g.,
V2, V3; Figure 182A). In a two-compartment model, transfer of
drug between the central and the peripheral compartment is
relatively fast compared with the rate of elimination. A plot of the
natural log of concentration after bolus reveals two distinct slopes
(rate constants, and ; see Figure 182B). Consequently, the
time-concentration profile is commonly described using a
polyexponential function:
.
C(t) = A . e . t . + B . e t
These parameters have little connection with underlying
physiology and an alternative parameterization is to use a central
volume and three rate constants (k10, k12, k21) that describe drug
distribution between compartments. Another common method
is to use two volumes (V1, V2) and two clearances (CL, Q). Q is
the intercompartment clearance, and volume of distribution at
steady state (Vss) is the sum of V1 and V2.
Students are commonly taught to estimate compartment model
PK parameters through interpretation of graphs representing
time-concentration profiles. Conversion of concentration to a log
scale (CL) allows estimation of elimination constants and compartment volumes (see Figure 182C). Integration of the function
describing this profile yields an area under the curve (AUC), from
which CL can be determined
Dose
CL = AUC
Computers have made use of nonlinear regression to directly
estimate parameters through iterative techniques using leastsquares curve fitting. Models with two or more compartments are
now commonly solved using differential equations, for example,
for a two-compartment mammillary model
dC1 (ratein + C2 Q) C1 (Q + CL)
=
dt
V1
dC2 Q (C1 C2)

=
dt
V2
These parameter estimates can be used to predict dose. A
loading dose raises concentration in the plasma to TC promptly
and may be desirable in anesthesia when rapid effect is required.
In a one-compartment model, the volume of distribution is the
proportionality factor that relates total amount of drug in the body
to plasma concentration:
Loading dose = V . TC
This calculation may not be applicable to many anesthetic
drugs that are characterized using multicompartment models. The
use of V1 results in a loading dose too high; too high a dose may
cause transient toxicity.
An alternative technique is to use the TE dose. The time to peak
effect (Tpeak) is dependent on clearance and effect-site equilibration half-time (Teq or T / keo). At a submaximal dose, Tpeak is
independent of dose. At supramaximal doses, maximal effect will
occur earlier than Tpeak and persist for longer duration because
of the shape of the sigmoid Emax (maximum effect change) model
(see The Sigmoid Emax Model). This is due to similar considerations described in time course of immediate effects. The Tpeak
concept has been used to calculate optimal initial bolus doses,2
1
Figure 18-2. A: A mammillary two-compartment pharmacokinetic (PK) model. B: Time-concentration profile for a twocompartment model. C: Conversion of concentration to a log
scale allows estimation of elimination constants and compartment volumes.
because V1 poorly reflects the required scaling factor. A new
parameter, the volume of distribution at the time of peak effect-site
concentration (Vpe), is used and is calculated as
V1
Cpeak
C 0
C0 is the theoretical plasma concentration at t = 0 after the

bolus dose, and Cpeak is the predicted effect-site concentration at
the time of peak effect. Loading dose can then be calculated as
LD = Cpeak . Vpe
Vpe =
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Clearance is the most important parameter when defining a

rational steady-state dosage regimen. At steady state,
Dosing rate = rate of elimination = CL . TC
ss
ss
Maintenance dose = dosing rate dosing interval

When a drug is given by constant infusion,
Infusion ratess = dosing ratess
Once the TC of a drug is defined, the infusion rate is determined by CL. This equation is true at steady state, but many
anesthetic drugs distribute to peripheral compartments and steady
state may not be achieved during the time that the patient is
anesthetized. Dose adjustment is required to achieve constant
effect until steady-state conditions are reached.
Propofol PK is usually described using a three-compartment
mammillary model. In order to achieve steady state of 3 g/mL in
children 3 to 11 years, dosing changes are required, for example,
a loading dose of 2.5 mg/kg followed by an infusion rate of 15 mg/
kg/h for the first 15 minutes, 13 mg/kg/h from 15 to 30 minutes,
11 mg/kg/h from 30 to 60 minutes, 10 mg/kg/h from 1 to 2 hours,
and 9 mg/kg/h from 2 to 4 hours. Target-controlled infusion (TCI)
pumps are capable of finer tuning by making adjustments at 10second intervals.3
The PK of drug disposition confined to a one-compartment
model is often expressed in terms of half-life. Half-life (T / ) is the
time required to change the amount of drug in a body compartment by one half (either by decreasing during elimination or by
increasing during a constant infusion):
1
V
CL
This half-life is related to the elimination rate constant (k), a

parameter representing the slope of the exponential decay curve:
k=
be clinically relevant because the percentage decrease in concentration required for recovery is not necessarily 50%.
Recirculatory Models
When a drug is given intermittently,
T12 = ln(2)
299
CL
V
Elimination half-life is of no value in characterizing disposition

of intravenous anesthetic drugs during dosing periods relevant to
anesthesia. A more useful concept is that of the context-sensitive
half-time in which context refers to infusion duration. This is
the time required for the plasma drug concentration to decline by
50% after terminating infusion.4 The context-sensitive half-time is
the same as the elimination half-life for a one-compartment model
and does not change with infusion duration. However, most drugs
in anesthesia conform to multiple-compartment models and the
context-sensitive half-times are markedly different from their
respective elimination half-lives.
Context-sensitive half-time may be independent of infusion
duration (e.g., remifentanil 2.5 min); moderately affected (propofol 12 min at 1 h, 38 min at 8 h); or display marked prolongation
(e.g., fentanyl 1 h at 24 min, 8 h at 280 min). This is caused by
return of drug to plasma from peripheral compartments after
ceasing infusion. Peripheral compartment size differs in children
from adults so that, at termination of infusion, more drug may
remain in the body for any given plasma concentration than in
adults. The context-sensitive half-time for children given propofol,
for example, is longer.3 The context-sensitive half-time gives
insight into the PK of a hypnotic drug, but the parameter may not
Standard compartment models are unable to accurately describe

drug concentrations immediately after bolus administration of an
anesthetic induction agent. Mixing in the central compartment is
not instantaneous, making it difficult to model the fast blood-tobrain concentration equilibrium.5 Pulmonary uptake may also
occur.6 Recirculatory models help explain these early phase PK.7
The pulmonary and peripheral intravascular and extravascular
systems, each consisting of volumes and time delays, are connected according to circulatory physiology.8 Parameters are estimable by administering the drug under investigation as well as an
intravascular marker. Such models have proved valuable in determining anesthetic induction doses9 and neuromuscular blocking
drug (NMBD) PD.10
Physiologically Based PK Modeling

Organ maturation, body composition, and ontogeny of drug
elimination pathways have marked effects on PK parameters in
the first few years of life. Clearance estimates from physiologically
based pharmacokinetic modeling (PBPK) use data on ontogeny
of individual clearance pathways, derived from measurements of
enzyme expression and activity in postmortem livers11,12 and from
in vivo data from drugs that are cleared by similar pathways.13
Continued input of information concerning genetic, physiologic,
organ and tissue size and composition, protein binding, and
demographic and clinical data into the library and algorithms for
PBPK programs has progressively improved their prediction
ability.1419 These models have been used to assist with first-time
dosing in children. A general PBPK program for drug disposition
in infants and children, covering the age range from birth to
adulthood, has been successfully evaluated using theophylline and
midazolam as model drugs.20 The introduction of population variability in enzyme abundance and activity, for example, contributes
to between-individual variability estimates.
PD MODELS
PK is what the body does to the drug, whereas PD is what the drug
does to the body. The precise boundary between these two processes is ill defined and often requires a link describing movement
of drug from the plasma to the biophase or effect site and its target.
Drugs may exert effect at nonspecific membrane sites, by interference with transport mechanisms, by enzyme inhibition or
induction, or by activation or inhibition of receptors.
The Sigmoid Emax Model

The relation between drug concentration and effect may be described by a sigmoid hyperbolic or Hill model, well known to anesthesiologists through the oxygen dissociation curve,21 according
to the equation
( E max Ce )
Effect = E0 +
( EC + Ce )
N
N
50
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Figure 18-3. The sigmoid Emax (maximum effect change)

model for three drugs, each with a different Hill coefficient. The
median effective concentration (EC50) and efficacy are the same
but the EC80 is different for each drug. A higher concentration of
the drug with the lower Hill coefficient will be required if an effect of 80% of maximal effect is desired.
where E0 is the baseline response, Emax is the maximum effect
change, Ce is the concentration in the effect compartment, EC50 is
the concentration producing 50% Emax, and N is the Hill coefficient defining the steepness of the concentration-response curve
(Figure 183).22 At low concentrations, the nonlinear relationship
may approach linearity.
Efficacy is the maximum response on a dose or concentrationresponse curve. EC50 can be considered a measure of potency
relative to another drug provided N and Emax for the two drugs are
the same. The opioid receptor agonists can be compared in this
manner. The spectral edge frequency of the electroencephalogram
(EEG) has been used as a PD measure to compare opioids. The
steady-state serum concentration that caused one half of the
maximal EEG slowing was 6.9 standard deviation (sd) 1.5 g/
L for fentanyl, compared with 520 sd 163 g/L for alfentanil.23
Quantal Effect Model

The potency of anesthetic vapors may be expressed by minimum
alveolar concentration (MAC); this is the concentration at which
50% of subjects move in response to a standard surgical stimulus.
MAC appears at first sight to be similar to EC50, but is an expression of quantal response rather than magnitude of effect. There
are two methods of estimating MAC. Responses can be recorded
over the clinical dose range in a large number of subjects and
logistic regression applied to estimate the relationship between
dose and quantal effect; the MAC can then be interpolated. Large
numbers of subjects may not be available, and so an alternative is
often used. The up and down method described by Dixon
estimates only the MAC rather than the entire sigmoid curve.24,25
It involves a study of only one concentration in each subject and,
in a sequence of subjects, each receives a concentration depending
upon the response of the previous subject; the concentration is
either increased if the previous subject did not respond or
decreased if she or he did (Figure 184). The MAC is usually
calculated either as the mean concentration of equal numbers of
responses and no responses or as the mean concentration of pairs
of response/no response.
Figure 18-4. Estimation of minimum alveolar concentration

(MAC) using the up and down method. The nominal sample
size is six subjects and is the number of tests after and including
the first pair of tests that have opposite results.
This quantal effect model has application beyond that of estimating MAC. Frawley and coworkers have used the model to
determine an effective spinal dose of levobupivacaine (1 mg/kg)
and of ropivacaine (1.08 mg/kg) in neonates.26,27
Logistic Regression Model

When the pharmacologic effect is difficult to grade, it may be useful to estimate the probability of achieving the effect as a function
of plasma concentration or MAC. Effect measures such as movement/no movement or rousable/nonrousable are dichotomous.
Logistic regression is commonly used to analyze such data, and
the interpolated EC50 value refers to the probability of response.
For example, an EC50 of 0.52 mg/L for arousal after ketamine
sedation in children has been estimated (Figure 185) using this
technique.
LINKING PK WITH PD
Immediate Effects
A simple situation in which drug effect is directly related to
concentration does not mean that drug effects parallel the time
course of concentration. This occurs only when the concentration
Figure 18-5. The probability of being aroused after ketamine

sedation determined using logistic regression. The EC50 was
0.52 mg/L. Dichotomous data are shown as crosses. From
reference 61, with permission.
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is low in relation to EC50. In this situation, the half-life of the drug

may correlate closely with the half-life of drug effect. Many drugs,
however, have a short half-life but a long duration of effect. This
may be attributable to induced physiologic changes (e.g., aspirin
and platelet function) or may be because of the shape of the Emax
model. If the initial concentration is very high in relation to the
EC50, then drug concentrations 5 half-lives later, when we might
expect minimal concentration, may still exert considerable effect.
Delayed Effects
Observed effects may not be directly related to serum concentration. There may be a delay because of transfer of the drug to effect
site (NMBD), a lag time (diuretics), physiologic response (antipyresis), active metabolite (propacetamol), or synthesis of physiologic substances (warfarin).
Figure 18-8. Physiologic substance turnover model for

warfarin.
Physiologic Substance Turnover Model

Delayed-Effect Compartment Model
A plasma concentration-effect plot can form a clockwise hysteresis
loop because of this delay in effect (Figure 186). Hull and colleagues28 and Sheiner and associates29 introduced the effect compartment concept for muscle relaxants. The effect compartment
concentration is not the same as the blood or serum concentration
and is not a real measurable concentration (Figure 187). It has
negligible volume and contains negligible blood. A single firstorder parameter (Teq or T / keo) describes the equilibration halftime. This mathematical trick assumes concentration in the
central compartment is the same as that in the effect compartment
at equilibration but that a time delay exists before drug reaches
the effect compartment. The concentration in the effect compartment is used to describe the concentration-effect relationship.22
1
Many drug actions are mediated through synthesis or elimination

of a physiologic substance.30 The concentration at the site of drug
effect either stimulates or inhibits the rate of production or elimination of the physiologic substance (response variable). Warfarin,
for example, inhibits the recycling of vitamin K epoxide to the
active vitamin K form that is involved in the production of prothrombin complex (Figure 188).
The time course of prothrombin complex activity (PCA(t)) is
determined by the solution to
dPCA(t) = Rsyn . PD(W ) Kp. PCA

(t)
dt
where Rsyn is the PCA synthesis rate in the absence of warfarin, Kp is the elimination rate constant for PCA, W(t) is the PK
model for warfarin, and PD(W) is the inhibitory effect of warfarin
on PCA synthesis. The IC50 is the warfarin concentration that
inhibits synthesis by 50%.31
Cumulative Effects
Many antineoplastic drugs have an effect that is a consequence of
cumulative exposure. The extent of binding of the drug to DNA is
proportionate to drug concentration and is irreversible. Response
may be predicted by measures of cumulative exposure to the drug
(e.g., AUC).
Figure 18-6. The clockwise hysteresis loop observed after an
orally administered drug
PEDIATRIC PK CONSIDERATIONS
Growth and development are two major aspects of children not
readily apparent in adults. How these factors interact is not necessarily easy to determine from observations because they are quite
highly correlated. Drug elimination clearance, for example, may
increase with weight, height, age, body surface area, and creatinine
clearance. One approach is to standardize for size before incorporating a factor for maturation and organ function.32
Size
Allometry
Figure 18-7. The time-concentration profile for the effect compartment is delayed compared with that in the serum.
Allometry is a term used to describe the nonlinear relationship

between size and function. This nonlinear relationship is expressed as
y = a . BodyMassPWR
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Figure 18-9. A comparison of the

temperature-standardized relation for
whole-organism metabolic rate as a
function of body mass. The allometric 3/4 power model fits for unicells,
poikilotherms, and homeotherms,
uncorrected for temperature, are also
shown. From reference 101, with
permission.
where y is the variable of interest (e.g., basal metabolic rate), a
is the allometric coefficient, and PWR is the allometric exponent.
The value of PWR has been the subject of much debate. Basal
metabolic rate (BMR) is the most common variable investigated
and camps advocating for a PWR value of 2/3 (i.e., body surface
area) are at odds with those advocating a value of 3/4.
In all species studied, including humans, the log of BMR plotted
against the log of body weight produces a straight line with a slope
of 3/4 (Figure 189). Fractal geometry is used to mathematically
explain this phenomenon. The 3/4 power law for metabolic rates
was derived from a general model that describes how essential
materials are transported through space-filled fractal networks of
branching tubes.33 A great many physiologic-, structural-, and
time-related variables scale predictably within and between species
with weight (W) exponents (PWR) of 3/4, 1, and 1/4, respectively.34
These exponents have applicability to PK parameters such as
clearance (CL), volume (V), and half-time.34 The factor for size
(Fsize) for total drug clearance may be expected to scale with a
power of 3/4:
3
W /4
Fsize 70
( )
Instead of assuming a fixed value of Ffat in all cases, the idea of

NFM is to estimate the value of Ffat that is most appropriate for
the parameter being predicted. If Ffat is estimated to be zero, then
FFM alone is required to predict size.
Ffat has been estimated to be 0.21 to account for the fat mass
contribution to size associated changes in glomerular filtration
rate (GFR).37 Clearly, fat does not directly influence GFR but
appears to be a component of total body size that indirectly drives
the size of renal excretory capacity.
Maturation
Remifentanil clearance in children aged 1 month to 9 years is
similar to adult rates when scaled using an allometric exponent of
3 38
/4. Remifentanil is cleared by rapid hydrolysis by nonspecific
tissue and plasma esterases that do not appear to be influenced by
age after scaling for size. For most drugs, however, allometry alone
is insufficient to predict clearance in neonates and infants from
adult estimates (Figure 1810).39,40 The addition of a model describing maturation is required. The sigmoid hyperbolic has also
been found useful for describing this maturation process (MF).
MF =
Body Fat
PK properties of some drugs are known to be changed in obesity.
Fat mass contributes to overall body size and may have an indirect
influence on both clearance and volume of distribution. Lean body
mass (LBM) or fat-free mass (FFM)35 may be inadequate descriptors of body size. These ideas have led to the proposal for different
fractions of fat mass to explain how PK parameters vary with body
composition.
Normal fat mass (NFM) is an extension of the concept of
predicted normal weight36 that described the separate contribution
of FFM and NFM to prediction of drug clearance. The additional
feature of NFM is a parameter (Ffat) that accounts for different
contributions of fat mass (i.e., W FFM)
NFM(kg) = FFM + Ffat . (W FFM)
Fsize =
( NFM
Wstd )
PWR
PMA Hill
TM + PMA Hill
Hill
50
The TM50 describes the maturation half-time, whereas the Hill

coefficient relates to the slope of this maturation profile. It is
possible that there is asymmetry about the point of inflection, and
the addition of an extra parameter describing this asymmetry can
be used to provide extra flexibility for this empirical function.41
Maturation of clearance begins before birth, suggesting that
postmenstrual age (PMA) would be a better predictor of drug
elimination than postnatal age (PNA). The fetus is quite capable of
metabolizing some drugs from the second trimester, albeit at low
rates.
Organ Function
Only recently have changes associated with normal growth
and development been explicitly distinguished from pathologic
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Figure 18-10. Age-related clearance changes for a hypothetical drug. All three models show an increase in clearance over the first year of life because of maturation of metabolic pathways. Clearance
expressed using the per-kilogram model then decreases with age after 1 year to reach adult levels in
adolescence. This course is not evident with the allometric 3/4 power and surface area models. From
changes describing organ function (OF).32 Creatinine clearance,
for example, may be reduced in neonates, and this will affect
clearance of drugs eliminated through the renal system. The
contribution from maturation and organ dysfunction can be
difficult to distinguish. PK parameters (P) can be described in an
individual as the product of size (Fsize), maturation (MF), and
organ function (OF) influences in which Pstd is the value in a
standard-size adult without pathologic changes in organ function:
P = Pstd . Fsize . MF . OF
Application of PK Models
PK models that have used the modeling approach described earlier
in the section on PK models have clarified maturation of clearance
in the first year of life. Paracetamol,42 morphine,43 dexmedetomidine,44 propofol,45 and GFR37 clearance maturation have been
described. Current data suggest that GFR matures similar to
paracetamol or morphine clearance (Figure 1811). Paracetamol
and morphine are cleared by individual isoforms of glucuronosyl
transferase (UGT1A6 and UGT2B7), and it has been suspected
that these isoforms mature at different rates, consistent with
current estimated profiles. Further, paracetamol and morphine are
predominantly cleared by phase II conjugation processes that
convert xenobiotics to water-soluble forms that can be eliminated
from the body through the renal system. It seems logical that GFR
matures before or at the same time as these phase II processes.
Dexmedetomidine is cleared by both gluronidation and the renal
system. Unsurprisingly, maturation closely follows that of GFR.
Maturation of phase I metabolic processes have not been
described using the proposed size and maturation models. It is
believed, however, that maturation the P450 enzyme systems are
much faster than that of glucuronide conjugation.46 The maturation profile of propofol supports this contention (see Figure
1811). Glucuronidation is the major metabolic pathway of propofol metabolism and this pathway is immature in neonates,
although multiple cytochrome P450 isoenzymes, including
CYP2B6, CYP2C9, or CYP2A6, also contribute to its metabolism
and cause a faster maturation profile than expected from
glucuronide conjugation alone.47
Creatinine clearance is commonly used as a measure of renal
organ function; it is used as a covariate to alter drug dose for renally excreted drugs. Serum unconjugated bilirubin concentration
is a crude marker of hepatic organ function, and elevated paracetamol concentrations were associated with reduced paracetamol
clearance in a neonatal cohort.48
PEDIATRIC PD CONSIDERATIONS
Ontogeny of Drug Action
Childrens responses to drugs have much in common with the
responses in adults.49 The perception that drug effects differ in
children arises because the drugs have not been adequately studied
in pediatric populations who have size- and age-related effects as
well as different diseases.
There are, however, situations in which age-related PD changes
have been described, and many of these have application in anesthesia, for example, MAC age-related changes of anesthetic
inhalation agents. The proportion of type 1 fibers in the diaphragm that are more sensitive to NMBDs is also less in neonates,
influencing an earlier return of diaphragmatic muscle activity.
Calcium is an effective inotrope in neonates because cardiac
calcium stores in the endoplasmic reticulum are reduced. Amide
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Figure 18-11. Clearance maturation, expressed as a percentage of mature clearance, of drugs in

which glucuronide conjugation (paracetamol, morphine, dexmedetomidine) plays a major role.
These profiles are closely aligned with glomerular filtration rate (GFR). By contrast, cytochrome
P450 isoenzymes also contribute to propofol metabolism and cause a faster maturation profile than
expected from glucuronide conjugation alone.
local anesthetic agents induce shorter block duration and require
a larger weight-scaled dose to achieve similar dermatomal levels
when given by subarachnoid block to infants. This may be caused,
in part, by myelination, spacing of nodes of Ranvier, and length
of nerve exposed as well as size factors. Inhibitory gammaaminobutyric acid (GABA) receptors, which may not reach
maturity until 10 years of age, influence the response seen after
benzodiazepines in children.50 The coagulation cascade is immature at birth, influencing anticoagulant effect.51 There is an agedependent expression of intestinal motilin receptors and the
modulation of antral contractions in neonates. Prokinetic agents
may not be useful in very preterm infants, partially useful in older
preterm infants, and useful in full-term infants. Catecholamine
release and response to vasoactive drugs vary with age. Bronchodilators have reduced effect in those infants younger than 1 year
because of immaturity of bronchial smooth muscle at this age.
Measures of Effect
Outcome measures are more difficult to assess in children. Measurement techniques, disease and pathology differences, inhomogeneous groups, recruitment issues, ethical considerations, and
end point definition for establishing efficacy and safety confuse
data interpretation.52
The common effects measured in anesthesia are anesthesia
depth, pain and sedation, and neuromuscular blockade. A common effect measure used to assess depth of anesthesia is the EEG
or a modification of detected EEG signals (spectral edge frequency, BIS index, entropy). Physiologic studies in adults and
children indicate that EEG-derived anesthesia depth monitors can
provide an imprecise and drug-dependent measure of arousal.
Although the outputs from these monitors do not closely represent
any true physiologic entity, they can be used as guides for anesthesia and, in so doing, have improved outcomes in adults. In older
children, the physiology, anatomy, and clinical observations
indicate the performance of the monitors may be similar to that in
adults, although the clinical relevance of outcomes may be different. In infants, their use cannot yet be supported in theory or in
practice.53,54 During anesthesia, the EEG in infants is fundamentally different from the EEG in older children; there remains
a need for specific infant-derived algorithms if EEG-derived
anesthesia depth monitors are to be used in infants.55,56
The COMFORT pain scale has been used to model sedation in
nonventilated infants after craniofacial surgery.5759 The Wisconsin
sedation scale is a clinically used sedation score that is an integral
part of the structured model from American Academy of Pediatrics/American Society of Anesthesiologists (AAP/ASA) sedation
guidelines.60 The model is proposed to reduce risks during sedation. This score has been used to model ketamine PD.61 However,
despite the use of such scales in procedural pain studies, few
behavioral pain scales have been adequately validated in this
setting.62,63 Observed or self-reported analgesic effect measures
vary between ages and even within one age group.64 Interobserver
variability can be high.65
Electromyography response of the adductor pollicis is a consistent effect measure for investigation of neuromuscular blockade
in both neonates and adults. Differences are minor, for example,
neonates do not tolerate repetitive stimulations as long as older
children because of limited acetylcholine reserves. Early PKPD
modeling in children involved D-tubocurarine (dTc).66 Clearance,
standardized to a surface area model, is reduced in neonates and
infants compared with older children and adults. These agerelated clearances resemble age-related changes in glomerular
filtration. The T / keo, standardized for size, is high in neonates
1
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and infants, reduced in children, and further reduced in adults.

The cause of this is uncertain, but it may be related to increased
muscle bulk and concomitant increased muscle perfusion in older
children and adults.
In addition, covariate effects may be subtle and unaccounted
for in many studies. The placebo effect contributed 50% of analgesia attributed to paracetamol a few hours after tonsillectomy.67
A circadian night rhythm effect was noted in an investigation of
infant propofol sedation after major craniofacial surgery.59 Severity
of illness may further influence the sedation PD of propofol.68
305
propofol, and alfentanil) tripled the duration of effect compared

with propofol alone. Response surfaces can describe anesthetic
interactions, even those between agonists, partial agonists, competitive antagonists, and inverse agonists. Application of response-surface methodology permits characterization of the full
concentration-response relation and, therefore, can be used to
develop practical guidelines for optimal drug dosing.79
EXAMPLES OF PKPD MODEL USE

Defining TE or Side Effect
Measures of Adverse Effects

Neonates and young children may suffer permanent effects resulting from a stimulus applied at a sensitive point in development.
For example, congenital hypothyroidism, if untreated, causes
lifelong phenotypic changes. The incidence of vaginal carcinoma
is high in children of mothers treated with stilbesterol during
pregnancy.69 There are concerns that neonatal exposure to some
anesthetic agents (e.g., ketamine, midazolam) may cause widespread neuronal apoptosis and long-term memory deficits.70,71
Anesthesia, however, generally involves examination of immediate adverse effects such as Post-operative nausea and vomiting
(PONV), hypotension, or respiratory depression. A dose-response
curve for intravenous morphine and vomiting was investigated in
children having day-stay tonsillectomy. Doses above 0.1 mg/kg
were associated with a greater than 50% incidence of vomiting.72
These data are similar to those in children undergoing inguinal
herniorrhaphy,73 suggesting that lower doses of morphine are
associated with a decreased incidence of emesis after day-stay
surgery and encourage the use of alternative analgesic recipes.
PKPD modeling has been used to define the relationship between remifentanil concentration and arterial carbon dioxide
pressure (PaCO2). Simulations demonstrated that remifentanil
concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration,
confirming the acute risk of bolus administration of fast-acting
opioids in spontaneously breathing patients.74
Drug Interactions
An increase in the T / keo of dTc with increasing inspired halothane concentrations has been demonstrated.75 Halothane is a
negative inotrope76 and reduces skeletal muscle blood flow,77 so it
seems reasonable to interpret changes in T / keo as caused by
changes in blood flow. Inhalation anesthetic agents can also
prolong duration of block; this effect is agent-specific. Sevoflurane
potentiated vecuronium more than halothane; when compared
with balanced anesthesia, the dose requirements of vecuronium
were reduced by approximately 60% and 40%, respectively.78
Anesthetic drug interactions traditionally have been characterized using isobolographic analysis or multiple logistic regression. Minto and coworkers have proposed a model based on
response-surface methodology.79 The combination of two or more
drugs is considered to act like a single drug with a concentrationresponse relationship. The properties of this virtual drug and the
parameters of its concentration-effect relationship are dependent
on the ratio of the concentrations of the two drugs. Computer
simulations based on interactions at the effect site predicted that
the maximally synergistic three-drug combination (midazolam,
1
Achievement of the TE is the aim of drug therapy. The dose may be

considered inappropriate and lead to adverse effects if the TE is
over- or undershot. Monitoring of anesthetic depth with modified
EEG signal is increasingly popular during inhalational anesthesia
because adverse events caused by underdosing (awareness)80 or
overdosing (hypotension)81 are reduced. The use of MAC is helpful
because it guides us with age-related changes in dose, but by itself,
it is unsatisfactory because 50% of subjects will move in response
to a standard surgical stimulus at 1 MAC. A MAC value is
associated with between-individual variability, and some patients
will require a greater concentration delivered. This between-subject
variability is common for all drugs used in anesthesia.
A nighttime COMFORT score of 12 to 14 and a BIS index of
70 to 75 were used as a TE for sedation in nonventilated children
admitted to a pediatric intensive care unit. A dose of midazolam
1 mg/kg followed by an infusion of 0.5 mg/kg/h57 or a propofol
infusion of 30 mg/h59 in a 10-kg infant achieved this target. Large
interindividual variability warrants individual titration of sedative
drugs.
In chronically opioid-consuming patients, doses causing respiratory depression and analgesia may differ from those in opioidnaive individuals. The dose-response relationship for analgesia
and respiratory depression was defined by giving patients a
fentanyl infusion of 2 g/kg/min until the respiratory rate was
lower than 5 breaths/min. It is assumed that adequate analgesia is
achieved at an effect-site concentration that is 30% that causing
respiratory depression. PK simulations were used to estimate
effect-site concentration at the time of respiratory depression and
to predict the patient-controlled analgesia settings that would
provide an effect-site fentanyl concentration that was 30% of the
concentration associated with respiratory depression.82
Defining TC
An effect-site TC has been estimated for many drugs used in
anesthesia. For example, a propofol TC of 3 mg/L in a typical
patient can be achieved using preprogrammed TCI devices. A BIS
monitor can then be used to manually adjust infusion rate to
achieve a desired TE in the specific individual. Of note, the PDof
fentanyl and remifentanil in children (>1 y) were similar to those
reported in adults.83 The luxury of such a feedback system is not
available for most drugs. Instead, a concentration known to be
associated with a quantified effect is targeted.
A TC of 10 g/L is used for morphine analgesia. Observations
in children after cardiac surgery suggested that steady-state serum
concentrations higher than 20 mg/L resulted in hypercarbia
(PaCO2 > 55 mmHg) and depressed CO2 response curve slopes.
During washout, morphine concentrations more than 15 g/L
resulted in hypercarbia in 46%, whereas concentrations less than
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Figure 18-12. The median-concentration

profile and 95% confidence intervals for
1000 simulated children given intravenous
ketamine 1 mg/kg. Shading shows ketamine concentrations associated with
anaesthesia, arousal after anesthesia, and
analgesia in awake patients. From reference
15 g/L were associated with hypercarbia in 13% of children. No
age-related differences in respiratory effect were seen in these
studies at the same serum morphine concentration.84 Observation
or self-reporting pain scales are used as part of the feedback loop
for dose incremental changes.
Paracetamol is a mild analgesic. An effect-site concentration of
10 mg/L was associated with a pain reduction of 2.6 (Visual
Analogue Score [VAS] 010) after tonsillectomy in children.85 This
concentration is achievable with standard dosing regimens in
children. Although increased dose may achieve greater pain relief,
the risk of hepatotoxicity limits dose and duration of therapy.
The TC may vary, depending on the desired TE. The TC for
ketamine analgesia (0.25 mg/L) is quite different from that of
anesthesia (2 mg/L) (Figure 1812).86
Achieving TC
PK parameter estimates (e.g., CL, V) and covariate information
(e.g., age, size) are used to predict dose. Morphine infusion, based
on clearance changes with age, has been predicted in children. A
mean steady-state serum concentration of 10 g/L can be achieved
in children after noncardiac surgery in an intensive care unit with
a morphine hydrochloride infusion of 5 g/h/kg at birth (term
neonates), 8.5 g/h/kg at 1 month, 13.5 g/h/kg at 3 months,
18 g/h/kg at 1 year, and 16 g/h/kg for 1- to 3-year-old children.87
Paracetamol dosing guidelines that achieve a TC of 10 mg/L from

premature neonates through to adolescents have also been
proposed.88
A single dose of racemic ketamine 1.25 mg/kg for a typical
6-year-old child (20 kg) undergoing procedural sedation in the
emergency department may be inadequate for procedures that last
beyond 8 minutes. An understanding of the PKPD relationship
allows prediction of when a top-up dose (0.625 mg/kg) is required
(Figure 1813).89 This top-up dose could be timely if the child
requires cast molding after initial reduction of a fractured limb.
The Delayed-Effect Link

The parameter (T / keo) describing the delay between observed
plasma concentration and effect is anticipated to be reduced in
children and related to size.90 The T / keo for paracetamol has been
described using such size scaling.67 This parameter relating
propofol concentration to effect (BIS) is reported as less than
adults in children91,92 and is related to age, with a smaller T / keo as
age decreases.83 Similar results are reported for sevoflurane.93
Effect observed will be dependent on the rate at which the drug is
infused along with other hypnotic drug interactions and the effect
desired.94,95 Anxiety and catecholamine release may further
complicate this measure.94 Processing delays of EEG signals render
T / keo monitor-specific. Failure to appreciate changing T / keo
1
Figure 18-13. Time concentration and sedation

profiles for a typical 6-year-old child (20 kg).
A target effect below 2 (arouses slowly to consciousness, with sustained painful stimulus) for
15 min was achieved using bolus (1.25 mg/kg)
with a top-up dose (0.625 mg/kg) at 8 min.
From reference 89, with permission.
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values with age will result in excessive dose in a young child if the
effect site is targeted and Tpeak is anticipated to be later than it
actually is because it was determined in a teenager or adult.
Interactions Between Hypnotics

and Analgesics
Synergism between propofol and alfentanyl has been demonstrated
using response-surface methodology. Remifentanil alone had no
appreciable effect on response to shaking and shouting or response
to laryngoscopy, whereas propofol could ablate both responses.
Modest remifentanil concentrations dramatically reduced the
concentrations of propofol required to ablate both responses.96
When comparing the different combinations of midazolam,
propofol, and alfentanil, the responses varied markedly at each end
point assessed and could not be predicted from the responses of
the individual agents.97 Similar response-surface methodology has
been taken for investigation of the combined administration of
sevoflurane/alfentanil98 and remifentanil/propofol99 on ventilatory
control. These combinations have a strikingly synergistic effect on
respiration, resulting in severe respiratory depression in adults.
These synergistic associations can be extended to pediatric sedation
techniques. It is little wonder that the use of three or more sedating
medications compared with one or two medications was strongly
associated with adverse outcomes.100
CONCLUSIONS
Achievement of a TE with minimal adverse effect is the key to
anesthetic drug use. PD models are useful tools to identify a TE
and a TC at which that occurs. PK models, in turn, point to a dose
that will achieve that YC. The population approach to modeling
has proved beneficial to exploring PKPD differences in children.
Size, age, and organ function models have been used to explore
PK. PD differences, particularly in neonates and infants, have been
elucidated for common anesthetic vapors. The impact of other
drugs, active metabolites, stereoisomer interactions, and pharmacogenomics on the concentration-response relationship remain
undefined for many drugs. Lacking from our armamentarium are
similar concentration-response relationships for adverse effects.
These must also be understood to define the TC.
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73. Weinstein MS, Nicolson SC, Schreiner MS. A single dose of morphine
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76. Prys-Roberts C, Lloyd JW, Fisher A, et al. Deliberate profound hypotension induced with halothane: studies of haemodynamics and
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79. Minto CF, Schnider TW, Short TG, et al. Response surface model for
anesthetic drug interactions. Anesthesiology. 2000;92:16031616.
80. Myles PS, Leslie K, McNeil J, et al. Bispectral index monitoring to prevent
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81. Keenan RL, Shapiro JH, Kane FR, Simpson PM. Bradycardia during anesthesia in infants. An epidemiologic study. Anesthesiology. 1994;80:
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82. Davis JJ, Swenson JD, Hall RH, et al. Preoperative fentanyl challenge as
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83. Jeleazcov C, Ihmsen H, Schmidt J, et al. Pharmacodynamic modelling of
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84. Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of
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85. Anderson B, Kanagasundarum S, Woollard G. Analgesic efficacy of
paracetamol in children using tonsillectomy as a pain model. Anaesth
86. Herd D, Anderson BJ. Ketamine disposition in children presenting for
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pharmacokinetics of morphine and its metabolites in neonates, infants
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88. Anderson BJ, van Lingen RA, Hansen TG, et al. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled
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89. Dallimore D, Herd DW, Short T, Anderson BJ. Dosing ketamine for pediatric procedural sedation in the emergency department. Pediatr Emerg
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90. Anderson BJ, Meakin GH. Scaling for size: some implications for
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91. Munoz HR, Cortinez LI, Ibacache ME, Altermatt FR. Estimation of the
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92. Munoz HR, Cortinez LI, Ibacache ME, Leon PJ. Effect site concentrations of propofol producing hypnosis in children and adults: comparison using the bispectral index. Acta Anaesthesiol Scand. 2006;50:
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97. Short TG, Plummer JL, Chui PT. Hypnotic and anaesthetic interactions
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bispectral index. Anesthesiology. 2001;94:982991.
99. Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface
modeling of remifentanil-propofol interaction on cardiorespiratory
control and bispectral index. Anesthesiology. 2003;98:312322.
100. Cote CJ, Karl HW, Notterman DA, et al. Adverse sedation events in
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101. Gillooly JF, Brown JH, West GB, et al. Effects of size and temperature on
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Mechanisms of Action
of General Anesthetics
Vincent P. Laudenbach, Souhayl Dahmani, Hawa Keta-Meyer, and Jean Mantz
INTRODUCTION
The common definition of the state of general anesthesia includes
different componentsanxiolysis, amnesia, hypnosis (loss of consciousness and of neuronal synchronisation), sedation (reduced
awakeness), analgesia, blunting of the adrenergic response, immobility, and myorelaxationall of which may vary in intensity. The
three main drug categories used in combination in order to obtain
such a state include hypnotic drugs, opioids, and neuromuscular
blocking drugs.1 The present chapter excludes the two latter categories.
Ever since they became available in the field of clinical practice
and even after more than 100 years of research, the mechanisms of
action and sites of action of anesthetic agents remain incompletely
deciphered. It remains difficult to explain how agents that differ
from a chemical point of view may induce that grossly similar state
of anesthesia.2 New investigation techniques such as patch-clamp,
targeted mutagenesis, transgenesis, or functional neuroimageing
have allowed tremendous insights into the precise comprehension
of such mechanisms. This is how multiple targets, anatomic sites,
and the prominent role of ion channels have been demonstrated.3
The aim of this chapter is to review recent data concerning targets and sites of action of general anesthetic agents. We also discuss anatomic and molecular locations for anesthetic effects of
immobility, sedation, hypnosis, and amnesia. Possible contributions to between-individual response attributable to genetics and
gender are reviewed.
PRINCIPAL INVESTIGATION
TECHNIQUES THAT ALLOW FURTHER
INSIGHTS INTO ANESTHETIC
MECHANISMS OF ACTION
The patch-clamp: This technique allows the detection in real time
of the activity of a single ion channel.
The targeted mutagenesis: This technique allows the targeted
mutation of one or several amino acids of a given neurotransmitter
receptor, allowing analysis of the contribution of this amino acid
to the global properties of the receptor.
Transgenic animals, knock-out, and knock-in animals: These
animals have been engineered at the molecular level in order to
invalidate a given gene (knock-out) or to introduce a mutant version a given gene (transgenic or knock-in animals). The gene of interest may be, for instance, a subunit of a neurotransmitter receptor.
Neuroimaging functional techniques: These techniques encompass, for the main part, functional magnetic resonance imaging and positron emission tomography scanning.
GENERALITIES ABOUT MOLECULAR

TARGETS OF ANESTHETIC AGENTS
Compelling data strongly suggest that clinically relevant concentrations of anesthesia agents (from 1 M to 1 mM) preferentially
target ion channels coupled to neurotransmitter receptors.4,5
Gamma-hydroxybutyric acid (GABA) receptors, subtype A, appear to be the best candidate given their wide distribution within
the central nervous system, their physiologic role, and their high
sensitivity to anesthetic agents.3,6 Of note, in the newborn rat hippocampus (and in cultures derived from newborn neocortex), the
endogenous GABA has a depolarizing activity, due in part to
differences in chloride concentration and conductance compared
with adults.7,8 Yet, whether this is clinically relevant, that is, underlying some developmentally regulated, possibly paradoxical
effects of anesthetics in human neonates, has still not been
demonstrated.
Some anesthetic agents also act at the level of other receptors,
for example, glycine receptors (involved in the immobility produced by general anesthesia at the level of spinal cord), nicotinic
acetylcholine receptors (nAChRs), serotonin-3 (5-HT3) receptors,
or glutamate receptors (-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid [AMPA], kainite, and N-methyl-D-aspartate
[NMDA]sensitive receptors). Sodium, potassium, or calcium
voltage-gated channels have also been identified as important targets.4 Some recent data also highlight the particular contribution
of (1) 2P-K+ (two-pore domain leak K+) channels, which are
involved in the maintenance of the membrane potential, (2) HCN
channels (hyperpolarization-activated, cyclic nucleotidegated),
which belong to a family that give rise to pacemaker currents,
and (3) voltage-dependent Na+ channel expressed at the presynaptic level.3
Finally, apart from mechanisms directly acting on neurotransmission systems, numerous anesthetic agents act via the modulation of high-affinity uptake and release of neurotransmitors by
neuronal, but also non-neuronal, cells (i.e., astrocytosis).911
MOLECULAR STRUCTURE OF
CHANNEL RECEPTORS AND
ACTION OF ANESTHETIC AGENTS
GABAA, glycine, 5-HT3, and nAChRs belong to a common superfamily.10 All members of this family have five subunits constituting
a ligand-gated channel. Each subsunit has a long extracellular Nterminal domain, four transmembrane domains (TM1TM4), an
intracellular loop between TM3 and TM4 (regulating domain of
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Figure 19-1. Schematic representation of one ionotropic receptor of the superfamily that includes gamma-aminobutyric acid
A (GABAA), glycine, nicotinic, and serotoninergic receptors and
of the five subunits forming the ion channel. Subunits have long
N-terminal extracellular domains on which the ligand binds,
four transmembrane domains (TM), an intracellular loop
between TM3 and TM4, and a short C-terminal domain. For
each receptor, the ion channel pore is made of the assembly of
the TM2 of the different subunits.
the receptor, site of phosphorylation), and a short C-terminal
extracellular domain11 (Figure 191). Agonist binding sites are
located on the extracellular domain. The intramembrane TM2
domains constitute the ion channel itself (see Figure 191). At this
level, glutamate ligand-gated ion channel belong to a particular
family. They have three transmembrane domains (M1, M3, and
M4) plus a cytoplasmic re-entering loop (M2), which is the site of
the transmembrane ion channel. Here, the N-terminal domain
is extracellular, whereas the C-terminal domain is intracellular
(Figure 192). Glutamatergic ligand-gated ion channel are either
tetrameric or pentameric.11
It is now commonly admitted that most inhaled agents, among
which ethers (isoflurane, sevoflurane, desflurane, enflurane) as well
as some alkanes (e.g., halothane) act by enhancing the chloride
conductance of the GABAA receptor, thereby reinforcing inhibitory
synaptic and extrasynaptic transmission3,12 (Figure 193).
The majority of intravenous anesthetic agents, including
propofol and etomidate, selectively modulate the GABAA receptor
by reinforcing and lengthening the binding of GABA released by
presynaptic neurons.3 Thus, they increase the duration of the
opening of the channel.3 Some intravenous anesthetics, at higher
concentrations, may also elicit the GABAA channel opening with-
311
Figure 19-2. Schematic drawing of ionotropic glutamate receptors. The N-methyl-D-aspartate (NMDA)sensitive receptor is
coupled to a Ca2+-, K+-, and Na+-permeable channel. It also
possesses glycine, Zn2+, phencyclidine (PCP), and Mg2+ binding
sites that regulate function. Kainate-sensitive receptors are
coupled to a Na+- and K+-permeable channel. Alpha-amino-3hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)sensitive
receptors are also highly permeable to Na+ and K+ and harbor a
Zn2+ regulatory binding site.
out the need for the endogenous neurotransmitter. Propofol also
delays the GABAA desensitization, a mechanism that plays an
important role if inhibitory synapses are rapidly and repetitively
activated.13
In addition to their predominant action on GABAA receptors,
halogenated volatile anesthetics inhibit excitatory neurotransmission at the presynaptic level, mainly by decreasing the release of
glutamate.3 Conversely, nonhalogenated volatile anesthetics like
Figure 19-3. When applied to cultures of rat spinal ganglionic

neurons, halothane (0.86 mM) potentiates by three- to fourfold
the GABAA channel receptor response to low concentrations
(3.106 M) of GABA. From reference 64.
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Pharmacology
The potentiation of the GABAA receptor by propofol is altered

by the mutation of specific amino acid located within theTM2
domain on the subunit.26
The sensitivity of NMDA receptors to ketamine is dependent
on arginine residues located at the level of the NR2B and
NR1 subunits. These arginines are part of the Mg2+ blockade
sensitive site of the NMDA channel.25,27
These landmark works outline the high specificity of the interactions between anesthetic agents and neurotransmitter receptors.
They demonstrate the complexity of such interactions because, for
example, two anesthetics modulating the activity of a given receptor may act at different sites of this receptor.
ROLE OF 2P-K+ AND HCN CHANNELS
Figure 19-4. Cellular currents measured by application of the

patch-clamp technique, in cell-attached configuration, after
applying 10 M NMDA on hippocampal neurons. Currents
were measured on two different cells, with or without 0.1 M
ketamine. Entering currents generate negative deflexions of the
graph. From reference 4.
xenon,14 nitrous oxide,15 cyclopropane,16 as well as some intravenous agents (i.e., ketamine)17 have little if any effect on the different subtypes of GABAA receptors tested to date. Actually, they
mainly depress the excitatory neurotransmission at the postsynaptic level by blunting the activation of NMDA receptors by glutamate (Figure 194). However, their action at the level of NMDA
channel receptors is somewhat different: whereas ketamine acts
by entering and blocking the channel itself in a noncompetitive
manner,18 xenon inhibits the glycine co-activating site located on
the NR1 NMDA subunit on its extracellular domain.19 Nitrous
oxide blocks the glutamatergic transmission at both the pre- and
the postsynaptic level, but its precise site of action on NMDA
receptors has not been identified to date.20 Numerous volatile
anesthetics, as well as propofol, applied at subclinical concentrations, also inhibit nAChRs. This latter mechanism is likely to be
involved in the antinociceptive, rather than the immobilizing,
effects of anesthetic agents.21,22
Molecular genetic techniques (like targeted mutagenesis or the
engineering of chimeric receptors) have enabled the precise
location of some regions and/or sites critical for the action of anesthetics. The current literature on this field is extremely important
and still growing. Some of the more important facts are
Experiments conducted on the glycine receptor 1 subunit and

on the 1, 2, 1, and 1 subunits of the GABAA receptor have
identified some amino acid residues located between transmembrane domains TM2 and TM3, which are mandatory for
volatile anesthetics to potentiate these receptors in the presence
of their endogenous agonists.2325
The activation of 2P-K+ ion channels by clinically relevant concentrations of volatile anesthetics was first observed in snail neural
cells, then in mammals. Such activation results in (1) an increase
in K+-mediated conductance and subsequent hyperpolarization,
(2) a reduction in postsynaptic excitatory potentials, and (3) a
disruption in neuronal synchronization. Mutant mice in which
the TREK-1 type 2P-K+ channel gene has been invalidated show a
reduction of the immobilizing effects of volatile anesthetics (by
737%) when compared with normal control mice.28 This is strong
evidence supporting the involvement of this channel in the effects
of some anesthetics.
Halothane also depresses K+ currents mediated by HCN channels, resulting in a reduction of pacemaker potentials and in a
reduction of the frequency of depolarization of some neurons
showing basal self-rhythmicity. Recently, it has been shown that
two clinically relevant concentrations of halothane depressed both
HCN1 and HCN2.29 Among intravenous anesthetics, pentobarbital inhibits K+ currents in thalamic neurons.30
ROLE OF VOLTAGE-DEPENDENT
NA+ CHANNELS
Voltage-dependent Na+ channels are key actors of the propagation
and integration of neuronal signals. In particular, they underlie
the initial step of depolarization when action potentials spread.
Published works analyzing their contribution to the mechanisms
of action of anesthetics have raised different conclusions.3134 This
could be caused, in part, by their high level of structural variability.35 Indeed, depending on the kind of voltage-dependent Na+
channel analyzed, different pharmacologic effects of a given
anesthetic can be observed, quantitatively as well as qualitatively.
Moreover, the same neuron can bear different kinds of channels
that may be more or less sensitive to an anesthetic agent.
Different isoforms of voltage-dependent Na+ channels may
have distinct cellular and subcellular locations.36 In mammals,
neuronal isoforms Nav1.2, Nav1.4, Nav1.5, and Nav1.6 are inhibited
by isoflurane and some other volatile agents. Contrarily, the Nav1.8
isoform is not sensitive to these agents.3 At clinically relevant
concentrations, volatile anesthetics inhibit Na+ channels of spinal
ganglionic neurons.3
Several lines of evidence strongly suggest that the inhibition of
presynaptic Na+ channels is involved in the reduced release of
excitatory neurotransmitters by volatile anesthetics.37,38 In primary
cultures of rat hypopituitary neurons, isoflurane inhibits Na+
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currents on nerve endings, thus decreasing the amplitude of action
potentials.39,40 On rat central neurons, the same agent reduces the
presynaptic vesicular exocytosis as well as the amplitude of postsynaptic excitatory potentials. In parallel, a small reduction of the
amplitude of the presynaptic action potential is seen, with no
observed direct action on Ca2+ currents.41
WHICH ANATOMIC AND

MOLECULAR LOCATION FOR
WHICH ANESTHETIC PROPERTY?
Immobility
The blockade of movement, either spontaneous or evoked by a
stimulus, seems mainly related to a depression of spinal reflex
pathways. This can be caused by a reinforcement of inhibitory
neurotransmission or by a decrease in excitatory transmission by
spinal neurons. A large amount of data demonstrate that intravenous agents (i.e., propofol) elicit immobility via the GABAA
receptor.42,43 In vivo studies have shown that the systemic administration of antagonists of the GABAA receptor prevents the inhibitory effects of propofol on spinal reflexes.43 At the molecular level,
only the 2, 3, 3, and 2 subunits of the GABAA receptor are
detected at the spinal level, whereas 1, 1, and 2 subunits are
more abundant at the level of the cortex, hippocampus, and
thalamus. Studies conducted on mutant mice have demonstrated
that the immobilizing action of propofol and etomidate was
directly mediated by 3-containing GABAA receptors at the spinal
level.42,44 Similar studies have shown that the myorelaxant effect
of diazepam is mediated mainly by 2-containing spinal GABAA
receptors.45
As far as halogenated volatile anesthetics are concerned, some
studies show that the invalidation of the gene encoding the 3
subunit of GABAA receptors results in the loss of the inhibition of
the paw withdraw reflex in the presence of halothane, enflurane,
or isoflurane.42 Higher concentrations of anesthetic gases (1524%
when compared with wild-type controls) are required to obtain the
same immobilizing effect.42 This strongly suggests the involvement
of spinal 3-containing GABAA receptors in the immobilizing effect
of these agents. Halogenated gasinduced immobilization also
involves K+ channels and glycine receptors.28
Finally, the inhibition of excitatory channel receptors also takes
part in the immobilizing effects of halogenated volatile anesthetics.
In mouse spinal cord slices, enflurane inhibits AMPA- and
NMDA-mediated currents. In vivo, intrathecal administration of
NMDA receptor antagonists reduces isoflurane minimuml alveolar concentration (MAC) by about 30%.45
Sedation and Hypnosis

In humans, a possible definition of sedation is a state of reduced
arousal with lengthened response times, reduced motor activity,
and difficulty producing clear speech. Hypnosis is most commonly
defined as a complete lack of response to verbal orders.
Hypnosis
Etomidate is known to have high selectivity for 2 and 3 subunits
containing GABAA receptors via a single asparagine residue.26 At
hypnotic concentrations, it decreases the firing activity of primary
313
cultures of cortical neurons.45 In mice bearing a mutant, etomidateinsensitive 2 GABAA subunit, the loss of pedal withdrawal reflex
and the burst suppression response in the electroencephalogram
after etomidate administration (which are thought to reflect the
hypnotic component of etomidate effects) are still observed,
suggesting that these effects are mediated mainly via the 3 subunit
of cortical GABAA receptors.44 Cortical 3 subunitcontaining
GABAA receptors also seem to play a pivotal role in propofol
effects.45
Sedation
Hentschke and coworkers have studied the effects of volatile
agents on spontaneous action potentials in the rat somatosensory
cortex, both in vivo and in vitro.46 In vivo, the mean rate of cortical
neurons firing were significantly reduced by concentrations much
lower than MACawake. At MACawake, spontaneous action potentials
were blunted by about 50%. Isoflurane and enflurane had similar
efficiency on primary cultures of cortical neurons, that is, in the
absence of subcortical structures. At concentrations equivalent to
MACawake, exposure of neuronal cultures to isoflurane and enflurane elicited an increase in the inhibitory GABAergic synaptic
activity.46 Thus, cortical GABAA receptors seem to play a critical
role in the sedative effects of halogenated agents. This was corroborated by results of functional neuroimaging studies conducted
in the human. Subhypnotic, sedative concentrations of anesthetics
reduce cortical metabolism by 30 to 50%, whereas the metabolism
of subcortical structures is not much altered.47
Taken together, these different results suggest that the sedative
and hypnotic effects of general anesthetics largely involves cortical
2- and 3-containing GABAA receptors. The 1 subunit of GABAA
receptors plays an important role as well, notably in sedation and
amnesia elicited by diazepam.48 It must be emphasized that, at the
protein level, 2 and 1 subunits of GABAA receptors are most
frequently associated with 2 subunits49 and that 2 subunit
containing GABAA receptors are the most widely distributed
isoforms in the central nervous system.
Finally, even though 2- and 3-containing GABAA receptors
are expressed in the thalamus, animal and human studies failed
to demonstrate any effect of etomidate on thalamic functions.45
Amnesia
Amnesia is defined as a loss of memory. Memory is commonly
categorized as short (active) and long term. Notably, the process
of information by short-term memory involves the prefrontal and
sensory cortex.50 Short-term memory has limited ability to stock
information, whereas the capacity of long-term memory is virtually unlimited. Information processed by short-term memory is
subsequently transferred to long-term memory.
Anesthesia-related amnesia most probably results from depression of hippocampus activity. Pyramidal hippocampal cells express
predominantly extrasynaptic 5-containing GABAA receptors.
These are extremely sensitive to volatile anesthetics.51 This could
explain why low, subhypnotic concentrations of these agents alter
learning capability. However, animals invalidated for the 5GABAA subunit or bearing mutant 5-GABAA subunits with low
level of expression have better learning capability. Therefore, it
seems unlikely that amnesic properties of anesthetic agents are
related to a single selective action on the 5-GABAA subunit in the
hippocampus. Other anatomic structures like amygdala, a part of
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Figure 19-5. Multiple sites and targets of anesthetic agents. Hypothetic mechanisms of volatile agents
(sevoflurane and isoflurane) and of intravenous anesthetics (propofol and etomidate) at clinically relevant
concentrations.
the limbic system, are also considered an important target for
anesthetics.52,53 Volatile anesthetics alter the process of information
at this level, by interfering with both GABAergic and glutamatergic transmission.54
In summary, as far as volatile anesthetics are concerned, sedation and hypnosis are induced at the level of the brain whereas
immobility is mainly related to an inhibition of spinal neurons.
Immobility from intravenous anesthetics results from both spinal
and supraspinal actions. Effective concentrations required to
induce anesthesia differ notably between volatile and intravenous
anesthetics. For halogenated agents, a concentration of around
1 mM is required, whereas for intravenous drugs, efficient concentrations are about three orders of magnitude lower. Moreover,
concentrations required for induction of sedation and hypnosis
are lower than those necessary for immobility. Ion channels
involved in sedation and hypnosis are members of the GABAA
receptor family. Sedation involves mainly 2-containing GABAA
receptors, whereas hypnosis involves mainly 3-containing
GABAA receptors (Figure 195). These generalizations are probably true for intravenous as well as for volatile anesthetics. A major
difference resides in the way those two categories of anesthetic
agents induce immobility. Volatile anesthetics reduce the excitability of spinal neurons via multiple sites. On the contrary, the
spinal action of intravenous anesthetics is mediated almost exclusively by GABAA receptors. These differences could explain the
higher efficiency of volatile anesthetics in inhibiting motor responses to noxious stimuli. Amnesia is mainly but not exclusively
linked to the action of anesthetic agents on hippocampal 5
subunitcontaining GABAA receptors.
GENETIC AND GENDER-RELATED

VARIABILITY IN RESPONSE
TO ANESTHETIC AGENTS
The role of gender in pharmacokinetics and pharmacodynamics
of various agents have been discussed.55 Volatile anesthetics (en-
flurane, halothane, isoflurane, sevoflurane, and desflurane) and

intravenous anesthetics (midazolam, thiopental, propofol) have
been studied.55 These works suggest that differences in pharmacokinetics related to gender may be counterbalanced by pharmacodynamics.55 In the clinical setting, differences in pharmacodynamics,
metabolism, and/or clearance less than 20 to 30% between male
and female seem not to have any clinical relevance.55 Males are
more sensitive to propofol than females, with delayed awakening
after a single dose. Although the mechanisms underlying this
difference between male and female are not precisely deciphered,
a reduction of dose of about 30 to 40% has been proposed in men
in order to obtain the same awakening time.55
Despite tremendous strides in the field of genetics since the
2000s, pharmacogenetic knowledge of anesthetic drugs remains
sparse.56 This scope of research aims to determine the contribution
from genetic differences to between-individual differences in
metabolism, efficiency, and adverse effects of a given drug. Such
differences may result from variations in genes involved in the
pharmacokinetics or pharmacodynamics of anesthetic agents. To
date, most studies conducted in humans have focused on benzodiazepines.5761 Most benzodiazepines are metabolized by hepatic
enzymes of the cytochrome P450 (CYP) family, metabolites being
subsequently eliminated by the bile or the urine. Genetic polymorphisms at the level of genes encoding these enzymes alter
drugs metabolism. For example, diazepams elimination half-life is
fourfold longer in individuals carrying two alleles of the A type of
the cytochrome CYP2C19 G681A than individuals homozygous
for the G type allele.59 Consequently, these homozygous patients
have longer sedation and loss of consciousness.57 Contrary to
diazepam, pharmacogenetic studies focusing on midazolam have
found little variations depending on the genetic status, even
though midazolam clearance is reduced in patients bearing the
CYP3A4 and CYP3A5 genes. This has little clinical consequences
because there are alternative pathways for the metabolism and
excretion of this agent.57,58,60
Genetic studies of inhaled volatile anesthetics have mainly
focused on the propensity to life-threatening adverse effects such
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as malignant hyperthermia. About 50% of malignant hyperthermia cases have mutations within the gene encoding the ryanodine
receptor (RYR1).62,63 At least 23 different mutations of RYR1 have
been shown to be linked to the malignant hyperthermia syndrome.56 Conversely, there is little if any literature about the
pharmacogenomics of inhaled anesthetics related to hypnosis in
humans.
CONCLUSION
The knowledge about cellular and molecular mechanisms of
anesthesia, as well as its effects on neuronal circuits, has increased
significantly since the beginning of the 2000s. In summary, a large
body of evidence establishes the major contribution of synaptic
and extrasynaptic GABA and glutamate ion channel receptors to
the effects of anesthetic agents applied at clinically relevant
concentrations. Conversely, other ion channels as well as other
receptors also intervene. Molecular engineered cells and animals,
as well as functional neuroimaging, are powerful tools for the
understanding of phenomena associated to the state of anesthesia,
that is, amnesia, hypnosis, sedation, or immobility. Nonetheless,
the pharmacogenomics of anesthetics remains only partially
explored and will probably provide additional useful information
for the design and safe use of new drugs in the future.
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20
Nitrous Oxide
Conor McDonnell
C H A P T E R
INTRODUCTION
PHYSICAL PROPERTIES OF N2O
Joseph Priestly first synthesized nitrous oxide (N2O) in 1772 while

experimenting with a new device of his own invention that
allowed him to collect gases over mercury; this in the same year he
was elected to the French Academy of Sciences.1 The psychotropic
effects of N2O were first appreciated and publicized in 1799
by Humphrey Davy.2 His recommendations for private and
recreational use of N2O were immediately taken up by, among
others, Samuel Coleridge. However, his observation that nitrous
oxide appears capable of destroying physical pain and it may
probably be used with advantage during surgical operations went
unheeded for some time. In 1844, the American dentist Horace
Wells attended a lecture by Garner Colton on chemical phenomena, and the next day, Wells inhaled N2O gas administered by
Colton and had an aching third molar tooth painlessly extracted.
This was the first operation performed under N2O inhalation
anesthesia. Although some public demonstrations around this
time were unsuccessful, the use of N2O as a surgical analgesic took
root with the advent of inhaled anesthesia and enjoyed a long and
seemingly innocuous period of use until the mid to latter 20th
century. The first clear association of N2O with morbidity came
from a report in 1956 describing the development of aplastic
anemia in patients treated for days with inhaled N2O.3 N2O still
enjoys widespread use in anesthesia, dentistry, obstetrics, and
emergency medicine.
N2O is a sweet-smelling, colorless gas that is nonflammable

but supports combustion. Other properties are shown in Table
201.
PRODUCTION AND STORAGE

N2O is produced commercially by heating ammonium nitrate at
240C. Water vapor and impurities, which include higher oxides
of nitrogen, ammonia, and nitric acid, are subsequently removed
by passing through a series of scrubbers and washers. N2O is
stored in French-blue cylinders and pressurized to approximately
4400 kPa. N2O is usually stored below its critical temperature and
so is in simultaneous liquid and vapor phases. These cylinders
have a filling ratio of 0.75 in temperate countries and 0.67 in
tropical climates. Unlike cylinders filled with pressurized gas,
cylinder pressure remains effectively constant until all liquid N2O
is vaporized. Most institutions use a pipeline supply of N2O
comprising a central bank of large cylinders, reserve banks, and a
pipeline to appropriate sites within the hospital. In addition, all
modern anesthesia machines are equipped to supply N2O but
continue to hold reserve cylinders on the back of the machine
should the central pipeline supply fail.
N2O as an Anesthetic Agent

N2O, along with sevoflurane and isoflurane, remains one of the
most widely used agents in pediatric anesthesia today. It has
a rapid onset and offset of action, but a low anesthetic potency
with a minimum alveolar partial pressure of 110 kPa (minimum
alveolar concentration [MAC] of 104% at sea level). Therefore, as
well as the need to supply oxygen, it cannot be administered under
atmospheric conditions as the sole agent to maintain anesthesia.
However, because of its analgesic properties and its ability to
decrease the required partial pressures of volatile inhaled agents
(and, therefore, the cardiovascular depression that occurs with
some volatile agents), N2O remains in common use as a carrier
gas. N2O is a low-cost agent and its use can further decrease costs
associated with increased use of more potent volatile agents. N2O
also speeds uptake of these more potent inhaled agents.
The relative insolubility of N2O results in the expansion of gascontaining spaces because it is 34 times more soluble in blood
(blood/gas partition coefficient of 0.47) than it is in nitrogen
(blood/gas partition coefficient of 0.014). Previous work has
demonstrated that alveolar N2O concentrations increase faster in
infants and children than in adults.4 This property, in addition to
the fact that N2O usually composes a large fraction of the inspired
gas mixture, results in the rapid egress of N2O from alveoli to
blood during induction of inhaled anesthesia (Figure 201). The
resulting concentration of remaining alveolar gases increases the
TABLE 20-1. Physical and Anesthetic Properties
of Nitrous Oxide
Property
Value
Molecular weight
Melting point, C
Boiling point, C
Critical remperature, C
Blood/gas partition coefficent
Oil/gas partition coefficient
MAC, %
44
90.8
88.5
36.5
0.47
1.4
105
MAC = minimum alveolar concentration.
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Cardiovascular
Figure 20-1. Nitrous oxide (N2O) equilibration curves. The

10% adult curve was taken from data reported by Salanitre et
al.4; the 70% adult curve was obtained by recalculation of data
from Severinghaus. Solid circles, infants 06 months, 60% N2O;
open circles, children 15 years, 60% N2O; solid squares, adults,
10% N2O; open squares, adults, 70% N2O. FE = expired gas; FI =
inspired gas. (source: Salanitre E, Rackow H. The pulmonary
exchange of nitrous oxide and halothane in infants and children.
Anesthesiology 1969;30(4):38894 with permission)
uptake of volatile agent into the blood, accelerating the onset of
anesthesia.
N2O has an affinity for many different receptor types.5 It has
an inhibitory action on the N-methyl-D-aspartate (NMDA) receptor and confers some neuroprotection from excessive NMDA
receptor activation and resulting glutamate release.6 N2O has
demonstrated stimulatory activity at dopaminergic, 1 and 2
adrenergic, and opioid receptors.79
N2O is eliminated unchanged from the body almost entirely
through the lungs, although a small amount diffuses through the
skin. A very small contribution is made to elimination through
reductive metabolism by anaerobic bacteria in the gut.
THE EFFECTS OF N2O ON

PHYSIOLOGIC SYSTEMS
Respiratory
N2O causes a decrease in tidal volume and an increase in respiratory rate, usually demonstrating maintenance of minute volume.
The increase in respiratory rate is caused by central nervous
system activation. N2O-induced respiratory depression causes
elevation of alveolar carbon dioxide in a dose-related manner.10,11
N2O also leads to reductions in the ventilation response to hypoxia
and hypercapnia. Although N2O is less of a ventilation depressant than the potent volatile agents, it is not free of significant
effect. Inhalation of N2O also depresses tracheal mucociliary flow
and neutrophil chemotaxis.12 At low concentrations, N2O has no
effect on hypoxic pulmonary vasoconstriction; at higher N2O
concentrations, hypoxic pulmonary vasoconstriction may be
impaired.
The discontinuation of N2O at the end of anesthesia results in
a rapid outpouring of insoluble N2O from pulmonary arterial
blood into the alveoli. This causes volume displacement of alveolar gas, and high partial pressures of N2O can lower arterial
oxygen pressures (PaO2). This is commonly referred to as diffusion
hypoxia but, in the absence of significant ventilation-perfusion
mismatch or shunting, is unlikely to be of important clinical
relevance.
N2Os hemodynamic effects are inconsistent. Administered as a

40% mixture in oxygen, it can decrease cardiac output.13 When it
is added to halothane in healthy volunteers, N2O lowers cardiac
output but stimulates the sympathetic nervous system, therefore
resulting in increased arterial pressures because of increased
systemic vascular resistance.14 N2O administered to patients with
heart disease or compromised cardiac output (especially when
combined with opioids) can result in hypotension and decreased
cardiac output.15,16 Pulmonary vascular resistance is increased
because of constriction of the pulmonary vascular smooth muscle.
This may lead to an increase in right atrial pressure, and as a
consequence, N2O is usually avoided in the setting of pulmonary
hypertension. However, studies in infants have not demonstrated
additional increases in pulmonary vascular resistance when N2O
is administered.17
Increased vascular resistance results in decreased renal and
hepatic blood flow. The addition of N2O to halothane anesthesia
can cause further splanchnic blood flow decreases.18
Central Nervous System

N2O increases cerebral blood flow, cerebral metabolic rate for
oxygen (CMRO2), and intracranial pressure.19 Likely, the increase
in cerebral metabolism rather than any direct vasodilatory effect
accounts for the increase in cerebral blood flow. N2O added to
isoflurane is a potent vasodilator, and this effect increases in a
dose-dependent manner.20 Although sevoflurane at a MAC of 1.2
decreases cerebral blood flow velocity compared with awake
parameters, the addition of N2O increases flow toward the values
obtained in the awake state.21 Cerebral blood flow velocity correlates reasonably well with total cerebral blood flow and is
increased by N2O in awake subjects.22 Neither the addition nor the
removal of N2O in children receiving 1 age-adjusted MAC of
desflurane altered the cerebral blood flow velocity.23 N2O was even
demonstrated to increase cerebral blood flow velocity and CMRO2
in the presence of electroencephalographic silence established by
propofol infusion.24 Addition of N2O to the inspired gas mixture
after induction of hypocapnia reversed those decreases in cerebral
blood flow associated with hyperventilation. This would suggest
that administration of N2O may offset the beneficial effects of
hyperventilation-induced hypocapnia in patients with intracranial
pathology.25
N2O may also exert direct effects on neural tissue. In rat
hippocampal slices, exposure to N2O impaired electrophysiologic recovery after severe hypoxia.26 Although administration
of isoflurane protected against microtubule-associated protein
degradation during ischemic insult to the brain, N2O significantly
decreased this protective effect, leading to a recommendation
that N2O be discontinued should accidental cerebral ischemia
occur during anesthesia.27 The neurotoxic potential of N2O
was further described in another study that reported that these
effects could be prevented by drugs that enhance GABAergic
inhibition. The authors attributed the favorable safety record of
N2O to the low concentrations used and the fact that it is usually
combined with anesthetic agents that counteract its neurotoxic
potential.28
Anesthesia that includes N2O administration trends toward
increasing the voltage and decreasing the frequency of the electroencephalogram (EEG). N2O decreases the amplitude of brainstem
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auditory-, cortical somatosensory-, and visual-evoked potentials
as well as increasing the latency of visual-evoked potentials.
These factors should be considered when encountering not
only patients for neurosurgical procedures but also for patients
with acute head injuries or the possibility of raised intracranial
pressure present during nonneurosurgical procedures.
Analgesic and Sedative Effects

N2O demonstrates analgesic actions thought to be mediated by
activation of opioid receptors in the periaqueductal gray matter
of the midbrain.5 This results in modulation of nociceptive
pathways through the release of norepinephrine and activation of
2 adrenoceptors in the dorsal horn of the spinal cord. This may
help explain the acute tolerance that develops to N2O as a consequence of central opioid peptide depletion.
N2O provides excellent analgesia for acutely painful procedures
such as fracture manipulation and dressings or cast changes.29 N2O
may also have an expanding role in the emergency room or in
preparation for positioning for radiologic procedures. N2O is also
used in the operating room as supplementation to regional or local
anesthetic techniques.
N2O was first used as an analgesic in the obstetric setting in
1881 by Stanislaw Klikovich who administered premixed N2O
80% in oxygen. N2O can provide adequate labor analgesia for
parturients, but coordination of administration with contractions
may prove difficult. Maternal side effects include nausea, dizziness, paraesthesia, and dry mouth.
Adverse Effects
Gas-Filled Spaces
N2O is 34 times more soluble in blood than nitrogen.30 Therefore,
N2O transported through the blood stream will enter gascontaining cavities significantly faster than the nitrogen in those
cavities can be removed. This results in pressure-volume changes
that can result in significant patient discomfort and morbidity.
Expansion of the middle ear, especially during middle ear surgery,
can result in disruption of grafts and/or the ossicular chain.31
Tympanic membrane rupture during anesthesia with N2O has
been reported.32 In certain ophthalmic surgeries, gas bubble
tamponade is employed. Diffusion of N2O into this space results
in increased intraocular pressure, although the overall effects on
outcome of surgery are not clear.33
More rapid and serious expansion can occur in the presence of
pneumothorax or lung bullae with resultant enlargement of
ventilation-perfusion inequality and development of hemodynamic instability if the situation expands toward tension.30
Certain surgeries carry an attendant risk of acute air embolism.
Administration of N2O during such surgeries results in a more
rapid expansion of air emboli entering the circulation, and this
increases the risks and morbidity associated with such intraoperative complications.34
N2O should be avoided in patients undergoing treatment for
decompression sickness because rapid gas expansion of intravascular nitrogen containing bubbles will result in worsening of
symptoms and increased morbidity.
The administration of N2O during bowel or laparoscopic surgery can cause significant distention of the gas-containing bowel.30
The amount of distention depends on three factors: (1) The
Nitrous Oxide 319
amount of gas in the bowel. In the presence of obstruction, bowel

may contain many times more gas than normal (normal content
is ~100 mL). The greater the amount of gas contained in the bowel,
the greater the potential expansion and distention in the presence
of N2O. (2) The duration of administration. At approximately 100
minutes of N2O administration, bowel gas cavity will have
increased by 75 to 100%. (3) If the alveolar concentration of N2O
is 50%, the maximum possible increase in bowel gas is twofold. At
an alveolar N2O concentration of 80%, maximum increase in
bowel gas approaches fivefold.
The administration of N2O for a prolonged time during bowel
or laparoscopic surgery results in operative difficulties for surgeons and difficulties with abdominal closure. This may result in
more postoperative respiratory problems for the patient and likely
results in prolonged hospitalization.30,35 In the patient with
suspected bowel obstruction or compromised splanchnic perfusion, the higher gas content of the bowel accelerates the degree to
which N2O-induced expansion may occur. This can proceed to
the point of bowel ischemia, necrosis, and perforation.
Nausea and Vomiting

Postoperative nausea and vomiting is a significant source of
patient discomfort and may result in unanticipated hospital
admission. The contribution of N2O has been extensively examined and debated.3643 The mechanism for any emetogenic potential
of N2O is not fully elucidated but is thought to be related to
changes in middle ear pressures, bowel distention, decreased lower
esophageal sphincter pressure, and activation of dopaminergic
receptors. Although pediatric studies in the past have failed to
demonstrate significant increases in the incidence of postoperative
nausea and vomiting associated with the use of N2O,3638 more
recent studies have refuted these findings and demonstrated an
increased incidence.39,40 N2O may even reverse the antiemetic
effects of continuous propofol infusion.40
Adult evidence review concluded that 24 of 27 published
studies demonstrate an increase in postoperative nausea and
vomiting attributable to the use of N2O.41 Possibly because postoperative nausea and vomiting is such a multifactorial entity, the
absolute effects of N2O differed per publication relative to the type
of surgery, patient population, and patient characteristics under
review. A meta-analysis published that same year (1996) concluded that there was a 28% risk reduction to be observed by
omitting the use of N2O.42 This trend revealed a greater benefit in
the female population but a lesser effect in patients undergoing
abdominal surgery.
If it were simply a choice between decreasing the incidence of
postoperative nausea and vomiting by omitting N2O versus the
potential risk for increased incidence of awareness, the decision
on whether or not to employ N2O could not be equally applied to
all patient populations or surgical procedures.43
Metabolic Derangements
Prolonged administration of N2O results in inhibition of methionine synthetase.44 This results in megaloblastic changes, growth
retardation, psychomotor retardation, and neurologic problems
similar to subacute combined degeneration of the spinal cord. It
also interferes with DNA synthesis in both leukocytes and
erythrocytes.45 In 1956, it was reported that several patients sedated with N2O for some days developed aplastic anemia.46 Having
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isolated the use of N2O as the likely culprit, it was prospectively

examined by the authors in a 10-year-old boy. On the fourth day
of 50% N2O administration, the boy developed granulocytopenia.
N2O was discontinued but thrombocytopenia developed over
subsequent days. Bone marrow biopsy demonstrated pernicious
anemia with megaloblastic changes. Similar findings were reported in cardiac surgical patients receiving 50% N2O for 24 hours
during and after surgery.47
Inhibition of methionine synthetase by N2O was first demonstrated in rats. More recently, it has been demonstrated that
4 hours of exposure to 70% N2O in the equivalent of late middleaged (18-mo-old) rats produced lasting memory impairment that
was preceded by a reduction in cerebral cortical methionine
synthetase activity.48 Enzyme activity in patients with pre-existing
methionine synthetase deficiency is presumably not worsened by
the administration of N2O; however, the resultant superimposed
inhibition of vitamin B12mediated related metabolic pathways is
not yet known and the implications of brief exposures of clinically
relevant levels of N2O in children with methionine synthetase
deficiency remain unknown.
Homocysteinuria is the second most common disease of amino
acid metabolism. In 2003, a case report described a fatal outcome
in a 3-month-old boy with type III homocysteinuria who had
twice been exposed to N2O in a 4-day period.49 Death was presumed to have resulted from N2O-induced methionine synthetase
inhibition that led to methionine deficiency in the setting of
tetrahydrofolate reductase deficiency associated with the genetic
defect (Figure 202). Another type III patient developed myelopathy and macrocytic anemia after double exposure to N2O over
a 10-week period.50 The inhibition of methionine synthase may
also result in an increase in plasma homocysteine concentrations,
because the enzyme aids in the conversion of homocysteine to
methionine, and short-term exposure to N2O has demonstrated
significant increases in plasma homocysteine.51 Although hyperhomocysteinemia is an independent risk factor for coronary artery
and cerebrovascular disease, the significance of this observation in
the perioperative period is currently unknown.52 If it is known that
a patient or family member has elevated homocysteine concentrations in concert with decreased methionine concentrations, it
would likely be prudent to avoid N2O administration. With

methylmalonic acidemia, patients can acutely develop severe
metabolic acidosis, ketosis, and hyperammonemia at times of
increased protein catabolism. It has previously been demonstrated
that 24 hours of exposure to N2O increases urinary methylmalonic
acid levels threefold in healthy patients,53 and it would also seem
prudent to avoid the use of N2O in patients with known methylmalonic acidemia.
Case reports of sensory polyneuropathies resulting from
recreational use and/or environmental exposure with N2O were
published in the 1970s.54,55 N2O irreversibly oxidizes the cobalt
atom of vitamin B12, transferring it from the active to the inactive
state. A survey of 18,000 dentists and dental assistants demonstrated that, with N2O exposure, there was a gender-independent
association of neurologic findings similar to those observed with
pernicious anemia.56 An 8-month-old baby developed bone marrow failure and severe neuropathy following 80 minutes of exposure to N2O.57 It was subsequently discovered that the mother
was vitamin B12deficient and had been breast feeding the baby
with no other dietary supplementation. Similar nutritionalinduced vitamin B12 deficiencies have been described in reports
of N2O-induced bone marrow failure and neuropathy.58
It would appear prudent at present to omit N2O when anesthetizing patients with known metabolic conditions, dietary
restrictions on vitamin B12 intake, or as an agent for prolonged
sedation.
Teratogenicity
There is strong evidence that prolonged exposure to N2O is teratogenic in mammalian models. Mechanism is likely multifactorial
rather than a simple consequence of impaired DNA synthesis. In
animal models, 1 adrenoceptor antagonists partially prevent N2O
teratogenesis.59 Studies in pregnant patients receiving N2O early
in pregnancy have not demonstrated increased fetal loss or
incidence of fetal abnormalities.60,61 However, exposure in the
workplace is more controversial, and it is likely that workplace
exposure to N2O has an adverse effect on the outcome of pregnancy with an increased risk of spontaneous abortion among
women working with N2O for 3 or more hours per week in the
Figure 20-2. Metabolic pathways affected

by N2O. Hatched bars, points of inhibitio
by N2O; roman numerals, the three types
of homocysteinuria. MTHFR = methylene
tetrahydrofolate reductase. (Source:
Baum V. When nitrous oxide is no laughing
matter: nitrous oxide and pediatric anesthesia. Pediatric Anesthesia 2007;17:82430
with permission)
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CHAPTER 20
absence of scavenging equipment.62 Current wisdom states that,
providing anesthetic gases are scavenged and the levels of ambient
N2O are maintained below 100 ppm, the safety of those with
long-term occupational exposure to N2O is not compromised. In
some patients undergoing resection of malignant tumors, blood
L-methionine concentration was lower and blood amino acid
significantly altered by the administration of N2O.63 Recommendations from that publication were that consideration should be
made for avoiding the use of N2O in patients with cancer.
RECREATIONAL USE
N2O has remained a potential drug of abuse since its introduction
to society in the early 1800s. When inhaled in high concentrations,
it produces an intense high with sensations of flying and floating.
However, this practice has many adverse effects including subacute combined degeneration of the cord from chronic abuse,
hypoxic injury owing to self-administration of hypoxic mixtures,
and frostbite of the vocal cords, which has been reported following
inhalation direct from N2O cylinders.
ENVIRONMENTAL CONCERNS
Like carbon dioxide, methane, and perfluorocarbons, N2O is a
greenhouse gas. N2O is approximately 300 times more effective
than carbon dioxide at trapping heat and contributes to global
warming. However, N2O accounts for less than 5% of total
greenhouse gases. The vast majority of environmental N2O is
produced by the burning of fossil fuels, nitrogen-based fertilizers
in agricultural practice, and sewage management programs. The
contribution of anesthesia to the quantities of N2O in the atmosphere are likely ever-declining with the advent of scavenging, lowflow inhalational anesthesia, and total intravenous anesthesia.
EMERGING RESEARCH CONCERNS

As a weak anesthetic, N2O is often administered as a 70% or higher
portion of the inspired gas mixture. This limits the inspired concentration of oxygen that can be delivered. In a recently published
study examining the effects of N2O in the adult postoperative
population, major postoperative complications including fever,
wound infection, pneumonia, pulmonary atelectasis, and severe
nausea and vomiting were significantly decreased if N2O was
omitted from the anaesthetic.64 This did not translate into decreased hospital stay for these patients, and the question remains
whether it was the absence of N2O or the increase in inspired
oxygen that resulted in decreased postoperative complications.
CONCLUSIONS
N2O has maintained longevity as an anesthetic agent for nearly
200 years. However, the low toxicity of modern agents, the effects
of N2O on bowel distention, nausea and vomiting, methionine
synthetase, and teratogenicity as well as emerging evidence examining the effects of N2O on the immature brain, homocysteine
concentrations, and major postoperative complications are fast
making an argument against the continued widespread use of
N2O. As more health care professionals and specialties seek to
provide sedation without formal anesthesiology training or supervision, it is our responsibility as anesthesiologists to investigate
Nitrous Oxide 321
safer alternative options and to maintain a high profile in the

development of sedation protocols and guidelines designed for use
outside the operating room.
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17. Hickey P, Hansen D, Stratford M, et al. Pulmonary and systemic hemodynamic effects of nitrous oxide in infants with normal and elevated
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19. Misfeldt BB, Jorgensen PB, Rishoj M. The effect of nitrous oxide and
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23. Karsli C, Luginbuehl IA, Bissonnette B. The effect of nitrous oxide on
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24. Matta BF, Lam AM. Nitrous oxide increases cerebral blood flow velocity
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25. Watts D, Luney SR, Lee D, Gelb AW. Effect of nitrous oxide on cerebral
blood flow velocity after induction of hypocapnia. J Neurosurg Anesthesiol.
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26. Amorim P, Chambers G, Cottrell J, Kass IS. Nitrous oxide impairs
electrophysiologic recovery after severe hypoxia in rat hippocampal slices.
27. Sugaya T, Kitani Y. Nitrous oxide attenuates the protective effect of isoflurane on microtubule-associated protein 2 degradation during forebrain
ischemia in the rat. Brain Res Bull. 1997;44:307309.
28. Jevtovic-Todorovic V, Todorovic SM, Mennerick S, et al. Nitrous oxide is
an NMDA antagonist, neuroprotectant and neurotoxin. Nat Med. 1998;
4:460463.
29. Annequin D, Carbajal R, Chauvin P, et al. Fixed 50% nitrous oxide oxygen
mixture for painful procedures: a French survey. Pediatrics. 2000;105:47.
30. Eger EL III, Saidman LJ. Hazards of nitrous oxide in bowel obstruction
and pneumothorax. Anesthesiology. 1965;26:61.
31. Karabiyik L, Bozkirli F, Celebi H, Goksu N. Effect of nitrous oxide on
middle ear pressure: a comparison between inhalational anaesthesia with
nitrous oxide and TIVA. Eur J Anaesthesiol. 1996;13:2732.
32. Ohryn M. Tympanic membrane rupture following general anesthesia with
nitrous oxide: a case report. AANA J. 1995;63:4244.
33. Briggs M, Wong D, Groenewald C, et al. The effect of anaesthesia on the
intraocular volume of the C3F8 gas bubble. Eye. 1997;11:4752.
34. Nyarwaya JB, Pierre S, Mazoit JX, et al. Effects of carbon dioxide
embolism with nitrous oxide in the inspired gas in piglets. Br J Anaesth.
1996;76:428434.
35. Scheinin B, Lindgren L, Scheinin TM. Peri-operative nitrous oxide delays
bowel function after colonic surgery. Br J Anaesth. 1990;64:154.
36. Splinter WM, Komocar L. Nitrous oxide does not increase vomiting after
dental restorations in children. Anesth Analg. 1997;84:506508.
37. Splinter WM, Roberts DJ, Rhine EJ, et al. Nitrous oxide does not increase vomiting in children after myringotomy. Can J Anaesth. 1995;42:
274276.
38. Pandit UA, Malviya S, Lewis IH. Vomiting after outpatient tonsillectomy
and adenoidectomy in children: the role of nitrous oxide. Anesth Analg.
1995;80:230233.
39. Bloomfield E, Porembka D, Grimes-Rice M. Avoidance of nitrous oxide
and increased isoflurane during alfentanil based anesthesia decreases the
incidence of postoperative nausea. Anesth Prog. 1997;44:2731.
40. Crawford MW, Lerman J, Sloan MH, et al. Recovery characteristics of
propofol anaesthesia, with and without nitrous oxide: a comparison with
halothane/nitrous oxide anaesthesia in children. Paediatr Anaesth. 1998;
8:4954.
41. Hartung J. Twenty-four of twenty-seven studies show a greater incidence
of emesis associated with nitrous oxide than with alternative anesthetics.
Anesth Analg. 1996;83:114116.
42. Divatia JV, Vaidya JS, Badwe RA, Hawaldar RW. Omission of nitrous
oxide during anaesthesia reduces the incidence of postoperative nausea
and vomiting. A meta-analysis. Anesthesiology. 1996;85:10551062.
43. Tramer M, Moore A, McQuay H. Meta-analytic comparison of prophylactic antiemetic efficacy for postoperative nausea and vomiting: propofol
anaesthesia vs omitting nitrous oxide vs total i.v. anaesthesia with
propofol. Br J Anaesth. 1996;76:186193.
44. Deacon R, Lumb M, Perry J, et al. Selective inactivation of vitamin B12 in

rats by nitrous oxide. Lancet. 1978;2:10231024.
45. Maze MJ, Fujinaga M. Recent advances in understanding the actions and
toxicity of nitrous oxide. Anaesthesia. 2000;55:311314.
46. Lassen HCA, Henricksen E, Neukirch F, et al. Treatment of tetanus. Severe
bone marrow depression after prolonged nitrous-oxide anaesthesia.
Lancet. 1956;1:527530.
47. Amess JAL, Rees GM, Burman JF, et al. Megaloblastic haemopoiesis in
patients receiving nitrous oxide. Lancet. 1978;2:339342.
48. Culley DJ, Raghavan SV, Yukhananov R, et al. Nitrous oxide decreases
cortical methionine synthase and produces lasting memory impairment
in rats [abstract]. Anesthesiology. 2006;105:A1182.
49. Selzer RB, Rosenblatt DS, Laxova R, et al. Adverse effect of nitrous oxide
in a child with 5,10-methylenetetrahydrofolate reductase deficiency. N
Engl J Med. 2003;349:4550.
50. Lacassie H, Nazar C, Yonish B, et al. Reversible nitrous oxide myelopathy
and a polymorphism in the gene encoding 5,10 methylenetetrahydrofolate reductase deficiency. Br J Anaesth. 2006;96:222225.
51. Baum VC. When nitrous oxide is no laughing matter: nitrous oxide and
pediatric anesthesia. Pediatr Anesth. 1997;17:824830.
52. Badner NH, Drader K, Freeman D, Spence JD. The use of intraoperative
nitrous oxide leads to postoperative increases in plasma homocysteine.
Anesth Analg. 1998;87:711713.
53. Rask H, Olesen AS, Mortensen JZ, et al. N2O and urine methylmalonic
acid in humans. Scand J Haematol. 1983;31:4548.
54. Layzer RB, Fishman RA, Schafer JA. Neuropathy following abuse of
nitrous oxide. Neurology. 1978;28:504506.
55. Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide.
Lancet. 1978;2:12271230.
56. Brodsky JB, Cohen EN, Brown BW, et al. Exposure to nitrous oxide and
neurologic disease among dental professionals. Anesth Analg. 1981;60:
297301.
57. Felmet K, Robins B, Tilford D, et al. Acute neurologic decompensation
in an infant with cobalamin deficiency exposed to nitrous oxide. J Pediatr.
2000;137:427428.
58. .McNeely JK, Buczulinski B, Rosner DR. Severe neurological impairment
in an infant after nitrous oxide anaesthesia. Anesthesiology. 2000;93:
15491550.
59. Ohara A, Mashimo T, Zhang P, et al. A comparative study of the
antinociceptive action of xenon and nitrous oxide in rats. Anesth Analg.
1997;85:931936.
60. Aldridge LM, Tunstall ME. Nitrous oxide and the fetus. A review and the
results of a retrospective study of 175 cases of anaesthesia for insertion of
shirodkar suture. Br J Anaesth. 1986;58:13481356.
61. Crawford JS, Lewis M. Nitrous oxide in early human pregnancy.
Anaesthesia. 1986;41:900905.
62. Rowland AS, Baird DD, Shore DL, et al. Nitrous oxide and spontaneous
abortion in female dental assistants. Am J Epidemiol. 1995;141:531538.
63. Crespo ML, Gimenez A, Bas T, et al. Effect of nitrous oxide and propofol
on amino acid metabolism in neoplastic patients. Nutr Cancer. 1997;27:
8083.
64. Myles PS, Leslie K, Chan MTV, et al. Avoidance of nitrous oxide for
patients undergoing major surgery. Anesthesiology. 2007;107:221231.
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George D. Politis
C H A P T E R
INTRODUCTION
Inhalational agents have been the centerpiece of pediatric anesthesia from the time of the earliest known pediatric anesthetics
described in 1848 in the case logs of John Snow.1 The advent of
the easily titratable short-acting intravenous anesthetics, propofol
and remifentanil, has offered pediatric anesthetists an attractive
option to volatile anesthesia. Nonetheless, volatile anesthetics will
maintain center stage for the foreseeable future owing to their ease
of use, low variability in response, lack of development of tolerance, low frequency of organ toxicity, and rapid recovery profiles.
They allow induction without prior placement of an intravenous
line, are easily titrated, and satisfy the basic requirements of
general anesthesia: provision of immobility, unconsciousness,
amnesia, muscle relaxation, and blunting of autonomic reflexes.
The two newest volatile anesthetics, sevoflurane and desflurane,
have gained favor owing to several advantages over their predecessors, although only sevoflurane has achieved widespread popularity in pediatric anesthesia. In fact, sevoflurane has now displaced
halothane as the dominant anesthetic for children, after halothane
maintained that role for nearly a half a century.2 The key role of
volatile anesthetics in pediatric anesthesia makes it imperative for
the pediatric anesthetist to command a working knowledge of the
pharmacology, clinical aspects, and potential detrimental effects of

these extraordinary agents.
PHYSICOCHEMICAL PROPERTIES
OF VOLATILE ANESTHETICS
Commercially available modern potent inhalational agents, with
the exception of halothane, are based on either a methyl ethyl or
a methyl isopropyl halogenated ether skeleton (Table 211).
Enflurane (CHF2-O-CF2-CHClF), isoflurane (CHF2-O-CHClCF3), and desflurane (CHF2-O-CHF-CF3) are methyl ethyl ethers,
and sevoflurane (CH2F-O-CH-(CF3)2) is a methyl isopropyl ether.
Halothane is a polyhalogenated alkane (CH3CHBrCl).
Numerous similarities exist in these molecules, as can readily
be seen from the diagrams in Table 211. For example, isoflurane
and enflurane are stereoisomers, meaning that they share the same
chemical formula and bond structure but the geometric position of the atoms differs in space. In addition, desflurane and
isoflurane are identical molecules except for a difference of one
halogen atom on the alpha carbon; desflurane has a fluoride and
isoflurane has a chloride in that position. These seemingly minor
molecular differences lead to substantial changes in the physical,
TABLE 21-1. Structures, Physical Properties, and Volatile Anesthetic Blood/Gas and Tissue/Blood Solubilities ()at 37C
Halothane
Chemical structure
Molecular weight
Boiling point, C
Vapor pressure, mmHg
Metabolized, %
blood/gasadults
blood/gasneonates
brain/bloodadults
brain/bloodneonates
muscle/bloodadults
muscle/bloodneonates
fat/bloodadults
Enflurane
Isoflurane
Sevoflurane
F H
F
F Cl
F
Cl F
CF3 F
F
F F
F
| |
|
| |
|
| |
|
| |
|
|
|
F C C Br H C O C C H H C O C C F F C O C C F H C O C C F
|
| |
|
| |
| |
|
| |
|
|
|
F Cl
F
F F
F
H F
H
H F
H
H F
197.4
50.2
244
20
2.5
2.1
1.9
1.5
2.3
1.3
67
184.5
56.5
172
2.4
1.9
1.8
1.3
0.9
1.6
0.8
46
184.5
48.5
240
0.2
1.4
1.2
1.7
1.3
2.1
1.1
56
200.1
58.6
185
5
0.66a
0.66a
1.7
3.1
48
Data for blood/gas for sevoflurane comes from reference 19.

Metabolized percentages are from references 278 to 282.
All pediatric and adult (refers to middle-aged adults) solubility data for halothane, enflurane, and isoflurane come from reference 21.
All solubility data for sevoflurane and desfluranee are from reference 283 except where indicated.
Desflurane
168
23.5
664
0.02
0.42
1.3
2.0
27
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pharmacokinetic, and pharmacodynamic properties of these

agents. For example, Table 211 shows that there are considerable
differences in lipid solubility, and anesthetic potency increases
with increasing lipid solubility.
Enflurane, halothane, desflurane, and isoflurane are chiral
molecules, meaning that they have an asymmetrical center, in
which a carbon atom is attached to four different substitution
groups. These agents are marketed as racemic mixtures of the
R and S enantiomeric mirror images. The S- form of isoflurane has
been shown to have as much as 53% increased potency over the
R- form.3 In addition, the R- form of halothane has been found to
have increased metabolism, leading to increased formation
of trifluoroacetylated proteins in the liver. Those proteins are
believed to form neo-antigens that are responsible for the immunemediated hepatic necrosis known as halothane hepatitis, which
is discussed in the section on Hepatic Toxicity Caused by Volatile
Anesthetic Metabolites.4 Whereas some believe that specific
clinical uses may develop for individual chiral volatile anesthetic
molecules based on selective potency and toxicity,5 others believe
that clinically significant advantages are not likely and that these
stereoselective actions are mainly of scientific interest.6
PHARMACOKINETICS OF
VOLATILE ANESTHETICS
The study of the human pharmacokinetics of volatile anesthetics
examines the fate of those drugs over time when presented to
humans. A safe pediatric anesthetic can best be conducted when
one understands the pharmacokinetic principles that govern the
speed with which partial pressures of inhaled anesthetics rise in
body tissues (the washin), and how those principles differ for
infants and children. In addition, understanding the factors that
govern the elimination of volatile agents (the washout) is important to achieve proper timing of the termination of the anesthetic.
The next section examines factors affecting volatile anesthetic
washin, namely, the alveolar anesthetic delivery, anesthetic uptake
from alveoli into pulmonary blood, and uptake from the arterial
blood into tissues, and discusses ways in which these are interrelated. Anesthetic washout is also addressed.
Volatile Anesthetic Washin

Anesthetics move along partial pressure and not concentration
gradients within and between fluids and tissues. In addition, the
partial pressure of the anesthetic, and not its concentration, is
responsible for the level of anesthesia achieved. Nonetheless, we
are more used to seeing amounts of anesthetics expressed in
percent rather than millimeters of mercury, and most manuscripts
use these terms interchangeably. That said, this chapter also interchanges those terms when appropriate.
The rate of increase of a volatile anesthetics partial pressure at
the target tissue depends on multiple steps, and the relationship
between the inspired and the alveolar partial pressures is critical.
The alveolar anesthetic partial pressure (PA) and concentration are
referred to collectively as the alveolar anesthetic fraction (FA), and
the inspired anesthetic partial pressure (PI) and concentration are
referred to as the inspired anesthetic fraction (FI). The alveolar
anesthetic fraction rises toward FI at a rate determined by the
balance between alveolar delivery and uptake. That relationship is
typically expressed graphically as the FA/FI ratio (or the PA/PI ratio)
Figure 21-1. The rate of rise of the ratio of end-tidal (alveolar)

to inspired volatile anesthetic concentrations in adult humans.
versus time (Figure 211). The relationship between these two
fractions is simple if one considers that when uptake removes four
fifths of inspired anesthetic molecules, then the FA/FI ratio equals
0.2; and if uptake removes one fifth of inspired molecules, then the
ratio equals 0.8. For the FA/FI ratio to increase toward 1.0, the rate
of delivery must exceed the rate of uptake. At equilibrium, once
uptake is no longer operative, the FA/FI ratio would equal 1.0.
Salanitre and Rackow demonstrated that the rate of rise of
alveolar to inspired anesthetic partial pressures was greater for
children than for adults. Figure 212 shows their findings in
comparison with two prior adult studies.7 The inverse relationship
between age and the rate of rise of FA/FI is reflected in the increased
speed of induction of the youngest pediatric patients and is caused
by several physiologic differences between children and adults.
Those differences are listed in Table 212 and are expounded on in
the next section on Alveolar Anesthetic Delivery: The Effect of the
Alveolar VentilationtoFunctional Residual Capacity Ratio.
Alveolar Anesthetic Delivery: The Effect

of the Alveolar VentilationtoFunctional
Residual Capacity Ratio
Anesthetic delivery to the alveoli is determined largely by alveolar
ventilation and functional residual capacity (FRC); larger alveolar
ventilation and smaller FRC lead to greater anesthetic delivery
and, therefore, a more rapid rise of FA/FI. The most-soluble agents
experience the greatest augmentation in rise of FA/FI because of
this effect, as demonstrated in Figure 213. More soluble agents
are more dependent on alveolar ventilation to establish alveolar
concentration because of their greater uptake (see Alveolar
Anesthetic Uptake: Factors That Determine Uptake).
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Figure 21-2. The rate of rise of the ratio of end-tidal (alveolar)

to inspired halothane concentration for children 1 to 5 years old
(upper curve) versus adults (two lower curves). Adapted from
reference 7.
The most prominent factor in the more rapid rise of FA/FI for
children than in adults (see Figure 212) is almost certainly the
increased alveolar ventilation in children, which leads to greater
anesthetic delivery. For children compared with adults, FA/FI rises
considerably more quickly for halothane,7 and if increased minute
ventilation is a principle reason for that acceleration, then one
might expect less difference for less-soluble agents such as sevoflurane. Although this author is unaware of such a comparison
using sevoflurane, a comparison using the even less soluble N2O
did demonstrate less of a difference, but maintained a moderately
faster rise for children.7 In addition, infants tend to have smaller
FRC than adults because they have similar lung compliance but
considerably greater chest wall compliance; the balance of these
two determines FRC. In addition, the more compliant thoraces of
TABLE 21-2. Factors That Increase the Rate of Rise of
Alveolar to Inspired Volatile Anesthetic Partial Pressure
and the Mechanism Involved
Factor Increasing FA/FI
Alveolar ventilationa
Functional residual capacitya
Inspired concentration of N2O
Cardiac output
Blood/gas anesthetic solubilitya
(PA PV) caused by tissue/
blood solubility tissue
equilibrationa
Mechanism of Effect
on FA/FI
Anesthetic delivery
Anesthetic delivery
Anesthetic delivery
Anesthetic uptake
Anesthetic uptake
Anesthetic uptake
FA = alveolar anesthetic fraction; FI = inspired anesthetic fraction; PA = alveolar

anesthetic partial pressure; PV = venous anesthetic partial pressure.
(PA PV) equals the alveolartovenous partial pressure difference.
a
Denotes factors that lead to a more rapid rise in FA/FI for neonates compared
with adults. Decreased (PA PV) in neonates is also augmented by an increased
percentage of blood flow going to the vessel-rich group.
325
Figure 21-3. The effect of alveolar ventilation on the rate of rise

of alveolar to inspired anesthetic concentration for ether (soluble), halothane (intermediate solubility) and N2O (insoluble).
An increase in alveolar ventilation speeds the rise most for the
more-soluble agents. Adapted from reference 11.
infants and small children might be expected to have even greater
reductions in FRC than adults after initiation of anesthesia and
muscle relaxation.8 Lower FRC in children compared with adults
increases alveolar anesthetic delivery and leads to a faster rise in
FA/FI.
Alveolar Anesthetic Delivery: The Concentration

and Second Gas Effects
Anesthetic delivery may also be affected by the concentration of
the anesthetic, with higher concentrations leading to greater
delivery and, therefore, a faster rise in FA/FI. This effect, known
as the concentration effect, is operative for N2O but not for volatile
anesthetics administered in oxygen because their working
concentrations are relatively low. Even desflurane with its higher
working concentrations does not demonstrate a concentration
effect.9 N2O is often administered at 50 to 70%, leading to a more
rapid rise in FA/FI than when using low concentrations.9
The concentration effect is a complicated concept and has
usually been explained in an overly simplistic form to facilitate
understanding. An in-depth analysis of the concentration effect
and the second gas effect has been done by Korman and
Mapleson who described variations according to either a constant
inflow model in which the amount of gas coming into the lungs
remains constant (and outflow decreases) or a constant outflow
model in which case the amount of gas leaving the lungs remains
constant (and inflow increases).10 The model that applies depends
on whether the effect is experienced with spontaneous or mechanical ventilation, and in fact, the truth may be somewhere in
between these two extremes. For our discussion of these two
effects, we consider only the case of constant outflow, which
corresponds with the typical pediatric situation of spontaneous
ventilation during an inhalational induction.
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The concentration effect is caused by two elements, the first of

which is a concentrating effect and the second is an increase in
minute ventilation.11 The concentrating effect dictates that uptake
and removal of anesthetic gas from the lung will result in less of a
relative diminution of the lungs anesthetic concentration when
administering an anesthetic gas in a high concentration. The
reason for less diminution is that replacement gas, coming from
the fresh gas flow, arrives in the lungs to replace anesthetic that
was taken up. Relative to anesthetics administered in low concentration in which replacement gas volume is small compared with
lung volumes, high administered concentrations of N2O early in
the anesthetic lead to large replacement volumes. Consequently, a
large amount of fresh gas at the inspired anesthetic concentration
returns to the lung and the fall in concentration is small. The
second element of the concentration effect is related to the first in
that a high concentration of anesthetic gas leads initially to a large
volume of anesthetic taken up from the lungs. The gas that replaces the uptake augments alveolar ventilation. The result is an
increase in alveolar anesthetic concentration beyond what which
would be expected from the concentrating effect alone. The
magnitude of the impact of the concentration effect on FA/FI can
best be understood by comparison with the impact of anesthetic
solubility on FA/FI. N2O administered at an inspired concentration
of 75% could be expected to have a similar rate of rise of FA/FI as
an anesthetic with one fourth the solubility administered at 1%.5
The quicker rise in FA/FI for N2O compared with desflurane (see
Figure 211) is caused by the concentration effect; they have
similar blood/gas partition coefficients.
The same two elements that cause the concentration effect,
namely, concentration of residual gases and augmentation of
inspired ventilation, also influence concentrations of a second gas
that is administered together with N2O. That effect, known as the
second gas effect, can lead to a more rapid rise in FA/FI of volatile
anesthetics administered in low concentrations when they are
administered simultaneously with a high concentration of N2O.12
Questions have been raised about the clinical applicability of the
second gas effect13 and, in fact, regarding whether or not the
second gas effect exists.14 However, the second gas effect was
recently shown to exist for sevoflurane15,16 and for desflurane,9 with
a 10% faster rise in the FA/FI of 2% sevoflurane at 2 minutes when
using 67% N2O versus 100% oxygen.15 Peyton and coworkers
showed that the second gas effect of N2O on arterial partial
pressure of sevoflurane was two to three times greater than the
effect on end-expiratory partial pressure, as shown in Figure
214. In addition, bispectral (BIS) index values (known to change
minimally with N2O) decreased more rapidly during sevoflurane
administration with N2O.15 These data argue that the second gas
effect does have clinical applicability.
Alveolar Anesthetic Uptake: Factors

That Determine Uptake
Alveolar anesthetic uptake into the pulmonary blood slows the
rate of rise of alveolar to inspired anesthetic concentration.
Anesthetic uptake from the lung is summarized by the following
formula11 and is directly related to the product of the blood/gas
solubility (b/g), the cardiac output (Q), and the alveolar-to-venous
partial pressure difference (PA PV):
Uptake = [(b/g) (Q) (PA PV)]/Barometric pressure
Figure 21-4. The magnitude of the second gas effect is demonstrated by showing the rate of rise of sevoflurane end-tidal
(diamonds) and arterial (squares) partial pressures relative to
inspired partial pressures, administered both with (solid figures)
and without (open figures) 70% N2O. Adapted from Figure 1 in
reference 15.
Uptake is minimal when any of the three factors in the numerator approach zero, in which case the unopposed effects of ventilation cause the FA/FI ratio to rise rapidly toward 1.0. The initial
steep rise in FA/FI for all agents is caused by low uptake because
alveolar partial pressure has not yet risen enough to mount a
significant drive for anesthetic uptake, and the effect of anesthetic
delivery is therefore unopposed.
Alveolar Anesthetic Uptake: Blood/Gas

Solubility of Volatile Anesthetics
The blood/gas solubility of an anesthetic agent is expressed by its
blood-gas partition coefficient (b/g), which describes the way in
which that agent partitions itself between blood and alveolar gas
at equilibrium (equal partial pressures in blood and alveolar gas).
The partition coefficient reflects an agents affinity for two phases.
For example, sevoflurane has a blood/gas partition coefficient
of 0.66, which indicates that, at equilibrium, the concentration
of sevoflurane in blood is 0.66 times the concentration in the
alveolar gas.
Blood/gas partition coefficients for inhaled anesthetics vary
widely between agents and, in fact, vary between age groups
(see Table 211). Those with lower b/g have less anesthetic uptake
and, therefore, manifest a faster rise in the FA/FI. Consequently,
the rate of rise of FA/FI for volatile anesthetics follows the order
desflurane > sevoflurane > isoflurane > enflurane > halothane (see
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Figure 211).11,17 The blood/gas partition coefficients for halothane and isoflurane are approximately 10% lower in children and
20% lower in neonates than in adults.18 Those same values for
preterm neonates do not differ according to gestational age and
are similar to those for full-term neonates.19 In contrast, the b/g for
sevoflurane does not differ according to age.19 The more rapid rise
in neonatal alveolar halothane and isoflurane partial pressures is
to a small degree explained by this solubility difference.20
Alveolar Anesthetic Uptake: Cardiac Output

Alveolar anesthetic uptake is directly proportional to cardiac
output.11 Greater cardiac output leads to greater anesthetic uptake,
which slows the rate of rise of FA/FI. Therefore, increased cardiac
output typically slows anesthetic induction. Conversely, lower
cardiac output decreases anesthetic uptake, speeds FA/FI, and
typically speeds induction. Figure 215 shows that decreases in
cardiac output cause the greatest augmentations of FA/FI for those
volatile anesthetics that are most soluble.11 Soluble anesthetics are
affected to a greater degree than insoluble ones because their
alveolar partial pressures rises are more dependent on anesthetic
uptake.
Tissue Anesthetic Uptake and Its Effect

on Alveolar Uptake
The tissue/blood solubilities of volatile anesthetic agents are
critical in determining the speed with which tissue anesthetic concentrations (and partial pressures) rise. The brain/blood solubility
for neonates is 20 to 30% lower than that for adults, with similar
lower values for other vessel-rich group (VRG)/blood solubility
(vr/b) values. The lower solubilities are due to increased water
Figure 21-5. The effect of cardiac output on the rate of rise of

alveolar to inspired anesthetic concentration for ether (soluble),
halothane (intermediate solubility), and N2O (insoluble). A
decrease in cardiac output speeds the rise most for the moresoluble agents. Adapted from Figures 7 and 8 in reference 11.
327
content and lower protein and lipid concentrations in neonates.21

The effect of that change in solubility can best be understood in
terms of time constants. The time constant () describes the rate
that a body compartments anesthetic partial pressure approaches
that of the blood and is the time required to achieve 63% equilibration. Ninety-five percent equilibration is achieved by three time
constants. The time constant can be calculated by dividing the
product of the compartments volume capacity and tissue/blood
solubility by the blood flow that is delivering anesthetic to the
compartment. The time constant for the VRG is reflected by the
equation:
vrg = Volume of the VRG (L) vr/b
VRG blood flow (L/min)
The for the VRG for adults and infants can be estimated using
known values for tissue volumes, cardiac output, and tissue/blood
solubility.11,22 For a 70-kg adult with a cardiac output of 5 L/min
and approximately 75% of that output going to the 6-L VRG
volume, and an anesthetic agent with vr/b equal to 2 (i.e., the
approximate adult value for both halothane and sevoflurane), vr/b
= (6 2)/3.75 3.2 min, and 95% equilibration of VRG partial
pressure would occur by just under 10 minutes. For a 5-kg infant
with an approximate cardiac output of 1 L/min and 80% of that
going to approximately 1 L of VRG tissue, and with vr/b for the
infant equal to 75% of the adult value (or in this case equal to 1.5),
vrg = (1 1.5)/0.8 1.9 min. Ninety-five percent equilibration
would occur by 6 minutes. Therefore, the depressant effects of
inhalational anesthetic agents on the brain and heart can be
expected to occur faster for infants than for adults.
The muscle group/blood solubility (mg/b) of volatile agents
increases with age in a logarithmic linear fashion.21 The mg/b for
neonates is approximately half that for adults, and therefore,
neonates have a considerably quicker equilibration of blood and
muscle group (MG) partial pressures than adults. Figure 216
shows the total anesthetic uptake and the individual tissue uptakes
(in adults) over time for N2O and halothane, which are similar in
Figure 21-6. Total and individual tissue group uptake (mL/min)

of 1% halothane in adults, demonstrating the early uptake and
saturation by the vessel-rich group (VRG), followed by the
muscle group (MG) and later by the fat group (FG). These curves
are identical in shape to curves for other volatile anesthetics.
Adapted from Figures 3 and 4 in reference 11.
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shape to other inhaled anesthetics.11 The VRG is the primary

tissue involved in anesthetic uptake during the initial 5 to 10
minutes of an anesthetic, but by 10 minutes, uptake by the MG
has surpassed the VRG. Those curves would be expected to be
shifted to the left for neonates.
The neonates faster anesthetic equilibration of the VRG and
the MG leads to earlier decline in tissue anesthetic uptake. That
results in higher anesthetic partial pressures in the mixed venous
blood and lower alveolartovenous partial pressure differences.
The end result of the neonates faster rise in tissue anesthetic
partial pressures is a quicker fall in alveolar uptake, which speeds
the rise of FA/FI. As eluded to in the previous example, the
neonates higher cardiac index (CI) and higher percentage of
cardiac output going to the VRG augments the speed of tissue
anesthetic equilibration. Although it may seem paradoxical that
the higher CI of neonates would contribute to a faster induction
(based on the discussion of cardiac output and anesthetic uptake
just discussed), neonates appear to be an exception to the rule of
increasing cardiac output slowing induction. In this case, increased VRG blood flow and rapid VRG partial pressure equilibration hasten the fall in anesthetic uptake and speed induction.22
Anesthetic Uptake: Effect of Ventilation-Perfusion

Mismatches and Shunting at the Cardiac Level
/Q
) occurs
An increase in the ratio of ventilation to perfusion (V
when there is ventilation of unperfused (deadspace ventilation) or
/Q
do not alter the rate of rise
underperfused alveoli. Increases in V
of FA/FI as long as arterial CO2 remains normal because the overall
increase in ventilation necessary to maintain normocarbia also
maintains the ventilation of perfused alveoli at normal levels.
/Q
that occur with segmental pulmoConversely, decreases in V
nary disease such as atelectasis or pneumonia (pulmonary rightto-left shunting) or with cardiac right-to-left shunting do have a
substantial effect on anesthetic partial pressure rise. Decreased
uptake of anesthetic leads to a faster rise in FA/FI. However, arterial
partial pressure rise is slower because the end mixture of blood
returning to the left heart is diminished by blood that had not
passed ventilated alveoli. The result is a gap between the alveolar
and the arterial partial pressures, which is indicative of right-toleft shunting. A minor amount of right-to-left shunting and
mismatch is present in healthy individuals, and anesthesia has long
been known to exacerbate that mismatch.23 Larger mismatches are
pathologic and slow anesthetic induction. Slowing occurs to the
greatest extent with the least-soluble anesthetics, and the reason is
as follows. In order to maintain normocarbia in the face of a rightto-left shunt, overall ventilation is increased, which increases ventilation to areas of normally perfused lung. More-soluble volatile
anesthetics are most able to augment their rate of rise of FA/FI by
increasing alveolar ventilation, (see Alveolar Anesthetic Uptake:
Blood/Gas Solubility of Volatile Anesthetics) and in this case, they
do so in the regions of the lung that are overventilated and normally
perfused. Therefore, more-soluble anesthetics maintain an end
mixture of blood returning to the left heart that has an arterial
anesthetic partial pressure close to that expected without shunting.11
Left-to-right shunts have different effects than right-to-left
shunts. Normally, with left-to-right shunting, cardiac output is
increased so that systemic tissue perfusion is maintained at normal
levels. In that case, the amount of mixed venous blood returning
to the right heart ready for anesthetic uptake is normal. There is
no effect on alveolar anesthetic uptake by the shunted saturated
blood, and therefore, no change occurs in the rate of alveolar

partial pressure rise. However, if cardiac output is not increased
and peripheral perfusion is not maintained, there will be less
anesthetic uptake at the lung and a more rapid rise in alveolar
anesthetic partial pressure but a slower rise in tissue partial
pressure. The anesthetic effect is, therefore, delayed.
Volatile Anesthetic Elimination

Many of the factors that dictate the washin and establishment of
adequate brain partial pressure also dictate the washout and
diminution of that same partial pressure.11 For example, at the
termination of anesthesia, FA falls relative to alveolar concentration just prior to cessation of anesthesia (FAO) at a rate that is
accelerated by increased ventilation and opposed by factors that
increase anesthetic output from the blood to the alveoli. In addition, increasing alveolar ventilation hastens the fall in the ratio
of FA/FAO, with that effect being most pronounced for the mostsoluble anesthetics. Similar to anesthetic uptake from the alveoli,
anesthetic output to the alveoli increases with increase in cardiac
output, increase in b/g, and increase in venoustoalveolar
anesthetic partial pressure difference. The ratio of FA/FAO falls
rapidly for all volatile anesthetics during the first 1 or 2 minutes
after discontinuation, as shown in Figure 217, owing to the initial
small venoustoalveolar partial pressure gradient; output to the
lungs is minimal and the effect of alveolar ventilation is unop-
Figure 21-7. Alveolar anesthetic washout is portrayed for ether

(soluble), halothane (intermediate solubility), and N2O and
cyclopropane (insoluble). Washout is expressed by the ratio of
alveolar anesthetic fraction (FA) to alveolar concentration at the
time anesthesia is discontinued (FAO). The FA/FAO ratio initially
declines very rapidly because of the unopposed effect of ventilation prior to the establishment of anesthetic output to the lungs
(output occurs only after establishment of a venoustoalveolar
partial pressure difference). The first arrow shows where output
begins to balance ventilatory elimination and designates the beginning of a slower, but still rapid, fall owing to washout from
the VRG. The second arrow demonstrates slowing of alveolar
washout owing to slowing of VRG anesthetic elimination.
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posed. A subsequent less rapid but more sustained (1015 min)
fall in FA/FAO occurs during washout of the anesthetic from the
VRG. During that phase, the fall remains relatively rapid because
the VRG partial pressure decrease leads to a rapid decline in mixed
venous partial pressure, a decline in the venoustoalveolar pressure gradient, and therefore, decreased output to the alveoli. The
subsequent slower decline in FA/FAO occurs because of slower
output of volatile agents from muscle and fat. As with anesthetic
washin, right-to-left shunting slows the anesthetic washout, and
does so to the greatest extent for the least-soluble volatile anesthetics.
Despite these similarities to the washin process, there are
considerable differences for anesthetic washout. For example, a
decrease in cardiac output will decrease anesthetic output from
blood to the alveoli and speed the fall in FA/FAO. One might expect
from lessons learned regarding washin that recovery would,
therefore, be faster. However, unless cerebral perfusion is maintained at normal levels, there is an opposing effect of the lower
cardiac output to slow the anesthetic time constant at the brain.
The overall effect is that brain partial pressure falls more slowly
with decreasing cardiac output.11 That effect is most pronounced
for the least-soluble anesthetics, but even halothane recovery is
slowed by decreased cardiac output. Also, hypothermia may be
present on emergence and can affect anesthetic elimination
because lower temperature increases blood and tissue solubility
and, therefore, slows the fall in both alveolar and tissue partial
pressures. Hypothermia may also alter the point at which patients
awaken (see Anesthetic Potency, later).
Another major difference between anesthetic washin and
washout is that, at termination of the anesthetic, tissues are variably equilibrated with volatile agent and the degree of equilibration
depends on the duration of the anesthetic and the tissue time
constants. With shorter anesthetic duration, there is less opportunity for transfer of anesthetic into muscle and fat, and the fall in
FA/FAO is rapid. The effect of anesthetic duration on the rate of
fall of FA/FAO is more pronounced for more-soluble agents, but
when anesthetic duration is brief, even halothane alveolar washout
is rapid.
Ultimately, the speed with which a patient awakens is determined by how rapidly the brain anesthetic partial pressure falls.
When anesthetic duration is short, muscle and fat groups are far
from equilibration, and VRG washout occurs not only by redistribution to the alveoli but also by redistribution to muscle and fat.
When the depot of muscle and fat anesthetic is high (after prolonged anesthetic administration), washout is slower. The timesensitive nature of anesthetic washout has been demonstrated
nicely by Bailey who designed a five-compartment computer
model that used adult values for anesthetic solubility, ventilation,
and perfusion and showed that brain anesthetic partial pressure
falls at a rate that is influenced by anesthetic duration; the shorter
the duration, the faster the fall.24 He examined the fall of brain
partial pressure according to the amount of time to achieve a
sought-after degree of decrement (decrement time) from the
partial pressure at the time of anesthetic discontinuation.24 Figure
218 shows that decrement times increase with increasing
anesthetic duration and do so most for the more-soluble anesthetics. However, 50% decrements occur rapidly (<5 min) no matter
what anesthetic or anesthetic duration has been employed.
However, when one seeks a decrement of 80% after a long anesthetic, only sevoflurane and desflurane can be expected to rapidly
329
Figure 21-8. The 50%, 80%, and 90% decrement times

(shown in min as predicted according to a computer model)
for desflurane, sevoflurane, isoflurane, and enflurane as a
function of anesthetic duration. The decrement times depict the
predicted amount of time to achieve a particular percent drop
in brain anesthetic partial pressure compared with the partial
pressure at the time an anesthetic is discontinued. Adapted
from reference 24.
obtain that goal. In addition, with anesthetics lasting longer than
11/2 hours, sevoflurane may not produce a rapid 90% decrement.
Similar pediatric simulations have not yet been performed, but
one might expect that for neonates the lower tissue time constants,
higher CI, and higher alveolar ventilation/FRC ratio would lead
to more rapid tissue washout than demonstrated in Figure 218.
Whereas Baileys model is helpful for understanding the concept
of time sensitivity for different agents and different decrements,
the model does not consider the effects of changes in ventilation
and perfusion. In reality, anesthetic washout is more complicated
than portrayed by this model because ventilation and perfusion
are changing at the end of an anesthetic.
A final difference for anesthetic elimination is that some
volatile anesthetics undergo hepatic metabolism (see Table 211).
Halothane is reported to undergo as much as 20 to 25% metabolism. However, the fraction of halothane removed by hepatic
blood flow is inversely proportional to its partial pressure.25 At
typical anesthetizing concentrations, hepatic halothane removal
is extremely small, and metabolism does not become a significant
factor in the elimination process until the tail end of the recovery
curve.11 Other volatile anesthetics are metabolized to considerably
lesser degrees.
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PHARMACODYNAMICS OF
VOLATILE ANESTHETICS
The study of pharmacodynamics of volatile anesthetics examines
the affect of those anesthetics on the body. In particular, the effects
of volatile anesthetics on the central nervous system, the cardiovascular system, and the respiratory system are most relevant. The
following discussion examines those effects. Mechanisms of action
of general anesthetics are discussed in chapter 19 and, therefore,
receive minimal attention here. One of hottest topics in pediatric
anesthesiology in decades is the potential of volatile and other
anesthetic agents to cause neurotoxicity in the developing brain.
Animal data for many species, including primates, have shown
that anesthetic agents that antagonize N-methyl-D-aspartate
receptors or agonize gamma-aminobenzoic acid-A receptors produce neurodegenerative changes in the developing brain.2630
Epidemiologic data in a population-based cohort recently demonstrated that the risk of developing a learning disorder was
increased in children who had received two or more general anesthetics prior to 4 years of age.31 The discussion of neurodegenerative changes following anesthetic exposure is the topic of
Chapter 3 and is, therefore, not discussed further here.
Anesthetic Effect of Volatile Agents

on the Central Nervous System:
Volatile Anesthetic Potency
Hypnosis, derived from the Greek work for sleep, and immobility
are the two most critical clinical end points of general anesthesia.
Minimum alveolar concentration (MAC) is the principal measure
of anesthetic potency and is defined as the concentration of
volatile anesthetic required to prevent response to a noxious stimulus in 50% of a population (an ED50). Classically, the response
is extremity movement and the stimulus is a skin incision, and
the term MAC is, therefore, used in reference to this classic
stimulus/response combination, unless otherwise specified. Volatile anesthetics ablate movement to a skin incision largely through
action at the spinal level; perhaps through their effect on nociceptive transmission in reflex pathways,32 through action on the ventral spinal locomotor networks, or a combination.33 One additional
type of MAC worthy of discussion is the MAC-awake which
measures the potency of a volatile anesthetic with respect to
hypnosis and delineates the concentration at which 50% of subjects are able to follow a command.34,35 Hypnosis, with prevention
of awareness, is at least as important as immobility, so that MAC-
awake can be considered just as meaningful a measurement of

anesthetic potency as MAC. Intraoperative awareness in the
pediatric population has been found to be approximately six times
higher than in adults.36,37 Nonetheless, MAC-awake has received
much less attention and has not been well defined across all
pediatric age groups, most likely owing to difficulty studying this
end point in young children. Other types of MAC have been
defined, such as MAC for tracheal tube and laryngeal mask
placement and removal.3845 These types of MAC values have
limited utility for defining anesthetic potency and are largely
outside the scope of this chapter. The following discussion of
anesthetic potency covers mainly MAC, but also what is known
about MAC-awake in children, with all data referring to racemic
mixtures of volatile agents (where applicable). The discussion also
covers how volatile anesthetic potency changes when volatile
anesthetics are combined with various adjuvants.
Anesthetic potency varies with age (Table 213), such that
MAC for all volatile agents decreases with age in a predictable
manner for patients older than 1 year, decreasing 6 to 7% per
decade of life.35,46 Numerous studies demonstrate that MAC for all
agents remains relatively uniform between 1 and 12 years of age,
with 10%t or less change during that period (see Table 213).4750
MAC values reported for that age tend to be 15 to 40% higher than
values for young adults.35 Peak MAC values for all volatile
anesthetics occur during the first year of life, and different agents
peak at different time points during that year (see Table 213). For
example, the peak MAC value for desflurane occurs between 6 and
12 months, whereas for isoflurane and sevoflurane MAC peaks
earlier. No data exist for MAC of halothane for the 6- to 12-month
period, so that the highest known MAC of halothane is between
1 and 6 months of age. For all agents except sevoflurane, MAC
during the first month of life is lower than later in infancy. That
relationship is most notable for halothane, for which the MAC
decreases by 28% for neonates, down to 0.87%, compared with
1.2% at 1 to 6 months of age.51 Sevoflurane MAC actually reaches
its highest value in the neonatal period with a value of 3.3%, which
is where it remains until 6 months of age when it decreases and
remains at 2.5% until 12 years of age. The reasons for the decrease
in MAC with age and for these mentioned MAC variations during
the first year of life are unknown.
Preterm neonates who were less than 37 weeks of gestational
age at birth were found to have lower isoflurane MAC values than
those previously reported for full-term neonates.49,52 The MAC for
isoflurane for preterm neonates born at less than 32 weeks of
gestational age (mean of 30 wk postconceptual age [PCA] at time
TABLE 21-3. Age-Related MAC in % Concentration (sd when available) According to Volatile Anesthetic Agent
Halothane
Isoflurane
Sevoflurane
Desflurane
01 mo
16 mo
612 mo
13 y
35 y
512 y
0.87 (0.03)
1.6 (0.01)
3.3 (0.2)
9.16 (0.02)
1.20 (0.06)
1.87 (0.12)
3.2 (0.1)
9.42 (0.06)
No data
1.8 (0.01)
2.5 (0.2)
9.92 (0.44)
0.97a
1.6 (0.16)
2.6 (0.3)d
8.72 (0.59)
0.91b
1.6 (0.06)
2.5 (0.2)
8.62 (0.45)
0.87c
No data
2.5 (0.1)
7.98 (0.43)
MAC = minimum alveolar concentration; sd = standard deviation.

Data for isoflurane are from reference 49; for halothane, from references 48 and 51; for sevoflurane, from reference 50; and for desflurane, from reference 47.
When the age studied did not fit cleanly into this tables age categories,a, b, and c note such an occurrence and the actual ages studied:
a
MAC value for 0.52.5 y.
b
MAC value for 2.57 y.
c
MAC value for 711 y.
d
MAC value 2.0 (0.2) for sevoflurane when combined with 60% N2O.
e
MAC value was 7.5 (0.1) for infants and 6.4 (0.2) for 15 y when combined with 60% N2O according to reference 70.
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of surgery) was 1.28%, which was lower than the value of 1.41% for
preterm neonates born at 32 to 37 weeks of gestational age (mean
of 35 wk PCA at time of surgery).52 Similar studies involving other
volatile agents have not been performed. However, these isoflurane
data suggest that the more immature the neonate, the lower the
anesthetic requirement and that even the most immature neonates
do indeed require anesthesia.
The MAC of halothane for children 4 to -18 years old who have
both cerebral palsy and mental retardation was shown to be
approximately 25% lower than for healthy children.53 That study,
which used tetanic stimulation instead of skin incision as the
stimulus, found halothane MAC to be 0.62% and 0.71% for those
impaired children who were on anticonvulsants and those who
were not, respectively (a statistically insignificant difference),
compared with 0.9% for healthy children. That finding was
consistent with animal data that showed no significant difference
in halothane MAC for dogs after 10 days of phenobarbital.54 One
possible explanation for the lower anesthetic requirement in these
children with mental retardation and cerebral palsy is an alteration
in the balance of inhibitory/excitatory regulatory neurons within
the brain and spinal cord. Although somatic responses to painful
stimuli appear to be mediated primarily at the spinal level, the
brain does appear to influence those responses.55
A few other factors have been examined as potential influences
on MAC. MAC appears to decrease with decreasing body temperature. For isoflurane, the MAC of children 4 to 10 years old,
with left-to-right shunts, decreased 5.1%/C decrease in temperature; isoflurane MAC was 1.69% at 37C and decreased to 1.47%
at 34C.56 Human MAC alteration by body temperature has yet to
be demonstrated for other volatile agents. The etiology of the effect
of temperature on MAC is poorly understood and cannot be
explained solely by increasing lipid solubility associated with lower
body temperature.56 The impact of gender on the MAC of volatile
anesthetics has not been investigated in children; however, in
nonpregnant adults, there does not appear to be a gender effect.57
The second defining effect of volatile anesthetics is their ability
to produce hypnosis and ablate recall. MAC-awake is close to the
anesthetic concentration that suppresses memory and learning
and is known to decrease with increasing age in a manner that
parallels the effect of age on MAC.35 The ratio of MAC-awake to
MAC remains constant across age groups, and for desflurane,
sevoflurane, and isoflurane is 0.34 (0.02).35 Pediatric data
regarding MAC-awake is sparse. Inomata found that sevoflurane
MAC-awake in 3 to 8 year olds was 0.81%, with a MAC-awake
toMAC ratio of 0.35.58 Davidson and colleagues reported lower
MAC-awake values, 0.66% in 2 to 5 year olds and 0.43 to 45% in
5 to 12 year olds, and noted that differences in MAC-awake values
for children do not explain the higher incidence of awareness.34
Depth-of-anesthesia monitors have been developed in an
attempt to quantitate the hypnotic effect of general anesthetics.
These monitors use complex adult-based algorithms to translate
multidimensional aspects of the raw electroencephalographic
(EEG) into a single number. The bispectral index (BIS) monitor is
the most studied of these monitors and has been shown to have
several limitations in the pediatric population. Considerably
higher BIS values (indicating less depth of anesthesia) were
reported in children during halothane anesthesia, compared with
sevoflurane, desflurane, and isoflurane anesthesia administered
at the same age-adjusted MAC.5961 However, the BIS values at
awakening were similar for both halothane and isoflurane. BIS
values during sevoflurane induction in children did not correlate
331
with depth of anesthesia; BIS was lowest at 2 minutes from the

start of induction and then increased despite increasing depth of
anesthesia.62 Further concern regarding the BIS monitors ability to
predict pediatric anesthetic depth during volatile anesthesia was
raised by Kim and associates in a study that demonstrated increasing BIS values despite increasing end-tidal sevoflurane
concentration from 3% up to 4%, a finding that spanned all ages
studied (0.5- to 12-y-olds).63 A subsequent study did not produce
that paradoxical BIS increase when a predicted effect site sevoflurane concentration of greater than 3% was compared with
the BIS value, although a plateau effect was found. Lastly, BIS
values at age-adjusted 1.0 MAC of desflurane and sevoflurane
increase with decreasing age, making interpretation of BIS difficult
in younger children.61,64 These drawbacks suggest that BIS has
limited ability to predict pediatric anesthetic depth under volatile
anesthesia.
Volatile anesthetics combine with other drugs to produce
immobility and hypnosis in either a synergistic, an additive, or an
infra-additive manner, implying that the effect of the anesthetic
combinations exceed, equal, or are less than the sum of the
individual effects.65 The decrease in volatile anesthetic requirements due to co-administration of another drug is referred to as a
MAC reduction. Volatile anesthetics combine with one another in
an additive manner, so that administration of 0.5 MAC of two
volatile anesthetics equals a total of 1 MAC. N2O combines additively with all volatile anesthetics in adults, including sevoflurane
and desflurane.66,67 Interestingly, in children, N2O is additive when
administered with either halothane68 or isoflurane69 but appears
to be infra-additive with sevoflurane and desflurane.50,70 The MAC
reduction provided by 60% N2O was only 23% and 25% for
children receiving sevoflurane and desflurane, respectively, instead
of the 55% that would have been expected with additivity.50,70 The
infra-additive interaction of N2O with sevoflurane in children is
further supported by a finding of only 40% reduction of MAC for
tracheal intubation when 66% N2O was added to sevoflurane.40
Numerous noninhaled adjuvant medications combine with
volatile agents to reduce anesthetic requirements, with the amount
of reduction dependent mainly on the class of adjuvant.65 All
opioid receptor agonists interact synergistically with volatile
agents with respect to prevention of movement to incision,
producing a dose-dependent MAC reduction with a ceiling effect.
Remifentanil in adults produced isoflurane MAC reductions of
approximately 70 to 80% when running infusion rates of 0.15 to
0.3 g/kg/min.71 In children, Castanelli and coworkers found a
sevoflurane MAC reduction of just over 60% with remifentanyl
infused at 0.12 g/kg/min, and they appeared destined to demonstrate a greater than 80% MAC reduction for 0.25 g/kg/min but
truncated the study in that group when the up-down protocol decreased sevoflurane concentration to 0.29%.72 Fentanyl in adults
produced 61% and 74% MAC reductions at serum levels of
3 ng/mL and 6 ng/mLl, respectively73 and produced similar MAC
reductions and ceiling effects for desflurane and isoflurane (Figure
219).65,74,75 The reduction in MAC awake by fentanyl is not nearly
as pronounced as for MAC, with sevoflurane MAC-awake reductions of 24% and 15% in conjunction with serum levels 3 ng/mL76
and 2 ng/mL,77 respectively. Evidence in children also indicates that
opioids have minimal impact on production of hypnosis by volatile
anesthetics.78
Midazolam also combines in a synergistic manner with volatile
agents and, in adults, produced a 40% halothane MAC reduction
after a bolus dose of 0.1 mg/kg followed by an infusion designed
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Figure 21-9. Minimum alveolar concentration (MAC) for both

isoflurane and desflurane at various fentanyl concentrations.
Volatile anesthetic requirements are reduced greatly by the first
few ng/mL. A ceiling effect is demonstrated (consistent with a
synergistic interaction), showing that escalating amounts of fentanyl do little to further reduce anesthetic requirements.
to maintain that postbolus serum concentration.79 Pediatric preanesthetic sedation with midazolam might be expected to produce
a MAC reduction at the beginning of the case, and especially affect
anesthetic requirements for tracheal intubation. Propofol interacts
with sevoflurane in an additive manner, with respect both to
producing hypnosis and to prevention of movement.80 2 Adrenergic agonists reduce volatile anesthetic requirements, but the nature
of their interaction has yet to be adequately classified.65,81 Two
studies in children demonstrate that oral clonidine 2 g/kg as a
premedication decreased sevoflurane MAC-awake by 50%, down
to 0.37 to 0.40%,58,82 with only one of those studies showing greater
MAC-awake reduction at higher dosage. Preoperative oral
clonidine reduced sevoflurane MAC in children to a lesser degree
than it reduced sevoflurane MAC-awake; MAC reductions were
22 to 28% and 42 to 44% for doses of 2 and 4 to 5 g/kg,
respectively.58,83 Pediatric data for combinations of dexmedetomidine and volatile agents are not available, but in adults, dexmedetomidine has been shown to decrease isoflurane MAC by 31%
and 50%84 and sevoflurane MAC by 0% and 17%,81 with target
dexmedetomidine levels of 0.3 ng/mL and 0.6 ng/mL, respectively.
The reason for these discrepant results with isoflurane and
sevoflurane is unknown. Lidocaine reduces MAC in dogs by 10 to
28% when used in concentrations common in clinical practice.85
There does not appear to be any human data for volatile agent
MAC reduction by lidocaine.
Effects of Volatile Anesthetics

on Cerebrovasculature and on
Cortical Electrical Activity
elevated intracranial pressure (ICP) because the brain is at

immediate risk of injury. The effects of volatile agents on cerebral
metabolism and cerebral blood flow (CBF) have been investigated
at length, including numerous pediatric studies. Volatile agents
produce dose-dependent decreases in the cerebral metabolic rate
for oxygen (CMRO2), and adult studies have shown that global
CBF and global CMRO2 remain coupled at 1 MAC of sevoflurane.86 Volatile anesthetics in low concentrations produce vasoconstriction of cerebral vessels because of their effect on CMRO2
but, with increasing concentrations, have a direct vasodilatory
effect on cerebral vasculature.87 Changes in CBF during volatile
anesthetic administration are agent-specific.
CBF in children has been studied mainly using transcranial
Doppler sonography measurements of middle cerebral artery
blood flow velocity. Cerebral blood flow velocity (CBFV) has been
shown to correlate well with changes in CBF.88 Fairgrieve and
colleagues demonstrated that sevoflurane at 0.5 to 1.5 MAC in
healthy children did not change CBFV despite significant decrease
in arterial pressure, suggesting that sevoflurane maintained cerebral autoregulation, and did not appear to increase CBF in that
anesthetic range.88 However, desflurane does appear to increase
CBF in that same MAC range, with maximal effect reached by 1.0
MAC, and it has been suggested that desflurane should be used
with caution in patients with suspected elevation in ICP.89 However, when desflurane at 1.0 MAC replaced an age-adjusted
equipotent amount of isoflurane, there was no change in CBFV,
though there was a large increase in CBFV when desflurane
replaced propofol.90 In children, N2O combined with 1.0 MAC of
sevoflurane increases CBFV, but not when combined with 1.0
MAC of desflurane.91,92 The effect of N2O on CBF when used in
combination with sevoflurane creates further doubt regarding
whether N2O has any role in pediatric neuroanesthesia.91
Manipulation of end-tidal carbon dioxide tension (ETCO2)
remains an important tool for manipulation of CBF and brain
volume, and therefore, maintenance of cerebrovascular CO2
reactivity during volatile anesthesia is important. In children,
CBFV remains responsive to changes in ETCO2 between 20 and
60 mmHg during anesthesia with 0.5 to 1 MAC of sevoflurane or
isoflurane.93,94 The same is true for halothane for ETCO2 between
20 and 40 mmHg, and similar CBFV occurs with 0.5 to 1.0 MAC
of halothane and isoflurane when the ETCO2 is the same.93
Cerebral perfusion pressure (CPP), ICP, and mean arterial
pressure (MAP) alterations during the addition of sevoflurane,
desflurane, and isoflurane were measured in young children with
suspected elevated ICP. When these volatile agents were added to
a background of 60% N2O in amounts equal to nonage-adjusted
partial pressures up to 1 MAC (7080% of age-adjusted MAC for
that population), subjects experienced dose-dependent mild
increases in ICP and larger decreases in MAP and CPP.95 Those
variables did not differ significantly among volatile agents. Decreases in CPP were largely the result of volatile agentinduced
decreases in MAP rather than increases in ICP, emphasizing the
importance of maintaining MAP in order to maintain cerebral
perfusion.
Effects of Volatile Anesthetics on Cortical

Electrical Activity: EEG Changes, Epileptic
The effects of volatile anesthetic agents on the brain and the blood and Epileptiform Activity
Cerebrovascular Effects
flow to the brain are of enormous importance during the management of patients with cerebral ischemia, cerebral edema, or
EEG activity in children during volatile anesthesia is similar to

that of adults and follows the general pattern of progression from
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rapid alpha rhythms while awake to beta-type oscillations (1330
Hz) seen during sedation, into global slowing with theta- and then
delta-type waves (04 Hz). Constant and associates monitored the
electroencephalogram in children during induction with 8%
sevoflurane and N2O and noted an increase in the total spectral
power (TSP) of the EEG signal and a shift toward low-frequency
spectral bands, with a maximal change at near 2 minutes into
induction. In the third minute of induction, fast oscillations of the
alpha- and beta-type increased at a point at which pupils had
returned to central position and anesthetic depth was increasing.
Burst suppression occurred in 20% as anesthesia deepened.96,97
Constant and associates also compared pediatric EEG patterns
during halothane induction with those during sevoflurane induction and found an initial similar increase in TSP and shift
toward low-frequency bands. At loss of eyelash reflex, halothane
induced a greater frequency of fast beta-type rhythms and less
slow delta-type waves than sevoflurane, but at the time of central
pupils, spectral components were similar. Five minutes after
intubation, halothane induced EEG changes composed of slow
waves with superimposed fast alpha- and beta-type rhythms,
compared with mainly slow, sharp waves with sevoflurane.98
Seizures during volatile anesthetic administration are rare,
though the incidence is unknown and mainly occur at the beginning and the end of anesthesia. Nonpurposeful movements occur
around the second minute of sevoflurane induction with a frequency of 42 to 60%, and coincide with a rapid increase in delta
wave EEG activity.97,98 There is no correlation with those involuntary movements and EEG seizure activity. Many case reports
document seizure occurrence during volatile anesthesia, most
notably with sevoflurane and enflurane, though few of those
reports have supporting EEG data.96,99 A single case report does
document EEG evidence of seizure activity in a child with no prior
history of seizures who was receiving sevoflurane.100 Reports of
seizures induced by volatile agents in patients with a history of
epilepsy are more common, and nonconvulsive seizures have been
documented.101 Volatile agents paradoxically appear to possess a
proconvulsant activity, yet have been used to treat status epilepticus because of their ability to produce electrical silence. Despite
this apparent rare proconvulsant activity of sevoflurane, there is
no contraindication to its use in patients with a history of epilepsy,
though cautious use has been recommended.96,99
Considerable discussion has been given to the volatile
anestheticinduced EEG pattern termed epileptiform activity,
which is mainly associated with sevoflurane96,102108 but has also
been described with isoflurane109 and enflurane.110 Definitions of
epileptiform activity vary among authors, emphasizing the difficulty in describing this phenomenon. The terminology is broken
down into categories according to the intensity and rhythmicity
of spikes and the background EEG at the time. The nomenclature
includes terms such as polyspikes, which imply occurrence of more
than two negative and positive deflections, rhythmic polyspikes,
which refers to polyspikes occurring at regular intervals,106 and
periodic epileptiform discharges (PED), which refer to periodic
complexes occurring in a bilateral and synchronized manner.104
Epileptiform discharges occur in patients with and without
epilepsy and have been reported to occur with an incidence of up
to 100%.104,111 One group of authors performed extended EEG
recordings on eight young men receiving sevoflurane and reported
epileptiform activity in seven of eight at 1.0 MAC and in all eight
at 2.0 MAC, with EEG seizure activity in three subjects (including
one with clinical seizure correlate).111 They claimed that sevo-
333
flurane is epileptogenic and noted a distinct pattern of progression

of epileptiform activity prior to seizure activity. To my knowledge,
no other study has been done that either corroborates that finding or signifies that anesthesia-induced epileptiform activity is
detrimental. Nonetheless, Constant and associates put forth pediatric guidelines that emphasize a need to avoid conditions that
make epileptiform activity more likely to occur and suggested
avoiding hyperventilation and maintenance concentrations of
sevoflurane in excess of 1.5 MAC.96 They recommended consideration of preanesthetic midazolam because their previous work
suggested epileptiform activity did not occur after midazolam.98
Data have been inconsistent regarding hyperventilation and
epileptiform activity, with one author demonstrating suppression
of spikes with hyperventilation in children109 and another author
failing to find an association.112 The one consistent finding has
been that greater epileptiform activity is associated with higher
sevoflurane concentration.104,105,109,112 Further work needs to be
done to demonstrate whether there is a progression of epileptiform discharges to frank seizures in children and whether this
EEG pattern has any short- or long-term detrimental effects on
cognitive function.
Cardiovascular Effects of
Volatile anesthetics affect the cardiovascular system in many ways,
most notably through direct myocardial depression, by altering
cardiac conduction, and by increasing the likelihood of cardiac
dysrhythmias. Volatile anesthetics may cause peripheral vasodilation and alter the balance of the sympathetic and parasympathetic
nervous systems. These affects, which differ according the maturation state of the cardiovascular system,113 lead to alterations in
contractility, cardiac output, blood pressure (BP), heart rate (HR),
rhythmicity, and the electrocardiogram. These volatile anesthetic
induced alterations in cardiovascular parameters in infants and
children are analyzed in the following sections.
Hemodynamic Effects
All volatile anesthetics administered to children at typical working
concentrations produce moderate decreases in BP and agentdependent alterations in the HR. Age-dependent differences in
hemodynamic effects are best looked at by reviewing studies that
examined these effects across the full spectrum of pediatric ages
(such as those studies that determined age-related MAC values).
Lerman and coworkers reported hemodynamic responses to
1 MAC of sevoflurane and found systolic blood pressure (SBP)
decreased 0 to 11% in children 1 to 12 years of age and 15 to 35%
in age groups younger than 1 year (compared with awake values).50
They found a 30% or greater decrease in SBP in over 50% of infants
younger than 6 months, in 27% of infants 6 to 12 months, and in
0 to 8% of children 1 to 12 years. HR was unchanged with sevoflurane for subjects younger than 3 years of age and increased
slightly for those 3 years and older. Taylor and colleagues performed a similar study with desflurane and found that 1.0 MAC
resulted in SBP decreases of 22 to 28% in children and in 25 to 34%
in infants, with a 30% or greater decrease in SBP occurring in 42 to
58% of infants and in 17 to 42% of children (no statistical difference).47 HR decreased modestly with desflurane in the age range
of 6 months to 5 years but did not change from baseline in all other
groups including neonates. In contrast to Taylor and colleagues
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data, others reported 15 to 20 beats/min increases in HR in

children with desflurane concentrations of 1.0 MAC and only
modest decreases in BP.89,95 Studies that determined age-related
MAP of halothane and isoflurane did not evaluate hemodynamic
variables. However, Friesen and Wurl determined hemodynamic
consequences of age-adjusted 2.0 MAC of halothane for five age
groups (01 mo, 16 mo, 624 mo, 26 y, and 612 y) and found
a greater decrease in MAP and SBP for infants younger than
6 months (2930 mmHg decrease) versus all older age groups
(decreases of 1318 mmHg).114 There was no difference in pressure
alteration between neonates and infants 1 to 6 months. Also, there
was no significant difference in HR decreases across age groups,
which decreased 10 to 22 beats/min.
The relative effects of different volatile agents on HR and BP
are best looked at in head-to-head comparisons. In children,
comparisons of effects of 1.0 to 1.5 MAC of sevoflurane versus
halothane115,116 and isoflurane versus halothane117 found statistically indistinguishable modest (721 mmHg) decreases in BP and,
surprisingly, could find no statistical difference in HRs according
to volatile agent or from baseline awake values. Even in infants, a
comparison of SBP and HR when anesthetized with 1.0 MAC of
either sevoflurane or halothane found no anesthetic-related
differences in those variables.118 Sponheim and associates compared the effects of 1.0 MAC of sevoflurane, isoflurane, and
desflurane in patients aged 0.5 to 5 years and found a 15 beats/min
increase in HR compared with awake values with desflurane, a
5 beats/min increase with isoflurane, and no change for sevoflurane. BP decreased a similar amount with all three agents,
dropping 9 to 15 mmHg.95
Although sevoflurane administration at maintenance concentrations of 1.0 to 1.5 MAC does not appear to affect HR, high
inspired sevoflurane concentrations during induction do transiently increase HR 20- to 40%.98,116,119 That effect, not observed
with similar halothane inductions, is thought to be caused by
sevoflurane-induced preferential withdrawal of parasympathetic
cardiac activity.98,120 Rapid increases in desflurane and isoflurane
concentrations in adults transiently increase both HR and BP, with
the increases being much more prominent with desflurane.121
Those increases were shown to be mediated by elevations in
plasma epinephrine, norepinephrine, and vasopressin. Rapid
increases in desflurane concentration in children have been
associated with increases in HR and BP during induction122 and
increases in HR during maintenance,89 but it is unclear whether
those increases were similar in nature than those reported in
adults.
Echocardiographic (ECHO) examinations may be better than
simple hemodynamic variables for demonstration of volatile
agentinduced differences in myocardial depression. Some ECHO
measurements of myocardial performance such as stroke volume
index (SVI), left ventricular shortening fraction (LVSF), and
velocity of circumferential fiber shortening (VCFS) may be altered
independently or collectively by changes in HR, afterload, and
preload.117 Other measurements are advantageous in that they are
considered to be independent of load and HR.115,118 Several comparisons of ECHO variables have been performed in children
during administration of different volatile anesthetics. Wolf and
coworkers found halothane and isoflurane administered to
children 2 to 7 years old did not alter preload or HR, but halothane
decreased LVSF by 18% and 25% at 0.5 and 1.5 MAC, respectively.117 Isoflurane did not alter LVSF, suggesting that halothane
caused greater myocardial depression than isoflurane. One study

by Murray and colleagues corroborated more pronounced myocardial depression with halothane than isoflurane,123 and two other
reports by the same author (all three reports in infants and young
children) found those same agents produced statistically indistinguishable decreases in SVI and ejection fraction, suggesting
similar depression of myocardial function.124,125 Murray and associates also found no difference in those variables when comparing
neonates with older infants.125 A direct comparison of 1.0 and 1.5
MAC of halothane and sevoflurane in children found significant
decrease in LVSF and VCFS and in load-independent measures of
myocardial function with halothane but not with sevoflurane.
However, the clinical significance of those findings is questionable
because those same authors found no detectable difference between agents with respect to SVI or CI.115 Another comparison of
halothane and sevoflurane in children at 1.0 and 2.0 MAC found
a statistically indistinguishable dose-dependent decrease in SVI
for both agents. CI tended to decreased for both agents and both
concentrations, but those decreases were not statistically different
from baseline values or from one another.126 A comparison of
halothane and sevoflurane at 1.0 and 1.5 MAC in infants found
that both agents caused decreases in LVSF and VCFS and in loadindependent measures of myocardial depression, but decreases
were more pronounced with halothane. Sevoflurane decreased
systemic vascular resistance (SVR) and did not alter CI at both
concentrations, whereas halothane did not alter SVR and
decreased CI by approximately 30% at 1.0 MAC.127 In contrast, a
recent study in infants receiving 1 MAC of sevoflurane or halothane found nearly equivalent values for CI, LVSF, and VCFS
regardless of agent but did not compare those values with awake
baselines.118 A head-to-head comparison of anesthetic effects in
infants versus children with respect to ECHO or magnetic resonance imaging (MRI) obtained load-dependent or -independent
cardiac variables to my knowledge has not been performed.
Few studies have examined the hemodynamic effect of volatile
anesthetics in patients with congenital heart disease. Infants and
children with myriad types of congenital heart disease who received 1.0 and 1.5 MAC of halothane, sevoflurane, and isoflurane
had decreased SVI, CI, and LVSF with halothane but no decrease
in those variables with the other anesthetics.128 Cardiac MRI found
no difference in values for SVI, CI, and EF in patients with
congenital heart disease who were receiving 1.0 MAC of either
sevoflurane or isoflurane.129 Volatile anesthetics do not appear to
alter the ratio of pulmonary to systemic blood flow in infants and
children with atrial or ventricular septal defects.130
Overall, existing data would suggest that all volatile agents
produce moderate dose-dependent myocardial depression in
infants and children and that halothane may cause slightly more
depression than other agents, especially for infants and for patients
with congenital heart disease. Also, volatile anestheticinduced
depression of baroreceptor response may leave infants more
vulnerable to myocardial depressant effects.131,132 Volatile anesthetics are believed to depress myocardial function by decreasing
intracellular Ca2+ flux via action on calcium channels, ion exchange pumps, and sarcoplasmic reticulum.133,134 A summary of
that literature, along with discussion of why infants may be more
susceptible, has been provided in a detailed review by Baum and
Palmisano.113
Intravenous atropine has been found to restore decreased
cardiac output caused by halothane and sevoflurane, largely by
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increasing HR and to a small degree by counteracting the volatile
anestheticinduced decrease in myocardial contractility.118,135,136
Volume expansion has been shown to ameliorate the myocardial
depressant effects of isoflurane but not halothane.124 Minimization
of infants fasting time appears to lessen hypotension caused by
halothane.137 Reduction of volatile agent by substitution with N2O
does not limit myocardial depression; equipotent (1.5 MAC)
mixtures of halothane or isoflurane in oxygen or in 60% N2O
administered to infants and young children produced similar
levels of myocardial depression.123
Effects on Cardiac Rhythm and

the Electrocardiogram
All volatile anesthetics affect cardiac rhythm. Even in patients
without heart disease, halothane and sevoflurane are associated
with bradycardia, nodal rhythms, minor as well as life-threatening
ventricular dysrhythmias, and asystole.138,139 Sevoflurane and other
ethyl ethers promote dysrhythmias less than halothane. Kataria
and coworkers reported sevoflurane induced bradycardia in 2%
of infants and children as opposed to 12% with halothane.139
However, a different report noted nodal rhythm in 20% of infants
induced with sevoflurane.140 Second-degree heart block (Mobitz
type 1) has been reported in a patient receiving sevoflurane,
though evidence that sevoflurane was causative is lacking.141
Adult and pediatric studies show that sevoflurane, desflurane,
and isoflurane all prolong the electrocardiographic QT interval,
though results differ substantially from one report to another. An
investigation in infants younger than 6 months found that sevoflurane caused prolongation while halothane did not,142 and
another study in children demonstrated that desflurane caused
prolongation while sevoflurane did not.138 The mechanism of QT
interval prolongation by sevoflurane has been described, and it
has been noted that sevoflurane combines synergistically in an
animal model and in cloned human cardiac cells to dramatically
prolong repolarization when used in combination with class III
antiarrhythmic drugs.143 Torsades de pointes (Tdp) is associated
with prolongation of the QT interval, and numerous manuscripts
referenced here express concerns that volatile agentinduced
prolongation of repolarization may increase susceptibility. No
report exists of a pediatric patient with a normal heart developing
Tdp because of volatile anesthetics, but one pediatric case report
noted that Tdp occurred in a patient with congenitally prolonged
QT interval caused by sevoflurane and suggested use of propofol
in that setting.144 Others doubt that volatile anesthetics promote
Tdp and argue that QT interval prolongation is neither necessary
nor sufficient for Tdp to occur, whereas transmural dispersion of
repolarization is necessary and sufficient and is not affected by
sevoflurane.145,146 The clinical significance of QT prolongation by
volatile anesthetics is unknown and will most likely remain a topic
of debate.
Halothane sensitizes the myocardium to epinephrine-induced
ventricular dysrhythmias.147149 Ethyl ether anesthetics may also
sensitize the myocardium, but to a lesser extent.149151 The pediatric
population appears to be much less susceptible to this phenomenon, and it has been suggested that up to 10 g/kg of
epinephrine can be given safely to pediatric patients without heart
disease who are receiving halothane.148 Maintenance of a normal
magnesium level lessens sensitization,147 as does administration
of epinephrine in lidocaine.149
335
Respiratory System Effects

of Volatile Anesthetics
Volatile anesthetics affect the pediatric respiratory system in a
variety of ways. They depress the respiratory center, depress
activity of chest wall and diaphragmatic musculature, alter upper
and lower airway dimensions, and diminish airway response to
noxious stimuli. Those effects are examined individually in this
section.
Respiratory Depression and Effects

on Airway Musculature
Halothane, isoflurane, enflurane, desflurane, and sevoflurane all
depress spontaneous respiration in children in a dose-dependent
manner as evidenced by decreased tidal volume and minute
ventilation and by either attenuated response to CO2 stimulus or
elevated partial pressure of CO2 during spontaneous ventilation.152157 Respiratory drive, measured with occlusion testing, was
lower in children breathing 1.5 MAC of halothane than 0.5 and
1.0 MAC.152 The degree of volatile anestheticinduced respiratory
depression varies with age; infants manifest greater decrease in
minute ventilation and greater increase in ETCO2 with increasing
halothane concentration than do children.158 Substitution of N2O
for an equal MAC fraction of volatile agent may lead to slightly
less respiratory depression.159
Differences in the amounts of respiratory depression caused
by halothane, sevoflurane, desflurane, and isoflurane in spontaneously ventilating pediatric patients appear to be relatively small.
Some evidence shows that sevoflurane relative to halothane
produces higher ETCO2 at 1.5 MAC,157 as well as lower minute
ventilation and respiratory rate, but no difference in respiratory
drive at approximately 0.9 MAC volatile agent plus 66% N2O.154 A
compensatory respiratory rate increase to counteract the decrease
in tidal volume occurs with halothane and, to a lesser degree, with
sevoflurane and desflurane but does not seem to occur with
isoflurane.154156 Despite compensatory respiratory rate increases
with some volatile anesthetics, minute ventilation decreases.
Respiratory rate decreases with enflurane, and extra caution
should be exercised when administering enflurane to spontaneously ventilating infants and children.155
Volatile anesthetics depress the intercostal muscles and diaphragm to varying degrees, changing the relative rib cage contribution to tidal volume. Halothane depresses inspiratory intercostal
function with relative diaphragm sparing, resulting in paradoxical
respiration.152 That effect, which is more pronounced in infants
than in children, is lessened when a laryngeal mask is used as
opposed to an endotracheal tube.160 Sevoflurane and desflurane
cause less paradoxical respiration than halothane because they act
more on the diaphragm than on intercostals muscles.154,156
Effects on Upper Airway Dimensions

Upper airway narrowing occurs in a dose-dependent manner as a
result of administration of sevoflurane to spontaneously breathing
children. Sevoflurane at 1 MAC caused 13 to 18% reduction in
upper airway cross-sectional area of children accessed by MRI,
and at 1.5 MAC caused 28 to 34% reduction, with the majority of
narrowing occurring in the anteroposterior dimension.161 That
effect is believed to be caused mainly by inhibition of upper airway
musculature, but other mechanisms have been proposed.161,162
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Isoflurane has a similar effect, but narrowing has not been shown
to be dose-dependent. Continuous positive airway pressure
(CPAP) has been shown to completely reverse anesthesia-induced
upper airway narrowing in infants.163 In order to avoid upper
airway narrowing and obstruction, it is prudent to routinely
implemented CPAP shortly after commencing inhalational
induction of anesthesia in infants and children.
Effects on the Lower Airway

Volatile anesthetics predominantly relax airway smooth muscle
and increase airway dimension and, therefore, lower airway resistance. Halothane, isoflurane, and desflurane all produced
airway smooth muscle relaxation in a human in vitro model, with
the amount of relaxation dependent on the airway caliber, the
airway precontraction level, and the volatile agent.164 The bronchodilatory effect of volatile agents has led to their occasional use
in the treatment of children with refractory status asthmaticus.
Sevoflurane, isoflurane, and halothane transiently attenuated
severe allergy-induced bronchospasm in animal models, whereas
desflurane led to exacerbation.165,166 Both desflurane and halothane
produced bronchodilation in a dog model of acetylcholineinduced bronchospasm.167 Although some evidence indicates that
desflurane has a bronchodilatory effect, a preponderance of data
indicates that other volatile agents would be preferable in a patient
with an active bronchospastic event.
Sevoflurane was shown to have a slightly favorable effect on
lower airway respiratory mechanics in healthy children and in
those with reactive airways, whereas desflurane produced a
deleterious effect in both groups.168 Von Ungern-Sternberg and
colleagues demonstrated that, relative to measurements made
during propofol anesthesia, 1.0 MAC of desflurane led to an 18%
increase in airway resistance in healthy children and a 54%
increase in children with airway susceptibility defined as either
a history of reactive airways or an upper respiratory infection in
the previous 2 weeks. Figure 2110 shows that the degree of
resistance increase was independent of the cause of airway susceptibility, and the increase reached maximal effect within
3 minutes of desflurane administration. Adult data for sevoflurane
and desflurane have shown similar findings,169 although one study
found that desflurane had a bronchodilatory effect at 1.0 MAC but
increased airway resistance at 2.0 MAC.170 Smoking increases
bronchoconstriction associated with desflurane,169 and the question of whether secondhand smoke has a similar effect has yet to
be addressed.
Volatile anesthetics appear to exert a protective effect against
induction of bronchospasm by chemical or noxious stimuli.
Animal studies show that, at 1.0 MAC, sevoflurane, desflurane,
isoflurane, and halothane protect against bronchoconstriction
induced by methacholine and by histamine.171,172 Sevoflurane at
1.6 MAC has been shown to completely blunt the bronchoconstrictive response to endotracheal tube placement occurring
in children with a history of asthma.173
Volatile Anesthetic Effect on Skeletal Muscles

Effect on Muscle Relaxation
Volatile anesthetics potentiate the relaxant effect of nondepolarizing neuromuscular blockers174178 and, at high concentrations,
decrease neuromuscular transmission.179 The potentiation effect
has been recognized for many decades, yet the mechanism
Figure 21-10. Airway resistance is shown to increase during

desflurane anesthesia, but not during sevoflurane, in patients
with airway susceptibility owing to either asthma or an upper
respiratory tract infection in the prior 2 weeks. Airway resistance was measured after various time intervals of 1.0 MAC of
each volatile anesthetic. During desflurane, resistance increases
rapidly and to a similar degree for both causes of increased
airway susceptibility, whereas during sevoflurane, the resistance
remains similar to resistance during propofol. Adapted from
reference 168.
remains poorly understood. The effect site is thought to be
postjunctional at the neuromuscular junction.180 Isoflurane and
enflurane produced equivalent potentiation of curare blockade,
which was greater than potentiation by halothane.175 Sevoflurane
potentiates rocuronium blockade more than isoflurane; 1.0 MAC
of sevoflurane reduced by 50% the amount of rocuronium needed
to produce 90 to 99% twitch depression.176 Recovery from neuromuscular blockade is also slower during sevoflurane anesthesia
than with isoflurane.177
Effects Caused by Volatile

Anesthetic Metabolites
Toxic metabolites of volatile anesthetics were considerably more
important with methoxyflurane and halothane than with the more
recently introduced agents. The development of modern volatile
anesthetics has been carved with a vigilant eye toward prevention
of metabolite-induced kidney and liver injury. Understanding the
nature of these toxic metabolites is important for historic reasons
but also because the possibility of injury from toxic metabolites
has not been completely eliminated.
Inorganic Fluoride Metabolite and Renal Toxicity

In vivo metabolism of volatile anesthetics, through action of the
cytochrome P450 (CYP450) isozyme system, occurs to a minimal
extent for most modern volatile anesthetics. Hepatic metabolism
of the ether anesthetics occurs principally through the CYP450
2E1 (CYP450 2E1) microsomal enzyme, which leads to release of
inorganic fluoride and production of organic fluoride moieties
that are conjugated and excreted in the urine.181,182 The rank order
of metabolism as judged by fluoride concentrations at saturating
substrate concentrations is methoxyflurane > sevoflurane >
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enflurane > isoflurane > desflurane > 0.183 Halothane metabolism
does not result in appreciable levels of inorganic fluoride. When
using methoxyflurane, inorganic fluoride plasma concentrations
that exceeded 50 M/L were associated with subclinical nephrotoxicity, and concentrations greater than 90 M/L produced frank
renal tubular injury in humans.184 Because of that association,
methoxyflurane fell into disuse. The cause of metabolite-induced
renal injury was assumed to be circulating serum inorganic
fluoride acting alone. The concentration of 50 M/L associated
with methoxyfluorane-induced subclinical nephrotoxicity was
adopted as a threshold level to be avoided for all volatile agents.
Peak inorganic fluoride plasma concentrations for sevoflurane
used at typical working concentration and duration are typically
well below 50 M/L,50 but prolonged use results in concentrations
over 100 M/L. Interestingly, sevoflurane, enflurane, and isoflurane may all induce inorganic fluoride plasma concentrations in
this toxic range but have not produced renal toxicity even after
prolonged exposure.181 That fact led to further investigation of the
cause-effect relationship being ascribed to plasma concentrations
of inorganic fluoride. Kharash and associates demonstrated that
volatile anestheticinduced nephrotoxicity appeared to depend
not only on metabolism by hepatic P450 isozymes but also on
renal metabolism. They found that renal isozymes catalyzed
defluorination of methoxyflurane 3 to 10 times faster than for
sevoflurane.185 The same lead author recently demonstrated that
a second metabolite of methoxyflurane, dichloroacetic acid,
enhanced toxicity produced by inorganic fluoride.186 Those findings work together to explain why renal injury has not been
reported to occur with other methyl ethyl ethers capable of producing elevated plasma inorganic fluoride concentrations. Even
in patients with pre-existing renal insufficiency, sevoflurane does
not appear to cause deterioration of renal function.187 None of the
volatile anesthetics in current clinical use causes a clinically significant effect on renal function, but it is possible that we have not
yet seen the last chapter of this saga.
Hepatic Toxicity Caused by Volatile

Anesthetic Metabolites
Halothane, isoflurane, enflurane, and desflurane have all been
implicated as causative of postoperative liver dysfunction,188193
though halothane is most notorious for that complication. Metabolic byproducts are implicated in volatile anestheticinduced
hepatotoxicity. Halothane is metabolized to a much greater extent
than the ether anesthetics, with 20 to 25% metabolized. The degree
of metabolism depends on age; metabolism increases during the
first 2 years of life, reaching adult levels by the age of 2 years. Two
types of adverse hepatic effects are associated with halothane
337
metabolites, including a common reversible subclinical form that

results in mild transaminase elevations194196 and a severe fulminant hepatic necrosis commonly referred to as halothane hepatitis
that often results in death. Halothane hepatitis has been shown to
result from a hypersensitivity reaction to an oxidative metabolite
of halothane.197 The same CYP450 2E1 is largely responsible for
conversion of halothane into trifluoroacetyl chloride, which binds
to liver proteins. In susceptible individuals, this neoantigen
stimulates formation of antibodies such that re-exposure to
halothane (or, rarely, to other volatile anesthetics) causes massive
immune-mediated hepatic necrosis. Fatal hepatic necrosis occurs
overall in between 6000 and 35,000 halothane anesthetics,181 but it
occurs much less frequently in children than adults. The entity is
considerably rarer with enflurane, isoflurane, or desflurane and
has never been reported with sevoflurane (presumably because
it does not undergo metabolism that results in formation of
trifluoroacetylated liver proteins). A pediatric case of presumed
desflurane-induced severe hepatic dysfunction occurred in a
15-month-old with Moebius syndrome previously exposed to
isoflurane. That patient developed elevated liver enzymes and
coagulopathy associated with gastrointestinal bleeding but
eventually had resolution of symptoms.193
VOLATILE ANESTHETIC
DEGRADATION WITH
CO2 ABSORBENTS
Degradation of volatile anesthetics by CO2 absorbents that incorporate strong bases such as potassium hydroxide (KOH) and
sodium hydroxide (NaOH) can result in formation of carbon
monoxide (CO) and haloalkenes such as 2-fluoromethyl-2difluoro-1-(trifluoro-methyl) vinyl ether (known as compound
A). The preferential binding of CO over oxygen to hemoglobin
leads to the neurotoxic and cardiotoxic effects of CO poisoning.198
Compound A is nephrotoxic in rats and causes measurable laboratory changes in humans, but it has not been shown to lead to
clinically significant human renal injury. The composition of the
most commonly used absorbents are listed in Table 214 and
demonstrate that soda lime and Baralyme (barium hydroxide
lime), which have been popular for decades, contain considerable
amounts of the strong bases KOH and NaOH. Novel absorbents,
the first of which was Amsorb, have been developed to minimize
anesthetic degradation to toxic byproducts. Amsorb does not
contain KOH or NaOH, maintains moisture with a calcium chloride (CaCl2) humectant rather than depending on hygroscopic
properties of NaOH and KOH, is unreactive with modern volatile
anesthetics, and yet maintains adequate CO2 absorption.199,200
TABLE 21-4. Percent Base Composition of Commonly Used Carbon Dioxide Absorbents
Absorbent Name
Ca(OH)2
Baralyme
Carbolime
Soda lime
Sodasorb II
Dragersorb Free
Amsorb
LiOH
72
83.2
79.8
76.5
7482
>75
0
KOH
NaOH
Ba(OH)2
CaCl2
LiOH
H2O
5.3
0
0
2.3
0
0
0
0
3
3
2.3
<2
0
0
10.5
0
0
0
0
0
0
0
0
0
0
35
0.7
0
0
0
0
0
0
0
99
12.2
13.8
17.2
18.9
1418
14.5
1
Data derived from references 201 and 199 with listed values for Amsorb Plus identical to those for Amsorb.
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Lithium hydroxide is also unreactive with volatile agents, but cost

and the corrosive quality remain an issue.201 Once novel absorbents are universally available and affordable, concerns over
volatile anesthetic degradation products are likely to become
nonexistent. Until then, the following discussions of each of the
problematic consequences of degradation remain quite relevant.
CO Production
Volatile anesthetics can react with desiccated soda lime or
Baralyme to form CO.202,203 Although the production of a clinically
significant amount of CO is rare, such a degree of CO can appear
in the anesthesia circuit given the right conditions.204 Volatile
anesthetics with a difluoromethyl group (desflurane, enflurane,
and isoflurane) are most prone to this type of degradation.203 The
tendency to degrade to CO follows the order: desflurane >
enflurane > isoflurane >> sevoflurane = halothane.205 Despite the
lower tendency for sevoflurane breakdown to produce CO, it has
been associated with clinically significant carboxyhemoglobin
levels in children205 and in an adult who had a CO level of 29%
(see section on Sevoflurane Degradation, later).206 CO formation
is more likely with Baralyme than with soda lime as the CO2
absorbent.202 CO generation increases with increasing desiccation
of the absorbent.207,208 Reduction of absorbent water content to 5%
or less is associated with clinically significant CO formation, and
that degree of desiccation requires 24 hours or longer of 10 L/min
flows through the absorbent canister.208 Other factors may play a
role in desiccation, including infrequent use of an anesthesia
machine.
Prevention is the solution to this problem. When CO2 absorbents with strong bases are being used, several simple rules can be
implemented that will help avoid this potentially catastrophic
problem. The most important rule is to turn off all fresh gas flow
in between cases and, certainly, at the end of the day. Additional
safeguards have been suggested, including disconnecting fresh gas
hoses to the absorbent canister and leaving the circuit reservoir
bag attached to the canister to decrease potential gas flow through
the canister, should one forget to turn off the gas flow. Vigilance
should always be exercised at the beginning of the day to identify
gas flow that has remained on overnight. When soda lime or
Baralyme desiccation is suspected, the absorbent should be
replaced.
Compound A Production
Sevoflurane undergoes Baralyme- and soda limedependent degradation in the absorbent canister to compound A, a haloalkene
that is known to cause renal tubular necrosis in rats.181,203 Production of compound A is increased with increasing sevoflurane
concentration, increasing temperature (as occurs with lower fresh
gas flow), and desiccation of absorbent. Absorbents containing
KOH are more prone to this problem than those containing
NaOH; compound A production is more pronounced with
Baralyme than with soda lime.209 Compound A does not form to
any appreciable extent when using Amsorb CO2 absorbent or the
more recently manufactured Amsorb Plus or Dragersorb Free,
even when using 2% sevoflurane at a flow rate of 1 L/min for
prolonged time periods.199,200 Whereas Amsorb has slightly decreased absorptive capacity than Baralyme and soda lime, Amsorb
Plus and Dragersorb Free have comparable activity.
Compound A is formed through a complex dehydrofluorination process and then undergoes glutathione-dependent
metabolism that can lead to formation of reactive and toxic
intermediates.203 Humans experience less metabolic toxification
of compound A than rats and have proximal tubular cells that
are more resistant to compound A cytotoxicity.181 Considerable
debate has taken place over the potential nephrotoxic effects of
compound A, and some investigations have found mild dosedependent effects of sevoflurane anesthesia on variables such as
urinary albumen and serum creatinine.210 However, investigations
to date have found no clinically significant effects from compound
A in humans undergoing sevoflurane anesthesia.181,203,211 To date,
no human case of compound Ainduced renal injury has been
reported since the early 1990s and over 100 million anesthetic with
sevoflurane.
Severe Exothermic Reactions and Explosions

Associated With Sevoflurane Degradation
Degradation of volatile anesthetics is an exothermic process.
Sevoflurane degradation by desiccated absorbents that contain
strong bases can lead to excessive heat production causing combustion and even explosions.206,212214 Sevoflurane degradation is
complex, and there may be two sets of degradation processes
taking place: an initial reaction that generates compound A but
not CO and a second reaction that occurs at higher temperatures
and does produce substantial CO.205 One case report of an adult
patient noted that this degradation process occurred approximately 2 hours into maintenance with sevoflurane, which resulted
in the melting of the absorbent canister, the generation of fumes,
high carboxyhemoglobin, and the development of acute respiratory distress syndrome.206 Two other case reports noted that
explosions occurred during, or in close proximity to, pediatric
inhalational inductions with 8% sevoflurane.213,214
Sevoflurane reacts with desiccated absorbents that contain a
strong base (particularly KOH), and this reaction can reach temperatures in excess of 100C during laboratory experiments.205,212
Extreme heat generation and explosions have taken place in both
laboratory and clinical settings when high concentrations of
sevoflurane, along with high gas flows, and desiccated Baralyme
are used.206,213,214 Sevoflurane degradation produces heat, and heat
increases sevoflurane degradation, so that this reaction feeds on
itself. Production of methanol and formaldehyde may contribute
to the explosive nature of this reaction.212
A lack of rising inspired sevoflurane concentration despite
a high dialed concentration on the vaporizer should prompt
investigation of CO2 absorbent temperature and may be a harbinger that this dangerous degradation process is occurring. However,
one case of a sevoflurane explosion is reported to have occurred
without an unexpectedly low inspired sevoflurane concentration
prior to the sudden explosion.213 CO production can be significant just prior to and after combustion and explosion, and
therefore, CO should be measured by co-oximetry whenever
this reaction has occurred in a circuit connected to a patient.
Vigilance in detection of this type of degradation is critical, but
as with other degradation processes, prevention is paramount.
All measures avoiding absorbent desiccation and disposal of
suspected desiccated absorbent should be taken (see CO production). Soda lime is less likely than Baralyme to degrade sevoflurane in this manner, and absorbents that are nonreactive with
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sevoflurane, such as Amsorb, eliminate the possibility of this type
of reaction.
MALIGNANT HYPERTHERMIA
Malignant hyperthermia (MH) is a hypermetabolic lifethreatening condition that occurs in susceptible individuals after
receiving specific triggering agents. All modern volatile anesthetics have triggered MH.215224 MH occurs in all races and age
groups and has an overall incidence of between 1:5,000 and
1:100,000 patients. It is most frequent in the pediatric population;
52% of cases occur in patients younger than 15 years of age.225
Although MH has been reported in a newborn, the youngest confirmed case is in a 6-month-old. The average number of anesthetic
exposures prior to developing MH is three, but MH may develop
on the first exposure.225 Patients who are susceptible to MH, such
as those with central core disease, multi-minicore disease, King
Denborough syndrome, hypokalemic periodic paralysis, myotonia
fluctuans, and those with a positive family history of MH should
receive anesthetics that are free of triggering agents such as
succinylcholine or volatile anesthetics. Patients with dystrophinopathies, such as Duchennes muscular dystrophy, have not been
demonstrated to have a predisposition to MH, but they should
also have a trigger-free anesthetic in order to avoid the possibility
of rhabdomyolysis with associated hyperkalemic arrest.226
Studies in MH-susceptible swine have found that MH onset is
faster with halothane than with isoflurane and faster with isoflurane than with desflurane.227 Two cases of suspected MH during
desflurane had initiation of symptoms at 3 and 7 hours after the
initiation of desflurane.218,219 Caffeine-induced contractures are
augmented to a greater degree by halothane than by isoflurane or
enflurane,228 but there is no clinical evidence showing a volatile
anestheticspecific difference in MH incidence or severity.
VOLATILE ANESTHETICS IN
CLINICAL PRACTICE
Volatile Anesthetic Inhalational Induction:
Choice of Agents and Techniques
Inhalational induction is by far the most common technique of
anesthetic induction for children in the United States229 and is a
heavily utilized technique internationally. Halothane had been for
decades the principal volatile anesthetic used for inhalational
induction, but sevoflurane has proved to be at least as good an
induction agent, with just as low incidences of breath holding,
coughing, laryngospasm, and oxygen desaturation as halothane.50,230234 The other ether anesthetics, desflurane, isoflurane,
and enflurane, have proved to be unsuitable for inhalational induction owing to their high incidences of respiratory complications.122,235239 The incidence of laryngospasm during desflurane
induction was reported to be 49% and with isoflurane was
23%.122,235 A few studies have claimed similar induction conditions
for isoflurane and either sevoflurane or halothane in infants and
children,240,241 but a preponderance of evidence implies that the
only two suitable volatile anesthetics for inhalational induction
are sevoflurane and halothane. Sevoflurane may be a better choice
in children with congenital heart disease owing to lesser hemodynamic effects and a lower incidence of dysrhythmias (see
Cardiovascular Effects of Volatile Anesthetics).128,242
339
The addition of N2O may smooth sevoflurane induction in

children by substantially decreasing excitation.233,243 Addition of
50% N2O has also been shown to speed sevoflurane induction.243
In this authors opinion, N2O has a role in inhalational induction
of children and older infants, but should be omitted for infants
younger than 6 months old because their induction is extremely
rapid with volatile agent alone, and they may benefit from additional oxygen owing to the rapid speed with which their oxygen
saturation typically declines.
Incremental increases in inhaled anesthetic concentration at
induction, rather than immediate increase to maximum, is believed by some to provide a smoother, albeit a slower, induction.
Studies have demonstrated that incremental increases of sevoflurane during induction slowed induction, did not improve mask
acceptance, and did not decrease coughing, compared with
immediate administration of 7 or 8% sevoflurane.243,244 Incremental increase of halothane has been common practice, despite a lack
of evidence of benefits with that technique.
The single-breath vital capacity induction technique is a particularly useful method for inducing anesthesia in older children.
Agnor and coworkers demonstrated that the time to loss of eyelash
reflex was only 33 seconds when children aged 5 to 12 years took
and held a single vital capacity breath of 8% sevoflurane in oxygen,
and speed of induction did not change when N2O was added.245
The ability to cooperate with this type of induction is only 10% in
patients aged 4 to 5 years and approaches 50% by 8 years.246
Compared with the standard tidal volume technique, the singlebreath method produced slightly shorter time to loss of eyelash
reflex, was equally well tolerated, and produced better patient
satisfaction.247 Lack of airway irritability when using the singlebreath technique draws into question any purported benefit of
incremental anesthetic increases during induction.
Onset of Anesthesia in Clinical Practice:

Anesthetic Induction and the
Overpressure Technique
Induction with sevoflurane could be expected to be more rapid
than with halothane owing to sevofluranes lower solubility.
However, speed of induction is determined not only by the washin
characteristics of an anesthetic but also by the maximum inspired
anesthetic partial pressure administered and the rapidity with
which that maximum partial pressure is dialed in. Halothane
vaporizers typically deliver a maximum of 5%, which equates to
four to six times the MAC for halothane. Sevoflurane vaporizers
typically deliver a maximum of 8% sevoflurane, which equals
approximately three to four times MAC. Overpressure of an
anesthetic refers to using an inhaled partial pressure above the
anesthetic partial pressure one desires in the VRG, in order to
obtain the desired VRG pressure more quickly. Vaporizers for
sevoflurane and halothane are typically turned to maximum
concentration rapidly, if not immediately, at the start of induction.
The ability to apply greater overpressure when using halothane
compensates for its lower solubility compared with sevoflurane.
In fact, the speed of induction with halothane dialed immediately
to 4% is similar to that when using immediate 8% sevoflurane.234
Interestingly, the similarity in speed and induction characteristics
of these two agents is noted by the fact that anesthesiologists who
were blinded to whether they were using sevoflurane or halothane
during induction could not tell the difference.248 In a similar study,
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blinded observers were able to guess the anesthetic, despite identical induction times, most likely because sevoflurane induction
was associated with tachycardia.234
The ability to overpressure with both sevoflurane and halothane is critical to achieve necessary rapidity of inhalational
induction, especially for older children in whom washin occurs at
a slower rate than infants. The advantage of the overpressure
technique, however, comes with the inherent peril that the patient
may receive an anesthetic overdose, especially when using halothane. Two in vivo feedback mechanisms act to modulate the
speed with which one might approach the extremely high inspired
concentration during overpressure of anesthesia. The first is a
negative-feedback mechanism, which leads to a protective effect
for the patient. This negative-feedback loop results from the
inhaled anesthetic lowering the minute ventilation of spontaneously ventilating patients. The lower minute ventilation leads
to a slowing of the rise of alveolar to inspired partial pressure,
which acts to slow the rising VRG partial pressure. If controlled
ventilation is employed during inhaled induction while using the
overpressure technique, this protective negative-feedback mechanism is bypassed, and alveolar partial pressure will rise much more
rapidly.11 Dogs that were administered 4% halothane using
controlled ventilation had nearly 50% higher alveolartoinspired
partial pressures at 10 minutes, compared with when they breathed the same concentration spontaneously, and nearly all dogs
that received 4% by controlled ventilation went on to cardiovascular collapse compared with none that breathed 4% spontaneously.249 Recall from the Pharmacokinetic section, earlier, that
halothane partial pressure rise will be most affected by augmentation of ventilation because it is more soluble than sevoflurane.
Controlled ventilation should be avoided when using halothane
overpressure inductions; if controlled ventilation becomes necessary, the inhaled halothane concentration should be substantially
decreased. The same precautionary measure should be considered
during sevoflurane overpressure induction of infants. Children
receiving 8% sevoflurane induction appear more resistant to
cardiovascular depression; 8% sevoflurane used in conjunction
with rapid control of ventilation and administered up to the time
of tracheal intubation did not cause appreciable cardiovascular
depression in patients 1 to 8 years of age.119
The second feedback mechanism results in a dangerous
positive-feedback loop. As VRG anesthetic partial pressure rises,
cardiac output falls, leading to a faster rise in alveolar and VRG
partial pressures, which causes further fall in cardiac output. This
downward spiral caused by this positive-feedback mechanism
demands that overpressure of inhaled agents is carried out with
extraordinary care, especially in infants who already have a more
rapid anesthetic washin and who may be more sensitive to the
cardiovascular depression of volatile agents. Again, this feedback
loop would be expected to be more prominent with halothane
than with sevoflurane because rates of rise of partial pressures of
more-soluble agents are affected more by cardiac output changes.
Emergence in Clinical Practice:

Speed of Emergence
One might predict that the least-soluble agents would lead to
considerably more rapid emergence than the more-soluble agents.
Pediatric studies that have administered a set MAC multiple until
the end of surgery, and then measured time to awaken, have
demonstrated quicker emergence for the least-soluble agents.250253
In studies with that type of design, early emergence after desflurane or sevoflurane is generally quicker than after halothane.250,252 Emergence from desflurane is faster than emergence
from either sevoflurane or isoflurane.252,253 In clinical practice,
anesthesia is adjusted during the case and weaned at the end, and
pediatric studies that have used a design that allows anesthetic
titration have shown less differences in time to emergence, but
have still demonstrated faster early emergence when comparing
desflurane or sevoflurane with halothane.254,255 One comparison
of isoflurane plus N2O versus sevoflurane plus N2O found no
difference in emergence times in children when 1.2 MAC (ageadjusted) total was continued until the end of surgery (average of
135 min).256 That model may have given isoflurane an unfair
advantage in that it took into consideration that N2O seems to
reduce pediatric MAC for isoflurane more than for sevoflurane,
so that the starting volatile agent MAC fraction for isoflurane was
less than for sevoflurane. Similar studies in adults have found
slightly quicker early emergence for sevoflurane plus N2O over
isoflurane plus N2O.257,258 All of the studies that did demonstrate
quicker early emergence were unable to show a difference in time
to discharge from the recovery room.250,252,254,255 However, Nordman and colleagues did find that children older than 4 years did
leave the recovery room 8 minutes earlier after desflurane than
those who received isoflurane.253 That author also found that
increasing anesthetic duration increased emergence time after
isoflurane but not after desflurane, as might be predicted by
Baileys computer models as shown in Figure 218.
Emergence in Clinical Practice:

Emergence Delirium
Emergence delirium (ED; also known as severe emergence
agitation) has been a major focus in pediatric anesthesia since the
early 2000, but it is by no means a new phenomenon. Patients
with ED typically cry uncontrollably, make no eye contact or have
their eyes shut, do not recognize familiar persons or objects, and
exhibit nonpurposeful thrashing movements. Severe agitation on
emergence puts patients at risk of self-injury, dislodging intravenous lines or drains, or damaging their surgical site, and they
may require increased nursing support. Studies of ED had been
hampered by lack of a uniform validated definition, but Sikich and
Lerman validated and published an ED scoring system that should
solve that problem.259
The incidence of ED depends on the volatile anesthetic used
but also on which of the myriad definitions of ED were used. The
reported incidence of ED is as high as 80%, and in general, the
incidence follows the order: desflurane > sevoflurane > halothane.250,252,260263 The increased interest in ED has largely been
because of the increased incidence when using desflurane or
sevoflurane. Whereas differences in the incidence of ED between
those two agents and halothane are apparent, differences with
isoflurane are less apparent. Voepel-Lewis and associates found
that sevoflurane induction combined with isoflurane maintenance
increased the incidence of ED twofold compared with all other
anesthetic combinations.264 However, some have found no difference in the incidence of ED after sevoflurane or isoflurane,265 and
others have found less ED after isoflurane.266
The etiology of pediatric ED remains an enigma, though
pain, when not adequately controlled, is a contributing factor.267
However, emergence agitation (EA) does occur in a large percentage of children who undergo anesthesia for imaging studies and,
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therefore, have no surgical pain.260,262,268 Some believe that ED arises
from a direct effect of volatile anesthetics on the central nervous
system. Preschool age, preoperative anxiety, and otolaryngologic
procedures appear to put children at higher risk of ED.264,269271
Numerous agents have been shown to prevent ED, and given
the high incidence of ED after sevoflurane, isoflurane, or desflurane, one should consider prophylaxis. Dexmedetomidine,
clonidine, fentanyl, propofol, ketamine, and nalbuphene have all
been shown to decrease the incidence of ED, with numbers needed
to treat in the 2.5 to 5 range.260,268,272277 Strategies for treatment
of ED are nonevidence-based, but commonly used treatments
include small doses of fentanyl, propofol, midazolam, and dexmedetomidine.
CONCLUSIONS
Volatile anesthetics are likely to remain the dominant tool of the
pediatric anesthesiologist for years to come. Increased understanding of the consequences of metabolites and degradation
products has allayed some fears of negative consequences of the
newer anesthetic agents. However, the potential for volatile
anestheticinduced life-threatening events has not vanished, and
those who administer these agents must maintain a thorough
working knowledge of all the possibilities that may occur. Understanding the nuances of the washin and washout of these anesthetics, their age-related potency, how they interact with other
agents, and their effects on key organ systems will help the
practitioner administer an efficient and safe anesthetic.
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1997;87:12981300.
271. Kain ZN, Caldwell-Andrews AA, Maranets I, et al. Preoperative anxiety
and emergence delirium and postoperative maladaptive behaviors.
272. Ibacache ME, Munoz HR, Brandes V, Morales AL. Single-dose dexmedetomidine reduces agitation after sevoflurane anesthesia in children.
273. Tesoro S, Mezzetti D, Marchesini L, Peduto VA. Clonidine treatment for
agitation in children after sevoflurane anesthesia. Anesth Analg. 2005;
101:16191622.
274. Abu-Shahwan I, Chowdary K. Ketamine is effective in decreasing the
incidence of emergence agitation in children undergoing dental repair
under sevoflurane general anesthesia. Paediatr Anaesth. 2007;17:
846850.
275. Dalens BJ, Pinard AM, Letourneau DR, et al. Prevention of emergence
agitation after sevoflurane anesthesia for pediatric cerebral magnetic
resonance imaging by small doses of ketamine or nalbuphine administered just before discontinuing anesthesia. Anesth Analg. 2006;102:
10561061.
276. Abu-Shahwan I. Effect of propofol on emergence behavior in children
after sevoflurane general anesthesia. Paediatr Anaesth. 2008;18:5559.
277. Aouad MT, Yazbeck-Karam VG, Nasr VG, et al. A single dose of propofol at the end of surgery for the prevention of emergence agitation in
children undergoing strabismus surgery during sevoflurane anesthesia.
278. Morio M, Fujii K, Satoh N, et al. Reaction of sevoflurane and its degradation products with soda lime. Toxicity of the byproducts. Anesthesiology. 1992;77:11551164.
279. Liu J, Laster MJ, Eger EI 2nd, Taheri S. Absorption and degradation of
sevoflurane and isoflurane in a conventional anesthetic circuit. Anesth
Analg. 1991;72:785789.
280. Ebert TJ, Frink EJ Jr, Kharasch ED. Absence of biochemical evidence for
renal and hepatic dysfunction after 8 hours of 1.25 minimum alveolar
concentration sevoflurane anesthesia in volunteers. Anesthesiology.
1998;88:601610.
281. Ebert TJ, Messana LD, Uhrich TD, Staacke TS. Absence of renal and
hepatic toxicity after four hours of 1.25 minimum alveolar anesthetic
concentration sevoflurane anesthesia in volunteers. Anesth Analg. 1998;
86:662667.
282. Higuchi H, Sumikura H, Sumita S, et al. Renal function in patients with
high serum fluoride concentrations after prolonged sevoflurane
283. Yasuda N, Targ AG, Eger EI 2nd. Solubility of I-653, sevoflurane,
isoflurane, and halothane in human tissues. Anesth Analg. 1989;69:
370373.
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Xenon and Anesthesia:

Pharmacology
Peter H. Tonner
22
C H A P T E R
INTRODUCTION
HISTORY
The biologic activity of noble gases was first described in the 1950s
when their anesthetic properties were discovered.1,2 Noble gases
have been subdivided into three groups according to their
anesthetic effect. Xenon belongs to the first group, revealing an
anesthetic effect under normal atmospheric pressure when mixed
with oxygen at a ratio of 70 to 30%. Compared with xenon, argon
and krypton belong into the second group, which exerts an
anesthetic effect only in the hyperbaric environment. The third
group includes helium, neon, and radon; these are completely
without an anesthetic effect3 (Table 221). Since its first reported
use in humans, xenon was accompanied by the belief that it was
the closest candidate for an ideal anesthetic gas.4 Although the
anesthetic use of xenon was not followed up rigorously, through
the following years, sporadic reports continued to support the
superior properties of this gas compared with the available inhalational and intravenous anesthetics. Thus, xenon was demonstrated
in studies in animals and humans to exert superior hemodynamic
stability, possibly being the anesthetic of choice for cardiovascularly compromised patients. Since 1990, there has been renewed
interest in xenon, and more studies were published examining
various aspects of clinical anesthesia with xenon. At the end of
2005, xenon was approved for clinical use in Germany, and it was
approved in the rest of Europe in 2007. It is likely that approval
for the Northern American continent will follow. Although considerable clinical experience of the use of xenon in anesthesia has
accumulated in adults, only very limited experience exists in pediatric patients. In this chapter, general aspects of xenon pharmacology in anesthesia are reviewed, and aspects relevant to pediatric
anesthesia are emphasized.
Xenon was discovered in 1898 by Ramsay and Travers after evaporation of liquid air components. In 1962, it was categorized as
a noble gas together with helium, neon, argon, krypton, and
radon, all of them found in the troposphere in minute amounts.
Compared with the other noble gases, xenon is the heaviest stable
compound with a molecular weight of 131.3 (Table 222). With a
relative concentration of 0.0000087 vol%, it is rather rare. After
the demonstration of its analgesic effects in mice in 1946,2 the first
use of xenon as an anesthetic in humans can be traced back to
1951, reported by Cullen and Gross.4 They described a rapid loss
of consciousness and a quick recovery using the gas at an 80 vol%
concentration (Figure 221).
CHEMICAL REACTIVITY
Because of its unique electron structure, xenon is chemically
nearly inert. It is nonexplosive; however, under extreme conditions, it may form molecular compounds with highly reactive
elements, such as oxygen or fluoride. During anesthesia, it is
extremely unlikely that xenon participates in a chemical reaction.
However, although biotransformation of xenon has not been
TABLE 22-1. Physicochemical Properties and Relative

Anesthetic Potencies of Noble Gases (Reference Gas:
Nitrogen)
Gas
Molecular
Weight
Lipid
Solubility
He
Ne
N2
Ar
Kr
Xe
4
20
28
40
84
131
0.015
0.019
0.067
0.14
0.43
1.17
Relative
Anesthetic
Potency
0.2
0.3
1
2.3
2.5
25.6
Figure 22-1. Pharmacokinetics of inhalational anesthetics.

Compared with the inhalational anesthetics halothane, isoflurane, sevoflurane, desflurane as well as nitrous oxide, the uptake
of xenon is extremely rapid, thus rendering xenon anesthesia
highly adjustable. For example, when halothane is administered
for 20 minutes only little more than 50% of the inspired fraction
is reached in the alveoli whereas more than 90% is reached after
only 5 minutes of xenon inhalation. Similarly, the elimination of
xenon is more rapid than that of any of the other inhalational
anesthetics. FA/FI = alveolar fraction/inspired fraction.
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TABLE 22-2. Physicochemical Properties of Xenon and

Nitrous Oxide
Molecular diameter,
Blood/gas partition coefficient
Oil/gas partition coefficient
MAC (in humans)
Greenhouse effect
Molecular weight
Freezing point, C
Boiling point, C
Density, g/L
Viscosity (micropoises)
Thermal conductivity, mW*cm1*K1
Thermal capacity, cal*K1*mol1
Xenon
Nitrous Oxide
4.0055
0.47
1.4
1.05
131.29
111.9
108.2
5.40
226
0.057
4.97
3.879
0.14
1.9
0.71
+
44.02
90.0
88.5
1.81
145
0.173
9.19
demonstrated, it is conceivable that xenon may be involved in

biochemical processes.
ACTIONS OF XENON
AT SUBCELLULAR AND
CELLULAR LEVELS
Although the analgesic and anesthetic properties of xenon have
been known for more than five decades, the exact mechanisms of
action at the cellular or molecular level are not known yet.
However, a number of studies have been performed to define
parameters that are relevant for the action of these compounds
(Figure 222). It is known that many anesthetics exert their actions
at a variety of molecular targets. Among these, the superfamily of
ligand-gated ion channels has been shown to be more likely to be
influenced in their function at clinical concentrations than other
receptor or channel proteins. It has been demonstrated that most
anesthetics such as volatile anesthetics act primarily on gammaaminobutyric acid (GABA) A receptors. However, it was shown
that xenon potently inhibits N-methyl-D-aspartic acid (NMDA)
receptor function and that the effect of xenon on GABAA receptors
is only minimal.58 However, xenon inhibits excitatory NMDA
receptor channels. NMDA receptors have important functions in
synaptic mechanisms that underlie learning, memory, and the
perception of pain. In addition to xenon, the NMDA receptor is
also a target of the intravenous general anesthetics ketamine and,
at least partially, nitrous oxide.5,9 The inhibition of the NMDA
receptor has been reported to be the main action of xenon and its
anesthetic and analgesic effects.10 A study compared the effects of
nitrous oxide, xenon, isoflurane, and ethanol directly on nine
different recombined ligand-gated ion channels including GABAA,
NMDA, 5-hydroxy-tryptamine (5-HT3), and acetylcholine (ACh)
receptors by employing a voltage clamp technique.11 Xenon exerted a stronger effect on NMDA receptors than on GABAA
receptors, rendering this anesthetic distinctly different from
isoflurane and ethanol, which exerted their highest potencies at
GABAA receptors. Studies looking at ether, nitrous oxide, or xenon
already indicated that GABAA receptors are not as strongly
affected by xenon as by other anesthetics.58 In this respect, xenon
is markedly different from other inhalational anesthetics.
Another molecular target site shared by xenon with gaseous and
volatile anesthetics is the nicotinic acetylcholine receptor (nAChR).
It has been demonstrated that central nervous system nAChRs,
especially those composed of the 2 subunit, are inhibited in their
function by many anesthetics at relevant concentrations.1216 Xenon
is a potent analgesic at subanesthetic concentrations.17,18 It has been
speculated that this antinociceptive effect is caused by an action on
glutamate receptors, namely, the NMDA receptor, in a manner
similar to that of ketamine.19 A target site for xenon is part of the
two pore-domain potassium channels. It was shown that xenon as
well as nitrous oxide and cyclopropane activate the TREK-1 channel at clinical concentrations. By contrast, the TASK-3 channel,
which is very sensitive to volatile anesthetics such as halothane, is
not insensitive to xenon.20
ANESTHESIA AND MIMINUM

ALVEOLAR CONCENTRATION
Figure 22-2. Meyer-Overton correlation of inhalational anesthetics: When anesthetic potency (minimal alveolar concentration [MAC]) is plotted against lipid solubility (oil/gas partition
coefficient) on a bilogarithmic plot, most anesthetics are lying
on a straight line. Xenon obeys this so-called Meyer-Overton
rule, supporting the view that the molecular target site that
binds xenon is of lipophilic nature.
In an early study, the minimum alveolar concentration (MAC) of

xenon was estimated to be 71% at 1 atm surrounding pressure21
(see Table 222). Later, xenon was described to be more potent in
an elderly population with a MAC of 63%.22 Accordingly, the
anesthetic potency of xenon is too weak for its use as a single
anesthetic. One cannot deliver more than 1 MAC of xenon at an
inspired oxygen fraction (FIO2) of 0.3, which is the standard for
most healthy patients. At a concentration of 1 MAC, however, it is
impossible to safely perform a surgical operation. The MAC of
volatile anesthetics has been reported to be decreased when xenon
is co-administered. It has been demonstrated in patients that
sevoflurane fails to attenuate the cardiovascular response when
administered by itself.23 However, in combination with either
nitrous oxide or xenon, the cardiovascular response to skin incision was completely blocked. A follow-up study evaluated whether
a difference in the effect of nitrous oxide or xenon in combination
with sevoflurane existed. Forty-three patients undergoing elective
surgery were studied and the MAC was determined according to
the up-and-down method.24 This study demonstrated that the
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suppression of cardiovascular responses by xenon and nitrous
oxide was similar at 70 vol%, possibly reflecting their nearly identical analgesic properties. Although there is evidence that the
MAC of xenon is age-dependent, there are currently no sufficient
data for an exact MAC of xenon in children.
EFFECTS ON THE
CARDIOVASCULAR SYSTEM
Xenon has been reported to possess a remarkably safe hemodynamic profile. A study in pigs was demonstrated that hemodynamic parameters as well as plasma catecholamine levels
remained within normal limits during xenon anesthesia. Even at
subanesthetic concentrations of xenon, a significant decrease of
adrenaline was observed, possibly reflecting the high analgesic
potency of xenon.25 In a study looking at the hemodynamic effects
of xenon versus. nitrous oxide, 32 adult patients undergoing
gynecologic, plastic, or orthopedic surgery were evaluated.26 In
each group, anesthesia was maintained using either 70 vol%
nitrous oxide or 70 vol% xeno; fentanyl was added when blood
pressure increased by more than 20% from baseline. The anesthetist was unaware of the gas used. In this setting, it was found
that incremental fentanyl was necessary in all patients receiving
nitrous oxide and in only 50% of the patients receiving xenon,
whereas awareness did not occur in both groups. No differences in
blood pressure, heart rate, or the changes during surgery were
observed between the groups. By contrast to these clinical parameters, the adrenaline levels demonstrated a difference between
the nitrous oxide and the xenon groups. Whereas in the xenon
group, the adrenaline level remained below the baseline levels
throughout the operation and returned to control values only at
the end of surgery, the nitrous oxide group showed a continuous
increase in plasma adrenaline concentrations with a significant
difference at the end of the operation. In addition, the nitrous
oxide group showed increased adrenaline values immediately
postoperatively, returning to baseline only after about 6 hours
postoperatively. There was no apparent difference in recovery time
or quality of recovery, and the attending anesthetists were not able
to tell which gas was used.26 In a subsequent study examining
otherwise healthy American Society of Anesthesiologists (ASA)
class 1 patients undergoing open cholecystectomy or hysterectomy, the effect of xenon was studied by echocardiography. No
alterations in mean fractional area change were observed during
induction with xenon.27
In a large multicenter trial of xenon in elective surgery on
224 patients, xenon exerted stable respiratory and circulatory
conditions. In comparison with the isoflurane group, the hemodynamic parameters of the xenon group appeared superior.28
However, most of the earlier data were obtained in patients
lacking cardiovascular risk factors. Recently, studies have become
available elaborating on the hemodynamic effects of xenon in
patients with pre-existing cardiovascular disease. Thus, it was
demonstrated in patients with low cardiac ejection fraction undergoing implantation of a cardioverter-defibrillator that xenon
provided greater hemodynamic stability than propofol.29 Heart
rate was reduced in both groups, but mean arterial pressure
(MAP) remained stable in the xenon group and was reduced in
the propofol group without changes in left ventricular ejection
fraction (LVEF) in both groups. Even in this high-risk group of
patients, xenon anesthesia resulted in more stable hemodynamics
Xenon and Anesthesia: Pharmacology 349
than propofol-based anesthesia.29 In another study in high-risk

patients undergoing aortic surgery with xenon or propofol anesthesia, global cardiac performance and myocardial contractility
were assessed using transesophageal echocardiography and myocardial cell damage with troponin T and CK-MB (MB isoenzyme
of creatine kinase).30 No significant differences between groups
were found in global myocardial performance, myocardial contractility, or laboratory values at any time during the study period.
Duration of stay on the intensive care unit or in the hospital did
not differ significantly between the groups. It was concluded that
there was no advantage of xenon-based anesthesia over total intravenous anesthesia (TIVA) in high-risk surgical patients.30 However,
it was demonstrated that xenon increased parasympathetic and
reduced sympathetic activity in patients at high risk of cardiac
complications compared with propofol.31 Using heart rate variability as a measure of autonomic nervous system regulation, a
correlation to hemodynamics was demonstrated; however, there
was no benefit in terms of postoperative short- and long-term
outcome.31
These results of recent studies on cardiovascular risk patients
indicate that xenon may provide a more stable hemodynamic
control than TIVA and may exert beneficial effects on autonomic
nervous system regulation. However, at present, there are no data
on a large group of patients in order to conclusively demonstrate
that cardiovascular outcome is improved when patients receive
xenon anesthesia.32 Unfortunately, currently, no data are available
on hemodynamics in children under xenon anesthesia.
EFFECT ON CEREBRAL CIRCULATION

The effect of xenon on cerebral blood flow seems to vary according to the model used and the species studied.3336 In radiology,
radioactive xenon isotopes have been in use for a long time for
determination of cerebral blood flow. In volunteers, administration of 33 vol% xenon lead to a significant increase in cerebral
perfusion. Increases in perfusion were also noted in patients with
traumatic brain injury. Thus, some authors recommended the
prophylactic use of hyperventilation in patients receiving xenon
for diagnostic purposes.3740 An experimental setting involving
swine demonstrated that xenon left cerebral autoregulation intact
under different conditions.41 Studies using transcranial Doppler
ultrasonography found differing results. Increases as well as
nonsignificant changes in cerebral blood flow velocities have been
reported.27,4244
EFFECTS ON THE
GASTROINTESTINAL TRACT
Xenon has a low blood/gas partition coefficient of 0.12 to 0.14.45,46
A publication compared the effects of xenon and nitrous oxide on
gut distention directly under well-controlled conditions.47 In
21 pigs, anesthesia was induced and maintained intravenously.
Three groups of animals were studied, one receiving 75 vol%
xenon, one 75 vol% nitrous oxide, and one 75 vol% nitrogen
for 240 minutes. After a laparotomy was performed, segments of
15 cm in length were isolated in a gas-tight manner, filled with
30 mL of air, and pressure was measured through an inserted
catheter. In both the nitrous oxide and in the xenon group, the
volume of the bowel increased compared with the nitrogen control
group. In the nitrous oxide group, however, there was an increase
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of up to 88 mL, whereas in the xenon group, the volume increased

to only 39 mL (21 mL control). There was also a significant increase in intraluminal pressure in the nitrous oxide group compared with the xenon and the control groups. No difference in
intraluminal pressure was found when the xenon group and the
control group were compared.
The low partition-coefficient of xenon predicts a lower
transport capacity of the blood and a low rate of diffusion of xenon
into gas-filled volumes. However, the ability of various substances
to diffuse into adjacent space is also influenced by their respective
molecular diameters (xenon 4.0055 ; see Table 221) and their
diffusion coefficients, which may be modified by a number of
factors such as the polarity of the substance. Inhalation of xenon
is swine did not alter mesenteric metabolic balance compared with
intravenous anesthesia.48 One study in swine showed that xenon
does not alter mesenteric blood flow and, thus, may be of advantage for abdominal surgery.49 It may be concluded that xenon can
be used in abdominal surgery when factors such as hemodynamic
control are of concern. Data on the gastrointestinal effects of
xenon in pediatric anesthesia are still lacking.
XENON AND RESPIRATORY

MECHANICS
The physical parameters of xenon render this gas distinctly
different from the other gases used in anesthesia; especially the
high density and viscosity alter the physical properties of a gas
mixture used for anesthesia when a high fraction of xenon is used.
Some implications of this fact have to be dealt with by anesthetists:
(1) Anesthesia machines need to be upgraded so they can deal
with the more dense and more viscous gas mixtures. (2) The
behavior of monitoring devices for respiratory monitoring may be
influenced. (3) Respiratory mechanics of patients may be altered,
especially in the case of patients whose lung function is compromised. (4) In neonates, small airway diameters may inhibit the
use of xenon because excessive breathing pressures may need to be
applied.
Flowmeters have been demonstrated to be affected by the
different physical properties of xenon. Although most flowmeters
are designed to correct their readings according to the composition of the gas used, most of them are not designed for use with
xenon and may, thus, show false readings without compensating
for the possible errors. A study on the practicability of flowmeters
for xenon anesthesia demonstrated that only rotating vanes give
sufficiently accurate readings when xenon was used, whereas three
other types of flowmeters did not.50
In addition, in patients with lung diseases, the physical properties of a gas may affect respiratory mechanics.5153 Both the
density of xenon and its viscosity are higher than those of other
clinically used gases, an effect that demanded a producer of anesthesia machines to redesign one of their machines for administration of xenon because its ventilator did break after only short
periods of administration.
The effect of xenon on respiratory mechanics was studied in
comparison with nitrous oxide in pigs.54 Groups of eight pigs were
ventilated either with 70 vol% nitrous oxide or 70 vol% xenon and
airway pressure as well as resistance was measured. Both groups of
animals were then subjected to a metacholine infusion for induction of bronchoconstriction and measurements were repeated.
Both under normal conditions and throughout bronchoconstric-
tion, the airway resistance was significantly higher in the xenon

group than the nitrous oxide group. Airway pressure did not differ
during normal airway conditions; however, during bronchoconstriction, there was a significant increase in airway pressure in the
xenon group compared with the nitrous oxide group (Ppeak xenon
33.2 5.5; nitrous oxide 28.4 5.7 cmH2O).54 Another study
looked at the effect of xenon on respiratory mechanics under both
normal conditions and bronchoconstriction.55 By contrast to the
previously cited study, the authors did not administer 70 vol%
xenon throughout the study but instead used 50 vol% xenon
during bronchoconstriction. This change in experimental conditions possibly led to the finding that there was no difference in
airway resistance between normal ventilation and ventilation
during bronchoconstriction.55 In addition, airway resistance in
dogs is different from that in pigs and conditions are also different
if airway resistance is measured in an open-chest situation. The
main factor responsible for the change in airway resistances if one
switches from nitrous oxide to xenon appears to be the change in
both viscosity and density of the gas as predicted by the laws of
fluid dynamics.56 However, gas exchange was not affected during
ventilation with xenon.54 The authors of the first study concluded
that, although there is a change in respiratory mechanics during
xenon anesthesia, these changes are not of clinical relevance for
the following reasons54: (1) During general anesthesia, the ventilator and not the patient has to overcome increases in airway resistance, (2) the increase in airway resistance is small under
healthy conditions and only moderate during bronchoconstriction. and finally, (3) gas exchange does not deteriorate during
xenon anesthesia.
In our own study in a neonatal lung model, we were able to
demonstrate that xenon can be safely administered even when
internal tube diameters of 3.0 to 4.5 mm are used as long as
weight-adjusted tidal volumes are used (10 mL/kg). When tidal
volumes were increased, nonlaminar flow occurred and peak
pressures rose dramatically (unpublished data).
Diffusion Hypoxia
As the inert gas volume moving between capillary blood and
alveolar space differs with varying gas solubility, specific gases may
concentrate or dilute during uptake or elimination. This is the
reason why an outpour of gas occurs at the end of a nitrous oxide
based anesthesia, an effect called diffusion anoxia by Fink.57 The
solubility of nitrous oxide is higher (0.47) than that of nitrogen
(0.015); thus, the concentration of nitrous oxide is rising during
washout in the alveolar space. The mechanism of hypoxia is
twofold: (1) oxygen may be displaced and oxygenation inhibited,
(2) carbon dioxide may be diluted in the alveoli, thus decreasing
respiratory drive and ventilation. Because the solubility of xenon
is smaller than that of nitrous oxide but higher than that of
nitrogen, it may be concluded that a similar effect also occurs
during xenon anesthesia but may be less pronounced. In pigs,
diffusion hypoxia after nitrous oxide versus xenon anesthesia was
studied.58 The lungs of pigs were ventilated either with a mixture
of 30 vol% oxygen and 70% nitrous oxide or 70 vol% xenon for
30 minutes. At the end of this period, all animals were ventilated
with 30 vol% oxygen and 70 vol% nitrogen. Arterial oxygen partial
pressures were determined during nitrogen washin. A PO2 of
17 mmHg was found in the nitrous oxide group. In the pigs receiving xenon, the PO2 was much smaller (6 mmHg), thus, confirming
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the notion that inert gas exchange is mainly determined by the
blood/gas/patient coefficient (solubility in lipids). Although the
lipid solubility of xenon is greater than that of nitrous oxide, more
xenon may be taken up during an anesthetic than nitrous oxide.
However, only the part of the gas that is actually dissolved in the
blood and passes the lungs may diffuse into the alveolar space so
that lipid solubility is only of minor importance to these effects.
ORGAN PROTECTION
Experimental settings demonstrated that xenon exerts protective
effects on several organ systems. This was first demonstrated in
its effects on the brain. Here, xenon possesses protective properties
in several models of neuronal injury. In hypoxic neurons, it was
demonstrated that xenon exerts its action through a calciumdependent mechanism.59 However, xenon was also reported to
have no neurotoxic effect such as other NMDA antagonists; this
has been questioned at least for higher concentrations of xenon.60,61
The heart is another important organ that appears to be protected
by xenon. Similar to volatile anesthetics that exert a preconditioning effect comparable with ischemic preconditioning, xenon has
been demonstrated to protect the myocardium through this
mechanism, too.62,63
NEUROPROTECTION
Perinatal hypoxic ischemia is a serious complication during
childbirth. It has been estimated that 2 to 4 per 1000 term infants
suffer an episode of hypoxic ischemia during labor.64 Fifteen to
20% of the infants developing hypoxic ischemic encephalopathy
will die. Another quarter of the surviving children develop chronic
neurologic deficits such as cerebral palsy.65,66 When a hypoxic
ischemic insult occurs, an evolving process is started characterized
by an initial primary injury followed by a self-sustaining cascade
of events that lead to additional brain injury.67,68 The brain damage
is produced by apoptotic and necrotic processes.69,70 The initiation
of excitotoxicity by excess neurotransmitter release causes receptor
overstimulation and cell death. Up to date, cooling is the only
intervention that has been proved to be effective in many models
of in vivo hypoxic-ischemic injury as well as in clinical trials with
either selective head cooling or systemic hyperthermia.7176 Studies
such as the Cool Cap Study showed significant benefits of the
treatment with mild hypothermia (3435C) in children suffering
from mild to moderate perinatal hypoxic ischemia.77
NMDA receptor antagonists have long been believed to possess
neuroprotective efficacy. In neuronal cell cultures as well as in an
in vivo mouse model, the effect of xenon on neuronal injury was
tested against nitrogen.60 Xenon at a concentration of 60% reduced
lactate dehydrogenase release as a measure of cell integrity to
baseline values. Consequently, in vivo xenon reduced injury by
45% at a concentration of 75% in a concentration-dependent
manner. This effect is in contrast to other NMDA antagonists that
have been proposed to exert neuroprotective effects. In preclinical
studies, these drugs clearly reduced neuronal injury. When tested
clinically, unfortunately, these promising results could not be
translated into significant clinical effects.78,79 NMDA antagonists
such as ketamine or MK801 have been shown to possess inherent
neurotoxic effects, to produce effects at receptors or channels
different from the NMDA receptor, thus provoking side effects,
or to not reach the site of injury because of their difficulties in
crossing the blood-brain barrier.80,81 Xenon readily crosses the

blood-brain barrier, thus reaching a potential site of injury quickly
and has been demonstrated not to exert neurotoxic effects.
In a rat model mimicking hypoxic-ischemic effects in newborns possibly continuing after delivery, xenon was administered
to 7-day-old rats after they received a 90-minute unilateral carotid
ligation.82 In xenon-treated animals, short-term neuroprotection
demonstrated by histology was present compared with animals
treated with nitrogen. Accordingly, xenon was proposed to be an
effective treatment after perinatal hypoxia-ischemia. It was concluded that xenon is devoid of neurotoxic effects and with minimal other side effects, thus, presenting an ideal candidate for
treatment of brain injury after human perinatal asphyxia.
Xenon also induces preconditioning in neuronal tissues, thus,
preventing damage when administered before an injury occurs.83
This preconditioning action of xenon has been demonstrated in in
vitro as well as in vivo models of neonatal asphyxia. These actions
of xenon have been demonstrated to occur because prosurvival
proteins are up-regulated83 (Figure 223).
Because xenon as a therapeutic treatment is very expensive and
delivery systems for it are not widely available, a better mode of
action of delivering xenon to newborns suffering from hypoxicischemic injury might be to first administer hypothermia and, in
a second step, add xenon during the therapy.84 It has been demonstrated recently that this type of asynchronous administration
of xenon and hypothermia can also significantly reduce the
hypoxic-ischemic injury in neonatal rats.84 Asynchronous administration of xenon and hypothermia at intervals of 1 and 5 hours
significantly reduced cerebral infarctions in a rat model of hypoxic
Neuronal survival
Figure 22-3. Suggested model of xenon-induced neuroprotection. After activation of protein kinase C (PKC) by xenon
mitogen-activated protein (MAP), mitogen-activated kinases
(MAPKs) such as p38 MAPK and extracellular signalrelated
kinase (ERK) are phosphorylated. Subsequently, cyclic adenosine monophosphate response elementbinding protein (CREB)
is phosphorylated into pCREB and induces several survival
genes via CREB-binding protein (CPB). Thus, the proteins
brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 protein (Bcl-2) are generated, enhancing cellular
tolerance to hypoxic/ischemic injury. Through activation of
Ras, MAPKs are stimulated and thereby increase the protection
pathway. Adapted from reference 83.
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In order to determine possible adverse effects of a long-term
exposure to xenon, dogs were exposed to 80 vol% xenon in oxygen
every third day for 2 weeks.94 At the end of the study, no side
effects of xenon such as morphologic, hematologic, or biochemical
parameters were found. By contrast to a long-term exposure to
nitrous oxide after xenon, no effects were noted on methionine
synthetase and vitamin B12 metabolism.
ECONOMIC AND ECOLOGIC ASPECTS
Figure 22-4. Global pathology scores for xenon- and/or

hypothermia-treated rats 10 weeks after hypoxic/ischemic brain
injury. The score was assessed from HE-stained brain sections
and injury was graded from 0 to 4 (mean sem). The combination of xenon and hypothermia results in additive protection
against hypoxic/ischemic injury that is greater than the effects
of either treatment by itself. Adapted from reference 85.
ischemia.84 Recently, it was demonstrated that the combination
of xenon and hypothermia conferred greater protection after
hypoxic-ischemic injury than either treatment alone. Functional
improvement was almost complete and was sustained long term85
(Figure 224).
General anesthetics have been demonstrated to alter synaptic
function by modulating specific ligand-gated ion channels such
as the GABAA receptor and the NMDA subtype of the glutamate
receptor.86 It has been postulated that the synaptic actions of
general anesthetics may have long-term consequences, especially
in the developing brain. The changes in neuronal tissues brought
about by general anesthetics have been demonstrated to be very
similar in morphology and functional impairments to the effects
of alcohol.8789 Xenon not only does not affect neurodegeneration
but also even exerts effects against apoptosis induced by general
anesthetics such as isoflurane. This was demonstrated in both an
in vitro and an in vivo model. During late fetal and early postnatal
life, there is an extremely rapid turnover of synapses with a high
level of physiologically occurring apoptosis.90,91 Exposure of
neonatal rats to general anesthetics produces an up to 50-fold
increase in the number of neurons degenerating and- these changes are also associated with the functional neurologic deficits
when tested in behavioral tests in later life.92
TERATOGENIC AND TOXIC EFFECTS

In a study comparing the teratogenic effects of nitrous oxide and
xenon, pregnant rats were exposed to either 70 vol% nitrous oxide
or xenon in 30 vol% oxygen.93 Twenty days after exposure, the
fetuses were evaluated for anomalies. The rats of the nitrous oxide
group showed a high rate of fetal absorption, skeletal anomalies,
and macroscopic anomalies such as encephalocele, anophthalmia,
microphthalmia, and gastroschisis of up to 37%. By contrast, in
the xenon group, only 3% anomalies were found. Thus, it may be
concluded that xenon does not exert teratogenic effects when
compared with nitrous oxide.93
Because of its rarity, xenon is relatively expensive. Consequently,

many projects are under way to reduce the amount of xenon
needed for anesthesia. The use of closed systems in anesthesia
machines like the Physioflex (Draeger, Luebeck, Germany) allows
a saving of more than half of the xenon compared with its use
in standard anesthesia machines. By connecting the anesthesia
machine to a scavenging device, a major fraction of the delivered
xenon may be recovered. Unfortunately, no xenon scavenger systems are for sale at the moment. It may be possible that systems
based on molecular sieves will become available in the near future.
Medicolegal issues prohibit the direct reuse of the recycled gas. The
captured xenon needs to be transferred to the manufacturer to be
cleaned and purified before it can be used on another patient. It
will depend on the manufacturers if this setup makes sense
economically. In the not too distant future, however, the use of
xenon may not be confined to only some highly specialized centers.
SUMMARY
As reflected by recent publications, hemodynamic stability of
xenon in adults may not be as superior as previously thought, and
data in the pediatric population are missing. Neuroprotection is an
important issue, especially in the prevention and therapy of
neonatal hypoxic-ischemic brain injury. The initial findings look
promising, although further clinical studies are necessary. Widespread use of xenon is critically dependent on the availability of
adequate anesthesia machines and possibly scavenging systems.
At present, xenon has not been approved for anesthesia in
children; rather, it has been registered for anesthesia only in adults
and more clinical studies in children are necessary to determine
whether the beneficial properties seen in adults such as rapid
induction and emergence as well as a relative lack of adverse effects
will also be obtainable in neonates and children.
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23
Intravenous Agents
Peter D. Booker and Neroli Chadderton
INTRODUCTION
Infants and young children are not merely small versions of adults
but are immature individuals in a continuous state of anatomic
and physiologic development. Hence, drug dosage schedules
determined in adults cannot necessarily be safely transferred to
children. Similarly, information about the pharmacology of intravenous anesthetic drugs obtained from studies in healthy children
cannot usually be extrapolated to critically ill infants.
Pharmacologic studies tend to examine the effects of giving a
single drug to an individual, whereas in clinical practice, this is
unusual, because drug combinations are commonly employed.
Co-administration of interacting drugs may make it possible to
use lower doses of each individual drug and so reduce the incidence of undesirable side effects. Studies of drug interactions in
anesthesia have revealed that the mechanism can be pharmacokinetic as well as pharmacodynamic. The nature of the interaction
may differ according to the end point studied, because the various
effects produced by one or more drugs are propagated through
many different receptor complexes at different sites within the
central nervous system (CNS).
The pharmacology of individual drugs used in pediatric
anesthesia can be discussed sensibly only once the most important
differences between infants, children, and adults affecting their
response to intravenous drug administration have been fully
understood. For the purposes of this chapter, a neonate has a postconceptional age of between 38 and 44 weeks, an infant is between
1 and 12 months of age, and a child is between 1 year of age and
puberty. Although these age groupings represent convenient labels
for comparative purposes, their validity and clinical application
are open to criticism, because physiologic maturation and development of vital organ function is a continuous and uninterrupted
process. Nevertheless, in general, it may be assumed that pharmacologic maturation takes place within the first year of life, though
this does not imply that children older than 1 year should be given
a weight-related adult dose of drug. The dosage of many anesthetic
drugs, when related to body weight, may need to be higher in
young children than in adults.
Since the beginning of the 2000s, marked improvements have
been seen, first, in our understanding of the pharmacokinetics of
intravenous drugs in the very young and, second, in the influence
of pharmacogenomics on hepatic metabolism and drug receptors.
From birth onward, changes in drug pharmacokinetics occur as a
consequence of organ maturation, changes in body composition,
and the ontogeny of drug elimination pathways. Traditionally,
we have used body weight or body surface area to adjust
pharmacokinetic parameters to body size. However, these linear
C H A P T E R
weight models are inappropriate for scaling infants and children to

adults because there is a nonlinear relationship between weight and
drug elimination capacity. Drug clearance in the very young is often
determined by the activity of the relevant hepatic cytochrome P450
(CYP) enzyme; hence, the continuing efforts to determine the
postnatal age when each CYP isoform attains adult levels.
The purpose of this chapter is to outline the main age-related
factors that influence drug pharmacokinetics and pharmacodynamics and to review the pharmacology of intravenous drugs
commonly used to induce and maintain anesthesia in infants and
children.
DEVELOPMENTAL FACTORS
AFFECTING DRUG DISTRIBUTION
Anesthetic drugs exert their effects by binding reversibly to
various receptor proteins such as ion channels and/or intracellular
proteins. However, before a drug can exert an effect, it must pass
from its site of administration and reach its site(s) of action.
Plasma concentrations of drug do not always relate to clinical
effect, because drug plasma concentration does not necessarily
correlate with concentration of drug near the receptor. This is
because a drug molecule given intravenously must cross several
phospholipid membranes to reach its receptor. Small molecules
tend to cross membranes more rapidly than large ones, but a
highly ionized molecule, whatever its size, will be unable to cross
passively through a lipid membrane and will have to use active or
facilitated transport mechanisms. In contrast, lipid-soluble drugs,
which are mostly un-ionized at physiologic pH, can cross lipid
membranes in significant quantities by passive diffusion downconcentration gradients. The degree of drug ionization depends
on the dissociation constant (Ka) of the drug and on the local pH.
Most intravenous anesthetic drugs are weak bases (B) that combine with hydrogen ions in solution to form a charged molecule:
B + H+ BH+
The equilibrium will shift to the right in an acid pH. When the
local pH equals the pKa of the drug, 50% of the drug will be
ionized. Hence, small changes in pH can affect the distribution of
a drug with a pKa close to 7.4. The degree of ionization is only one
of many physicochemical factors affecting the ability of a drug to
passively diffuse through lipid membranes. The relative solubility
of drug in blood and tissue, the blood-tissue partition coefficient,
is another individual drug constant that can be assessed in vitro
by measuring drug solubility in organic and aqueous solvents.
These physicochemical factors may vary between and within
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tissues, but they are unaffected by a patients age or maturity.

However, other important factors influencing anesthetic drug
distribution are subject to developmental change. These include
regional tissue perfusion, permeability of the blood-brain barrier
(BBB), the relative size of body compartments into which the drug
is distributed, and the degree of protein binding.
Regional Blood Flow

The initial phase of distribution reflects regional blood flow.
Hence, a major determinant of drug distribution is cardiac output
and how it is distributed to the various tissues of the body. Indexing cardiac output to body surface area rather than weight provides a reasonable means of comparing grouped data. The
1-month-old infant has a cardiac index of about 2.6 L/min/m2,
which increases to 3.2 L/min/m2 by 1 year of age and 4.0 L/min/m2
by 2 to 15 years.1,2
Organs that are well-perfused, such as brain, heart, and liver,
are the tissues first exposed to the drug. The second phase of
distribution involves other relatively well-perfused tissues such as
skeletal muscle, with much slower tertiary distribution to relatively
underperfused tissues of the body usually assuming importance
only with long-term drug infusions. Acute changes in the neonatal
circulation that affect organ blood flow take place in the first few
days and weeks after birth, secondary to functional closure of the
ductus venosus and ductus arteriosus. In addition, differences in
relative organ mass and regional blood flow change with growth
and development during the first few months of life. Renal and
hepatic blood flows achieve adult levels by about 12 months of age.
The most important differences in regional perfusion between
neonate, child, and adult are illustrated in Figure 231.
Although cerebral mass as a proportion of body weight is much
higher in the infant than in the adult, mean cerebral blood flow
per 100 g of brain tissue is similar in the neonate and in the adult
(50 mL/min).3 Mean cerebral blood flow increases during infancy
and early childhood to reach a peak of about 70 mL/min/100 g at
about 3 to 8 years of age.4 Recent studies using a magnetic resonance
continuous arterial spin labeling technique have confirmed that
cerebral blood flow subsequently decreases with age from early
childhood.5 Because highly lipophilic drugs in cerebral arterial
blood diffuse rapidly across the BBB to achieve concentration
Figure 23-1. Regional blood flow expressed as a percentage of

cardiac output (C.O.): changes with age. From reference 220.
equilibrium with brain tissue, the rate of entry of drug is determined

largely by cerebral blood flow. Hence, onset times for intravenous
anesthetic agents tend to be shorter in early childhood than in
neonates, adolescents, or adults.
Blood-Brain Barrier
The BBB allows precise control over the substances that leave or
enter the brain. An elaborate network of complex tight junctions
between specialized endothelial cells restricts the paracellular
diffusion of hydrophilic molecules. Transcellular passage of
molecules is inhibited by a lack of fenestrations and very low
pinocytic activity in the endothelial cells. Specific transport systems selectively expressed in the barrier endothelial cell membranes mediate the transport of nutrients into the CNS and of
toxic metabolites out of the CNS.
The permeability of the fetal BBB to large molecules is probably
very similar to that of the adult BBB. In contrast, small molecules
access fetal and neonatal brains more readily than they do adult
brains.6 BBB function does not suddenly increase at a certain
gestational age, but improves gradually throughout fetal brain
development. Although the bloodcerebrospinal fluid (CSF)
barrier and BBB are not identical, developmental changes in the
blood-CSF barrier probably reflect analogous changes in the BBB.
Two-month-old infants demonstrate CSF-to-plasma ratios of
fentanyl similar to those of older children, suggesting that by the
end of the neonatal period, BBB function approaches adult levels.7
The fully differentiated BBB consists of a complex system of
highly specialized endothelial cells, a large number of pericytes
embedded in the basal membrane, perivascular macrophages, and
astrocytic endfeet. Although endothelial cells form the barrier
proper, the interaction with adjacent cells is a prerequisite for
normal barrier function. Pathologic conditions within the CNS,
such as ischemia, inflammation, infection, or tumor, which change
the CNS microenvironment, are often accompanied by BBB
dysfunction.8 Hence, not only the development but also the maintenance of the BBB is tightly regulated by the permanent
interaction of endothelial cells with the neuroectoderm.
The tight intercellular junction is composed of various transmembranous proteins and represents the main barrier to passive
diffusion of drugs with low lipophilicity, protein macromolecules,
and smaller hydrophilic molecules such as glucose. In addition,
drug-metabolizing enzymes, such as CYP450 hemoproteins, and
transport systems, such as adenosine triphosphate (ATP)binding
cassette proteins, not only provide an enzymatic barrier to drug
entry but also promote drug efflux.8 Whereas drug bound to
plasma proteins will not normally cross the BBB, unbound lipophilic drugs passively diffuse across the BBB to achieve equilibrium very quickly. In addition, however, active transport of
lipophilic drugs across the BBB may occur in both directions.
Animal studies have shown that fentanyl is actively transported
across the BBB by a saturable ATP-dependent process that increases fentanyl uptake two- to threefold over that achieved by
simple diffusion alone.9 Furthermore, ATP-binding cassette proteins such as P-glycoprotein actively pump out opioids such as
fentanyl and morphine, reducing the tissuetoblood partition
ratio that would exist because of passive diffusion alone. PGlycoprotein modulation significantly influences opioid brain
distribution and onset time, magnitude, and duration of analgesic
response.10 Genetic polymorphisms affecting P-glycoprotein
related genes may explain some individual differences in CNS-
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Intravenous Agents 357
active drug sensitivity.11 Many different classes of drugs are

substrates for P-glycoprotein, including antidepressants, anticonvulsants, antibiotics, antiarrhythmics, antiemetics, opioids, and
steroids, but not propofol or midazolam.12 Developmental changes
in P-glycoprotein function have not been identified.
Body Water Content

Water constitutes about 80% by weight of a preterm and 75% of a
term newborn baby.13 After birth, total body water (TBW) decreases rapidly over the first month of life to about 65% of body
weight, and then more gradually to achieve adult proportions
(55%) by about 12 years of age (Figure 232).14 From adolescence
onward, females have a mean TBW of about 50% of their body
weight, compared with about 55% in males. These figures slowly
decline throughout adulthood to about 46% and 43% for men and
women, respectively, by 60 years of age.15
At equilibrium, ionized water-soluble drugs will be uniformly
distributed throughout the TBW and any changes in TBW will
have a significant effect on the distribution volume of water-soluble
drugs such as pancuronium. Conventionally, TBW is divided into
two discrete compartments: intracellular and extracellular fluid.
The former makes up about 35% of body weight at birth, but
quickly rises to 40% by 3 months of age. The proportion of body
weight contributed by intracellular water then falls in line with the
decrease in TBW until about 1 year of age, when it increases back
up again to the adult value of 40% by 4 years of age. In contrast, the
contribution of extracellular water to body weight decreases more
gradually from about 40% at birth to about 20% by 6 years of age.
Furthermore, the proportion of TBW found in each organ and the
relative size of intracellular and extracellular water in each organ
change with age.
Body Fat Content

In the term neonate, fat constitutes about 12% of body weight, the
proportion rapidly increasing to 30% by 3 to 6 months, before
Figure 23-3. Estimated change in fat content, expressed as a

percentage of body weight, during infancy and early childhood.
Data from reference 16, with permission.
gradually declining to 25% by 2 years of age (Figure 233).16
Gender differences in fat content become significant only just
before and during puberty. By 11 years of age, fat still constitutes
about 25% of body weight in girls, whereas it declines to about
22% in boys.17 However, more than 10% of children in developed
countries have a fat content more than 25% in excess of these
reference figures.18
Superimposed upon these overall changes in fat content is the
disproportionate growth of different organs. The CNS in the
neonate constitutes a higher proportion of body weight and has a
higher proportion of fat than in the adult. These developmental
changes in body and organ lipid content have obvious implications
for the apparent volume of distribution for highly lipid-soluble
drugs such as propofol. Moreover, any increase in adipose tissue,
which is often relatively poorly perfused, increases the potential
for producing a reservoir of drug, which diffuses back into the
circulation along concentration gradients after drug administration has ceased.
Protein Binding
Figure 23-2. Total body water as a percentage of body weight:

changes during childhood. Data from reference 14, with
permission.
The low inherent solubility of highly lipophilic drugs in plasma

water makes reversible protein binding essential for their transport
in plasma, but only the unbound moiety can readily diffuse across
biologic membranes to reach receptor sites or be eliminated from
the body. Alterations in the degree of protein binding affect the
apparent volume of distribution of certain drugs. Although
albumin has a greater binding capacity than 1-acid glycoprotein
(AAG), AAG has a much greater drug affinity, particularly for
weakly basic drugs. Neonates and young infants may have relatively low concentrations of albumin and AAG.19 However, plasma
protein binding is rarely of clinical significance even when drugs
are extensively bound, because any concentration gradient that
encourages passive diffusion of unbound drug from plasma to
tissue also results in dissociation of protein-bound drug. Hence, as
the total drug concentration in plasma decreases, the concentration of unbound drug tends to stay constant. Similarly, drug
dissociation from binding to plasma proteins is so fast that hepatic clearance and glomerular filtration of drugs are relatively
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insensitive to changes in the concentrations of plasma proteins.

However, low concentrations of binding proteins may become
clinically relevant if a fast injection of an extensively bound drug
is given at high dose, when pharmacodynamic effects may
be transiently greater than would otherwise be expected. For
instance, the induction dose of thiopental is significantly lower in
neonates than in older age groups and one of the reasons for this
may relate to decreased binding of thiopental to plasma albumin;
13% of the drug is unbound in newborns, 7% in adults.20 This
difference may be caused by competitive binding of available
receptor binding sites by bilirubin and/or structural differences
between adult and fetal albumin.21
DEVELOPMENTAL FACTORS
AFFECTING DRUG ELIMINATION
Metabolism and excretion together constitute the bodys mechanisms for elimination of drugs, and both processes demonstrate
marked age-related variation.
Hepatic Metabolism
Most anesthetic drugs are lipophilic compounds dependent on
biotransformation to more water-soluble metabolites for elimination from the body. The principal site for drug metabolism is in
the liver, where complex groups of enzymes are concentrated in the
membranes of hepatocyte endoplasmic reticulum. The numerous
biotransformation reactions are conventionally classified into two
main types, phase I and phase II, which often occur sequentially.
Phase I reactions convert by oxidation, reduction, or hydrolysis,
the parent drug to a more polar metabolite by introducing or
revealing a functional group such as a hydroxyl or ammonium
radical. Some phase I metabolites are renally excreted, whereas
others may then undergo a phase II conjugation reaction. Phase II
conjugation reactions include glucuronidation, methylation, and
sulphation, which serve to increase further the polarity of a
metabolite and promote its water solubility and renal excretion.
Many microsomal enzymes are polymorphically expressed and
subject to considerable variability in activity during development.
The CYP450 enzymes are quantitatively the most important
hepatic microsomal oxidative enzymes. The oxidative biotransformation of drugs involves multiple hepatic P450 enzymes that have
distinct substrate specificities and maturational sequences, which
result in varying rates of maturation of drug metabolism. The rate
of P450-mediated drug clearance cannot be extrapolated from
body weight adjustments or from data on P450 expression and
regulation in adults. Prediction of drug clearance in the very
young depends largely on determining when the activity of the
relevant CYP isoforms attains adult levels. Unfortunately, different
studies on the same CYP isoform often give very divergent results.
The CYP3A subfamily is the most abundant group of CYP
enzymes in the human liver and is involved in the metabolism of
many anesthetic drugs, including midazolam, alfentanil, fentanyl,
and propofol. Of its three isoforms, CYP3A4 is by far the most
important for postnatal drug metabolism and composes up to 50%
of total hepatic P450 enzyme activity in the adult.22 CYP3A5 is
found in the kidney, lungs, and liver, and its expression shows
great individual and ethnic variation, though it is generally
independent of age.22 CYP3A7 predominates in the liver before
birth and is gradually (but not totally) replaced by CYP3A4 during
the first few months of life. The catalytic activity of CYP3A7 is
lower than that of CYP3A4 by about two orders of magnitude.23

CYP3A4 protein concentrations increase only gradually during
the first 6 months of age. It has been suggested that the CYP3A4
activity achieves adult levels by 4 years of age,23 however others
have shown that activity may remain significantly lower than adult
levels even at 5 years of age.22
The CYP2C subfamily accounts for about 18% of the total adult
CYP450 content and is responsible for the metabolism of several
important anesthetic drugs, including non-steroidal anti-inflammatory drugs, diazepam, and probably, thiopental.24 In the fetus,
CYP2C19 activity predominates, whereas postnatally, CYP2C9 is
the principal enzyme. Fetal studies show progressive increases in
CYP2C9 activity during the second and third trimesters, to reach
levels about 30% of mature values at term. Postnatally, CYP2C9
expression is highly varied, suggesting that differences in developmental factors may have a genetic component. In about 50% of
individuals, adult levels are reached by 5 months of age, the remainder taking up to 18 years. CYP2C19 activity remains at about
18% of mature values during fetal and early neonatal life, irrespective of gestational age. Median CYP2C19 activity reaches
about 38% of adult values within 1 to 5 months of age but, thereafter, is highly variable, consistent with differences in developmental factors having a genetic component.
The CYP2B6 subfamily, one of the minor P450 enzymes, is
expressed in human liver and some extrahepatic tissues. The
number of substrates that are partially or completely metabolized
by CYP2B6 includes alfentanil, ketamine, and propofol. Interindividual variation in CYP2B6 activity may exceed 100-fold;
significant factors in this variation include gender, ethnicity, and
postnatal age. The potential for substantial individual differences
in the pharmacodynamics of drugs that are metabolized by
CYP2B6 are obvious.
Several enzymes involved in phase II conjugation reactions are
subject to substantial developmental and interindividual variation.
The uridine 5-diphosphate glucuronosyltransferase (UGT)
superfamily of enzymes is divided into the UGT1A and UGT2B
subfamilies, which contain nine and seven isoforms, respectively.
In general, activity of UGT isoforms is low in the neonate and
increase to adult values throughout infancy and early childhood.
Each of the 16 different isoforms achieves adult levels of activity at
different ages. For instance, UGT1A4 activity reaches adult values
at 1.4 years of age,25 whereas UGT1A6 activity does not reach adult
values until about 10 years.26 Given this wide variety of UGT1A
isoform maturation, prediction of how developmental influences
will affect a specific isoform is impossible without the relevant
clinical data.
Hepatic drug clearance is a function not only of microsomal
metabolic activity but also of hepatic blood flow. Hepatic blood
flow will influence the hepatic clearance of a drug differently if
metabolic activity is low or high. For drugs with a high intrinsic
hepatic clearance, overall changes in hepatic clearance will be
proportional to changes in liver blood flow. In contrast, changes in
enzyme activity such as occur during maturation will influence
hepatic clearance only if the drug has a low intrinsic clearance,
whereas highly extracted drugs, such as propofol, will be essentially unaffected.
Extrahepatic Metabolism
Important drug biotransformations also take place outside
the liver. Many P450 enzymes, including CYP3A4, CYP2C, and
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CYP2B, and phase II enzymes, including many UGT isoforms, are
found in intestinal mucosal cells, renal microsomes, and lung
parenchymal cells, though they usually contribute less than 20%
toward total body metabolic activity. Other important extrahepatic
drug biotransformations include esterase reactions in plasma and
many other tissues. Nonspecific esterase activity may be reduced
in neonates, though this does not appear to significantly compromise metabolism of drugs such as remifentanil.27 Furthermore,
remifentanil that crosses the placenta is rapidly metabolized by
the term newborn.28
Renal Excretion
Renal excretion of drugs and their metabolites may be necessary
to avoid the potential toxicity associated with accumulation of
these compounds. However, highly lipophilic drugs are usually
only partially ionized at physiologic pH and may also be bound
to plasma proteins. These drugs are not readily filtered at the
glomerulus. The lipophilic nature of renal tubular membranes also
facilitates the re-absorption of hydrophobic compounds following
glomerular filtration. Thus, the termination of action of anesthetic
drugs never depends solely on renal excretion. Nevertheless, the
kidney is a major route of elimination not only for water-soluble
drugs but also for water-soluble metabolites of lipophilic drugs.
The two basic processes involved in the renal elimination of drugs
are glomerular filtration and tubular excretion.
The glomerular filtration rate (GFR) of term neonates at birth,
when indexed to their surface area, is about 10% that of the adult,
but it increases rapidly in the early postnatal period, rising to 100%
of the figure expected for size by 1 year of age. The maturational
changes in GFR are caused by a combination of increasing systemic arterial blood pressure and decreasing renal vascular resistance. Furthermore, the porosity of the glomerular membrane and
the area available for filtration increase as glomeruli differentiate
morphologically. Changes in the intrarenal distribution of blood
may also lead an increase in GFR, as blood flow to the outer cortex
is enhanced compared with flow to the inner cortex and medulla.
This developmental change in GFR increases the clearance of
drugs and metabolites eliminated by filtration, such as glycopyrrolate. Hence, as would be expected, no significant age-dependent
differences in glycopyrrolate clearance occur after the age of
6 months.29 Similarly, tubular function in the neonate is relatively
poor but improves dramatically as renal mass and renal blood flow
increase. Proximal tubular secretion assumes adult values by about
6 months of age. The glucuronide metabolites of drugs such as
morphine and propofol are dependent on proximal tubular
secretion for their elimination.
Renal metabolism of certain anesthetic drugs, such as propofol,
can be clinically significant (see Pharmacology of individual
drugs). Renal propofol clearance is not linked to GFR, but limited
by renal blood flow; developmental influences on this important
extrahepatic metabolic pathway are unknown.
GENERAL FACTORS AFFECTING

DRUG PHARMACOKINETICS
Certain pathophysiologic factors may have a significant influence
on drug distribution and/or elimination and, although they are
not subject to developmental influence, may occur more frequently in pediatric than in adult anesthetic practice.
Hypovolemia and Hypotension

Hypovolemia and/or hypotension will result in reduced tissue
perfusion that can have profound effects on drug pharmacokinetics. The distribution of drugs between the blood and the
poorly perfused tissues will be restricted, which may result in
greater relative distribution to those tissues such as the brain
whose perfusion is maintained. Conversely, sick neonates may
have impaired cerebral autoregulation, such that systemic hypotension may result in subnormal cerebral blood flow and, hence,
reduced uptake of lipophilic drugs. In hypotensive children, drug
may become sequestered in poorly perfused fat, only to return to
the vascular compartment when perfusion is restored to normal.
If hepatic blood flow is significantly reduced, elimination of drugs
that have a high intrinsic hepatic clearance, such as propofol, may
be compromised. However, lipophilic drugs are not the only type
of drug to be affected by hypoperfusion. If renal perfusion is
reduced, elimination of water-soluble drug and/or metabolites
may be significantly compromised.
Hypoxia
Hypoxia can cause renal arteriolar vasoconstriction, which
adversely affects both glomerular and tubular function. Similarly,
decreased microsomal concentrations of CYP450 enzyme systems
may follow birth asphyxia. Experimental studies examining the
effects of hypoxia on the hepatic metabolism of certain drugs have
produced conflicting results. The limited clinical data that are
available suggest that water-soluble drug elimination in infants
with cyanotic congenital heart disease is not significantly different
from that in a matched acyanotic group.30
Hypothermia
Hypothermia is commonly induced during cardiac surgery and
used as a neuroprotective therapy after brain injury; hence, the
effects of temperature on drug pharmacokinetics can have important clinical significance. Many clinical studies have shown that
cardiopulmonary bypass utilizing profound hypothermia (18
24C) significantly decreases clearance of certain lipophilic drugs
such as fentanyl.31 However, hypothermia is just one of several
factors that have the potential to reduce drug clearance, so pharmacokinetic interpretation of bypass studies is highly problematic.32 Neonates treated with mild hypothermia (3334C) for
perinatal asphyxia were shown to have a reduced morphine
clearance compared with a normothermic control group.33 Similar
studies in hypothermic brain-injured adults have confirmed that
even mild hypothermia (3435C) results in a marked decrease
in midazolam clearance, presumably owing to depressed CYP3A4/
5 activity.34 Reduced blood and tissue esterase activity secondary
to hypothermia causes a 20% decrease in remifentanil clearance.35
Therapeutic hypothermia not only affects drug disposition
by affecting enzymatic function but may also have effects on
regional blood flow and drug pharmacodynamics. Experimental
studies have demonstrated that depressed metabolic activity
occurs during fentanyl and propofol infusions in hypothermic animals, even after controlling for hypothermia effects on
hepatic blood flow.34 Recent in vitro studies suggest that mild
hypothermia (32C) may suppress P-glycoprotein drug transport
across the BBB.36
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Cardiopulmonary Bypass
The institution of cardiopulmonary bypass (CPB) has profound
effects on the plasma concentration of drugs. These changes occur
secondary to a combination of factors, including acute hemodilution, altered plasma protein binding, hypotension, hypothermia,
use of heparin, lung isolation, and sequestration on the surfaces of
the bypass circuit. Onset of CPB causes an immediate and substantial decrease in the plasma concentration of both water-soluble
and lipophilic drugs owing to hemodilution. The decrease in total
drug concentration is particularly large with fentanyl, alfentanil,
and thiopental, in which a significant proportion of drug undergoes hydrophobic binding to the extracorporeal circuit.32 Hemodilution of plasma proteins would be expected to affect the protein
binding of highly bound drugs such as alfentanil, midazolam, and
propofol. Propofol has been extensively studied in this respect: a
twofold increase in its free fraction and relatively unchanged total
plasma concentration during CPB were demonstrated, consistent
with theoretical predictions.37 Propofol pharmacodynamics during CPB, as assessed using the bispectral index (BIS), are consistent with this increase in unbound fraction.38 Similarly, many
highly lipophilic opioids with a high apparent volume of distribution maintain relatively stable total drug concentrations during
initiation of CPB, because their rapid re-equilibration minimizes
any dilutional effect.
Acid-base balance and Arterial

Carbon Dioxide Pressure
Alterations in blood pH lead to significant changes in the degree
of ionization of drugs with a pKa close to physiologic pH. For
instance, 61% of thiopental is un-ionized at a pH of 7.4, whereas
at a pH of 7.1, 76% of the drug is un-ionized. This decrease in
ionization of thiopental alters its tissue distribution and increases
its apparent volume of distribution. More important, acidosis
increases the potency of thiopental and accentuates the druginduced depression in myocardial contractility.39
Drugs with very high lipid solubility tend to have cerebral
venous concentrations less than 50% of arterial concentrations
after a single passage through the brain because of rapid uptake
across the BBB. Hence, the rate of lipophilic drug entry is largely
determined by cerebral blood flow. Perturbations in arterial
carbon dioxide pressure (PaCO2) that cause significant alterations
in global and regional cerebral blood flow will affect the uptake
and distribution of many anesthetic drugs in the brain.
DRUG-RECEPTOR INTERACTIONS
The existence of specific drug receptors implies the existence of
endogenous ligands that exert their normal physiologic action by
binding to these receptors, as occurs with opioids and benzodiazepines. The affinity of the drug molecule for the receptor and the
proportion of receptors occupied determine the relative potency
of a drug at its site of action. However, it is not necessary for all
receptors to be occupied to obtain maximum effect, as a large
proportion of receptors can be spare. The formation of a drugreceptor complex leads to the production of a pharmacologic
signal that may initiate a further cascade of physicochemical
reactions before a measurable response is produced. The total
number of receptors in a given volume of tissue varies in response
to the presence of an agonist or antagonist and such downregulation may explain opioid tolerance.
Human and animal experimental studies have confirmed that
significant change in receptor binding, density, and initiation of
secondary messenger systems can occur during development.
Postmortem human experimental studies, using quantitative
tissue autoradiography techniques with radioligands for opioid
receptors, have shown that, although opioid receptor affinity does
not change during development, opioid receptor distribution
and binding capacities show significant variation with postnatal
age.40,41 In addition, animal experiments have suggested that
benzodiazepine binding sites not only may show quantitative and
qualitative age-related changes but also are distributed within the
brain differently in the term neonate than in the adult.42
PHARMACOLOGY OF
INDIVIDUAL DRUGS
This section does not attempt to be all-inclusive and is restricted
to discussing only those intravenous drugs that are commonly
used in current pediatric anesthetic practice to induce or maintain
anesthesia.
Propofol
In developed countries, propofol is now the most commonly used
intravenous induction agent. In addition, it has found widespread
application in the maintenance of anesthesia, total intravenous
anesthetic techniques, and sedation, reflecting its generally favorable pharmacokinetic and pharmacodynamic properties.
Propofol (2,6-di-isopropyl phenol) is a phenol derivative. It is
almost completely insoluble in water and is supplied as an isotonic
emulsion, formulated in 1.2% purified egg lecithin, 10% soybean
oil, and 2.25% glycerol. This lipid carrier supports bacterial and
yeast growth, so newer formulations contain antimicrobial agents
such as ethylenediaminetetraacetic acid (EDTA), metabisulfite, or
benzyl alcohol to retard growth of microorganisms. Nevertheless,
when drawing up propofol in advance of a case, an aseptic technique is advised.
Pharmacokinetics
Propofol is highly lipid soluble, rapidly reaching effect sites in the
CNS. This is reflected by a rapid onset of action with loss of
consciousness seen within one arm-brain circulation time following bolus injection. The pharmacokinetics of propofol is most
commonly described using a three-compartment model: a large
central compartment, a (lean) peripheral compartment that is
relatively well-perfused, and a deep peripheral (fat) compartment
that has limited perfusion. The central compartment models
plasma concentrations of propofol. The size of this compartment
parallels developmental changes in blood volume and plasma
protein levels, and in children, the central compartment is nearly
twice the size of that in adults on a per-kilogram basis.43 This larger
volume of distribution explains why small children require higher
infusion rates than adults to maintain the same blood concentrations of propofol. The central compartment is rapidly cleared by
redistribution to peripheral compartments, so that the arterial
blood concentration of propofol starts to decrease about 1 minute
after bolus injection. Termination of drug effect occurs primarily
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changes in CYP2B6 activity are relatively insignificant compared

with the 100-fold inter-individual differences demonstrable
throughout life (see Hepatic Metabolism). Propofol glucuronidation is catalyzed by UGT1A9; no data exist to determine
developmental changes in this specific isoform. Nevertheless, it is
unsurprising that median propofol clearance in neonates is only
442 mL/min/70 kg, compared with values of 1957 mL/min/70 kg
in 1- to 3-year-old children, 1479 mL/min/70 kg in 4- to 7-yearold children, and 1827 mL/min/70 kg in adults.53,54 It should be
noted that these (median) values hide a very wide interindividual
variation; for instance, propofol clearance varies more than 300%
in the neonatal period, making age-related changes seem almost
trivial by comparison.55
Pharmacodynamics
Figure 23-4. Context sensitive half-times (CSHTs) for propofol
and remifentanil: changes with age. Data from references 45 and
because of this redistribution, although metabolism of drug in the
central compartment also contributes, albeit at a slower rate.
The peripheral fat compartments act as reservoirs for propofol.
Hence, the volume of distribution and context-sensitive half-time
(CSHT) of propofol are significantly greater in obese than in
nonobese patients.44 Similarly, in children aged 0.6 to 2 years, who
have proportionally greater fat content as a percentage of body
weight than adults, these peripheral compartments contain a large
quantity of propofol following prolonged infusions.45 Redistribution of propofol from the peripheral fat compartments to the
central compartment occurs once concentrations in the central
compartment fall below those in the peripheral compartments. In
young and critically ill children, redistribution from the peripheral
fat compartment is relatively slow and elimination of propofol
from the body may take many hours.46 These factors explain the
slower recovery and longer CSHT seen in the young child having
a prolonged infusion (Figure 234).47
The liver is the principal site of propofol metabolism. Because
propofol has an extraction ratio of about 0.9, metabolism is
dependent on hepatic blood flow; reduced metabolic clearance is
seen in children with low cardiac output.46 Approximately 53% of
injected propofol is excreted in urine as the glucuronide and 38%
as hydroxylated metabolites.48 Recent studies have demonstrated
that metabolic clearance by the kidney accounts for about 27% of
the total body clearance of propofol, owing to glucuronidation by
UGT1A9 found in renal cortical microsomes.49,50 A similar proportion of propofol is converted to the glucuronide by UGT1A9 in
hepatic microsomes. The hydroxylated metabolites are produced
mainly by CYP2B6, with some contribution from CYP2C9 activity, in hepatic microsomes; activity of renal CYP2B6 and CYP2C9
is insignificant.48 About 0.3% of propofol is excreted unchanged
in urine.
Clearance of propofol in children changes with postnatal age
and reflects maturation of CYP2B6 and UGT1A9 enzyme activity.
Developmental changes affecting CYP2B6 activity have not been
studied in detail, but sparse existing data suggest that infants
younger than 10 months old have enzyme activity only about 14%
of those aged 2 years and older.51 On the basis of available clinical
data, it has been predicted that 50% of adult activity should be
achieved by 1.3 years of age.52 Nonetheless, these developmental
The hypnotic actions of propofol result from its interaction with

the gamma-aminobutyric acid (GABA) A receptor.56 The GABAA
receptor is a major mediator of rapid synaptic inhibition in the
brain. Binding of propofol to the GABAA receptor results in
an influx of chloride ions, leading to hyperpolarization of the
neuron: in consequence, the neuron becomes unresponsive to
external stimuli. Propofol also influences presynaptic mechanisms
of GABAergic transmission, because a high concentration of
neurotransmitter-gated ion channels is a prerequisite for rapid
presynaptic transmission.57
The mean dose required for easy insertion of a laryngeal mask
airway in 50% of unpremedicated children (312 y old) is 3.8 mg/
kg, significantly higher than that for adults (2.4 mg/kg).58,59
Premedication with midazolam, or pretreatment with a shortacting opioid, reduces mean dosage requirement by at least 30% in
all age groups.58,60 Similarly, infusion rates for maintenance of
anesthesia and sedation with propofol are about 50% greater in
children than in adults.47,61
There are, however, conflicting data on whether children
require higher plasma concentrations than adults in order to
achieve a comparable anesthetic endpoint. In a study by Munoz
and colleagues, anesthesia was titrated to a BIS value of 50 and the
effect site concentration of propofol was calculated for both adult
and pediatric subjects.62 They found the predicted effect-site
concentration for children was 3.65 g/mL, not significantly
different from that of 3.75 g/mL for adults. In a comparable study
by Rigouzzo and coworkers, in which anesthesia during surgery
was titrated to a BIS of 50, the measured plasma propofol concentration was significantly higher in children than adults (4.3
1.1 g/mL vs 3.4 1.2 g/mL).63 Similarly, studies assessing
adequate depth of anesthesia based on clinical parameters found
the median effective dose (EC50) for propofol was greater in
children than in adults.64,65 In contrast, one study using auditory
evoked potentials as a measure of the depth of hypnosis found that
the predicted effect-site concentration of 3.56 g/mL for children
was much less than that predicted for adults (6.45 g/mL).66 It is
likely that the differences in the pharmacokinetic models used to
calculate the effect-site and plasma concentrations account for the
discrepancies observed.
Following an induction dose of propofol, mean arterial pressure (MAP) is reduced by 15 to 30% in healthy children, caused
mostly by a reduction in systemic vascular resistance (SVR).6769
This decrease in SVR is caused by a combination of a reduction
in sympathetic activity and smooth muscle relaxation. Animal
studies have suggested that propofol activates sarcolemmal
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ATP- and calcium-sensitive potassium channels in arteriolar

smooth muscle cells, causing closure of voltage-gated calcium
channels and subsequent small vessel vasorelaxation. Propofol
may also enhance the activity of endothelial nitric oxide synthase
(NOS) and the related cyclic guanosine monophosphate (cGMP)
pathway, hence promoting local nitric oxide (NO) release.70
Propofol does not reduce pulmonary vascular resistance or
pulmonary artery pressure.68 In children with congenital heart
disease, the combination of these hemodynamic changes may alter
the direction and magnitude of intracardiac shunts.
A fall in heart rate of up to 20% may also be observed after
propofol administration,67 although this is not a consistent finding
in children.68,69,71 Bradycardia can occur despite significant decreases in MAP. Risk factors in children include age younger than
2 years, poor American Society of Anesthesiologists (ASA) status,
concurrent use of opioid, and strabismus surgery, where it can
accentuate the oculocardiac reflex despite pretreatment with
anticholinergics.72 Other rhythm disturbances (rarely) observed
with propofol include junctional rhythm, complete heart block,
asystole, and atrial premature beats.72 The mechanism(s) underlying this effect on myocardial conduction remain unclear, but
recent in vitro studies have shown that propofol can modify the
activity of human atrial muscarinic cholinergic receptors.73
Although experimental and clinical studies have demonstrated
that propofol has negative inotropic effects, determining the
precise cause has proved problematic.74,75
Animal studies have shown that propofol attenuates
isoproterenol-stimulated increases in calcium ion influx, intracellular calcium ion concentration, and cyclic adenosine monophosphate (cAMP) production.76 The inhibitory site of action
within the adrenergic signal transduction pathway involves
activation of a protein kinase C (PKC)dependent pathway. In
addition, propofol may also decrease myofilament calcium ion
sensitivity,76 and modulate sodium-calcium exchanger function,
again mediated by effects on PKC-dependent pathways.78 It seems
probable that propofol activates one or more of the protein kinase
isoforms involved in the regulation of intracellular calcium ion
concentration.74 Because these negative inotropic effects of propofol are greater at higher heart rates, fast injection of propofol in
sick infants and children is inadvisable. Even in healthy children,
fast injection of propofol produces more hypotension than an
equipotent dose of thiopental, though this effect is caused by
vasodilation rather than decreased contractility and is generally
well tolerated.69,71
The major action of propofol on the CNS is dose-related hypnosis and sedation (Table 231). Propofol has no analgesic
properties. Neuroexcitatory phenomena, including involuntary
movement, seizure-like activity, tremor, opisthotonus, twitching,
and coughing, may occur in children administered propofol, usually at induction or emergence. Epileptiform activity coinciding
with this movement has not been shown in electroencephalogram
studies, and it has been postulated that these reflect subcortical
discharges. The use of a higher induction dose is less likely to be
associated with neuroexcitatory events. This dose-dependent
effect on CNS depression is also demonstrated when considering
propofols anticonvulsant activity; in subanesthetic dosesm propofol may exert proconvulsant effects, but at higher doses,
propofol suppresses neuronal activity and is anticonvulsant. A
recent controlled study of children with epilepsy confirmed that
propofol possesses antiepileptic activity and did not promote
epileptic activity in any children without epilepsy.79
TABLE 23-1. Main Characteristics of Propofol

Pharmacokinetic Characteristics
Highly lipid soluble (loss of consciousness within one armbrain circulation time)
Cessation of effect after single dose owing to redistribution
(all ages)
Volume of distribution in children twice that of adults
Clearance: hepatic (62%); renal (27%)
Hepatic extraction ratio = 0.9; renal extraction ratio = 0.7
Cytochrome P450 CYP2B6 activity reduced in neonates;
highest in children 13 y
Pharmacodynamic Characteristics
Dose-dependent CNS depression
Mode of action: GABA agonist
A
Reductions in MAP, CO, and SVR more than those seen with
other induction agents
No change to PVR or PAP; therefore, may affect intracardiac
shunting
Dose-dependent respiratory depression (less than that
produced by other induction agents)
Depression of laryngeal/pharyngeal reflexes (less than that
produced by other induction agents)
Reduces cerebral oxygen consumption and ICP without
reduction of CPP
Spontaneous excitatory movements common on induction
and recovery
Decreases intraocular pressure
Antiemetic properties
Clinical Use
Solubilized in egg lecithin, soybean oil, and glycerol
Potential for bacterial contamination, so draw up using
aseptic technique
IV induction dose for healthy children: 35 mg/kg
Duration of action of single dose: 510 min
Maintenance regimen in children > 3 yr of age: initial 60 min
@ 151311 mg/kg/h; subsequent 14 h @ 109 mg/kg/h
Adverse Effects
Cardiovascular: hypotension (common); arrhythmias (rare)
Respiratory: respiratory depression; apnea; hiccups
Neurologic: transient seizure-like movements; opisthotonus
Pain on injection (reduce incidence by adding 1 mL lidocaine
1% to 20 mL propofol)
Propofol infusion syndrome (metabolic acidosis, rhabdomyolysis, renal and cardiac failure), usually following highdose exposure (>4 mg/kg/h for >48 h)
Anaphylaxis (rare); use with caution in patients with egg or
nut allergies
CNS = central nervous system; CO = cardiac output; CPP = cerebral perfusion

pressure; GABAA = gamma-aminobutyric acid type A; ICP = intracranial
pressure; MAP = mean arterial pressure; PAP = pulmonary arterial pressure;
PVR = pulmonary vascular resistance; SVR = systemic vascular resistance.
Cerebral autoregulation and cerebrovascular responsiveness to

carbon dioxide are preserved during propofol administration.80
Propofol infusions given to patients with either normal or elevated
intracranial pressure result in reductions in cerebral metabolic rate
and intracranial pressure without producing any significant
decrease in cerebral perfusion pressures. Cerebral blood flow is
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decreased by propofol, in a dose-related manner, but the reduction
exceeds the decrease in accompanying MAP, suggesting that
propofol is a cerebral vasoconstrictor.81 Decreases in intraocular
pressure are seen with propofol, similar to those observed with
thiopental.
Propofol is a respiratory depressant, probably acting directly
on the medullary respiratory center.82 Apnea following an induction dose of propofol is seen in up to 40% of unpremedicated
children.83 During an infusion of propofol, minute ventilation is
reduced, mainly because of a reduction in tidal volume, and depression of ventilatory responses to hypercapnia and hypoxia have
been observed.84 Animal studies have confirmed that propofol
impairs both central and peripheral (carotid body) chemoreceptor
sensitivity, the magnitude of the depression relating to the severity
of the hypoxia. The mechanism of this effect remains unclear,
though interaction with neuronal nicotinic acetylcholine receptors, which have similarities with GABAA receptors, seems
likely.85
Propofol has significant dose-dependent bronchodilating properties, making it beneficial for use in asthmatics.86 Nonetheless,
some episodes of bronchospasm have been observed following
injection of propofol, most likely owing to an anaphylactoid
reaction to one or more of the additives. Anaphylaxis to propofol
itself is rare, although the added formulation ingredients egg
lecithin and soybean oil can produce allergic reactions. Hence,
propofol should be used with caution in individuals with known
allergies to eggs or nuts. Egg allergy is most common in infants
and then becomes progressively less of a problem as they get older;
few children are allergic to egg after the age of 6. Metasulfitecontaining formulations should be avoided in patients with sulfite
allergies.
Propofol depresses pharyngeal and laryngeal reflexes, so
allowing atraumatic insertion of a laryngeal mask airway. Propofol
has been used as a sole agent to facilitate tracheal intubation in
children, without use of muscle relaxants. However, in the absence
of a co-administered opioid, high doses (>6 mg/kg) may be required to achieve acceptable intubating conditions. Propofol may
have a useful role in the management of laryngeal spasm, because
it has been shown that a small dose of propofol (0.8 mg/kg) can
relieve laryngospasm in 77% of children.87 Similarly, it has been
shown that propofol 0.5 mg/kg, given just before extubation, can
significantly reduce the incidence of postextubation laryngeal
spasm in children undergoing adenotonsillectomy.88
Propofol has useful antiemetic properties, and clinical studies
have shown that replacing an inhalation agent with intravenous
propofol significantly reduces the incidence of postoperative
nausea and vomiting (PONV), even in high-risk patients.89,90
However, the effect, even after an infusion, is relatively short-lived,
because a minimum plasma concentration is necessary to produce
an antiemetic effect.91 The mechanism of action for this effect is
thought to be indirect activation of cannabinoid receptors, because
propofol inhibits fatty acid hydrolase, an enzyme that degrades
the endogenous cannabinoid receptor agonist anandamide.56
Propofol has relatively mild effects on immune function,
particularly compared with drugs such as barbiturates, opioids,
and nitrous oxide.92 In vitro and clinical studies have shown that
propofol has no significant effect on neutrophil or lymphocyte
function.9395 Propofol has no significant effects on renal, metabolic, or endocrine function.
Pain on injection is the most commonly reported adverse effect
in children, with a reported incidence ranging from 30 to 80%.
A number of different strategies have alleviated, but not eliminated, the severity and incidence of this problem. One simple and
relatively effective method is to add 10 mg lidocaine (1 mL of 1%)
to 20 mLof propofol immediately before injection. Starting a
remifentanil infusion before injecting the propofol is equally
effective, in adults, in reducing the incidence of pain to about
30%.96 The injection pain is at least partially owing to generation
of bradykinin produced by contact between the lipid solvent and
the plasma kallikrein-kinin system. Release of bradykinin causes
hyperpermeability of the vein wall, such that the propofol in the
aqueous phase has access to free nerve endings, causing pain.
Soybean oil normally consists of long-chain triglyerides: use of a
different formulation, containing a 1:1 ratio of long- and mediumchain triglycerides, decreases the concentration of aqueous-phase
propofol and significantly reduces the incidence and severity of
injection pain in adults.97,98 Similarly, dilution of the new formulation to a 0.5% concentration reduced the incidence of severe
discomfort to 23% in children.99 Addition of lidocaine is a more
effective prophylactic measure than use of the new formulation, at
least in children,100 though recent adult clinical studies suggest that
best results will be obtained by using a combination of these
strategies.101
Propofol Infusion Syndrome

Prolonged infusions of propofol have been associated with a rare,
but life-threatening, condition termed the propofol infusion
syndrome (PRIS). This syndrome is characterized by an otherwise
unexplained metabolic acidosis and/or rhabdomyolysis with
cardiac and renal failure. Cardiac manifestations include arrhythmias, bradycardia that is refractory to treatment including
pacing, and circulatory collapse that is often resistant to largevolume infusion and high doses of inotropic drugs. Increases in
serum lactate, creatinine kinase, myoglobinuria, or hyperlipidemia
may herald the onset of the syndrome. Specific electrocardiographic changes, consisting of coved ST segment elevation in leads
V1 to V3, may precede cardiac instability and arrest.102
Initial reports of PRIS were in critically ill children, many with
sepsis related to respiratory tract infections, although subsequently, there have been reports in adults.103,104 Development of
PRIS is usually associated with prolonged, high-dose infusions
(i.e., rates > 4 mg/kg/h for > 48 h). However, more recently, there
have been anecdotal reports of this syndrome developing following short-term use of propofol infusions for anesthesia and
sedation.105
The underlying pathophysiology remains poorly understood;
indeed, even the very existence of this syndrome remains a subject of controversy.106 It is true that causality is not unequivocally
proved by the available data. However, the consistency of reports
from different institutions and from patients with different
underlying disease processes, the specific temporal association
with propofol infusions, together with plausible pathophysiologic
mechanisms, all strongly suggest a causal relationship.107
It is probable that PRIS is the result of impaired fatty acid
utilization.103,105 PRIS mimics some of the mitochondrial myopathies, conditions with mitochondrial DNA abnormalities that
result in specific defects in mitochondrial respiratory chain function. It is debatable as to whether a propofol metabolite directly
causes mitochondrial dysfunction or whether affected patients are
particularly susceptible because of an unknown underlying mitochondrial disorder (Figure 235).
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Figure 23-5. Summary of factors that

predispose to the development of the
propofol infusion syndrome.
Free fatty acids, derived from catecholamine-mediated lipolysis, are the most important fuel for the myocardium and skeletal
muscle under fasting conditions and in the critically ill. Long-term
propofol infusion is associated with an increase in malonylcarnitine.108 Malonylcarnitine inhibits the mitochondrial transport
protein carnitine palmityl transferase, so preventing the entry of
long-chain fatty acids into the mitochondria. Prolonged propofol
infusions have been also associated with muscle cytochrome
oxidase deficiency and decreased complex IV activity.109 These
anecdotal reports in children, suggesting that propofol inhibits
critical enzymes involved in the mitochondrial electron transport chain, have been confirmed in animal studies.103 Although
medium- and short-chain free fatty acids can freely cross the
mitochondrial membrane, because they do not require enzymemediated transfer, they cannot be utilized. This detrimental effect
on fatty acid metabolism is further compounded by curtailed
entry of long-chain fatty acids into the mitochondrion. ATP
production is reduced, and the imbalance between energy demand
and supply may lead to cardiac and skeletal muscle necrosis. The
propofol-induced block of mitochondrial fatty acid oxidation
causes accumulation of fatty acids, which may be exacerbated both
by the influx of triglycerides contained in the propofol solvent and
by those given for reasons of nutrition. The resulting buildup of
toxic fatty acid intermediates, coupled with cellular hypoxia,
worsens the acidosis and promotes ventricular arrhythmias.
Some reports of the use of prolonged propofol infusions in
children receiving intensive care suggest that propofol is safe to
use, albeit in lower doses and for shorter durations than those
reported previously.110 Clearly, not all individuals administered
propofol for prolonged periods develop PRIS, so some unexplained factor(s) is involved. Risk factors for PRIS include prolonged propofol infusion, critical illness, low carbohydrate intake
leading to impaired regulation and metabolism of lipids in the
liver, hepatic dysfunction, catecholamine administration, glucocorticoids, systemic inflammation, cytokine production, young
age, and subclinical mitochondrial disease (see Figure 235).
The management of PRIS is largely supportive. Propofol
administration should be stopped immediately and appropriate
measures instituted to support cardiorespiratory function, including extracorporeal membrane oxygenation (ECMO). A number
of case reports attest to the usefulness of hemofiltration.
Thiopental
Thiopental is still used to induce anesthesia in children, but its
popularity is on the wane, even in developing countries. Wherever
it is readily available, propofol is now preferred to thiopental for
intravenous induction of anesthesia in children. The reason for
this change in pediatric anesthetic practice resides in the different
pharmacokinetic properties of the two drugs.
Pharmacokinetics
Thiopental has a rapid onset of action because passive diffusion
into brain tissue from cerebral capillaries is facilitated by the drugs
high lipid solubility. Hence, peak concentrations are reached in
the brain and other well-perfused organs within one circulation
time. After injection, the concentration of thiopental in arterial
blood declines rapidly, owing to distribution to well-perfused
tissue, followed by a slower decline in concentration lasting 40 to
50 minutes, owing to redistribution to less well perfused tissue.
Hence, pharmacokinetic data are usually consistent with a threecompartment model and do not appear to vary significantly with
age after the neonatal period.111 The recovery of consciousness
following a single sleep dose of thiopental is caused entirely by
redistribution of drug into muscle, because, although thiopental is
extensively metabolized by the liver to inactive metabolites, elimination of drug normally plays an insignificant role in termination
of effect. Hence, although thiopental clearance is greater in young
children than in adults, recovery time following a single injection
is not age-related (Table 232).
Thiopental has a low hepatic extraction ratio (0.3), consistent
with capacity-limited elimination. Hence, thiopental given by
infusion leads to delayed recovery, because the relevant hepatic
oxidative enzyme systems quickly become saturated. Immature
hepatic function in the neonate causes significantly reduced
clearance of drug and a prolonged elimination time.112
Pharmacodynamics
In common with other induction agents, the average dose of
thiopental required to induce anesthesia (ED50) in healthy children
is significantly reduced by premedication with sedative drugs.113
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TABLE 23-2. Main Characteristics of Thiopental
High lipid solubility (loss of consciousness within one
circulation time)
Clearance greater in young children but recovery of
consciousness (following single dose) similar in all ages
(depends on redistribution only)
Hepatic extraction = 0.3; capacity limited elimination
Volume of distribution: no significant age-related variation
after the neonatal period
Elimination half-time: age-dependent but no clinical
implication after a single dose
Mode of action: inhibits opening of Cl channels and GABAA
agonist in CNS
ED
varies with age
50
Reduction in mean arterial pressure (less marked than with
propofol)
Little direct effect on vascular smooth muscle
Cardiovascular depression by direct myocardial depression
and central inhibition of sympathetic activity
Bronchoconstrictive effects
Anticonvulsant properties and burst suppression EEG pattern
at therapeutic doses
Decreases intraocular pressure and intracranial pressure
Depresses T lymphocyte function
Recovery of psychomotor skills slower than that following use
of propofol
Clinical Use
2.5% solution has pH 10.5; dilute for neonates
Chemically and bacteriologically stable for 24 h at room
temperature
Contraindications: porphyria, status asthmaticus, allergy to
barbiturates (unusual), cardiovascular collapse, respiratory
obstruction
Induction dose (slow IV injection): <6 mo, 35 mg/kg; 6 mo
4 y, 68 mg/kg; >4 y, 46 mg/kg
Sleep state obtained in 1030 s; duration of action 510 min
Adverse Effects
Cardiovascular: hypotension, arrhythmias
Respiratory: depression, apnea, laryngospasm, bronchospasm,
cough, hiccup
Neurologic: prolonged somnolence, delirium, confusion,
headache
Cutaneous: thrombophlebitis, tissue necrosis if extravascular
injection; ischemia if given by intra-arterial route; rash
(secondary to histamine release)
Anaphylaxis: rare
CNS = central nervous system; ED50 = median effective dose; EEG =

electroencephalogram; GABAA = gamma-aminobutyric acid type A.
The ED50 of thiopental also varies somewhat with age, owing

primarily to developmental changes in many of the factors
affecting drug distribution, as discussed earlier in the section on
Developmental Factors affecting Drug Distribution, as discussed
earlier. The ED50 in the neonate is 3.4 mg/kg, 6.3 mg/kg in infants,
3.9 mg/kg in children aged 1 to 4 years, 4.5 mg/kg in children 4 to
7 years, 4.3 mg/kg in children 7 to 12 years, and 4.1 mg/kg in

children aged 12 to 16 years.114116 Furthermore, the effect site
(brain) concentration of thiopental needed to induce anesthesia
in neonates may be lower than in infants because the neonate has
relatively immature cerebral cortical function, rudimentary
dendritic arborizations, and relatively few synapses.117
Infants and children recover more quickly after receiving
propofol for induction of anesthesia than after receiving an equipotent
dose of thiopental.118 The difference between the two drugs is usually
demonstrated in the completeness of recovery rather than time to
extubation.119 Recovery of psychomotor skills is usually significantly
faster in children receiving propofol than in those receiving
thiopental,120 though by 4 hours after awakening, there may be no
significant difference between groups.121 Recovery from anesthesia
is more dependent on the maintenance agent than the induction agent
for anesthesia lasting longer than 30 minutes.118 For children
requiring daycare surgery, therefore, thiopental is not the induction
agent of choice, though for children requiring more major surgery,
it may still retain some advantages over its current competitors.
The reduction in MAP produced in healthy children by
inducing anesthesia using propofol is significantly greater than
that produced by an equipotent dose of thiopental.69 Thiopental
has little direct effect on vascular smooth muscle tone and causes
cardiovascular depression by centrally mediated inhibition of
sympathetic nervous activity and direct myocardial depression,
the latter probably related to its effects on trans-sarcolemmal and
sarcoplasmic reticulum calcium flux.122
One significant advantage that thiopental has over propofol is
that it does not cause pain on injection, even when injected into
small veins. Thiopental is slightly less expensive than propofol,
particularly if bulk solutions are used until depleted. The prepared
solution can be used safely for up to 6 days even when stored at
room temperature and much longer if refrigerated.123 In contrast
to propofol, the alkaline, bacteriostatic environment of the
prepared thiopental solution (pH = 10.5) means that significant
bacterial colonization is extremely unlikely.124
Ketamine
Ketamine has been in widespread use since the 1980s. Unlike
other anesthetic agents, ketamine produces profound analgesia as
well as anesthesia, amnesia, and sedation. It produces dissociative
anaesthesia, a cataleptic state characterized clinically by a
functional and electrophysiologic dissociation between thalamic,
cortical, and limbic systems in the brain.
Ketamine contains a chiral carbon and is available either as a
racemic compound of two enantiomers, R() and S(+) ketamine,
or as the single S(+) ketamine enantiomer. Racemic ketamine has
been withdrawn from clinical use in mainland Europe and
replaced with the S(+) enantiomer. Clinically, the anesthetic
potency of the S(+) isomer is approximately four times that of the
R() isomer, attributable to the higher affinity of the S(+) isomer
to the phencyclidine binding sites on the N-methyl-D-aspartate
(NMDA) receptors. The S(+) enantiomer is twice as potent as the
racemate and exhibits different pharmacologic properties.125
Ketamine noncompetitively inhibits NMDA receptors within the
CNS, although interactions with opioid, muscarinic, and dopaminergic receptors have also been demonstrated. However, the
results of interactions with receptors other than NMDA receptors
are observed only when the plasma concentrations of ketamine
exceed those seen normally in clinical practice.126
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Pharmacokinetics
Ketamine is highly lipid-soluble and, after intravenous administration, rapidly distributes to well-perfused tissues, including sites of
action within the CNS, and then more slowly to less well-perfused
tissues. The onset of anesthesia is within 30 seconds of intravenous
administration of 2 mg/kg, and peak plasma concentrations are
achieved within 1 minute. The offset of hypnotic effect coincides
with redistribution from brain to other tissues and occurs 10 to
15 minutes after a single intravenous induction dose of racemic
ketamine.127 Analgesic effects, which occur at lower plasma concentrations, are more prolonged and may persist for up to 4 hours
after bolus administration.126,128
Between 35 and 55% of ketamine is bound to serum albumin
at 37C, the bound fraction being independent of plasma drug
concentrations but dependent on temperature and the presence
of metabolites. At 30C, the average fraction of bound drug is 69%
for dehydronorketamine, 60% for ketamine, and 50% for
norketamine.129 The presence of metabolites reduces the fraction
of ketamine bound to albumin from about 66 to 59%.
Ketamine has a high hepatic extraction ratio (0.9), and clearance is dependent on hepatic drug flow. When pharmacokinetic
parameters are modeled using allometric scaling, clearance in
children (6090 L/h/70 kg) is similar to that in adults (5383
L/h/70 kg),128,130 though it is reduced in infants (39 L/h/70 kg).131
The decreased clearance in infants is caused by reduced hepatic
microsomal activity. Ketamine undergoes extensive hepatic metabolism by the CYP450 isoforms CYP3A4, CYP2B6, and CYP2C9,
with the formation of norketamine by N-demethylation, and
dehydronorketamine by oxidation.132 The maturation of these
different isoforms during the first year of life has been discussed
Previously (see Hepatic Metabolism).
Animal studies suggest that norketamine has an analgesic
potency about one third that of the parent compound (Table 233).
Dehydronorketamine is inactive. These compounds undergo further biotransformation to glucuronide conjugates before excretion,
primarily in urine. The remaining drug is excreted in feces (3%) or
sequestered in tissues (5%). The elimination half-life for norketamine (1.13 h) in children is less than that of the parent compound
(2.1 h) and does not appear to change with age after infancy.128
Available pharmacokinetic data suggest that norketamine does not
have a significant effect on the duration of action of racemic
ketamine, whether given by bolus injection or by infusion.
Clearance of S(+) ketamine (2636 mL/kg/min) is much greater than that of R() ketamine (14 mL/kg/min) or of the racemate
(15 mL/kg/min).133,134 This finding is consistent with the faster
recovery demonstrated after S(+) isomer administration compared with the racemate.126 R() ketamine inhibits the metabolism
of S(+) ketamine, probably by competitive interaction of the
metabolizing enzymes.133 Thus far, there is no pharmacokinetic
data for the S(+) enantiomer administered to children, but the
pharmacokinetic data for the racemate suggest that, after infancy,
there will be no significant difference from adult values. Furthermore, all reported pharmacokinetic data are subject to wide
variability, secondary not only to methodologic problems but also
to the large interindividual variability of CYP expression; reported
genetic polymorphism of CYP isoforms may also be contributory
(see Hepatic Metabolism).
Pharmacodynamics
In children, an induction dose of intravenous racemic ketamine is
2 mg/kg.127 S(+) ketamine doses are approximately 50 to 75% of
TABLE 23-3. Main Characteristics of Ketamine

Highly lipid soluble
Termination of effect with redistribution
Volume of distribution: no significant age-related variation
Hepatic extraction ratio = 0.9
Clearance reduced in neonates (reflecting reduced hepatic
enzyme activity)
Clearance similar in adults and children
Higher clearance for S(+) ketamine than R() ketamine or
racemate
Two major metabolites: norketamine and
dehydronorketamine
Norketamine has one third the potency of parent drug
Main effects: hypnosis, analgesia, amnesia
Mode of action: NMDA receptor antagonist
Cardiac stimulator; MAP, heart rate, SVR, and CI maintained
or increased
PVR unchanged, therefore, little effect on intracardiac
shunting
Respiratory function preserved
Preserves laryngeal and pharyngeal reflexes better than other
anesthetic agents
Bronchodilator
Cerebral blood flow, ICP, and cerebral autoregulation
maintained if PaCO2 controlled
Intraocular pressure unchanged
Clinical Use
Available as racemate or as the S(+) enantiomer
Dosing: induction 12 mg/kg
Maintenance: 1050 g/kg/min
Sleep state achieved within 30 s of administration of 2 mg/kg
induction dose
Duration of action: 1015 min after induction dose
Duration of analgesia up to 4 h after single dose
Adverse Effects
Hypersalivation may be associated with laryngospasm
(administer with antisialogogue)
Emergence reactions less likely in children than in adults
Emergence reactions less likely if co-administered with
benzodiazepine
Spontaneous involuntary activity common; poor muscle
relaxation
Postoperative emesis relatively common
CI = cardiac index; ICP = intracranial pressure; MAP = mean arterial pressure;

NMDA = N-methyl-D-aspartate; PaCO2 = partial pressure of carbon dioxide in
arterial blood; PVR = peripheral vascular resistance; SVR = systemic vascular
resistance.
the racemate. When ketamine is used for maintenance of anesthesia by continuous infusion, an infusion rate of 3 to 5 mg/kg/h
is recommended, titrated against desired effect.135137 The plasma
concentration that produces anesthesia in 50% of children and
adults (EC50) is 2 mg/L; the EC95 for arousal (child becoming
conscious following moderate tactile or loud verbal stimulus) is
about 1.0 mg/L.138
In most individuals, ketamine stimulates the cardiovascular
system and an induction dose will maintain or increase heart rate,
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MAP, SVR, and cardiac index.137,139 S(+) ketamine inhibits both
neuronal and extraneuronal catecholamine uptake and increases
efferent sympathetic neural outflow to muscle.140 Hence, concentration of plasma norepinephrine is increased. Animal studies
suggest that R() ketamine inhibits neuronal but not extraneuronal uptake of catecholamines.141 In vitro studies of human
atrial myocardium show that racemic and S(+) ketamine increase
myocardial contractility at clinically relevant concentrations by
10.4 and 22.1%, respectively,142 probably by increasing norepinephrine concentration in the extracellular space.143 However,
racemic and S(+) ketamine reduce myocardial contractility at high
concentrations and during adrenoreceptor blockade by 52.9 and
57.4%, respectively.142,143 The negative inotropic effect of ketamine
observed during adrenoreceptor blockade appears to be caused
by reduced calcium ion influx via L-type calcium channels. In
conclusion, therefore, induction of anesthesia using ketamine is
not advocated in patients taking adrenoreceptor blockers or
those in whom chronic endogenous cardiac sympathetic stimulation is likely, such as patients in congestive cardiac failure. Ketamine given to these patients may cause hypotension, because the
direct negative inotropic effects of ketamine will be unmasked if
norepinephrine concentrations in the myocardium are low, owing
to either pharmacologic inhibition or depletion of cardiac norepinephrine stores.
Another mechanism by which ketamine increases arterial
blood pressure is by its effect on vascular smooth muscle. In vitro
studies of human umbilical vein endothelial cells have shown that
ketamine, at a clinically relevant concentration, decreases endothelial NOS.144 This is caused not only by pretranslational inhibition of endothelial nitric oxide synthase (eNOS) protein and
mRNA concentration but also through a post-translational decrease in eNOS activity. Ketamine also has a direct vasodilator
effect, but probably only at supraclinical concentrations: ketamine
inhibits both the interactions of bradykinin with its B2 receptor
and the trans-sarcolemmal influx of calcium ions through L-type
voltage-dependent calcium channels, both mechanisms acting to
reduce intracellular calcium ion concentrations.144,145
Peripheral vascular resistance (PVR) does not change significantly in spontaneously breathing children given ketamine who
have normal or elevated PVR, as long as they do not become
hypercarbic.139 As ketamine maintains pulmonary-to-systemic
blood flow ratios, it has little effect on shunting magnitude or
direction in children with cyanotic heart disease.146 Ketamine
increases the QT interval in animals, and its sympathomimetic
properties suggest that it should be avoided in children with long
QT syndrome.147 In vitro experiments on human atrial myocardium have shown that racemic and S(+) ketamine induce preconditioning, at least in part by stimulation of adrenergic receptors,148
and despite S(+) and R(-) ketamine both inhibiting sarcolemmal
ATPsensitive potassium channels in a concentration-dependent
manner.149
The dissociative anesthesia produced by ketamine is characterized by analgesia, amnesia, and a lack of awareness of surroundings, but this is not always associated with loss of consciousness.
The patient may exhibit open eyes, nystagmus, vocalization, and
spontaneous movements. Hypertonia is often observed with ketamine, but this agent is safe to use in children susceptible to malignant hyperpyrexia and in those with neurologic or neuromuscular
disorders. Intraocular pressure is not significantly altered after
ketamine administration and may be the agent of choice if
accurate measurement of intraocular pressure is required.150 There
are qualitatively different morphologic electroencephalographic

changes produced by each ketamine enantiomer, each of which is
dose-dependent.151 These differences at least partially account for
the conflicting clinical evidence regarding the pro- and anticonvulsant effects that have been documented after racemic
ketamine administration.152 Ketamine has been used to treat
refractory status epilepticus153 but has also provoked seizures in
epileptic patients.154 The drug is probably best avoided in poorly
controlled epileptic patients.
Historically, ketamine was contraindicated in patients with a
closed head injury. Early studies reported that ketamine administration was associated with increases in intracranial pressure,
cerebral oxygen consumption, and cerebral blood flow. However,
more recent studies in patients with traumatic brain injury, tumor,
or aneurysm have shown that, under conditions of controlled
ventilation, ketamine does not increase intracranial pressure,
impair autoregulation, or reduce blood flow within the middle
cerebral artery.155 Furthermore, ketamine sedation affords better
hemodynamic stability than opioids when used in patients with
severe head injury. However, these properties may be lost if nitrous
oxide is used in combination.155
Agitation and emergence reactions are the most commonly
reported adverse reactions associated with ketamine anesthesia.
Behavioral manifestations include altered mood, crying, hallucinations, involuntary muscular movements, and delirium, sometimes persisting for weeks. The incidence of these problems in
children younger than 10 years ranges from 0 to 48%, the variation
depending largely on the definition of behavioral reaction and
the duration of follow-up.137,156158 Prior or concomitant administration of midazolam does not reliably reduce the incidence of
reactions.156,157 Used in a lower sedative dose (0.51.5 mg/kg),
and given together with intravenous midazolam, a study examining the use of ketamine in an emergency department found that
the incidence of unpleasant emergence phenomena in children
aged between 6 months and 18 years was about 3% and that it did
not change significantly with age.159 Similarly, a Cochrane review
confirmed that the incidence of psychotomimetic effects following
low-dose ketamine ranges from 0 to 9% in adults.160 When
equipotent doses are administered, there is a similar incidence in
emergence reactions in patients receiving S(+) ketamine and those
receiving the racemate.161
Respiratory function is generally preserved by ketamine. In
comparison with other anesthetic agents, respiratory rate, tidal
volume, functional residual capacity, and minute ventilation are
usually maintained in children given an intravenous bolus of
2 mg/kg and subsequent infusion of ketamine (24 mg/kg/h).135
Decreased responsiveness to carbon dioxide may be produced,
although induced hypercapnia (end-tidal carbon dioxide pressure
[ETCO2] 47 mmHg) is unusual.162,163 Nevertheless, anecdotal
reports of prolonged apnea after intramuscular administration of
modest doses to healthy children continue to be reported.164166
Such episodes are presumably the result of a transient high concentration of ketamine within the CNS, coupled with decreased
carbon dioxide responsiveness, in particularly susceptible individuals. An anesthetic dose of ketamine induces less upper airway
relaxation than other intravenous anesthetic agents and, to some
extent, preserves airway and laryngeal reflexes.167,168 Incidents of
troublesome laryngospasm have been reported during ketamine
anesthesia.169 It would seem prudent, therefore, that ketamine is
administered only by personnel with the relevant airway skills and
where facilities for airway management are readily available.
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Ketamine has significant bronchodilator properties. It has been

advocated as the induction agent of choice in children with severe
asthma and as a treatment for children with asthma that is refractory to conventional treatment.170,171 In vitro studies show that
ketamine has direct actions on bronchial smooth muscle, though
probably only at supraclinical concentrations. Animal studies
suggest that ketamine acts principally by attenuating neurally
mediated bronchoconstriction.172 The use of ketamine is associated with increased salivation and tracheobronchial mucous
secretions and is commonly administered with an antisialogogue
such as atropine (20 g/kg) or glycopyrrolate (510 g/kg), particularly because increased salivation may predispose to laryngospasm. However, a recent study of over 1000 children given
ketamine (admittedly at subanesthetic doses), but with no antisialogogue, found that only 4.2% required intervention (such as
suctioning) for excessive salivation.173
Children undergoing adenotonsillectomy given only ketamine
and nitrous oxide have a 68% incidence of emesis in the first
4 hours after surgery, reducing to 18% from 4 to 24 hours.156 When
combined with midazolam, the incidence of postoperative emesis
in the 24 hours after surgery was 25%.158 In contrast, the combination of ketamine and propofol is associated with only a 2%
incidence of emesis.174 A recent comparative study has confirmed
that the incidence of postoperative emesis is much higher if
ketamine is given as the sole anesthetic agent (38%), compared
with administration together with propofol (7%).157
Etomidate
Etomidate is a carboxylated imidazole hypnotic drug with a rapid
onset time and a short duration of action. It is frequently used in
adults with limited hemodynamic reserve because it does not
usually provoke any significant change in cardiovascular status.
Although reports of its use in children date back since the 1980s,
it is only relatively recently that properly conducted studies of its
effects in young children have been published. Various small-scale
clinical studies have shown that a bolus dose of etomidate 0.3 mg/
kg given to children between 2 and 12 years of age does not produce any clinically significant changes in any measured hemodynamic parameter. These studies included children undergoing
cardiac catheterization,175 children with severe traumatic brain
injury,176 and children requiring rapid-sequence induction in the
emergency department, including those with decompensated
shock.177,178 In one comparative study, it was shown that propofol
produced better intubating conditions than etomidate, when both
were used in combination with remifentanil but without the use of
a muscle relaxant.179
In 1984, it was shown that etomidate, when used for long-term
sedation, resulted in an increased mortality rate in adult intensive
care unit patients.180 Subsequently, it was established that etomidate inhibits adrenal function mainly by inhibiting the enzyme
11-hydroxylase, the final step in the biosynthesis of cortisol.181
However, many clinicians have continued to use etomidate for
induction of anesthesia, assuming that a single bolus dose was safe
and produced only transient and clinically insignificant hormonal
changes. This assumption was based on small-scale studies in
healthy adults undergoing elective surgery. Relevant pediatric
studies have shown, however, that even a single dose of etomidate
produces decreased adrenal function and 11-hydroxylase activity.182 Moreover, one recent study suggests that a single dose of
etomidate negatively influences adrenal function for at least

24 hours.183
However, despite these conclusive reports, the use of etomidate
in some countries remains relatively high.184 Considering that the
main use for etomidate remains the shocked patient requiring
intubation and intensive care, this is particularly worrisome. It is
our unambiguous advice that etomidate is absolutely contraindicated in shocked or septic children, because adrenal insufficiency
is common in such patients.185,186
TOTAL INTRAVENOUS ANESTHESIA

As well as delivery by single or multiple bolus dosing, intravenous
anesthesia may also be delivered by continuous, variable-rate
infusion(s), and this may form the basis of a complete anesthetic
technique with induction and maintenance using only intravenous
agents. In adult anesthetic populations, total intravenous anesthesia (TIVA) is an increasingly common mode of anesthesia
delivery, brought about by developments in pharmacokinetic
modeling, technologic advances in delivery systems, and the
introduction into clinical practice of suitable agentsnamely,
propofol and remifentanil. In the pediatric population, these
techniques have not yet become mainstream because the pharmacokinetics of appropriate agents have not been well described
in children and there is a lack of suitable, licensed equipment. For
instance, the Diprifusor technology used in adults for propofol
infusion utilizes adult population pharmacokinetics, patient age,
and weight to estimate plasma propofol concentrations and is not
licensed or programmed for use in children younger than 16 years.
When used in children, such devices programmed on the basis of
adult pharmacokinetic data consistently underperform.187 Work
on the development of a target-controlled infusion (TCI) system
for propofol in children that utilizes published kinetic parameters
for this population,188 the Paedfusor, is under way but as yet there
is no commercially available algorithm-controlled infusion device
aimed at the pediatric market.
TIVA has a number of purported advantages over traditional
inhalation anesthetic techniques, including controllability, rapid
and predictable recovery, fewer side effects, and reduction in air
pollution. TIVA is particularly useful when inhalation agents are
contraindicated, such as in patients with Duchennes muscular
dystrophy. However, economic evaluation studies have shown that
TIVA may be more costly than inhalational anesthesia when a
target-controlled anesthesia technique is used.189 Drug wastage is
a major factor in the increased cost involved.
The underlying principle of TIVA is administration of an
anesthetic agent to produce a concentration of drug within the
CNS (the effect site) that mimics the anesthetic requirements and
avoids the peaks and troughs associated with intermittent bolus
dosing. Mathematical algorithms based on pharmacokinetic
models are used to calculate infusion rates. These pharmacokinetic models describe the elimination and redistribution of the drug
and may include a lag time that accounts for the delay in drug
concentration changes between the central compartment (blood)
and the effect site. This lag time, or effect-site equilibration time,
is specific for each drug but dependent on many pharmacodynamic factors. The estimation of this variable makes it possible to
model the concentration of drug at the effect site and improve
precision of individual dosing requirement.
Delivery of intravenous anesthetic drugs by continuous
infusion can have a significant effect on drug clearance and, hence,
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TABLE 23-4. Infusion Rate Recommendations for
Propofol in Children Aged 3 to 11 Years for Target
Blood Concentration of 3 g/mL
TABLE 23-5. Infusion Rate Recommendations for

Propofol in Children Younger Than 3 Years, Based on
Clinical Effect
Propofol Infusion Rates
Propofol Infusion Rates, mg/kg/h
Bolus dose
2.5 mg/kg
Infusion rates
g/kg/h
g/kg/min
15
13
11
10
9
250
215
185
165
150
015 min
1530 min
3060 min
12 h
24 h
Infusion rates
From reference 47.
recovery time. Clearance is dependent on both redistribution and

elimination of drug from the central compartment. After prolonged infusions, where equilibration has been reached between
the peripheral and the central compartments, redistribution may
play only a minor role in clearance, at least initially. This has led
to the introduction of the concept of the CSHT. The CSHT is the
time it takes for the drug concentration to decrease by 50% after
stopping an infusion, where the context refers to the duration
of the infusion. For example, propofol has a CSHT of less than
25 minutes after an infusion of 3 hours, and a CSHT of approximately 50 minutes after a 12-hour infusion.
One method of administering TIVA is by a TCI. TCI utilizes a
computer-controlled syringe pump that controls the rate of
infusion of a drug to attain a defined target concentration at the
patients effect site. These are seldom used in pediatric practice. The
commonly used alternative to TCI is a manually controlled regime;
several have been proposed for use with propofol in pediatric
patients. McFarlan and associates47 developed a simple infusion
regime for children older than 3 years, based on pharmacokinetic
work from Kataria and coworkers,190 to maintain a plasma concentration of about 3 g/mL (Table 234). A recent assessment of
the performance of this regime found it was able to produce
distinct differences in plasma concentrations and there was no
significant differences between predicted and measured plasma
concentrations.191 Steur and colleagues have reported a dosage
scheme for children aged 1 to 3 years based on clinical assessment
and not on target plasma concentrations (Table 235).192 These
studies have confirmed that age and weight are important covariates in determining the infusion rate in children.
Drugs Used in TIVA

A useful drug for TIVA will exhibit a close relationship between
plasma concentration and effect, expressed by a short equilibration
half-time, and a short CSHT. These properties will allow for rapid
onset and offset of action and the ability to rapidly titrate drug in
response to surgical stimuli and depth of anesthesia. Of the intravenous drugs in current use, those agents that are most suitable for
TIVA and TCI are propofol and remifentanil (see Chapter 25). Other
agents that have been used for TIVA include ketamine, thiopental,
etomidate, alfentanil, and fentanyl. Fentanyl and thiopental have long
CSHTs, leading to prolonged recovery, and the side effect profiles
of etomidate and ketamine limit their use. Alfentanil has a shorter
CSHT than fentanyl, though it is still substantially longer than
remifentanil if used for longer than 4 hours.
First 10 min
Second 10 min
Third 10 min
Fourth 10 min
Consecutive 1 h
Remaining time
<3 mo
36 mo
612 mo
13 y
25
20
15
10
5
2.5
20
15
10
5
2.5
15
10
5
2.5
12
9
From reference 192.
DRUG INTERACTIONS
Combinations of drugs are often used to maintain anesthesia
because no single agent offers all the components of anesthesia
without producing unwanted effects. Drug interactions may occur
between co-administered agents and these may be pharmacodynamic or pharmacokinetic. In some instances, these drug
interactions may be used purposefully to exploit the synergistic
action of drugs, thereby reducing the doses required of each or
either drug and the incidence or severity of adverse effects.
Pharmacodynamic Interactions
Propofol is often administered together with an opioid because it
lacks any analgesic properties. In adult studies, remifentanil has
been shown to decrease the dose of propofol required for induction, the effect-site concentration of propofol, and time to loss
of consciousness, as measured by loss of response to verbal
stimuli.193,194 Time to return of consciousness after termination of
propofol-remifentanil infusions is reduced. In children, remifentanil halved the concentration of propofol required for laryngeal mask and laryngeal tube insertion195 and decreased propofol
requirements for maintenance of anesthesia.196 Increasing the
infusion rate of remifentanil to more than 25 ng/kg/min yields
minimal reductions in propofol requirements. The effect of remifentanil on the BIS and electroencephalogram during propofol
anesthesia is unclear, with some studies suggesting remifentanil
has an additive effect with propofol,193,197 whereas others suggest
that it has no hypnotic effect in clinically relevant doses.198,199 Unfortunately, in anesthetic doses, remifentanil potentiates propofols
respiratory depressant and hypotensive effects, though children
younger than 3 years are relatively tolerant to the respiratory
effects of this interaction.200 Similar interactions have been demonstrated with propofol and other opioids, including alfentanil,
fentanyl, and sufentanil.201 The effects of propofol on remifentanil
have also been studied using response surface modeling. Despite
propofol having no analgesic properties, when combined with
remifentanil, the remifentanil requirements to ablate responses to
laryngoscopy, intubation, and intra-abdominal surgical stimulation decrease with increasing concentration of propofol in a
synergistic manner.202 This effect has also been demonstrated with
alfentanil.201
There is no synergistic interaction between propofol and ketamine with regard to hypnosis or anesthesia and their effects are
additive. The ED50 of propofol to produce apnea was unaffected
by concomitant ketamine administration. However, ketamine
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significantly reduces the hemodynamic effects associated with

propofol, minimizing changes in heart rate and arterial pressure.203
Sedative agents also show synergism with propofol. Oral
premedication with midazolam reduces the dose of propofol
required for hypnosis and laryngeal mask airway insertion in
children,58 but benzodiazepines do not reduce the dose of propofol
required to maintain anesthesia. In adults, the pineal hormone
melatonin, which is an effective sedative premedication in both
children and adults, has been shown to reduce the anesthesia
induction dose for both propofol and thiopental.204 Qualitatively
similar effects are expected in children.
Pharmacokinetic Interactions
Pharmacokinetic interactions involve changes to the distribution,
metabolism, or elimination of concomitantly administered drugs.
Almost all data relating to intravenous anesthetic agents are
derived from studies in adults.
In vitro studies demonstrate reduced clearance of drugs, notably the opioids, by modulation of the CYP450 enzyme systems by
various anesthetic agents. Propofol, midazolam, diazepam, and
etomidate all inhibit activity of some P450 cytochromes. For
example, propofol inhibits CYP3A activity responsible for the
metabolism of alfentanil, which may partly explain prolongation of the CSHT of alfentanil during combined infusion with
propofol.205
In practice, however, the majority of drug interactions are
related to changes in hemodynamic factors, such as cardiac output
and hepatic perfusion, which affect distribution and elimination.
This is especially true for drugs that show high extraction ratios
and are more likely to be affected by changes to hepatic perfusion.
Reductions in arterial pressure and SVR produced by propofol
alter the kinetics of all the opioids, including remifentanil, with
the result that plasma concentrations of these drugs are increased
in the presence of propofol, and subsequently, there are reduced
dosage requirements for suppression of responses to stimuli.
Propofol reduces the volume of distribution and clearance of
remifentanil by up to 40%.206 Propofol is itself a high extraction
drug and may be subject to pharmacokinetic interactions. In the
presence of oral clonidine premedication, propofol shows reduced
elimination and smaller propofol doses are required for hypnosis
and anesthesia, but time to return of consciousness after an
infusion is prolonged because of pharmacodynamic interaction.207
There are (rare) specific circumstances when total intravenous
anesthesia will be required, and inhalational agents contraindicated, as with children susceptible to malignant hyperpyrexia and
those with Duchennes muscular dystrophy. Similarly, there will
always be situations in which inhalation induction is preferred,
for instance, in the needle-phobic child or when intravenous
access is likely to be difficult. Practically, a combination of the two
techniques remains popular, for reasons of both expense and
experience. Indeed, interactions between the intravenous agents
and the inhalation anesthetic agents are commonly utilized by
anesthetists. The combination of nitrous oxide and propofol is an
example: inhalation of 66% nitrous oxide in oxygen for 1 minute
prior to intravenous induction with propofol reduces the induction dose of propofol and time taken for induction. Similarly,
when propofol is used for maintenance of anesthesia, nitrous oxide
reduces the risk of awareness, movement, and dose of propofol
required.208,209 Likewise, propofol and sevoflurane interact in an
additive manner to produce loss of consciousness and immobility

to surgical stimuli.210
ANESTHESIA AND NEUROAPOPTOSIS

General anesthesia causes widespread and dose-dependent neuronal cell death (neuroapoptosis) in neonatal rats, guinea pigs, and
subhuman primates. The existing experimental data implicates
NMDA antagonists and GABAA receptor agonists, so barbiturates,
propofol, ketamine, benzodiazepines, etomidate, and all the inhaled anesthetic agents including nitrous oxide are potentially
neurotoxic to the developing brain.211 The exact mechanism of
anesthesia-induced neurotoxicity is unknown.
Unfortunately, the developing CNS shows marked interspecies
variation and correlating periods of brain growth and synaptogenesis between species as diverse as the rat, guinea pig, and
human is fraught with difficulty. Experimental animals were often
subject to prolonged exposure of high doses of anesthetic agents,
often in concentrations exceeding those used clinically. Physiologic parameters were not always monitored, so it is possible that
derangements of oxygenation, cerebral perfusion, glucose, or
hypothermia may have contributed to the effects seen. To complicate matters further, it has been shown that exposure to pain or
surgical stress can have long-term behavioral and physiologic
effects in humans.212,213 Moreover, anesthetic agents may be neuroprotective.214
Hence, extrapolation of this experimental animal data to the
human neonate remains problematic and controversial. International multicenter trials are ongoing, though it may be many years
before this issue is completely resolved. At this time, there is no
evidence that any particular anesthetic technique is more dangerous to the immature brain than any other. The interested reader
is referred to several recent reviews on the subject.215218
CONCLUSIONS
In the past, inhalation anesthesia was often considered the technique of choice for pediatric patients. However, modern intravenous anesthetic agents are effective and well tolerated and
generally have good safety profiles, and the majority of direct
comparisons between inhaled and intravenous anesthetics have
failed to demonstrate significant differences in recovery times. The
development and use of topical anesthetic creams have made
intravenous access less traumatic and intravenous induction of
anesthesia a practical proposition in most children. Intravenous
techniques reduce some of the deleterious consequences associated with the use of inhalation agents, especially given concerns
over the role inhalation agents play as environmental polluters.
Notably, nitrous oxide, a greenhouse gas, has been implicated in
the destruction of the ozone layer, as has isoflurane.219
A major disincentive to the greater use of intravenous anesthetic agents in the pediatric population is the relative paucity of
pharmacokinetic and pharmacodynamic data, especially in the
very young and critically ill. Where information in children is
available, it is often limited in value by the relatively small number
of patients studied. Recent pediatric pharmacologic studies have
increased our understanding but have also highlighted the large
interpatient variability and complexity of development-related
changes.
By about 2020, as the complex mechanisms underlying
anesthesia are further elucidated, there exists the possibility of the
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development of new intravenous anesthetic agents. In reality,
however, commercial factors will limit anesthetic drug development and it is unlikely that the near future will see the introduction of completely new agents; novel application or reformulation
of existing drugs appears more probable.
Further exploration and elaboration into the developmental
pharmacology of intravenous anesthetic agents are necessary.
Improving our understanding of infusion pharmacokinetics,
effects of maturation, pharmacogenomics, and concentrationeffect relationships in children will make currently available agents
more predictable and advance the development and increase the
use of intravenous anesthesia in children.
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laryngoscopy, bispectral index, and electroencephalographic approximate entropy. Anesthesiology. 2004;100:13531372.
194. Jee YS, Hong JY. Effects of remifentanil on propofol requirements for
loss of consciousness in target-controlled infusion. Minerva Anestesiol.
2008;74:1722.
195. Park HJ, Lee JR, Kim CS, et al. Remifentanil halves the EC50 of propofol
for a successful insertion of the laryngeal mask airway and laryngoscopy
196. Drover DR, Litalien C, Wellis V, et al. Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children. Anesthesiology. 2004;100:13821386.
197. Ropcke H, Konen-Bergmann M, Cuhls M, et al. Propofol and remifentanil pharmacodynamic interaction during orthopedic surgical procedures as measured by effects on bispectral index. J Clin Anesth. 2001;
13:198207.
198. Wang LP, McLoughlin P, Paech MJ, et al. Low and moderate remifentanil
infusion rates do not alter target-controlled infusion propofol concentration necessary to maintain anesthesia as assessed by bispectral
index monitoring. Anesth Analg. 2007;104:325331.
199. Nieuwenhuijs DJ, Olofsen E, Romberg RR, et al. Response surface
modeling of remifentanil-propofol interaction on cardiorespiratory
control and bispectral index. Anesthesiology. 2003;98:312322.
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200. Barker N, Amari E, Malherbe S, Ansermino JM. Relationship between
age and spontaneous ventilation during intravenous anesthesia in
201. Vuyk J, Mertens MJ, Olofsen E, et al. Propofol anesthesia and rational
opioid selection. Determination of optimal EC50EC95 propofol-opioid
concentrations that assure adequate anesthesia and a rapid return of
consciousness. Anesthesiology. 1997;87:15491562.
202. Mertens MJ, Olofsen E, Engbers FH, et al. Propofol reduces perioperative remifentanil requirements in a synergistic manner: response
surface modeling of perioperative remifentanil-propofol interactions.
203. Hui TW, Short TG, Hong W, et al. Additive interactions between
propofol and ketamine when used for anesthesia induction in female
patients. Anesthesiology. 1995;82:641648.
204. Naguib M, Samarkandi AH, Moniem MA, et al. The effects of melatonin
premedication on propofol and thiopental induction dose-response
curves: a prospective, randomized, double-blind study. Anesth Analg.
2006;103:14481452.
205. Mertens MJ, Vuyk J, Olofsen E, et al. Propofol alters the pharmacokinetics of alfentanil in healthy male volunteers. Anesthesiology. 2001;94:
949957.
206. Bouillon T, Bruhn J, Radu-Radulescu L, et al. Non-steady state analysis
of the pharmacokinetic interaction between propofol and remifentanil.
207. Morris J, Acheson M, Reeves M, Myles PS. Effect of clonidine premedication on propofol requirements during lower extremity vascular
surgery: a randomized controlled trial. Br J Anaesth. 2005;95:183188.
208. Ng JM, Hwang NC. Inhaling nitrous oxide reduces the induction dose
requirements of propofol. Anesth Analg. 2000;90:12131216.
209. Akhtar TM, Kerr WJ, Kenny GN. Effect of nitrous oxide on postoperative nausea and vomiting during propofol anaesthesia for short
surgical operations. Eur J Anaesthesiol. 1993;10:337341.
210. Harris RS, Lazar O, Johansen JW, Sebel PS. Interaction of propofol and
sevoflurane on loss of consciousness and movement to skin incision
during general anesthesia. Anesthesiology. 2006;104:11701175.
211. Fredriksson A, Ponten E, Grodh T, Eriksson P. Neonatal exposure to a
combination of N-methyl-D-asparatate and gamma-aminobutyric acid
type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology. 2007;107:
427436.
212. Sternberg WF, Scorr L, Smith LD, et al. Long term effects of neonatal
surgery on adulthood pain behaviour. Pain. 2005;113:347353.
213. Hermann C, Hohmeister J, Demirakca S, et al. Long term alteration of
pain sensitivity in school-aged children with early pain experiences.
Pain. 2006;125:278285.
214. Clarkson AN. Anesthetic-mediated protection/preconditioning during
cerebral ischemia. Life Sci. 2007;80:11571175.
215. Loepke AW, Soriano SG. An assessment of the effects of general
anesthetics on developing brain structure and neurocognitive function.
Anesth Analg. 2008;106:16811707.
216. Wang C, Slikker W Jr. Strategies and experimental models for evaluating
anesthetics: effects on the developing nervous system. Anesth Analg.
2008;106:16431658.
217. Rizzi S, Carter LB, Pri C, Jevtovic-Todorovic V. Clinical anesthesia causes
permanent damage to the fetal guinea pig brain. Brain Pathol. 2008;
18:198210.
218. Perouansky M. General anesthetics and long-term neurotoxicity. Handb
Exp Pharmacol. 2008;182:143157.
219. Logan M, Farmer JG. Anaesthesia and the ozone layer. Br J Anaesth.
1989;63:645647.
220. Bjorkman S. Prediction of drug disposition in infants and children by
means of phsyiologically based pharmacokinetic (PBPK) modelling:
theophylline and midazolam as model drugs. Br J Clin Pharmacol.
2005;59:691704.
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Ketamine
Elsa Taylor
INTRODUCTION
Ketamine is a versatile drug that was introduced widely into
clinical practice in the early 1980s. Ketamine has had limited use
in developed nations because of its unfavorable emergence profile.
There is a resurgence of interest in ketamine because of evolving
roles in pain medicine and procedural sedation. Its use in the
head-injured patient was once considered unacceptable but has
moved through controversy to the suggestion that it may have a
role in neuroprotection. The use of ketamine in the first few
months of life is currently controversial.
PHARMACOLOGY
Chemistry and Preparations
Ketamine is a phencyclidine derivative, present as two isomers,
with a molecular weight of 237.5 daltons. Ketamine was historically formulated as the racemic mixture of the S and R isomers
presented as a hydrochloride salt with a preservative (benzethonium chloride). The pH of this solution is 3.5 to 4.1. Preservativefree forms are available. The S isomer is now more commonly
available in many countries.
Ketamine has an octanol buffer partition coefficient of 60 and
high lipid solubility and undergoes rapid redistribution. Ketamine
is 45 to 50% protein-bound. Ketamine is a weak base with a pKa
of 7.5. At physiologic pH of 7.4, it is 44.3% un-ionized. It has a
pKa close to physiologic pH, and consequently, small changes in
pH result in a wide variation in the ionized and un-ionized
fractions. A fall in pH to 7.1 results in a change in the un-ionized
percentage to 28%. This slows the availability of ketamine at effect
sites. By contrast to thiopentone, a weak acid, with pKa close to
physiologic pH, the percentage of un ionized drug rises with
falling pH. Thiopentone has faster onset and a more pronounced
clinical effect with acidosis.
Pharmacokinetics
The pharmacokinetic (PK) profiles of the racemates S(+) and
R () isomers are similar. The oral, nasal, rectal, intramuscular,
intravenous, epidural, and caudal routes all have clinical utility.
Bioavailability differs depending on route of administration (Table
241).
The PK parameters for a two-compartmental model for
ketamine are presented in Table 242.1,2 The parameter estimates
are standardized to a 70-kg person using allometric one-quarterpower models. Parameter estimates in children when standardized
TABLE 24-1. Ketamine Bioavailability

Route
Bioavailability, %
Oral
Intramuscular
Rectal
Intranasal
Epidural/caudal
20%
90%
25%
50%
77%
From reference 113.
using allometric one-quarter-power models are similar to those

in adults. Table 243 illustrates clearance changes with age.
Ketamine is metabolized in the liver by N-demethylation to
norketamine, which has potency one third that of ketamine.
Norketamine is further metabolized by oxidative metabolism to
the less potent dehydronorketamine or by hydroxylation followed
by conjugation with gluconoride to water-soluble products excreted by the kidney. Ketamine is also hydroxylated. The low oral
bioavailability of ketamine results in significant levels of the active
metabolite norketamine. It is suggested that a ketamine blood
TABLE 24-2. Ketamine Pharmacokinetic Parameters
Clearance, T / , and Volumes of Distributions Scaled to a
70-kg Person using One-Quarter-Power Allometric Models
1
Parameter
Value
CV%
T / alpha
T / beta
Initial volume of
distribution (V1)
Steady-state volume
of distribution
Clearance
Intercompartmental clearance
Protein binding
Concentration steady state EC50
for sedation level 4 (arousal
to verbal stimulus)
Concentration steady state EC95
for sedation 2 (rouses slowly
to consciousness with sustained
painful stimulus)
1117 min
1.63.1 h
38.7 L/70 kg
64
102 L/70 kg
51.7
90 L/h/70 kg
215 L/h/70 kg
50%
560 ng/mL
38.1
1
1
2
2
1500 ng/mL
CV = between-subject variability; EC50 = median effective dose; EC95 = effective

dose at 95%.
From references 1, 2, and 5.
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TABLE 24-3. Pharmacokinetic Parameters Scaled With Allometric One-Quarter-Power Models to Different
Age and Weight Children
Parameter
Adult (70 kg)
CL, L/h
Central volume of distribution (V1), L
Intercompartmental clearance (Q), L/h
Peripheral volume of distribution (V2), L
60.2 (CV, 38.1%)

22 (CV 89.6%)
216 (CV 54.5%)
129 (CV 30.9%)
12 Y (40 kg)
6 Y (20 kg)
2 Y (12 kg)
39.6
12.6
142.0
73.7
23.5
6.3
84.4
36.9
16
3.78
57.6
22.1
CL = clearance; CV = between-subject variability.

From reference 6.
concentration of 40 ng/mL following oral ketamine is equianalgesic to a concentration of 150 ng/mL of ketamine after intravenous
administration.3 This apparent paradox may be explained by the
greater norketamine concentrations following oral administration
and their contribution to analgesia.
Very little ketamine (15%) is excreted unchanged in urine;
therefore, no dose adjustment is required for the short-term use of
ketamine in renal disease. However, the role of norketamine during prolonged infusions has not been fully elucidated. Norketamine is both renally excreted and further metabolized by the liver.
The relative importance of each clearance pathway has not been
investigated in renal disease. Account may need to be taken of
norketamine accumulation when a prolonged infusion is planned
in the child with renal impairment. Adult patients suffering renal
failure had ketamine concentrations 20% higher than those
without renal failure when ketamine was used for analgesia and
sedation.4 During hemodialysis, 10% of the administered ketamine is eliminated, but during continuous hemodiafiltration, only
0.5% of ketamine is eliminated in the ultradiafiltrate.4
Ketamine inhibits the activity of cytochrome P450 (CYP)
CYP2D1 and CYP3A by 10- to 20% after a single dose. Ketamine
is largely metabolized by the liver before renal excretion, so it
would be expected that the handling of ketamine would be altered
in liver disease. In humans free of liver and renal disease, 3% of
ketamine metabolites are recovered in the feces (excreted in the
bile) and 91% of ketamine and its metabolites are recovered in the
urine over a 5-day period. The literature provides little guidance
on the appropriate use of ketamine in liver disease. Metabolism is
probably maintained until moderate to severe liver failure. Singledose or short (<10 min) infusions are likely to be clinically indiscernible from the nonliver failure patient because of the
predominance of redistribution in termination of effect. Longer
infusions for either anesthesia or analgesia are likely to result in
higher blood concentrations and a longer duration of effect in the
patient with moderate to severe liver failure.
The plasma clearance at 16 to 19 mL/min/kg approximates liver
blood flow. Despite this high clearance, redistribution after an
intravenous bolus dose is important for the termination of clinical
effect.
There is a paucity of adult and pediatric data exploring the PK
and pharmacodynamic relationships. A 2.2-mg/kg dose of ketamine in the adult human results in plasma concentrations of
30,000 ng/mL within 30 seconds; these concentrations fall to 1000
ng/mL at around 10 minutes.1 Ketamine 1 mg/kg in children of
an average age of 8.3 years (range, 1.514 y) results in useful
sedation with blood concentrations at 10 minutes having fallen,
in the majority, to below 750 ng/mL.5 This is a concentration associated with arousal to stimuli. When used to provide anesthesia
for longer than 10 minutes, it is more rational to give ketamine as
either an intermittent decreasing dose regime or an infusion at a

de-escalating rate.6,7 The rate and/or repeat bolus size must decline
over time as tissues become saturated and elimination kinetics
predominate over distribution kinetics. An appropriate infusion
rate will avoid both peaks and troughs associated with intermittent
dosing. The context-sensitive half-life rises with increasing
duration of infusion; therefore, timely arousal becomes more
elusive with increasing duration of anesthesia7 (Figure 241).
Thus, despite adjusting the rate of delivery to maintain steadystate plasma levels, awakening becomes prolonged.
Mechanism of Action
The predominant clinical effects of ketamine are produced by
antagonism at the N-methyl-D-aspartate (NMDA) receptor.
Ketamine also interacts with the cholinergic (muscarinic and
nicotinic), dopaminergic D2 and opioidergic (mu and kappa)
receptors.8 Ketamine has been reported to interfere with gammaaminobutyric acid (GABA) inhibition, but this is not significant at
usual clinical doses. Ketamine has higher affinity to interaction
with the phencyclidine-binding site on the NMDA receptor
compared with other receptors or voltage-gated channels. This
suggests that, at subanesthetic doses, it is the primary binding
site for ketamine and the receptor that accounts for its analgesic
effects. However, activation of monoaminonergic descending inhibitory pathways by ketamine and interaction with the mu opioid
receptors are also implicated in the analgesic effect of ketamine.
There is an NMDA-mediated decrease in the central nervous
system acetylcholine release. However, ketamine increases basal
Figure 24-1. The context-sensitive half-time after an infusion

that maintains blood levels of 3000 ng/mL. From reference 7,
with permission.
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hippocampal acetylcholine release.9 There may be neurodevelopmental differences in the central nervous system neurotransmitter
effects of ketamine. For example, the percentage increase of
acetylcholine in the basal hippocampus is greater in old rats
(>18 mo) than in young rats (<2 mo). Hippocampal cholinergic
mechanisms are essential for cognition, memory, and learning.
Ketamines explicit interactions with receptors depend on the
ketamine concentration. For example, ketamine has two distinct
mechanisms of interaction with the NMDA receptor. It blocks the
open channel, reducing mean open time, and it binds to the closed
receptor, decreasing the frequency of opening. Both mechanisms
are in play at high concentrations of ketamine, whereas at low
concentrations, the latter mechanism predominates. Ketamine is
a use-dependent noncompetitive antagonist at the NMDA receptor in that the rate of onset and recovery are both increased with
increasing NMDA agonists.10
NMDA receptors are evoked by pain signals and result in
hyperexcitability of the dorsal route neurons. The resulting clinical
effects are hypersensitization, pain facilitation, and wind-up.
Opioids used in large doses induce tolerance to opioid effects and
also induce hyperalgesia. The mu receptor activation increases
glutamate effectiveness at the NMDA receptor. Ketamine, by antagonizing the NMDA receptor, blocks the development of opioid
tolerance.
Anesthesia Pharmacodynamics
Ketamine produces dissociative anaesthesia. The primary sites of
action are the cerebral cortex, thalamocortical pathways, and limbic
system and not the brainstem. Pharmacokinetic-pharmacodynamic
(PK-PD) data in children support a graded sedation response to
ketamine and reject an all-or-nothing dissociated state.11 Anesthesia
is likely in blood concentrations above 1100 ng/mL, awakening/
arousal from anesthesia occurs at 500 to 1100 ng/mL and analgesia
at 60 to 150 ng/mL. These effects are on a continuum, and there is
considerable between-subject variability. A study of children undergoing surgical procedures in a pediatric emergency department
estimated a median effective dose (EC50) for arousal of 560 ng/
mL (90% confidence interval [CI] 220, 1170 ng/mL) and an
EC95 for a Childrens Hospital of Wisconsin Sedation Scale level 2
(rouses slowly to consciousness with sustained painful stimulus) of
1500 ng/mL.11
Ketamine anesthesia/sedation produces a trancelike state with
associated amnesia, sedation, and analgesia. The patient appears
dissociated from the environment, but the eyes may remain open
and spontaneous involuntary movements can occur. Nystagmus
and hypertonus are common. Vital brainstem functions are preserved.
The morphologic electroencephalographic (EEG) changes with
ketamine are described by three phases. Phase 1: loss of alpha
rhythm (614 Hz) in combination with a decreased amplitude and
frequency; phase 2: persistent rhythmic theta activity (46 Hz)
with increasing amplitude; phase 3: intermittent polymorphic
delta activity (0.52 Hz) of large amplitude.12 Phases 1 to 3 are
observed with the administration of racemate and S(+) ketamine.
It is not possible to suppress the EEG activity beyond phase 2 with
R() ketamine. Maximum effect change (Emax) values of the
R () and S(+) are different when serum concentrations are related
to EEG changes. The potency ratios are 1:1.7:5.6 (R()-to-racemate: S(+)). The R() enantiomer is a partial antagonist relative to
S(+) ketamine.12
The depth of sedation or anesthesia with ketamine cannot

be tracked with bispectral index monitoring (BIS), entropy
monitoring or auditory evoked potentials.13 The EEG effects of
ketamine result in a higher BIS or entropy value for a given depth
of sedation or anesthesia. Furthermore, the BIS or entropy value
does not decrease in a concentration-dependent manner with
increasing ketamine sedation or anesthesia. Ketamine does not
suppress the midlatency auditory evoked potentials. When given
as the primary anesthetic, the midlatency auditory evoked potentials remain similar to those in the awake state. An antihyperalgesic dose or as a low-dose infusion during anesthesia with either
propofol or sevoflurane increases BIS and entropy values along
with between-subject variability. BIS, entropy monitors, and auditory evoked potential monitors correlate poorly with ketamine
sedation depth. The use of ketamine with other primary anesthetic drugs can falsely suggest a lessening of sedative or anesthetic
depth13 with these monitors despite a clinical increase in depth of
anesthesia.
Other Organ System Effects

Ketamine is a sympathomimetic. There is an increase in circulating catecholamines from both centrally mediated stimulation and
inhibition of peripheral neuronal uptake. Ketamine also exhibits
a moderate parasympatholytic effect on the heart,14 mediated
through a direct inhibition of both nicotinic and muscarinic
acetylcholine receptors, inhibition of NMDA-mediated acetylcholine release, and decreased parasympathetic excitation in the
brainstem.
Increases in mean aortic pressure, pulmonary artery pressure,
heart rate, and cardiac index occur. Individual response can vary
widely and the blood pressure rise does not correlate with preexisting hypertension and may be attenuated by benzodiazepines.
However, direct application of ketamine to cardiac myocytes
results in myocardial depression. The patient who is reliant on
maximal sympathetic stimulation for cardiovascular stability may
experience cardiac depression with ketamine induction.
Respiratory System
Pharyngeal and laryngeal reflexes remain active. Aspiration is less
likely compared with other sedative or anesthetic agents, but may
still occur. Ketamine increases salivation. Laryngospasm can be
provoked by airway irritation from blood or secretions or by
pharyngeal stimulation. Antimuscarinics will reduce hypersalivation but not all clinicians advocate their routine use. Most contemporary use of ketamine for sedation omits an antimuscarinic
from the sedation guidelines.
Resting respiratory rate, tidal volume, and minute ventilation in
children are unchanged by 2 mg/kg intravenous bolus of ketamine
followed by a 40 g/kg/min infusion.15 Functional residual capacity is preserved.16 Despite the unchanged nature of respiratory
variables, the slope from the plot of minute ventilation versus endtidal CO2 decreases after a 2-mg/kg bolus. It returns to control
values during continued ketamine anesthesia with 40 g/kg/min,15
suggesting respiratory depression only with higher blood concentrations.
Low-dose ketamine (0.5 mg/kg) added to a propofol sedation
regime attenuates propofol-induced hypoventilation.17
Ketamine is a bronchodilator.
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Other
Nausea and vomiting are increased compared with thiopentone or
propofol. Skeletal muscle tone is increased, but this rarely is
clinically problematic. Ketamine should be avoided in the hyperthyroid patient because marked hypertension can occur. Ketamine
use in acute intermittent porphyria is controversial. Biochemical
markers have been reported to rise with ketamine use without clinical
evidence of a porphyric crisis.18 If other nonporphyric agents are
available, they should be used in preference to ketamine. A small
rise in intraocular pressure occurs because of both increased tone
in the extraocular eye muscles and a rise in carbon dioxide pressure
(PCO2) in the spontaneously breathing patient. The increase in
intraocular pressure is less than that produced with laryngoscopy.
Adverse Effects
The side effect profile of ketamine includes hypertension, diplopia,
nystagmus, dizziness, confusion, seizures, cardiac arrythmias,
nausea, vomiting, sedation, and psychomimetic reactions. Psychic
emergence phenomena such as dysphoria, altered body image,
hallucinations, and vivid dreams occur in up to 10% of children
during recovery from ketamine anesthesia/sedation. However,
only 1 to 2% of children presenting for anesthesia have distressing
psychic emergence phenomena. Unpleasant emergence phenomena are less likely in children than in adults. Ketamine has both
proepileptic and antiepileptic effects.
Drug Interactions
Halothane decreases liver blood flow. Ketamine has a high extraction ratio, and thus, ketamine clearance falls with a decrease in
liver blood flow.
Diazepam reduces ketamine clearance by approximately 15%
and, consequently, prolongs the sedative effect of ketamine by both
a PK (reduced clearance) and a PD mechanism (sedative effect of
diazepam).19 Ketamine decreases cytochrome P450 (CYP) CYP3A
enzyme activity, and diazepams metabolism may also be slowed.20
Methylphenidate, used commonly in the treatment of attention
deficit hyperactivity disorder (ADHD), may lead to increased
deleterious effects with ketamine. Methylphenidate blocks the action
of dopamine and norephinephrine transporters. These transporters
transport the neurotransmitters out of the synapse. Potentiation of
ketamines dopamine and sympathetically mediated effects is
possible. This is a theoretical concern and is not backed by clinical
cases apart from Potentiation of ketamines dopamine and
sympathetically mediated effects such as severe nausea and
vomiting might be possible in patients on methylphenidate. This
is a theoretical concern and is not backed by clinical cases.
In combination with other proconvulsant drugs, such as cyclosporine, ketamine may induce seizure activity.21 Paradoxically,
ketamine is known to have both proconvulsant and anticonvulsant
effects. Caution and potential for interaction should be considered
when combining ketamine with any chronic central nervous
system drug.
CURRENT AREAS OF CLINICAL USE

Anesthesia
Ketamine can be used as a sole agent or with other adjuvants for
anesthesia maintenance. The context-sensitive half-time rises with
Figure 24-2. The decrement time to 50% (DC50) and to 80%

(DC80). DC50 is associated with reusability and DC80 with return
to full consciousness. From reference 7, with permission.
increasing duration of delivery (Figure 242). The target concentration for anesthesia remains undefined and will vary depending
on supplemental agents used. A proposed target concentration of
3000 ng/mL can be maintained in children 1.5 to 12 years with a
loading dose of 2 mg/kg, followed by an infusion rate of 11 mg/
kg/h for the first 20 min, 7 mg/kg/h from 20 to 40 min, 5 mg/kg/h
from 40 to 60 min, and 4 mg/kg/h from 1 to 2 h. However, arousal
would be expected only 3 hours and 47 minutes after cessation of
a 2-hour infusion in a 6-year-old child.7
Other agents with more favorable wake-up characteristics
would usually be preferable to ketamine for procedures longer
than 10 to 20 minutes. Niches because of resource constraints or
patient factors remain for the use of ketamine as the primary
anesthetic agent. It can be used in combination with other agents
to minimize ketamine disadvantages.
Ketamine provides a stable induction in trauma and patients
with major blood loss, provided sympathetic reserve has not been
exhausted. It is a reasonable choice for anesthesia in the child
presenting for biopsy with an anterior mediastinal mass who has
airway and/or cardiovascular compromise. It provides more stable
hemodynamics than volatile anesthetic agents or fentanyl in
preterm neonates.22 In the sick premature or term neonate undergoing surgery, this may translate into greater hemodynamic
stability and lower inotrope requirements. A case report favorably
discusses a propofol-ketamine combination for providing stable
hemodynamics for this group of patients.23 There is little objective
information to guide the anesthesia choice in this group of
patients, and there are growing neurodevelopmental concerns and
questions around many drugs used in this vulnerable population.
Some advocate ketamine as an agent of choice either alone
or in combination with propofol, midazolam, sevoflurane, or
dexmetomidine for cardiac catheter studies. A regime combining
ketamine with another agent, usually propofol, is preferable to
ketamine alone. Lowering the total amount of each agent leads to
stable hemodynamics with timely arousal. In infants and children
with cardiac lesions that render them reliant on maintenance of
systemic vascular resistance for adequate pulmonary blood flow,
ketamine provides stable anesthesia both prebypass for cardiac
surgery and for noncardiac surgery.
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Concern has been raised regarding the potential for increases

in pulmonary vascular pressure to adversely affect shunt degree
or direction in children with cyanotic heart disease. There has also
been concern regarding the potential for sympathetic stimulation
to precipitate a hypercyanotic spell in children with tetralogy of
Fallot. However, stable hemodynamics and shunt fractions have
been demonstrated with the use of ketamine in children undergoing cardiac catheter studies.24 Ketamine maintenance provides
stable hemodynamics, better pulmonary blood flow, lower
inotrope requirements, and better blood gases than isoflurane
maintenance for children with tetralogy of Fallot in the period
before cardiopulmonary bypass.25
Deep Sedation and Anesthesia

for Procedures
Forced restraint of children for procedures is unacceptable in
many countries. Distraction techniques, play therapy, and analgesia are all helpful in gaining a cooperative relaxed child. There
remain numerous occasions when these techniques are insufficient. When they fail, the options are either sedation or general
anesthesia. The majority of hospitals with a large pediatric commitment have insufficient anesthesiologists to cover all situations
in which pharmacologic assistance is required for procedural
cooperation.
Ketamine is widely used by nonanesthesiologists in the United
States, Canada, and Australasia for deep sedation for minor procedures in the emergency department, intensive care, burns suite,
and cardiology, radiology, and endoscopy suites.2631 The use of
ketamine may also be extending beyond intrahospital use into
prehospital care for pain and infield extraction.32 The use of
ketamine in the United Kingdom and Europe is expanding for
pediatric procedural sedation.3337 Tensions exist between specialties with regard to domains of practice, competencies, training,
credentialing, and safety.38 Several decades of audits and research,
largely from the United States, testify to a remarkable overall safety
profile.27,3437,3941
When ketamine is used for pediatric procedural sedation,
oxygen desaturation is reported in 1 to 5% of patients and airway
obstruction in 0.5 to 1% of patients. Apnea is rare (<1%) but can
occur,42 especially with rapid intravenous injection and larger
doses. Laryngospasm occurs in 0.1 to 0.4%42 of children undergoing procedural sedation except where there is instrumentation
of the hypopharynx or larynx 29 when it occurs more frequently
(up to 9.5% reported). The majority of these airway incidents are
managed without intubation of the airway.37,42 Emesis occurs in
approximately 10% (043%)36,37,42 of children with the majority
occurring postprocedure and a minority intraprocedure.36 Emergence phenomena are reported in 0 to 10% of children. Moderate
to severe emergence phenomena occur less than 2% of the time.31
Nystagmus, ataxia, myoclonus, and opisthotonus are rarely clinically troublesome and resolve with recovery.37
Although serious adverse effects are rare, it is imperative that
ketamine sedation is undertaken only by those with the appropriate skills to rescue a child from general anesthesia or any of the
potential complications of ketamine sedation. Furthermore, it is
mandatory that suction, oxygen, and resuscitation equipment and
drugs are available.
Several groups favorably compare ketamine with other agents
for emergency department or procedural sedation.30,31,35,37,43
Ketamine results in overall better quality of sedation judged by

parents and procedural doctors, but a longer time to recovery
thanh midazolam. Ketamine has more stable hemodynamics
and less oxygen desaturation than propofol as the primary
sedating agent. Recovery, however, is longer with ketamine. Combinations of ketamine and either midazolam or fentanyl compare
well to midazolam-fentanyl or propofol-fentanyl combinations
(Table 244).
The addition of midazolam to a ketamine sedation regime does
not prevent emergence phenomena and increases the incidence
of oxygen desaturation, but it does reduce the incidence of postprocedure emesis.37,44,45 Postprocedure emesis may also be decreased by the addition of ondansetron.46
Doses of ketamine commonly range from 2 to 5 mg/kg intramuscularly or 0.5 to 2 mg/kg intravneously in sedation protocols
for procedural sedation.37 A dose of 1 mg/kg intravenously gives
adequate sedation with a significantly shorter duration of sedation
than 4 mg/kg intramuscularly.47 A recent time-concentration and
sedation profile simulation provides a PK-PDbased guideline for
choice of intravenous dose and dosage regime. The key points are
the milligram per kilogram dose increases with decreasing age and
size; a single dose greater than 1.5 mg/kg is associated with delayed
recovery compared with smaller repeated top-up doses or an
infusion.6
Analgesia
Ketamine has been investigated perioperatively as a sole analgesic
and as a co-analgesic for the prevention of hyperalgesia48 and
allodynia, for the reduction of opioid use, and for the prevention
of acute opioid tolerance and opioid-induced hyperalgesia.49
Ketamine may also have a role in the prevention48 and treatment
of complex pain.
Neuroplasticity in response to nociception and to analgesics
may be significant in both acute and chronic pain outcomes after
surgery. Postnociceptive neuroplasticity affects both excitatory
and inhibitory pathways and spinal as well as supraspinal sites.
The relationship of pain measures, analgesics, and neuroplasticity
is poorly defined. Most clinical studies use pain scores or analgesic
use as outcome measures. Few formally seek to detect and quantify
neuroplasticity.
Ketamine As a Primary Analgesic

Low-dose ketamine (0.5 mg/kg) has analgesic effects on both
acute visceral pain and acute cutaneous pain.8 Ketamine has been
investigated as the primary analgesic in pediatric tonsillectomy in
which it has been used instead of an opioid. This may be advantageous in children with obstructive sleep apnea or abnormal
airways. Ketamine (0.5 mg/kg) offers analgesia similar to that of
morphine (0.10.15 mg/kg),50,51 although higher initial pain scores
and more frequent use of rescue paracetamol have been reported.52
Postoperative vomiting and dreaming were equivalent to that in
control groups.53
Ketamine Perioperatively As Part

of a Multimodal Analgesic Strategy
INTRAOPERATIVE USE: Intraoperative intravenous or epidural
ketamine in doses of 0.1 to -0.5 mg/kg with or without an intra-
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Ketamine
381
TABLE 24-4. Comparison of Ketamine With Other Agents for Procedural Sedation
Ketamine or Ketamine
Combination
Compared With
Key Results
IV ketamine 1 mg/kg and

midazolam 0.1 mg/kg
Intranasal midazolam
0.4 mg/kg
Ketamine
Midazolam
Shorter time to adequate sedation,

better quality of sedation, longer
recovery, more children at
deeper than required level of
sedation in ketamine group
Better sedation and less restraint
in ketamine group
IV Ketamine 1 mg/kg and

midazolam 0.10.15 mg/kg
IV ketamine 1 mg/kg with
midazolam 0.1 mg/kg
IV midazolam 0.10.15 mg/

kg and fentanyl 1.6 g/kg
Propofol 2 mg/kg
morphine 0.1 mg/kg
Ketamine 1 mg/kg with

propofol 1.2 mg/kg
Ketamine and midazolam
titrated to effect, average
dose 1.99 mg/kg and
0.04 mg/kg
Ketamine 1 mg/kg and
midazolam 0.1 mg/kg
Fentanyl 1 g/kg with

propofol 1.2 mg/kg
Propofol and fentanyl
titrated to effect, average
doses propofol 4.55 mg/
kg fentanyl 1.21 g/kg
50% N2O in 50% O2 plus
hematoma block
Oral ketamine 10 mg/kg
Oral midazolam 0.7 mg/kg
Ketamine 1 mg/kg
Fentanyl 1 g/kg
Less procedural distress and less

desaturation in ketamine group
Slower onset, longer recovery,
more stable hemodynamics, and
less desaturation in ketamine
group.
Less restlessness
Similar sedation, quicker time to
ideal sedation, slower recovery,
less oxygen desaturation in
ketamine group
Procedural behavior similar
between groups, but less pain
and distress in N2O group, more
minor adverse effects, including
desaturation in ketamine group
Tolerance to long-acting injection
better with ketamine, quicker
onset with ketamine, more
dysphoric reactions with
midazolam
Both groups 1.2 mg/kg propofol
plus additional propofol prn;
more propofol required in
fentanyl group, more
restlessness in fentanyl group,
more minor postoperative side
effects in ketamine group
operative infusion of ketamine can reduce postoperative pain,

hyperalgesia, allodynia, and opioid requirements.5464 Some
investigators fail to show a reduction in either pain or analgesic
use.65,66 This inconsistency may be caused by inadequate ketamine
dosing schedules or small doses of ketamine (<0.15 mg/kg) that
fail to add benefit on a background of multimodal analgesics
including epidurals. Alternatively, ongoing intense pain or high
opiate use may require continued NMDA antagonism for analgesic
benefit to be seen.
Ketamine may have either a pre-emptive effect or a preventive
analgesic benefit. A literature review in 2004 found that only 60%
of ketamine studies seeking a preventive benefit demonstrated it.64
Few pediatric studies assess the addition of intraoperative
ketamine to a multimodal pain regime and again results are mixed.
Ketamine (0.15 mg/kg) added to fentanyl 2 g/kg did not modify
postoperative tonsillectomy pain.53 However, when added to
fentanyl 1 g/kg, it resulted in reduced swallowing evoked pain,
Prospective, Retrospective, and

Number of Patients
Prospective, single-blind,
randomized, 53 children31
Variety of regimes, IM, no

blinding, and no randomizsation37
Prospective, randomized,
single-blind, 260 children114
Prospective, 50 children35
Prospective, double-blind,
randomized, 32 children43
Prospective, not blinded,
randomized, 113 patients115
Prospective, randomized, not
blinded, 102 children116
double-blind, 59 children
double-blind, 100 children117
reduced paracetamol use, and increased oral intake.67 Both oral

intake and swallowing evoked pain may reflect the equivalent of
movement-related pain in limb and trunk surgery.
Children (N = 30) undergoing major urologic surgery did not
demonstrate a clinically relevant difference between the Sketamine (bolus 0.2 mg/kg, then infusion 5 g/kg/min) and
placebo groups.66 A 0.5-mg/kg racemic ketamine bolus followed
by a 4-g/kg/min intraoperative infusion failed to decrease pain or
opioid use in the first 72 hours postoperatively in adolescent
scoliosis patients (N = 34).68
KETAMINE FOR THE PREVENTION OF ACUTE OPIOID TOLERANCE

AND OPIOID-INDUCED HYPERALGESIA: Animal and human
volunteer laboratory researches establish that acute opioid
tolerance and opioid-induced hyperalgesia occur and do so via
separate pathways and mechanisms.69 The separation of tolerance
and opioid-induced hyperalgesia is difficult in the clinical setting
because both are characterized by a decreased effect of a given
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dose. High-dose opioids such as remifentanil greater than 0.1 mg/

kg or large-dose fentanyl do result in hyperalgesia and acute opioid
tolerance.7072 These findings are not consistently shown.73,74 Intraoperative remifentanil is associated with the development of
clinically relevant increased opioid requirements postoperatively
in pediatric scoliosis surgery.68
A multitude of receptors and mechanisms have been investigated for their role in the development of the pathologic pain
processes of secondary hyperalgesia, opioid-induced hyperalgesia,
and acute opioid tolerance. They include the NMDA receptor,
postsynaptic density proteins -95 and -93, which connect the
NMDA receptors to the cytoskeleton and to key signaling systems
such as neuronal nitric oxide synthase, intracellular protein kinase
C, tyrosine kinase, nitric oxide synthetase, heme oxygenase, and
increased cytokine production by glial cells.69 The NMDA receptor
is integral in the development and maintenance of pathological
pain. Ketamine can prevent the development of hyperalgesia and
acute opioid tolerance.72,75 Supplementing remifentanil-based
anesthesia with small-dose (4 g/kg/min) ketamine reduces perioperative opioid requirements,54 but not always.65 Intraoperative
ketamine, in appropriate doses, failed to reduce postoperative
morphine requirements for pediatric scoliosis patients.65 Ketamine
may need to be infused postoperatively when there is ongoing
intense pain and high opioid use because it is unrealistic to expect
intraoperative ketamine to cover the entire postoperative period.
Ongoing noxious stimuli lead to secondary hyperalgeisa and high
opioid use results in opioid-related acute tolerance/hyperalgesia
phenomena.
POSTOPERATIVE MODALITIES: Ketamine can be beneficial

postoperatively for major surgery in adults as a separate constantrate infusion in addition to the primary pain treatment modality
(usually patient-controlled analgesia [PCA]).90 Decreased mechanical hyperalgesia, increased patient satisfaction, decreased morphine consumption, and decreased pain both at rest and during
mobilization with the use of postoperative ketamine infusion have
been demonstrated. Not all groups have shown benefit.91
Few studies have positive findings for ketamine added into a
morphine PCA.92 In the majority, adding ketamine into a morphine
PCA is not beneficial.63,93,94 The dose administered by this method
may be too small to be effective. A single pediatric study with a
postoperative ketamine infusion failed to show any analgesic
benefit for children undergoing appendicectomy.95
Clinical Implications for Ketamine in Acute Pain

Ketamine is morphine-sparing and may lead to improved pain
control in some types of surgery. It is yet to be demonstrated
whether the addition of ketamine to postoperative pain management leads to tangible benefits such as faster recovery, decreased
side effects, earlier resumption of oral intake, earlier return of
bowel function, or reduction of future complex pain.
Ketamine is able to prevent the development of the rapid
tolerance that develops to remifentanil analgesia. When an infusion of remifentanil is planned for longer than 1 hour, the addition
of ketamine may be useful. However, in the presence of ongoing
intense pain and high opioid use, ketamine used only intraoperatively may be insufficient.
KETAMINE FOR MORPHINE-RESISTANT PAIN: Acute pain that is

not easily controlled with morphine can be reduced by the
addition of ketamine.76 Adult patients in the postanesthetic care
unit (PACU) with morphine-resistant pain were randomized in a
double-blind trial to either morphine 30 g/kg boluses or
ketamine 0.25 mg/kg and morphine 15 g/kg. The ketamine
group had lower 10- and 120-minute pain scores, had fewer
boluses to achieve analgesia, were less sedated, and had higher
oxygen saturation of hemoglobin monitored with pulse oximetry
(SpO2), and had less nausea and vomiting.76
NEUROAXIAL KETAMINE: Epidural (and caudal) ketamine gain

rapid access to the systemic circulation with a high bioavailability.
Epidural ketamine results in greater postoperative analgesia than
the same dose given systemically despite similar plasma concentrations.77,78 This suggests that ketamine has a direct neuroaxial
action.
Caudal ketamine alone or with local anesthetic provides
analgesic benefit to children undergoing minor urologic and
herniotomy surgery.79,80 The optimal dose of racemic ketamine
appears to be 0.5 mg/kg81 and that of S(+) ketamine appears to be
1 mg/kg. Few studies have examined the comparison of ketamine
with other caudal additives such as clonidine, fentanyl, epinephrine, midazolam, tramadol, or neostigmine. Those that have
report that other additives may offer equal79,80 or superior82,83
analgesia. A combination of caudal additives may84 or may not8587
confer additional analgesic benefit, but this has been poorly
defined. Few studies have sought the comparison of caudal
ketamine with a multimodal oral regime or alternative regional
blockade.88,89
Concern regarding the potential neurotoxicity of ketamine
applied directly to the neuroaxis persists. Short-term exposure to
preservative-free ketamine appears to be safe.
Complex Pain
The NMDA receptor is implicated in central sensitization and
wind-up with the resulting allodynia and hyperalgesia seen in
complex pain. Human volunteers have decrease pain intensity and
wind-up evoked by experimental stimuli in the presence of an
NMDA antagonist. NMDA antagonists reduce hyperalgesia and
allodynia associated with neuropathic pain following nerve
injuries, burns, or topical capsaicin in adult volunteer studies,
clinical studies, and case reports.8
Premedication
Oral or rectal ketamine (1.56 mg/kg) has less ideal separation
characteristics, a higher incidence of airway stridor, and occasional
psychomimetic adverse effects than a benzodiazepine.96,97 Higher
doses may provide good induction characteristics but prolong
emergence.98 In combination with a benzodiazepine, it can provide
superior anxiolysis and separation characteristics compared with
a equipotent dose of either agent alone.99,100
Fringe Uses of Ketamine in Anesthesia

Ketamine has been found to have beneficial effects for a diverse
range of minor anesthetic or perioperative problems. Oculocardiac reflex during pediatric strabismus surgery is less likely and
less profound with a ketamine-based anesthetic regime than with
propofol- and volatile-based regimes.101 Ketamine may enhance
the amplitude of motor evoked potentials especially in younger
children in whom they are more difficult to elicit.102 Ketamine
(0.5 mg/kg) has been found to be effective in both treating and
preventing postoperative shivering.103 This dose is as equally
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effective as pethidine. Propofol injection pain is relieved more
successfully with 0.5 mg/kg of ketamine than with lignocaine.104
Ketamine 0.2 mg/kg preinduction reduces postinduction withdrawal to rocuronium in pediatric patients.105 Ketamine in doses
above 0.2 mg/kg prevents tourniquet-induced increases in arterial
blood pressure.106 Interestingly, despite the potential psychomimetic effects of ketamine premedication, there is reduced postoperative delerium compared witho placebo or midazolam after
sevoflurane anesthesia. Ketamine 0.5 mg/kg is also successful in
managing paradoxical midazolam reaction in children.107
AREAS OF CONTROVERSY
Necessity for Fasting
Many emergency department ketamine sedation protocols mandate either no minimum fasting period or a period shorter than
that required for general anesthesia.31,108 Airway reflexes are preserved with ketamine sedation and aspiration unlikely. Aspiration
pneumonitis is rare and no study or audit is large enough to
definitively establish the safety of this practice. Current research
and audit reports demonstrate postprocedure vomiting, rare intraprocedure vomiting. and no reports of aspiration pneumonitis.
Neuroprotection
Modulation of excessive NMDA receptor stimulation is suggested
as part of a multitargeted approach to lessen secondary brain
injury. Preclinical studies report neuroprotective effects for
racemic ketamine in cell and animal models. Regenerative effects
in cultured neurons are seen with S(+) ketamine. No human
clinical trial data assess the neuroprotective effects of ketamine.109
The 6-month outcomes after ketamine use for intensive care unit
sedation in the head-injured adult patient are equitable to those
when an opioid-based regime is used.
Intracranial pressure (ICP), cerebral blood flow (CBF), and
cerebrospinal fluid (CSF) pressure remain the same in the presence of ketamine, provided normocapnia is maintained. A pig
model demonstrates that cerebrovascular autoregulation is preserved with ketamine,110 and this is likely to be true in humans
too. In addition, the hemodynamic stimulation resulting from
ketamine administration may improve cerebral perfusion. Intensive care unit data indicate that when Ketamine is used for
sedation of head-injured patients, less vasopressers are required
and the outcomes are the same compared with an opioid-based
sedation regime.109
Ketamine in association with nitrous oxide or hypercapnia has
deleterious effects on CBF, cerebral metabolism, and ICP. In the
presence of nitrous oxide even with controlled ventilation,
ketamine may increase CBF.
Ketamine may be beneficial in the injured brain. Rat studies in
brain ischemia found that ketamine decreased injury-triggered
cascades. There was dampening of interactions between the
NMDA receptor, postsynaptic density proteins, and protein
kinases. This ultimately resulted in reduced nitric oxiderelated
neurotoxicity and brain damage.
Neurodevelopmental and
Neonatal Use of Ketamine
In rodents and primates, profound NMDA blockade is neurotoxic.
High-dose (40 mg/kg) ketamine caused reversible pathologic
Ketamine
383
vacuolation in the cingulate and retrosplenic regions of the adult

rat brain. Repeated large-dose ketamine increases apoptosis in the
developing rat and primate brain. Both immaturity and prolonged
intense blockade of the NMDA receptor by ketamine are necessary
for increased brain apoptosis to occur. Signal transduction via
NMDA receptors is necessary to express neurotrophins and survival-promoting proteins. Large-dose NMDA receptor antagonists
during the vulnerable phase of synaptogenesis in the developing
rat brain lead to apoptosis, synaptic defects, and cognitive
impairment.109 This vulnerable stage occurs postnatally in the rat,
prenatally in the full-term human, and postnatally in the premature human neonate. As with most other anesthetic agents, there
is insufficient evidence to determine how damaging, if at all,
ketamine is to premature and full-term neonates. The large-dose
repeated exposure in laboratory animals does not have a clinical
therapeutic equivalent. We induce a less profound clinical NMDA
blockade in our neonatal patients during anesthesia with ketamine
and, if used for analgesia, a repetitive exposure without a profound
blockade.
Whereas NMDA receptors are integral in synaptogenesis and
neuronal survival, they also have key roles in cell death induced by
excitotoxicity. Thus, the effect of unopposed persistent pain on the
developing brain must also be considered. Repetitive pain in the
premature human is associated with future learning difficulties
and emotional and behavioral changes.111 The clinical course of
the premature neonate is complex, and it is impossible to currently
determine the contribution of the many aspects of the preterm
neonates early life. Unopposed pain in neonatal rats detrimentally
alters both the structure and the function of the rat brain.111 These
effects are ameliorated by analgesic doses of ketamine. Furthermore, both the ketamine-treated groups (ketamine plus pain and
ketamine alone) show similar brain structure and behavior to the
controls (pain-free, ketamine-free), whereas the treatment group
(unopposed pain) had deleterious outcomes.
Questions clearly remain with the use of ketamine (and many
other anesthetic agents) in neonates and especially premature neonates. However, current evidence would suggest that unopposed
pain and surgery is not only unethical but also neurodevelopmentally damaging. Ketamine may provide some protection for
the developing brain in the circumstance of prolonged pain or
intense surgical stimulation. Certainly, high-dose ketamine in the
absence of surgical stimulation does not reflect clinical practice
and we cannot translate current laboratory-based high-dose
ketamine in rats into a meaningful therapeutic equivalent.
The Child with Pulmonary Hypertension

Pediatric and animal studies have largely but not consistently
shown minimal, nonsignificant changes in pulmonary vascular
resistance in those without pre-existing pulmonary hypertension.25 Maintaining normal pH, normocarbia, and normoxia is
important in preventing significant changes in pulmonary vascular resistance in infants and children with congenital cardiac
disease. Ketamine can be used safely in the child without preexisting pulmonary hypertension. The use of ketamine in children
with known raised baseline pulmonary vascular resistance, from
both cardiac and other causes, is more controversial.
Animal investigations demonstrate complex interactions of
ketamine with pulmonary vasculature. Ketamine causes direct
vasodilation via mechanisms decreasing intracellular calcium in
vascular smooth muscle. Ketamine also has an opposing effect on
endothelium-mediated vasodilation. The net clinical effect of
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ketamine depends on the interplay of these direct, opposing

mechanisms and the sympathetically mediated ketamine effects
on the vasculature. Case reports detail the successful use of ketamine for anesthesia in patients with known pulmonary hypertension. Nonetheless, the use of ketamine in this group of patients
is controversial. A recent open-label study of 18 children with preexisting pulmonary hypertension of multiple etiologies demonstrated no rise in pulmonary arterial pressure in spontaneously
breathing children given ketamine in addition to 0.5 minimum
alveolar concentration (MAC) sevoflurane anesthesia.112 These
authors argue that ketamine offers benefits to children with pulmonary hypertension requiring anesthesia. Ketamine maintains
systemic vascular resistance and systemic arterial pressure and,
thus, preserves coronary blood flow to the hypertensive right
ventricle. Furthermore, this maintenance of systemic pressures
might prevent the unfavorable left shift of the septum and consequent fall in cardiac output and coronary blood flow that can
occur with lowered systemic pressures in the patient with pulmonary hypertension. Ketamine also preserves the ratio of pulmonary and systemic blood flow better than other anesthetics in
patients with intracardiac shunt such as in Eisenmengers syndrome. Finally, ketamine may increase cardiac performance mediated through the sympathetic nervous system.
NONANESTHESIA AND ANALGESIC

USES OR AREAS OF RESEARCH
Ketamine is known to have anti-inflammatory effects. Ketamine
suppresses natural killer cell activity, stabilizes neutrophil activation, reduces the release of inflammatory mediators, and decreases
tumor necrosis factor-, interleukin-6, and interleukin-8 levels.
These effects have been observed in vitro, in animal models, and
in human patients receiving ketamine.
Ketamine may have effects in ameliorating deleterious cascades
in sepsis and may have roles in immune modulation. Ketamine
may either exacerbate tumor metastasis after surgery by suppressing natural killer cell activity or attenuate this effect because of
improved analgesia attenuating the suppression of natural killer
cell activity. These questions and the magnitude of effect, if any, are
currently unable to be answered without further preclinical and
clinical research.
CONCLUDING COMMENTS
Ketamine was synthetized in 1962 during a search for an ideal
anesthetic. Although it falls short of the ideal anesthetic, it remains
an integral part of clinical practice since its introduction in the
1970s. Its unique characteristics offer safety and stability across
diverse physical locations and patient groups. It is not a mainstay
of pediatric anesthesia but is likely to remain as an agent able to fill
a number of niches in pediatric anesthesia and sedation. It has
much to offer in furthering analgesia, although clarity of how best
to use this agent in acute and chronic pain is still developing. It
may have the additional clinical benefits of neuroprotection and
inflammatory modulation, but current research does not establish
the absolute presence or the magnitude of these effects.
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46. Langston W, Wathen J, Roback M, Bajaj L. Effect of ondansetron on the
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47. Roback M, Wathen J, Mackenzie T, Bajaj L. A randomized, controlled trial
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48. De Kock M, Lavandhomme P, Waterloos H. Balanced analgesia in the
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51. Aspinall R, Mayor A. A prospective randomized controlled study of the
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52. Umuroglu T, Eti Z, Ciftci H, Gogus Y. Analgesia for adenotonsillectomy
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53. OFlaherty J, Lin C. Does ketamine or magnesium affect posttosillectomy
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385
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55. Taura P, Fuster J, Blasi A, et al. Postoperative pain relief after hepatic resection in cirrhotic patients: the efficacy of a single small dose of ketamine
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56. Fu E, Miguel R, Scharf J. Preemptive ketamine decreases postoperative
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57. Ozyalcin N, Yucel A, Camlica H, et al. Effect of pre-emptive ketamine on
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64. McCartney C, Sinha A, Katz J. A qualitative systemic review of the role of
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65. Engelhardt T, Zaarour C, Naser B, et al. Intraoperative low-dose ketamine
does not prevent a remifentanil-induced increase in morphine requirement after pediatric scoliosis surgery. Paediatr Anaesth. 2008;107:
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66. Becke K, Albrecht S, Schmitz B, et al. Intraoperative low-dose S-ketamine
has no preventive effects on postoperative pain and morphine consumption after major urological surgery in children. Paediatr Anaesth. 2005:
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67. Elhakim M, Khalafallah Z, El-fattah A, et al. Ketamine reduces
swallowing-evoked pain after paediatric tonsillectomy. Acta Anaesthesiol
Scand. 2003;47:604609.
68. Crawford M, Hickey C, Zaarour C, et al. Development of acute opioid
tolerance during infusion of remifentanil for pediatric scoliosis surgery.
Anesth Analg. 2006;102:16621667.
69. Angst M, Clark J. Opioid-induced hyperalgesia. Anesthesiology. 2006;
104:570587.
70. Vinik H, Kissin I. Rapid development of tolerance to analgesia during
remifentanil infusion in humans. Anesth Analg. 1998;86:13071311.
71. Guignard B, Bossard A, Coste C, et al. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement.
72. Joly V, Richebe P, Guignard B, et al. Remifentanil-induced postoperative
hyperalgesia and its prevention with small-dose ketamine. Anesthesiology.
2005;103:147155.
73. Cortinez L, Brandes V, Munoz H, et al. No clinical evidence of acute
opioid tolerance after remifentanil-based anaesthesia. Br J Anaesth. 2001;
87:866869.
74. Schraag S, Checketts M, Kenny G. Lack of rapid development of opioid
tolerance during alfentanil and remifentanil infusions for postoperative
pain. Anesth Analg. 1999;89:753761.
75. Laulin J, Maurette P, Corcuff J, et al. The role of ketamine in preventing
fentanyl-induced hyperalgesia and susequent acute morphine tolerance.
Anesth Analg. 2002;94:12631269.
76. Weinbroum A. A single small dose of postoperative ketamine provides
rapid and sustained improvement in morphine analgesia in the presence
of morphine-resistant pain. Anesth Analg. 2003;96:789795.
77. Koinig H, Marhofer P, Krenn C, et al. Analgesic effects of caudal and
intramuscular S(+)-ketamine in children. Anesthesiology. 2000;93:976980.
78. Martindale S, Dix P, Stoddart P. Double-blind randomized controlled trial
of caudal versus intravenous S(+)-ketamine for supplementation of caudal
analgesia in children. Br J Anaesth. 2004;92:344347.
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79. Akbas M, Akbas H, Yegin A, et al. Comparison of the effects of clonidine

and ketamine added to ropivacaine on stress hormone levels and the
duration of caudal analgesia. Paediatr Anaesth. 2005;15:580585.
80. Choudhuri A, Dharmani P, Kumari N, Prakash A. Comparison of caudal
epidural bupivacaine with bupivacaine plus tramadol and bupivacaine
plus ketamine for postoperative analgesia in children. Anaesth Intensive
Care. 2008;36:174179.
81. Panjabi N, Prakash S, Gupta P, Gogia A. Efficacy of three doses of ketamine with bupivacaine for caudal analgesia in pediatric inguinal herniotomy. Reg Anaesth Pain Med. 2004;29:2831.
82. Kumar P, Rudra A, Pan A, Acharya A. Caudal additives in pediatrics: a
comparison among midazolam, ketamine, and neostigmine coadministered with bupivacaine. Anesth Analg. 2005;101:6973.
83. Gunes Y, Secen M, Ozcengiz D, et al. Comparison of caudal ropivacaine,
ropivacaine plus ketamine and ropivacaine plus tramadol administration
for postoperative analgesia in children. Paediatr Anaesth. 2004;14:
557563.
84. Hager H, Marhofer P, Sitzwohl C, et al. Caudal clonidine prolongs analgesia from caudal S(+)-ketamine in children. Anesth Analg. 2002;94:
11691172.
85. Almenrader N, Passariello M, DAmico G, et al. Caudal additives for postoperative pain management in children: S(+)-ketamine and neostigmine.
86. Wheeler M, Patel A, Suresh S, et al. The addition of clonidine 2 mcg/kg
does not enhance the postoperative analgesia of a caudal block using
0.125% bupivacaine and epinephrine 1:200000 in children: a prospective,
double-blind, randomized study. Paediatr Anaesth. 2005;15:476483.
87. Passariello M, Almenrader N, Canneti A, et al. Caudal analgesia in
children: S(+)-ketamine vs S(+)-ketamine plus clonidine. Paediatr
Anaesth. 2004;14:851855.
88. Gauntlett I. A comparison between local anaesthetic dorsal nerve block
and caudal bupivacaine with ketamine for pediatric circumcision.
89. Findlow D, Aldrige L, Doyle E. Comparison of caudal block using bupivacaine and ketamine with ilioinguinal block for orchidopexy in children.
Anaesthesia. 1997;52:11101113.
90. Guillou N, Tanguy M, Seguin P, et al. The effects of small-dose ketamine
on morphine consumption in surgical intensive care patients after major
abdominal surgery. Anesth Analg. 2003;97:843847.
91. Edwards N, Fletcher A, Cole J, Peacock J. Combined infusions of morphine and ketamine for postoperative analgesia. Can J Anaesth. 1993;
48:124127.
92. Michelet P, Guervilly C, Helaine A, et al. Adding ketamine to morphine
for patient-controlled analgesia after thoracic surgery: influence on morphine consumption, respiratory function, and nocturnal desaturation. Br
J Anaesth. 2007;99:396403.
93. Sveticic G, Farzanegan F, Zmoos P, et al. Is the combination of morphine
with ketamine better than morphine alone for postoperative intravenous
patient-controlled analgesia? Anesth Analg. 2008;106:287293.
94. Reeves M, Lindholm D, Myles P, et al. Adding ketamine to morphine for
patient-controlled analgesia after major abdominal surgery: a doubleblinded, randomized controlled trial. Anesth Analg. 2001;93:116120.
95. Dix P, Martindale S, Stoddart P. Double-blind randomized placebocontrolled trial of the effect of ketamine on postoperative morphine
consumption in children following appendicectomy. Paediatr Anaesth.
2003;13:422426.
96. Filatov S, Baer G, Rorarius M, Oikkonen M. Efficacy and safety of
premedication with oral ketamine for day-case adenoidectomy compared
with rectal diazepam/diclofenac and EMLA. Acta Anaesthesiol Scand.
2000;44:118124.
97. Horiuchi T, Kawaguchi M, Kurehara K, et al. Evaluation of relatively low
dose of oral transmucosal ketamine premedication in children: a
comparison with oral midazolam. Paediatr Anaesth. 2005;15:643647.
98. Tanaka M, Sato M, Saito A, Nishikawa T. Reevaluation of rectal ketamine

premedication in children. Anesthesiology. 2000;93:12171224.
99. Ghai B, Granhe R, Kumar A, Chari P. Cpmparitive evaluation of midazolam and ketamine with midazolam alone as oral premedication.
100. Darlong V, Shende D, Subramanyam M, et al. Oral ketamine or midazolam or low dose combination for premedication in children. Anaesth
101. Hahnenkamp K, Honemann C, Fischer L, et al. Effect of different anaesthetic regimes on the oculocardiac reflex during paediatric strabismus
surgery. Paediatr Anaesth. 2000;10:601608.
102. Erb T, Ryhult S, Duitman E, et al. Improvement of motor-evoked
potentials by ketamine and spatial facilitation during spinal surgery in
a young child. Anesth Analg. 2005;100:16341636.
103. Dal D, Kose A, Honca M, et al. Efficacy of prophylactic ketamine in preventing postoperative shivering. Br J Anaesth. 2005;95:
189192.
104. Barbi E, Marchetti F, Gerarduzzi T, et al. Pretreatment with intravenous
ketamine reduces propofol injection pain. Paediatr Anaesth. 2003;13:
764768.
105. Liou J, Hsu J, Liu F, et al. Pretreatment with small-dose ketamine reduces
withdrawal movements associated with injection of rocuronium on
pediatric patients. Anesth Analg. 2003;97:12941297.
106. Satsumae T, Yamaguchi H, Sakaguchi M, et al. Preoperative small-dose
ketamine prevented tourniquet-induced arterial pressure increase in
orthopedic patients under general anesthesia. Anesth Analg. 2001;92:
12861289.
107. Golparvar M, Saghaei M, Sajedi P, Razavi S. Paradoxical reaction
following intravenous midazolam premedication in pediatric patients
a randomized placebo controlled trial of ketamine for rapid tranquilization. Paediatr Anaesth. 2004;14:924930.
108. Treston G. Prolonged pre-procedure fasting time is unnecessary when
using titrated intravenous ketamine for paediatric procedural sedation.
Emerg Med Australas. 2004;16:145150.
109. Himmelseher S, Durieux M. Revising a dogma: ketamine for patients
with neurological injury? Anesth Analg. 2005;101:524534.
110. Schmidt A, Ryding E, Akeson J. Racemic ketamine does not abolish
cerebrovascular autoregulation in the pig. Acta Anaesthesiol Scand. 2003;
47:569575.
111. Anand K, Garg S, Rovnaghi C, et al. Ketamine reduces the cell death
following inflammatory pain in newborn rat brain. Pediatr Res. 2007;62:
283290.
112. Williams G, Philip B, Chu L, et al. Ketamine does not increase pulmonary vascular resistance in children with pulmonary hypertension undergoing sevoflurane anaesthesia and spontaneous ventilation. Anesth
Analg. 2007;105:15781584.
113. Malinovsky J, Servin F, Cozian A, et al. Ketamine and norketamine
plasma concentrations after I.V., nasal and rectal administration in
114. Kennedy R, Porter F, Miller J, Jaffe D. Comparison of fentanyl/
midazolam with ketamine/midazolam for pediatric orthopedic emergencies. Pediatrics. 1998;102:956963.
115. Godambe S, Elliot V, Matheny D, Pershad J. Comparison of propofol/
fentanyl versus ketamine/midazolam for brief orthopedic procedural
sedation in a pediatric emergency department. Pediatrics. 2003;112:
116123.
116. Luhmann J, Shootman M, Luhmann S, Kennedy R. A randomized
comparison of nitrous oxide plus hematoma block versus ketamine plus
midazolam for emergency department forearm fracture reduction in
children. Pediatrics. 2006;118:10781086.
117. Tosun Z, Aksu R, Guler G, et al. Propofol-ketamine vs propofol-fentanyl
for sedation during pediatric upper gastrointestinal endoscopy. Paediatr
Anaesth. 2007; 17:983988.
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Opioid Analgesic Agents

Jason A. Hayes and Daisy T. Joo
INTRODUCTION
In the past, the administration of analgesic drugs to pediatric
patients was thought to be unnecessary and even unsafe. However,
it is now recognized that the management of pain is integral to the
care of children undergoing anesthesia and surgery. In addition,
the role of anesthesiologists as providers of pain control now
extends beyond the recovery room and includes not only surgical
patients but also those with pain secondary to medical conditions
such as cancer and sickle cell disease.
Opioid drugs have always been a central component of the
armamentarium available for the management of pain in children,
and significant advances in their use continue to be made. These
include the introduction of new agents with unique pharmacokinetic and pharmacodynamic properties and new uses for
established opioids. Unfortunately, there continues to be a relative
paucity of data regarding the use of opioids in children.
This chapter summarizes current knowledge of opioid pharmacology, including the expanding role of pharmacogenetics, and
reviews opioid that are commonly used in children, with an emphasis on the effects of age on opioid pharmacology.
25
C H A P T E R
cases, however, opioids have similar receptor affinities but very

different physiologic effects. This is explained by different potencies or ability to activate the receptors. For example, morphine,
OPIOID RECEPTORS
Opioids produce analgesia by binding to opioid receptors, which
are located in the peripheral nervous system (following inflammation); on pre- and postsynaptic neurons in the spinal cord
including those which form the ascending pain transmission
pathway and, in particular, brain nuclei in the thalamus, midbrain,
and medulla as well as in neurons composing the descending
inhibitory pathway that modulates spinal cord pain transmission.1
Activation of opioid receptors produces an analgesic response by
three main mechanisms.2 First, calcium ion entry through calcium
channels is decreased resulting in a decrease in presynaptic excitatory neurotransmitter release, that is, of glutamate. Second,
potassium ion efflux through specific potassium channels is enhanced resulting in the hyperpolarization of postsynaptic neurons
and inhibition of action potentials. Third, there is inhibition of
adenyl cyclase activity and a reduction in intracellular cyclic
adenosine monophosphate (cAMP). These processes occur via the
activation of an opioid receptorassociated G protein that regulates transmembrane signaling through the activation of effect or
proteins (Figure 251).
There are currently four known opioid receptors, mu, sigma,
kappa, and delta, with subtypes of each. Different opioids have
different affinities for each receptor type, which partly explains
the different pharmacodynamic effects of each opioid. In some
Figure 25-1. Mu opioid receptor activation. A: In the absence of

agonist binding, the receptor remains in an inactive state. The inhibitory G protein (Gi/o) consists of three subunitsalpha, beta,
and gamma. It is bound to the guanosine 5-diphosphate (GDP)
at its alpha subunit. B: During binding with the opioid receptor
agonist, a change in the shape of the receptor facilitates binding
of the Gi/o with the receptor. C: The association between the opioid receptor and the Gi/o reduces the affinity of the GDP to its alpha subunit. The presence of Mg2+ ions favors the guanosine 5triphosphate (GTP) binding to the alpha subunit over the GDP.
D: The GTP bound Galphai/o dissociates from Gbeta-gammai/o
which allows these components to modulate the proteins of the
effector adenyl-cyclase and the ion channels. The affinity of the
opioid receptor is reduced by the dissociation of the Gi/o subunits from the receptor. E: The intrinsic GTPase hydrolyzes the
GTP to GDP by releasing the phosphate anion which drives the
effector protein process. Yaster M, Kost-Bayerly S, Maxwell LG.
Opioids agonists and antagonists. In: Schechter NL, Berde CB,
Yaster M, editors. Pain in Infants, Children and Adolescents.
2nd ed. Lippincott Williams & Wilkins, 2003, p. 7185.
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TABLE 25-1. Receptor Activity of Opioid Drugs

Receptor Subtype
Drug
Mu
Kappa
Morphine
Hydromorphone
Meperidine
Fentanyl
Sufentanil
Alfentanil
Remifentanil
Methadone
Tramadol
Oxycodone
Pentazocine
Nalbuphine
Buprenorphine
Naloxone
+++
+++
+++
+++
+++
+++
+++
+++
++
+++
+/
Sigma
Delta Receptors
++
++
+/
++
Kappa1 opioid receptor stimulation produces analgesia at the spinal level, sedation, miosis, and inhibition of antidiuretic hormone
release. Activation of kappa3 opioid receptors, which are the most
ubiquitous type of opioid receptor in the brain, produces supraspinal analgesia. The role of the kappa2 opoid receptor is unknown.
++
Key: +++ = agonist; +/ = partial agonist; = antagonist.

Adapted from Yaster M, Kost-Byerly S, Maxwell LG. Opioid agonist and
antagonists. In: Schechter NL, Berde CB, Yaster M, editors. Pain in Infants,
Children, and Adolescents. 2nd ed. Philadelphia: Lippincott Williams & Wilkins;
2003. pp. 181224; and Miyoshi HR, Leckband SG. Systemic opioid analgesics.
In: Loeser JD, editor. Bonicas Management of Pain. 3rd ed. Philadelphia:
nalbuphine, and naloxone each have similar affinities for the mu,
kappa, and delta opioid receptors3 but almost opposite effects
(Table 251).
Delta opioid receptors are located in the pontine nucleus, amygdala, olfactory bulbs, and deep cortex. Both delta opioid receptor
subtypes (delta1 spinal, delta2 supraspinal) produce euphoria and
analgesia. Delta opioid receptors may have a role in the activation
of the development of tolerance.
Although each opioid drug binds with relatively greater affinity
to mu1 opioid receptors in order to provide analgesia, there is also
nonspecific binding of the opioid at other opioid receptor subtypes
resulting in varying side effect profiles. As well, opioids can be
classified into three categories depending upon their intrinsic
activity or pharmacologic effect once bound to the opioid receptor.
Pure opioid receptor agonists, such as morphine and fentanyl,
initiate cellular alterations resulting in the pharmacologic effect
characterized by analgesia and commonly recognized opioidrelated side effects. Partial agonists or mixed agonist-antagonist
opioids, such as nalbuphine, have some agonist effects when
bound to opioid receptors but produce less than a maximal response by competing with endogenous full agonists for binding
sites. These drugs are often full or partial agonists at the kappa and
sigma opioid receptors and partial agonists or antagonists at the
mu opioid receptor. Pure opioid antagonists, such as naloxone,
occupy the receptor-binding sites without producing any cellular
response (Table 252).
Mu Receptors
Mu opioid receptors are located in the cortex (cortical laminae III
and IV, thalamus) and brainstem (periaqueductal gray matter) and
are the most common type of opioid receptor in the spinal cord
(substantia gelatinosa). Two subtypes have been identified: stimulation of mu1 opioid receptors produces supraspinal analgesia
(brainstem and higher), whereas activation of mu2 opioid receptors
produces spinal analgesia. The most common opioid side effects
such as respiratory depression, inhibition of gastrointestinal motility,
decreased heart rate, and sedation are mediated by mu2 opioid
receptors in the brainstem. Peripheral mu opioid receptors exist and
produce localized analgesia in the absence of systemic absorption.3
Sigma Receptors
Sigma receptors tend to be concentrated in the brain in areas involved in motor functions and in limbic areas, sensory areas, and
areas associated with endocrine function. Peripheral organs, such
as the gastrointestinal tract, liver, and kidneys, contain high concentrations of sigma opioid receptors. Two subtypes have been
postulated, but exact roles of each are not clear. With respect to
pain, sigma1 opioid receptor agonists, such as haloperidol, have
been shown to potentiate opioid analgesia but have no intrinsic
analgesic activity.
Kappa Receptors
Kappa opioid receptors are located in the hypothalamus, periaqueductal gray matter, and substantia gelatinosa of the spinal cord.
DEVELOPMENTAL ASPECTS
All opioid receptors exist in the newborn. The development of
nociceptive pathways is well understood in animals but not in
humans. Ascending nociceptive pathways are immature at a time
period corresponding to the third trimester of the human fetus:
C fibers are not functionally mature, and A fibers terminate in
the spinal cord. In addition, there may be an age-related change in
receptor function or location (pons and medulla in newborns)
based on findings of increased sensitivity of newborn rats to the
respiratory depressant effects of opioids despite a 40-fold higher
dose requirement for analgesia.4 Therefore, although neonates
experience pain, it probably differs considerably from that of an
adult. Otherwise, children appear to be similar to adults with respect to opioid requirements and risk of side effects.5
PHARMACOGENETICS
The effect of genetic differences on opioid pharmacokinetics,
pharmacodynamics, and interactions with other drugs is becoming
better understood. One example is decreased or absent metabolism
of codeine to morphine caused by mutations of cytochrome (CYP)
P450 2D6. It has been estimated that 47% of children are poor
metabolizers and 4% are nonmetabolizers of codeine.6 Because
codeine is a much weaker mu opioid receptor agonist than morphine, it has limited or no analgesic activity in such individuals.
However, these patients still experience typical opioid-related side
effects owing to the binding of mu opioid receptors by codeine.
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Opioid Analgesic Agents 389
TABLE 25-2. Equianalgesic Dose Ratiosa

Drug
Equipotent I.V.
Dose, mg/kg
Ratio of Potency
to Morphine I.V.
I.V. to p.o.
Conversion Ratio
Equipotent p.o.
Dose, mg/kg
Ratio of Potency
to Morphine p.o.
References
Morphine
Hydromorphone
Meperidine
Fentanyl
0.1
0.020.03a
0.501
0.010.0125
1
3.55b
0.10.14
80100
1:23
1:5c
1 :3
1:1d
1
3.55b
0.10.14
70100
48
40, 48, 84
105, 275, 276
40, 48, 137
Sufentanil
Alfentanil
Remifentanil
Methadone
Tramadol
0.0010.0025
0.040.0875
0.0670.01
0.1
12
4001000
1125
5575
1
0.070.14
n/a
n/a
n/a
1:1
1:1g
n/a
n/a
n/a
414e
0.1
139
154, 158
180
40, 48
208210, 277
Oxycodone
Pentazocine
Nalbuphine
Buprenorphine
0.1
0.20.4
0.050.2
0.00150.003
0.71
0.250.5
1
40
0.50.8:1
1:3
n/ag
1:2
0.20.3
0.040.08
13
Minimum
12.5 g/hd
n/a
n/a
n/a
0.1
12 (tabs)
23 (liquid)
0.1
0.61.2
n/a
0.006h
1.52
0.250.5
n/a
40
278280
244
130, 255, 258
266, 267
a
Equianalgesic dose ratios apply to patients on stable doses of opioids and should be used as guidelines only. Appropriate patient evaluation and clinical judgment are
necessary before the use of equianalgesic dose ratios. Ranges reflect the high degree of interpatient variability.
b
If converting morphine hydromorphone, use lower dose; if converting hydromorphone morphine use higher dose.
c
Data from bioavailabilty studies with high variability reported (1:15).
d
Conversion to transdermal fentanyl patch based on average hourly consumption of intravenous fentanyl. Transition from fentanyl I.V. should be done in a stepwise
fashion.
e
Conversion ratio for morphine methadone is highly dependent on dose of morphine: < 90 mg/d morphine p.o.:methadone p.o. = 49:1; 90300 mg/day
morphine p.o.:methadone = 810:1; >300 mg/d morphine p.o.:methadone p.o. = 1214:1.
f
Oral bioavailability increases from 68% to almost 100% with repeat doses.
g
n/a = not available in oral form.
h
Sublingual administration.
A study of CYP2D6 polymorphism in neonates found only 30%

carried the wild-type with a normal level of activity.7 Duplications
of active CYP2D6 alleles can also result in increased activity levels
resulting in an ultrarapid metabolizer phenotype, which occurs in
1 to 7% of the white population,8 with at least two reported cases of
codeine-related morbidity.9,10
The single nucleotide polymorphism (SNP) A118G of the
mu opioid receptor causes a decreased potency of morphine,
morphine-6-glucuronide, and alfentanil at these receptors.8
However, heterozygous and homozygous carriers of the A118G
SNP may benefit from protection against opioid- and metaboliterelated side effects, resulting in a broadened therapeutic index for
opioid analgesics in such individuals.11,12
OPIOID-RELATED ADVERSE EFFECTS

Respiratory
Respiratory depression is dose-dependent and is most pronounced
with opioids that have a high affinity for mu opioid receptors
located in the brainstem, such as morphine, fentanyl, alfenatnil,
remifentanil, and sufentanil. Small doses of opioids reduce respiratory rate and disrupt the rhythm of breathing. With increasing
doses, the tidal volume is reduced as well; however the doseresponse for respiratory depression is extremely variable between
patients.13 In addition, the increase in alveolar ventilation in
response to elevated arterial carbon dioxide pressure (PCO2) or
decreased arterial oxygen pressure (PaO2) levels is blunted by
opioids.14
Cardiovascular
In general, all opioids reduce the tone of the sympathetic nervous
system. Arterial hypotension may ensue in patients who require an
elevated sympathetic tone to maintain cardiac output and systemic
perfusion (hypovolemia, low cardiac output states). All opioids
reduce heart rate, with the exception of meperidine, which causes
tachycardia.15 This may be related to the structural similarity
between meperidine and atropine. Morphine may also cause a
reflex tachycardia in response to vasodilatation owing to histamine
release. Bradycardia, particularly with fentanyl, is mediated by
stimulation of the central vagal nucleus and can be blocked pharmacologically with atropine. By contrast, remifentanil-induced
bradycardia appears to be mediated by parasympathetic activation or a direct negative chronotropic effect, which cannot be
blocked by antichiolinergic drugs,16 but resolves rapidly after
discontinuation of remifentanil administration.17 Meperidine
has a dramatic detrimental effect on myocardial contractility18 and
is not suitable for use as an anesthetic in patients with cardiovascular disease. Changes in vasomotor tone occur primarily
because of histamine release after morphine and meperidine
administration.19 Arterial dilatation occurs first in humans, followed by venodilatation, which lasts longer and results in a decrease in preload.
Gastrointestinal
All opioids reduce gastrointestinal motility by binding primarily
to mu and delta opioid receptors in the bowel, with little or no
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central mechanisms.20 The effect on bowel peristalsis occurs at

significantly lower doses than analgesic effects, and tolerance to
constipation does not develop as it does to other opioid effects,
such as analgesia.21 Opioids also produce an increase in tone of
the pyloric sphincter, sphincter of Oddi, and ileocecal valve. There
is debate as to whether some opioids, such as morphine, produce
more biliary spasm and a greater increase in sphincter of Oddi
tone than other pure mu opioid agoinsts (fentanyl, meperidine).22
However, one review suggests that there is no difference in this
effect between morphine and meperidine at equianalgesic doses.23
Opioid agonist-antagonists may cause less increase in sphincter
tone than pure agonists and may be the best choice in high-risk
patients.24
Opioids induce nausea and vomiting by binding to mu and
delta opioid receptors present in the chemoreceptor trigger zone,
located in the area postrema of the medulla.25 Activation of
peripheral opioid receptors (mu and delta) located in the stomach
and small and large bowel decrease motility and delay gastric emptying. All opioids produce emetic symptoms when administered
in equianalgesic doses.
Urinary Tract
Opioids can cause urinary retention by partially inhibiting parasympathetic nerve innervation of the bladder, which causes total
bladder relaxation and reduces the sensation of fullness, and by
increasing the tone of the bladder sphincter by sympathetic overstimulation.26
Pruritus
Opioid-induced pruritus is mediated primarily by mu opioid
receptors located in multiple sites in the brain, such as the medullary dorsal horn, and spinal cord.27 Activation of central dopamine
(D2) and serotonin (5-HT3) receptors may also play a role in
mediating opioid-induced pruritus.27 Degranulation of mast cells
and release of histamine by systemically administered opioids,
particularly morphine, are thought play a minor role in the
pathogenesis of opioid-induced pruritus.
Drug Interactions
There is growing evidence that the phenylpiperidine class of
opioid analgesics, such as meperidine, tramadol, methadone, and
fentanyl (and congeners), are weak serotonin re-uptake inhibitors.28 When used in combination with monoamine oxidase
inhibitors (MAOIs), this group of opioids can potentially precipitate acute serotonin toxicity, which is characterized by neuromuscular and autonomic hyperactivity and altered mental status. The
vast majority of case reports have occurred with meperidine and
tramadol. Serotonin toxicity occurs in a dose-dependent fashion
and is not idiosyncratic, as once thought. The serotonin re-uptake
potency of fentanyl and its derivatives, such as remifentanil, is so
low that its use in the presence of MAOIs is probably not strongly
contraindicated.28 Although the morphine analogues, including
codeine, oxycodone, and buprenorphine, do not appear to have
any serotonin re-uptake activity,28 toxicity with the combination of
oxycodone and a selective serotonin re-uptake inhibitor (SSRI;
fluvoxamine) has been reported.29
Management of Opioid-Related Side Effects

Although the severity of opioid side effects is generally dosedependent, the potential for side effects varies from patient to
patient. Therefore, it may be possible to reduce the severity of side
effects in a patient by switching to a different opioid instead of
reducing the dose. The addition of different classes of analgesic
agents, such non-steroidal anti-inflammatory drugs and N-methylD-aspartate (NMDA) receptor antagonists, such as ketamine, may
allow for a reduction in opioid consumption without loss of analgesic efficacy.
Opioid antagonists, such as naloxone, and mixed agonistantagonists, such as nalbuphine, can be used to counteract opioidrelated side effects. Studies in both adults and children have shown
that the incidence and severity of nausea and pruritus can be
reduced without affecting analgesia.30 However, the incidence of
vomiting, sedation, and urinary retention appears to be unchanged, and these drugs may be effective only for prevention, not
treatment, of pruritus.31,32 Although epidural33 and oral34 naloxone
has been shown to reduce postoperative ileus, a systematic review
concluded that insufficient evidence exists for the efficacy of
naloxone in the treatment of opioid-induced bowel dysfunction
and that the incidence of anxiety or jitteriness caused by reversal
of central opioid effects may be higher.35 Two mu opioid receptor
antagonists that do not cross the blood-brain barrier, methylnaltrexone and alvimopan, are currently in development. Studies
to date suggest that methylnaltrexone is an effective treatment for
opioid-induced constipation and postoperative ileus in humans
and nausea and vomiting in animals.3537 Alvimopan has also been
shown to reduce postoperative ileus in humans with no detrimental effects on analgesia.35,38,39
PERIOPERATIVE PAIN MANAGEMENT

Management of perioperative pain is an increasingly important
component of modern pediatric anesthesia practice and often
involves the conversion of one opioid to another, because of side
effects or analgesic inefficacy, or from one route of administration
to another, such as intravenous to oral dosing. Although all opioid
agonists produce similar analgesic effects at equipotent doses,
there is a large amount of interindividual variability in opioid
requirements, and equianalgesic dose ratios between opioids can
vary depending on patient comorbidities, duration of treatment
with opioids, and the dose of opioid before a switch from one
agent to another.40 A table of equianalgesic dose ratios is provided
as a guideline for conversion between opioids and routes of administration. However, dosing guidelines are an oversimplification
of a complex process, and exact doses should be guided by appropriate patient assessment and clinical evaluation.
The use of parent-, nurse-, or patient-controlled analgesia
(PCA) administration has become more widespread in children.41
A pump is programmed to deliver a bolus amount of drug on demand, with or without a continuous infusion, with an appropriate
lockout interval and dose limit over 2 or 4 hours. The addition of
a continuous or background infusion may not provide additional
analgesia despite a larger cumulative dose of opioid42 but may be
necessary for younger children. In children too young or physically incapable of using a PCA device, nurse- or parent-controlled
analgesia is an option. However, it has been suggested that nurses
underestimate the severity of patients pain and underdose relative
to PCA.42
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OPIOID TOLERANCE
Opioid therapy for acute and chronic pain control is often complicated by the development of tolerance. Acquired tolerance is the
reduction in analgesic effect resulting from repeated administrations of an opioid. This is different from innate tolerance determined by pharmacogenetic factors, which is apparent upon
administration of the first dose of an opioid.43 From herein, this
discussion of tolerance refers to acquired tolerance to opioids.
Cross-tolerance to other opioids often occurs with tolerance development to one of the opioids.44
Mechanisms of opioid tolerance may include reduced internalization and membrane recycling of opioid receptors, superactivation of adenyl cyclase and increase in intracellular cAMP,
altered association of from inhibitory to stimulatory G proteins
with the opioid receptors, calcium channel up-regulation and
enhanced glutamate release, and postsynaptic NMDA receptor upregulation.45 There are few if any studies on these mechanisms in
the pediatric population. Based on these mechanisms, which presumably are intact in the pediatric patient, strategies for opioid
rotation, use of low-dose opioid receptor inhibition with naloxone,
and use of NMDA receptor inhibitor therapy with methadone or
ketamine have been attempted with limited efficacy after opioid
tolerance development. Unfortunately, tolerance to opioid administration continues to hinder analgesic therapy with this class of
medications for which there are few solutions.
OPIOID AGONISTS
Morphine
Morphine provides analgesia that is equivalent to46 or better than47
that provided by other opioids and is the standard against which
other opioids are evaluated.
Pharmacokinetics
The bioavailability of oral morphine is approximately 38% (range
1565%)48 owing to extensive metabolism in the intestinal mucosa
and liver. The volume of distribution (Vd) is proportionately larger
in preterm than in full-term neonates and is independent of both
gestational age and postnatal age in both groups.49 In preterm
infants, less than 20% of morphine is bound to plasma proteins
compared with 35% in adults.48,50 The Vd reaches adult values
within the first few months after birth. Morphine clearance is
lowest in preterm infants (0.54 mL/kg/min) and highest in young
children (2040 mL/kg/min), with older children and adults
roughly in between (1020 mLl/kg/min).5,4954 The age-dependent
changes in clearance result in large differences in elimination,
ranging from 10 to 20 hours in preterm infants to 1 to 2 hours in
young children and 2 to 4 hours in older children and adults.5054
Although morphine elimination is primarily by hepatic metabolism, it is not significantly affected by liver disease. Approximately
10% of morphine is excreted unchanged in the urine.55 Sick preterm infants, however, excrete larger amounts of unmetabolized
morphine than older children or adults.56 Morphine is glucuronidated at the 3- and 6-positions by the age-dependent enzyme
uridine 5-diphosphate gluronosyl transferase (UGT)-2B7 to
morphine-3-glucuronide and morphine-6-glucuronide in at
least a 2:1 ratio, respectively.57,58 Morphine-6-glucuronide is 100
times more potent than morphine, but its greater hydrophilicity
impedes passage across the blood-brain barrier. It is still active

systemically but provides minimal contribution to the analgesic
efficacy of morphine.59 Morphine-3-glucuronide is pharmacodynamically inactive.60 Excretion of morphine-6-glucuronide
is renal as opposed to hepatic for morphine; thus, accumulation
can occur with renal impairment, making the metabolite the
predominant agent responsible for analgesia and side effects.3,60
Neonates younger than 7 days old metabolize morphine to a lesser
degree than older neonates, as evidenced by a lower ratio of
plasma morphine-6-glucuronide to morphine despite similar
doses.13
Pharmacodynamics
Analgesia following systemic administration is mediated predominantly by activation of supraspinal mu1 opioid receptors.
Morphine analgesia at the level of the spinal cord is mediated by
mu2 opioid receptors, which has become more important with the
use of intrathecal and epidural routes of administration.61 Morphine may also have a synergistic effect when administered concomitantly at spinal and supraspinal levels.3 Thus, intense
analgesia after epidural or spinal morphine administration may
be explained by the combined effects of high concentrations at the
spinal cord and systemic levels similar to those after intramuscular
injection.
Oral morphine is available in immediate- and controlledrelease formulations. Short-acting morphine is administered every
3 to 4 hours as required, and long-acting every 12 hours. The dose
of long-acting morphine is determined by dividing the total
amount of morphine administered over 24 hours into two doses.
Parenteral morphine can be given via intravenous, subcutaneous, and intramuscular routes approximately every 3 to
4 hours. A continuous intravenous infusion of morphine is commonly used in pediatric patients for postoperative analgesia at a
dose range of approximately 5 to 40 g/kg/h. Postoperative
morphine requirements increase with gestational and postnatal
age13,62 and noncardiac versus cardiac surgery.63 A steady-state
plasma morphine concentration of 10 to 15 ng/mLl can be achieved in children after noncardiac surgery with a morphine infusion
of 5 to 7.5 g/kg/h at term birth, 8.5 to 12.5 g/kg/h at 1 month of
age, 13.5 to 20 g/kg/h at 3 months of age, 18 to 28 g/kg/h at
1 year of age, and 16 to 25 g/kg/h at 1 to -3 years of age.11,64 However, plasma morphine levels do not directly correlate with
analgesic efficacy owing to the low lipid solubility of morphine
and its inability to cross the blood-brain barrier. Therefore, the
dose for each patient must be titrated to effect carefully, because
there is a wide variation in the dose required to achieve analgesia.65
In neonates, the duration of postoperative mechanical ventilation
directly correlates with the dose and duration of morphine
infusion.66 Intravenous administration of morphine by a PCAa
device is commonly used in children older than 5 years.67
Morphine can be administered into the epidural or caudal
space as a single dose or continuous infusion either alone or in
combination with other drugs, such as local anesthetics. Morphine
has a relatively low lipid solubility compared with other opioids,
such as fentanyl, and thus, relatively less morphine is absorbed
into the systemic circulation from the epidural space and cerebrospinal fluid. Plasma morphine concentrations are negligible for
the first 2 hours after the administration of epidural morphine
0.025 mg/kg,68 and morphine is detectable in cerebrospinal fluid,
but not plasma, 18 hours after an intrathecal injection.69 Lumbar
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epidural or caudal morphine can be administered as a bolus dose

of 25 to 100 g/kg.62,68,7072 The onset of analgesia of epidural
morphine occurs within 5 minutes.68 Single doses of epidural morphine 0.025 and 0.05 mg/kg are equivalent in terms of analgesic
efficacy and duration of action (~78 h).68 Larger doses may result
in a longer duration of action but will likely produce more severe
side effects. A single dose of caudal morphine 30 g/kg does not
blunt the neuroendocrine stress response to surgery compared
with local anesthetic despite similar postoperative analgesia.73
Intrathecal morphine spreads in a cephalad direction with the flow
of cerebrospinal fluid, reaching the brainstem within 6 hours after
administration. Thus, ventilatory depression is maximal 6 hours
after administration and lasts for over 18 hours.69 Infants do not
appear to be more sensitive to ventilatory depression than older
children.69 Doses of intrathecal morphine used in children undergoing a variety of surgical procedures range from 2 to 30 g/kg,
but the trend is to use the lowest dose possible to minimize
the incidence of side effects.74,75 The time to first postoperative
analgesic requirement appears to be dependent on the dose of
intrathecal administered, with doses as low as 2 g/kg showing
benefit compared with placebo after pediatric scoliosis surgery.76
Although the administration of intrathecal morphine reduces
postoperative opioid consumption, there does not appear to be a
concomitant reduction in opioid-related side effects compared
with intravenous opioids alone.76,77 The administration of intrathecal morphine 5 g/kg or higher, alone or with intrathecal
sufenatnil, reduces intraoperative blood loss during scoliosis correction surgery, possibly through a reduction of intraoperative
mean arterial pressure.7678
Morphine has been shown in animals to have a peripheral analgesic effects via opioid receptors expressed in inflamed tissue.79,80
Intra-articular injection in humans produces intense analgesia
with no systemic absorption.81
Hydromorphone
Hydromorphone is a semisynthetic hydrogenated ketone derivative of morphine. Despite its similarities, hydromorphone is
generally viewed as a second-line alternative to morphine and is
often used as part of an opioid rotation in an attempt to improve
analgesia and reduce opioid-related side effects.82
Pharmacokinetics
Oral hydromorphone is available in a liquid preparation and
immediate-release and controlled-release tablets. Oral bioavailability is approximately 60% with high interindividual variability83,84
Maximum plasma levels are reached about 1 hour after administration of an immediate-release dose83 and 4 to 6 hours after
a controlled-release dose.85 The bioavailability of intranasal hydromorphone is approximately 55%, with a time to peak plasma
concentration of 20 to 25 minutes.46 The degree of lipid solubility
and Vd of hydromorphone (1.2 L/kg) are similar to that of morphine in adults.83,86 Approximately 7% of hydromorphone is protein
bound in adults.87 Systemic clearance of hydromorphone is dependent on hepatic blood flow and affinity to erythrocytes.87 The
clearance of hydromorphone in children shows great variability,
with a mean of 51 mL/kg/min88 compared with 14 mL/kg/min in
adults.87 Hydromorphone is metabolized to hydromorphone-3glucuronide in a ratio similar to that of morphine and morphine3-glucuronide.85 This metabolite has been shown to produce
excitatory nervous system effects, including seizures in rats, but

there are no clinically relevant studies in humans supporting a
neuroexcitatory effect of hydromorphone-3-glucuronide. Both
unconjugated hydromorphone and its conjugated metabolites are
renally excreted. Approximately 6% of the parent drug is excreted
in unconjugated form.89 The elimination half-life (t / ) of hydromorphone is approximately 2.5 hours.83 In the presence of even
mild renal impairment, the plasma levels of hydromorphone-3glucuronide may reach 100 times that of the parent drug85 and may
potentially produce symptoms signs of opioid toxicity, including
increasing pain.
1
Pharmacodynamics
The pharamcodynamic characteristics of hydromorphone are very
similar to those of morphine, such that the World Health Organization has recommended hydromorphone as the opioid alternative to morphine. Hydromorphone provides equivalent analgesia
to other potent opioids when given in equianalgesic doses for
chronic (primarily cancer-related) and acute (trauma, postoperative) pain.84,90
Immediate-release hydromorphone has an onset of action of
approximately 30 minutes and a duration of action of about
4 hours. A typical oral dose is 40 to 80 g/kg every 3 to 4 hours.
In children undergoing burn wound dressing care, immediaterelease hydromorphone 60 g/kg provided equivalent analgesia
to oral transmucosal fentanyl 10 g/kg, with a low incidence of
side effects.91
The onset of action of hydromorphone after intravenous
administration is approximately 5 minutes, although peak effect
does not occur for 20 minutes owing to relatively low lipid solubility and delayed passage across the blood-brain barrier.46 Early
studies described a lower incidence of side effects with hydromorphone than with morphine.92,93 However, a large systematic
review did not find any differences between the two opioids with
respect to analgesic efficacy or side effect profile.90
The epiduraltoparenteral dose ratio of hydromorphone has
been estimated at 1:2.94 Hydromorphone may be preferable to
either morphine or fentanyl for epidural administration in pediatric patients.93 Epidural hydromorphone administered at 1 g/
kg/h provides equivalent analgesia to morphine with fewer side
effects and, potentially, may provide better analgesia than fentanyl
in cases in which the epidural catheter placement is not placed at
the surgical level.93 When combined with local anesthetic, a
hydromorphone concentration of 10 g/mL can be used.95 Caudal
hydromorphone 10 g/kg has been compared with caudal morphine 50 and 100 g/kg in children undergoing urologic96 and
cardiac97 surgery, respectively. No significant differences in quality
of analgesia and side effects were detected between the two
opioids.
Meperidine
Meperidine, or pethidine, is a synthetic opioid derived from
phenylpiperidine.
Pharmacokinetics
Meperidine can be administered orally in tablets and liquid form.
Oral bioavailability is approximately 50%. The median steady-state
volume of distribution in preterm and term neonates and infants
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is 7.2 L/kg (range 3.311.0 L/kg),98 and 2.8 L/kg (standard deviation [sd] 0.6 L/kg) in children.99 Clearance of meperidine is approximately 8 to 10 mLl/kg/min98 and is typically lower in
neonates and infants than in older children. Meperidine is
metabolized by N-demethylation to normeperidine, which is 50%
less active as meperidine as an analgesic but twice as active as a
convulsant. Normeperidine is renally excreted or further metabolized to normeperidinic acid.60 Patients administered repeated
doses of meperidine, particularly in the context of renal dysfunction,100 are at increased risk of normeperidine accumulation
and toxicity,101103 which manifests as tremors, myoclonus, and
seizures. The metabolism of meperidine to normeperidine is
approximately seven times less in neonates than adults.104 The
elimination t / in neonates and infants is also much longer (10.7 h,
range 3.359.4 h)98 than in older children (3.0 h, sd 0.5 h).99
1
Pharmacodynamics
The pharmacodynamic profile of meperidine is very similar to
that of morphine and offers no significant clinical benefits, other
than for the treatment of shivering. The negative aspects of
meperidine have greatly reduced its use in children.
The time to onset of analgesia of oral meperidine is approximately 15 to 30 minutes, with a time to peak plasma concentration
of 1 to 2 hours.
Peak serum levels occur within 5 minutes after intravenous
administration in children.99 Meperidine is associated with fewer
opioid-related side effects than fentanyl when used for postoperative analgesia in children.105 Meperidine has been used as part
of a lytic cocktail (meperidine-promethazine-chlorpromazine)
to sedate children for nonpainful diagnostic procedures. However,
concerns regarding the safety of this mixture have been raised, with
calls for strict guidelines for its use.106 Meperidine can be used
to treat postoperative shivering, which appears to be mediated
by binding to kappa opioid receptors.107 A smaller dose, such as
0.35 mg/kg, is usually effective.108
Fentanyl
Fentanyl, sufentanil, alfentanil, and remifentanil are synthetic opioids belonging to the anilidopiperidine family of agents.
These opioids have a higher potency of action that is selective for
the mu opioid receptor.
Pharmacokinetics
The pharmacokinetics of fentanyl in children are best described by
a two-compartment model using both age and weight as covariates.109 The bioavailability of fentanyl administered by the transmucosal route is approximately 33%.110 Fentanyl is highly lipid
soluble compared with morphine and is widely distributed in
tissues. The Vd at steady state is largest in term neonates and
infants, decreasing to mature levels by adolescence.111 Critically ill
and neonates and children administered fentanyl by continuous
infusion for longer than 24 hours have a larger steady-state volume
of distribution (1517 L/kg) compared with children receiving
single-dose administration, with a resultant prolongation of the
terminal elimination t / .111 Children with cyanotic heart disease
undergoing cardiac surgery have a smaller Vd and higher plasma
fentanyl concentrations than adults.112 This appears to be related
to the severity of hemodynamic disturbance as measured by PaO2
1
levels.113 Clearance of fentanyl is highest in infants, most likely

because of a higher hepatic blood flow per kilogram body weight.111
Clearance in neonates correlates positively with postnatal age but
is still greater than that in older children and adults.114 In patients
with decreased hepatic blood flow or metabolic activity, such as
neonates undergoing abdominal surgery, clearance of fentanyl will
be reduced with a corresponding increase in the duration of
action.115 Because of its high protein binding and lipid solubility,
large volume of distribution, and relatively high molecular weight,
fentanyl cannot be removed by hemodialysis.116 Metabolism of
fentanyl occurs in the liver by the CYP450 enzyme system. The
activity level of this enzyme system reaches maturity within a few
weeks of birth and is not a significant limiting factor to metabolism
and clearance. Fentanyl metabolites are inactive. Because fentanyl
has a high hepatic extraction ratio, its elimination is primarily
dependent on hepatic blood flow. A small amount of fentanyl is
excreted unchanged by the kidneys and may accumulate in patients
with renal failure.116
Pharmacodynamics
These age-related differences in fentanyl pharmacokinetics translate into different pharmacodynamics in pediatric patients compared with adults. For example, after cessation of a fentanyl
infusion, the context-sensitive half-time for fentanyl elimination
is significantly shorter in children.109 Despite larger bolus doses
per kilogram body weight, plasma fentanyl concentrations are
lower in infants than young children, which in turn, are lower than
in adults.117 This translates into higher dose requirements for
children.117
A continuous infusion of fentanyl is commonly used to provide analgesia and sedation in mechanically ventilated pediatric
patients. In this setting, fentanyl reduces the need for additional
sedation and pharmacologic hemodynamic support118 and reduces
markers of neuroendocrine stress response.119 Typical infusion rates
range from 0.5 to 2.5 g/kg/h.118120 A bolus dose of fentanyl 3 g/kg
has been shown to reduce heart rate and measures of pain in
mechanically ventilated preterm neonates.121
Intravenous fentanyl for pediatric surgery blunts the perioperative hormonal stress response and provides greater hemodynamic stability compared to morphine.122 An initial bolus dose
greater than 10 g/kg has been shown to provide 75 to 90 minutes
of anesthesia in neonates,123 with a reduction in intraoperative and
postoperative catecholamine levels.124 Typical cumulative doses
for cardiac surgery are 50 to 150 g/kg.122,125,126 The addition of a
continuous fentanyl infusion at 10 g/kg/h does not reduce the
perioperative hormonal stress response compared with high-dose
bolus fentanyl alone.125 Fentanyl 25 g/kg, when combined with
low concentrations of isoflurane, may be as effective as much
higher doses in controlling the neuroendocrine stress response
and hemodynamic responses to surgical stimulation during the
prebypass phase of pediatric cardiac surgery.126 Chest wall rigidity
is a commonly mentioned side effect of rapid intravenous fentanyl
administration in neonates and children. Doses as low as 2 g/kg
can produce this effect.127 The mechanism may be increased
muscle tone128 and can include muscles of the larynx,129 leading to
laryngospasm, and the tongue,127 resulting in complete airway
obstruction. The increase in muscle tone can be reversed with the
administration of muscle relaxants or naloxone.129
Because of its lipophilicity, epidural fentanyl does not spread
much beyond the level of administration and, therefore, must be
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delivered at or near the level of surgery. Increasing the infusion

rate to achieve analgesia at higher levels may result in higher
fentanyl plasma levels, which may lead to opioid-related side
effects. When compared with epidural morphine, the incidence
of side effects, such as nausea and vomiting and respiratory
depression, are lower but the duration of analgesia is shorter.93
Epidural fentanyl is typically combined with local anesthetic at a
concentration 2 g/mLl and provides improved analgesia compared with local anesthetic alone.62,130
Fentanyl is also available in an oral transmucosal formulation,
which has been used for preoperative sedation and analgesia for
painful procedures or after injuries.91,131133 Children are sedated
within 10 minutes of administration, but whether this translates
into improved conditions at induction of anesthesia is controversial.110,134,135 Nausea or vomiting occurs in up to 30% of patients
and mild pruritus in up to 90%.134 Patients must be closely monitored for decreases in respiratory depression. Side effects are dosedependent, and doses less than 15 g/kg should be used in
pediatric patients. Transmucosal fentanyl can also be administered
intranasally or by nebulizer.
The transdermal route offers an attractive method of fentanyl
administration in children with chronic stable opioid requirements who cannot take oral medications or are not compliant with
oral medications. Transdermal fentanyl patches are available in
12.5-, 25-, 50-, 75-, and 100-g/h preparations. Conversion ratios
between intravenous and transdermal routes are controversial. In
adults, a 1:1 conversion from intravenous to transdermal fentanyl
is generally recommended. Product monograph conversion ratios
for oral morphine to transdermal fentanyl appear to be very
conservative (>100:1)136 compared with clinically determined
ratios (70:1).137 Because the time to onset of analgesia is at least
12 hours, conversion to the transdermal route requires an overlap
of opioid therapies and should be done in a stepwise fashion.48
Children taking more than 30 mg/d of oral morphine can be
converted to transdermal fentanyl 12.5 g/h. Compared with
adults, children may take longer to reach steady-state plasma
concentrations, drug clearance is higher, and younger children
require comparatively higher doses.138 The suggested 72-hour
dosing schedule is probably not applicable in children and should
be reduced to 48 hours instead.138 Given the limited doses available
and gradual onset and offset times, the transdermal route is not
appropriate for the management of pain in the acute setting.
Although drowsiness occurs in the majority (70%) of children,

respiratory depression appears to be much less common.149
Steady-state Vd is largest for neonates and infants younger than
10 months of age (3.74.2 L/kg).141,145 By 2 to 8 years of age, the Vd
is reduced to approximately 2.9 L/kg,140 and in adults, this value
approaches 1.7 L/kg.143 Clearance of sufentanil is lowest in neonates and highest in infants and children,140,145 gradually decreasing to adult levels by 10 to 15 years of age.142,143 Therefore, larger
doses for maintenance of analgesia during surgery may be required in children.140 Clearance of sufentanil is reduced in children
with congenital heart disease.145
The metabolism of sufentanil is mainly by O-demethylation
and N-dealkylation in the liver. Decreased hepatic delivery will
reduce sufentanil metabolism and clearance and increase elimination half-time.140 In children, increased levels of certain isozymes of the CYP450 system have been reported,140 resulting in
enhanced metabolism and clearance of sufentanil compared with
adolescents and adults. Renal elimination of sufentanil is minimal.
In children with chronic renal failure, the Vd and rate of clearance
of unbound sufentanil are unchanged.142
Pharmacodynamics
Sufentanil is a synthetic opioid that is 5 to 10 times more potent

than fentanyl.139
Bolus doses of sufentanil 1 to 3 g/kg reduce the response to

surgical incision. Doses greater than 0.5 g/kg used during short
surgical procedures have been associated with a higher incidence
of vomiting and respiratory depression.150 In pediatric cardiac
surgery, large doses of sufentanil 10 to 15 g/kg have been used as
an analgesic agent after induction145 and as the sole induction
agent.141,144,145 Minimum serum levels of sufentanil required to
maintain suppression of sympathetic-hemodynamic responses
during cardiac surgery are greater for neonates than for infants,
children, and adults.145 This suggests that the efficacy of sufentanil
at mu opioid receptors may be reduced in neonates.
Perioperative analgesia with epidural sufentanil 0.70 to 0.75 g/
kg has been used successfully in children.149,151,152 The onset of
analgesia is rapid with a duration of over 3 hours.149 Administration of epidural sufentanil blunts the neuroendocrine stress
response during cardiopulmonary bypass to a greater degree than
intravenous sufantanil alone.152 Compared with fentanyl, epidural
sufenatnil produces superior analgesia but a higher incidence of
pruritus when administered as a continuous infusion.151
In children, intranasal sufentanil has been used at a dose of 1.5
to 4.5 g/kg with good effect for preoperative sedation and facilitates intubation after induction of anesthesia.153 A transdermal
formulation of sufentanil is currently under development. It has
the advantage over transdermal fentanyl in that it needs to be
applied only once a week.
Pharmacokinetics
Alfentanil
After intravenous administration, sufentanil plasma concentrations decay biexponentially over time consistent with a twocompartment pharmacokinetic model in some studies.140142 In
other studies, the decay is more consistent with a triexponential,
three-compartment model.143145 Maximum serum concentrations
are reached 10 minutes after an intranasal sufentanil dose of
15 g, with a bioavailability of approximately 56%.146 Epidural
sufentanil bolus doses between 10 and 75 g are detectable in
serum within 2 to 5 minutes and can result in respiratory depression in adults.147,148 In children, maximal serum levels occur
30 minutes after administration of epidural sufentanil 0.75 g/kg.
Alfentanil is a potent but short-acting synthetic opioid. Compared

with fentanyl, it has a fourfold shorter time to peak effect but
threefold reduced duration of action.154,155
Sufentanil
Pharmacokinetics
There is controversy as to whether a two-compartment or threecompartment model best describes alfentanil pharmacokinetics
in adults and children.156161 Alfentanil has lower lipid solubility
than fentanyl and is highly protein-bound (>90%).157 Choice of
inhalational anesthetic agent and duration of anesthesia do not
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affect alfentanil pharmacokinetics.162 The Vd of alfentanil has been
reported to be 2.8 times greater in adults (0.57 L/kg) than in
children (0.29 L/kg), presumably owing to lower body fat content
in children.158 However, other studies in preterm infants and
children describe values similar to those in adults.161,163,160 Clearance is lowest in preterm infants (0.87 mL/kg/min)163 and comparable in infants (8.4 mL/kg/min),161 children (7.711.1 mL/kg/
min),161,164 and adults (5.97.6 mL/kg/min).161,164 Cardiopulmonary bypass increases the Vd, but clearance is not significantly
different.160,165
Alfentanil is rapidly eliminated by the liver through oxidation
(mono-oxygenase system)164 with only 1% excreted unchanged by
the kidneys. Both unbound (free) and bound fractions of alfentanil are extracted by the liver and metabolized.159 In liver failure,
there is reduced metabolism and clearance of alfentanil whereas
fentanyl, sufentanil, and remifentanil clearance is maintained.166
The pharmacokinetic profile of alfentanil is unchanged in patients
with chronic renal failure.159 In patients with burn injuries, the
unbound fraction, Vd, and clearance of alfentanil are decreased
and elimination t / is increased.167 The elimination t / is shorter in
children compared with adults (63 min vs 95 min) owing to faster
clearance and similar Vd.164
1
Pharmacodynamics
Alfentanil has a faster onset and offset of action than fentanyl.
After a single bolus dose, redistribution is the most important
mechanism for the termination of alfentanils effects, whereas
elimination is more important after repeated doses or continuous
infusion. Intravenous bolus doses of 10 to 100 g/kg have been
used for induction of anesthesia in children.158,161,163,164,168,169 A
minimum dose of 10 g/kg is required for good to excellent
intubation conditions.168 The pharmacokinetic profile of alfentanil
makes it an excellent choice for administration as a continuous
infusion. The time to a 50% decrease in plasma levels of alfentanil
gradually increases to approximately 60 minutes with infusion
durations of up to 3 hours, then remains relatively constant.170
Typical infusion rates are 1 to 3 g/kg/min.165,169 For pediatric
cardiac surgery, bolus doses up to 200 g/kg have been administered followed by repeat doses of 80 g/kg, with patients ready for
extubation 2 hours after surgery.160 Epidural alfentanil provides
only slightly better analgesia than intravenous alfentanil, with little
to no clinical advantage to its use.148
Remifentanil
This highly potent opioid is the newest of the anilidopiperidine
agents in use. It has a rapid onset of action and exceptionally short
T / . This property of remifentanil makes it particularly useful in
neurosurgical and other procedures requiring intraoperative
wake-up tests, neuromonitoring, and rapid recovery of airway
reflexes at emergence from anesthesia. Pharmacodynamically,
remifentanil is similar to other opioids in terms of its ability to
produce analgesia, respiratory depression, nausea and vomiting,
and somnolence. Remifentanil is administered almost exclusively
by the intravenous route in clinical settings. Neuraxial administration in humans has not been reported.
1
Pharmacokinetics
Unlike other opioids, remifentanils pharmacokinetics are highly
predictable, with less interindividual variability.171 Remifentanils
pharmacokinetic parameters are more closely related to calculations based on lean body mass than total body weight.172 Central
Vd is 0.15 0.099 L in a 70-kg adult.173 As with the other opioids,
the Vd is largest in newborns (0.45 L/kg) and infants (0.31 L/kg),
decreasing to adult levels by age 2 years (0.24 L/kg).171 Plasma
levels decline in a biexponential fashion with an average distribution t / (1) of 0.94 0.57 minutes and average terminal t / (2)
of 9.52 3.95 minutes.173 Clearance is greatest in newborns
and infants (9092 mL/kg/min), gradually decreasing in childhood and adolescents (from 76 to 57 mL/kg/min) to adult levels
(46 mLl/kg/min).171 Clearance rates are not appreciably affected
by cardiopulmonary bypass.174 Because remifentanil is an anilopiperidine with an ester tail,173 it undergoes ester hydrolysis by
nonspecific serum and tissue esterases to a metabolite, GI90291,
which has a 4600-fold reduction in potency at the mu opioid
receptor.175177 Patients with pseudocholinesterase deficiency have
normal metabolism and clearance of remifentanil.178,179 Contextsensitive t / and context-sensitive time for an 80% decrease in
serum concentration of remifentanil are approximately 10 minutes
with infusion durations of up to 360 minutes.173 Elimination t / is
decreased in infants, children, and adolescents (3.43.7 min) compared with neonates, preadolescents, and adults (5.35.7 min).171
Therefore, a higher infusion rate may be required in infants and
young children.
1
Pharmacodynamics
Remifentanil is relatively selective for mu opioid receptors.180
However, activity at delta opioid receptors has been suggested in
the context of remifentanil-induced hyperalgesia and tolerance.181
Compared with other anilidopiperidine opioids, remifentanil
produces a deeper state of analgesia and anesthesia with more
frequent episodes of bradycardia and hypotension.182 Postoperative recovery and extubation times are shorter, but analgesia
requirements are higher. Remifentanil does not increase the
incidence of postoperative nausea or vomiting in children or
adults.182,183
Remifentanil is particularly useful for neurosurgical anesthesia,
which requires agents that have minimal effects on intracranial
physiology and promote a rapid emergence from general anesthesia. With controlled ventilation, remifentanil does not increase
intracranial pressure in patients undergoing craniotomy184 and
does not affect cerebrospinal fluid formation or resorption rates.185
It has also been demonstrated to be useful in awake craniotomy
and for wake-up tests during corrective spinal procedures.186188
Remifentanil is also beneficial for ophthalmologic surgery by
reducing intraocular pressure, increasing intraocular compliance,
and preventing increases in intraocular pressure associated with
succinylcholine-facilitated intubation.189,190
Remifentanil doses during sevoflurane anesthesia required to
block both somatic and autonomic responses to surgical stimuli
are higher in children 2 to 10 years old than in adults (0.220.27
g/kg/min vs 0.100.11 g/kg/min, respectively).191
There is a large safety margin in adults for remifentanil
infusions of up to 2 g/kg/min.177
Remifentanil can also be administered as a bolus for intubation.
The calculated 95% effective dose (ED95) of remifentanil for
intubation without muscle relaxant with 5% sevoflurane in 100%
oxygen is 0.75 g/kg192 in children and 3 g/kg with propofol
4 mg/kg in infants.193 Intranasal administration of remifentanil
4 g/kg with sevoflurane 5% in nitrous oxide and oxygen provides
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good to excellent intubating conditions in 92% of children after

3 minutes.194
The combination of remifentanil and propofol has been shown
to provide effective anesthesia in children undergoing shortduration procedures such as lumbar puncture,195 esophagogastroscopy,196 and radiologic imaging studies.197 The addition of a small
amount of remifentanil can greatly reduce the amount of propofol
required, which may allow for more rapid emergence and shorter
recovery times.
Tramadol
Tramadol is a synthetic derivative of codeine composed of two
enantiomers, (+) and () forms.198 Similar to other opioids, the
pharmacokinetic profile of tramadol is highly variable between
individuals. However, much of the variability is caused by polymorphism of the enzyme responsible for metabolism and is not
age-related.
Pharmacokinetics
Tramadol bioavailability in adults is 68% after the first dose and 90
to 100% after subsequent doses.199 Absorption is more rapid in
children than in adults.199 Maximum serum concentration is reached within 30 minutes after oral liquid tramadol 1.5 mg/kg and
remains above analgesic levels for 7 hours.200 The Vd reaches 120%
of adult values by 1 year of age,201 then decreases to mature levels
(>2 L/kg) by 2 years of age.202 Tramadol and its metabolites are
excreted primarily by the kidneys.203 Total body clearance is
approximately 1.3 mL/kg/h in preterm neonates and reaches 84%
of mature levels by 44 weeks of conceptional age.201 Clearance is
highest in 2- to 8-year-olds (10.3 mL/kg/min).202 Tramadol is
metabolized by CYP450 2D6 to 11 desmethylated compounds, of
which O-demethyltramadol predominates.12,204 CYP450 2D6
activity is detectable by 25 weeks of postconceptional age.201
Patients with decreased CYP450 2D6 enzyme function experience
reduced analgesic efficacy from tramadol and require higher doses
of tramadol and more rescue analgesics for postoperative pain
relief.12,205 In a study of 82 neonates, only 24 expressed the wildtype CYP450 2D6 polymorphism with normal activity.7 Of the
remainder, 52 had below-normal activity polymorphisms and
6 had above-normal activity polymorphisms. The degree of
tramadol metabolism correlated directly with CYP450 2D6 activity and gestational age. The elimination T / is approximately 3
hours in children compared with greater than 5 hours in adults.202
1
on spinal and peripheral nerves.207 Advantages of tramadol over

stronger opioids are a lower incidence of opioid-related side
effects, with less than 10% of pediatric patients experiencing
nausea or vomiting and pruritus,208 and no clinically relevant
effects on heart rate or blood pressure. Excessive doses can result
in sympathomimetic side effects such as sweating, dysphoria, and
agitation. Tramadol increases the risk of seizure in patients taking
medications that lower the seizure threshold or those with a preexisting seizure disorder.
Tramadol can be administered by parenteral, epidural/caudal,
oral, and rectal routes every 4 to 6 hours. Tramadol is formulated in
tablet and liquid form, and a combined tramadol-acetaminophen
preparation is available. Larger dose appears to provide superior
analgesia with no increase in side effects.208
Intermittent intravenous bolus doses should be administered
slowly to minimize side effects. When administered via a PCA
device, a bolus dose of tramadol 0.2 mg/kg has been used.209,210
The dose range for continuous intravenous infusion is 0.1 to
0.25 mg/kg/h. A pharmacokinetic study determined that an
analgesic serum concentration can be achieved with an intravenous bolus of tramadol 1 mg/kg and maintained by an infusion
of 0.17 to 0.19 mg/kg/h in infants and children between 35 weeks
and 3 years of postconceptional age, decreasing to 0.12 mg/kg/h by
adulthood.201 This study, however, did not take into account
CYP450 2D6 polymorphism and its effects on analgesia mediated
by the O-desmethyltramadol metabolite.
Tramadol has been injected into the caudal space for postoperative analgesia after pediatric herniorrhaphy and hypospadias
repair.211214 The addition of tramadol 1.5 to 2 mg/kg to bupivacaine increases the duration of analgesia threefold to greater than
10 hours compared with bupivacaine alone with no increase in
side effects.212 Caudal tramadol 2 mg/kg provides quality and
duration similar to those of caudal morphine 0.03 mg/kg.214 The
prolonged duration of action of epidural tramadol is caused by
slow diffusion across the dura to spinal cord receptors and not
slow uptake into the systemic circulation.211 However, the risk of
neurotoxicity with tramadol in animals has not been determined.
In addition, the efficacy and duration of analgesia between
epidural/caudal and intravenous or oral routes are equivalent.215
For these reasons, it has been suggested that tramadol should not
be administered by the epidural route in children.199
Oxycodone
Pharmacodynamics
Tramadol produces analgesia through synergistic action of its
two enantiomers and their metabolites.204 The metabolite Odesmethyltramadol has an affinity for the mu opioid receptor that
is 200 to 300 times greater than that of the parent compound.199,204
Thus, it is responsible for the majority of opioid-related analgesia.
The (+) enantiomer of tramadol is a weak agonist at mu opioid
receptors and has almost no delta or kappa opioid receptor
affinity.199 The (+) enantiomer inhibits the re-uptake and promotes
the release of serotonin, whereas the () enantiomer inhibits
norepinephrine re-uptake and promotes its release.199 Because
5-HT3 receptors play a role in the transmission of pain at the spinal
level, 5-HT3 antagonists may reduce the efficacy of tramadol.206
Some evidence indicates that tramadol has local anesthetic action
Oxycodone is a semisynthetic opioid that is often administered in

combination with non-steroidal anti-inflammatory drugs such as
acetaminophen and aspirin.
Pharmacokinetics
The pharmacokinetic profile of oxycodone is highly variable
between children of similar age and begins to approach that of
adults within the first few months of life.
Oxycodone is available in tablet and liquid formulations. The
liquid form can be administered by orogastric and transmucosal
(oral or nasal) routes.216 In infants and children, the time to peak
plasma concentration is similar for oral transmucosal and orogastric routes (~200 min),217 with plasma levels detectable after
30 minutes and 60 minutes, respectively.217 Oral transmucosal
bioavailability is 55% compared with 37% for the orogastric
route.217 There is no difference in the absorption characteristics
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between oxycodone tablets or liquid.218 The pharmacokinetic
profile of intranasal administration is similar to that of the oral
transmucosal route, with a bioavailability of 46% and median time
to peak plasma level of 25 minutes.216 The steady-state Vd (between
2 and 5 L/kg) is relatively constant across pediatric age groups219
and is not significantly different from adult values.218 Similar to
morphine, the lipid solubility of oxycodone is low, and protein
binding is 38%.220 Clearance values increase with age but are highly
variable, particularly in neonates (median 9.9 mL/min/kg, range
2.317.2 mL/kg/min).219 After 2 months of age, values are similar
to those in older children and adults (1015 mL/kg/min).219
Oxycodone undergoes O-dealkylation by CYP450 2D6 to oxymorphone, which has mild intrinsic opioid activity and
N-demethylation by CYP450 3A4 to noroxycodone, which has no
opioid activity.60 Plasma levels of oxymorphone are undetectable
in patients with normal renal function,221 and thus, it has no
significant pharmacodynamic effects. About 7% of oxycodone is
excreted unchanged in the urine.221 The elimination T / of
oxycodone is inversely related to age and is especially variable in
neonates (median 4.4 hr, range 2.414.1 h).219 Values reach those
of older children and adults (~23 h) within a few months of
age.219 Renal dysfunction prolongs the elimination T / of oxycodone and reduces the excretion of metabolites, such as oxymorphone, which may result in excessive opioid effects.
1
Although oxycodone is usually described as a mu opioid receptor

agonist, evidence from rats suggests that its antinociceptive effects
may be mediated primarily by the kappa opioid receptor.222
Oxycodone has been extensively studied for the management of
acute, chronic, and cancer pain in adults. Relatively little data exist
on the use of oxycodone in children.
Oxycodone is available in immediate-release and controlledrelease formulations. Oral controlled-release oxycodone has been
used in pediatric patients transitioned from intravenous PCA
morphine after scoliosis surgery.223 Pain control was equivalent,
and a greater number of patients reported no opioid-related side
effects when taking oxycodone.
Administration of a single dose of intravenous oxycodone 0.1
mg/kg to children after eye surgery results in a decrease in arterial
oxygen saturation and respiratory rate and a corresponding increase in end-tidal carbon dioxide levels in less than 8 minutes.224
The ventilatory depressant effects of oxycodone may be greater
than that of other opioids.225
Methadone
Methadone is a synthetic opioid receptor agonist composed of a
racemic mixture of R and S enantiomers. Methadone has unique
pharamcokinetic and pharmacodynamic properties, such as a long
elimination t / , and intrinsic NMDA receptor antagonist activity.
Agonism of the NMDA receptor is associated with hyperalgesia
and opioid tolerance. These factors, among others, make methadone an excellent choice for patients with stable, chronic pain or
as an alternative when other opioids fail to provide adequate
analgesia or produce intolerable side effects.
1
Pharmacokinetics
Similar to other opioid drugs, there is substantial variability in the
pharmacokinetic parameters of methadone among children, and
there are no pharmacokinetic data from children younger than

1 year of age. Values for Vd, elimination, and clearance are not
dependent on age or weight in children 1 to 18 years of age.226 The
bioavailability of oral methadone is approximately 80% in adults,
with plasma levels detectable within 30 minutes of administration.227 Approximately 85% of the drug is bound to plasma
proteins in adults.5 Methadone is very lipid soluble and, thus, has
a large volume of distribution (mean sd = 7.1 2.5 L/kg in
children and 6.1 2.4 L/kg in adults).228,229 The plasma clearance
rate of methadone in children 1 to 18 years of age is 5.4 3.2
mL/kg/min (mean sd), which is significantly lower than for
other opioids. Methadone is metabolized by N-demethylation in
the liver to inactive pyrolidine and other metabolites that are
excreted in the urine and bile, along with small amounts of the
parent drug.5 Acidification of the urine increases the amount of
unchanged methadone excreted.5 The excretion of methadone is
unaffected by renal insufficiency. As oliguria worsens, increasing
amounts of methadone and metabolites are excreted in the bile,
such that anuric patients excrete the entire daily amount of
methadone in the bile.230 Almost no methadone is removed from
the plasma by hemodialysis.230
Plasma levels of methadone decrease in a biexponential fashion
after intravenous administration, with an initial rapid distribution
phase followed by a long elimination phase. The distribution and
elimination T / are less in children (mean sd, 1.9 0.88 min and
19.2 13.6 min, respectively) than in adults (mean sd, 6.1 5.7
min and 35 22 h, respectively).229
1
Pharmacodynamics
Pharmacodynamics
The clinical activity of methadone is caused almost exclusively by
the R methadone isomer, which has a 10-time greater affinity than
S methadone for the mu1 and mu2 opioid receptors, and both have
low affinity for delta and kappa opioid receptors.231
The duration of analgesia after a single oral dose of methadone
is approximately 4 hours, which reflects the short distribution T / .
Reaching a steady-state plasma level may take between 2 and 10
days of repeated doses owing to the large volume of distribution.232
Once a steady-state concentration is reached, the dosing interval
should be decreased from every 4 to 6 hours to 8 to 12 hours to
avoid accumulation.
Oral methadone is used primarily for the management of
cancer-related and other types of chronic pain in children233 and
is usually started as an alternative to other opioids when inadequate pain relief or excessive opioid-related side effects are a
problem.234,235 The conversion to methadone often results in a
dramatic improvement in side effects and pain control, often with
a fraction of the equivalent morphine dose.234 Conversion ratios
for morphine to methadone appear to vary inversely with the
amount of morphine being administered (morphine-to-methadone ratio of 1:2 to 60:1).233 Thus, methadone may be particularly
suitable for patients using high doses of mu opioid receptor
agonists owing to its higher intrinsic activity at the receptor, which
is inversely related to the degree of tolerance.236 Methadone has
been used to wean patients in the pediatric intensive care from
high-dose intravenous fentanyl infusions.237 The mean fentanyl
dose at the start of the conversion was 5 g/kg/h, and the mean
duration of fentanyl infusion was 18 days. The starting dose of
enteral methadone was approximately 0.5 mg/kg/d, and about one
third of patients required an escalation in dose to 0.9 mg/kg/d.
The median time to fentanyl discontinuation was 2.6 days and best
correlated with the duration of fentanyl therapy.
1
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Because of the rapid distribution but very slow elimination of

methadone, an intravenous loading dose large enough to maintain
the plasma level above the minimal analgesic plasma concentration can provide prolonged postoperative analgesia.238 Methadone
appears to have a slight advantage with respect to pain scores and
opioid consumption in the immediate postoperative period
compared with equivalent doses of morphine given to children at
the start of surgery.41 However, administration of too large a dose
of methadone (0.3 mg/kg) can result in significant postoperative
hyperventilation or somnolence.41 Methadone produces a greater
and longer-lasting decrease in arterial oxygen saturation and
increase in exhaled CO2 than morphine or meperidine.225
OPIOID AGONIST-ANTAGONISTS
Mixed agonist-antagonist opioids are typically weak agonists at
sigma and/or kappa opioid receptors and partial agonists or antagonists at the mu opioid receptor. As such, these drugs can precipitate opioid withdrawal in patients who have been receiving
pure agonist opioids.239 An additional drawback to the use of
mixed opioid agonists-antagonists is sex-related antianalgesia.240
Specifically, drugs that provide analgesia by predominantly kappa
opioid receptor activity provide significantly greater analgesia in
women and may even cause increased pain in men, at lower doses.
Co-administration of low-dose naloxone,241 morphine,242 or the
sigma opioid receptoractive neuroleptics haloperidol and chlorpromazine243 blocks the antianalgesic effects in males and may
improve analgesia in females as well.
in approximately 30 minutes.251 The Vd in children is 3.6 L/kg,

which is not significantly different from adults (45.5 L/kg).249
Protein binding in young healthy adults has been estimated at
50%.252 Clearance decreases with age from approximately 43 mL/
kg/min in children to 23 mL/kg/min in elderly adults.249 Because
the Vd is constant but clearance decreases with age, the elimination
t / of nalbuphine increases with age from 0.9 hours in children to
over 2 hours in elderly adults.249 Neonates have the longest elimination t / at 4 hours owing to immature hepatic metabolic function.253 Nalbuphine is extensively metabolized to two metabolites
and conjugates and is excreted primarily through the biliary
system.252 Only 7% of a single dose is accounted for in the urine as
unchanged nalbuphine, its conjugates, and two metabolites.252
1
Pharmacodynamics
Currently, nalbuphine is available for parenteral administration
only. Cumulative doses greater than 0.4 mg/kg fail to increase pain
tolerance or reduce anesthetic requirements compared with morphine, suggesting a ceiling effect for analgesia.254,255 A similar
effect occurs with respect to respiratory depression.256 Parenteral
nalbuphine has been used for preoperative sedation,245 intraoperative analgesia,257 and postoperative pain management in
children.130,258,259
Although nalbuphine has gained popularity for the management of opioid-related side effects in adults, the only study in
children showed no benefit with nalbuphine 50 g/kg for the
treatment of pruritus.31 In adults, a combination of morphine and
nalbuphine administered in a 1:1 ratio via a PCA device may
provide the best balance of analgesia and prevention of pruritus.260
Pentazocine
Pharmacokinetics
Buprenorphine
The pharmacokinetic parameters of pentazocine in children 4 to

8 years of age are similar to those in adults. The steady-state Vd is
4 L/kg with a clearance of 21 mL/kg/min and elimination t / of
3 hours. Over 85% of pentazocine is metabolized in the liver by
oxidation, and approximately 30% of the metabolites undergo
glucuronidation.244
Buprenorphine is a semisynthetic derivative of thebaine.
Pharmacodynamics
Pentazocine has been used as a premedicant before surgery245 and
for postoperative analgesia.246 A single intravenous dose provides
approximately 2.5 hours of analgesia.247 Pentazocine produces a
quicker onset and greater change in respiratory parameters than
roughly equipotent doses of morphine and meperidine, but otherwise has a similar side effect profile.99,248 A ceiling effect for analgesia has been demonstrated with pentazocine 0.15 to 1.2 mg/
kg in adults.
Nalbuphine
Pharmacokinetics
The bioavailability of oral nalbuphine increases with age, from
11% in young adults to over 44% in elderly patients, presumably
because of the age-dependent decrease in hepatic blood flow.249
Peak plasma concentration of nalbuphine occurs approximately
1 hour after an oral dose (liquid or tablet).250 Intrarectal nalbuphine administration appears to have greater bioavailability than
the oral route with higher peak plasma concentrations achieved
Pharmacokinetics
Buprenorphine undergoes extensive first-pass metabolism, with
an estimated oral bioavailability of 15% in adults.261 Sublingual
administration results in much higher plasma concentrations, with
an estimated bioavailability of over 50% in adults, but with
significant interindividual variability.261 Buprenorphine is highly
(96%) bound to plasma proteins, with an estimated steady-state
Vd in children of 3.2 L/kg, which is similar to adults.262 Clearance
is caused almost exclusively by hepatic extraction and metabolism.
Thus, patients with decreased hepatic blood flow will have a
prolonged duration of pharmacologic effect. Clearance after a
single bolus dose in children is approximately 60 mL/kg/min,
which is much higher than in adults.262 Buprenorphine undergoes
extensive hepatic metabolism to N-dealkylbuprenorphine (norbuprenorphine), which is considered to be an inactive metabolite.
The majority of buprenorphine and its metabolites are excreted
through the biliary system, with the remainder eliminated in the
urine. The elimination t / in children aged 4 to 7 years is estimated
to be approximately 60 minutes compared with over 3 hours in
adults.262 The difference is most likely caused by the higher rate of
clearance in children.
1
Pharmacodynamics
Buprenorphine is a true partial agonist with higher affinity
but weaker activity compared with morphine at the mu opioid
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receptor.263 In animals, the dose-response curve of buprenorphine
exhibits a ceiling effect, and at doses above a certain level, the
pharmacologic effect may actually decrease with increasing dose.264
Another unique feature of buprenorphine is the availability for
sublingual administration with almost equal efficacy to the
parenteral route, with an onset of analgesia within 30 to 60 minutes,
peak analgesic effect in 2 to 3 hours, and duration of analgesia of
6 to 9 hours.265 In adults, the administration of 0.4 mg sublingually
provides similar analgesia to 0.2 to 0.3 mg of intramuscular buprenorphine. Comparisons of buprenorphine and morphine for
postoperative pain in children demonstrated equivalent analgesic
efficacy with 1 to 2 hours longer mean duration of action with
buprenorphine.266,267 Sublingual buprenorphine, however, did not
have a similar long duration of action.266 The changes in ventilatory
parameters in children are greater with equianalgesic doses of
buprenorphine than morphine.268 In particular, buprenorphine
causes a greater and longer-lasting decrease in respiratory rate, with
a later time to peak effect (45 min vs 11 min for morphine).268
Compared with parenteral buprenorphine, the caudal route
provides a much longer duration of analgesia (up to 24 hours), with
a much lower incidence of nausea and vomiting.269,270 Doses for
caudal buprenorphine are 2.5 to 4 g/kg. Because of the high
binding affinity of buprenorphine for the mu opioid receptor,
reversal of buprenorphine-induced respiratory depression requires
a relatively large dose of naloxone (~0.030.043 mg/kg) followed by
an infusion (0.06 mg/h).271 Buprenorphine does not appear to have
any significant effects on cardiovascular parameters.267
OPIOID ANTAGONISTS
Naloxone
Naloxone has virtually no agonist activity at any of the opioid
receptors and reverses all opioid effects, including sedation,
respiratory depression, decreased gastrointestinal motility, and
analgesia.
Pharmacokinetics
Naloxone undergoes rapid glucuronidation in the liver with minimal bioavailability after oral administration. Intramuscular injection of naloxone in term neonates produces peak plasma levels in
a mean time of 1.2 hours and acts as a depot, maintaining detectable plasma levels for another 24 to 36 hours.272 The Vd and
clearance are approximately 2 L/kg and 10 mL/kg/min, respectively, in term neonates.272 Naloxone is primarily eliminated by
glucuronidation to naloxone-3-glucuronide.273 Because this metabolic pathway is typically deficient at birth, the elimination t / is
much longer in neonates than in adults (2.53.5 h vs 1 h,
respectively).272
1
Pharamcodynamics
The rapid onset of opioid antagonism is related to the high lipid
solubility of naloxone which allows for high concentrations to be
rapidly achieved in the brain.274 For this same reason, the short
duration of action of naloxone can be attributed to its rapid
diffusion from the central nervous system. Therefore, repeat bolus
doses or an infusion may be required to prevent renarcotization
when the anatgonistic effects of naloxone wane in the presence of
a longer-acting opioid.
The usual starting dose for reversal of opioid-induced respiratory depression in children is 0.01 mg/kg, with subsequent
doses doubled until the desired clinical effect is achieved. Caution
must be used when administering naloxone to patients who have
been receiving prolonged opioid therapy because a life-threatening
withdrawal syndrome, characterized by tachycardia, tachypnea,
hypertension, dysrhythmias, anxiety, pupillary dilatation, and
sweating, can be precipitated.
The use of low-dose naloxone, administered intravenously as
an infusion or mixed with opioids delivered by a PCA device or
into the epidural space, can prevent or reduce the severity of some
opioid-related side effects, particularly pruritus and nausea. In
older children and adolescents receiving opioids for postoperative
pain control, an infusion of naloxone at 0.25 g/kg/h reduced the
incidence and severity of pruritus and nausea, but not vomiting,
with no effect on analgesia or opioid consumption.30
SUMMARY
Opioids remain the cornerstone of moderate to severe pain
management in children, and a thorough understanding of
opioid pharmacology is necessary for the optimal use of these
drugs. The ultimate opioid, one that offers intense analgesia with
no side effects, has yet to be invented and may never be. Instead,
the choice of opioid for an individual patient may depend on
each persons pharmacogenetic profile, which will be used to
predict which opioid will provide the greatest analgesia, at the
lowest dose, and with the least likelihood of side effects. Until
then, a rational approach to the use and choice of opioid therapy
should take into account factors such as intensity and duration
of pain, available routes of administration, and patient age and
comorbidities, all of which can have a significant impact on
the pharmacokinetics and pharmacodynamics of a particular
opioid.
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Non-Opioid Analgesic Agents

Greta M. Palmer
INTRODUCTION
Nonopioid analgesics are used widely in the management of acute
pediatric postoperative pain. They are used alone or as part of a
multimodal analgesic approach to reduce opioid requirements and
opioid-associated side effects. All agents used in adults are employed in children, but they are frequently used off-license.
Children, particularly neonates, remain therapeutic orphans.
Limited pediatric studies are available on the pharmacokinetics
(PK) and pharmacodynamics (PD) of commonly employed nonopioid analgesics and they are often small in sample size. Dose
recommendations are commonly scaled down from adult schedules. As we increase our understanding of the pharmacology
(including the pharmacogenomics) of these agents from the preterm and term neonate to the infant and older child age range,
appropriate dosing recommendations can be made and then comparative effectiveness can be better assessed.
ACETAMINOPHEN (PARACETAMOL)
Use and Formulations Available
Acetaminophen is used widely in pediatrics as an antipyretic or a
first-line nonopioid analgesic for mild to moderate pain relief. It
is available in multiple formulations that are all used in children.
These include enteral preparations such as oral tablets (including
soluble and extended release), drops, capsules, and suppository
formulations. Two intravenous (I.V.) formulations exist; an I.V.
prodrug (propacetamol, N-acetylpara-aminophenoldiethyl aminoacetic ester) that is hydroxylated to yield 50% acetaminophen,
and a more recent I.V. acetaminophen (perfalgan)14 that is solubilized in mannitol, sodium phosphate, and cysteine.
Pharmacokinetics
Acetaminophens volume of distribution (Vd) is reported to decrease with increasing age from 110 L/70 kg at 28 weeks of postmenstrual age (PMA) to 73 L/70 kg by 60 weeks.5 The magnitude
of this change may not be as great as originally reported because
a recent neonatal cohort aged 28 to 45 weeks PMA had a Vd of
76 L/70 kg (95% confidence interval [CI] 6687)3 compared with
the adult value of 66.6 L/70 kg. Clearance estimates using either
the enteral I.V. acetaminophen or the I.V. prodrug are similar for
neonates (56.8 L/h/70 kg).3,57 Clearance increases with age and
is 10.8 L/h/70 kg at 60 weeks PMA5 and 12.5 to 14 L/h/70 kg in
older children and adults.5,8,9 In neonates and infants, clearance
following I.V. propacetamol administration was associated with
increasing PMA7 from 1.87 L/h/70 kg at 27 weeks to reach 84% of

the mature value (16.3 L/h/70 kg, Coefficient of variation (CV)
40.4%) by 1 year of age.9,10 Clearance following I.V. acetaminophen
administration similarly increased for neonates from 4.4 L/h1/70
kg1 at 34 weeks to 6.3 L/h1/70 kg1 at 46 weeks PMA.3 Clearance
of acetaminophen has not been linked to postnatal age (PNA) in
neonates.3,11
Acetaminophen is predominantly metabolized by phase 2
hepatic conjugation pathways (>95%) through both glucuronidation
and sulfation, with renal excretion of the metabolites. Uridine 5diphosphate glucuronosyltransferases (UGT) metabolize both
bilirubin (UGT1A1) and acetaminophen (UGT1A6). Neonates rely
more on sulfate pathways.8 The glucuronide-to-sulfate ratio
increases with increasing PMA: from 0.12 in premature neonates
of 28 to 32 weeks PMA12 to 0.34 in term neonates (PNA 02 d).13
Oral dosing is subject to minimal first-pass metabolism and
oral bioavailability is high.8 Time to reach a plasma maximum
concentration (Cmax) after enteral administration will be influenced by the presence of food in the stomach, pathology, and
the formulation used (elixir is more quickly absorbed than tablet).
It is reached at 29 to 45 minutes in adults after oral administration14 and 90 to 120 minutes after oral15 and 66 to 114 minutes
after nasogastric administration in infants, neonates, and children.8 The absorption rate is slowest in premature neonates.5 Rectal
absorption is slow and variable: Cmax is reached at 150 minutes in
children aged 1 to 17 years16 to 198 minutes in children aged a
mean of 3.4 (standard deviation [sd] 0.5) years.17 Solution administered rectally is more rapidly absorbed than the triglyceride
or capsule suppositories with wide variability in bioavailability of
50 to 92%. Relative bioavailability is higher with capsules than
triglyceride-based suppositories and decreases with age.5 Depth
of insertion of suppositories, leakage from the rectum, and incomplete dissolution will influence the degree of absorption
achieved. Elimination half-life is 4.8 to 11 hours in preterm
neonates, 1.6 to 1.7 hours in infants, and 2.6 to 2.8 hours in children.8 Some studies have estimated a longer half-life following rectal
administration. This is likely influenced by continuing unaccounted absorption influencing elimination estimation. The use of
the I.V. acetaminophen formulations allows greater dosing accuracy with less PK variability attributable to absorption and more
rapid effect onset.11
Mechanism of Action
Acetaminophens mechanism of action is currently hypothesized
as central only and mediated through descending serotonergic pathway activation.18,19 Its primary site of action is still debated
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Non-Opioid Analgesic Agents 407
Figure 26-1. Prostaglandin H2 synthetase

(PGHS) is the enzyme responsible for
metabolism of arachidonic acid to the unstable
prostaglandin H2 (PGH2). Formation of
tyrosine-385 radical (Tye385*) at the cyclooxygenase (COX) site is dependent on the reduction of a ferryl protoporphyrin IX radical
cation (Fe4+ = OPP*+) at the peroxidase (POX)
site. Paracetamol is a reducing cosubstrate that
partially reduces (Fe4+= OPP+), decreasing the
amount available for regeneration of Tyr385*.
Adapted from reference 113 by the author of
as either through prostaglandin synthesis inhibition at the
peroxidise site (POX) of the prostaglandin H2 synthetase (PGHS)
enzyme (Figure 261) or through an active metabolite (Narachodonolphenylamine) influencing cannabinoid receptors.18
Pharmacodynamics
A mean effect-site concentration of 10 mg/L is associated with pain
score reduction of 26% in children aged 2 to 15 years after tonsillectomy.20 Effect-site concentrations associated with analgesia
for the pains experienced as a neonate are unknown. Pain relief
occurs between 15 and 30 minutes after I.V. acetaminophen,1
consistent with a delay achieving effect-site concentrations
(context-sensitive half-life [t / keo] 56 min21). These delays mirror
plasma cerebrospinal fluid (CSF) equilibration.15,22,23 The slow
rectal absorption maintains plasma concentrations longer than oral
and formulations and this can be advantageous. Time to first rescue
analgesia was longer after rectal dosing of 40 mg/kg compared with
I.V. acetaminophen 15 mg/kg (median 10 h vs 7 h) after singledose use for tonsillectomy.4 I.V. acetaminophen was associated with
slightly higher postoperative pain scores but less sedation and
earlier preparedness for discharge than intramuscular meperidine
after tonsillectomy24 and dental restoration.25
1
Adverse Effects
Acetaminophen use is associated with a very low risk of serious
adverse events. Hepatotoxicity is the major concern with use of
this agent and is related to production of the toxic metabolite
N-acetyl-p-benzoquinone-imine (via phase 1 oxidative metabolism). It is generally a problem of overdose, in which the usual
phase 2 clearance pathway becomes saturated or when the metabolite mop, glutathione, is depleted.8 The latter occurs in systemic illness such as prolonged fasting or vomiting, dehydration,
obesity, or pre-existing hepatic impairment. Children receiving
repeated doses of acetaminophen (>7590 mg/kg/d) may show
abnormalities in liver function.26 Neonates may be somewhat
protected because of immaturity of oxidative clearance pathways.3
Unconjugated hyperbilirubinemia, a crude marker of glucuronide
conjugating function, is associated with reduced acetaminophen clearance; serum unconjugated bilirubin concentrations of
150 mol/L were associated with 40% reduction in clearance.3

Further understanding of acetaminophen metabolism is required
to interpret this clinical finding. No link with changes in other
liver function tests was demonstrable in this neonatal group.3
Pain on injection is a problem with I.V. propacetamol and
occurs less commonly with the I.V. acetaminophen formulation.1
Slow infusion over 15 minutes is recommended.
Dose and Licensing

Oral and rectal formulations are licensed worldwide for use in the
older pediatric age groups. Some countries specify precautionary
use in term and preterm neonates. Licensing of the two I.V. formulations varies. Australian product information precautions against
I.V. acetaminophen use in preterm neonates,3 whereas in Europe
neither ise licensed for infants weighing less than 10 kg.27 I.V.
formulations are currently unavailable in the United States. Table
261 lists the various acetaminophen doses used, studied, and
recommended for loading and maintenance in the various pediatric age groups. Recommendations for doses of the I.V. formulations in preterm and term neonates either reduce the dose or
increase the dosing frequency to allow for the reduced clearance
that occurs in this age group.3,27,28
Use of the I.V. formulation should be restricted to patients who
cannot tolerate enteral or rectal formulations, to reduce hospital
pharmacy budget expenditure.2,29 I.V. administration should not
replace oral premedication or intraoperative rectal administration
during routine anesthesia; nor should it replace postoperative oral
or rectal administration unless severe vomiting, ileus, or diarrhea
is expected. The superiority of the I.V. route over the oral and
rectal formulations is not yet proved. The latter routes are effective
provided absorption is not impaired and doses are timed to allow
for differences in time to peak effect.29
NONSTEROIDAL ANTIINFLAMMATORY DRUGS

The nonsteroidal anti-inflammatory drugs (NSAIDs) include a
group of heterogeneous compounds with analgesic, antipyretic,
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TABLE 26-1. Suggested Acetaminophen Dosing

Route
Loading
Dose, mg/kg
Oral
Maintenance Dose, mg/kg; Frequency
Daily Maximum, mg/kg/d
2040
10; q4h (United States)

1520; q46h
Rectal
40 (60)
20; q6h
I.V. propacetamol
I.V. acetaminophen
304027
102027,28
30; q6ha
Children, infants: 15; q6ha,c
Term neonates: 1027153,28; q6h.
Preterm neonates 3336 wk PMA:
7.52812.53; every 63,28 to 827 h
Preterm neonates 2832 wk PMA:
7.510; every 63 to 828 to 1227 h
Older children
Short-term 23 days: 90
Longer-term: 60
Premature neonates 3034 wk PMA: 25455,b
Infants > 3 mo: 80908
Premature neonates > 32 wk PMA to infants
< 3 mo: 608
Premature neonates: 30 wk PMA: 25 (capsule)
or 30 (triglyceride)5
2832 wk PMA: 308
Double below recommendations
Children, infants: 601,2
Term neonates 36 wks PMA: 4027603
Preterm neonates 2836 wk PMA: 20403,27
PMA = postmenstrual age.

a
Every 4 h permitted in older children: the product information for I.V. acetaminophen recommends this for those patients weighing > 33 kg but pediatric centers
tend to reserve this frequency of dosing once children weigh > 4550 kg.2
b
This dosing achieves a mean steady-state target concentration > 10 mg/L at trough.5
c
This dosing achieves a steady-state concentration in a term neonate between 10 and 23 mg/L.3
and anti-inflammatory effects. Acetaminophen lacks the latter

effect. These agents are used as first- or second-line analgesics in
children with mild to moderate pain. Their anti-inflammatory
properties lead to use in inflammatory conditions such as arthritis,
myalgia, ureteric and biliary colic, and dysmenorrhea and endometriosis. A further pediatric use is to induce patent ductus
arteriosus (PDA) closure in expremature infants. Like acetaminophen, multiple formulations are available. These vary between countries: oral tablet (including extended release), capsule,
syrup, rectal suppository, and parenteral forms.
Pharmacokinetics
The PK of NSAIDs have been explored in children of varying
ages, and generally, the half-life decreases with increasing age as
does the volume of distribution.30,31 Clearance increases with age,
appearing to peak in infancy when scaled per kilogram.31
Neonatal NSAID PK have been explored during use for PDA
closure. Ibuprofen clearance increases from 2.06 mL/h/kg at 22 to
31 weeks PMA32 to 9.49 mL/h/kg at 28 weeks PMA33 to 140 mL/
h/kg at 5 years.34 Data have also been reported for indomethacin
and is similar35: clearance was 7.11 mL/h (standardized to 1.17 kg
median weight), increasing by approximately 3.4% per postnatal
day. Between-individual variability in clearance was 41% and
between-occasion variability was 43%.
Ibuprofen is metabolized by the cytochrome P450 (CYP)
CYP2C9 and CYP2C8. CYP2C9 is variably expressed, and its gene
demonstrates functional polymorphism.36,37 CYP2C9 activity is
low immediately after birth, increasing to peak at a young age.38
Diclofenac is principally metabolized by CYP2C9 and also by
CYP3A4 and 3A5. In humans, CYP2C9 forms a 4-hydroxyl diclofenac derivative, which in animals has 30% of its parents activity.39
Diclofenacs PK have been investigated in children (N = 26)
undergoing tonsillectomy, given 2 mg/kg followed by 1 mg/kg q8h.
Rectal administration of diclofenac, in these children aged 2 to
8 years, was associated with a higher relative bioavailability (1.26)

than oral administration of enteric-coated tablets and an earlier
Cmax: 50 min versus 108 min.40 Clearance was estimated as
45 L/h/70 kg,40 Recently, a larger population PK study of children
aged 1 to 12 years (N = 70) given an oral suspension of diclofenac
1 mg/kg suggests that Cmax is achieved in less than 1 hour after
this formulation, with a similar result for clearance of 54 L/h/
70 kg.41 The PK after 20 mg/kg rectal ibuprofen administration
have been compared in postsurgical neonates, infants, and adults.42
The Cmax was higher but reached later in adults and the half-life
was longer in infants aged 1 to 7 weeks.
NSAIDs exhibit stereoselectivity. In premature neonates (<28
wk PMA), dosed with 10 mg/kg given within 6 hours after birth
followed by two 5-mg/kg doses at 24-hour intervals, the halflives of ibuprofen enantiomers were approximately 10 hours for
R ibuprofen and 25.5 hours for S ibuprofen. The former has a
higher mean clearance: 12.7 mL/h versus 5.0 mL/h.43 The difference
in the enantiomers half-lives was not as apparent after rectal administration in older infants and adults.42 PK predictions based on
racemic assays may, therefore, underestimate the duration of effect
in premature neonates. Single-isomer NSAIDs are being developed
and may offer fewer adverse effects than the racemic combinations.44,45
CSF concentrations have been measured in infants and children after I.V. ibuprofen 10 mg/kg. These peaked and were higher
than that of unbound plasma concentrations when sampled more
than 30 minutes after dosing.46
Pharmacodynamics
NSAIDs induce their effects centrally and peripherally by reducing
prostaglandin biosynthesis through COX enzyme inhibition on
the PGHS enzyme. The commonly used NSAIDs vary in their
selectivity for the two major COX-isoforms (COX-1 and COX-2)
(Table 262).
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TABLE 26-2. COX-2 Versus COX-1 Inhibitory
Concentration 50% (IC50) Ratio for the Commonly
Used NSAIDs
NSAID
COX-2/COX-1 IC50
Relatively COX-1-Selective
Piroxicam
Aspirin
Indomethacin
Ibuprofen, ketorolac
600
166
60
6.77.0
Nearly Equal in their COX-1 vs

COX-2 Selectivity
Diclofenac, naproxen
0.71.0
COX-2-Selective
Numesulide, meloxicam
Celecoxib
Rofecoxib
0.060.09
0.15
0.03
COX = cyclooxygenase; IC50 = inhibitory concentration of 50%; NSAIDs =

nonsteroidal anti-inflammatory drugs.
Clinical pediatric studies after tonsillectomy47; myringotomy48;

various surgery types49; orthopedic, urologic, and soft tissue surgery50; and inguinal hernia repair (IHR)51 comparing NSAIDs and
acetaminophen or different NSAIDs suggest similar effectiveness.
The combination of NSAID with acetaminophen is superior to
use of either agent alone after orthopedic, urologic, and soft tissue
surgery,50 IHR,51 tonsillectomy,52 and adenoidectomy.53 Comparative and combined effectiveness can be assessed only when appropriate doses of each drugs are used, and there is more study to
be done in this area, particularly for repeat dosing.54
A plasma analgesic concentration has been reported after I.V.
ibuprofen 10 mg/kg for herniotomy (under spinal anaesthesia, N
= 19) and is a median of total (bound and unbound) ibuprofen 21
(range 1025) mg/L and unbound ibuprofen 26 (15157) g/L.46
Adverse Effects
The risk of serious adverse events after short-term ibuprofen
use in pediatrics is low.55 Adverse effects of NSAIDs include
gastrointestinal symptoms and mucosal effects, renal and platelet
dysfunction, and exacerbation of respiratory disease (NSAIDERD) including bronchospasm in sensitive asthmatic patients.
Glomerular filtration rate is reduced by 20% in premature
neonates treated with ibuprofen (independent of PMA).56 This
reduction was associated with reduced aminoglycoside clearance.57 Renal electrolyte balance (of sodium and potassium) is also
altered as vasodilatory prostaglandin production in the renal
cortex is reduced.58 The use of NSAIDs in hypovolemic, septic,
and shocked patients in whom renal blood flow is compromised
is to be avoided, and there are precautions against use in patients
with renal impairment or on diuretics and angiotensin-converting
enzyme inhibitors. Precipitation or exacerbation of renal failure
has occurred in neonates,59,60 older children, and adults59 treated
with NSAIDs, usually in the setting of other hemodynamic compromise. Renal side effects are felt to be NSAID drug type, dose-,
and duration-dependent.59
NSAIDs inhibit thromboxane synthesis exerting antiplatelet
effects that, except for aspirin, are reversible, and bleeding time is
usually only slightly increased with these agents. Use of ketorolac
after congenital heart surgery was not associated with increased

risk of bleeding complications.61 Intraventricular hemorrhage
(IVH) was not increased in neonates given ibuprofen to induce
PDA closure.60,62 Concern has been raised that I.V. indomethacin
may be associated with increased risk of IVH.63 The use of
NSAIDs in tonsillectomy (an operation with known risk of postoperative bleeding) has long been debated. The odds ratio (OR) of
posttonsillectomy hemorrhage with aspirin was significantly
higher than in the ibuprofen and diclofenac group: 1.94 (95% CI
1.093.42) compared with 0.93 (95% CI 0.441.95) after assessing
seven studies (N = 1368).64 The conclusion was that NSAIDS but
not aspirin were safe.64 The incidence of postoperative bleeding
was nearly doubled by NSAIDs from 5.3 to 9.2% (OR 1.8; 95% CI
0.93.4), and the number requiring reoperation increased from
0.8 to 4.2% (OR 3.8; 95% CI 1.311.5) with a number-needed-toharm (NNH) of 29 in seven studies (N = 505).65 The largest
metanalysis (25 studies, N = 1853) determined that the rate of
reoperation was significantly increased by NSAIDs with a lower
NNH of 60, concluding that NSAIDs should be used cautiously
until further evidence is available.66 The most recent meta-analysis
(13 studies; N = 955) drew the opposite conclusion, stating NSAID
use is not associated with an increased risk of bleeding requiring
either nonsurgical or surgical intervention (respective ORs: 1.23
[95% CI 0.443.43] and 1.46 [95% CI 0.494.40]).67 Significantly
less nausea and vomiting was experienced in NSAID-treated
tonsillectomy patients (OR 0.4, 95% CI 0.230.72).67 The latter
benefit is an advantage of this drug class that has greater statistical
and clinical weight (because it is a frequent and distressing symptom with this surgery) than the theoretical disadvantage of the
rarer possibility of increased blood loss that is not statistically
supported. NSAID use for pediatric tonsillectomy is frequent in
the United Kingdom68 and New Zealand,69 whereas it is avoided in
this surgery type in the United States and Australia. Cerebral
blood volume and flow and cerebral tissue oxygenation index have
been assessed in neonates receiving ibuprofen and placebo, without significant differences between treatment groups.70
Aspirin-sensitive asthma was thought to be a disorder only
of adults. Cross-sensitivity with other NSAIDs became evident
and the new term NSAID-ERD was applied with episodes in
children subsequently reported.71 Short-term ibuprofen use has
been reported without adverse effects in pediatric patients with
asthma. Hospitalization rates were low and did not differ from the
acetaminophen-treated group, whereas outpatient visits were
significantly lower (by 50%) in the ibuprofen-treated group.72
Single-dose oral (effervescent) diclofenac 1 to 1.5 mg/kg did not
affect spirometry (tested at three time points up to 30 min postdosing) in asthmatic children (N = 70).73 It has been suggested
that the use of NSAIDs can reduce severity of viral upper respiratory tract infections (URTIs) in both children (anecdotally) and
adults in small-scale trials.74 Thus, only a subset of pediatric and
adult patients, with moderate to severe asthma associated with
nasal disease, is felt to be at risk of NSAID-ERD.71 Patients with
mild asthma may improve with NSAID therapy in the setting of an
URTI-associated asthma flare, because NSAID therapy modifies
the leukotriene response.72,74
Nitric oxidereleasing NSAIDs offer increased potency and reduced side effects and may be the preferred therapy in the future.75
Dose and Licensing

Table 263 lists the doses of NSAIDs that are commonly employed in children for fever, analgesia, and PDA closure. It has been
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TABLE 26-3. Common Pediatric Nonsteroidal Anti-Inflammatory Drug Doses for Analgesiaa and Patent Ductus
Arteriosus Closure
NSAID Type
Dose, mg/kg; frequency
Maximum Dose
Analgesia
Ibuprofen oral: elixir, capsule/tablet
(200 mg); parenteral
510; q68h
(lower dose for fever)
200400 mg
600800 mg may be used for acute
pain management
5075 mg
100 mg
100 mg
60 mg (United States)
20 mg
10 mg
Ketorolac therapy is limited to 5 d
duration.
Diclofenac, oral: tablet (2550 mg)

Diclofenac, rectal suppository (12.5100 mg)
Indomethacin, oral tablet rectal suppository
Ketorolac, parenteral: varying preparations
(1030 mg/mL)
NSAID for PDA closure

Ibuprofen I.V.56 and oral63
Ibuprofen I.V.
(dosing independent of gestational age
adjusted for postnatal age (PNA)111)
Indomethacin I.V.112
11.5; q812h
12; q812h40,68
0.52; q12h
Loading doses 1 mg/kg (United States)
Maintenance: 0.5 mg/kg; q6h
0.3 mg/kg q6h (Europe)49
0.20.25 mg/kg q6h (Australia)
10 mg/kg then 5 mg/kg daily for 2 d

10, 5, 5 mg/kg daily for PNA < 70 h
14, 7, 7 mg/kg daily for PNA 70108 h
18, 9, 9 mg/kg daily for PNA 108180 h
0.2 mg/kg q12h for three doses
NSAID = nonsteroidal anti-inflammatory drug; PDA = patent ductus arteriosus; PNA = postnatal age.
a
A review article describes other dosing regimens.49
suggested that oral ibuprofen therapy for PDA closure may offer
a better adverse event profile over indomethacin,63 but study numbers are small. Optimal and maximum doses are debated; the latter
because a ceiling effect has been suggested for NSAIDs.41 An oral
diclofenac PK study suggests that 1 mg/kg (maximum 50 mg) is
optimal in children based upon comparison of simulated area
under the curves for plasma concentration compared with time
in the initial 0 to 12 hours after 0.5 to 2 mg/kg.41 This needs to be
confirmed in a study of effectiveness.41
NSAIDs are licensed for use in children with the precaution in
Australia that safety younger than the age of 2 years is not established. Licensing in the United Kingdom is limited for ibuprofen
to children weighing greater than 7 kg and for diclofenac to older
than 12 months for use in juvenile arthritis. Clinicians and hospital
pharmacopoeias generally recommend limitation of NSAID use
for pain and fever in infants and children in Australia and the
United Kingdom to older than 6 months and in the United States
in children older than 12 months. Pediatric anesthetists in the
United Kingdom (N = 337) report prescribing NSAIDs in infants
younger than this: 4% state they prescribe for those younger than
1 month, 19% for 1 to 3 months, 48% for 3 to 6 months, and 78%
for 6 to 12 months of age.68 Short-term use (e.g., three doses) is
well reported for PDA closure in neonates. The parenteral formulation of ketorolac, although licensed only for intramuscular use,
is administered intravenously:
CYCLOOXYGENASE-2SELECTIVE
INHIBITORS (ALSO CALLED
CYCLOOXYGENASE-2 RECEPTOR
ANTAGONISTS OR COXIBS)
Cyclooxygenase-2 (COX-2) inhibitors are selective NSAIDs that
were developed to avoid the adverse effect profile of the non-
selective NSAIDs while maintaining their beneficial analgesic and

anti-inflammatory effects. They are effective for mild to moderate
pain and inflammatory conditions (prescribed for arthritic conditions including juvenile chronic rheumatoid arthritis and
hemophiliac arthropathy). They have been developed in capsule
(celecoxib), tablet (valdecoxib, which is a prodrug of parecoxib),
and parenteral forms (parecoxib). Rofecoxib has been withdrawn.
Pharmacokinetics
The PK of these agents have not been studied in pediatrics.
Limited adult data are available.76
Pharmacodynamics
COX-2selective inhibitors are active centrally and peripherally.
Relative COX-2/COX-1 ratios are 30:1 for celecoxib, 60:1 for
valdecoxib/parecoxib, 276:1 for rofecoxib, and 433:1 for lumaricoxib.76 The use of these agents is increasing in children, although
only a few pediatric perioperative studies are available that have
involved rofecoxib in pediatric tonsillectomy. These trials have
studied different doses of rofecoxib administered at different times
perioperatively: single dosing with 0.625 mg/kg has been compared with ibuprofen 5 mg/kg (combined with 20 mg/kg acetaminophen) and found to be inferior52; single dosing 1 mg/kg has
been compared with placebo and found to be superior77,78; and
multiple postoperative dosing (5 d) of 1 mg/kg (maximum 50 mg)
has been compared with acetaminophen 15 mg/kg q4h and found
to be superior in terms of pain scores on postoperative day 0
through to day 3 and for fluid intake on day 1.79 It has also been
administered preoperatively and postoperatively for 3 days as
1 mg/kg daily and compared with q6h hydrocodone 0.2 mg/kg in
combination with acetaminophen (N = 40, aged 517 y).80 Pain
scores were lower in the rofecoxib-treated patients only when
assessed after swallowing at 24 and 48 hours.
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Adverse Effects
Rofecoxib was shown to cause less gastrointestinal ulceration,
whereas celecoxib had similar rates of ulceration to the NSAIDs
naproxen and diclofenac in adults following long-term use.81 Dyspepsia symptoms are similar to that experienced with NSAIDs, as
is the renal effect side effect profile. The COX-2 inhibitors were
initially thought to lack platelet effects and were used in conditions
in which NSAIDs were relatively contraindicated owing to bleeding risk. However, a concern regarding prothrombotic effects
(possibly through effects upon the platelet-endothelial interface)
has occurred with reports of increased cardiovascular and cerebrovascular events in older adults and those with known vasculopathy.82 This resulted in rofecoxibs subsequent withdrawal from
the market. It is not certain how this risk relates to pediatric
patients. COX-2 inhibitors have been used and are probably safe
in patients at risk of NSAID-ERD.71,83 Celecoxib is a sulfonamide
and is to be avoided in patients with sulfur allergy. Angioedema
and rash can occur with these agents and fluid retention, particularly ankle edema, is also reported.
Dose and Licensing

Pediatric dose-ranging studies of these agents are limited. Consequently, dose recommendations are scaled from adult dosing
including 1.5 to 3 mg/kg (maximum 200 mg) twice daily for oral
celecoxib and 1 mg/kg (maximum 40 mg) daily I.V. for parecoxib.
Lower doses have been used in adults of valdecoxib 10 to 20 mg
maximum daily. These agents are licensed only for use in adults
(>18 y of age).
TRAMADOL
Tramadol is effective for moderate to severe pain and is used
increasingly in pediatrics for perioperative analgesia.84 It has also
been used in postoperative shivering and chronic pediatric pain
including complex regional pain syndrome. It is available in
capsule (including extended release), oral drops, and parenteral
formulations. The latter has been used epidurally in children and
subcutaneously in adults. Some countries have a suppository form
(100 mg), whereas the solution can be rectally administered or the
capsule compounded for smaller rectal dose administration. In
Europe and the United States, a combination preparation with
acetaminophen is available.
Pharmacokinetics
Studies of systemic tramadol use in neonates and infants are
limited with minimal PK data. In adults, the bioavailability after
single oral dosing is 68%, which increases with repeat dosing.
Cmax is reached at 2 hours after oral dosing, 0.5 hour in children
after oral drop and caudal administration, 0.3 hour after I.V.
administration, and 2.4 hours after rectal administration.84 In the
neonate, there is a significant delay (4 h after administration)
before blood and CSF tramadol concentrations fully equilibrate.85
Absorption from the rectal route was assessed in a small number
of children aged 1 to 6 years (B = 12) and demonstrated low
interindividual variability.86
Tramadol undergoes extensive liver metabolism and is subject
to first-pass effect after oral administration. Its primary metabolite
is O-demethyl tramadol (M1), which is formed by CYP2D6. There

is evidence that CYP2D6 activity is present as early as 25 weeks
PMA.87,88 Formation clearance to M1 contributes to 26% of
tramadol clearance in neonates88 and increases with PMA.88,89 An
understanding of the CYP2D6 enzymes polymorphism is increasing.89,90 Individuals vary in their expression of functional
alleles and, depending on the number, can be classified across a
spectrum from poor to normal to extensive to ultrametabolizers.
In addition, there is known age-associated maturation. This has
been also been explored in children for codeine, which requires
CYP2D6 to convert to its active metabolite morphine.91 The
impact of this enzymes polymorphism upon tramadols PK, metabolism, and PD requires further exploration.87,89 Size and PMA,
more than CYP2D6 polymorphism, are now felt to contribute to
the wide variability in the PK of tramadol seen in premature
neonates.88 Maturation of CYP2D6 is rapid and single nuclear
polymorphisms of this gene have considerable impact by 50 weeks
PMA.88 Tramadol clearance increases more rapidly from 5.5 L/
h/70 kg at 25 weeks to 17.188 to 17.587 L/h/70 kg at 40 weeks PMA
and 19.4 L/h/70 kg by 45 weeks PMA, which is 80% that of the
adult value of 24 L/h/70 kg. The central volume of distribution
decreased from 25 weeks PMA (256 L/70 kg) to reach 120% of its
mature value by 87 weeks PMA.87 Other authors report similar
parameter values.92
The absorption characteristics after subcutaneous administration have not been studied.
Pharmacodynamics
Tramadol has effect via its two enantiomers that influence noradrenaline and serotonin turnover and the mu opioid receptor
centrally. It is uncertain whether analgesic action is effected
primarily in the brain or at the spinal cord level. The active M1
metabolite has a mu opioid affinity approximately 200 to 300 times
greater than that of tramadol. Naloxone administration partially inhibits tramadols analgesic effect by 30%. Analgesic effect
in children having urologic or abdominal surgery is associated
with a plasma concentration of tramadol 100 ng/mL and M1 of
15 ng/mL.92
A review of tramadols effectiveness reports 20 positive studies
or case series with administration through various routes in
the pediatric setting.84 A few further comparative9397 and PK
studies85,87,88 or of adjunctive3 or rescue use98 are available, two of
which were negative.93,94 All studies to date have had small sample
sizes and were performed across various pediatric age groups.
Doses assessed ranged from 0.5 to 3 mg/kg via oral,84 I.V. bolus,84,93
intramuscular bolus,84 rectal (single and repeat dosing),84 and
caudal/epidural.84 I.V. bolus and infusions of 100 to 333 g/
kg/h84,85,87,90 and patient-controlled analgesia (PCA; 200 g/kg
bolus)97 and nurse-controlled analgesia84 (300 g/kg bolus) (10min lockout) have also been assessed. Tramadol was compared
with itself at different doses, with opioids (intramuscular and I.V.
pethidine,84,93 nalbuphine,84 epidural,84,95 and PCA morphine97),
NSAIDs,84,94 paracetamol,84 local anesthetic (nerve blocks84 and
epidural84,95,96). The equianalgesic doses of the comparators are
not established. The majority of reports have been in adenotonsillectomy patients84,97; the other surgery types have included
neurosurgery,84,85 urogenital,84,95 inguinal hernia,84,96 neonatal
general3,84,87,88,99 and cardiac84,87,88 surgery, post burns, multitrauma,
and malignancy.84
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Adverse Effects and Drug Interactions

Flushing, sweating, dizziness, and nausea are frequent with rapid
I.V. administration. Tramadols adverse effects are otherwise similar
to those of opioids84 with similar or reduced rates of nausea and
vomiting (1040%), sedation and fatigue, less constipation and
pruritus, and no pediatric reports of respiratory depression.
Sedation, if experienced, can be reversed in part by naloxone
administration. A study in adult gynecology patients demonstrated
oxygen desaturation with morphine but not with tramadol,100 and
a placebo-controlled study of children undergoing halothane
anesthesia showed lowest respiratory rates and highest end-tidal
carbon dioxide pressure (ETCO2) recordings in pethidine-treated
patients 1 mg/kg compared with tramadol 1 and 2 mg/kg.101 A
postoperative neonatal study (N = 20, English abstract only
available) reports elevation of ETCO2 dose-dependently in association with tramadol infusions of 0.1 to 0.2 mg/kg/h, but this was
not placebo-controlled and comments that the neonates were
frequently asleep during the assessment period.99 The respiratory
impact of tramadol may require further evaluation. Abusedependence potential of tramadol is low.
Tramadol lowers the seizure threshold and may cause seizures
in seizure-prone patients (i.e., epilepsy or head injury). The incidence of seizures with tramadol is estimated as greater than 1%.
These have occurred in the setting of overdose, but also with
higher than current dosing recommendations. Care should be
taken in administering tramadol in conjunction with other agents
that alter monoamine oxidase turnover because serotonergic
syndrome can occur.84 Co-administration with the antiemetic
ondansetron (a serotonin [5-HT]3 antagonist that acts at other
5-HT receptor subtypes) significantly reduces the efficacy of
tramadol102 (via 5-HT receptor effects and/or competition for
CYP2D6 metabolism).
Dose and Licensing

Tramadol is not licensed for oral or parenteral use for children
younger than 16 years worldwide. There is significant study and
off-license use of this agent in pediatrics.
Recommendations are for loading dose of up to 3 mg/kg then
1 to 2 mg/kg (maximum 100 mg) q6h. orally or I.V. and 1.5 to
3 mg/kg q6h rectally; some institutions use 4-hour dosing intervals. Others document a loading dose 2 to 3 mg/kg and infusion
of 5 to 8 mg/kg/24 h (200333 g/kg/h) in neonates.90 The 1- to
2-mg/kg dose has been used as a single epidural injection, but
tramadol is not licensed for use via this route. Animal studies
report neurotoxicity and, because systemic absorption is high
from the epidural space, continued administration by the epidural
route is not recommended.84 Wound infiltration and use of tramadol in nerve blocks has been performed (in adults) and requires
further assessment. Maximum dosing recommendations are for
8 or 400 mg daily, although some institutions use higher daily
maximums.
A bolus of tramadol hydrochloride 1 mg/kg will achieve a
target concentration of 300 g/L. This concentration can be
maintained by infusion of tramadol in different age groups of
0.09 mg/kg/h at 25 weeks PMA, 0.14 mg/kg/h at 30 weeks PMA,
0.17 mg/kg/h at 35 weeks PMA, 0.18 mg/kg/h at 40 weeks PMA,
0.19 mg/kg/h at 50 weeks PMA to 1 year, 0.18 mg/kg/h at 3 years,
and 0.12 mg/kg/h in adulthood.87
GLUCOSE AND SUCROSE

(SUGAR) SOLUTIONS
Lay people and medical staff alike have used sugar to settle neonates over the decades. Sucrose (a disaccharide of glucose and
fructose), glucose (monosaccharide) or dextrose (which is the biologically active stereoisomer form: D-glucose) solutions of varying
concentrations have been used.
Mechanism of Action and Efficacy

Cerebral opioid peptide systems have a role in emotional, stress,
and pain responses. Those in the ventral striatum are thought to
regulate the affective response to sugar-containing foods.103
Although it is not well understood, oral sugar solutions likely provide analgesia for procedural pain in neonates possibly by endogenous opioid mechanisms or pathways. Oral sucrose activates
neurons in the periaqueductal gray and nucleus raphe magnus,
two brainstem sites involved in descending pain modulation.104
The interaction may even be indirect with glucose inducing release
of endogenous opioids.105
A Cochrane review confirms that sucrose is effective for reducing pain from single painful events (heel lance, venipuncture).106
This is affirmed in a recent large study in neonates of diabetic and
nondiabetic mothers alike.107 Repeat oral drops of a 24% sucrose
solution improved the effectiveness of local anesthetic eye drops to
relieve pain associated with eye examinations for retinopathy of
prematurity.108 A clinical policy document produced by an Emergency Medical Services for Children expert panel summarizes the
literature for sucrose.109 They conclude that use in conjunction
with a pacifier may improve its effectiveness, that the optimal timing for administration is 2 minutes before the painful procedure,
and that the evidence is most established for neonates (including
those that are preterm) younger than 28 days having minor painful
procedures. Sucrose has been used in older infants (<6 mo old),
but its effect is more modest than in neonates and possibly higher
concentrations are required for benefit. Sucrose was not effective
for reduction of the distress associated with bladder catheterization.
Adverse Effects
Adverse events associated with sucrose administration have not
been reported. The Cochrane review affirms safety of its use.106
Choking, which spontaneously resolved, has occurred in a
placebo-treated patient. Desaturation during the intervention
occurred infrequently and similarly in sucrose- and placebotreated neonates.109
Dose
The optimally effective sucrose dose for preterm and/or term
infants is not yet established: doses that have been used include
0.1 mL of 24% to 2 mL of 50%; the most commonly studied
dose is 2 mL of 24%. Sucrose use in combination with other
behavioral (e.g., swaddling, kangaroo care) and pharmacologic
(e.g., morphine, fentanyl) interventions requires further investigation.107
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reflect its inhibition of the two prostaglandin H2 synthases. Clin Pharmacol Ther. 2006;79:919.
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Neuromuscular Blocking
Agents in Children
Olli A. Meretoja and Hannu Kokki
INTRODUCTION
Neuromuscular blocking drugs (NMBDs; muscle relaxants) are
commonly used to enable smooth endotracheal intubation in
pediatric practice. During surgical procedures, muscle relaxants
are used, as adjuncts to general anesthetics and analgesics, to
prevent muscle movements and to provide muscle flaccidity
making surgical procedures easier and safer to perform. These
drugs are also used to facilitate mechanical ventilation in intensive
care patients who fail to respond to sedation alone.
Muscle relaxants act at the neuromuscular junction. Striated
muscle fibers are in close contact with motor nerve terminals to
form neuromuscular junctions containing millions of receptors
per single muscle fiber. A nerve impulse will generate an ejection
of the neurotransmitter, acetylcholine, from the storage vesicles of
the nerve terminals into the junctional cleft (a narrow space
between the nerve terminal and the motor endplate of the muscle
fiber). The postjunctional acetylcholine receptor consists of five
protein subunits in a rosette shape with a central ion channel
(Figure 271).
Two receptive sites, formed by and subunits, are the
binding sites for acetylcholine and the NMBDs. The ion channel
activation takes place only if both receptive sites are simultaneously attached with acetylcholine molecules. Activation of
the receptor allows sodium and potassium currents to cross the
ion channel based on their concentration gradients. Sodium
current into the muscle cell is enhanced by the negative resting
potential inside the cell. This current makes the inside of a muscle
cell less negative. If hundreds of thousands of receptors become
activated simultaneously, the depolarization will create an action
potential with subsequent contraction of the muscle fiber.
Figure 27-1. A schematic view of an acetylcholine receptor

with five subunits and a central ion channel in a cell membrane
of a muscle fiber. The subunits contain the binding site for
acetylcholine and muscle relaxants. In neonates, the subunit is
replaced by a subunit.
Acetylcholine is continuously inactivated by acetylcholinesterase, an enzyme present in the junctional cleft. The amount
of released acetylcholine and its capacity to attach with the
postjunctional acetylcholine receptor determines whether the
ion channel of the muscle cell membrane will be open or closed.
Because the same receptive sites are the binding sites of nondepolarizing muscle relaxants, the competition between acetylcholine,
the muscle relaxant, and acetylcholinesterase ultimately determines the probability of a successful neurotransmission across the
junctional cleft.
Since about 2000, we have witnessed significant changes in the
use of muscle relaxants. Our understanding of the overall actions
of muscle relaxants and performance of different compounds has
expanded. This, combined with the knowledge of the variability of
the effects of NMBDs both in healthy children and in children
with diseases and conditions that may affect the neuromuscular
block, has resulted in more rational and safe use of muscle
relaxants in pediatric patients.
The use of muscle relaxants has declined in pediatric anesthesia
and intensive care.1,2 There have been several reasons for this
development. First, the current widespread use of laryngeal mask
airway has decreased the number of patients requiring tracheal
intubation to maintain the airway. Contrary to endotracheal tube
placement, laryngeal mask airway is inserted without aid from
muscle relaxants. Second, the introduction of the short-acting
anesthetics and analgesics remifentanil, propofol, and sevoflurane
has allowed intubation and maintenance of sufficient muscle
flaccidity during procedures without muscle relaxation.3 However,
a balanced approach combining intravenous or inhalation anesthesia with intravenous analgesia and muscle relaxation provides
the best intubating conditions with the lowest level of adverse
effects. Third, the common use of regional anesthesia techniques
as adjuncts to general anesthesia has also decreased the need
for muscle relaxants because higher concentrations of local
anesthetics produce not only analgesia but also muscle relaxation.
In these cases, there is no need for repeat doses or continuous
infusion of muscle relaxant, only the intubation dose may be
sufficient. A constant need for deep muscle paralysis during
surgery is uncommon, and consequently, the dose of muscle
relaxant should be administered according to surgical needs.
Sugammadex, a novel NMBD antagonist, may allow more liberal
use of muscle relaxants especially in daycase surgery because the
risk of residual curarization becomes minimal.
Contrasting this overall decrease in the use of muscle relaxants,
the benefits of muscle relaxants in other situations have been
recognized. It has been demonstrated that the use of a muscle
relaxant facilitates intubation in nonemergency conditions in
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neonates, thereby decreasing the incidence and duration of
hypoxia and time and number of attempts needed to successfully
complete the procedure. During muscle relaxation with mivacurium, easy mask ventilation and superior intubation conditions
are achieved, permitting a high success rate.4,5
The impact of residual neuromuscular blockade on patients
safety is better recognized since the beginning of the 2000s. Now
it is understood that full recovery of neuromuscular function (i.e.,
train-of-four [TOF] ratio > 0.9) at the end of surgery is mandatory
before the patient can be required to breathe spontaneously and
in order to avoid the risk of aspiration associated with the impairment of pharyngeal muscle function.6 Recent studies have
established a high between-individual variation in the response to
muscle relaxants. There are up to fivefold differences in both the
onset time and the duration of block even with short-acting
compounds. Thus, the monitoring of block level is essential for
safe use of relaxants and in order to avoid residual block after
surgery.
The high between-individual variation in the response is the
main reason why priming, once a popular approach, is not used
anymore. In sensitive children, even the small priming dose of
muscle relaxant may provide relatively deep muscle blockade,
whereas in more-resistant children, a small priming dose achieves
minimal response.
There are two main types of NMBDs: (1) competitive, nondepolarizing muscle relaxants and (2) depolarizing neuromuscular
blockers. The nondepolarizing muscle relaxants may further be
divided into two structurally different types: the aminosteroidal
muscle relaxants and the benzylisoquinolinium muscle relaxants.
This division is important because sugammadex, a novel new
neuromuscular antagonist, encapsulates aminosteroidal nondepolarizing muscle relaxants, but it does not interact with the
benzylisoquinolinium relaxants or with succinylcholine. Thus,
benzylisoquinolinium relaxants could be used when neuromuscular block is needed shortly after sugammadex administration.
Moreover, some benzylisoquinolinium compounds have unique
patterns of elimination: atracurium and cisatracurium undergo
partial spontaneous degradation via Hofmann elimination, and
mivacurium is inactivated mainly by plasma cholinesterase. Thus,
the changes in the hepatic and renal function only marginally
affect the pharmacokinetics of these three compounds.
All inhalation anesthetics enhance the action of nondepolarizing muscle relaxants.7,8 The potentiation seems to be of a pharmacodynamic origin.9 This is important to remember especially
when repeat doses or continuous infusion of neuromuscular
blocker is used. When inhalation anesthetics are used concurrently with muscle relaxants, smaller and less frequent dosages are
required. A growing body of data has shown that the potentiation
is both time- and age-dependent.10 In infants, it may take up to
45 minutes before the maximum potentiation is achieved, whereas
in school-age children, the maximal potentiation in present only
after 90 minutes. In addition, there seems to be some differences
between different inhalation anesthetics in their potential for
pharmacodynamic interaction with muscle relaxants. Both isoflurane and sevoflurane inhalation may decrease the need of
muscle relaxants by up to 50 to 70% compared with the dosage
needed during a total intravenous anesthesia. With isoflurane and
sevoflurane, the enhancement is dose-dependent, but with similar
minimum alveolar concentrations (MAC), both seem to provide
similar potentiation of the block. Nitrous oxide and halothane are
less potent adjuvants; the effects of nitrous oxide inhalation on
417
muscle relaxant doses are minimal, and halothane may decrease

relaxant dosage by a maximum of 20 to 30%.
It was long uncertain how neonates, infants, or children differ
from adults in their response to nondepolarizing muscle relaxants.
Some early studies showed neonates to be particularly sensitive to
the effects of pancuronium and D-tubocurarine.1114 Conflicting
results also existed because of nonuniform or absent monitoring
or different anesthesia methods.1517 More recent pharmacokinetic
and pharmacodynamic studies have made it possible to better
understand infants sensitivity and childrens resistance to nondepolarizing muscle relaxants.1820
It is mandatory to monitor the neuromuscular function while
using neuromuscular blockers in clinical practice because of
significant between-individual variability in the response and
the numerous pharmacodynamic interactions with other drugs
given during anesthesia. There are no clinical clues, especially
during inhalation anesthesia, to guess the depth of neuromuscular
blockade before the child is fully awake after anesthesia.
DEVELOPMENTAL PHYSIOLOGY
IN NEUROMUSCULAR FUNCTION
The five subunits of a postjunctional acetylcholine receptor are
the two , one , , and subunits. Both subunits are stereochemically different owing to their neighbor subunits (see Figure
271). This may result in different affinity of the two subunits
with acetylcholine or NMBD molecules. Neonates have a subunit
instead of an subunit in their neuromuscular receptor. New
neuromuscular receptors are created every minute because their
survival times are 1 to 2 weeks. If nondepolarizing relaxant molecules are attached to one or both subunitsor more precisely at
the and bordersof the receptor, the ion channel cannot
become activated. Because only a fraction of receptors need to
become activated simultaneously to generate contraction of a
muscle fiber, at least 75% of the receptors have to be blocked by a
muscle relaxant to diminish the muscle contraction. Muscle
paralysis will be established when 75 to 92% of the receptors are
blocked simultaneously.
There are basically three ways to overcome the muscle paralysis. The first is to increase the amount of acetylcholine to promote
acetylcholine to swamp muscle relaxant in competition for the
and the binding sites. This can be done by reducing the metabolic breakdown of acetylcholine with cholinesterase inhibitors
like neostigmine or edrophonium. Because the amount of acetylcholine released during nerve stimulation is limited, cholinesterase
inhibitors cannot reverse a very profound neuromuscular block.
The second way to overcome muscle paralysis is to wait until the
concentration of the muscle relaxant in junctional clefts decreases
low enough to allow acetylcholine to dominate the competition
for binding sites. The muscle relaxant concentration will decrease
by at least two important phenomena: (1) by metabolic breakdown
or excretion related to elimination half-life and (2) by redistribution from the junctional cleft to elsewhere in the body. Metabolism
is important when using relaxants with a short elimination halflife (e.g., mivacurium, atracurium, or cisatracurium) and redistribution for drugs such as rocuronium or vecuronium.
A new approach to reverse muscle relaxation induced with
the aminosteroidal muscle relaxants is the administration of
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the cyclodextrin sugammadex that will encapsulate rocuronium

and, to a lesser degree, vecuronium and pancuronium. Sugammadex enables the reversal of even deep blockade in a relatively
short time, a scenario that was not possible with other existing
reversal agents.
Succinylcholine is the only depolarizing muscle relaxant
currently in use.21 Its mode of action is not fully understood and
differs from that of competitive muscle relaxants. Succinylcholine has great affinity to neuromuscular receptors and acts like
acetylcholine: when succinylcholine molecules are associated with
both receptive sites of the receptor, the ion channel will become
activated and, if the numbers are large enough, ion currents
will establish a muscle contraction. Because the motor endplate
may remain depolarized owing to the continuous presence of
succinylcholine, no further neurotransmission will be generated
and no more channel activation can take place. Prolonged depolarization of the endplate may also produce desensitization of the
receptor that prevents further neurotransmission. A muscle
paralysis will follow the primary muscle contractions. The muscle
flaccidity produced by succinylcholine wears off within minutes
owing to diffusion of succinylcholine from neuromuscular junction and its rapid metabolic breakdown.
Neuromuscular transmission is immature in neonates and
infants until the age of 2 months.22,23 The response to tetanic nerve
stimulation and the rate of muscle contraction are less in neonates
and infants than in children (Figure 272). Tetanic fade in young
infants may indicate that newborns deplete their readily releasable
acetylcholine vesicles more quickly than children. This may be
caused by a small quantal release of acetylcholine in neonatal
neuromuscular transmission.24 Timing of events that contribute
to maturation of neuromuscular transmission is multifactorial. In
general, this maturation process depends more on the duration of
extrauterine life than on postconceptional age.
The type of muscle fibers influences the response to muscle
relaxants. Type I fibers (slow-twitch, high-oxidative) are generally
more sensitive to nondepolarizing muscle relaxants than type II
fibers (fast-twitch).25 The character of muscle fibers changes
during infancy. Although 55% of muscle fibers in the diaphragm
of 2-year-old children are slow marathon fibers (type I) only 25%
in a term newborn and only 10% of the diaphragmatic muscle
fibers in a premature neonate of less than 37 weeks gestation are
slow-type fibers.26 Because the neonatal diaphragm has fewer type
I fibers that are more sensitive to neuromuscular blockers than the
type II fibers during neuromuscular block, the diaphragm function is better preserved than that of peripheral muscles.
It should be remembered that, during the recovery from muscle
paralysis, neonates start to express diaphragmatic movements at a
deeper level of neuromuscular block monitored from the hand
muscles than older pediatric patients.18 It has also been clinical
observed that the human diaphragm requires close to twice the
amount of muscle relaxant than hand muscles to become equally
paralyzed.2729
Differences in the body composition during growth may
explain some of the differences in dose requirement. During early
life, there are major changes in the water, fat, and muscle compartments of the human body.30 NMBDs are distributed to a
theoretical space that mirrors the volume of the extracellular fluid
compartment. This volume is close to 40% of the body weight in
neonates and decreases to 22% of body weight by 1 year of age to
remain relatively constant thereafter.3032 The fat compartment
increases from 12 to 30% of body weight during the first year of
life. Thereafter, its relative size diminishes toward puberty.
The muscle compartment decreases during the first year of life
to one tenth of the total body mass. Thereafter, the proportion of
the muscle compartment in relation to body weight increases to
reach a maximum of one third of body weight by the end of the
active growth of a child. The increase in the proportion of muscle
compartment is fastest after the age of 3 to 4 years.30 The actively
growing muscle tissue contributes a massive number of new
acetylcholine receptors. New receptors may be more resistant to
nondepolarizing muscle relaxants, and because of their great
number, large doses of relaxants are required to block activation
of ion channels in children. Adults have relatively more fat and
less muscle tissue in their body than children, and thus, the need
for muscle relaxant per kilogram of body weight is higher in
children than in adults. However, to avoid excessive dosage in
obese children, dose should be calculated on the basis of ideal
weight for height.
Table 271 shows effective doses of muscle relaxants (ED95; a
dose that produces a 95% neuromuscular block) in infants,
children, and adolescents. These data have been taken from the
studies in which at least two different pediatric age groups have
been analyzed. Although several investigators have found that
children require greater doses of nondepolarizing muscle relaxants
TABLE 27-1. ED95 Doses of Muscle Relaxants (in g/kg)
During Nitrous OxideOpioid Anesthesia in Infants,
Children, and Adultsa
Compound
Figure 27-2. The neuromuscular response of a neonate and an

older infant to a steadily increasing stimulation frequency from
1 to 100 Hz. The neonate cannot sustain the response, which is
reduced by more than 50%. Modified from reference 235.
Alcuronium
Atracurium
Cisatracurium
Doxacuriumb
Mivacurium
Pancuronium
Pipecuronium
Rocuronium
D-Tubocurarine
Vecuronium
Succinylcholineb
a
Infants
Children
Adults
196
231
43
25
129
66
48
251
414
47
700
271
327
47
53
139
93
75
409
499
81
430
220
210
48
41
80
67
59
350
480
43
270
Values are mean.

Denotes that adult data are for adolescents.
References
53, 231
124, 231
137, 143, 232
66
154, 156, 233
55, 231
70, 71
101
53, 231
82, 231
189, 191
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419
TABLE 27-2. Distribution Volume at Steady State and Total Plasma Clearance of Nondepolarizing Muscle Relaxants in
Infants and Children
Vss, mL/kg)
Compound
Atracurium
Cisatracurium
Pipecuronium
Rocuronium
D-Tubocurarine
Vecuronium
CLp, mL/kg/min)
Infants
Children
Adults
Infants
Children
Adults
References
210
225
231
520
357
129
207
185
165
410
204
100
118
208
194
300
269
7.9
10.0
1.5
4.2
3.3
5.6
6.8
6.8
2.3
6.7
4.0
5.9
5.3
3.7
2.5
4.5
3.0
5.2
37
77, 81
38
39
33
35
CLp = total plasma clearance; Vss = volume at steady state.

Taken all the data together, infants have 42% greater Vss than children. For atracurium, the CLp is 16%, and for cisatracurium, 47% greater in infants than in children.
For other muscle relaxants, infants have a 26% smaller CLp than children.
(in mg/kg of body weight) than any other age group of patients,
the observation has not been fully explained. Changes in extracellular fluid volume cannot offer a proper explanation because
this volume (as a percentage of total body weight) is relatively
unchanged after the first year of life.3032
Pharmacokinetic Principles
During the first year of life, the distribution volume of muscle
relaxants decreases when calculated as milligrams per kilogram
of body weight (Table 272). On an average, infants have a 42
20% greater distribution volume of nondepolarizing muscle
relaxants than children.3339 However, infants require a 20 to 50%
lower plasma concentration of muscle relaxants than children or
adults to produce the same level of neuromuscular block (Table
273).33,35,37,39 Because the dose requirement is the product of the
required concentration times distribution volume, dose requirements of muscle relaxants (in mg/kg) are fairly similar in infants
and in adults (see Table 271).
Because the age-related changes in distribution volume and
required plasma concentration are drug-specific, different muscle
relaxants have slightly different age-dependent potencies. Furthermore, elimination of muscle relaxants from the body takes
place via metabolism, renal or hepatic excretion, or spontaneous
degradation. All these depend on the maturation of elimination
pathways and explain the different age-dependent time duration
of effect of various muscle relaxants. Total plasma clearance of
nondepolarizing muscle relaxants D-tubocurarine, pipecuronium,
rocuronium, and vecuronium are 10 to -40% smaller in infants
than in children.3335,38,39 Plasma clearance of atracurium takes
place partially by spontaneous degradation, which results in
different pattern of drug elimination (see Table 272).
The question remains: why do infants require a smaller plasma
concentration of muscle relaxants than children or adults for a
standard neuromuscular block? Two theories that may supple-
ment each other have been proposed. Meretoja and coworkers

investigated drug synergism and found children to have greater
synergism between atracurium and vecuronium than infants.40,41
Synergism was explained by saying that, if one type of muscle
relaxant diminishes the likelihood of a relaxant of different
structure becoming attached to the second . subunitreceptive
sites of the same receptor ( vs), then more separate receptors
become occupied and fewer relaxant molecules are needed for a
neuromuscular block than in the case of a single muscle relaxant
(Figure 273).40 Infants low degree of synergism could be explained if any nondepolarizing muscle relaxant occupies predominantly
only one of the two subunitreceptive sites in infants as opposed
to two relaxant molecules in children and adults.41 Consequently,
infants use the relaxant molecules most efficiently, which is
reflected in a low required plasma concentration. In children and
adults, a greater proportion of relaxant molecules are wasted by
attachment to the second set of . subunits of the receptors that
are already blocked by the presence of one relaxant molecule
(see Figure 273).
Wareham and colleagues explained the low required plasma
concentration of muscle relaxants in neonates and young infants
based on analysis of the quantal content of released acetylcholine
vehicles in growing rats.24 The authors found that neonatal rats
had a smaller amount of acetylcholine released upon a nerve
stimulation than older rats. It was suggested that a smaller concentration of muscle relaxants are needed to compete with this low
concentration of acetylcholine to establish a neuromuscular block.
This results in a small safety factor for neuromuscular transmission in neonates and infants.24
Importance of Anesthesia and

Monitoring Technique
The type of anesthesia and monitoring technique employed
greatly influences the results from muscle relaxant studies.
TABLE 27-3. Plasma Concentration of Muscle Relaxants (in ng/mL) Required for 50% Neuromuscular Blocka
Compound
Infants
Children
Adults
References
Atracurium
Rocuronium
D-Tubocurarine
Vecuronium
363 118
1190 380
270 60
57 18
444 121
1650 380
420 140
110 28
436 122
820 160
530 140
94 34
37
39, 234
33
35
Values are mean sd.
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Figure 27-3. Different patterns of surgical neuromuscular

block. A: In children and adults, most receptors are occupied
by two relaxant molecules. This means a two-molecule block.
B: In infants, most receptors may be occupied by only one
relaxant molecule. This means a single-molecule block.
C: When synergism takes place, most receptors are occupied
by only one type of relaxant molecules. A = atracurium; V =
vecuronium.
A mechanomyographic (MMG) force transducer has long been
regarded as a gold standard of neuromuscular monitoring. However, electromyographic (EMG) recordings have values similar to
those from neuromuscular studies, for example, a force measurement and an adductor pollicis EMG recording produced similar
dose-potencies: ED50 of mivacurium was 51 g/kg from MMG
studies and 52 g/kg from EMG studies, whereas those for
doxacurium were 19 and 19 g/kg, respectively.4245 In all these
studies, a TOF mode of stimulation was used at 10-second intervals. A standardized stimulation interval is crucial because, when
TOF stimulation is used less frequently, the ED values of muscle
relaxants increase. A 30% difference in ED values has been observed if stimulation is given once every 10 seconds instead of once
every 20 seconds (Figure 274).46
Figure 27-4. A: Adductor pollicis electromyographic (EMG)

response to train-of-four stimulations at 10-second intervals.
The responses before rapacuronium 2.5 mg/kg (mark 1) represent 100% neuromuscular function. Twenty seconds after rapacuronium, the first EMG response has decreased to 3% of
control, which indicates a 97% neuromuscular block (arrow).
B: Adductor pollicis EMG response to single-twitch stimulations
at 10-second intervals. The control responses before rapacuronium 1.0 mg/kg (mark 1) represent 100% neuromuscular function. Twenty seconds after rapacuronium, the EMG response
has decreased to 8% of control, which indicates a 92% neuromuscular block (arrow).
A third objective monitoring technique uses acceleration of the
moving thumb and transforms this acceleration to mimic force
based on simple mathematics. This acceleromyography has been
shown to not be interchangeable with the other techniques but
correlates with results from EMG monitoring in children.47,48
Volatile anesthetic agents potentiate the effects of muscle
relaxants; isoflurane and sevoflurane produce a greater potentiation than halothane (Figure 275).7,8,49,50 However, this potentiation is not an all-or-none phenomenon but bears a clear time- as
well as age-dependent pattern. Maximal potentiation of neuromuscular block produced by 1 MAC end-tidal concentration of
halothane or isoflurane was not established before 60 minutes of
inhalation of the volatile agent (Figure 276).10 Younger children
develop maximal potentiation quicker than older children (Figure
277). This potentiation makes comparisons between studies
performed under inhalational anesthesia difficult.
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CHAPTER 27
Figure 27-5. Dose-response curves of vecuronium during

nitrous oxideopioid, halothane, and sevoflurane anesthesia.
Vecuronium has greatest potency during sevoflurane and lowest
potency during opioid anesthesia. Modified from reference 50.
Jalkanen and Meretoja have shown that 30 minutes of inhalation of 1.5% isoflurane produces much shorter onset and
longer duration of neuromuscular block than inhalation for
10 minutes of the same concentration of isoflurane.51 Thus, the
degree of potentiation may be different in separate studies
even though the basic anesthesia (e.g., halothane or isoflurane)
has been the same. This interaction between inhalation anesthetics
and muscle relaxants is especially important when the influence of
age on the response to muscle relaxants is to be evaluated. The
effects of nitrous oxide inhalation, barbiturates, and opioids
on muscle relaxant effects are minimal. This is the reason why
pharmacodynamic data are taken from studies carried out under
nitrous oxidebarbiturate/propofolopioid anesthesia whenever
possible.
Figure 27-6. The effect of duration

of inhalational anesthesia on infusion
rate of mivacurium to maintain a
constant 95% neuromuscular block.
The maximal potentiation is reached
not before 60 to 90 minutes of 1
minimum alveolar concentration
(MAC) end-tidal concentration of
the inhalational agent. The degree
of potentiation is sensitive to the
duration of inhalational anesthesia
if that is shorter than 1 hour. From
reference 10.
421
Figure 27-7. Children younger than 6 years old express a faster

potentiation of the neuromuscular block produced by isoflurane
than older children even though the maximal potentiation is
similar. From reference 10.
LONG-ACTING MUSCLE RELAXANTS

Long-acting muscle relaxants are characterized by the establishment of surgical relaxation for 30 to 60 min after a 1.5 ED95 dose
(Table 274). Time to complete spontaneous recovery of the
neuromuscular function after this dose is 60 to 150 minutes with
a 25 to 75% recovery time of 30 to 60 minutes. Most long-acting
muscle relaxants undergo little or no metabolism.
Long-acting muscle relaxants should not be used in routine
elective surgery owing to the slow spontaneous recovery of
neuromuscular function and the risk of residual neuromuscular
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TABLE 27-4. Main Clinical Characteristics of Long-Acting Muscle Relaxants in Children

Compound
First Dose, mg/kg
Onset Time, min
Clinical Duration, min
Reversal Necessary?
0.30
0.05
0.10
0.10
0.50
34
57
23
23
45
30
40
30
40
40
Yes
Yes
Yes
Yes
Yes
Alcuronium
Doxacurium
Pancuronium
Pipecuronium
D-Tubocurarine
Common Side Effects

No
No
CV
No
CV, histamine
CV = cardiovascular.
block in the recovery room. When long-acting muscle relaxants

are used, careful monitoring of neuromuscular function is mandatory to properly control the depth of relaxation and to ensure
sufficient recovery of neuromuscular function, that is, a TOF ratio
greater than 0.9 after surgery.
These agents may be indicated for maintenance of muscle
paralysis during long surgical procedures owing to their low direct
drug costs. Some of these agents (e.g., doxacurium) have such a
long onset time (time from administration to maximal effect) that
they are not optimal agents to induce paralysis for endotracheal
intubation. Long-acting muscle relaxants are useful in certain
clinical situations such as cardiovascular anesthesia because of their
relatively safe cardiovascular profile. However, D-tubocurarine may
produce hypotension. Pancuronium is associated with sympathomimetic effects, whereas doxacurium and pipecuronium are
devoid of cardiovascular adverse effects (Table 275). Doxacurium,
owing to its lack of cardiovascular or cumulative properties, may be
an appropriate choice in pediatric intensive care units. Alcuronium
may give more protection against an oculocardiac reflex than
D-tubocurarine, pancuronium, or vecuronium.
D-Tubocurarine
D-Tubocurarine
is a monoquaternary isoquinolinium muscle

relaxant with a molecular weight of 771.7 daltons (Da). Less than
TABLE 27-5. Cardiovascular Effects of Muscle Relaxants
and Their Antagonists
Alcuronium
Atracurium
Cisatracurium
Doxacurium
Edrophonium
Mivacurium
Neostigmine
Pancuronium
Pipecuronium
Rapacuronium
Rocuronium
Succinylcholine
D-Tubocurarine
Vecuronium
Minimal effects
No effects (possibility for histamine release)
No effects
No effects
Bradycardia (cholinergic)
Minimal effects (possibility for histamine
release)
Bradycardia (cholinergic)
Tachycardia, increased blood pressure
(vagolytic action)
No effects
No data available
Increase in heart rate and blood pressure
(vagolytic effect)
Multiple arrhythmias (cholinergic)
Decreased blood pressure (ganglion
blockade, histamine release)
No effects (possibility for bradycardia with
opioids)
50% is bound to plasma proteins. Up to 75% of the dose administered is excreted unchanged in the urine and 10 to 12% in the
bile. Only a small fraction of a dose is metabolized. Biliary excretion is more important in patients with renal impairment, in
whom the effects may become prolonged. Because of ganglion
blockade and histamine release associated with D-tubocurarine, it
frequently produces a fall in blood pressure and a reflex tachycardia and may also produce significant bronchospasm.
The pattern of dose-requirement age-dependency of Dtubocurarine has not been reviewed since three pediatric doseresponse studies were carried out during the 1970s through
1990s.16,52,53 Patients in the oldest study received varying concentrations of halothane.16 The study could not demonstrate any
difference in the ED95 between neonates, infants, and children.
The average ED95 was 320 g/kg, with greater variability of response in younger patients.
Goudsouzian and associates also evaluated D-tubocurarine in
one age group of children under a nitrous oxidethiopental
opioid anesthesia and found an ED95 of 600 g/kg.52 The last of
the three studies included infants, children, and adolescents
during nitrous oxidethiopentalopioid anesthesia.53 That study
also failed to find statistical age-related differences in ED95 even
though values in infants were 20% lower than values in children
(414 g/kg vs 499 g/kg) (see Table 271).
The onset time of D-tubocurarine is shorter in infants than
that in children.53,54 Time to establish a 90% neuromuscular block
was 1.6 and 5.2 minutes in infants and children, respectively,
following a dose of 400 g/kg during halothane anesthesia.54 The
5-minute onset time of D-tubocurarine is clinically so long that it
is unpractical (and sometimes unsafe) to use this agent for endotracheal intubation.16,34 Duration of effect and rate of spontaneous
recovery of neuromuscular function following D-tubocurarine
are similar in infants and children16,34 and may be slightly longer
in infants.54
Two pediatric pharmacokinetic D-tubocurarine studies are
conflicting.33,34 Both studies demonstrate that neonates and infants
have a larger distribution volume than children or adults. Fisher
and coworkers noticed that neonates and infants require a lower
plasma concentration of curare than children or adults to maintain
a standard neuromuscular block.33 By contrast, Matteo and
colleagues did not find any difference in the plasma concentration
of curare between neonates, infants, children, and adults required
to produce similar degrees of neuromuscular block (see Table
273).34 Both studies showed that elimination of D-tubocurarine
was slower in neonates and infants than in children or adults (see
Table 272). This would indicate a prolonged duration of effect in
infancy after multiple doses or a large single dose. The 24-hour
urinary excretion of D-tubocurarine is much less in neonates than
in adults (27% vs 45% of a total dose).34
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423
Figure 27-8. The dose-response curves of long-acting nondepolarizing muscle relaxants in infants (I)
and children (C).53,55,66 The curves for children are to the right of the respective curves for infants.
Pancuronium
Pancuronium is a steroidal bisquaternary muscle relaxant with a
molecular weight of 732.7 Da. About 80% may be bound to plasma
proteins. Pancuronium is partially (1520%) deacetylated in
the liver to produce 3-OH, 17-OH, and 3,17-diOH metabolites,
the first of which has a weak neuromuscular activity. A major
proportion of pancuronium is excreted in the urine (4060%) and
in the bile (11%). Slightly prolonged effect can be expected when
pancuronium is given to patients with renal or hepatic failure.
The dose producing a 95% neuromuscular block is 30% less in
infants than in children (Figure 278; see Table 271).28,55 When
pancuronium is used during balanced general anesthesia without
volatile inhalation agents, the initial dose is generally 0.1 mg/kg.
This is only 1.1 to 1.2 times greater than the ED95 dose for children
during a nitrous oxide-thiopental-opioid anesthesia.52,55 In infants
and children the ED95 values of pancuronium are 30% less during nitrous oxidehalothane than during nitrous oxideopioid
anesthesia.17,28,52,55
The maximal effect following pancuronium is reached faster
in infants than in children or adults (Table 276), for example, the
onset time to 90% neuromuscular block following pancuronium

70 during halothane anesthesia is 1.3 minutes in infants and 2.7
minutes in children 10 years of age (see Table 275).56 Larger doses
of pancuronium establish 95% neuromuscular block more quickly,
for example, a dose of 150 g/kg has an onset time of 1.3 0.6
minutes in children 2 to 8 years old.57
In children, pancuronium has a much shorter clinical duration
of effect than D-tubocurarine. This duration following an ED95
dose is 18 to 24 minutes after pancuronium and 41 minutes
after D-tubocurarine.16,17,55 In addition, the rate of spontaneous
neuromuscular recovery is much faster after pancuronium than
after D-tubocurarine; time from 5 to 25% recovery of muscular
force takes place in 16 minutes when pancuronium and in
32 minutes when D-tubocurarine is used during halothane
anesthesia.52
The duration of neuromuscular block following an equipotent
dose of pancuronium (e.g., an ED95 dose) is similar in infancy and
childhood.17,55,56 The hourly requirement of pancuronium to
maintain 95% neuromuscular block in children is, on average,
60 g/kg (65% of an ED95 dose) (Table 277).55 Following an initial
dose, incremental doses of pancuronium are usually required
TABLE 27-6. Onset Time (Time From Intravenous Administration to Maximum Response) of Muscle Relaxants in
Pediatric Patientsa
Onset Time, Min
Compound
Alcuronium
Atracurium
Cisatracurium
Mivacurium
Pancuroniumb
Rocuroniumb
Vecuroniumb
D-Tubocurarine
Succinylcholine
a
Dose, g/kg
Infants
Children
Adolescents
References
200
500
150
300
70
600
70
400
1000
1.5
1.2
1.9
1.6
1.3
1.1
1.5
1.7
2.4
1.7
2.9
1.8
2.4
1.3
2.4
2.7
0.7
2.9
2.2
3.7
2.9
3.0
2.0
2.9
2.5
0.9
53
122, 130
139, 142
162
56
106
85
53
186
Data are in min and collected from studies in which at least two different age groups are evaluated.
Denotes that data for adolescents are from adults.
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TABLE 27-7. Average Hourly Maintenance Requirement of

Nondepolarizing Muscle Relaxants for 9095% Neuromuscular
Block in Children During Nitrous OxideOpioid Anesthesiaa
Compound
g/kg/h
Alcuronium
Atracurium
Cisatracurium
Doxacurium
Mivacurium
Pancuronium
Pipecuroniumb
Rocuronium
Vecuronium
110 25
530 70
120 19
56 12
950 50
59 15
38 8
1000 140
154 51
ED95 Doses/h
References
0.4
1.6
2.5
1.1
6.8
0.6
0.7
2.2
1.9
64
116
143
66
156
55
74
7
93
ED95 = 95% effective dose.

a
Values are mean sd.
b
Denotes halothane anesthesia.
within the next 30 to 45 minutes for maintenance of muscle

relaxation. Thus, surgical relaxation can be maintained for almost
2 hours by incremental doses of pancuronium totaling the same as
the dose used for endotracheal intubation.
In clinical practice, incremental doses of one quarter of the
initial dose of pancuronium are required every 20 to 40 minutes.
The infusion requirement of pancuronium was found to be similar
in pediatric intensive care unit as during general anesthesia, that
is, 59 g/kg/h during the first day of infusion.58
Meakin and associates analyzed the reversal of 90% neuromuscular block induced by pancuronium in babies, infants,
and children. They found that edrophonium produced quicker
neuromuscular recovery than neostigmine and that the recovery
of the TOF ratio was fastest in babies.59 Neuromuscular recovery
was noticed to be more rapid in children than in adults. In general,
neuromuscular recovery is slower when a deeper level of block is
to be reversed; when neostigmine 36 to 40 g/kg was used at 90%
or 75% neuromuscular block induced by pancuronium, it took
6 to 7 minutes or 2 to 3 minutes, respectively, until the TOF ratio
recovered to 0.70.59,60
The pharmacokinetics of pancuronium in children are poorly
described and there are no studies comparing pharmacokinetics
between different age groups. Volume of distribution (203
36 mL/kg) and plasma clearance (1.7 0.2 mL/kg1/min1) of
pancuronium are associated with a long elimination half life
(103 23 min) in children under halothane anesthesia.61 Plasma
concentrations of pancuronium at constant neuromuscular block
levels are similar to the required concentrations of vecuronium
in children.
Alcuronium
Alcuronium is a semisynthetic agent derived from toxiferine,
a naturally occurring alkaloid. It is a bisquaternary molecule
and has a molecular weight of 827.9 Da. It is mainly excreted
unchanged in the urine (8085%) with small amounts excreted in
the bile. The neuromuscular effects of alcuronium are markedly
prolonged in patients with renal impairment. Alcuronium has
minimal effects on blood pressure. It may cause a mild histamine
release.
Only one study has evaluated the dose-response of alcuronium
in pediatric patients. In that study, the ED95 dose was 30% less in
infants than in children (see Table 271).53 This age-dependency

is similar to that observed with pancuronium.29,55 The maximal
effect after alcuronium is reached faster in infants than in children
(see Table 276). In children, time to maximum neuromuscular
block is reached within 4.3 2.8 minutes after a dose of 0.3
mg/kg.62
When alcuronium is used during general anesthesia without
volatile agents, the first dose is generally 0.3 mg/kg. This is only
slightly greater than the ED95 for children (0.27 mg/kg) and produces an early recovery of neuromuscular function.47 This early
recovery creates the false impression that alcuronium is an agent
with intermediate duration. Alcuronium is, however, a clear longacting agent with a plasma clearance of 2.7 1.3 mL/kg/min and
an elimination half-life of 131 57 minutes in children.63 Pharmacokinetic data suggest that alcuronium has a shorter onset time
and duration of effect in children than in adults.63
Rate of spontaneous recovery after alcuronium is somewhat
slower than recovery after pancuronium.64 The hourly requirement to maintain 95% neuromuscular block in children is 0.11
mg/kg. This is 40% of the individual ED95 (see Table 277).64 This
requirement is less than that for pancuronium and, together
with pharmacokinetic data, indicates that alcuronium is a longeracting agent than pancuronium in children. Comparisons between
alcuronium and D-tubocurarine are not possible because of a lack
of sufficient data. Surgical relaxation can be maintained with
alcuronium for 2 to 3 hours by incremental doses totaling the
same as the dose used for endotracheal intubation. In clinical
practice, an incremental dose of one fifth of the initial dose is
usually required every 30 to 40 minutes.
If the same dose in milligrams per kilogram of body weight
is used for all pediatric age ranges, it is occasionally difficult
to reverse residual neuromuscular block at the end of shortduration anesthesia because alcuronium is more potent in
neonates and infants. Therefore, younger patients are particularly
prone to postoperative problems such as compromised spontaneous breathing.
After reversal of residual neuromuscular blockade, the
neuromuscular function recovers much slower following the use
of alcuronium than following an intermediate-acting muscle
relaxant in children.65 It took up to 13 minutes to attain a TOF
ratio of 0.70 and even 26 minutes to attain a TOF ratio of 0.9 when
alcuronium-induced 85% neuromuscular block was reversed with
neostigmine 50 g/kg in children.65 These times were significantly
longer than the 10 minutes required to attain a TOF ratio of 0.9
when atracurium was used in that same study.
Doxacurium
Doxacurium is a bisquaternary benzylisoquinolinium muscle
relaxant with a molecular weight of 1106.1 Da. It is mainly
excreted unchanged in urine and bile but is also slowly hydrolyzed
by plasma cholinesterase. The neuromuscular effects are slightly
prolonged in patients with renal failure. Doxacurium does not
produce vagal or sympathetic blockade and has only minimal
effect on histamine release. Therefore, doxacurium is unlikely to
cause untoward cardiovascular effects (see Table 275).
Doxacurium is the most potent NMBD available. The reported
ED95 of doxacurium in 2- to 12-year-old children is 27 to 32 g/kg
during halothane anesthesia.42,43 During balanced anesthesia
without halogenated inhalation agents, the ED95 of doxacurium
is 25 g/kg in infants, 53 g/kg in children, and 41 g/kg in
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adolescents.66 Thus, doxacurium presents with a typical pediatric
age-related profile: children require greater doses than either
infants or adolescents (see Table 271). However, the magnitude
of age-related changes seems to be greater with doxacurium than
with any other muscle relaxant: infants requirement is 50% less
than the requirement of children (see Figure 278).
Doxacurium has a long onset of action in children even at high
doses. This fits well with the theory that the more potent the
muscle relaxant, the more prolonged the onset of action. The onset
time is 7 minutes after 30 g/kg of doxacurium and 3 to 5 min after
a dose of 50 g/kg.42,43 This long onset time is likely related to the
greater molar potency of doxacurium: when only a small number
of molecules are administered to establish an effect, then the
concentration gradient at the neuromuscular junction becomes
small and it takes longer to reach the maximal effect. More rapidly
acting relaxants are preferable for endotracheal intubation.
Doxacurium has a long duration of action, like D-tubocurarine
or pancuronium. In children, clinical duration of effect and the
25 to 75% recovery time after doxacurium 50 g/kg are 44 to
51 minutes and 30 to 33 minutes, respectively, during halothane
anesthesia.42,43 Although these times are close to those after
pancuronium administration, they are much shorter than the
respective times after doxacurium in adults.67 Volatile anesthetics
do not affect the recovery times of doxacurium when equipotent
doses are used.68 When doxacurium-induced neuromuscular block
is reversed with neostigmine 40 g/kg at 25% of neuromuscular
recovery, the TOF ratio recovers to 0.70 in 4.2 4.2 minutes.60
However, the recovery to TOF ratio greater than 0.9 has not been
established, but it presumably should be significantly longer.
The long duration of action and lack of cardiovascular effects
make doxacurium an alternative for use in intensive care units.
However, the spontaneous recovery of neuromuscular function
after doxacurium infusion lasting several days may be very slow.69
The hourly maintenance requirement of doxacurium is 56 g/kg
in children during nitrous oxideopioid anesthesia for a 90 to 95%
neuromuscular block.66 This requirement represents 1.1 ED95
and is greater than the respective value for pancuronium (see Table
277). This may indicate that maintenance doses of doxacurium
have a shorter duration of effect than maintenance doses of
pancuronium.
425
found that the neuromuscular block recovers significantly slower

after repeated administration than after a single dose.74 This would
suggest that the plasma concentration of pipecuronium after a
single dose decreases quicker in infants than in children and adults
owing to significant early distribution. When a large or repeated
dose is administered, plasma concentration decreases slowly in
infants owing to slow clearance and the typical long duration of
effect is present. Thus, pipecuronium is a long-acting agent in all
age groups.
The 25 to 75% recovery time after an ED95 of pipecuronium is
similar in infants and children, averaging 25 minutes.7173 Hourly
maintenance requirements of pipecuronium for 90 to 95%
neuromuscular block are 38 g/kg in children and 32 g/kg in
infants during halothane anesthesia. These requirements represent
0.7 to 0.8 ED95/hr,74 typical for a long-acting muscle relaxant
(see Table 277).
The only pharmacokinetic study of pipecuronium in pediatric
patients showed that plasma clearance of pipecuronium is smaller
in infants than in children or adults (see Table 272).38 Differences
in plasma clearance may explain the long duration of effect when
repeated or large doses of pipecuronium are administered to
infants. Volume of distribution were not found to be different
between the age groups but the elimination half-life was longest in
infants (135, 69, and 61 min in infants, children, and adults).38
Reversal of Long-Acting Muscle Relaxants

A major hazard of long-acting muscle relaxants is the potential for
residual neuromuscular blockade. In one study, half of the children
paralyzed with alcuronium had a TOF ratio of less than 0.70
at arrival into a postanesthesia care unit (PACU) and only a few
had a TOF ratio greater than 0.9.65 When reversed from 15% of
neuromuscular recovery, time from neostigmine 50 g/kg to a
TOF ratio of greater than 0.90 was significantly longer in the
alcuronium group than in the atracurium group (26 15 min vs
10 5 min). This difference is expected to be even greater if
reversal takes place at deeper levels of neuromuscular block
(Figure 279).65 Consequently, an intermediate-acting muscle
Pipecuronium
Pipecuronium has a steroidal structure close to that of pancuronium with a molecular weight of 762.7 Da. A major proportion (40%) of the administered dose is excreted unchanged
in the urine, and consequently, the duration of action is prolonged
in renal failure. A smaller proportion is deacetylated in the
liver and excreted in the bile. Pipecuronium has no significant
cardiovascular or histamine-related effects.
The ED95 of pipecuronium in children during nitrous oxide
opioid anesthesia is 70 to 84 g/kg,7073 and 48 to 62 g/kg during
halothane anesthesia.45,46,48 Infants have 30% and neonates 40%
smaller ED95 values than children (see Table 271).71,74 Neonates
and infants younger than 1 year have similar potencies.72
Pipecuronium differed from all other nondepolarizing muscle
relaxants in that its ED95 has a significantly shorter clinical
duration of action in infants than in children and adults.71,73,74 This
rapid recovery in infants is, however, seen only with low single
doses. When pipecuronium was given in small incremental doses
to maintain a 90 to 95% neuromuscular block in infants, it was
Figure 27-9. Time to train-of-four ratio of 0.90 after reversal of

atracurium or alcuronium from different levels of neuromuscular block. The deeper the block at the time of reversal, the longer
it takes for full neuromuscular recovery. Times for alcuronium
are longer than those for atracurium. From reference 65.
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relaxant seems to offer a safer recovery profile than a long-acting

muscle relaxant in pediatric patients.
Bevan and coworkers studied reversibility of neuromuscular
block induced by the long-acting muscle relaxants doxacurium and
pancuronium.60 No difference between these two agents was found
for the dose of neostigmine needed or in the time to sufficient
recovery. The dose of neostigmine needed for reversal was less in
children than in adults and neuromuscular recovery after reversal
was significantly faster in children than previously reported in
adults.60 In addition, infants recover from pancuronium-induced
neuromuscular block quicker than adults when either edrophonium or neostigmine is used for reversal.59
Residual postoperative neuromuscular block in pediatric daycare setting has been found to be minimal at 15 to 18 minutes after
reversal of either atracurium, vecuronium, or pancuronium with
neostigmine 60 g/kg.75 However, the level or duration of neuromuscular block was not documented in that study. In general,
it takes longer and interindividual variability may be greater
when more profound neuromuscular block is to be reversed (see
Figure 279).
Special care should be taken to avoid any overdose of longacting muscle relaxants because it takes one elimination half-life
to return to a correct level of block if twice the estimated dose has
been given. This would mean an extra hour of deep neuromuscular
block, in contrast to only 20 to 30 minutes for an intermediateacting agent. Sugammadex may be used in emergency situations to
reverse pancuronium-induced neuromuscular block. Whether
sugammadex is able to reverse pipecuronium-induced block has
not been evaluated.
INTERMEDIATE-ACTING
MUSCLE RELAXANTS
Intermediate-acting muscle relaxants are characterized by established surgical relaxation for 15 to 30 minutes after 1.5 ED95
(Table 278). Time to complete spontaneous recovery of the
neuromuscular function following this dose is 30 to 60 minutes
with a 25 to -75% recovery time of 10 to 20 minutes.
The use of intermediate-acting nondepolarizing muscle relaxants allows improved control of neuromuscular block and low
incidence of postoperative residual paralysis in children.65 Some
intermediate-acting agents have particular beneficial characteristics, such as the short onset time with rocuronium76 or the short
and predictable elimination half-lives of atracurium and cisatracurium.36,37,77 These advantages make intermediate-acting muscle
relaxants preferred for most surgical cases when children are extubated and spontaneously breathing postoperatively. These agents
can be used successfully for endotracheal intubation in patients in
whom mask ventilation is possible awaiting onset of sufficient
neuromuscular block.
It is important to note that unnecessarily high doses of muscle

relaxants bring about far extended duration of neuromuscular
block and do not improve intubation conditions.78,79 Sugammadex
may increase the use of intermediate-acting muscle relaxants
especially in daycase surgery because the risk of residual curarization becomes negligible.
Vecuronium
Vecuronium is a monoquaternary steroidal muscle relaxant with
a molecular weight of 637.7 Da. Vecuronium is an example of
agents that have a fairly short duration of clinical effect but a
relatively long elimination half-life. The intermediate duration
of effect is caused by its rapid redistribution from effect site. It is
partially (3040%) deacetylated to 3-OH, 17-OH, and 3,17-diOH
metabolites in the liver; the 3-OH metabolite has moderate muscle
relaxant properties.
Because of its relatively long elimination half-life and the
metabolite effects, vecuronium has a slow neuromuscular recovery
if administered as prolonged infusion.80,81 Consequently, vecuronium is not indicated for assisted ventilation in intensive care.
About 30% of vecuronium is excreted unchanged in urine.
Vecuronium has a prolonged effect in patients with liver failure.
Vecuronium has little vagolytic or ganglion blocking activity, and
it does not produce significant adverse cardiovascular effects (see
Table 275).
Vecuronium has been studied extensively in pediatric patients.
The age-dependency of the potency of vecuronium is one of the
greatest among muscle relaxants (Figure 2710). During nitrous
oxideopioid anesthesia, the ED95 is 47 to 48 g/kg in neonates
and infants younger than 1 year, 81 g/kg for children 3 to 10 years
old, and 55 g/kg for adolescents 12 to 15 years old.82 Variance of
the ED95 in 10 different age groups was 20 5% g/kg with a range
from 22 to 103 g/kg.82
This fivefold between-individual variability in response suggests that it is not good clinical practice to administer a constant
dose of vecuronium to every pediatric patient. The average ED
values of vecuronium are 40% less in infants and 30% less in adolescents than in children (see Table 271).82,83 Volatile anesthetic
agents have a significant effect on ED values; halothane reduces
ED values by 30%, isoflurane by 40%, and sevoflurane by 60% (see
Figure 275).50,84
When vecuronium is used to establish muscle relaxation during
general anesthesia, the first dose is commonly 100 g/kg. This
dose is ideal only for children and should be reduced to 70 g/kg
in neonates and infants. Onset time of a paralyzing dose of
vecuronium, 70 g/kg during halothane anesthesia, is 1.5 0.6
and 2.4 1.4 minutes in infants and children, respectively,83,8588
but shorter onset times have been reported.89,90 The onset times of
vecuronium are shorter in infants and children than in young
TABLE 27-8. Main Clinical Characteristics of Intermediate-Acting Muscle Relaxants in Children

Compound
Atracurium
Cisatracurium
Rocuronium
Vecuronium
a
First Dose, mg/kg

0.50
0.10
0.60
0.10
Onset Time, min

1.52.0
2.02.5
1.01.5
1.52.5
Not necessary if no fade in double-burst stimulation for the last 15 min.

2535
2535
2030
2035
Reversal Necessary?
a
Yes
Yesa
Yesa
Yesa
Common Side Effects

Histamine if rapid
No
No
No
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Figure 27-10. The 95% effective dose (ED95) value of vecuronium in 10 different age groups of pediatric patients.82 The one
standard deviation (sd) range shows that individual variation
is very much the same across different age groups even though
mean ED95 values differ greatly. The same uniform variation can
be seen in Table 141.
adults (see Table 276). However, even these onset times of
vecuronium are more than twice those of succinylcholine.90
The rate of neuromuscular recovery and the duration of clinical
effect are comparable after vecuronium 70 g/kg during halothane anesthesia and after 100 g/kg during thiopental-opioid
anesthesia.85,88,89 Vecuronium is unusual in that infants have a
427
100% longer recovery times of neuromuscular function than

children after similar milligrams per kilogram of body weight
doses (Figure 2711).85,88,89 Even if an equipotent dose of vecuronium (an ED95 dose) is administered in infants, children, and
adults, infants have longer duration of effect and slower rate of
recovery of neuromuscular function than older patients.91
It has been speculated that spontaneous recovery after a single
bolus of vecuronium takes place during the distribution phase
of the drug in children but during the elimination phase in
infants.89,91 This would result in a short duration and fast recovery
in children but in a long duration and slow recovery in infants.
Vecuronium is an intermediate-acting muscle relaxant; in children,
the duration of effect following vecuronium is one third that of Dtubocurarine and half that of pancuronium.83,92
Maintenance requirements of vecuronium are 60% less in
neonates and infants and 40% less in adolescents than in children
(62 g/kg/h vs 154 g/kg/h vs 89 g/kg/h).93 Variance of the infusion requirement did not depend on the age of a patient and
averaged 26%. However, because the smallest infusion rate was
37 g/kg/h and the greatest 270 g/kg/h, it would be impossible to
administer an individual requirement of vecuronium without
appropriate neuromuscular monitoring.
Halothane and isoflurane reduce the vecuronium infusion
requirement in children by 25% and 40%, respectively.94 The same
study also found that neuromuscular recovery after 2 hours of
vecuronium infusion is rather rapid and predictable. As a constant
dose of vecuronium can maintain a 90% neuromuscular block
for three times longer in infants than in children, and because
the maintenance requirement of vecuronium is much less in
Figure 27-11. Spontaneous recovery of neuromuscular function after an individual ED95 dose of vecuronium or rocuronium in infants and children.91,101 Rocuronium is intermediate-acting also in infants, whereas
vecuronium becomes a long-acting agent in infants.
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infants than in children in terms of ED equivalents, vecuronium

is regarded to mirror a long-acting muscle relaxant in infants
younger than 1 year old (see Figure 2711).95
After an initial vecuronium dose of 100 g/kg in children,
the first increment is usually required within 20 minutes. If
subsequent doses are one third of the initial dose, these doses
are required every 10 to 15 minutes. In neonates and infants, the
first increment after the initial dose of 70 g/kg is required
within 30 to 40 minutes. If subsequent doses are one third of
this initial dose, they are needed on an average every 20 to 30 minutes. During volatile anesthesia, the doses should be reduced
appropriately.
The volume of distribution is greater in infants than in children
(357 70 mL/kg vs 204 116 mL/kg), whereas plasma clearances
are similar (5.6 1.0 mL/kg/min vs 5.9 2.4 mL/kg/min) (see
Table 272).35 This produces a longer mean residence time (and
the duration of action) in infancy (66 min vs 34 min). Infants also
had a greater neuromuscular sensitivity for vecuronium than
children (see Table 273). Another study in children found that
both the distribution volume and the total plasma clearance of
vecuronium were 1.6 times greater than those of pancuronium.61
Elimination half-lives of vecuronium and pancuronium were
similar. It was explained that vecuronium had a shorter duration of
action than pancuronium owing to its greater lipophilicity and
active liver uptake, which favors a rapid decline of plasma concentration early after administration.61 This kinetic explanation
corroborates nicely with the clinical observations of age-dependent
dynamic effects of vecuronium.
Rocuronium
Rocuronium is a monoquaternary vecuronium derivative, that is,
a steroid-based nondepolarizing muscle relaxant with a molecular
weight of 609.7 Da. About 30% of rocuronium is bound to plasma
proteins. It undergoes significant redistribution, rendering rocuronium a muscle relaxant with intermediate duration of effect. One
third of rocuronium is excreted unchanged in urine. The main
metabolite, 17-OH-rocuronium, has weak neuromuscular blocking
Vecuronium
Infants
Children
activity. Clinical effects of rocuronium become prolonged in

patients with liver failure.
Rocuronium has some vagolytic activity and large doses are
associated with increases in heart rate and blood pressure.
Rocuronium has no significant cardiovascular side effects after
normal clinical doses. However, there has been a lot of discussion
on the potential of rocuronium to elicit anaphylaxis. In some
countries, there have been claims of increased risk that has not
been reported from other countries.96 Rocuronium produces a
rather strong local pain when injected rapidly. This pain sensation
can be minimized by prophylactic use of remifentanil, alfentanil,
or a small dose of ketamine.9799 One percent lidocaine 0.1 mL/kg
is less effective to prevent such pain.100
Infants, children, and adults have an ED95 of 251, 409, and
350 g/kg, respectively, during nitrous oxidethiopentalopioid
anesthesia (see Table 271).101 Thus, ED values of rocuronium are
30% less in infants and 20% less in adults than in children.
A similar age-dependent pattern could be established also when
a target-controlled infusion of rocuronium was used.102 EC50 were
calculated to be 650, 1200, and 950 ng/mL in infants, children, and
adults, respectively.
Rocuronium has a lower potency than either pancuronium
or vecuronium, whose ED95 values in infants and children are
one quarter and one fifth, respectively, of the ED95 of rocuronium (Figure 2712).101 The ED values of rocuronium are 20%
lower during halothane than during nitrous oxideopioid
anesthesia.101,103105
The onset time of rocuronium is 1 to 1.5 minutes following
a 2 ED95 in both infants and children during different types
of anesthesia (see Table 276).103110 Rocuronium has clearly a
shorter onset time than either atracurium or vecuronium.109
However, in children, this onset time is about twice as long as
that after succinylcholine,104,107 whereas in infants, it is somewhat
closer to that after succinylcholine.106 The short onset time of
rocuronium is attributed to its relatively low potency that
requires large molar doses to be administered for a desired effect.
Several studies have confirmed that excellent or good intubation
conditions can be reached within 60 seconds in children when
Rocuronium
Rapacuronium
Infants Children Infants
Children
Neuromuscular block (%)
95
50
5
10
50
100
500
1000
Muscle relaxant (g/kg)

Figure 27-12. The dose-response curves of vecuronium, rocuronium, and rapacuronium in infants and
children.82,101 Vecuronium is roughly four times as potent as rocuronium, which is four times as potent as
rapacuronium.
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either succinylcholine or rocuronium has been used to induce
paralysis.105,107109,111,112
Duration of effect and rate of recovery from neuromuscular
block after rocuronium are very similar to those after vecuronium.
In children, clinical duration of effect of rocuronium 600 g/kg
is 21 to 29 minutes,103105,107,109111,113 and the 25 to 75% recovery
time is 9 to 11 minutes.103,111 This same dose of rocuronium had a
duration of effect twice as long in infants as in children.106
Rocuronium mirrors vecuronium: it behaves like a long-acting
agent in infancy.
However, when used on a basis of an individual ED95, rocuronium, unlike vecuronium, had a roughly similar duration of action
in infants, children, and adults (see Figure 2711).39,101 Based on
these studies, it is apparent that neuromuscular recovery after a
small dose of rocuronium (1 ED95) is terminated by distribution
rather than elimination. By contrast, recovery from a larger dose
of rocuronium (2 ED95) will take longer in infants than in
children because of slower elimination of rocuronium in infancy.
Timing of posttetanic count numbers can predict the spontaneous recovery of a profound rocuronium-induced neuromuscular block.114 Woloszczuk-Gebicka and colleagues showed that
the infusion requirement of rocuronium to maintain a 90 to 99%
neuromuscular block averaged 1.0 mg/kg/h during nitrous oxide
fentanyl anesthesia.7 This rate was reduced by 20 to 30% during
halothane or isoflurane and by 50% during sevoflurane anesthesia.
The maintenance requirement of rocuronium in pediatric
intensive care unit was estimated to average 0.8 mg/kg/h.115 In
general, the hourly maintenance requirement of an intermediateacting muscle relaxant is 1.6 to 2.2 ED95 (see Table 277).7,93,116,117
OKelly and associates found that the plasma clearance of
rocuronium increased with increasing body weight in infants and
children from 3 months to 8 years of age.118 Vuksanaj and Fisher
did not confirm this finding because they found heavier patients
to have lower clearance than patients with lower body weightto
height ratios in an age range of 4 to 11 years.119 They also found
older children to have a longer elimination half-life of rocuronium.
However, results of this last study may be biased by an inclusion
of grossly overweight older children. In obese children, dosage of
muscle relaxants should be based on ideal body weight for their
age and height.
Wierda and coworkers showed that infants have a smaller
plasma clearance, larger distribution volume, and lower concentration for 50% neuromuscular block than children (see Tables
272 and 273).39 The study also showed that infants have a more
than 100% longer mean residence time than children. The
pharmacokinetic dynamic modeling verified that following a large
or constant dose of rocuronium infants have a slower rate of
recovery of neuromuscular function and a longer duration
of effect than children.39 This means that not only redistribution
but also reduced clearance play an important role in the longer
duration of effect of a large dose of rocuronium in infancy.
Atracurium
Atracurium is a benzylisoquinolinium muscle relaxant with
a molecular weight of 1243.5 Da. Atracurium is composed of
10 different stereoisomers, one of which is cisatracurium, and this
isomer is responsible for most pharmacologic properties. About
80% of atracurium is bound to plasma proteins. It is broken down
spontaneously by a nonenzymatic Hofmann elimination that is
429
dependent on physiologic pH and temperature.36,37 Atracurium is

also inactivated by nonspecific plasma esterases. Both elimination
pathways are independent of renal or liver function.
Laudanosine, a central nervous system stimulant, is a major
metabolite of atracurium but has not been reported to produce
adverse effects in children.120 Atracurium can be administered as
prolonged infusion to maintain its pharmacodynamic characteristics. It is excreted in the urine and bile, mostly as inactive metabolites. Atracurium does not have any vagolytic or ganglion
blocking activity, but it may release histamine, especially after
large or rapidly administered doses. Atracurium has negligible
cardiovascular effects after normal clinical doses administered
slowly (see Table 275).
Atracurium has been studied extensively in pediatric patients.
Four groups of investigators have determined the ED95 of atracurium in pediatric patients.121124 A detailed study was undertaken during nitrous oxidethiopentalopioid anesthesia in 10 age
groups.124 The study showed neonates and infants to have
ED values that are 30% less than those for older children or
adolescentsa typical finding for most nondepolarizing muscle
relaxants (see Table 271). Others have confirmed this agedependency of the potency of atracurium even though it seems
like mechanomyography has produced 30 to 40% lower ED values
for atracurium than electromyography (ED95 in children 200230
g/kg vs 320350 g/kg).121124 Halothane anesthesia reduces the
ED values by 20%.121,123 If these results are interpreted clinically, a
sufficient initial dose of atracurium for all pediatric patients would
be 400 to 500 g/kg during balanced anesthesia. This dose represents often more than 1.5 ED95 and produces good intubation
conditions within 2 minutes after intravenous administration.125,126
Maximum neuromuscular block after atracurium occurs
quicker in neonates and infants than in children or adolescents.
The maximum effect after a small dose of 150 g/kg is reached in
2.6 minutes in neonates, 3.3 minutes in infants, and 5.5 minutes in
children and adolescents.124 The respective onset times are 1.1, 1.2,
and 1.7 minutes after a 500-g/kg dose.122 The onset time of
atracurium in children is similar to or somewhat shorter than the
onset time of vecuronium, D-tubocurarine, or pancuronium (see
Table 276).127129
Atracurium is an intermediate-acting neuromuscular blocking
agent in all age groups of pediatric patients. The rate of spontaneous recovery after a constant dose (mg/kg of body weight) is
only minimally effected by the age of the patient.121,122,130132 In
some of these studies, the duration of effect after either a constant
or an equipotent dose of atracurium has been slightly shorter,131
similar,121,122 or slightly longer132 in infants than in children. The
differences in the duration of effect have always been of no significant clinical importance. The clinical duration of effect of a
500-g/kg dose of atracurium is 29 to 37 minutes in pediatric
patients.121,122,126 This duration is one third to one half of that
following a long-acting muscle relaxant.128,130,131
Hourly atracurium requirements in children for maintenance
of 95% neuromuscular block during nitrous oxidebarbiturate
opioid anesthesia is 0.5 to 0.6 mg/kg/h (see Table 277).116,133,134
This result has been consistent, although the methods of evaluating
the neuromuscular block have been either mechanomyography
or electromyography. In infants, the infusion requirement is similar
to childrens requirement,116,135 but neonates require 25% less.116
Halothane, isoflurane, and enflurane reduce these infusion requirements by 20%, 35%, and 50%, respectively.133,134 These infusion
rates mean that increments of one third of the initial dose of
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atracurium are required approximately every 15 minutes to

maintain a deep surgical relaxation.
Atracurium is an agent that may produce histamine liberation.
The greater the bolus dose and the quicker it is administered, the
more histamine is likely to be released. The amount of histamine
liberation and the severity of untoward reactions caused by
histamine are less in children than in adults.129 High doses of
atracurium may be associated with hypotension, particularly if
the dose is administered rapidly. However, normal clinical doses
of atracurium injected slowly do not have any cardiovascular
effects.128
Pharmacokinetics of atracurium show that infants have a 30 to
60% greater volume of distribution and a 20 to 70% greater total
plasma clearance than children (see Table 272).36,37 These studies
found that the elimination half-life of atracurium is very similar
in infants and children (14-20 min). The steady-state plasma
concentration resulting in 50% neuromuscular block did not
differ between infants, children, or adults (363, 444, or 436 ng/mL,
respectively).37 The pharmacokinetics of atracurium is in accordance with the clinical findings that recovery from neuromuscular
effects of atracurium is minimally affected by age.
Cisatracurium
Cisatracurium is one of the 10 stereoisomers of atracurium
and has the same molecular weight as the parent drug. It is also
spontaneously degraded by Hofmann elimination and possibly
metabolized by nonspecific esterases.77 The potency of cisatracurium in children is three to four times greater than that of atracurium,117 Thus, the concentration of metabolites of cisatracurium,
including laudanosine, is one third to one fourth of those after an
equipotent dosing of atracurium, which is an important safety
factor.120 Cisatracurium does not release histamine and will
provide an even more stable hemodynamic profile than atracurium. Cisatracurium constitutes approximately 15% of racemic
atracurium.136 Therefore, cisatracurium provides about 60% of the
neuromuscular blocking activity of atracurium.
In a study in children 2 to 12 years old during 1 MAC halothane
anesthesia, the ED50 and ED95 doses of cisatracurium were 23 and
41 g/kg.117 It was estimated that during nitrous oxideopioid
anesthesia, the ED95 value would be 55 g/kg.137 In infants, the
onset time of cisatracurium is shorter and the duration of action
is longer than those in older children.138
At a dose of cisatracurium 150 g/kg in infants and children
during halothane and opioid anesthesia, 100% of infants and 94%
of children have good or excellent intubation conditions at
2 minutes.139 Keenan and colleagues showed that 98% of children
had acceptable (good or excellent) intubation conditions at
90 seconds after cisatracurium 0.2 mg/kg during both halothane
and an opioid anesthesia.140
Because cisatracurium is four times more potent than racemic
atracurium, higher multiples of ED95 doses are needed for similar
onset. The time to maximal effect after a 2 ED95 of cisatracurium
is 2.5 0.8 minutes in children under halothane anesthesia.117 This
time is roughly similar during thiopental-opioid and during
halothane anesthesia (see Table 276).137 A 90% block is reached
within 1.7 0.4 minutes. These times are 1 minute longer than
those of an equipotent dose of atracurium or vecuronium.
Clinical duration of effect following a 2 ED95 during
halothane or opioid anesthesia is 27 to 31 minutes with a 25 to
75% recovery time of 10 to 11 minutes.117,137,139,141 These times are
similar to those following atracurium. The clinical duration after

150 g/kg of cisatracurium is slightly (20%) longer in infants than
in children, whereas the 25 to 75% recovery times are similar.142
Cisatracurium is noncumulative because repeated bolus doses
produce exactly similar durations of neuromuscular block.
Maintenance requirement of cisatracurium for a 90 to 95%
neuromuscular block during halothane anesthesia is 90 to 100 g/
kg/h.117,141 During nitrous oxidenarcotic anesthesia, the infusion
requirement is 120 g/kg/h in both infants and children.143 This
means that cisatracurium is required approximately 2.2 ED95 in
an hour, similar to the requirements for other intermediate-acting
muscle relaxants (see Table 277). No drug-related adverse effects
of cisatracurium have been reported in children even though an
infant erroneously received a massive dose of 860 g/kg.144
Reversal of IntermediateActing Muscle Relaxants

Meistelman and associates found that time from administration of neostigmine 30 g/kg to a TOF ratio of 0.70 was shorter
when a lower degree of vecuronium-induced paralysis was
antagonized.145 This time was reduced from 10 to 3 minutes when
a 75% instead of a 99% block was reversed. Total time elapsed from
the 99% block to full recovery was similar, indicating that there
was no advantage to antagonizing an intense neuromuscular block
in children. This was confirmed with atracurium in a study that
clearly showed time to full recovery of neuromuscular function is
similar whether the block is antagonized at deep level or whether
spontaneous recovery is allowed before reversal.146
Reversal of vecuronium-induced 90% neuromuscular block
is similar in infants, children, and adults during halothane
anesthesia.147 The residual block was less than 5% and the TOF
ratio had recovered to greater than 0.80 within 8 minutes after
neostigmine 30 g/kg in both infants and children.
Kirkegaard-Nielsen and coworkers reversed an atracuriuminduced 90% neuromuscular block in infants and children by
either neostigmine 50 g/kg or edrophonium 1.0 mg/kg.148 The
reversal was fastest in the youngest age groups after either anticholinesterase. Time to attain a TOF ratio of 0.70 was 4 minutes in
neonates and infants, 6 minutes in 2- to 10-year-old children, and
8 minutes in adolescents. Edrophonium established a faster onset
of effect, whereas final recovery was greater with neostigmine,
which also had less variable effect. The authors recommended the
use of neostigmine for routine pediatric practice.148 Gwinnutt and
colleagues also found neostigmine more effective than edrophonium in children.146 The effectiveness of neostigmine to reverse a
cisatracurium-induced neuromuscular block is similar to that of
atracurium.117
The time from neostigmine 50 g/kg to a TOF ratio of greater
than 0.90 was shorter when atracurium instead of alcuronium was
reversed from 85% neuromuscular block (10 5 min vs 26 15
min).65 Fewer children arrived in the postanesthesia recovery
room with TOF ratio of less than 0.70 if atracurium was used to
maintain muscle paralysis. Thus, an intermediate-acting muscle
relaxant offers a safer recovery profile than a long-acting muscle
relaxant in pediatric patients. Fifteen to 18 minutes after reversal,
there was a very low incidence of residual postoperative neuromuscular block in a pediatric daycare setting when atracurium,
vecuronium, or pancuronium was antagonized with neostigmine
60 g/kg.75
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431
TABLE 27-9. Main Clinical Characteristics of Short-Acting Muscle Relaxants in Children

Compound
Mivacurium
Rapacuronium
Succinylcholine
First Dose, mg/kg
Onset Time, min
Reversal Necessary?
Common Side Effects
0.25
2.50
1.00
1.52.0
0.71.1
0.60.9
610
610
24
No
No
No
Histamine if rapid
Bronchospasma
Several serious effectsb
Removed from clinical use in 2001 because of even fatal complications.

Arrhythmias, hyperkalemia, rhabdomyolysis, myoglobinuria, increased intraocular pressure, increased salivation, masseter spasm, hypersensitivity, muscle pain,
and malignant hyperthermia.
b
When rapid reversal of deep paralysis is necessary, such as in

the scenario cant ventilate, cant intubate, sugammadex may be
used to reverse neuromuscular block induced with rocuronium
or vecuronium. However, there are no pediatric data to suggest
appropriate timing or dosing of sugammadex in this scenario.
Based on adult studies, it is possible to antagonize rocuroniuminduced deep block early after its administration or when 1 to
2 posttetanic counts are detected when high enough doses of
sugammadex are used.
SHORT-ACTING MUSCLE RELAXANTS

Short-acting muscle relaxants establish surgical relaxation for
10 to 15 minutes after 1.5 ED95 (Table 279). Time to complete
spontaneous recovery of the neuromuscular function after this
dose is 15 to 30 minutes with a 25 to 75% recovery time of 4 to
8 minutes.
Short-acting muscle relaxants guarantee even more precise
control of neuromuscular block than intermediate-acting agents.
Mivacurium does not normally (assuming that there is no abnormality or deficiency of the cholinesterase) present with postoperative residual paralysis. This is because of its short distribution
and elimination half-lives and relatively fast de-occupancy of
acetylcholine receptors from their attachments. This is the reason
why it is usually unnecessary to pharmacologically reverse the
residual effects of mivacurium. Mivacurium is an ideal agents for
daycare surgery, and it can be used successfully for endotracheal
intubation in situations in which prolonged relaxation is not
needed.4,5
Mivacurium
Mivacurium is a benzylisoquinolinium muscle relaxant with a
molecular weight of 940.2 Da. It is metabolized by plasma
cholinesterase at a rate of 70 to 85% that of succinylcholine into
inactive metabolites. Renal or liver failure is associated with
slightly prolonged duration of effect of mivacurium. The duration
of clinical effect of mivacurium, like that of succinylcholine, is
markedly prolonged in patients with homozygous atypical
cholinesterase. Mivacurium may release histamine at large doses
(0.250.3 mg/kg) to produce skin flushing and possible hypotension and tachycardia.
Mivacurium consists of three stereoisomers, two of these
being short-acting agents with elimination half-lives of 1.8 to 1.9
minues.149 These isomers constitute greater than 90% of the
neuromuscular activity of mivacurium. Plasma clearance of these
trans-trans and cis-trans isomers are 60 to 90% greater in children
than in adults.150,151 Mivacurium seems to be a unique agent in
that infants and children have similar ED values of the drug.152155
The ED95 is 103 to 139 g/kg during nitrous oxideopioid anesthesia and 85 to 95 g/kg during nitrous oxidehalothane
anesthesia.44,45,156,157 These doses are 30 to 40% greater than the
ED95 dose for adults (see Table 271).158
In children, times to 90 and 100% neuromuscular block after a
2 ED95 dose of mivacurium during halothane or balanced
anesthesia are 1.1 to 1.7 and 1.4 to 2.4 minutes in different
studies.44,45,157,159162 In infants, these times are half a minute
shorter.153,155,162 Conditions for endotracheal intubation are
good or excellent in infants and children at 1.5 min after either
0.2 or 0.3 mg/kg of mivacurium, that is, 2 to 3 ED95, during
different anesthesia methods.157,162,163 One study showed that
mivacurium 0.2 mg/kg establishes better intubation conditions
than remifentanil 1 to 3 g/kg during propofol anesthesia.164
For clinical purposes, it would be safest to administer maximally
0.25 mg/kg of mivacurium as a rapid intravenous injection
because greater doses produce significant amount of histamine
release.160162
Spontaneous recovery from mivacurium-induced neuromuscular block is fast irrespective of dose or duration of its
administration. Clinical duration of effect after a dose of 0.2 to
0.3 mg/kg is 7 to 9 minutes with time to full neuromuscular
recovery of 14 to 19 minutes in infants and children.153,155,157,165 The
25 to 75% recovery time of 3.5 to 4.4 minutes after mivacurium is
not affected by age of a child, dose of mivacurium, or anesthesia
method.44,45,153,161,165,166 In children, 0.2 mg/kg and 0.3 mg/kg
of mivacurium have a 2.5 times longer clinical duration of effect
and four times longer 25 to 75% recovery times as equipotent
doses of succinylcholine (10 min vs 4 min and 4 min vs 1 min,
respectively).159 The very fast rate of neuromuscular recovery
after mivacurium makes it necessary to carefully monitor the
neuromuscular function to avoid large fluctuations of muscular
activity during surgery.
Short duration and fast recovery makes mivacurium easy to
administer as a continuous infusion. A new steady neuromuscular
response is established within less than 10 minutes after an infusion
rate change. The steady-state infusion requirement of mivacurium
does not depend on the age of a pediatric patient.150,153,154 Infusion
rate to maintain a 90 to 95% neuromuscular block averages 0.78
to 0.95 mg/kg/h during nitrous oxideopioid anesthesia.154,156,166,167
This represents 6.6 to 6.8 times an individual ED95 of mivacurium
per hour (see Table 277).154,156
The infusion requirement of mivacurium has been found to
correlate with plasma cholinesterase activity.166,168 Children who
recover from succinylcholine-induced neuromuscular block
quickly would also recover from mivacurium-induced neuromuscular block quickly.169 One MAC of halothane and isoflurane
reduces the infusion requirement of mivacurium exponentially
with time (see Figure 276). The maximal reductions were 32%
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and 70%, respectively, when the volatile anesthetic was administered for more than 1 hour.50 Sevoflurane potentiates mivacurium to the same extent as isoflurane.160,168
Because of fast spontaneous recovery, it may not be necessary
to antagonize the residual effects of mivacurium at the end of
surgery169171 However, it should be remembered that neuromuscular block after mivacurium can be significantly prolonged
because of a decreased level of plasma cholinesterase or the
presence of an atypical plasma cholinesterase.
curium is desired, mivacurium should not be used after another

nondepolarizing muscle relaxant.
Mivacurium can be administered after succinylcholine. Under
propofolnitrous oxidealfentanil anesthesia, succinylcholine had
no effect on the duration of action of mivacurium in children.169
Under halothane anesthesia, the clinical duration of mivacuriuminduced paralysis became prolonged if preceded by succinylcholine
because of long exposure of halothane and subsequent potentiation
of the effects of mivacurium.159
Mivacurium After Another Muscle Relaxant
Rapacuronium
Mivacurium has a significant interaction potential with other

nondepolarizing neuromuscular blockers. If it is used in adjunct
with another intermediate- or long-acting muscle relaxant, the
duration of action of mivacurium is prolonged and it behaves
like intermediate-acting compounds. For example, when a 10-g/
kg dose of mivacurium is administered at 25% recovery of
pancuronium-induced neuromuscular block, surgical relaxation
lasts another half hour in adults with that tiny dosage of mivacurium (Figure 2713).172 When a small dose of pancuronium (one
sixth of an ED95) instead of saline was used as a priming dose
before mivacurium 0.20 mg/kg, maximal neuromuscular block
became established more quickly (1.8 min vs 3.0 min).173 However,
clinical duration of neuromuscular block was several times longer
when pancuronium was the priming agent (21 min vs 9 min).
Disadvantages of prolonged neuromuscular block are far greater
than the benefit of a short onset time when mivacurium is
preceded by pancuronium. Synergism is the likely explanation for
these interactions.
Interaction between mivacurium and either atracurium,
cisatracurium, or vecuronium has been evaluated.174177 Jalkanen
and associates administered 1 ED50 of either atracurium,
mivacurium, or vecuronium, or a combination of a half ED50
mivacurium together with a half ED50 of either atracurium or
vecuronium. Potencies of the combinations were 36 to 48% greater
than potencies of the parent agents.174 If mivacurium is administered after atracurium or cisatracurium, the duration of
effect is expected to mirror that of an intermediate-acting muscle
relaxants.177 Subsequent requirements of mivacurium are very
small early after onset of block, but increase steadily during the
90 minutes after the previous bolus dose of either atracurium,
rocuronium, or vecuronium.175,176,178 These results indicate that
mivacurium does not behave like a short-acting agent if preceded
by a longer-acting muscle relaxant. If rapid recovery after miva-
Rapacuronium was a recently introduced nondepolarizing compound. Rapacuronium is a steroidal monoquaternary vecuronium
derivative with a molecular weight of 650 Da. It was characterized
as a short-acting muscle relaxant owing to its fast redistribution
from effect site to other tissues.
In infants and children, rapacuroniums potency was lower than
that of any other nondepolarizing muscle relaxant. The ED95
during nitrous oxidethiopental anesthesia was 0.7 mg/kg in
infants and 1.5 mg/kg in children.179 Maximal neuromuscular effect
after rapacuronium was established within 0.7 to 1.1 minutes in
infants and young children. This was likely related to the low
potency and great molar dose administered.180 Intubation conditions were good or excellent in infants and children within less
than 1 minute after rapacuronium of at least 1.5 ED95. Neuromuscular function recovered completely after this dose in 8 to 16
minutes in infants and young children and in 16 to 23 minutes in
children older than 7 years. A 25 to 75% recovery time was 2.1 to
3.8 minutes in infants and young children and 4.2 to 6.0 minutes
in older children.181
Unfortunately, the use of rapacuronium was associated with a
relatively high incidence of severe bronchospasm including
mortality,182 and the compound was voluntarily withdrawn from
the market in 2001.
Neuromuscular recovery (%)
Mivacurium 10 g/kg preceded by

Mivacurium
100
DEPOLARIZING MUSCLE RELAXANTS

Succinylcholine
Succinylcholine has a molecular structure of diacetylcholine
with a molecular weight of 397.3 Da. Plasma cholinesterase
(pseudocholinesterase) produces its rapid hydrolysis with an
elimination half-life of less than a minute. In patients with atypical
cholinesterase, the effects are prolonged. The neuromuscular
Pancuronium
80
60
40
20
Mean SEM
0
0
20
40
Time following mivacurium (min)
60
80
Figure 27-13. The neuromuscular function

following a tiny 10-g/kg dose of mivacurium
when administered at 25% neuromuscular
recovery after mivacurium or pancuronium.172
The clinical duration of effect is 30 minutes and
time to complete recovery more than an hour
when pancuronium preceded mivacurium.
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effects become prolonged also if succinylcholine is administered as
a continuous infusion to induce a phase II block (characterized
by fade).
Succinylcholine stimulates all cholinergic autonomic receptors
and is typically associated with frequent cardiac arrhythmias
including sinus bradycardia, junctional rhythms, and ventricular
arrhythmias ranging from single premature beats to ventricular
fibrillation. Other severe adverse effects of succinylcholine include
hyperkalemia, rhabdomyolysis, myoglobinemia, malignant hyperthermia, increased intragastric and intraocular pressure, masseter
spasm, increased salivation and bronchial secretions, muscle
pains, and hypersensitivity.
Since the beginning of 2000, there has been a lot of controversy
and discussion on the use of succinylcholine, especially in
children, because of its rare but life-threatening adverse effects.21
Since the mid-1990s in the United States, succinylcholine was
considered contraindicated in children and adolescents, except
when used for emergency tracheal intubation or in instances in
which immediate securing of the airway is necessary.183,184
However, this view met much criticism and the U.S. Food and
Drug Administration was advised to reconsider banning the
routine use in children and instead to update the package insert
about the potential risks of succinylcholine.185
Succinylcholine is still the muscle relaxant with the shortest
onset time (see Table 276). The onset time of a paralyzing dose
(1.0 mg/kg) of succinylcholine is 0.6 to 0.9 minutes.57,86,159,186188
Cook and coworkers compared onset times of equipotent doses
of succinylcholine and mivacurium in infants and in children.159
They found that onset times of these muscle relaxants differed
minimally in infants, a finding indicating that infants have such
short onset times of muscle relaxants that succinylcholine is hardly
needed for routine tracheal intubation. Succinylcholine does
not influence the level or duration of paralysis induced by a
nondepolarizing muscle relaxant given after succinylcholine.169,189
By contrast to nondepolarizing muscle relaxants, the doserequirement of succinylcholine is greater in neonates and infants
than in children or adolescents.186,190,191 Infants have 70% greater
ED95 of succinylcholine than children (700 g/kg vs 410 g/kg).191
In children, the ED95 is 70% greater than in adolescents (450 g/kg
vs 270 g/kg) (see Table 271).186
A dose of 1.5 to 2.0 mg/kg (i.e., 2 ED95) is commonly used
for neonates and infants compared with 1.0 to 1.5 mg/kg (i.e.,
23 ED95) in older patients to establish muscle relaxation
sufficient for endotracheal intubation. Because these doses are
several times ED95, a longer period of muscle relaxation is achieved
than with the minimal sufficient intubating dose.186,191 After a 1.0
to 1.5 mg/kg dose of succinylcholine, the neuromuscular block
recovers spontaneously in 4 to 5 minutes in both infants and
children.190
Tachyphylaxis and phase II block develop in children when
succinylcholine is administered at a dose of 3.0 1.8 and 4.1 2.7
mg/kg, respectively.192
Succinylcholine produces an increase in the resting tension of
different skeletal muscles.193 This increase is most significant in
masticatory muscles during volatile anesthesia.193197 The reduction in mouth opening and jaw stiffness may last for more than
10 minutes.194,196 Masseter spasm is a situation in which jaw
stiffness prevents normal mouth opening after induction of
general anesthesia and may occur with a frequency of 1% after
succinylcholine in halothane anesthesia.198 Children with strabismus may be even more likely to establish a masseter spasm.199 The
433
exact mechanism of increased muscle tension produced by

succinylcholine is not known. Masseter muscles themselves
are more sensitive to the neuromuscular blocking effects of
succinylcholine than are hand muscles.193
Goudsouzian and Liu found that young infants, mean age of
2 months, required a much greater infusion rate of succinylcholine
than older infants, mean age of 6 months, to maintain a 95%
neuromuscular block. The infusion rates during halothane
anesthesia were 25 and 9 mg/kg/h, respectively.200 Both rates were
greater than the rate required by children, 6 mg/kg/h. This great
requirement in younger patients would indicate higher plasma
clearance of succinylcholine in infancy than in childhood.
Succinylcholine has a prolonged effect in children with abnormal plasma cholinesterase or myasthenia gravis.201 Adults with an
abnormal plasma cholinesterase gene in one chromosome have a
50% prolonged effect and those with an abnormal gene in two
chromosomes have at least a three times prolonged effect after
succinylcholine.202
Fasciculation and gross muscular movements after succinylcholine are common in infants and children.203 Fasciculation can
be prevented by a priming dose of a nondepolarizing muscle
relaxant,203,204 volatile anesthetic agent,205,206 or an opioid.204,207 The
precurarization technique prevents myoglobinemia and serum
creatine kinase concentrations from increasing even in young
children.203,208 However, precurarization does not prevent the
succinylcholine-induced increase in jaw tension.188 Other adverse
effects of succinylcholine include hyperkalemia, risk of hyperpyrexia, and increased intracranial and intraocular pressure.
The risk for malignant hyperthermia is especially high in
children with muscular dystrophies. Normally, serum potassium
rises 0.1 to 0.2 mmol/L after succinylcholine 1 mg/kg. In large
burns, massive release of potassium between the second and the
sixth week may cause rises in serum potassium (>4 mmol/L)
sufficient to cause cardiac arrest. The extent of rise is related to
burn area and the dose. In addition, the depth and duration of
neuromuscular block produced by succinylcholine are related to
the time and extent of the burn.209 Hyperkalemia may also occur
in patients with spinal injuries after major trauma.
Dysrhythmias after succinylcholine, especially bradycardia
during inhalational anesthesia, are common. These are present
more frequently if repeated doses of succinylcholine are used.
A classic method aiming to prevent succinylcholine-induced heart
rate changes has been administration of an anticholinergic agent
before succinylcholine.210 However, a group from Toronto evaluated the use of atropine when 1- to 6-year-old children were given
placebo or atropine 10 to 20 g/kg before succinylcholine.211,212
They found that atropine is not at all necessary before succinylcholine and recommended reconsideration when using an
anticholinergic agent to prevent cardiac arrhythmias feared with
succinylcholine.
Succinylcholine has been the traditional drug to provide good
or excellent intubation conditions within 1 minute after its administration. Partly because of a fear for serious adverse effects of
succinylcholine, several anesthesiologists have practiced tracheal
intubation by using the nondepolarizing muscle relaxant that is
subsequently used for maintenance of relaxation. This practice has
been very successful in pediatric patients because onset times of
muscle relaxants are relatively short. Tracheal intubation without
using a muscle relaxant has been documented in several publications to be successful when propofol together with different doses
of alfentanil has been employed.213215
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REVERSAL OF MUSCLE RELAXATION

There are currently several ways to recover neuromuscular function following the use of nondepolarizing muscle relaxants. First,
spontaneous recovery allows the muscle relaxant molecules
to become metabolized, redistributed, or excreted, whereas the
amount of acetylcholine remains constant around the neuromuscular junction. This process can take a long time especially
when the elimination half-lives of relaxants are commonly long.
Exceptions are mivacurium, atracurium, and cisatracurium whose
neuromuscular blocking properties may be allowed to wear off
owing to rapid elimination.
The second possibility is to use anticholinesterases that decrease the breakdown of acetylcholine in neuromuscular cleft and
increase the concentration of acetylcholine available to compete
with muscle relaxant molecules. If the neuromuscular block is very
intense, that is, the concentration of a muscle relaxant in the cleft
is great, anticholinesterases cannot override the effects of relaxant
molecules. Only a relatively shallow block can be effectively
antagonized by anticholinesterases.
The third possibility is to use the novel chelating agent sugammadex that irreversibly removes rocuronium and vecuronium
from their effect sites and, thus, allows normal acetylcholine concentration to have an effect at neuromuscular receptors. Sugammadex creates an irreversible and inert complex with these
steroidal muscle relaxants and abolishes their effects. Sugammadex is capable of antagonizing deep block and even rocuronium
very soon after its administration. Sugammadex opens a new page
to human pharmacology.
Neuromuscular monitoring is a prerequisite for reversal of
neuromuscular block. Before any change in neuromuscular
transmission can be recorded, 75 to 80% of the neuromuscular
receptors have to be occupied by a nondepolarizing muscle
relaxant.216 At the time of 95% neuromuscular block, 90% of the
receptors are occupied. The more receptors are blocked, the less is
the reserve of muscular power. Even after complete reversal, a
major proportion of acetylcholine receptors remain occupied by
a muscle relaxant. The longer this occupancy lasts, the longer the
elimination half-life of a particular muscle relaxant.
The deeper the neuromuscular block at the time of reversal,
the longer it takes until sufficient neuromuscular recovery takes
place (see Figure 279).65,145,147 A study evaluating antagonism
of alcuronium and atracurium in children found that, if the
clinicians decision to remove an endotracheal tube is based solely
on clinical signs of recovery, neuromuscular block is still
significant, 32 20%, and the TOF ratio is only 0.50 0.18.65 This
means that patients having a long-acting muscle relaxant will have
increased risk for residual paralysis if objective neuromuscular
monitoring is not used.
Neostigmine
Neostigmine is an anticholinesterase that inhibits the function of
acetylcholinesterase. In addition, neostigmine has some inhibitory
effect on pseudocholinesterase and may reduce the breakdown
of succinylcholine and mivacurium. It has a molecular weight
of 223.3 Da. Neostigmine is hydrolyzed by cholinesterases and also
metabolized in the liver. It and its metabolites are excreted in
the urine.
Renal failure produces a prolonged effect of neostigmine to
favor successful reversal of neuromuscular block even in patients
with renal impairment. Side effects of neostigmine include those

typical for excessive cholinergic stimulation: salivation, abdominal
cramps, nausea, and vomiting. Atropine or glycopyrrolate given
simultaneously with neostigmine will minimize these untoward
muscarinic effects.
The classic antagonist for nondepolarizing muscle relaxants is
neostigmine. Distribution half-life and steady-state distribution
volume of neostigmine are similar in infants, children, and
adults.217 However, plasma clearance tends to be greatest in infants
and produces a relatively short elimination half-life in infants
and children compared with adults (39 to 48 min vs 67 min).217
Smaller doses of neostigmine are needed in infants and children
than in adults when doxacurium, D-tubocurarine, mivacurium,
pancuronium, and rocuronium are reversed.60,171,217,218
The dose of 30 to 50 g/kg can be used for all pediatric age
groups, together with atropine 20 g/kg or glycopyrrolate 10 g/kg.
The maximum effect after neostigmine is reached in no less than
5 to 10 minutes after intravenous administration, although the
patient is usually extubated much earlier.59,65,145,147,148,217 The time
taken to reach sufficient muscle power (i.e., TOF ratio > 0.9) after
neostigmine is much longer when a long-acting rather than an
intermediate-acting relaxant is used.65
Edrophonium
Edrophonium has similar anticholinergic effects and adverse
effects to neostigmine. It does not affect the function of pseudocholinesterase. Edrophonium has a molecular weight of 201.7
Da. In humans, it has a faster onset of effect than neostigmine. It
does not affect the metabolic breakdown of mivacurium and may
be a preferred agent to reverse intense neuromuscular block
induced by mivacurium. However, purified human pseudocholinesterase may become a drug of choice for this purpose.
The major proportion of edrophonium is eliminated via the
kidneys and renal failure may increase its elimination half-life
threefold. This is more than the respective increase observed with
muscle relaxant clearance and guarantees a good recovery profile
if an adequate dose at the correct level of block is administered.
Edrophonium has a significantly shorter onset time than
neostigmine.59,148,170,219 Distribution half-lives and the steady-state
distribution volume of edrophonium are similar in infants,
children, and adults.219 Plasma clearance is greater in infants than
in adults and produces a slightly shorter elimination half-life in
infants and children than in adults (73 to 99 min vs 126 min).219
By contrast to neostigmine, larger doses of edrophonium
were needed in infants and children than in adults when Dtubocurarine was reversed.219 However, in clinical anesthesia,
constant doses of edrophonium produced faster reversal in infants
and children than in adults.59 Edrophonium 1.0 mg/kg produced
early recovery of atracurium-induced neuromuscular block than
neostigmine 50 g/kg in five age groups of infants and children.148
However, final recovery became more complete with neostigmine
and the authors recommended neostigmine for routine pediatric
anesthesia.
Edrophonium 1.0 mg/kg reverses a cisatracurium-induced 90%
neuromuscular block in children within 3 minutes, whereas
in adults, an adequate reversal was not established within the
10 minutes of follow-up.220 If edrophonium is used to reverse a
less than 90% neuromuscular block (two or three visualized twitch
responses after a TOF stimuli), the dose of 1.0 mg/kg may be used
for all pediatric patients.
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435
Sugammadex
Anticholinesterases are far from ideal reversal agents for muscle
relaxants. They cannot reverse a profound neuromuscular block,
are slow in onset, have numerous side effects, and require
co-administration of anticholinergic agents. Sugammadex is a
completely different molecule that consists of eight sugar molecules
in a ring structure like a donut.221 It is classified as a gammacyclodextrin. The ring structure is hydrophilic from outside and
lipophilic from inside. Sugammadex has a very strong binding
affinity to rocuronium, which is bound irreversibly inside the
donut hole. The complex has no significant pharmacologic activity
and is eliminated from the body via urine without metabolism.
When sugammadex chelates rocuronium, its free fraction
decreases in the central compartment. More rocuronium is then
transferred from the effect site into serum (down its concentration
gradient) to further bind with sugammadex. This process continues rapidly until the effect-site concentration of rocuronium
becomes too low to compete significantly with acetylcholine.
Consequently, the neuromuscular block is reversed via removal
of rocuronium from the effect site. The strong binding affinity of
sugammadex to rocuronium allows 1 mg/kg of sugammadex to
chelate up to 0.15 mg/kg of rocuronium.
Sugammadex has a slightly lower capacity to bind vecuronium
and lower still for pancuronium (two other aminosteroidal muscle
relaxants) compared with rocuronium. However, it can be used to
antagonize the neuromuscular effects of vecuronium and, in
emergency cases, may be tried for reversal of pancuronium.
Sugammadex does not have any clinically significant antagonism
of benzylisoquinolinium-induced neuromuscular block, and these
compounds may be used if subsequent muscle relaxation is
required shortly after sugammadex administration.
Only one pediatric study has been carried out with sugammadex.222 Adult studies show that when sugammadex 4 or
8 mg/kg is given 3 minutes after rocuronium 0.6 mg/kg, full
neuromuscular recovery, TOF ratio greater than 0.9, is attained
within 2 minutes.223 If sugammadex is given 5 or 15 minutes after
the rocuronium 0.6 mg/kg, recovery is faster with the same doses
of sugammadex owing to a lower serum concentration of rocuronium at the time of reversal.224 If rocuronium is reversed when
two twitch responses are detected with a TOF stimulation, a
2-mg/kg dose of sugammadex is adequate for rapid reversal.225
If rocuronium 1.2 mg/kg is to be antagonized with sugammadex at 3 minutes after its administration, a higher dose of
sugammadex, 12 or 16 mg/kg, is required for rapid effect.226 There
is a very similar type of dose-effect curve for vecuronium and
rocuronium that show that, when a dose of sugammadex is
increased, the full neuromuscular recovery is attained faster.227 In
adults, sugammadex seems to have very similar effects whether
rocuronium is antagonized under sevofluranenitrous oxide
oxygen or under propofolnitrous oxideoxygen anesthesia.228
Sacam and colleagues compared the antagonizing properties
of neostigmine, edrophonium, and sugammadex and reported the
fastest effect with sugammadex.229 They antagonized rocuronium
at an average of 90% neuromuscular block level. Time until TOF
ratio greater than 0.9 was 1.8 minutes with sugammadex, 5.5
minutes with edrophonium, and 17.4 minutes with neostigmine.
Within 5 minutes from the reversal agent, no edrophonium
patient and 1 neostigmine patient had attained the required TOF
ratio of 0.9 as opposed to all 20 sugammadex patients.229 Another
recent study showed that sugammadex reverses a rocuronium-
Figure 27-14. Relationship between the dose of sugammadex

and time till recovery of a train-of-four ratio to 0.9 in four age
groups of patients. Sugammadex was administered when the
second-twitch response became detectable with a train-of-four
stimulation. From reference 222.
induced neuromuscular block faster than neostigmine does for a
cisatracurium-induced neuromuscular block.230
The only currently available pediatric data on sugammadex
consist of four age groups of patients: infants from 28 days to
23 months, children from 2 to 11 years, adolescents from 12 to
17 years, and adults from 18 to 65 years of age.222 Each patient
received rocuronium 0.6 mg/kg under nitrous oxidepropofol
opioid anesthesia. The neuromuscular block was reversed when
the second-twitch response became detectable with a TOF
stimulation. Times from reversal to a recovery of TOF ratio greater
than 0.9 were of similar magnitude in all age groups of patients
(Figure 2714). With a 2- or 4-mg/kg dose of sugammadex, these
times were 0.6 to 1.4 minutes in all study groups. In this small
study, no sugammadex-related adverse effects were detected.
No significant changes in heart rate, blood pressure or corrected
QT-time were noted. However, owing to the limited number of
pediatric patients administered sugammadex, it is too early make
any conclusions on sugammadex safety.
CONCLUSIONS
Muscle relaxants are used to facilitate endotracheal intubation
and, less often, to maintain muscle relaxation during a surgical
procedure or in the intensive care unit. Currently, we have so many
muscle relaxants available that it may be difficult to select the
optimal for everyday use. The high incidence of residual neuromuscular block with long-acting muscle relaxants has limited their
use to few specific indications.
The intermediate-acting muscle relaxants cisatracurium and
rocuronium have superior neuromuscular and safety profiles than
their predecessors (atracurium and vecuronium, respectively).
Rocuronium has a significantly shorter onset time than cisatracurium. Conversely, cisatracurium has the unique unchanged
clinical profile even in children with metabolic, renal, or hepatic
diseases. Both agents can be used for endotracheal intubation and
for maintenance of muscle relaxation, but rocuronium is clearly
preferred when a rapid-sequence induction is required.
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Sugammadex may change some anesthesia practices because it

allows more liberal use of muscle relaxants than currently used.
This means that we may use muscle relaxants for endotracheal
intubation or very short surgical procedures more widely than we
have done in the past. Mivacurium is the shortest-acting nondepolarizing muscle relaxant. However, owing to the individual
variation in response it may take up to 20 to 30 minutes until
full recovery of neuromuscular function. Therefore, very short
procedures have usually been carried out without muscle relaxants. Sugammadex together with rocuronium or vecuronium
may allow us to reconsider our clinical practices.
Muscle relaxants will remain one of the corner stones of
pediatric anesthesia. Much of the old mist has disappeared and
there is a clear picture of their effects in different pediatric patients.
Muscle relaxants may be life-saving when correctly used, and the
correct use always requires proper monitoring of neuromuscular
function.
Neuromuscular monitoring by at least a peripheral neurostimulator is necessary owing to the wide interindividual and agerelated variability of the neuromuscular response of neonates,
infants, and children and owing to the marked and also individual
potentiation of neuromuscular block by inhalational anesthetics.
The cost of muscle relaxants in children is low compared with new
intravenous or inhalational anesthetics, and economic reasons are
justifiable to limit the use of neuromuscular blocking agents in
pediatric anesthesia and intensive care.
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206. Randell T, Yli-Hankala A, Lindgren L. Isoflurane inhibits muscle
fasciculations caused by succinylcholine in children. Acta Anaesthesiol
Scand. 1993;37:262264.
207. Yli-Hankala A, Randell T, Varpula T, Lindgren L. Alfentanil inhibits
muscle fasciculations caused by suxamethonium in children and in
young adults. Acta Anaesthesiol Scand. 1992;36:588591.
208. Asari H, Inoue K, Maruta H, Hirose Y. The inhibitory effect of intravenous
D-tubocurarine and oral dantrolene on halothane-succinylcholineinduced myoglobinemia in children. Anesthesiology. 1984;61:332333.
209. Brown TCK, Bell B. Electromyographic responses to small doses of
suxamethonium in children after burns. Br J Anaesth. 1987;59:1017
1021.
210. Lerman J, Chinyanga HM. The heart rate response to succinylcholine
in children: a comparison of atropine and glycopyrrolate Can Anaesth
Soc J. 1983;30:377381.
211. Shorten GD, Bissonnette B, Hartley E, Nelson W. It is not necessary to
administer more than 10 g kg1 of atropine to older children before
succinylcholine. Can J Anaesth. 1995; 42:811.
212. McAuliffe G, Bissonnette B, Boutin C. Should the routine use of atropine
before succinylcholine in children be reconsidered? Can J Anaesth.
1995;42:724729.
213. Hiller A, Klemola UM, Saarnivaara L. Tracheal intubation after
induction of anaesthesia with propofol, alfentanil and lidocaine without
neuromuscular blocking drugs in children. Acta Anaesthesiol Scand.
1993;37:725729.
214. McConaghy P, Bunting HE. Assessment of intubating conditions in
children after induction with propofol and varying doses of alfentanil. Br
J Anaesth. 1994;73:596599.
215. Steyn MP, Quinn AM, Gillespie JA, et al. Tracheal intubation without
neuromuscular block in children. Br J Anaesth. 1994;72:403406.
216. Hull CJ. Pharmacodynamics of non-depolarizing neuromuscular

blocking agents. Br J Anaesth. 1982;54:169182.
217. Fisher DM, Cronnelly R, Miller RD, Sharma M. The neuromuscular
pharmacology of neostigmine in infants and children. Anesthesiology.
1983;59:220225.
218. Abdulatif M, Mowafi H, al-Ghamdi A, el-Sanabary M. Dose-response
relationships for neostigmine antagonism of rocuronium-induced
neuromuscular block in children and adults. Br J Anaesth. 1996;77:
710715.
219. Fisher DM, Cronnelly R, Sharma M, Miller RD. Clinical pharmacology
of edrophonium in infants and children. Anesthesiology. 1984;61:
428433.
220. Abdulatif M, El-Sanabary M. Edrophonium antagonism of cisatracuriuminduced neuromuscular block: dose requirements in children and adults.
221. Hunter JM, Flockton EA. The doughnut and the hole: a new
pharmacological concept for anaesthetists. Br J Anaesth. 2006;97:123
126.
222. Plaud B, Meretoja O, Pohl B, et al. Reversal of rocuronium-induced
neuromuscular blockade with sugammadex in paediatric and adult
surgical patients. Anesthesiology. 2009;110:284294.
223. Gijsenbergh F, Ramael S, Houwing N, van Iersel T. First human exposure
of Org 25969, a novel agent to reverse the action of rocuronium bromide.
224. Sparr HJ, Vermeyen KM, Beaufort AM, et al. Early reversal of profound
rocuronium-induced neuromuscular blockade by sugammadex in a
randomized multicenter study: efficacy, safety, and pharmacokinetics.
225. Sorgenfrei IF, Norrild K, Larsen PB, et al. Reversal of rocuroniuminduced neuromuscular block by the selective relaxant binding agent
sugammadex: a dose-finding and safety study. Anesthesiology. 2006;104:
667674.
226. de Boer HD, Driessen JJ, Marcus MA, et al. Reversal of rocuroniuminduced (1.2 mg/kg) profound neuromuscular block by sugammadex:
a multicenter, dose-finding and safety study. Anesthesiology. 2007;107:
239244.
227. Suy K, Morias K, Cammu G, Hans P, et al. Effective reversal of moderate
rocuronium- or vecuronium-induced neuromuscular block with
sugammadex, a selective relaxant binding agent. Anesthesiology. 2007;
106:283288.
228. Vanacker BE, Vermeyen KM, Struys MM, et al. Reversal of rocuroniuminduced neuromuscular block with the novel drug sugammadex is
equally effective under maintenance anesthesia with propofol or
sevoflurane. Anesth Analg. 2007;104:563568.
229. Sacan O, White P, Tufanogullari B, Klein K. Sugammadex reversal of
rocuronium-induced neuromuscular blockade: a comparison with
neostigmine-glycopyrrolate and edrophonium-atropine. Anesth Analg.
2007;104:569574.
230. Flockton EA, Mastronardi P, Hunter JM, et al. Reversal of rocuroniuminduced neuromuscular block with sugammadex is faster than reversal
of cisatracurium-induced block with neostigmine. Br J Anaesth. 2008;
100:622630.
231. Shanks CA. Pharmacokinetics of the nondepolarizing neuromuscular
relaxants applied to calculation of bolus and infusion dosage regimens.
232. Belmont MR, Lien CA, Quessy S, et al. The clinical neuromuscular
pharmacology of 51W89 in patients receiving nitrous oxide/opioid/
barbiturate anesthesia. Anesthesiology. 1995;82:11391145.
233. Savarese JJ, Ali HH, Basta SJ, et al. The clinical neuromuscular pharmacology of mivacurium chloride (BW B1090U). A short-acting
nondepolarizing ester neuromuscular blocking drug. Anesthesiology.
1988;68:723732.
234. Plaud B, Proost JH, Wierda JM, et al. Pharmacokinetics and pharmacodynamics of rocuronium at the vocal cords and the adductor
pollicis in humans. Clin Pharmacol Ther. 1995;58:185191.
235. Crumrine RS, Yodlowski EH. Assessment of neuromuscular function in
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Jean Xavier Mazoit
INTRODUCTION
Cocaine was first isolated by Niemann in 1860 and used for its
local anesthetic properties by Kller in 1884. Since then, numerous
molecules have been synthesized as local anesthetics (LAs).1 Two
principal chemical compounds have been synthesized and used
for clinical purposes. Amino esters (commonly used drugs are
2-chloroprocaine, procaine, and tetracaine) were synthesized from
the early 1900s to the late 1930s by German chemists. Amino
amides have been synthesized from the early 1940s until now
by Swedish chemists. Amino esters are degraded in plasma by
pseudocholinesterases. Their hepatic metabolism is minimal.
Amino amides are more stable molecules that undergo hepatic
metabolism.
28
C H A P T E R
steric bulk, nonspecific binding, and departure from linearity in all

binding and partition processes). There is, therefore, an astounding complexity of the numerous mutually interacting processes
governing LA diffusion and ease of access to the site of action.
Chirality
Some molecules, although sharing the same primary formula
(i.e., all atoms in the molecule are identical) possess different
STRUCTURE AND
PHYSICOCHEMICAL PROPERTIES
LAs are weak bases with molecular weights between 220 and 288
Da. Their structure comprises an aromatic ring, an intermediate
chain, and a hydrophilic residue. They are usually categorized as
amino esters and amino amides, depending on the link between
the aromatic ring (hydrophobic moiety) and the intermediate
chain (Figures 281 and 282). Substitution on the aromatic
nucleus, steric bulk, and pKa (i.e., the pH at which half the molecules are in the charged [ionized] form and half are in the uncharged [free base] form) modulate hydrophobicity. Stability of
the ester bond governs the rate of hydrolysis of the ester molecule.
Partition between organic solvents and buffers, which reflects the
degree of solubility of LAs in biologic membranes, is relatively
high (between 1.7 [procaine] and 800 [etidocaine] [octanol:buffer
partition]) (Table 281).2 All LAs in clinical use have a tertiary
amine group between the intermediate chain and the hydrophilic
residue. The tertiary amine group leads to equilibrium between
ionized (water-soluble) and nonionized (lipid soluble) forms of
the molecule. Their pKa varies between 7.6 (mepivacaine) and 8.9
(procaine). At the physiologic plasma pH of 7.40, about 60 to 85%
of amide molecules and more than 90% of esters molecules are
in the ionized form, thus leading to free diffusion in the body
aqueous compartment. In the same physiologic conditions,
cellular pH is much lower (between 6.80 and 7.25), leading to a
much greater quantity of the ionized moiety (Table 282). LAs
cross phospholipid membranes mostly in their unionized form.
The number of molecules able to cross membranes is proportional
to their structure (i.e., molecules in the unionized form), the
proportionality factor being hydrophobicity (this simple scheme
does not take into account numerous confounding factors such as
Figure 28-1. Structure of local anesthetics. Two chemical

formulas are available, the ester family (left) and the amide
family (right). Lower portion: The bupivacaine molecule,
with the hydrophobic aromatic ring that is common to both
esters and amides (left) and the hydrophilic residue (right). In
aqueous solution, the tertiary amine is protonated. At pH 7.40
and 3240C, more than 75% of amide molecules are ionized.
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Figure 28-2. Amide local anesthetics. Properties of the different agents are related to the hydrophobicity and the length of the
residue on the amine group. Note that ropivacaines structure is very close to that of bupivacaine with only one carbon less in the lateral chain.
geometrical conformations: these are stereoisomers. Optical isomerism occurs when a molecule is different from its mirror image.
This isomerism is said to be chiral and the two mirror images are
called enantiomers.3 Chiral centers (usually a carbon atom) are
characterized by the RS convention, which is based on the priority
(based on molecular weight) of order of rotation of substituents:
if the substituents are circulating clockwise, the molecule is R; if
they circulate counterclockwise, the molecule is S. Enantiomers
are able to rotate polarized light to the right (dextrorotatory isomer
[+]) or to the left (levorotatory isomer []), but there is absolutely
no relationship between the order of substitution (R or S) and the
direction in which the molecule rotates polarized light. For
example, S bupivacaine rotates polarized light to the left; this is
the S() bupivacaine or levobupivacaine, whereas the S mepivacaine rotates polarized light to the right and is labeled S(+) mepivacaine. Numerous molecules such as sugars or amino acids are
naturally chiral. However, when these molecules are synthesized
from nonchiral reagents, an equal quantity of both enantiomers

is formed: this is a racemic mixture. Some amide LAs (mepivacaine, prilocaine, bupivacaine) have an asymmetrical carbon that
confers important stereoselective differences between the levorotatory and the dextrorotatory forms. In the case of bupivacaine,
binding to serum proteins is stereoselective.4 However, stereospecificity appears to vary depending on the ionic channel and
tissue studied.510 Moreover the S enantiomers (ropivacaine and
levobupivacaine) are less toxic for the heart than the corresponding racemic mixture.9,10 To date, ropivacaine and levobupivacaine
are the only LAs available as pure enantiomers.
Presentation
LAs are presented as hydrochloride salts, which are more soluble
than the free base forms. The solvent is saline and pH is maintained
between 4.0 and 5.5 for perfect solubility.1 Solutions with epinephrine
TABLE 28-1. Physicochemical Properties of Local Anesthetics

Drug
Molecular
Weight, Da
pKaa
Distribution
Coefficientb
Protein
Binding, %
Onset
of Action
Duration
of Action
Potencyc
Esters
Procaine
Chloroprocaine
Tetracaine
236
271
264
8.9
9.1
8.4
1.7
9.0
221
6
?
80
Long
Short
Long
1h
1/ 1 h
2
34 h
0.5
0.51
4
Amides
Lidocaine
Prilocaine
Mepivacaine
Bupivacaine
Etidocaine
Ropivacaine
234
220
246
288
276
274
7.8
8.0
7.7
8.1
7.9
8.1
43
25
21
346
800
115
65
55
75
95
95
94
Short
Short
Short
Intermediate
Short
Intermediate
11/22 h
11/22 h
11/22 h
331/2 h
34 h
3h
1
1
1
4
4
3.54
pKa at 37C.
Octanol:buffer partition.
cPotency is relative to lidocaine.
b
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TABLE 28-2. Fraction of Local Anesthetic Molecules in
Ionized Form at Normal pH in Plasma and Tissue
Drug
Plasma, %
Tissue, %
Procaine
Chloroprocaine
Tetracaine
Lidocaine
Prilocaine
Mepivacaine
Bupivacaine
Etidocaine
Ropivacaine
(pH 7.40)
97
95
93
76
76
61
83
66
83
(pH 7.10)
99
98
96
86
86
76
91
80
91
From Denson DD, Mazoit JX. Physiology and pharmacology of local anesthetics.
In: Sinatra RS, Hord AH, Ginsberg. B, et al., editors. Acute pain: mechanisms
and management. St. Louis: Mosby-Year Book; 1992, pp. 124139.
usually contain 5 g/mL epinephrine (1/200,000). Additives such

as ethylenediaminetetraacetic acid (EDTA) and para-oxibenzoate
have often been added in the past, particularly in solution with
epinephrine and in ester solutions. Amide LAs are perfectly stable
molecules,11 and commercial solutions are free of preservative and
antioxidants (except for the drugs used for topical anesthesia).
Solutions containing epinephrine are stable in modern presentations.
However, they still contain metabisulfite. It is not recommended
to prepare solutions with freshly added epinephrine because (1) the
pH will remain low because of the pH of the LA solution itself, and
(2) it is not sensible to take solutions prepared with great care in
controlled areas and then to add another solution prepared with
the minimal manipulations that might lead to precipitation of the
solution or to contamination with living organisms or foreign
material. Moreover, the clinical benefit of alkalinization is now
questioned by a great number of authors.
443
MECHANISM OF ACTION AND OTHER

EFFECTS AT THE CELLULAR LEVEL
Mechanism of Action at the
Molecular and Cellular Levels
Living organisms are characterized by the production of an
electric gradient across cell membranes. Whereas water freely diffuses
across the lipid bilayer, ionic movements are strictly controlled. In
the fifties, Hodgkin and Huxley demonstrated that nerve conduction
was mediated by ionic channels, for which they received the Nobel
Prize in 1963. LAs mainly act by inactivating fast sodium channels
that initiate the action potential. Whereas numerous toxins act at
the outer part of the phospholipid bilayer, LAs act at the inner
(cytosolic) part of the membrane and they must traverse it before
acting on the sodium channel.
Action on Excitable Membranes1214

The electric gradient between the inner and the outer sides of
the lipid bilayer is maintained primarily by the Na+-K+ATPase
(Na+ pump).14 This pump continuously exchanges three Na+ for
two K+ with an energy consumption of one molecule of adenosine
triphosphate (ATP). The respective outside and inside concentrations are 145 and 12 mM for Na+ and 4 and 155 mM for K+. The
potential created (governed by the Nernst equation) is negative
on the inner side of the membrane relative to the outer side (if
the outer potential is arbitrarily defined as zero, the resting inner
potential is between 80 and 95 mV). Similarly Ca2+ is continuously driven out of the cell or into intracellular vesicles (sarcoplasmic reticulum). When a nerve axon (or a Purkinje fiber)
is stimulated, an action potential is created that propagates along
the nerve fiber (or myocardium) (Figure 283). This action
potential results from opening of the Na+ and K+ channels. The
contribution of calcium channels also occurs, especially at the
cardiac level.1
Figure 28-3. Action potential. Left: A typical action potential (AP). The two main ionic conductances
generating an AP are sodium channel conductance (gNa+) and potassium channel conductance (gK+). Top
right: A typical AP from a nerve axon (a). Bottom right: A typical AP from a Purkinje fiber in the heart (b).
A larger proportion of calcium channels is the primary factor explaining the presence of a prolonged plateau
characterizing APs in Purkinje fibers.
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Techniques Used to Study Channel Physiology13

Direct recording of the action potential current is less and less
commonly used as a tool for studying nerve physiology. Two main
techniques are used: (1) the voltage clamp technique applied to
whole cells (axons, myocytes) where the two sides of the membrane are held at a predetermined voltage and the current flowing
between them is recorded; and (2) the patch clamp technique
applied to small membrane patches. This allows the recording of
a very small number of channels, whereas the whole-cell voltage
clamp technique permits the summation of a great number of
signals (Figure 284).
The Sodium Channel

STRUCTURE: The sodium channel is a massive glycoprotein with
a molecular weight of 316 kDa (Figure 285).14,15 It consists of a
central pore surrounded by four homologous structures. These
structures exhibit important interspecies and intraspecies differences, the latter being the most meaningful. For example,
sodium channels from the nerve node of Ranvier markedly differ
from those of ventricular Purkinje cells in both their structure and
their function. To date, nine channel isoforms have been identified
(Nav 1.11.9)16 (Table 283). These isoforms differ by their alpha
subunit. In addition, four isoforms of the auxiliary beta subunit
1
We only consider voltage dependant channels involved in nerve (or

cardiac) conduction. However, even with this restriction, the channel
family has more variety than presented here.
have been described. The sodium channels are also classified

depending on the ability of tetrodotoxin (TTX, a toxin extracted
from the fugu fish) to block the channels at nanomolar concentrations (TTXs, sensitive) or at micromolar concentrations (TTXr,
resistant). This latter classification has important implications for
the involvement of sodium channels in pain transmission.17,18
CHANNEL PHYSIOLOGY14,15: Numerous stochastic or deterministic models have been applied since the original empirical model used
by Hodgkin and Huxley was devised. Ionic channels have different states: the closed state (C) and the resting state (R), from which
the channel can rapidly become permeable to Na+ ions, and the open
state (O) (Figure 286). During the open state, Na+ ions flow through
the channel and the membrane rapidly becomes depolarized. Then,
the channel rapidly (12 ms) passes into the inactivated state (I),
during which the channel is insensitive to any stimulation. After
5 to 10 milliseconds of hyperpolarization, the channel returns to
the resting state (R). The probability (in Markovian stochastic models) or rate constant (in deterministic kinetic models) of passing from
one state to another is not symmetrical: LAs bind more tightly to
the channel in its open and inactivated state rather than in its resting state (see Effect of LAs on Na Channels).
EFFECT OF LAS ON NA CHANNELS: LAs mainly act by preventing

sodium channels from opening. LAs, class I antiarrhythmic agents
and anticonvulsants such as phenytoin and carbamazepine, act by
inhibiting ionic currents flowing through voltage-dependent
sodium channels.14 They bind to the channel preferentially in the
open and inactivated states, rather than in the resting state. In
addition, when the drug binds to the receptor, an allosteric change
in receptor conformation occurs, modifying drug affinity for the
Figure 28-4. Measurement of channel activity by the voltage clamp. Left: The classical axial wire
technique (A). The transmembrane potential (E) measured between an intracellular electrode (E) and
a ground electrode is held constant at a determined value by means of a current (I) instantaneously
delivered by electrode I. Time and voltage (E) are independent variables and I is the dependent variable.
B: In the double-gap technique, the extracellular compartment is divided by gaps of insulating solutions
such as sucrose or vaseline with precisely determined solutions between the gaps. C: The patch-clamp
method. A glass micropipette filled with an electrolyte solution measures the channel activity of a small
patch of membrane attached to it. The solution is chosen using the same criteria for choosing the substance filling of gaps in the voltage clamp method, and to the membrane side exposed (right). Right:
Four of the techniques used to record single-channel activity by the gigaseal-recording patch-clamp
technique. AC: Adapted from reference 13.
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Figure 28-5. The sodium channel. The large glycoprotein forming the core of the channel is constituted by four alpha subunits
(IIV) surrounded by beta subunits. B and C: Three-dimensional representations of the channel. D: A molecule of etidocaine is shown bound at the inner part of the pore to the IV S6
fraction on the right of part A. B: ScTx, TTX, and S-S represent
the toxin binding sites at the outer part of the channel, and P
represents sites of phosphorylation at the inner part, thus allowing modulation of channel activity. AD: Adapted from Catterall WA. Cellular and molecular biology of voltage-gated sodium
channels. Physiol Rev. 1992;72:S15S48, and reference 19.
445
receptor. This phenomenon is called a use-dependent block. When

the frequency of stimulation of the preparation increases, the
intensity of the block increases, creating a frequency-dependent
block (or phasic block), which superimposes its effect on the basal
tonic block (Figure 287). These phenomena represent the classic
modulated receptor model.12,14,1923
Unlike toxins that act at the outer surface of the channel, LAs
must cross the phospholipid bilayer to produce action both inside
the membrane in their unionized free base form (hydrophobic
pathway) and inside the pore itself (hydrophilic pathway).12,14,24
Agents that are neutral at intracellular pH produce a block of
immediate maximum intensity (tonic block), whereas the intensity
of the block induced by ionized agents such as lidocaine or bupivacaine increases with the frequency of stimulation. Hydrophobicity
is the major determinant of drug potency. Hydrophobicity is not
the only factor governing the potency of LAs and their ability to
produce a phasic block. The latency of action and the rate of
dissociation from the receptor also depend on molecular weight.20
Finally, pKa and the intracellular-extracellular pH gradient also
have a major effect: dissociation of ligand from its receptor is 10
to 50 times slower at pH 6.2 than at pH 9.21 Quaternary amides,
which are permanently charged, act by the hydrophilic pathway.
Today, their use is limited to research purposes, although some
authors anticipate future clinical use.25 The EC50 (concentration
leading to half-maximum blockade) of LAs varies from a few M
to several hundred M. The stereospecificity of blockade is also
highly variable. It is difficult to make precise comparisons because
the channel preparations vary from human cloned channels
expressed in mouse cells (without beta subunit effects) to isolated
cardiomyocytes or papillary muscles. The electrophysiologic conditions also vary (e.g., holding potential, pulse protocol, frequency
of stimulation for measuring the phasic block). Typically, heart
preparations are more sensitive and stereospecific than nerve. The
bupivacaine EC50 of the cardiac Nav 1.5 channel is between 1 M
(R(+) bupivacaine and 1.6 M (S() bupivacaine in isolated
cardiomyocytes and cloned channel transfected cells.7,8 However,
in the latter case, the block becomes markedly stereospecific in
the inactivated state of the channel, which explains the much
TABLE 28-3. Sodium Channel Isoforms and Their Function

Nav 1.1 TTXs
Channel distribution: Cell bodies of central neurons
Functions: Action potential initiation and repetitive firing
in neurons; excitation-contraction coupling in cardiac
myocytes
Pharmacologic target: Local anesthetics (CNS and cardiac
toxicity); antiepileptic drugs; antiarrhythmic drugs
Nav 1.2 TTXs
Channel distribution: Central neurons
Functions: Action potential initiation and conduction; repetitive
firing
Pathophysiology: A point mutation has been reported to cause
inherited febrile seizures and epilepsy
Pharmacologic target: Local anesthetics; antiepileptic drugs
Nav 1.3 TTXs
Channel distribution: CNS embryonic, cardiac myocytes
Functions: Action potential initiation and conduction; repetitive
firing
Pathophysiology: Up-regulated in DRG and dorsal horn

neurons after nerve injury; rapid recovery from inactivation contributes to hyperexcitability following nerve
injury.
Pharmacologic target: Local anesthetics; antiepileptic
drugs
Nav 1.4 TTXs
Channel distribution: Skeletal muscle
Functions: Action potential initiation and conduction
Pharmacologic target: Local anesthetics; antiepileptic drugs;
antiarrhythmic drugs
Nav 1.5 TTXr
Channel distribution: Cardiac myocytes, certain brain neurons
Functions: Action potential conduction
Pathophysiology: Long QT syndrome and idiopathic ventricular
fibrillation
Pharmacologic target: Antiarrhythmic drugs; cardiac toxicity
of local anesthetics
(Continued)
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TABLE 28-3. Sodium Channel Isoforms and Their Function (Continued)

Nav 1.6 TTXs
Channel distribution: Cell bodies and nodes of Ranvier,
astrocytes, and Schwann cells in the CNS; DRG; nodes of
Ranvier of sensory and motor axons in the PNS; cardiac
myocytes
Functions: Action potential initiation and transmission
Pharmacologic target: Antiepileptic drugs; analgesic drugs
Nav 1.7 TTXs
Channel distribution: All types of DRG neurons, sympathetic
neurons, Schwann cells, and neuroendocrine cells
Functions: Action potential initiation and transmission in
peripheral neurons
Pathophysiology: Mutation leads to insensitivity to pain,
inflammatory pain
Pharmacologic target: Local anesthetics in the PNS
Nav 1.8 TTXr

Channel distribution: Small and medium-sized DRG neurones
and their axons
Functions: Action potential in DRG neurones
Pathophysiology: Visceral pain, neuropathic pain; inflammatory
pain
Pharmacologic target: Local anesthetics; potential target for
analgesic drugs
Nav 1.9 TTXr
Channel distribution: c-Type DRG neurones, trigeminal
neurones and their axons; preferentially expressed in
nociceptive DRG neurons
Functions: Nav 1.9 current is increased by inflammatory
mediators such as PGE2
Pathophysiology: Inflammatory pain
Pharmacologic target: Local anesthetics
CNS = central nervous system; DRG = dorsal root ganglion; Nav = voltage channel isoform of sodium; PNS = peripheral nervous system; TTXr = tetrodotoxinresistant channels; TTXs = tetrodotoxin-sensitive channels.
higher toxicity of the R(+) enantiomer compared with the S()

enantiomer.8 Conversely, most Na+ channels expressed in nerve
fibers are more resistant to the effects of LAs, with EC50 ranging
from approximately 100 M to 800 M for lidocaine and from
approximately 50 to 150 M for bupivacaine.5,2628 Interestingly,
whole cardiac tissue preparations, such as cardiac papillary
muscle,29 are more sensitive to the effects of LAs than isolated
channels.
Effect of LAs on Other Channels

POTASSIUM CHANNELS: LAs also block potassium channels.30,31
The family of potassium channels comprises a huge number of
different channels32,33 that can be broadly classified into three
families: channels containing six transmembrane segments and
one pore including the voltage-gated Kv subfamily and the hERG
family among others; channels containing two transmembrane
domains and one pore (inward-rectifiers); channels containing
four transmembrane domains and two pores (often referred to as

the two-pore channels). Potassium channels are blocked by LAs,
but some at very high concentrations and some at very low concentrations. Voltage-gated delayed rectifiers channels Kv1.1, 1.2,
1.3 are responsible of repolarization in nerves and are blocked at
concentrations above 100 M.34,35 In the heart, K+ channels are
blocked at low concentrations similar to or slightly higher than
those blocking Na+ channels. Two channels are of particular
importance, the K v1.5 channel and the hERG (ether--go-go
related gene) channel.3638 These are considered as the two major
channels involved in the long QT syndromes.39,40 Moreover, their
stereospecificity for LAs binding is important. The EC50 of
bupivacaine binding to the K v1.5 channel ranges from 4.1 M for
the R(+) enantiomer to 27.3 M for the S() enantiomer.36 Other
K+ channels are blocked by amide LAs (e.g., two-pore channels
and APT channels) at concentrations higher than those blocking
the just-mentioned channels.41,42 Also, the association of the
channels with their subunits and other stabilizing proteins modify
Figure 28-6. Schematic diagram of the
modulated receptor hypothesis. R, O, and
I = rested, open, and inactivated states of
the channel (drug-free states); R-D, O-D,
and I-D = the corresponding drugassociated states (D = drug); k is (i = R, O,
or I) = association rate constants; lis =
dissociation rate constants associated
with transitions between drug-free and
blocked states. HH = the HogdkinHuxley rate constants between drug-free
states; HH = rate constants governing
transitions between drug-associated
states. The latter rate constants have their
voltage dependence shifted to more negative potentials than HH. This model has
been refined since the mid-1990s, but the
concept is still the same. Adapted from
reference 29.
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calcium current in ventricular myocytes from rats46 and 112 M

in isolated cardiomyocytes.47 The latter value appears more realistic because the global calcium current in whole cells represents
not only true calcium current but also part of potassium and
sodium currents. Interestingly, all experiments that studied R(+)
and S() bupivacaine action on Ca2+ channels failed to demonstrate any stereospecific effect. This is consistent with the fact that
no stereospecific effect of bupivacaine on contractility was found
in whole animals.48,49
Other Effects at the Cellular Level

Effect on the Mitochondria
LAs impair mitochondrial metabolism.50 Bupivacaine has been
found to uncouple oxidative phosphorylation.51 The uncoupling
effect has been blamed for bupivacaine cardiotoxicity.52 However,
mitochondrial respiration impairment has been observed only at
concentrations 100 to 1000 times higher than those measured in
serum, even after massive intoxication. This effect is not stereospecific, and ropivacaine appears less toxic than bupivacaine on
mitochondrial metabolism.53,54 Conversely, this effect may explain
the muscular toxicity observed after LA administration.55
Action on Inflammation Process

and Platelet Function
Figure 28-7. Characterization of the phasic block (also called

use-dependent or frequency-dependent block) with lidocaine
(top) and bupivacaine (bottom). Tracings are of sodium
channel currents from nodes of Ranvier after stimulations at a
frequency of 10 Hz. The first trace obtained after drug application corresponding to the tonic block is labeled 0. Successive
depolarizations induce a phasic block that adds its effects to
those of the tonic (basal) block until steady state is attained
(traces labeled 160). Adapted from Chernoff DM, Ph.D.
thesis cited in reference 12.
both the affinity and the frequency dependence of the receptors
for LAs. This is why preparations made of intact tissue, organ, or
whole animal often behave differently from channels cloned from
DNA sequence and transfected in cells.
CALCIUM CHANNELS: Voltage-gated calcium channels are grouped into three major families.43 Among these, L-type, high-voltage
activated, dihydropyridine-sensitive channels are responsible for
excitation-contraction coupling in the heart and pacemaker activity. The T-type, low-voltage channels are responsible for repetitive
firing at the central nervous system (CNS) and pacemaker activity
in the heart. In the peripheral nervous system, Ca2+ channels are
not as important as in the CNS. In pituitary gland cells, Xiong and
Strichartz reported high EC50concentrations for inhibition of Ca2+
channels, 2.6 mM and 0.18 mM for lidocaine and bupivacaine,
respectively.44 In the heart, EC50 are much lower. Coyle and Speralakis showed that lidocaine and bupivacaine blocked the slow
(calcium-dependent) part of the action potential of guineapig papillary muscle at an EC50 of 94 and 9 M, respectively.45
Further studies reported contrasting results with EC50 between
approximately 10 M in an experiment measuring the whole
Amide LAs possess anti-inflammatory properties. They decrease

inflammation mediated by leukocytes and platelet aggregation in
vitro and in vivo.56,57 They decrease leukocyte priming and the
production of free radicals.58,59 Accordingly, lidocaine has been
proposed as adjunct treatment for acute respiratory distress syndrome.60 LAs, when used at the wound site, may decrease inflammatory mediators and reduce pain by a mechanism independent
of nerve conduction.61,62 Systemically administered lidocaine has
been shown to have antinociceptive effects on neuropathic pain.63
LAs, by limiting the neuropathic inflammatory processes, can
prevent and even treat complex regional pain syndrome in adults
and in children.64,65 It has been suggested that lidocaine may speed
recovery after surgery.66 However, other authors have not reproduced these benefits from intravenous lidocaine, and the subject
is still debated.67
MECHANISM OF ACTION ON
NERVE CONDUCTION
Nerve Conduction
Nerve impulse conduction in nonmyelinated axons is related to the
propagation of the transmembrane electrical gradient flowing along
the fiber (Figure 288). The impulse cannot flow upstream because
the region that has been depolarized is not sensitive to any
stimulation (refractory state) for 5 to 10 milliseconds. Myelin is an
excellent electric insulator, and therefore, in myelinated axons, the
impulse propagation is not continuous but rather discontinuous from
one node of Ranvier to the next. There are almost no Na+ channels
between nodes in myelinated axons; conversely, the density of
channels is very high at nodes.13 The intensity of the electric field
created is sufficient to permit the depolarization of two and even
three nodes forward. Nodes act as amplifiers along the fiber. The
limiting step for conduction time is the node of Ranvier itself. LAs
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TABLE 28-4. Classification of Nerve Fibers
Nonmyelinated Fibers
C
Myelinated Fibers
B
Figure 28-8. Nerve propagation. The AP flows continuously in
nonmyelinated fibers (top). Because of the refractory period following depolarization, the influx cannot propagate backward. In
myelinated axons, influx is generated by the successive depolarization at nodes of Ranvier. These nodes possess a great number
of channels that together generate an electric field that enables
the forward depolarization of one, two, or even three nodes.
Conduction is much faster in myelinated than in nonmyelinated
fibers. Moreover, because the distance between nodes increases
as the fiber diameter increases, conduction becomes more rapid
as the thickness of the fiber increases. The maximum velocity
(~100 m/s) occurs in A fibers, which conduct motor influx.
Thus, the time that elapses between decision-making in the cerebral cortex level and the execution of the motor command to
move a muscle in the foot is about 1.5 times longer for a tall basketball player than for a shorter fighter pilot.
need to block more than two or three nodes to interrupt nerve
conduction in myelinated axons. This requirement forms the basis
for the differential block mechanism (see Differential Nerve
Block). In the heart, conduction is much more complicated.
Auricular and ventricular conduction depends on sodium channels,
whereas nodal conduction is mostly dependent on calcium channel
activity,46 although sodium channels may take some part in
auriculoventricular conduction.47
Differential Nerve Block

The effect of LAs is not the same for all axons. Nonmyelinated fibers
and thinly myelinated fibers are more sensitive to LAs than
thickly myelinated fibers (Table 284). This is not the result of
increasing thickness of the myelin sheath but rather of increasing
distance between adjacent nodes of Ranvier.68,69 In fact, large, thick
fibers generally have greater distance between nodes than thin fibers.
The impulse may skip over two or sometimes three consecutive
nodes of Ranvier. There are 15 to 25 nodes/cm in A fibers, whereas
there are only 6 nodes/cm in A fibers. This effect is reinforced by
the phenomenon of decremental conduction (see Decremental
Conduction). Differential blockade takes place at the spinal level
(for central blocks). It is mainly observed at the upper level of anesthesia because spinal roots length increases along the spine. At the
thoracic level, roots are relatively short (~3 cm for an adult at
T46) and the number of nodes is a crucial element of blockade,
whereas at the caudal level, roots are very much longer (15 cm for
an adult) and the block is rather an all-or-none phenomenon. It is
important to remember that the sympathetic innervation does not
have the same distribution as sensory or motor innervation of the
body. This simple fact explains why sympathetic blockade disappears more rapidly than sensory or motor block.
A
A
A
A
Cutaneous sensitivity mainly to

temperature
Postganglionic sympathetic
(vasomotricity)
Preganglionic sympathetic
(vasomotricity)
Motricity
Motricity, pressure, proprioception
Muscle tone
Pain, temperature (sensitivity to cold),
touch (pinprick)
Pain is mostly conducted by A fibers.
Decremental Conduction
Decremental conduction is directly related to the phenomenon of
use-dependence: the intensity of the block is directly related to the
frequency of impulse stimulation (Figure 289).68,69 Consider a
4-cm-long nerve segment bathed by bupivacaine 0.2 mM in
cerebrospinal fluid (CSF) at the T6 or T8 level. In this 4-centimeter
length, A fibers possess about 25 nodes whereas A fibers have
twice that number. After the first stimulation, the intensity of the
action potential progressively decreases from one node to the next
(in successive nodes, fewer and fewer channels attain the depolarization threshold because of the regular decrease in electrical field
and the tonic block caused by the LA). After the 4-cm length,
nerve conduction will normally be restored to its initial settings.
Nevertheless, because nerve conduction is propagated by trains of
impulse with a frequency greater than 10 Hz and because of the
use-dependent block, nerve conduction will rapidly fail. Because
A fibers possess twice the number of nodes as A fibers, this
phenomenon will be more important with A than with A fibers
(i.e., with fibers conducting pain and vasomotor tone rather than
with fibers conducting proprioception and motricity).
Developmental Aspects
Myelinization begins during the third trimester of pregnancy and is
incomplete at birth. After birth, myelinization progresses rapidly
and is almost complete at 3 to 4 years. A final step, corresponding
to the process of motor and intellectual maturation, continues until
adolescence. In rats, peripheral neurologic maturation is almost
complete at the age of 3 weeks.70,71 Nodes of Ranvier are fully mature
at the age of 2 to 3 weeks in rats. Interestingly, the internode distance
is similar between rats aged 2 weeks and adult rats. Experiments
comparing the effect of varying concentrations of bupivacaine
and ropivacaine in rats showed that the dose of bupivacaine or
ropivacaine inducing blocks of similar duration was identical in rats
aged 2 weeks and in rats aged 10 weeks, despite a difference in body
weight of more than eight times72 (Figure 2810). This may explain
why infants and children need a fixed dose, independent of age or
body size, instead of weight-scaled dosing (constant mg/mL).73 This
may also contribute to the short spinal anesthesia duration
in neonates and infants. In addition, infants and children need
only low concentrations to achieve blocks of intensity and duration similar to those in adults. At concentrations higher than 2 to
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Figure 28-9. Computer simulation of nerve conduction shows the effect of phasic block on decremental conduction. Top: A myelinated axon whose middle part is bathed in a solution of local anesthetic. Bottom: The APs generated by successive nodes. Left: After
stimulation of the nerve fiber, depolarization propagates from node to node. In the bathed part, the intensity of AP progressively decreases because fewer and fewer channels attain the depolarization threshold. However, the first node after the bathed portion fully
depolarizes, thus permitting transmission of nerve conduction. Because nerve conduction occurs by sequential depolarization, the
phasic block is then involved in the same manner as depicted in Figure 287, and because the phasic block adds its effects to those
of the basal tonic block, conduction is more and more impaired, and AP transmission completely stops after a few nodes. Right: The
effect obtained after 10 stimulations at 50 Hz. Modified from Raymond SA, Thalhammer JG, Strichartz GR. Axonal excitability:
endogenous and exogenous modulation. In: Dimitrijevic MR (ed). Altered Sensation and Pain. Recent Achievement in Restorative
Neurology. Vol. 3. Basel: Karger; 1990, cited in reference 68.
3 mg/mL bupivacaine or ropivacaine, a prolonged motor blockade
is often observed. This is consistent with the observation made by
Benzon and coworkers in the rabbit vagus nerve that similar
concentrations led to motor blockade of greater intensity in younger
animals than in older ones.74
Onset and Duration of Action and Potency

Our knowledge of the factors governing these parameters is
inversely proportional to the number of papers, opinions, and
hypotheses devoted to this subject.
The Onset of Action

Figure 28-10. Duration of sciatic nerve sensory block in infant
rats is related to the dose of bupivacaine used. Rats aged 5 days
had prolonged block compared with older subjects. Two-weekold rats had a duration of block similar to that of 10-week-old
rats despite an eight times difference in body weight. This observation is probably because the internode distance is fixed after
the age of 1 to 2 week. Drawn from the data in reference 72.
The onset of action is mainly dependent of the amount of free base

available for crossing the nerve fiber. Drugs with a low pKa
(lidocaine, mepivacaine) that are close to the pKa of extracellular fluids
are mostly in the neutral form, and therefore, easily diffuse across
membranes. Their onset of action is shorter than the onset of drugs
with higher pKa (tetracaine, bupivacaine). Some authors have tried
to increase this free base moiety by either changing the molecule itself
or by adding sodium bicarbonate (see Other Techniques Used to
Increase Onset, Potency, and Duration of the Block).
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Potency and Duration of Action
Opioids
Potency and duration of action depend mainly on hydrophobicity

and molecular weight. Potency is dependent on solubility in lipids,
which favors diffusion across cellular membranes. Higher concentrations of those drugs with lower lipid solubility such as procaine or chloroprocaine are needed to produce a block of similar
intensity to drugs with higher lipid solubility and higher molecular
weight such as tetracaine, bupivacaine, or etidocaine. The duration
of action is governed by the same factors. The environment of
the nerve structures also plays an important role. For example,
epidural fat markedly retains highly hydrophobic drugs such as
bupivacaine or etidocaine and this contributes to the duration of
action of these drugs (see Epinephrine).
Morphine (3350 g/kg) has been used to prolong the duration

of analgesia after caudal anesthesia.89 However, the main use of
opioids is in combination with LAs for continuous epidural
analgesia.90 Morphine, fentanyl, and sufentanil have been
used.9093 Continuous infusion of epidural fentanyl provides the
same quality of analgesia as morphine with fewer adverse effects
provided that infusion is administered at the right dermatome
level. Lerman and colleagues questioned the interest in fentanyl
associated with levobupivacaine,94 but they injected fentanyl at the
lumbar level for surgery often in the upper abdomen. Side effects
like nausea and vomiting or urinary retention also frequently occur with epidural opioids. Then, this very effective technique for
patients undergoing major surgery usually requires concomitant
use of gastric and urinary catheters.
Tachyphylaxis
Tachyphylaxis is characterized by the time-dependent decrease in
the observed effect of a drug: the same dose produces an effect of
lower intensity and/or shorter duration. Tachyphylaxis has long
been noted both with esters and amides with either central (usually
epidural) block and peripheral blocks.75 Both pharmacokinetic
factors, such as macroscopic changes in local distribution of the
drug molecules or modifications of diffusion capacity across nerve
sheets and cellular membranes, and/or pharmacodynamic factors
involving regulation of pain transmission have been advocated to
explain tachyphylaxis.
Adjuvant Drugs
Adjuvants are often used to shorten the onset of action or increase
the duration of action of LAs. They are also used to decrease the
peak concentration, thus permitting the use of higher doses.
Adjuvants other than epinephrine are usual for neuroaxial blocs.
Epinephrine
Epinephrine is the most commonly used adjuvant. Its addition to
LAs results in decreasing the peak concentration,7678 increasing
the duration of postoperative analgesia in children younger than
4 years of life after caudal anesthesia79 and facilitating detection of
an inadvertent intravascular injection.80,81 The usual concentration
is 5 g/mL (1/200,000). In infants, it has been suggested that the
use of 1/200,000 epinephrine might have been responsible for
ischemic neurologic syndromes leading to definitive sequelae after
central blocks because of a decrease in spinal blood flow.82 These
authors recommend the use of epinephrine at a concentration not
greater than 1/400,000 before the age of 1 year. However, because
the S enantiomers, ropivacaine and levobupivacaine, are marketed
only as plain solutions, this problem with epinephrine no longer
exists.
Ketamine
Ketamine has also been proposed to prolong the duration of
postoperative analgesia provided by epidural (usually caudal) LAs.
Both racemic and S() ketamine can be used provided that the
solution used does not contain any preservative. The usual dose is
0.5 mg/kg racemic ketamine or 1 mg/kg S() ketamine.95,96 However, some controversies still exist on the possible neurotoxicity of
ketamine.97
Other Techniques Used to Increase Onset,

Potency, and Duration of the Block
Increasing the pH of solutions is supposed to increase the free base
moiety and, therefore, the fraction able to cross membranes. However, alkalinization has shown inefficacy and perhaps toxicity.98
Encapsulation of LAs in microspheres is another method of
increasing the duration of action.99,100 This technique of slow
release is at present under investigation to assess its total safety
both for spinal cord and for the concentration released. The association of LAs with other molecules such as TTX or capsaicin is
also under investigation.25,101 Mixtures of LAs (especially the 1:1
mixture of lidocaine and bupivacaine) are very popular. Studies
performed in children lack a definite opinion on the subject.
However, in a study performed in adults receiving epidural
anesthesia, Seow and associates have clearly shown that, although
the addition of lidocaine to bupivacaine decreases the duration of
action compared with bupivacaine alone, the onset of action is not
significantly decreased when lidocaine is added to bupivacaine102
(Figure 2811). Another goal of mixing LAs is to decrease the
concentration of epinephrine by using a 1:1 mixture of a plain
solution and a solution with epinephrine 1/200,000, resulting in a
solution with 1/400,000 epinephrine that is claimed to be less toxic
in infants.82
PHARMACOKINETICS103
Clonidine
Clonidine increases the duration of action and the quality of
analgesia when added to LAs injected spinally or epidurally.83,84
Clonidine is supposed to act at the dorsal part of the spinal cord
by facilitating the descending inhibitory pathway,85 but a systemic
action seems probable,86,87 explaining why clonidine is also effective when used for peripheral block.88 The usual dose varies from
1 to 2 g/kg.
LAs are different from other anesthetic drugs. They are supposed
to act at the site of injection, and local concentration governs the
effect. Systemic disposition is the only elimination pathway, and
brain and cardiac absorption are side effects. Absorption from
the injection site, systemic disposition, hepatic metabolism, and
renal elimination of metabolites are the rule for amide LAs. Plasma
degradation by cholinesterases is the main metabolic pathway
for esters.
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Binding to Blood Components
Figure 28-11. Effect of mixing local anesthetics (LAs) on the

onset and duration of block after epidural injection at the L12
interspace. 4L = 4 volumes of lidocaine and 0 volume of bupivacaine; 4B = 0 volume of lidocaine and 4 volumes of bupivacaine.
Left: The time to onset depending on the dermatome in question. No difference between the different solutions is seen.
Right: The duration of anesthesia. Adding lidocaine to bupivacaine decreases the duration of anesthesia, but no effect on the
onset of anesthesia is seen. Modified from reference 102.
The use of a continuous perineural infusion of LA for postoperative pain relief has regained some interest in infants, although this
practice is not without risk.104,105 The importance of binding of LAs
to blood components has regained some practical interest. Binding
of esters to serum proteins varies from 6% (procaine) to 76%
(tetracaine) (see Table 281). Amides bind to red blood cells and
serum proteins with a bloodtoplasma concentration ratio between 65 and 80% and a serum protein binding between 65 and
96% (Table 285; see also Table 281). Drug binding in blood
protects against adverse effects caused by high drug concentrations because only unbound molecules are free to cross the bloodbrain barrier and the heart capillary wall. This is not always the
case because a complex relationship exists between rate of binding
to erythrocytes, rate of binding to serum proteins, rate of crossing
membranes, and organ transit time. Often, drugs largely bound
to serum proteins are rapidly cleared at the hepatic level, especially
because of prolonged transit time and complex cooperativity
between binding sites. Amide LAs are exclusively cleared by the
liver and their hepatic extraction ratio is dependent on the free
fraction (fu) in blood. Also, at first sight, toxicity of LA is dependent on the free drug concentration, although this assumption has
been shown to be true only during prolonged infusion.
TABLE 28-5. Amides Binding to Serum Proteinsa

Author
Lidocaine
McNamara, 1981107
Adults
Lerman 1989b
Neonates (AAG
= 0.33 g/L)
Infants (AAG
= 0.46 g/L)
Children (AAG
= 0.66 g/L)
Adolescents
(AAG = 0.63 g/L)
Bupivacaine
Veering, 1991109
Adult females
Adult males
Mazoit, 1996
Adults
Groen, 1998187
Adults
Mazoit, 1988117
Infants (16 mo)
Meunier, 1998123
Infant (1 m)
Infant (7 mo)
fu
Comments
g/mL
1.4
29
In vitro, ultrafiltration
48
In vivo, 5 min after 1.5 mg/kg

I.V., ultrafiltration
32
26
26
0.5
5.3 1.6
4.5 1.2
In vitro, equilibrium dialysis
S() bupivacaine
R(+) bupivacaine
1.0 g/mL1 fu = 7%
1.0 g/mL1 fu = 5%
16 g/mL1 fu = 18%
16 g/mL1 fu = 16%
In vitro, ultrafiltration
S() bupivacaine
R(+) bupivacaine
0.4 0.1
0.4 0.1
3.2
4.9
In vivo, equilibrium dialysis
0.97 0.42
19 8
In vivo, after 2.5 mg/kg caudal,

ultrafiltration
fu = 23% (30 min after 1.25 mg/kg epidural as bolus), fu = 13% (after 0.375 mg/kg/h
during 48 h), ultrafiltration
fu = 5.2% (30 min after 1.25 mg/kg epidural as bolus), fu = 3.8% (after 0.375 mg/kg/h
during 48 h)
(Continued)
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TABLE 28-5. Amides Binding to Serum Proteinsa (Continued)

Author
Ropivacaine
Lee, 1989110
Adult
Emanuelsson, 1995c
Adult
fu
Comments
1.43 0.40
61
In vivo after 50 mg I.V. in 15

min, ultrafiltration
0.4
1.2
4.7
6.1
In vivo after 21 h infusion,

ultrafiltration
AAG = 1-acid glycoprotein; C = the concentration at which fu has been measured; fu = free fraction.
aData are mean SD.
bLerman J, Strong HA, LeDez KM. Effects of age on the serum concentration of alpha1-acid glycoprotein and the binding of lidocaine in pediatrics. Clin Pharmacol
Ther. 1989;46:21925.
cEmanuelsson BM, Zaric D, Nydahl PA et al. Pharmacokinetics of ropivacaine and bupivacaine during 21 hours of continuous epidural infusion in healthy male
Binding to Red Blood Cells
BINDING TO AAG: The AAG or orosomucoid is also called stress
LAs have a low affinity for red blood cells (the bloodtoplasma
concentration ratio for amides lies between 60 and 85%).103,106
However, binding to red blood cells appears to be linear (i.e., not
saturable), and this may become meaningful when binding to
serum proteins (especially to 1-acid glycoprotein [AAG])
becomes saturated. Unfortunately, very few studies of LA binding
in blood have taken this important action into account (red blood
cells represent > 40% of blood volume), especially in infants with
physiologic anemia. The best reference paper is still from Tucker
and coworkers who studied lidocaine, mepivacaine, and
bupivacaine binding.106 At a total concentration of 2 g/mL, the
bloodtoplasma concentration ratio was 0.78, 0.72, and 0.60 for
lidocaine, mepivacaine, and bupivacaine, respectively. At 20
g/mL, this same ratio was 0.91, 0.91, and 0.83. These authors
have shown that the concentration ratio between washed red cells
and buffer varied between 2.0 for lidocaine and 2.7 for
bupivacaine. Moreover, this ratio was constant over a wide range
of concentrations. Thus, red blood cells may be considered as a
buffer system reaching significance when toxic concentrations
occur (i.e., >23 g/mL for bupivacaine or >710 g/mL for
lidocaine), especially in infants with a low AAG concentration
(Figure 2812). On the contrary, anemia seems to favor a rapid
rise in free drug concentration. This is most likely to occur in
infants younger than 6 months who have not yet reached their
definitive adult AAG concentration and have a low, though
physiologic, hematocrit.
protein. It is the major protein involved in amide binding in serum.

AAG is a glycoprotein with multiple physical states. The monomeric moiety has a molecular weight between 38,800 and 48,000
Da depending on numerous factors.113 The extent of polymerization and the association to fatty acids may lead to marked
differences in properties of the molecule. All basic drugs bind to
AAG. However, AAG concentration in serum is relatively low
(0.501.0 g/L in adults). AAG concentration is very low at birth
and increases slowly during the first year of life (Figure 2814).
After 1 year of age, orosomucoid concentration remains unchanged until at least the age of 80 years.114 AAG concentration markedly increases during inflammatory processes such as cancer,
burns, and the postoperative period.115118 In the postoperative
period, the increase occurs during the first 3 to 6 hours after surgery. It is important to remember that acidosis markedly decreases
the affinity of AAG to LAs, particularly bupivacaine.119,120
Binding to Serum Proteins

Esters are rapidly hydrolyzed by esterases in plasma, and protein
binding occurs only in toxic situations. Amide LAs bind tightly to
serum proteins. At total serum concentrations of up to 10 g/mL
for lidocaine and up to 2.5 g/mL for bupivacaine, the fu observed
in adults varies between 25 and 45% for lidocaine and between
4 and 7% for bupivacaine and ropivacaine.4,107111 Like all weak
bases, amide LAs mainly bind to AAG and to human serum
albumin (HSA) with minimal binding to 2 proteins and no
binding to globulins.112 HSA has a low affinity but a high (almost
nonsaturable) capacity for LAs, whereas AAG has a very high
affinity for them. Unfortunately, AAG is 50 to 80 times less
abundant than HSA (especially before the age of 6 mo) and the
capacity of binding is relatively low (i.e., saturation occurs rapidly
at concentrations usually observed in serum) (Figure 2813).
Figure 28-12. Lidocaine, mepivacaine, and bupivacaine binding

(fraction of total concentration in whole blood) at 2 g/mL (left
bars) and 20 g/mL in blood (right bars). Mepivacaine is
slightly more highly bound than lidocaine and the fu is nearly
constant in the concentration range studied. At 2 g/mL bupivacaine in blood (which represents the upper limit of nontoxic
concentrations), fu is low (~5%) and most of the drug is bound
to serum proteins. At 20 g/mL (which represents a highly
toxic concentration), fu is much greater (~20%) and the buffer
capacity of erythrocytes becomes evident. Drawn from adult
data obtained in reference 106.
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Figure 28-13. Left panel: Free lidocaine (dotted line) and free bupivacaine (solid line) concentrations in serum as a function of total concentration. This simulation was calculated using average adult parameters from references 107 and 108.
Inset: An enlargement of the first part of the curve (at clinical concentrations). When total bupivacaine concentrations are
greater than 24 g/mL, binding capacities are partly saturated and the free concentration increases dramatically. Right
panel: The effect of 1-acid glycoprotein (AAG) concentration on bupivacaine binding in serum. Middle curve: The free
versus total bupivacaine concentration in an adult subject with normal AAG binding capacity. Lower curve: Drawn with
parameters from a subject with twice this binding capacity (e.g., a subject with metastatic cancer). Upper part: Drawn with
parameters from a subject with half this normal binding capacity (e.g., an infant aged 12 mo). Adapted from Mazoit JX,
Vigu B. Les associations danesthsiques locaux sont-elles dangereuses? Ann Fr Anesth Ranim. 1988;7:211215.
Figure 28-14. 1-Acid glycoprotein (AAG)

and human serum albumin (HSA) concentrations in serum as a function of age. Upper
panel: Free fraction of sufentanyl is plotted
against AAG concentration for different aged
patients. Lower panels: The concentration of
AAG (left) and HSA (right), in a sample of
11 infants aged 16 months, plotted against
age. Upper panels: Adapted from reference
116. Lower panels: Drawn from data obtained in reference 117.
453
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BINDING TO HSA: HSA is the most abundant protein in serum

with an average concentration of 40 g/L in adult. Acidic drugs such
as thiopental bind strongly to HSA, to one site in particular.121 This
site is common to all acidic drugs and to bilirubin. Basic drugs
such as amide LAs bind less specifically to has, and the site
responsible for acidic drugs binding is not involved. Although the
affinity of LAs for HSA is much lower than the affinity of LAs for
AAG, the enormous binding capacity of HSA renders this protein
important in the binding equilibrium process. When binding to
AAG is saturated, two systems continue to bind LA, erythrocytes
and HSA. HSA concentration is slightly lower at birth when
compared with the values measured in older children. However,
changes in binding induced by the variations in HSA content are
generally of no practical clinical significance. Almost all circumstances that may lead to decrease in HSA induce an increase in
AAG that compensates or overcompensates for that change. It is
important to remember that HSA binds LA in children with
nephrotic syndrome. This disease is characterized by a decrease
in albumin concentration in serum. AAG is not concomitantly
increased so that protein binding is expected to be markedly
decreased in these circumstances.
Acidosis is a cause of increased unbound drug. Renal failure
and hyperbilirubinemia are known to increase the fu of acidic
drugs. However, the fu of basic drugs does not seem to be increased in hyperbilirubinemia (personal data not published). The
effect of renal failure on the fu of basic drugs is known to be
variable. Renal insufficiency has a number of different etiologies
that can lead to a decrease, an increase, or no change in AAG or
HSA concentrations. For example, Chauvin and colleagues did not
find any difference in fu between a group of American Society of
Anesthesiologists (ASA) 1 patients and a group of patients with
renal failure (fu = 6.8 0.8% vs 8.2 3.0%, respectively).122 This
result is in accordance with the fact that AAG concentration was
similar in both groups (0.89 0.30 mg/L vs 1.01 0.47 mg/L,
respectively).
PROTEIN BINDING EVOLUTION DURING THE FIRST YEAR OF

LIFE: Neonates have only one fifth to one third the AAG serum
concentration observed in adults116118 (see Figure 2814). They
also have a lower HSA concentration. However, HSA concentration changes between birth and 6 to 9 months are much less
important than the difference in AAG concentration. The net
result is a lower binding capacity during the first 6 to 9 months of
life compared with children or adults. This leads to a higher fu in
infants younger than 6 to 9 months than in children or adults 117,123
(Figure 2815). Young infants have also a decreased intrinsic
hepatic clearance of LAs. The combination of decreased clearance
and increased free fraction in infancy relative to the values
encountered in children and adults explains the high bupivacaine
concentrations observed at this age.124128
CHANGES IN PROTEIN BINDING IN THE POSTOPERATIVE

PERIOD: In the postoperative period, AAG concentration increases rapidly. Six hours after surgery, the binding capacities are
markedly increased in adults, children, and infants.115,118,123 However, neonates and young infants have a markedly lower basal
AAG concentration than children or adults. The increase in AAG
concentrations observed after surgery is proportional to the basal
concentrations, and AAG concentrations observed 24 to 48 hours
after surgery are lower in young infants than in older subjects in
the same circumstances.123
Figure 28-15. Bupivacaine free fraction (fu) in serum as a function of age in 11 infants aged 16 months after 2.5 g/kg caudal
bupivacaine. The curve corresponds to the AAG concentration
depicted in Figure 2814, lower left panel. As AAG increases
with age, fu decreases and the usual adult value (~5%) is reached
after the age of 6 months. From reference 117.
INTERACTION AND DISPLACEMENT FROM BINDING SITES WITH

OTHER DRUGS: Interactions at the binding sites have long been
thought to be of paramount importance. Drugs with a low therapeutic ratio such as bupivacaine may be displaced from their
serum protein binding sites by other molecules. This phenomenon
is not considered to be as important as it was believed to be some
years ago.129 However, displacement between LAs may be observed, and it is important to remember that mixtures of LAs
possess the toxicity of their most toxic component.130
Tissue Binding
Tissue binding is an important, though largely unknown, parameter in local and general disposition of drugs. Global, nonspecific tissue binding can be estimated from distribution data.131
Table 286 displays the relative percentage of amide LAs that
distribute in the body. It is evident that the vast majority of amide
molecules are bound in tissue.
Local Disposition and Absorption

Into the Bloodstream
Concentration at the Site of Action
Amide LAs are usually considered to have a bioavailability of one
and metabolism is exclusively hepatic. Absorption is slow and
varies depending on local conditions. Absorption after ilioinguinoiliohypogastric block is faster than after caudal injection. From
adult studies, we may extrapolate that the speed of absorption
decreases from head to foot for peripheral blocks and from
thoracic to caudal epidural space (with the possible exception of
children not yet walking). This is the consequence of the degree of
vascularization of tissues in relation with hydrostatic pressure
(humans are bipeds).
Concentrations of LAs are very high at the site of action (Table
287), and neurologic complications following spinal anesthesia
have been attributed to these excessive concentrations that lead to
a direct toxic effect on nerve fibers.132 Local disposition contributes
to both onset and duration of action as well as to absorption into
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TABLE 28-6. Lidocaine and Bupivacaine Distribution in Body Compartments

For each drug, the fraction in each compartment has been calculated using ie and Tozers formula131:
f
V = Vp (1 + R E /I ) + f u Vp (VE /VP R E /I ) + VR u
fu
R
where VP = the plasma volume (3 L); VE = the extracellular volume (12 L); VR = the remaining volume (total body water VE)
(27 L); RE/I = the ratio of the number of binding sites in the extracellular space and the number of sites in plasma (usually 1.4);
fu = the free fraction in plasma; and fu the free fraction in the compartment VR. Thus, fu is estimated to be 0.14 for lidocaine,
0.03 for bupivacaine, and 0.06 for ropivacaine. It is clear that, if tissue binding is the determining factor of volume of distribution,
plasma binding plays also an important role, inverse to that of tissue binding. Any increase in fu leads to an increase in V, whereas
any increase in fu leads to a decrease in V.
The figures are approximate and must be interpreted with care.
R
Lidocaine
Mepivacaine
Bupivacaine
Etidocaine
Ropivacaine
0.13
0.87
0.19
0.03
0.06
0.74
0.11
0.10
0.10
0.03
0.07
0.80
0.14
0.86
0.04
0.05
0.12
0.83
0.06
0.94
0.02
0.02
0.05
0.92
0.18
0.82
0.05
0.06
0.15
0.74
In extracellular fluids
Outside extracellular fluids
Free
Bound to plasma proteins
Bound to extracellular proteins
Bound inside cells
(including red blood cells)
the bloodstream. The latter phenomenon has been well studied

for epidural anesthesia. Absorption from the site of action may
vary with age. However, few authors have studied this dependence
and results are not totally conclusive. Some factors such as the
amount of fat in the epidural space133 or an increased mucosal
vascularization134 have been advocated to explain discrepancies
between adults, children, and infants. In the next section, we
describe the details of absorption for different routes of injection.
Between-individual variability is a significant factor for absorption
variability. Ester and amide LAs have different dispositions after
their absorption into the systemic circulation. However, neither
undergoes significant local metabolism or degradation. Bioavailability is then considered complete for all LAs.

After Spinal Injection
Spinal anesthesia requires a higher dose (mg/kg) in infants than in
older children, and the duration of the block is brief. It is commonly believed that the volume of CSF (relative to weight) together with a more rapid CSF turnover in infants than in children
and adults may explain why spinal anesthesia duration is shorter
despite the larger dose. In fact, the pharmacokinetics of LAs in the
CSF are unknown, particularly in the pediatric age group. At the
cephalic level, neonates and infants have a lower CSF volume and
turnover than children and adults.135 The shorter length of nerve
roots in infants than in adults and the relatively fixed internode
TABLE 28-7. Cerebrospinal Fluid Concentrations of Local Anesthetic Solutions After Spinal and Epidural Injectiona
1 g/mL lidocaine (base) = 4.3 M (mol/L), 1 g/mL bupivacaine = 3.5 M, 1 g/mL tetracaine = 3.8 M
Lidocaine
Bupivacaine
Concentrations in the Bottle

5% 214 mM
2% 85 mM
1% 43 mM
0.5%
0.25%
Tetracaine
1%
0.5%
17 mM
9 mM
Minimum Concentrations Needed to Block the Nerve (at the Outer Part of the Fiber)
0.51.5 mM
0.20.6 mM
38 mM
19 mM
0.250.6 mM
Average Concentration in CSF (Perfect Mixing in Half CSF Volume Is Supposed)

Spinal
Epidural
Spinal
Epidural
Spinal
100 mg (2 mL 5%)
9.513.4 mM
400 mg (20 mL 2%)

0.85.3 mM
15 mg (3 mL 0.5%)
1.13.2 mM
100 mg (20 mL 0.5%)

0.151.1 mM
20 mg (2 mL 1%)
1.74.8 mM
CSF = cerebrospinal fluid.

aAbout 25% of the dose injected in the epidural space crosses the meninges. This amount is significant and epidural anesthesia acts mainly by a delayed spinal
anesthesia.122,123 Sodium channel blockade occurs at in vitro concentrations outside the nerve fiber between 0.15 and 1.5 mM depending on the agent. Because of the
concentration gradient between fluids surrounding the nerve (or the cord) and the nerve fibers, the concentration bathing nerves or the cord needs to be higher.
Depending of the model used, CSF lidocaine concentration leading to neurologic sequelae is between 20 and 60 mM.
bCSF volume measured using MRI between T2 and S2 was found between 32 and 90 mL (median 50 mL) (Fink BR. Mechanisms of differential axial blockade in
epidural and subarachnoid anesthesia. Anesthesiology. 1989;70:851858). The volume of CSF (relative to weight) in which anesthetic molecules distributes is about
four times greater in neonates and infants than in adults.118
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distance contribute. In addition, because dural surface area is

related to body surface area rather than to weight, it is not surprising that LA clearance from CSF will be higher in younger
patients because the main factor governing clearance is the dural
surface area.136

After Epidural Injection
THE EPIDURAL SPACE: The epidural space is not as empty as it is
commonly asserted. It is a fatty region between the dura matter
and the vertebrae with numerous veins in the anterior portion.137
Although the epidural space is very compliant, intraepidural
pressure increases markedly after injection. For instance, after
injection of a volume as small as 2 mL in an adult, pressure in the
epidural space reaches 20 mmHg 138 (Figure 2816). This increased pressure is immediately transmitted to the CSF, and it has
been shown that the increased pressure in CSF lasted for more
than 10 to 20 minutes.138,139 The magnitude of this increase is
dependent on basal intracranial pressure. Patients with increased
intracranial pressure and decreased cerebral compliance will have
an increase in intracranial pressure that is of greater intensity and
greater duration than in normal subjects. Apart from direct action
on the nerve roots during their passage through the epidural
space, LAs act by crossing the meninges.140,141 Despite inaccuracies
in the measurement of the fraction of drug that crosses the meninges, an estimate of 2 to 3% of the injected dose is appears to do
so.140143
THE EPIDURAL SPACE AS A RESERVOIR: The balance between

systemic absorption and local disposition of a drug depends on
local properties of the epidural space. In fact, after epidural
injection, a drug is absorbed by epidural fat, which is the main
component of this body compartment and an important factor of
local disposition. In a series of experiments using an elegant
isotopic method in a series of experiments, Burm and associates
have shown that systemic absorption is a slow process with a halflife between 2 and 4 hours depending on the agent studied144147
(Figure 2817). Numerous factors such as drug hydrophobicity,
anatomic location, the addition of epinephrine, and the age of the
patient govern the rate of absorption. The more hydrophobic the
Figure 28-17. Upper panel: Fraction of lidocaine (open circles)

and bupivacaine (solid circles) absorbed from the epidural space
into the bloodstream in two patients. Three hours after a single
injection in the epidural space, 50% of bupivacaine and 30% of
lidocaine remain in the epidural space. Lower panel: The effect
of this delayed absorption on the decline in concentration in
blood (flip-flop effect). Lower curve (triangles and dotted
line),The concentration observed after intravenous injection of a
small amount of deuterated bupivacaine. Upper curve (squares
and solid line):The concentration of bupivacaine injected epidurally at the same time in the same subject. The slow decline in
bupivacaine concentration after epidural injection is caused by
continued absorption. Adapted from reference 144.
molecules, the more they are retained by epidural fat, slowing
absorption. Bupivacaine is between lidocaine and etidocaine in
speed of absorption. Absorption from the epidural space is a
biphasic process. After a single epidural injection of bupivacaine,
30% of the dose is rapidly absorbed (Table 288). A much slower
absorption process follows so that the absorption half-life is much
longer than the elimination half-life from the central compartTABLE 28-8. Fraction Absorbed and Their Corresponding
Half-lives for Absorption From the Epidural Spacea
F
T / , min
F
T / , min
Total recovery
1
Figure 28-16. Pressure measured in the lumbar epidural

space after a 2-mL injection (solid circles) or a 6-mL injection
(open circles). Pressure remains high for more than 30 minutes.
Lidocaine
Bupivacaine
Ropivacaine
0.38
9
0.58
82
0.96
0.29
8
0.64
371
0.91
0.52
14
0.48
252
0.87
F and F = fractions for the rapid and slow absorption processes; T1/2 and T /
= the corresponding half-lives.
aData are from adult volunteers.76,144,147
1
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457
than in children and in children than in adults.148,149 In a study

done in children aged 1 to 8 years, ropivacaine Tmax was inversely
related to age, from 115 minutes in children aged 1 to 2 years to
30 minutes in children aged 5 to 8 years.150 This phenomenon
seems to be less pronounced with levobupivacaine.151

After Other Routes
Figure 28-18. Continuous postoperative epidural analgesia:

simulation of bupivacaine concentrations in a child with an
initial bupivacaine clearance of 10 mL/min/kg and a final clearance of 2 mL/min/kg. This child received an initial dose of 1.875
mg/kg bupivacaine (0.75 mL/kg bupivacaine 0.25% with epinephrine) in the operating room, followed by a re-injection of
1.25 mg/kg (0.5 mL/kg) 90 minutes after the first injection. The
child was transferred to the postanesthesia care unit after surgery and postoperative analgesia was begun 150 minutes after
the first injection. Thereafter, two different modalities of analgesia are represented: continuous infusion or intermittent injections, both based on the same dosing. Continuous infusion ran
at a rate of 0.25 mg/kg/h (0.1 mL/kg/h with a 0.25% solution or
0.2 mL/kg/h of a 0.125% solution. Because of the delay between
the last injection in the operating room and the infusion start,
bupivacaine concentration begins to decline. If the continuous
infusion is not started immediately after the last bolus dose, the
amount of drug in the epidural space decreases and the time
needed to recover analgesia may be prolonged. Serum concentration decreases in a similar manner, albeit with a lag time because epidural fat possesses buffering properties. The second
dosing pattern is represented by intermittent bolus injections
through the epidural catheter. The first bolus is given 4 hours
after the last injection in the operating room. The dosing is
1 mg/kg every 3 hours from 4 to 20 hours, then every 4 hours
(0.4 mL/kg bupivacaine 0.25% or 0.8 mL/kg bupivacaine 0.125%
or 1 mL/kg bupivacaine 0.1%). As previously noted, the shape of
the curve shows an initial decline in concentration and then a
progressive rise until steady state is reached. The final concentration is relatively high (>2 g/mL) and steady state is not reached
until the second day of infusion. This is caused by the progressive decrease in clearance owing both to the decreased free fraction (related to the increase in AAG concentration in serum in
the postoperative period) and to the decrease in intrinsic hepatic
clearance. The practice of re-injections (top-up doses) leads to
peaks and valleys with the risk of toxic reactions. Adapted from
Mazoit JX, Bruguerolle B. In: Murat I et al. Anesthsie locorgionale chez lenfant. Confrence dexperts. Ann Fr Anesth Reanim. 1997;16:9851029.
ment. This phenomenon, called the flip-flop effect, is important
because kinetic parameters measured after a nonintravenous
injection are imprecise.144147 The epidural reservoir fills up when
more injections are performed. During prolonged administration,
top-up doses may then be deleterious (Figure 2818). It seems that
epidural fat is less abundant in neonates and infants than in older
children and in adults.133 However, the time to maximum peak
concentration (Tmax) of ropivacaine is much longer in infants
The level of injection is an important parameter affecting absorption. Injections in the cephalic part of the body have more rapid
absorption than caudal injection. This is true for central blocks
and an epidural block performed at the cervical level renders
higher systemic concentrations than a caudal epidural. This is
also true in other parts of the body: a subcutaneous injection in
the scalp or face has very rapid absorption (because of increased
circulation in these areas) whereas foot or knee blocks produce
only slow rises in concentration with much lower peak concentrations.
ABSORPTION AFTER TOPICAL ANESTHESIA OF THE AIRWAY: It

was long thought that topical anesthesia of the airway for ear, nose,
and throat procedures was dangerous in children younger than
4 years of age because rapid absorption may lead to toxic blood
concentrations. It seems that this assumption must be reviewed in
view of recent papers showing that precisely controlled administration allow the use of topical anesthesia with lidocaine without
risk.152
ABSORPTION AFTER TOPICAL CUTANEOUS ANESTHESIA OR

AFTER SUBCUTANEOUS INJECTION: Eutectic mixtures of local
anesthetic (EMLA) creams have now replaced unsafe combinations of lidocaine, tetracaine, and epinephrine (LAT) and
tetracaine-epinephrine-cocaine (TAC).153-155 However, care should
be taken in neonates and infants because prilocaine may induce
methemoglobinemia; observed, for example, when infants are
treated with trimethoprim-sulfamethoxazole.155 Dibucaine is an
amide LA commonly used for topical anesthesia in adults. However, this agent is toxic when ingested and acute poisoning in
children has been described.156
ABSORPTION AFTER OTHER ROUTES: After intercostal block,

absorption is rapid, leading to high concentrations in the blood.157
As with intercostal blocks, interpleural analgesia may lead to high
peak concentrations.158,159
RE-INJECTIONS: Re-injections are often required in the operating

room. Toxicity is a concern in neonates and infants and the choice
lies between (1) using a short-acting drug with limited toxicity but
necessitating frequent re-injections or (2) using a long-acting drug
that is more toxic but needs less frequent re-injections. Shortacting drugs are less hydrophobic and are much more rapidly
absorbed than long-acting drugs. Therefore, during the first hours
of anesthesia, short-acting drugs rapidly accumulate in the bloodstream, whereas long-acting drugs remain at the site of injection
for a much longer period of time (see Figure 2817). Moreover, it
is important to note that top-up doses may lead to sudden
transient increases in plasma concentration with the potential risk
of toxicity (see Figure 2818).
Systemic Distribution
More than 50% of amide LA molecules are ionized at pH 7.40
and, therefore, their volumes of distribution are important
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TABLE 28-9. Bupivacaine and Ropivacaine Pharmacokinetics in Infants and Children Compared With Adultsa
B/P
Bupivacaine
I.V. adults
Epidural adults
Infants caudal single shot
Children (510 y)
Infants epidural prolonged
Ropivacaine
I.V. adults
Epidural adults
Caudal single shot
Neonates
Infants
Children
Epidural prolonged
Neonates
Infants
Children
Levobupivacaine
I.V. adults
Caudal single shot
Infants
0.6
0.7
fu
CLU/f, mL/min/kg
T / , hb
4.58.1
4-5.6
7.1
100
1.8
5.110.6
5.57.5c
3.54d
3673
3673
CLT/f, mL/min/kg
0.05
0.851.3
0.16 (0.050.35)
2.7
(0.060.24)c
(0.030.18)d
3.9
10
0.05
0.50.6
4.25.3
4.05.7
100
70
5058
2.1
2.4
2.4
5.2
7.4
4.26
151
6.15
8.5
220
0.07
0.050.10
5.2 (1.37.3)
2.4
0.04
0.045
Vss, Lb
0.72
4.2
6.3e
116
1.7
2.95.4
2.6
B/P = bloodtoplasma concentration ratio; CL = clearance; CL/f = total body clearance over bioavailability (T = total fraction; U = unbound fraction); fu = free
fraction in serum; T1/2 = terminal half-life; Vss = volume of distribution at steady state. For adults, a mean body weight of 75 kg has been assumed.
aNote the differences in T1 between I.V. and epidural injections (owing to the flip-flop), the differences in CL between adults, children, and infants and between I.V.,
/2
single-shot epidural, and prolonged epidural administrations. These differences, because of the uncovering of a deep compartment effect (and possibly a decrease in
intrinsic clearance with time), are simply explained by the concept of context-sensitive half-life. After caudal or epidural injection, the maximum concentration
(Cmax) occurs 20(30 min (Tmax) after lidocaine, mepivacaine, or bupivacaine injection. Tmax is delayed after ropivacaine (4570 min).
bApparent value, T , and volumes measured after non-I.V. injections are overestimated because of a flip-flop effect (see text).
/
cAfter 3 h infusion.
dAfter 48 h infusion, CLT decreases with time because protein binding increases. For references, see reference 103.
eSampling was very short (4 h), thus leading to overestimation of CL.
1 2
(Table 289). This is reinforced by the fact that neonates and infants
have a greater water content relative to that of adults. It is difficult
to accurately measure the volume of distribution after a nonintravenous injection of LA (the absorption half-life from the site
of injection is usually longer than the elimination half-life, leading
to the flip-flop effect). Although volumes of distribution calculated
after nonintravenous routes of administration are markedly
overestimated, it is probable that LAs distribute to a larger volume
in neonates and in infants than in adults. If this hypothesis is true,
distribution into a large volume may reduce peak serum concentrations after a single administration, but not after several re-injections.
The apparent bupivacaine volume of distribution appears to be greater
in infants than adults.117 This large volume of distribution leads also
to a much lower venous concentration than arterial concentrations
that can last 2 to 3 hours after injection (Figure 2819).
Figure 28-19. Arterial and venous plasma concentrations of
lidocaine and bupivacaine after epidural injection of lidocaine
400 mg (2% solution with epinephrine 1/200,000) or bupivacaine 150 mg (0.75% solution with epinephrine 1/200,000).
Distribution into peripheral tissues leads to a difference between
arterial and venous concentrations. This difference that may be
as high as 40% lasts for 23 hours after injection. Adapted from
Mather LE, Cousins MJ. Local anaesthetics and their current
clinical use. Drugs. 1979;18:185205.
Extraction by the Organs

Extraction of drugs by organs is a complex function of transit time
through the organ and of association and dissociation rate constants with proteins and red blood cells. After systemic absorption,
LA molecules pass through the lung, where a significant part may
be retained before reaching the brain, heart, or liver. Depending on
their ability to cross membranes in the liver, drugs have been
classified as restrictively and nonrestrictively cleared (by the
liver).160 For restrictively cleared drugs, the fu is considered as
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the limiting factor of organ extraction. In fact, amide LAs follow
the free drug principle for their hepatic extraction (see Hepatic
Extraction and Clearance), but it seems that extraction by other
organs does not follow this rule. For example, the amount of lidocaine
or bupivacaine available for brain extraction after a single bolus
injection in the rat appears to be greater than the free moiety,161,162
but these two drugs do not follow the same kind of departure from
the free drug rule. Other drugs such as quinidine have also shown
a myocardial extraction different from that predicted by the free
drug rule.163 The phenomenon of organ extraction is complex and
poorly understood, but it has important therapeutic and toxic
implications.164,165
LUNG EXTRACTION: During the first few minutes after rapid

intravenous injection, amide LAs are retained by the lung.166,167
Bupivacaine seems to be more bound in the lung than lidocaine.
However, saturation occurs rapidly and the lung cannot totally
prevent a rapid increase in blood concentration.167
BRAIN EXTRACTION: After a rapid rise in arterial concentration,

brain extraction appears to be much higher than predicted by the
free drug rule (Figure 2820).161,162 This rapid transfer across the
blood-brain barrier has been questioned by Marathe and coworkers,168 but these authors based their arguments on near steadystate experiments. The rapid and slow rise in concentrations
observed after injection must be distinguished from observations
after continuous infusion. Bupivacaine toxicity appears to be
closely related to the free drug concentration rather than to the
total concentration during continuous administration for post-
Figure 28-20. Effect of protein binding on first-pass cerebral

extraction of bupivacaine in the rat. 3H-Bupivacaine and 14Cbutanol mixed with aliquots of human serum containing various
concentrations of AAG have been measured in brain after bolus
injection into the carotid artery. The difference between the theoretical curve calculated from in vitro binding parameters and
the experimental curve is impressive. It appears that, contrary to
the free drug principle, a large number of bupivacaine molecules
are available to cross the blood-brain barrier at first pass. However, although the in vivo exchangeable amount was about eight
times higher than the in vitro exchangeable amount (inset),
these two quantities appears strictly linearly related. Modified
from reference 162.
459
operative pain relief. This may not be the case after a rapid rise in
concentration.
MYOCARDIAL EXTRACTION: Among the huge number of papers

published on bupivacaine cardiac toxicity, almost none has
reported bupivacaine binding and/or extraction by the heart.
Lidocaine and bupivacaine myocardial extraction in isolated
rabbit hearts has been shown to be less intense than might be
expected.8,169,170 The bupivacaine myocardiumtoperfusate concentration ratio was only twice that of lidocaine at steady state.
Moreover, upon discontinuation of the infusion, washout from the
heart was similar for both drugs with a terminal half-life of about
10 minutes. However, in this preparation, coronary blood flow was
maintained constant throughout the study. Therefore, it seems
possible to speculate that as soon as coronary blood flow is maintained (with cardiac massage as the extreme measure), bupivacaine washout from the heart might be rapid.
Elimination
Metabolism
ESTERS: Like succinylcholine, cocaine, or heroin, esters are hydrolyzed in serum, red blood cells, and liver by nonspecific esterases
or pseudocholinesterases.171,172 Only cocaine undergoes significant
hepatic metabolism. Because of their rapid degradation in blood,
esters have long been thought to be very safe agents.173 The endproducts of ester metabolism are inactive and relatively nontoxic,
although para-aminobenzoic acid resulting from ester metabolism
can induce severe allergic reactions.174 Some patients have reduced
cholinesterase blood concentrations. There are a great number of
plasma cholinesterases genotypes, leading to wide variations in
plasma cholinesterase activity. These variations can be functionally
differentiated into three or four main categories172 (Table 2810).
This categorization of individuals according to their dibucaine
number is based on the fact that all amide LAs are potent
inhibitors of cholinesterases.175 Thus, mixtures of amide and ester
LAs carry a potential risk of toxicity. Similarly, the duration of
action of succinylcholine might be increased by the concomitant
use of an amide LA.176 In patients with esterase deficiency, ester
concentrations in blood rapidly reach high concentrations.177
However, neither procaine nor 2-chloroprocaine appears to be
responsible for severe toxic reactions such as those that occur with
long-lasting agents like tetracaine.
AMIDES: Amide LAs undergo exclusive hepatic metabolism by the

cytochrome P450 (CYP450) system. They are metabolized to
more polar products, which are excreted by the kidney (Figure
2821). Some of the metabolites are active, with possible toxicity
if accumulated.177 However, measured concentrations of metabolites are always lower than those associated with toxicity.
Lidocaine is mainly metabolized into glycine-xylidide (GX)
and mono-ethyl-glycine-xylidide (MEGX) by CYP1A2 and to a
lesser extent by CYP3A4.178,179 Bupivacaine (both the racemic
mixture and levobupivacaine) is predominantly metabolized into
pipecoloxylidide (PPX) by CYP3A4,180 which is very immature
before the age of 3 weeks and not fully effective before the age of
1 year.181,182 Ropivacaine is mainly metabolized into 3- and 4OH-ropivacaine by the CYP1A2 and to a minor extent to PPX by
CYP3A4.183 However, the major difference between these two
enzymatic systems is that CYP3A4 reaches 80 to 90% of the adult
capacity by the age of 9 to 12 months, whereas CYP1A2 may not
be totally mature before the age of 4 years. CYP3A4 possess a less
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TABLE 28-10. Frequency of Cholinesterases Genetic

Variations Leading to Decreased Metabolic Activity
Characterized by Their Dibucaine Numbera
Homozygous typical
Heterozygous
Homozygous atypical
Homozygous J, H
Frequency
Dibucaine
Number
Normal
1/480
1/2500
1/150,000
>70
4070
2040
< 20
This table holds for Caucasian subjects. Some populations such as Alaskan
Eskimos, Afrikaner South Africans, or Vysya castle group in India are at much
greater risk.
efficient fetal equivalent, CYP3A7. CYP1A2 has no fetal equivalent.181 Interestingly, Bsenberg and colleagues measured the
principal metabolites of ropivacaine in urine, pipecoloxylidide
(CYP3A4 and CYP3A7), and 3-OH-ropivacaine (CYP1A2). The

concentration of 3-OH-ropivacaine in urine increases from birth
to the age of 6 months.184 Studies measuring the differences in
microsomal metabolism of bupivacaine enantiomers are still
lacking, despite the fact that both urinary excretion of S() and
R(+) bupivacaine and intrinsic clearance are stereospecific in
humans.185187 The S() enantiomer (levobupivacaine) has a
slightly greater intrinsic clearance than the R(+) enantiomer.186
Hepatic Extraction and Clearance

Hepatic metabolism can be divided in two categories that are
dependent on whether their hepatic extraction ratio is high (>60
70%) or low (<2030%).160 Drugs with a high hepatic extraction
ratio are not restrictively cleared and their clearance mainly
depends on hepatic blood flow (i.e., cardiac output); these agents
are called flow-limited drugs. Drugs with a low hepatic extraction ratio depend on the fu and intrinsic hepatic clearance (the
Figure 28-21. Metabolism of lidocaine (left), bupivacaine (top right), and ropivacaine (bottom right). Only the major pathways in
humans are represented. Lidocaine metabolites are active or toxic but their concentrations in plasma are far below the threshold for
effect in adults. Bupivacaine metabolites are neither active nor toxic at the concentrations usually encountered. Although ropivacaines prominent metabolic pathways are similar to those of bupivacaine, some differences not shown on the figure do exist. Dotted
lines correspond to multiple steps not represented on the figure.
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metabolic capacity of microsomes); these agents are called ratelimited drugs. Lidocaine, which has an extraction ratio of 65%, is
considered nonrestrictively cleared whereas bupivacaine and ropivacaine, which have extraction ratios of 35% in adults, are
considered restrictively cleared. Infants exhibit a lower bupivacaine extraction ratio than that in children and adults. Lidocaine
clearance has been shown to be reduced in the presence of low
cardiac output.188,189 Lidocaine clearance is also markedly decreased after several hours of continuous administration.190 This
may appear paradoxical because lidocaine clearance is considered
flow-dependent. However, this phenomenon is caused by microsomal inhibition by lidocaine metabolites such as MEGX.188,191,192
Lidocaine plasma concentrations may be 30 to 40% greater than
expected and cause CNS toxicity. This is one explanation for the
loss of popularity of lidocaine in cardiology.
The elimination of bupivacaine and of ropivacaine is considered rate-limited (i.e., almost independent of hepatic blood flow
and cardiac output, but highly dependent on the metabolic capacity of microsomes and on the fu in serum). Decreased clearance
might be expected in hepatic failure. However, regional anesthesia
is generally contraindicated in this case because of clotting
disorders and it is uncommon for patients with hepatic failure to
receive bupivacaine. However, clearance of rate-limited drugs also
depends on unbound drug concentration (free drug is the only
moiety available for metabolism). AAG concentration increases
during the postoperative period and the fu decreases. Total
bupivacaine concentration continues to rise over several days of
continuous administration both in adults193 and in infants.123 The
apparent decrease in total clearance is of little clinical consequence
because the intrinsic clearance is relatively fixed (at least after
several hours of infusion) and the free unbound drug concentration rapidly reaches a steady-state plateau.
Bupivacaine clearance is low at birth and increases during the
first year(s) of life.117,123,148,151,194 Ropivacaine clearance is also very
low at birth and during the first 2 to 3 months of life.184,195 In a
study comparing neonates and infants, ropivacaine clearance was
five to six times lower in neonates younger than 30 days than in
infants aged 1 year.184 CYP1A2 activity is low at birth and the full
metabolic capacity may not be attained before the age of 4 to
8 years.196 It is probable that all amide LAs exhibit comparable low
clearance in neonates and young infants.
After a single-shot injection, clearance of bupivacaine, levobupivacaine, and ropivacaine is close to 5 to 8 mL/kg/min after the age
of 3 years.94,103,148,196,197 During continuous infusion of bupivacaine
or ropivacaine, a clearance higher than 3 to 4 mL/min/kg cannot be
expected.103,123,148,184,198 During continuous perineural infusion, it is
common to observe an increase in serum concentrations during
the 36 to 50 hours because of the increase in protein binding caused
by the inflammatory process (see Local Disposition and
Absorption After Epidural Injection). However, it has been shown
that contrary to adults, infants and children develop tachyphylaxis
less rapidly and that 0.2 to 0.3 mg/kg is an adequate dose for
postoperative pain relief in the pediatric age group123,199 (see Table
2812 for detailed dosing recommendations).
Chronopharmacokinetics
Absorption, distribution, metabolism, and elimination of LAs are
influenced by many different physiologic functions, all of which
vary with time. Such variations in pharmacokinetics have been
demonstrated in animals.199201 However, it seems premature to
461
consider that such an effect may occur in humans, although chronopharmacokinetics has demonstrated to be of clinical relevance
in many fields.202
Pharmacokinetic Basis of
Prescription in Infants
During anesthesia, toxic reactions may occur during or immediately after the first injection of the drug or after several injections.
During prolonged administration for postoperative analgesia, toxic
reactions usually appear several hours (or days) after infusion
initiation.104,105 Precise guidelines based on the pharmacokinetics
and pharmacodynamics of LAs, particularly in infants younger
than 6 months in whom clearance is reduced, should be adhered to.
In neonates and infants younger than 3 months, the free drug
concentration may be elevated despite total concentrations that are
below the threshold for toxicity.117,123,124,127,184 In these patients,
clinical manifestations of toxicity may be noticed during careful
examination.127
After single-shot administration, the Tmax of bupivacaine and
levobupivacaine is always close to 25 to 30 minutes, whatever the
route. This is not the case with ropivacaine. Ropivacaine has a
delayed Tmax, particularly after caudal injection, and this is more
important with the younger patients. However, the maximum
concentration observed with ropivacaine is similar to that of
bupivacaine.
In parallel to their low clearance, infants have a possible greater
volume of distribution than children or adults. This is because of
the large water content observed in infants younger than 4 to
6 months. Thus, after a single injection, the low clearance seems
offset by the large volume of distribution. However, after reinjections or prolonged infusion over several days, steady-state
conditions are determined by clearance. Moreover, because of the
low AAG concentration observed at this age group, concentration
may increase rapidly to cause toxicity. Finally, at the age of 1 month,
it is usual to observe a bupivacaine clearance of 3 to 5 mL/min/kg
and a fu of 15 to 25% at the time of first injection. After 1 or 2 days
of continuous perineural infusion for postoperative pain relief,
clearance decreases to 1 to 2 mL/min/kg and the fu is 8 to 16%.
Guidelines for prescription based on these considerations are given
at the end of the chapter.
ACTION ON THE ORGANS

Action on the CNS
Anticonvulsant/Convulsant Effects
LAs are antiepileptics at lower concentrations. Indeed, anticonvulsants either act on the gamma-aminobutyric acid (GABA)
glutamate regulation or block sodium channels such as phenytoin.
At serum concentrations lower than 5 to 7 g/mL, lidocaine possesses anticonvulsant properties (supposedly related to its sodium
channel blocking effect), and this agent is still used as an anticonvulsant, particularly in infants.203,204 The usual dose is 2 mg/kg
slow bolus, followed by a continuous infusion of 2 to 3 mg/kg/h.
At concentrations higher than 7 to 10 g/mL, lidocaine causes
convulsions because of imbalance between neuronal structures.
Finally, at serum concentrations higher than 15 to 20 g/mL,
lidocaine induces global depression with coma and cardiovascular
collapse. A direct effect of LAs on the GABA-mediated Cl currents may also be implicated in the generation of convulsions at
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high concentrations.205 A relative insensitivity to the convulsant

effects of lidocaine, bupivacaine, and ropivacaine has been demonstrated in newborn sheep, pigs, and rats in comparison with
adults.206,207
Analgesic Effect of Intravenous Lidocaine

Intravenous lidocaine induces analgesia, particularly in patients
with peripheral neuropathy.208 This effect seems to result from a
direct effect of lidocaine on spontaneous bursts of injured A and
C fibers.209,210 This subject is under investigation and this effect may
soon be elucidated. The analgesic effect of lidocaine seems to be
selective: pain resulting from orthopedic surgery appears to be
poorly reduced,211 whereas visceral pain and pain related to peripheral neuropathy appear to be more sensitive to this therapy.212214
Action on the Cardiovascular System

Action on the Heart
LAs are potent sodium channel blockers. Lidocaine is the typical
class Ib antiarrhythmic agent. LAs mainly act by preventing
fast inward sodium channels from opening. However, this block
has two components: the tonic block is time-insensitive and
concentration-dependent, whereas the phasic block (also called
use-dependent or frequency-dependent block) depends on the
rate of depolarization. When the rate of impulse increases, the
intensity of the phasic block increases, thus leading to the antiarrhythmic properties of lidocaine and the cardiotoxic effects of
bupivacaine. This difference between LA action is explained by
differences between the time constants of blockingwhether the
channels are in the resting, open activated, or inactivated states.29
Brain type (Nav 1.1, NaV 1.3, Nav 1.6) and cardiac-specific sodium
channels (Nav 1.5) are present in the cardiac muscle.215,216 Nav 1.5
are present in the intercalated disks at the cell-to-cell junction and
propagate the action potential, whereas the brain-type channels
are located in the transverse tubular system where they transmit
the signal from the cell surface to the inner part of tubules. Braintype channels contribute to synchronization of contraction and
Nav 1.5 contribute to the propagation of the action potential.
The effect produced by lidocaine seems much greater in
newborn rodents than in adults,217,218 whereas the effect produced
by bupivacaine seems to be similar in fetus, newborn, infant, and
adult animals.219,220 Newborns and infants are thought to be more
prone than adults to the phasic block produced by tertiary amine
agents such as bupivacaine because of their higher heart rate.220
LAs are also potent potassium channel blockers.30,31 Even lidocaine
blocks K-ATP channels.221 This action is presumed to partly
explain the favorable antiarrhythmic properties of lidocaine. The
effects of LAs on calcium current are less important. Lidocaine
seems to act through its effects on Na channels and by its direct
effects on the Na+-Ca2+ exchange. Bupivacaine and tetracaine have
a more potent effect on calcium channels in the heart.4547,222 This
may explain why bupivacaine is thought to produce atrioventricular block. However, LAs decrease contractility in isolated organs
as well as decrease heart rate in intact animals and humans.59,223,224
In dogs, bupivacaine does not appear to depress the myocardial
contractile force more than lidocaine until a concentration greater
than 4 to 5 g/mL is reached.225
In summary, by inhibiting Na+ and K+ currents, LAs depress
atrial and ventricular conduction. In addition to slowing conduction velocity, they increase dispersion. These effects are stereo-
specific and frequency-dependent. Their effect on the eHERG and

on the Kv 1.5 potassium channels explain why they may induce
torsades de pointes or ventricular fibrillation in subjects with long
QT syndrome. Their moderate effect on Ca2+ currents explains a
weak effect on the atrioventricular conduction and on contractility. It is interesting to note that the latter effect is not stereospecific.
Action on Blood Vessels

The effect of LAs on blood vessels is not fully understood. Their
direct action is different from the effect mediated by the sympathetic system, which is mainly vasodilation owing to sympathetic blockade. Until recently, S() enantiomers (ropivacaine and
levobupivacaine) were considered to be exclusively vasoconstrictors, whereas lidocaine and bupivacaine were considered as pure
vasodilators.226 LAs may exert either vasodilation or vasoconstriction depending on concentration and the nature of the vessel.
Lidocaine and bupivacaine have long been thought to exert a
dilating effect, whereas ropivacaine and levobupivacaine seemed
to have only vasoconstrictive effects.226,227 However, these differences may simply be related shifts in the dose-response curves.
All LAs exhibit a biphasic action, constriction at low concentrations, dilation at higher concentrations. Vasodilation exerted by
LAs appears to be both endothelium-dependent through the nitric
oxidecyclic guanosine monophosphate pathway and the prostaglandin system as well as endothelium-independent mediated
through anti-inflammatory properties.228231 The difference in
effect on arteries and venules is simply a difference in the doseeffect relationship.
TOXICITY OF LAS
LAs may exert toxic effects at the local site of injection (local
toxicity) and after absorption into the bloodstream (systemic
toxicity). Both toxic effects may be attributed either to the LA
agent itself or to additives.
Local Toxicity
Neuronal Toxicity
The toxic effect of LAs on nerve fibers were rediscovered in 1991
when cauda equina syndromes were described in adults after spinal anesthesia using lidocaine injected through microcatheters.232
234 Transient neurologic symptoms have also been described after
the use of 0.5% bupivacaine and 5% lidocaine.235,236 The compounds involved in local toxicity are mainly lidocaine and tetracaine; lidocaine 5% is no longer marketed in numerous countries.
Pediatric spinal anesthesia is commonly performed in ex
premature infants recovering from respiratory distress syndrome.
The duration of action is shorter than in adult patients; therefore,
the drugs generally used are tetracaine and bupivacaine.237,238
However, the advantages of spinal anesthesia in former preterm
babies have been questioned and safety is not absolute.239,240
Myotoxicity
LAs can cause myotoxicity, and bupivacaine has been implicated.
This effect has been related to calcium homeostasis disorder.241,242
This effect is not enantioselective, and the lack of stereoselectivity
is important because levobupivacaine is presumably as toxic
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as racemic bupivacaine, whereas ropivacaine appears less toxic
than bupivacaine. This perturbation of calcium homeostasis
seems related to the toxic effect of LAs on mitochondrial function.53,55 Care should be exercised in certain circumstances such
as regional anesthesia for eye surgery (the oculomotor muscles are
particularly sensitive), in children with myopathies (bupivacaine
is an in vitro model of Duchennes myopathy), and perhaps in
children with mitochondrial cytopathy. It is important to differentiate between central blocks, which have proven efficacy and
safety in these circumstances, and peripheral blocks in which the
injection may be directly in contact of muscle.243
Systemic Toxicity
At blood concentrations just above those measured after normal
absorption from injection site, LAs exert toxic effects. The concentration leading to toxicity is usually directly related to LA
potency. Most agents exert neurologic toxicity at lower concentrations, followed by cardiac toxicity at higher concentrations. This is
not true for racemic bupivacaine. Cardiac toxic reactions usually
appear at the same time as the neurologic manifestations with
ropivacaine and levobupivacaine. In adults, the concentration ratio
for toxicity between bupivacaine and lidocaine is 4:1. The systemic
concentrations attained are never high enough to block other
ganglia or affect neuromuscular transmission.
CNS Toxicity
At low to moderate plasma concentrations (15 g/mL), lidocaine
possesses anticonvulsant properties.203,204 The first signs of CNS
toxicity are subjective (dizziness, tinnitus, sensation of drowsiness). Objective signs (shivering, muscular twitching, tremors
initially involving the face) immediately precede the occurrence
of seizures. Subjective signs are not observed in patients under
general anesthesia or in very young patients. Seizures may represent the first sign of toxicity. In patients under general anesthesia,
hypercarbia is a factor facilitating the emergence of seizures
because of a direct effect on CNS and also because it increases the
fu of drug. At the highest concentration, a global CNS depression occurs with respiratory depression followed by apnea and
collapse. Seizures may occur (1) rapidly after either a massive
inadvertent intravenous injection or a rapid absorption at the site
of administration or (2) several hours (even days) after initiation
of perineural infusion for postoperative analgesia owing to
accumulation.105,244,245 In adults, convulsions occurring intraoperatively are usually free of major consequences when treated
immediately,246 but this might not be the same when seizures and
respiratory depression occur on the ward during prolonged
infusion. The treatment of convulsions, respiratory depression,
and/or coma is basically the same in children as it is in adults:
(1) oxygenation and airway management and (2) treatment of
seizures, if still persistent after oxygenation, by using small doses
of benzodiazepines or thiopental. A rapid infusion of a lipid
emulsion (1 mL/kg Intralipid 20% as a bolus followed by a rapid
infusion) seems to have revolutionized the treatment of systemic
toxicity.247249
463
may occur before any sign of CNS toxicity, especially in young

infants.104,250 Levobupivacaine seems to be much less toxic for
the heart than dextrobupivacaine or the racemic mixture9,10,251
(Figure 2822). Ropivacaine is synthesized as a single levorotatory
isomer such as levobupivacaine with only one carbon less on its
hydrophylic residue. It is also less toxic than racemic bupivacaine.252,253 However, it seems that CNS and cardiovascular system
toxic manifestations occur at the same time with these two pure
enantiomers. This is important because cardiac arrest may be
concealed by seizures that delay the diagnosis. At toxic concentrations, bupivacaine slows intra-atrial and intraventricular conduction with increased PR duration and major QRS widening9,10,254
(Figure 2823). Arrhythmias such as ventricular tachycardia (even
torsades de pointes255) or profound bradycardia may occur. These
arrhythmias are often followed by either ventricular fibrillation or
asystole.256 A major collapse occurs coupled with a concomitant
limited decrease in the myocardial contractile force.
Subjective and objective signs of CNS toxicity usually precede
cardiac manifestations in adults during continuous infusion for
pain relief, but this is not always the case in infants.104 General
anesthesia, commonly administered with regional anesthesia in
pediatric patients, may conceal CNS manifestations.257 The
increased threshold for CNS toxicity in infants compared with
adults206,207 and the equal sensitivity to bupivacaine cardiotoxicity220 may explain why cardiac signs may not be preceded by any
sign of CNS toxicity. Also, because of their higher heart rate,
newborns and infants are thought to be more prone than adults to
the frequency-dependent blockade of sodium channel produced
by tertiary amine agents such as bupivacaine (Figure 2824).
Cardiac complications require urgent and appropriate therapeutic
measures including oxygenation, ventilation, and cardiac massage.
Cardiac output is dependent on heart rate in infants, and
increasing that rate might be essential especially in the presence of
high-degree intraventricular block (and also during episodes
of torsades de pointes). Conversely, it must be remembered
that increasing heart rate also increases the phasic (frequencydependent) block.257 Prolonged cardiac massage has proved to be
effective in adults.258 In fact, bupivacaine washout from the heart
seems to be rapid when coronary perfusion is maintained in the
isolated rabbit preparation.170 Phenytoin, which mainly acts by
blocking sodium channels,259 is supposed to bind competitively to
the same receptor as bupivacaine.104 Its use has been recommended,104 but as with lidocaine, deleterious effects seem to be
additive.260 Despite its arrhythmogenic potential, epinephrine
appears to be the only useful drug, but it requires careful titration
using boluses of 0.01 g/kg261 in order to avoid ventricular
tachycardia or fibrillation.
The use of a lipid emulsion (lipid rescue) has totally transformed the treatment of both neurologic and cardiac toxicity of LAs.
Since the first publication of the use of Intralipid in rats,262 lipid
emulsions have been successfully used in humans.247249,263 They act
by binding LA molecules, and therefore, they rapidly decrease the
plasma concentration of anesthetics.262,264 A rapid bolus injection of
1 to 2 mL/kg of Intralipid 20% followed by the rapid infusion of
6 to 8 mL/kg is recommended by some authors.247,249 There is no
reason to continue the administration once signs resolve.
Cardiovascular System Toxicity

Toxic cardiac manifestations occur at concentrations usually much
higher that those at which CNS toxicity occurs. This is not true
for racemic bupivacaine with which cardiac toxic manifestations
Allergy
Allergy to LAs is rare and amide agents may exhibit antiallergenic
properties.265 Most often allergic reactions reported by patients
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Figure 28-22. Left panel: Effect of bupivacaine on the QRS duration in an isolated rabbit heart preparation (Langendorff preparation). Hearts were retrogradely infused at a constant flow with two successive infusions of bupivacaine (8 g/mL from 05 min,
then 2 g/mL from 520 min). Bupivacaine is stopped thereafter. The perfusate did not contain any protein, so the entire drug was
unbound. From bottom to top: The effects of racemic bupivacaine (a), R(+) bupivacaine (b), and S() bupivacaine. Inset: Individual
values are represented together with the mean standard deviation (sd) value of the group. The time scale is the same as the scale
of the large graphs. Note the different scales used for representing QRS duration. Because ropivacaine is very similar to levo (S-)
bupivacaine, it may be assumed from these results that the effect of ropivacaine on QRS duration will be almost the same as those
induced by levobupivacaine. Right panel: The effects of lidocaine and of bupivacaine on QRS widening in the same rabbit heart
preparation as a function of perfusate concentration. Bupivacaine (open symbols) induced a 15 times longer increase in QRS duration than lidocaine (solid triangles). However, C50, the free concentration leading to half Emax (the maximum theoretical effect),
was the same for both drugs (1316 g/mL). Left panel: Adapted from reference 9. Right panel: Adapted from Mazoit JX, Ph.D.
thesis, Universit de Paris Ren Descartes.
during dental surgery may be attributed to epinephrine.266 In fact,
allergy is a concern almost exclusively with esters because these
agents have para-aminobenzoic acid as a metabolite.174,267 Solutions with epinephrine contain metabisulfite, which may induce
adverse reactions.268 Some rare cases of proven allergy to amide
agents have been published.269271
Methemoglobinemia
In neonates and infants, methemoglobinemia may develop several
hours after the administration of prilocaine, benzocaine, and
occasionally, lidocaine.272 In patients prone to methemoglobinemia, O-toluidine, which is a normal metabolite of prilocaine,
accumulates. This powerful oxidizing agent may accumulate in
erythrocytes especially in neonates and infants in whom the
erythrocyte content of methemoglobin reductase is lower than in
adults. Patients become cyanotic when methemoglobin exceeds 20
to 30% of the total hemoglobin content, when dyspnea, tachycardia,
headache, vertigo, and hypoxia occur. Death, though rare, can

occur when the concentration exceeds 70%. Treatment of
methemoglobinemia consists of intravenous methylene blue (17
mg/kg) in order to convert methemoglobin to hemoglobin.
Prilocaine is contraindicated in infants younger than 6 to 9 months
and care should be taken in young children for whom dose should
be limited to 3 to 4 mg/kg. EMLA cream contains prilocaine.
However, in the absence of predisposing factors such as
hemoglobinopathies, glucose-6-phosphate dehydrogenase deficiency, and exposure to aniline dyes and oxidants (sulfonamides,
nitrites, nitrates, antimalarials, trimethoprim-sulfamethoxazole, or
inhaled nitric oxide), the use of EMLA cream in normal amounts
(2.5 g, i.e., half a small tube) is usually safe, even in neonates.273275
Breast Feeding
LAs are excreted in milk. In the study published by Ortega and
associates,276 the average milk-to-serum ratios were 1, 0.35, and
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465
0.6 for lidocaine, bupivacaine, and PPX, respectively. However,

none of these molecule undergoes significant absorption after oral
administration.
IN SUMMARY: THE BASIS FOR

PRESCRIPTION GUIDELINES
Table 2811 displays the concentrations usually encountered in
serum with bupivacaine, ropivacaine, and levobupivacaine, and
Table 2812 displays the recommended dosage for LA drugs
commonly used in pediatrics.
Figure 28-23. Ventricular epicardial mapping. Schematic drawing of the preparation used to map the velocities of the AP at the
surface of an isolated heart preparation with a 256-pin electrode.
T and L = the transversal and longitudinal velocities. LAs increase the effective refractory period (like all antiarrhythmic
drugs). However, the ventricular conduction velocity is also decreased (particularly by long-acting drugs such as bupivacaine).
The net result is a decrease in the wavelength, leading to an increased chance of re-entry phenomena. This is why lignocaine is
no longer used as a type Ib antiarrhythmic drug. Because of the
phasic block, there is a further decrease in velocity when the
heart rate increases. Adapted from reference 254.
Metabolism of Amide LAs is

Incomplete at Birth
Microsomal capacity increase rapidly after birth, and the rapid
maturation of the CYP450 system allows adequate metabolism
after 2 or 3 weeks of life. It is wise to use LAs carefully in neonates.
With that in mind, it is of particular importance to remember that
a neonate born after 42 weeks of gestation from a nonsmoking
mother without any history of alcohol intake or drug abuse, antibiotics, or other medication intake may be at greater risk of low
metabolism than a premature baby receiving antibiotics and other
drugs for more than 3 to 5 days. The maturation of the CYP450
enzymes are dependent not only on age but also on induction by
xenobiotics. The low AAG serum concentration observed in
Figure 28-24. Increases in QRS duration (ventricular conduction velocity) in neonatal or adult isolated rabbit hearts are
shown as a function of heart rate (from 180 to 360 beats/min) and dose of bupivacaine. The intensity of the block is similar
in the two groups. However, because neonates and infants have a higher heart rate than adults, they are at greater risk of
arrhythmias. Modified from reference 20.
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TABLE 28-12. Local Anesthetic Dosage Recommendationsa
TABLE 28-11. Absorption of Bupivacaine Versus

Ropivacaine After Single-Shot Administration
(Central Block, Venous Concentrations)
Dose
Ropivacaine 2 mg/mL or levobupivacaine 2.5 mg/mL

Tmax
Single Shot or First

Injection, mg/kg/h
Maintenance
Dose, mg/kg
0.53
21
2 mg/kg 60 mg
1.21.7
0.61.9
0.961.64
28
29
Central Blocks
Caudal
Lumbar or thoracic
Epidural
1.35
0.551.10
20
20
0.434.0
0.351.34
18
16
1.09
25
0.421.58
0.411.28
0.491.05
10143
767
65
0.550.72
0.540.75
60
60
0.681.84
0.904.77
0.644.77
45
52
45
Cmax
Bupivacaine
Adults epidural
100 mg 0.5%a
Children (caudal)
16 mo
2.5 mg/kg 0.5%
5.5 y
2.5 mg/kg 0.25%
Children (lumbar or thoracic epidural)
336 mo
3.75 mg/kg 0.5%
110 y
1.875 mg/kg 0.25%
Children (ilioinguinal block)
1015 kg
0.25 mL/kg 0.5%
1530 kg
Levobupivacaine
Adults epidural
127.5 mg 0.75%
Children (caudal)
<1 y
2 mg/kg 0.2%
a
0.2 (<1 mo)

0.20.3 (16 mo)
0.30.4 (>6 mo)
Peripheral Blocks
Ropivacaine
Adults epidural
150 mg 0.75%
Children (caudal)
03 mo
2 mg/kg 0.2%
312 mo
17 y
2 mg/kg 0.2%
Children (lumbar epidural)
311 mo
1.7 mg/kg 0.2%
1248 mo
Children (ilioinguinal block)

12 y
3 mg/kg 0.5%
34 y
512 y
(0.6251.25 mg/
mL solution)
1.20
15
0.80
30
With adrenaline.
neonates and infants until the age of 6 months is a second factor

that leads to potential increased toxicity of LA. The volume of
distribution seems to be increased in infants and, although this
may offer partial protection from an excessive concentration after
a single injection, saturation of body compartments occurs rapidly
and re-injections (top-up doses) are expected to cause excessive peak concentrations. It appears reasonable to perform reinjections with greater care in infants younger than 6 months.
After the age of 4 to 6 months, hepatic clearance and protein
binding are similar to those of adult patients; accumulation in
blood is not as likely as in younger infants. Therefore, re-injections
can be performed as they are in adults. However, it is evident that,
in light of these factors, some newborns or young infants may
benefit from techniques usually performed in older subjects
because the balance between risk and benefit may favor regional
techniques.
Use of epinephrine as an adjuvant, especially for epidural
anesthesia, decreases peak LA concentrations and increases the
duration of postoperative analgesia, at least until the age of 4
1 mg/kg
See Epidural
Spinal Anesthesia
1 mg/kg < 3 kg; 0.51 mg/kg 38 kg; 0.4 mg/kg > 8 kg; 0.2 mg/
kg > 25 kg
(These doses are for racemic bupivacaine 5 mg/mL. For
ropivacaine or for levobupivacaine, dosing must be slightly
increased in children greater than 68 kg.)
a
Racemic bupivacaine may be used for spinal anesthesia or penile block. For all
other blocks, only ropivacaine or levobupivacaine is recommended.
to 6 years. The usual dose of 5 g/mL (1/200,000) is considered

by some authors to be excessive and may induce spinal cord
ischemia in young infants.82 However, the new S() enantiomers
(ropivacaine and levobupivacaine) are marketed as plain solutions without epinephrine because of a moderate vasoconstrictive
effect.
Spinal Anesthesia
Spinal anesthesia is almost exclusively indicated for lower abdominal surgery in expremature infants. Three solutions are commonly used: hyperbaric tetracaine (0.5%), hyperbaric bupivacaine,
and isobaric bupivacaine. Doses are given in Table 2812.
Agents and Dosage

Anesthesia of short duration may be performed with 1% lidocaine
(maximum 810 mg/kg with epinephrine in single dose).
Mepivacaine can be used instead of lidocaine but it is important to
note that this agent is poorly metabolized until the age of 3 to 4
weeks and that its serum protein binding profile does not seem to
favor young infants. Better drugs are ropivacaine and levobupivacaine. These two agents have the advantage of providing prolonged postoperative analgesia when used as a single-shot injection
using a concentration of 2 mg/mL with associated general anesthesia during the intraoperative period. In addition, these agents
induce little motor blockade compared with racemic bupivacaine
when used for caudal or lumbar epidural analgesia.277280 The
maximum recommended dose for single-shot caudal injection is
2 mg/kg, irrespective of age.277279 The usual dose is 0.4 to 0.75
mL/kg of a 2-mg/mL solution 280,281 for lumbar epidural injection.
For peripheral nerve blocks, a dose of 0.5 mL/kg of a 2-mg/mL
solution is also adequate.282,283 A distinction needs to be made
between neonates and infants younger than 3 months, on one
hand, and infants older than 3 months and children, on the other
hand, for maintenance dosing (most publications deal with epi-
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dural administration).184,195 In neonates younger than 2 weeks, it is
wise to maintain analgesia with no more than 0.15 mg/kg/h of a
dilute solution (usually 0.1%). Between the ages of 2 weeks and
3 months, 0.25 to -0.3 mg/kg/h of a 0.1% solution is usually
adequate. In older infants and in children, a larger dose is often
needed for epidural analgesia (0.4 mg/kg/h). The addition of
opioids appears necessary for epidural administration after major
surgery.
Adjuvants
Clonidine (12 g/kg bolus for caudal or epidural blocks) is also
used in infants older than 4 to 6 months to increase the duration
of the block and the duration and quality of postoperative
analgesia. However, some authors inject clonidine intravenously to
achieve a similar quality of postoperative analgesia.88 The maintenance dose for an epidural infusion is 0.08 to 0.12 g/kg/h.284
Clonidine is also effective for peripheral blocks.285
Preservative-free ketamine (0.25 mg/kg of S(+) ketamine or
0.5 mg/kg racemic ketamine) prolongs the analgesia provided by
caudal LAs286,287). However, ketamine must be used with care
because this drug exerts neural toxicity.97
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hand surgery. Paediatr Anaesth. 2003;13:409412.
284. De Negri P, Ivani G, Visconti C, et al. The dose-response relationship
for clonidine added to a postoperative continuous epidural infusion of
ropivacaine in children. Anesth Analg. 2001;93:7176.
285. Cucchiaro G, Ganesh A. The effects of clonidine on postoperative analgesia after peripheral nerve blockade in children. Anesth Analg. 2007;
104:532537.
286. Panjabi N, Prakash S, Gupta P, et al. Efficacy of three doses of ketamine
with bupivacaine for caudal analgesia in pediatric inguinal herniotomy.
287. Martindale SJ, Dix P, Stoddart PA. Double-blind randomized controlled
trial of caudal versus intravenous S(+)-ketamine for supplementation of
caudal analgesia in children. Br J Anaesth. 2004;92:344347.
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Dilip Pawar
INTRODUCTION
Adjuvant is derived from Latin (ad = to, juvare = help, -ant
denotes action) and defined in Stedmans Medical Dictionary as,
that which aids or assists; denoting a remedy that is added to a
prescription to assist or increase the action of the main ingredient.
A wide range of drugs are used today as adjuvants to local anesthetics (LAs). These act at a variety of secondary sites of action,
different from that of the LA, and yet enhance the duration of
action of the LA. Some of these drugs also improve the quality of
analgesia produced by the LAs.
LAs are used primarily to block conduction in peripheral
nerve axons and their terminals. This is achieved by blocking
the voltage-gated Na+ channels; ion channels that cause rapid
depolarization during the first phase of the action potential in
excitable cells. LAs also block voltage-gated Ca2+ channels and
various types of K+ channels that may moderate Na+ channel
block.1
Single-shot caudal epidural is one of the most commonly
performed regional blocks in infants and children. Sanders, in a
survey in the United Kingdom, reported that 96% of pediatric
anesthesiologists use caudal anesthesia in their clinical practice.2
The main limitation of caudal block is the relatively short duration
of postoperative analgesia even with the use of relatively longacting LA agents such as bupivacaine or ropivacaine. Caudal
catheter has been used to administer repeated doses, but this
technique has not gained popularity because of the concern for
infection.
RATIONALE OF USE OF ADJUVANTS

In an attempt to prolong the duration of a single-shot caudal
analgesia, adjuvants to LA solution have been employed. The first
adjuvant used with LA was epinephrine (adrenaline). It was
initially used to decrease the toxic effect of LA by slowing the
absorption through vasoconstriction. This led to an increased
concentration of LA available at the nerve for a longer duration,
increasing the duration of the block. Sanders reported use of
adjuvants by 58% of pediatric anesthesiologists while performing
caudal block in the United Kingdom. The most frequently used
were ketamine (32%), clonidine (26%), diamorphine (13%), and
fentanyl (21%).2
Opioids, especially morphine, have been commonly used in the
caudal space either alone or as an adjuvant to consistently increase
the duration of analgesia. The potential of opioid adjuvants to
produce adverse effects like nausea, vomiting, pruritus, urinary
29
C H A P T E R
retention, and respiratory depression has stimulated interest in

alternative agents with reduced adverse effect profiles.
Subsequently, drugs such as ketamine and clonidine were
shown to increase the duration of action of LA caudal block.3,4
Adjuvants like ketamine, clonidine, and morphine on their own
can produce analgesia neuraxially. The mechanism by which
adjuvants prolong the duration of analgesia is primarily based
on our understanding of the pharmacologic profile of these drugs
and their site of action. Transmission of nociceptive stimuli is
primarily through well-described pain pathways. Other pathways
involving opiate, N-methyl-D-aspartate (NMDA), and 2 adrenergic receptors influence pain transmission. It is probably because
both LAs and adjuvants act at multiple and different sites that
analgesia is improved, evident by lower pain scores when adjuvants are added to LAs. The molecular mechanism contributing
prolongation of analgesia is not yet elucidated. However, this lack
of understanding of the mechanism should not be a hindrance to
clinical practice.
COMMONLY USED ADJUVANTS

Epinephrine
Epinephrine is an endogenous catecholamine that produces
a dose-related action. At low doses, it stimulates 2 receptors
producing arterial vasodilatation. Higher doses cause arterial vasoconstriction by stimulating 1 and 2 receptors. Vasoconstriction
reduces blood flow and slows systemic uptake of LAs, maintaining
concentration at the site of action for a longer period of time. It
also reduces the peak plasma concentration, thereby decreasing
the potential for toxicity. This not only prolongs the period of
blockade by 50% but also decreases the systemic absorption of LAs
by one third.5
It has long been thought that the prolongation of LA action
by epinephrine is caused by vasoconstriction only. It is now
understood that epinephrine can exert intrinsic analgesic effect
(produce segmental hypoalgesia) after epidural administration.
It gets absorbed into cerebrospinal fluid (CSF) and most likely
stimulates the 2 adrenoreceptors at the primary afferent terminals
in the spinal cord.6
Commonly available premixed solutions contain 1:200,000 or
5 g/mL of epinephrine. It seems to be effective in prolonging the
duration of action of short-acting LA agents such as lidocaine and
2-chloroprocaine compared with that of bupivacaine. It has been
used with the longer-duration LAs bupivacaine and ropivacaine,
primarily to test for intravenous administration of LA during
epidural administration.7
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Pharmacology
There is a concern of decreased blood supply to the spinal cord

when adrenaline-containing solutions are used. In animal studies,
bolus doses of subarachnoid epinephrine of up to 200 g directly
into the CSF did not decrease spinal cord blood flow in cats or
dogs.8 There was no evidence of spinal cord ischemia in humans
even after administration of very large bolus doses of adrenaline
(1000 g) directly into the CSF.9
Ketamine
Ketamine is a partially water-soluble (10 times more soluble than
thiopentone) phencyclidine derivative with a pKa of 7.5. It is
currently available both as a racemic mixture of two enantomers
(R() and S(+) in aqueous solution (with sodium chloride
and benzethonium chloride) and as a single enantomer (S(+)
ketamine). S(+) Ketamine has an approximately fourfold greater
affinity for the NMDA receptors than the R() enantomer.
Ketamine is a NMDA receptor blocker. NMDA receptors
have a role in excitatory synaptic transmission, plasticity, and
neurogeneration in the central nervous system. NMDA receptors
have been identified in myelinated and unmyelinated axons in
peripheral somatic tissues. Local administration of glutamate
results in nociceptive responses that are attenuated by peripheral
administration of NMDA antagonists. Ketamine probably enhances the LA effect of bupivacaine through this mechanism. In
addition, ketamine has LA properties. It produces anesthetic block
after spinal administration.10
Ketamine is an anesthetic agent with strong analgesic potency.
It has been used in infants and children in a wide range of applications.11 Ketamine as an adjunct for caudal analgesia was reported
by Naguib and associates in 1991, 3 years before the first published
report on clonidine.12 Sanders reported ketamine is the most
frequently used adjuvant by pediatric anesthesiologists in the
United Kingdom. Ketamine adjuvant use has been reported with
a variety of LAs such as lidocaine, bupivacaine, ropivacaine, and
levobupivacaine (Table 291).
The most commonly used LA was bupivacaine at a concentration of 0.25%. Ketamine has been used at doses of 0.25 mg/kg
to 1 mg/kg. Semple and coworkers18 and Panjabi and colleagues19
conducted dose-response studies with ketamine 0.25 mg/kg,
0.5 mg/kg, and 1 mg/kg combined with bupivacaine 0.25%. The
optimal dose to produce longer-duration analgesia without
significant side effects was 0.5 mg/kg. No major hemodynamic
disturbance, psychological, neurologic, or respiratory consequences have been reported with ketamine 0.5 mg/kg following
single-shot caudal administration in children (Table 292). Both
groups reported a higher incidence of behavioral adverse effects
in the ketamine 1 mg/kg group.18,19 The analgesic efficacy of S(+)
ketamine after caudal or intravenous administration has been
assessed.22 Patients administered caudal bupivacaine 0.25% were
given additional S(+) ketamine 0.5 mg/kg either caudally or
intravenously. The median time to first analgesic was longer in the
caudal ketamine group (10 h) than in the intravenous ketamine
group (4.6 h), indicating that the principal analgesic effect of S(+)
ketamine results from local neuraxial rather than any systemic
effect.22
The preservative-free S(+) ketamine is reportedly twice as
potent as the racemic mixture because of its greater affinity to
NMDA receptors. As adjuvant to ropivacaine, it prolongs the
duration of action by 10.3 hours23 and 11.7 hours,21 durations
similar to that with racemic ketamine. S(+) Ketamine has also
been reported to prolong a duration of analgesia when used

without LA at a dose of 1 mg/kg from 13 hours24 to 16.6 hours.25
Differences in the heterogeneity of the study design make it
difficult to compare the two medicants but an attempt has been
made to represent analgesic duration in Figure 291.
Ketamine has been used in combination with tramadol14 and
clonidine4,25 without LA. Gunduz and associates reported an
increase of only 14 minutes with the addition of tramadol 2 mg/kg
to S(+) ketamine 1 mg/kg.14 Hager and coworkers reported an
increase in duration of analgesia of 9.4 and 8.5 hours with clonidine 1 g/kg and 2 g/kg, respectively, compared with ketamine
1 mg/kg. Passariello and colleagues reported no increase in the
duration of analgesia with ketamine 0.5 mg/kg with clonidine
1 g/kg compared with ketamine 1 mg/kg alone. These conflicting
reports involve differing drug concentrations. Ketamine has yet to
be fully studied as an adjuvant to LAs. If this combination is
established to be effective, it would be an ideal alternative to opioids.
Adverse Effects
The preservative benzethonium chloride is neurotoxic; a
preservative-free ketamine should be administered neuraxially.
There has been a debate about possible preservative-free ketamine neurotoxicity, although animal studies show no detrimental
neurotoxicity after intrathecal ketamine.27,28 The origin of this
neurotoxicity debate goes back as far as 1999 when Ikonomidov
and associates reported that the NMDA receptor antagonist
MK801 and ketamine produced evidence of neurotoxicity.29
Vranken and coworkers reported spinal neurotoxicity after
continuous intrathecal administration of S(+) ketamine infusion
for 3 weeks in a patient with terminal cancerrelated neuropathic
pain.30 The cause of neurotoxicity produced by ketamine is
unknown. The preservatives benzethonium chloride and chlorbutanol have been implicated. Stortz and colleagues reported
spinal neurotoxicity after long-term intrathecal infusion of ketamine in a patient with cancer.31 That ketamine had benzethonium
chloride as a preservative and was administered along with bupivacaine, morphine, and clonidine. The risk of spinal toxicity is
probably higher after prolonged subarachnoid administration for
cancer pain.
In recent years, there are reports of neuroapoptosis after
exposure to general anesthetic agents that include ketamine,
nitrous oxide, isoflurane, halothane, and propofol in the developing brain of animals.3234 Anesthesia induces neuroapoptosis
throughout the forebrain structure in the neonatal rat brain. The
neurons of the ventral horn of the spinal cord are more susceptible
to anesthetic injury.34 Even a subminimal concentration of
isoflurane exposure for 1 hour can induce apoptosis in mice.35
These are serious concerns and the U.S. Food and Drug
Administration (FDA) constituted a panel to review available data
and make recommendations. The FDA panel determined that
based on current knowledge and lack of appropriate alternative,
there is no scientific basis to recommend changes in clinical
practice.36 As yet, no permanent neurologic injury has been
reported from use of single-shot caudal ketamine. There should be
no hesitation to continue using ketamine in the epidural space.
Clonidine
Clonidine is an 2 adrenergic agonist with 200-fold selectivity for
2 over 1 adrenoreceptors (Table 293). It is moderately lipid-
Surgery
Hernia
Orchidopexy
Hernia, genital
Orchidopexy
Hernia
Circumcision
Hernia
Orchidopexy
Hernia
Author
Naguib12
Cook13
Gunduz14
Johnston15
Akbas16
Gne17
Semple18
Panjabi19
60
6 mo10 y
AIIMS
Mod OPS
CHEOPS
Mod OPS
OPS
Delirium with
ketamine
1 mg/kg
Delirium with
ketamine
1 mg/kg
A) 8.84 sd 5.63 h
B) 22.14 sd 3.92 h
C) 21.8 sd 1.16 h
8.8 h
22.1 h
21.8 h
7.9 h
11 h
16.5 h
19.8 h
A) 1006 sd 506 min

B) 1188 sd 403 min
C) 1377 sd 204 min
A) 7.9 h
B) 11.0 h
C) 16.5 h
10 h
A) 4 sd 3.2 h
B) 10 sd 4.3 h
C) 14 sd 3.1 h
20.1 h
9.3 h
89.5 h
Median values
(Continued)
Increased Duration
of Analgesia
A) 9.5 h
B) 8 h
A) 1206 sd 377.5 min

B) 1220.5 sd 392.6
min
A) Not reported
B) Less analgesic
requirement in 24 h
in bupivacaineketamine group
A) 3.2 h
B) 5.8 h
C) 12.5 h
Remarks
9 y
110 y
212 y
15 y
CHEOPS
OPS
Three-point
pain scale
Results: Duration
Assessment Tool of Analgesia
CHAPTER 29
60
99
80
40
110 y
A) Bupivacaine
0.25%
B) Bupivacaine 0.25% +
ketamine 0.5 mg/kg
C) Ketamine 0.5 mg/kg
A) Bupivacaine 0.25% with
adrenaline 1:200,000
clonidine 2 g/kg
C) Bupivacaine 0.25% +
ketamine 0.5 mg/kg
A) Ketamine 0.25 mg/kg +
lidocaine 2%
B) Ketamine 0.25 mg/kg +
Tramadol 2 mg/kg
A) Bupivacaine 0.25% +
ketamine 0.5 mg/kg
ketamine 0.5 mg/kg
A) Ropivacaine 2%
B) Ropivacaine 2% +
ketamine 0.5 mg/kg
C) Ropivacaine 2% +
clonidine 1 g/kg
A) Ropivacaine 4%
B) Ropivacaine 2% +
ketamine 0.25 mg/kg
C) Ropivacaine 2% +
tramadol 1 mg/kg
ketamine 0.25 mg/kg
ketamine 0.5 mg/kg
ketamine 1 mg/kg
ketamine 0.25 mg/kg
ketamine 0.5 mg/kg
ketamine 1.0 mg/kg
Study Groups
4:17 PM
62
110 y
33.5 y
Age
4/13/11
60
50
TABLE 29-1. Details of Studies with Ketamine As an Adjuvant to Local Anesthetics
Bissonette-029-(F)
Page 475

475
Hernia
Orchidopexy
Passariello25
64
40
3 mo6 y
15 y
1 mo6 y
17 y
3 mo6 y
15 y
A) S(+) Ketamine 0.5 mg/kg

B) S(+) Ketamine 1 mg/kg
C) Bupivacaine 0.25% with
adrenaline 1:100,000
A) Ropivacaine 2%
B) Ropivacaine 2% +
clonidine 2 g/kg
C) Ropivacaine 2% + S(+)
ketamine 0.5 mg/kg
A) Bupivacaine 0.25%
B) Bupivacaine 0.25% & I.V.
S(+) Ketamine 0.5 mg/kg
C) Bupivacaine 0.25% + S(+)
ketamine caudal 0.5 mg/kg
A) Ropivacaine 2%
B) Ropivacaine 1% + S(+)
ketamine 0.5 mg/kg
A) S(+) Ketamine 1 mg/kg
B) S(+) Ketamine 1 mg/kg +
clonidine 1 g/kg
C) S(+) Ketamine 1 mg/kg +
clonidine 2 g/kg
A) S(+) Ketamine 1 mg/kg
B) S(+) ketamine 0.5 mg/kg +
clonidine 1 g/kg
A) Levobupivacaine 0.15% +
ketamine 0.5 mg/kg
B) Levobupivacaine 0.175% +
ketamine 0.5 mg/kg
C) Levobupivacaine 0.2%
CHEOPS
CHEOPS
OPS
Mod OPS
CHEOPS
OPS
Median value
2.42.8 h
16,6 h
A) 1004 sd 106 min

B) 1200 sd 499 min
A) 145.5 min
B) 167.5 min
C) 94.5 min
13.3 h
A) 13.3 sd 9.2 h
B) 22.7 sd 3.5 h
C) 21.8 sd 5.2 h
10 h
11.7 h
Increased Duration
of Analgesia
10.3 h
I.V. vs caudal
S(+) Ketamine
compared with
bupivacaine
not as adjuvant
Remarks
A) 285 sd 25 min
B) 620 sd 15 min
A) 4.75 h
B) 4.6 h
C) 10 h
A) 291 sd 30 min
B) 492 sd 23 min
C) 701 sd 33 min
A) 203 sd 117 min

B) 273 sd 123 min
C) 300 sd 96 min
Results: Duration
AIIMS = All India Institute of Medical Sciences pain discomfort scale; CHEOPS = Childrens Hospital of Eastern Ontario Pain Scale; Mod OPS = modified Objective Pain Scale; OPS = Objective Pain Scale;
sd = standard deviation.
Locatelli26
Hernia
Hager24
53
20
Hernia
De Negri23
63
3 mo6 y
Study Groups
4:17 PM
60
Hernia
De Negri21
49
Age
4/13/11
Martindale22 Hernia
Orchidopexy
Hernia
Marhofer20
Surgery
PART 2
Author
476
TABLE 29-1. Details of Studies with Ketamine As an Adjuvant to Local Anesthetics (Continued)
Bissonette-029-(F)
Page 476
Pharmacology
Bissonette-029-(F)
4/13/11
4:17 PM
Page 477
CHAPTER 29
TABLE 29-2. Practical Points About Ketamine As an
Adjunct to Local Anesthetics
1. Ketamine (both racemic and S(+) ketamine) prolong the
duration of analgesia for bupivacaine 0.25% and ropivacaine
0.2%.
2. The optimal caudal dose is 0.5 mg/kg.
3. The duration of analgesia is 812 h after caudal epidural.
4. Psychomimetic and behavioral symptoms are not seen after
single-shot caudal ketamine 0.5 mg/kg.
5. Neurotoxicity has been reported after prolonged
subarachnoid use in cancer patients.
soluble and has a large volume of distribution and a relatively
long elimination half-life of 12 to 24 hours.37,38 Potts and associates
describe a clonidine pharmacokinetic in children from 1 week
to 14 years. Clearance at birth was 3.8 L/h/70 kg and matured with
a half-time of 25.7 weeks to reach 82% of the adult rate by 1 year
of age. The population parameter estimates were clearance
14.6 L/h/70 kg, central volume of distribution 62.5 L/70 kg, peripheral volume distribution 119 L/h/70 kg, and intercompartment
clearance 157 L/h/70 kg.39
The use of clonidine in clinical practice is commonly limited by
hypotension and bradycardia mediated via central mechanisms.
It also induces sedation owing to depression of the locus cerebeus,
a brainstem nucleus that has been implicated in the sleepwake cycle.
Successful demonstration of epidural bupivacaine prolongation by clonidine in adults led to evaluation in pediatric caudal
blockade. Clonidine has been used as adjuvant to bupivacaine,
lidocaine, mepivacaine, and ropivacaine.The duration of analgesia
produced by clonidine in studies is detailed in Table 294 and
Figure 292.
There is an increased duration of analgesia with addition of
clonidine 1 to 2 g/kg to LA, although the prolongation is less than
that observed with ketamine (Table 295; see also Figure 292).
Figure 29-1. Duration of analgesia with

ketamine as adjuvant. The duration of
analgesia produced by the local anesthetic
when reported is represented as blue in
the staked bar.
477
TABLE 29-3. Mechanism of Clonidine Analgesia

1. Stimulation of 2 adrenergic receptors located on the dorsal
horn of the spinal cord.
2. Clonidine also stimulates intermediate spontaneously active
neurons located in the deeper layers of the dorsal horn of the
spinal cord.
3. Clonidine may induce nitric oxide release when administered
neuraxially, thereby causing its analgesic effect.
4. Nonspinal mechanisms:
a) Clonidine strengthens the depression of nerve fiber
action potentials produced by local anesthetics.
b) Clonidine exerts local analgesic effect intra-articularly.
From reference 40.
Akbas and associates reported an increased duration of 10 hours

with clonidine as an adjuvant to ropivacaine 2%.48 Jamali and
coworkers reported an increase of 8.9 hours with bupivacaine
0.25% with epinephrine 1:200,000.42 Motsch and colleagues used
a dose of 5 g/kg with bupivacaine 0.175% and reported an
increase of 6.5 hours.50 The duration of analgesia reported in other
publications is less than 6.5 hours and is generally increased only
up to 4.6 hours.
Klimscha and associates in 1998 had reported an analgesia
increase of only 14 minutes with clonidine 1 or 2 g/kg.44 A
number of reports have been published in which no additional
benefit could be demonstrated when clonidine was added to LA
for caudal block.7,5153 The exact cause of failure to demonstrate
the benefit of clonidine in these studies is speculative. De Mey
and associates51 and Sharpe and colleagues52 attributed this to
low volumes of bupivacaine. The studies of Joshi and coworkers53
and Wheeler and colleagues7 used higher volumes, so LA volume
alone is unable to explain these observations. It is unlikely that
epinephrine masked the effects of clonidine because epinephrine
was used only in Wheeler and colleagues study. Three of the
studies that failed to demonstrate any beneficial effect of clonidine
used bupivacaine 0.125% (whereas De Mey and associates used
Surgery
Lower limb
orthopedic
surgery
Subumbilical
Orchidopexy
Hernia
Circumcision
Orchidopexy
Hernia
Vesicoureteric
reflux
Lee41
Jamali42
Cook13
Luz43
Klimscha44
Constant45
64
36
36
6 mo9 y
6 mo6 y
B) Bupivacaine 0.25% with
epinephrine 1:200,000
clonidine 1 g/kg
D) Bupivacaine 0.25% +
clonidine 2 g/kg
E) Saline
epinephrine 1:200,000 +
lidocaine 1%
lidocaine 1% + fentanyl
1 g/kg
C) Bupivacaine 0.25% with
lidocaine 1% + clonidine
1.5 g/kg
D) Bupivacaine 0.25% with
Clonidine 0.75 g/kg +
fentanyl 0.5 g/kg
CHEOP > 5 y,
VAS > 5 y
Observational
discomfort
scale
OPS
A) 174 min
B) 253 min
C) 265 min
D) 287 min
A) 346 min
B) 300 min
C) 360 min
D) 360 min
E) 77 min
1.6 h
0.22 h
6.324 h
A) 6.3 sd 3.3 h
B) 7.1 sd 3.4 h
Almost half the

children did
not require
any analgesia
in first 24 h
Median value,
discharged
after 6 h from
PACU and 8 h
from ward
2.6 h
8.9 h
A) 460 sd 439 min

B) 377 sd 341 min
C) 987 sd 341 min
A) 3.2 h
B) 5.8 h
C) 12.5 h
4.6 h
Increase Duration
of Analgesia
A) 5.2 sd 1.2 h
B) 9.8 sd 2.1 h
Remarks
4:17 PM
110 y
OPS
Mod OPS
Results: Duration
4/13/11
60
clonidine 2 g/kg
clonidine 1 g/kg
clonidine 2 g/kg
ketamine 0.5 mg/kg
clonidine 1 g/kg
morphine 30 g/kg
Study Groups
17 y
110 y
Age
PART 2
45
46
478
Author
TABLE 29-4. Details of Studies with Clonidine As an Adjuvant
Bissonette-029-(F)
Page 478
Pharmacology
Subumbilical
Hernia
Circumcision
Ureteric
reimplant
Minor surgical
procedure
Hypospadias
Circumcision
Hernia
Circumcision
Orchidopexy
Hernia
Circumcision
Orchidopexy
Ivani47
Akbas48
Vetter49
Motsch50
De Mey51
Sharpe52
Joshi53
28 y
OPS
FACES scale
Categorical
observer
pain score
by parents
CHEOP > 5 y
VAS > 5 y
0.5 h
10 h
1.6 h
0.8 h 1.7 h
0.4 h
0.2 h
A) 200 sd 366 min

B) 224 sd 320 min
A) 70.9 sd 23.5 min
B) 84.5 sd 45.0 min
High incidence 6.5 h

of bradycardia
and hypotension in clonidine group
0h
Median
1.2 h
A) 280.7 sd
171.6 min
B) 327.8 sd 188.3 min
C) 382.0 sd 200.6 min
Analgesia
Same
A) 14.4 sd 10.9 h
B) 20.9 sd 7.4 h
A) 33 sd 36 min
B) 105 sd 197 min
C) 178 sd 251 min
11/20 vs 18/20
managed without
analgesia for 24 h
A) 4 sd 3.23 h
B) 14 sd 3.1 h
C) 10 sd 4.32 h
A) 143 min
B) 218 min
CHEOPS = Childrens Hospital of Eastern Ontario Pain Scale; FACES = FACES pain scale; FLACC = Face, Legs, Activity, Cry, and Consolability pain scale; Mod OPS = modified Objective Pain Scale; OPS = Objective
Pain Scale; OUCHER = Six faces self reporting pain scale; PACU = postanesthesia care unit; sd = standard deviation; VAS = Visual Analogue Scale.
30
B) Bupivacaine 0.25% + clonidine
1 g/kg
C) Bupivacaine 0.25% + sufentanil
0.5 g/kg
D) Bupivacaine 0.25% + clonidine
0.5 g/kg + sufentanil 0.25 g/kg
1 g/kg
C) Bupivacaine 0.25% + clonidine
2 g/kg
A) Bupivacaine 0.125% with saline
2 g/kg
B) Bupivacaine 0.125% with epinephrine 1:200,000 + clonidine 2 g/kg
Smiley
analogue
scale
FLACC
OUCHER
OPS
OPS
6 mo6 y
19 y
8 mo13 y
A) Mepivacaine 1%
B) Mepivacaine 1% + clonidine
2 g/kg
A) Ropivacaine 2%
B) Ropivacaine 2% + clonidine
2 g/kg
A) Ropivacaine 2%
B) Ropivacaine 2% + clonidine 1 g/kg
C) Ropivacaine 2% + ketamine
0.5 mg/kg
A) Ropivacaine 2% + clonidine 2 g/kg
B) Ropivacaine 2% + hydromorphone 10 g/kg
C) Ropivacaine 2% + morphine
50 g/kg
5 g/kg
CHAPTER 29
36
74
60
40
6 mo6 y
110 y
4:17 PM
60
75
40
42
4/13/11
Wheeler7
Subumbilical
Ivani46
Bissonette-029-(F)
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479
Bissonette-029-(F)
480
PART 2
4/13/11
4:17 PM
Page 480
Pharmacology
Figure 29-2. Duration of analgesia with

clonidine as adjuvant. The duration of
analgesic action of local anesthetics is
represented as blue in the staked bars.
0.25%). Positive effects were reported with higher concentrations
of bupivacaine. Is it that synergistic action may require a minimum
degree of blockade with LA? Is it that better study design of the
latter studies brought out the difference?
Clonidine has also been used in combination with fentanyl45
and sufentanil51 as adjuvants without any significant increase in
duration of analgesia with these drugs. Its combination with
ketamine has conflicting results.24,25
Adverse Effects
Clonidine is associated with sedation, hypotension, and bradycardia. Sedation is dose-dependent. Bradycardia is caused by an
increased in vagal tone resulting from central stimulation of
parasympathetic outflow as well as reduced sympathetic drive.
Hypotension results from stimulation of 2 inhibitory nerves in
the medullary vasomotor center of the brainstem.54 The hemodynamic side effects are less pronounced in children than in
adults. Like sedation, they are dose-dependent. Motsch and colleagues reported lower systolic pressure and heart rate during the
first 3 postoperative hours in children who received clonidine
5 g/kg1 compared with controls, although systolic pressures
in both groups were similar intraoperatively. Only 1 child out of
20 required atropine to treat bradycardia; no other resuscitative
measures were needed for other children given this relatively high
dose of clonidine.51 The addition of lower doses to LAs for neuraxial analgesia is unlikely to increase the degree of hypotension.55
Postoperative apnea has been reported in a 2-week-old term
neonate after hernia repair and orchidopexy. The baby had caudal
clonidine 2.2 g/kg with ropivacaine 0.2% 1 mL/kg. The baby
suffered apnea accompanied by bradycardia, hypotension, and a
fall in oxygen saturation below 80% 20 minutes later. Further

episodes of apnea followed that required mask ventilation or
tactile stimulation and oxygen therapy.56 Oxycardiorespiragraphy
on the fifth postoperative day revealed an abnormal breathing
pattern that probably contributed to the postoperative apnea.
Fellmann and associates reported apnea in a former premature
infant who underwent hernia repair under caudal block (with
bupivacaine 0.125% with epinephrine 1:200,000 and clonidine
1.5 g/mL solution 1.2 mL/kg) at 38 weeks postmenstrual age
(2540 g). Fifteen minutes after the block, the baby developed
apnea, bradycardia, hypotension, and a fall in oxygen saturation
that was managed with oxygen therapy alone. This child subsequently had an uneventful hernia repair under caudal block
without clonidine at 35 weeks postmenstrual age.57 Postoperative
apnea has also been reported in a preterm neonate who received
caudal clonidine 1.25 g/kg for hernia repair.58
The safety of clonidine as an adjunct for LA in neonates
has been reported by Rochette and associates in a case series of
75 neonates, half of them former preterm infants. All were scheduled for elective hernia repair and all received spinal subarachnoid block with plain isobaric bupivacaine 0.5% alone or with
addition of clonidine 0.25 g/kg, 0.5 g/kg, 1 g/kg, or 2 g/kg.
The incidence of transient hypotension occurred more often
with clonidine 2 g/kg. The duration of spinal block increased
from 67 minutes (range 5882) in controls to 111 minutes (range
93125) in the group receiving clonidine 1 g/kg. No significant
deleterious hemodynamic or respiratory side effects were recorded
from infants given clonidine 1 g/kg. With clonidine 2 g/kg, the
duration of analgesia showed a ceiling effect but the incidence
of hypotension and caffeine use in the postanesthesia care unit
were increased.59
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TABLE 29-5. Practical Points About Clonidine As an
1. Clonidine 12 g/kg prolongs the duration of analgesia of
bupivacaine 0.25%.
2. Clonidine does not prolong the duration of analgesia of
bupivacaine 0.125%.
3. The duration of analgesia after a caudal supplementation to
an epidural block is 46 h.
4. Clonidine 1 g/kg as a single-shot caudal does not usually
cause hypotension, bradycardia, or undue sedation.
5. Clonidine may produce apnea in newborns.
Postoperative apnea in former premature infants up to
50 weeks postmenstrual age is well recognized. The contribution
from caudal clonidine to the incidence of apnea is speculative.
Absence of life-threatening apnea in the case series from Rochette
and associates is reassuring, but larger cohorts are required to
establish safely.
Morphine
Morphine has been used neuraxially in adults since 1979.60 It is
the most commonly used opioid, with an excellent safety record
for local neuraxial injury.
Opioids diffuse in the spinal cord and exert spinal analgesia
by modulating A and C fibers to decrease afferent nociceptive
input.61 Both mu and delta receptor agonists act presynaptically
by inhibiting Ca2+ influx. Postsynaptically, mu receptor agonists
increase K+ conductance and hyperpolarize ascending neurons.
Opioids have minimal effect on dorsal root axons and somatosensory evoked potentials.62
The administration of epidural opioids for postoperative
pain is well established in infants and children. Epidural opioids
provide analgesia without the sympathetic or motor block associated with LAs. Neuraxial, as opposed to systemic, administration
reduces the supraspinal adverse effects of sedation and respiratory
depression. However, dose-dependent adverse effects like pruritus,
nausea, and urinary retention occur.
Morphine has been used in infants and children as an adjunct
to lidocaine, bupivacaine, and ropivacaine or has been administered alone (Table 296).
The dose of morphine in initial studies was 100 g/kg, whereas
later studies used reduced doses of 30 to 50 g/kg. Krane and
coworkers reported a duration of analgesia of 10.0 hours (
standard deviation [sd] 3.3), 10.4 hours ( sd 4.2), and 13.3 hours
( sd 4.7) for caudal morphine at a dose of 33 g/kg, 67 g/kg,
and 100 g/kg, respectively.65 Castillo-Zamora and colleagues
attempted to minimize the dose of single-dose caudal or lumber
epidural morphine further. They used doses of 11.2 g/kg, 15 g/
kg, or 20 g/kg and reported similar duration of analgesia for up
to 12 hours.73 The incidence of other side effects like pruritus,
urinary retention, and respiratory depression was absent with
11.2 g/kg (Table 297), although nausea and vomiting were
reported in more than 45% of patients.73 They attributed this high
incidence of postoperative nausea and vomiting (PONV) to
prolonged fasting longer than 8 hours and the use of a facemask
for maintaining anesthesia with resulting swallowed air.
Morphine has been used in major surgical procedures such
as orthopedic, upper abdominal, thoracic, and cardiac surgery.
481
Ketamine and clonidine were mainly studied in minor daycare

surgical procedures. There are consistent reports of increased
duration of analgesia, although many reports do not mention
quantitative duration. The duration of analgesia is shown in
Figure 293.
Lnnqvist questioned the use of caudal morphine in view of
the risk of respiratory depression and a higher incidence of other
adverse effects.74 The incidence of adverse effects following caudal
opioids is dose-dependent and can be minimized by appropriate
dose and titration to analgesic need (Table 298). The use of lower
doses of caudal morphine has decreased the incidence of side
effects without compromising analgesia. Teyin and associates
reported effective postoperative pain relief with caudal morphine
30 g/kg.72 I have been using caudal morphine (3050 g/kg)
along with bupivacaine since the late 1980s without any incidence
of respiratory depression. Recently, we concluded a study
combining morphine 30 g/kg with ketamine 0.5 g/kg and
bupivacaine 0.125% for caudal block in children undergoing
thoracic and upper abdominal surgery. Fifty percent of children
did not require any analgesia at all in the entire postoperative
period and the rest were pain-free for 24 hours.
Valley and Bailey reported 11 cases (8%) of clinically important hypoventilation. Ten of these occurred in infants; 8 patients
were younger than 3 months old. Seven of them had received
intravenous opioids in addition to caudal morphine,68 which
has been identified as a risk factor for respiratory depression in
adults.69 Infants younger than 3 months of age have reduced
morphine clearance, resulting in higher plasma concentrations
that contribute to respiratory depression. Mayhew and coworkers reported a case series of 500 children, including 23 neonates, who received caudal morphine 30 to 40 g/kg without any
episode of clinically significant respiratory depression.70 Rosen
and Rosen reported 16 children undergoing open heart surgery
who received caudal morphine 75 g/kg as well as intravenous
opioid supplementation without any incidence of respiratory
depression.71
Intrathecal morphine has been used effectively in adults and
children. It has been used in spinal, cardiac, and neurosurgical
procedures and for long-term management of cancer pain in
children. Doses ranged from 10 to 30 g/kg and there was a high
incidence of adverse effects.7583 Ganesh and colleagues used
lower-dose morphine (45 g/kg) intrathecally in 187 children.
They reported adequate analgesia in the first 24 hours with 80%
of patients not requiring rescue opioids in the first 8 hours and
52% receiving only oral analgesics in the first 24 hours.84
Epidural morphine alone or as an adjuvant has been in use in
adults since the early 1980s as well as in children. The fear of
respiratory depression seems to be overemphasized and has
contributed to inadequate analgesia in the postoperative period.
Other Adjuvants
A number of other adjuvants are reported, although their popularity in clinical practice is limited. This is because of limited prolongation of postoperative analgesia or an increased incidence
of adverse effects compared with clonidine, ketamine, and morphine. Lnnqvist appealed to resist using alternative adjuncts74
because often drugs are trialed for the sake of publication only.
Testing the limits of the caudal block in children is cautioned
against.4
46
32
28
30
136
60
500
32
Krane64
Krane65
Marco Valls66
Wolf 67
Valley 68
Glec69
Mayhew70
Rosen71
Circumcision
Hypospadias
Genitourinary
Lower limb
orthopedics
Surgery
Study Group
A) Bupivacaine 0.5%
B) Morphine 50 g/kg
A) IV Morphine 50200
116 y
g/kg
C) Lidocaine 1% +
morphine g/kg or
morphine 100 g/kg
A) Lidocaine 1% +
1.27.9 y
Major surgery
morphine 33 g/kg
below diaphragm
B) Lidocaine 1% +
morphine 67 g/kg
C) Lidocaine 1% +
morphine 100 g/kg
A) Morphine 50 g/kg
212 y
Urologic surgery
B) Bupivacaine 0.5%
C) No drug
9 mo11 y
Orchidopexy
morphine 50 g/kg
A) Duramorph 70 g/kg
116 y (54% 60% Abdominal,
<1 y)
38% thoracic,
2% orthopedics
112 y
Hernia, urogenital A) Bupivacaine 0.125%
morphine 50 g/kg
midazolam 50 g/kg
Bupivacaine 0.175% or
39% Orthopedic,
3 mo16 y
bupivacaine 0.25% +
29% genitourimorphine 30 g/kg1 or
nary, 20%
abdominal,
bupivacaine 0.25% +
4% craniofacial
morphine 40 g/kg
Open heart surgery A) Morphine 75 g/kg in
212 y
saline
29 y
Age
6 (range 212) h
624 h
A) 8.2 sd 1.3 h
B) 14.5 sd 1.6 h
C) 21.2 sd 1.2 h
Physiologic and
clinical data
20 h
1013.3 h
7h
7.2 h
Increased Duration
of Analgesia
Decreased analgesia 6 h
requirement in
24 h
Retrospective study 6.24 h
6.85 h
8/15 needed analge- 24 h

sia (A), no analgesia needed (B)
80% good, 7% fair,
12% poor
One patient in
100-g group
had respiratory
depression
Remarks
4:17 PM
A) 20 sd 5 h
Five-point
observer scale
Pain Scale Used
4/13/11
A) 10.0 sd 3.3 h
B) 10.4 sd 4.2 h
C) 13.3 sd 4.7 h
A) 245515 min
B) 6102145 min
A) 45 min
B) 5 h
C) 12 h
Results: Duration
of Analgesia
22
PART 2
Jensen63
Author
482
TABLE 29-6. Details of Studies With Morphine As Adjuvant
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Pharmacology
115 y
45
60
CastilloZamora73
Vetter49
Hernia
Hydrocele
Hypospadias
Open reduction of
hip with pelvic
osteotomy
or femoral
osteotomy
Ureteric reimplant
Hernia
Circumcision
Orchidopexy
A) Ropivacaine 2% +
clonidine 2 g/kg
B) Ropivacaine 2% +
hydromorphone
10 g/kg
C) Ropivacaine 2% +
morphine 50 g/kg
A) Morphine 11.2 g/kg

B) Morphine 15 g/kg
C) Morphine 20 g/kg
clonidine 1 g/kg
morphine 30 g/kg
A) Morphine 30 g/kg
B) Bupivacaine 0.25%
0.5 h
FLACC
A) 33 sd 36 min
B) 105 sd 197 min
C) 178 sd 251 min
0h
6.324 h
>12 h
Almost half the

children did not
require any analgesia in first 24 h
>12 h
Comparable
A) 6.3 sd 3.3 h
B) 7 sd 3.4 h
CHAPTER 29
FLACC = Faces, Legs, Activity, Cry, and Consolability pain scale.
6 mo6 y
416 y
28
Teyin72
6 mo6 y
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36
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TABLE 29-7. Measures to Improve the Safety of

Caudal Morphine
1. It should not be administered to daystay children.
2. Use in only children undergoing major surgery.
3. All the children should be monitored in a high-dependency
area for at least 24 h.
4. Children should be monitored for sedation score, respiratory
rate, pain score, and pulse oximetry. Sedation precedes
respiratory depression, and it is possible to preempt
respiratory depression by monitoring sedation.
5. Strict protocols limiting the use of supplemental I.V.
opioids should be followed because the concomitant use
of I.V. opioids increases the risk of serious respiratory
depression.
TABLE 29-8. Practical Points About Morphine As an

1. Morphine prolongs the duration of analgesia of bupivacaine
0.25% for 1224 h.
2. An effective dose of caudal morphine as adjuvant is 3050
g/kg.
3. Adverse effects like respiratory depression, nausea, vomiting,
pruritus, and urinary retention are dose-dependent and can
be minimized by dose reduction.
4. Concomitant use of I.V. opioids may increase the risk of
respiratory depression.
5. Avoided in daystay patients and used for patients after major
surgical procedures who are monitored in a highdependency area for at least 24 h.
From reference 85.
Fentanyl
Fentanyl is the most favored adjuvant for continuous infusion
at a concentration of 1 to 2 g/mL in the LA solution. Larman
and associates, in a multicenter study, could not demonstrate
any beneficial effect of fentanyl as an adjuvant when used with
low concentrations of levobupivacaine (0.06250.125%).86 It is
believed that the analgesic effect of fentanyl infusion is mediated
through systemic uptake and supraspinal effect.87,88
When fentanyl is used as an adjunct for single-shot caudal,
results are inconclusive. Gharsallah and coworkers reported
equianalgesic potency of fentanyl 1 g/kg or fentanyl 0.5 g/kg
with bupivacaine 0.25%, although the incidence of PONV was
higher with fentanyl 1 g/kg.89 Constant and colleagues reported
an increase of only 79 minutes duration of analgesia when
fentanyl 1 g/kg was used as adjuvant to 1% lidocaine and 0.25%

bupivacaine mix.45 Subsequent studies by Joshi and associates,90
Campbell and coworkers,91 Gaitinin and colleagues,92 and Baris
and associates93 could not demonstrate any additional analgesic
advantage of adjuvant with bupivacaine over bupivacaine alone.
Despite these unfavorable results, fentanyl was used by 21% of
pediatric anesthetists in the United Kingdom in 2002 as adjuvant
to single-shot caudal. Fentanyl should not be used as an adjunct to
LA in single-shot caudal block.
Intrathecal fentanyl has been used commonly as an adjuvant
to bupivacaine in adult surgical and obstetric populations.
Intrathecal fentanyl 0.25 g/kg, 0.5 g/kg, or 1 g/kg with 0.5%
hyperbaric bupivacaine (0.5 mg/kg in infants < 5 kg, 0.4 mg/kg in
infants 510 kg) was given to 58 infants undergoing lower
Figure 29-3. Duration of analgesia with morphine as adjuvant.

The duration of local anesthetic
where mentioned is represented
in blue in the staked bar. Results
from Mayhew and coworkers are
shown as two bars representing
most patients up to 24 hours and
some patients up to 6 hours.70
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CHAPTER 29
abdominal and urologic procedures. Fentanyl 1 g/kg increased
the duration of subarachnoid block significantly to 74 sd
6 minutes from 51 sd 5 minutes in the control group. The quality
of analgesia was also observed to be better.94 One of the limitations
of subarachnoid block in children has been its short duration of
action. The results of this study might increase the use of subarachnoid block in infants.
Diamorphine
Sanders reported that 13% of pediatric anesthetists in the United
Kingdom regularly used diamorphine as an adjuvant to LA.2 However, few published studies are available. Kelleher and coworkers
reported the use of diamorphine 30 g/kg with bupivacaine 0.25%
(0.5 mL/kg) and demonstrated a median duration of analgesia of
11.0 hours (range 8.614.2) compared with 8.5 hours (5.810.8)
for bupivacaine 0.25% alone.95
Tramadol
Tramadol is a synthetic analogue of codeine. It is a racemic
mixture of two enantiomers. The (+) enantiomer has a moderate affinity for the opioid receptor and inhibits serotonin uptake,
whereas the () enantiomer is a potent norepinephrine inhibitor. The analgesic effectiveness of epidural tramadol is controversial.
Prakash and colleagues conducted a dose-response study of
caudal tramadol with bupivacaine 0.25% in children aged 2 to
8 years. They compared tramadol 1 mg/kg, 1.5 mg/kg, and 2 mg/
kg. The duration of analgesia was 8 sd 0.9 hours, 11 sd 1 hours,
and 12 sd 0.9 hours, respectively. They suggested that tramadol
2 mg/kg was the optimal dose.96
Ozkan and associates compared the effect of caudal tramadol
2 mg/kg with bupivacaine 0.25% and reported a superior analgesia
with tramadol.97 Senel and coworkers reported longer duration of
analgesia for the tramadol-bupivacaine group by 13.5 sd 2.2
hours than the bupivacaine or tramadol-only group.98 Gne and
colleagues observed an increased duration of 6.3 hours with
tramadol as an adjuvant to ropivacaine 0.2% in children aged 1 to
10 years scheduled for hernia repair.17 Contrarily, Gunduz and
associates99 and Prosser and coworkers100 could not demonstrate
any significant increase in the duration of analgesia with tramadol
as an adjuvant to bupivacaine 0.25%.
Murthy and colleagues published a pharmacokinetic study.101
They reported that caudal tramadol is absorbed systemically and
is equally effective as intravenous administration.101 Published data
do not support a regular usage of tramadol as an adjuvant to LAs.
Buprenorphine
Buprenorphine is a partial agonist with a very high affinity for the
mu opioid receptors in the spinal cord. Girotra and associates
compared caudal buprenorphine 4 g/kg with morphine 50 g/kg
in children aged 1 to 10 years.102 They reported a duration of
action for buprenorphine of 25.6 hours compared with 19.9 hours
with morphine.
Kamal and Khan reported buprenorphine 2.5 g/kg as an
adjuvant to bupivacaine 0.5% and claimed good analgesia for up
to 24 postoperative hours.103 This study, however, was terminated
prematurely because of a high incidence of PONV (80%).
485
Butorphenol
Singh and coworkers evaluated the efficacy of caudal butorphenol
with or without bupivacaine in children aged 1 to 10 years undergoing infraumbilical surgery. Butorphanol 25 g/kg with 0.25%
bupivacaine was compared with butorphanol 25 g/kg or bupivacaine 0.25% alone. The duration of analgesia increased considerably in the combined butorphanol-bupivacaine group to 14.5
sd 4.8 hours compared with 8.8 sd 4.8 hours for bupivacaine and
6.8 sd 2.9 hours for butorphanol, respectively.104
Midazolam
Midazolam is a water-soluble benzodiazepine. It exerts its analgesic effect through the gamma-aminobutyric acid benzodiazepine system in the spinal cord. In children undergoing inguinal or
urogenital surgery, Glec and colleagues reported that bupivacaine
0.25% combined with midazolam 50 g/kg produced a mean
duration of analgesia of 21.1 sd 1.2 hours compared with 14.5
sd 1.6 hours for bupivacaine 0.25% combined with morphine
50 g/kg and 8.1 sd 1.3 hours for plain bupivacaine.69
Naguib and associates could not demonstrate similar prolongation of analgesic effect after caudal midazolam 50 g/kg alone
compared with bupivacaine 0.25%. However, midazolam 50 g/kg
as an adjuvant to bupivacaine 0.25% significantly increased the
duration of analgesia compared with midazolam or bupivacaine
alone.105 Mahajan and coworkers also reported an increase in the
duration of analgesia produced by caudal midazolam 50 g/kg
with bupivacaine 0.25% to 11 sd 5 hours from 7.4 sd 2.1 hours
for bupivacaine alone.106
Kumar and colleagues compared the effectiveness of caudal
midazolam, ketamine, and neostigmine as adjuvant to bupivacaine
0.25% in children aged 5 to 10 years scheduled for hernia repair.107
The duration of analgesia was longer in the neostigmine and
midazolam groups than in the ketamine and bupivacaine-alone
groups.
Despite the results of these studies, regular caudal administration of midazolam seems to be controversial and has not gained
popularity.
Neostigmine
The acetylcholine inhibitor neostigmine has been investigated as
a neuraxial analgesic adjuvant. An animal model has suggested
that it plays a role in spinal analgesia through stimulation of
cholinergic receptors in the substantia gelatinosa and superficial
laminae of the dorsal horn of the spinal cord.108
Abdulatif and El-Sanabary examined the analgesic effect
of caudal neostigmine, bupivacaine, or a mixture of both in
children.109 Time for first rescue analgesia was 22.8 sd 2.9 hours
in the neostigmine 2 g/kg with bupivacaine 0.25% group
compared with 8.1 sd 5.9 hours and 5.2 sd 2.1 hours for the
bupivacaine- and neostigmine-only groups, respectively. However,
very high incidences of PONV were reported, 25% in the neostigmine group and 30% in the neostigmine-bupivacaine group.
Almenrader and associates studied the use of S(+) ketamine
with or without preservative-free neostigmine 10 g/kg.110 The
analgesia effect was marginally prolonged in the neostigmine group, but as in Abdulatif and El-Sanaburys study, the
incidence of PONV increased to 30% from zero in the ketamine
group.
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Pharmacology
Batra and coworkers conducted a dose-response study of

caudal neostigmine 10, 20, 30, 40, and 50 g/kg in children aged
2 to 8 years scheduled for hypospadias surgery.111 Along with the
prolongation of duration of analgesia, a dose-dependent increase
in the incidence of PONV from 15 to 45% was reported.
Mahajan and colleagues published a dose-response study
of neostigmine as an adjuvant to bupivacaine 0.25%.112 The dose
of neostigmine used was considerably less than the previous two
studies. They reported prolongation of analgesia to 16.6 sd 4.9
hours, 17.2 sd 55 hours, and 17.0 sd 5.8 hours, respectively,
for neostigmine 2, 3, and 4 g/kg compared with 5.1 sd 2.3 hours
for bupivacaine only. The incidence of PONV, however, was
similar in the all groups.
In view of the high incidence of nausea and vomiting associated
with the use of caudal neostigmine, it should not be recommended
for caudal administration in children.
PERIPHERAL NERVES
AND ADJUVANTS
Although adjuvants have been used with LAs for peripheral nerve
blocks in adults, the published literature for children is scarce and
results are inconclusive.
Kaabachi and associates used clonidine as an adjuvant to
bupivacaine 0.25% for ilioinguinal and iliohypogastric nerve
block in 98 infants and children aged between 1 and 12 years and
compared it with bupivacaine 0.25% alone.113 There was no difference in the rate of rescue analgesia in the first 6 hours.
Cucchiaro and Ganesh114 reviewed the regional anesthesia database of Childrens Hospital of Philadelphia from October 2002 to
December 2005. Children (N = 215) underwent infraclavicular,
lumbar plexus, femoral, fascia iliaca, and sciatic nerve block for
postoperative analgesia. There were 47% of children who received
bupivacaine or ropivacaine alone and 53% clonidine as an
adjuvant to either of these LAs. The sensory block was extended
by a few hours by clonidine in both groups.
Giannoni and coworkers compared saline, ropivacaine 1%, and
clonidine 1 g/kg with ropivacaine 1% for local infiltration in the
tonsillar fossae in children before tonsillectomy.115 The children
in clonidine-ropivacaine group had better pain relief from postoperative days 2 through 5.
Ivani and colleagues conducted a pilot study of 40 children aged
1 to 2 years scheduled for hernia repair.116 Children received either
a caudal block or an ilioinguinal iliohypogastric nerve block with
ropivacaine 0.2% and clonidine 2 g/kg. Fourteen children in the
caudal group and 9 children in ilioinguinal-iliohypogastric group
did not require rescue analgesia. No difference in maximum pain
scores was detected between the groups.
EVALUATING THE LITERATURE

Kester Brown, in his memoirs, mentioned that the most useful
thing that he learned at university was from a comment by his
bacteriology professor, Willy Tulloch, Not to believe everything
written in the books.117
Assermino and associates systematically reviewed non-opioid
additives to LAs for caudal block in children.3 They collected a
total of 183 potentially relevant studies from Medline and MBASE
databanks. Analysis, however, was possible in only 17 studies.

Fifty-nine studies (48%) were discarded because of poor study
design and 12 studies were excluded because of inappropriate
outcome measures. Many practical and methodologic factors in
the design and performance of clinical pediatric trials limit the
quality and quantity of available research data. This not only has
impact on the grading of recommendations in clinical practice
guidelines but also should be considered by individual practitioners when reading and interpreting published data.118 While
reviewing the literature for this chapter, we noticed that some
studies have excellent study design but most did not. Factors in
these studies that could contribute to inadequate study sensitivity
are outlined in Table 299.
SUMMARY
A single dose of caudal morphine, ketamine, or clonidine as an
adjuvant to LA does result in prolongation of postoperative
analgesia. Fentanyl is the most widely used adjuvant in epidural
infusion. We have an adequate choice of drug options capable of
achieving prolonged postoperative analgesia after caudal block
that are effective and have an acceptable adverse effect and safety
profile.
TABLE 29-9. Factors Limiting Interpretation of Local
Anesthetic Adjunct Studies
1. Inadequate sample size. The number of patients studied was
too small; often 10 or 15 per group.
2. Patient population. Most of the studies have included
heterogeneous age groups ranging from a few months to
810 y and adolescents. Inclusion of children across a wide
range increases the sample size but at the cost of increased
variability because of age-related changes in physiology,
disease spectrum, pharmacokinetics, and analgesic
requirements.
3. Surgical procedures. The majority of the trials involve minor
surgical procedure such as hernia repair, circumcision, and
hypospadias, which are less painful procedures, and
differentiation of the effect of the analgesic can be difficult to
establish.
4. Use of pain measure tools. Many studies use one assessment
tool for all age groups. Age-appropriate tools have not been
used for assessment of pain even though studies include
infants through to older children and even adolescents,
which confound data interpretation. The most commonly
used tool was the OPS of Broadman and colleagues or its
modifications, which is validated for adolescents only and
not for infants and nonverbal children,119 and modifications
are not validated at all.
5. Outcome measure. Time to first analgesia has been taken as
the end point of analgesic duration. However, time to first
analgesia is dependent on other factors such as duration of
anesthesia, intraoperative analgesia, timing and dose of other
analgesic drugs, all of which are poorly accounted for.
6. The pain assessment was from 624 h only and not until
children were pain-free. It is difficult to record the total
analgesic consumption.
OPS = Objective Pain Scale.
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487
TABLE 29-10. Side Effects Observed With the Commonly Used Adjuvants
Side Effects
Ketamine
0.5 mg/kg
Ketamine
> 0.5 mg/kg
Clonidine
1 g/kg
Clonidine
2 g/kg
Morphine
50 g/kg
/
/
/Apnea in
neonates
Y
Y
/
/
/Apnea in
neonates
YY
YY
Heart rate
Blood pressure
Respiratory
Sedation
PONV
Pruritus
Urinary retention
Delirium
Y
Y at 1 mg/kg1
YY
Y
YY
Morphine
> 50 g/kg
/ In higher
doses
YY
Y
YY
Y = yes, mild effect; YY = yes, moderate effect; = no change or effect; = decrease; PONV = postoperative nausea and vomiting.
However, there is no doubt that every caudal adjuvant carries

some risk, although small (Table 2910). The report of adverse
effects of a particular drug should enlighten us to use it cautiously
rather than condemn it outright. As in life, everything cannot be
described in terms of black and white; there are gray zones, even
in our understanding of how these drugs act and their response
variability in different age groups. There is an urgent need for
improvement in our study designs for evaluation of drugs and
techniques to improve quality of pain relief. It is important to
understand developmental changes in nociceptive processing and
analgesic action in varying age groups of the pediatric study
population. In the absence of new longer-acting local anesthetic
agents and until any other alternative technique to prolong the
caudal block is established, the clinical practice of caudal adjuvant
is likely to continue. Safety as well as the effectiveness of the adjuvant should be the main criteria for choosing the right adjuvant for
any particular situation.
Present-day acute pain services employ skilled staff and use
costly equipment such as epidural infusions or patient-controlled
analgesia therapy. Lets think of a therapeutic approach in which
a single drug administration or technique in the intraoperative period can provide excellent postoperative analgesia without
any additional intervention of supplementary analgesia. If this
therapeutic measure can be supplemented easily by oral analgesic
medication in appropriate dose, it would not only reduce the
cost but also improve patient satisfaction. If we can manage to do
that, it will be a blessing especially for those situations in which
resources are limited, which is the situation for most children in
the world. Neuraxial ketamine, clonidine, and morphine have the
potential to provide that ideal situation. Morphine has had an
excellent neuraxial safety profile in adults and children for almost
three decades. Lets explore the possibility of minimizing adverse
effects, possibly by reducing the dose further in combination with
other drugs in a large multicenter study.
Caudal block is like a trusted old friend. The adjuvants have
been in clinical practice for a long time. We should explore the
possibility of safer combination of drugs and make best use of their
combined strength. Then only can we foster and nurture the old
friendship with caudal block appropriately.
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Pharmacology of Premedication
and Sedative Agents in Children
George A. Chalkiadis
30
C H A P T E R
INTRODUCTION
Pharmacokinetics
Several advances since the early 1990s have changed the

requirements for premedication. These include the introduction of
technologies for topical anesthesia before intravenous (I.V.) cannulation and child-friendly anesthesia induction and treatment
rooms, the recognition that play, distraction, and positioning for
comfort are effective, and allowing parents to accompany the child
into the induction or treatment room in many hospitals. In addition, antisialagogue and anticholinergic premedication to dry
secretions and prevent bradycardia and hypotension is no longer
necessary with modern anesthetic agents. Routine rectal and
intramuscular (I.M.) premedication would be considered unacceptable in many hospitals today. Premedication drugs are still
necessary to allay anxiety and to facilitate induction of anesthesia
in the uncooperative or fearful child, with the aim of avoiding
forceful restraint.
Many early premedication studies suffered from methodologic
problems including the absence of randomization, insufficient
power, variable drug administration times, multiple drug administration, and lack of control groups or statistical analysis. Few
studies identified the time interval to peak effect of any given
premedicant with the result that drugs may have been investigated
before, during, or after their peak sedative effect.
Interestingly, problems with premedication that plague the
modern-day anesthetist such as paradoxical excitation preoperatively and postoperatively were significant problems even with
what we would regard as heavy-handed polypharmacy that was
practiced in earlier years.
INTRANASAL: Peak plasma concentration (peak CP) (mean [sd]

72.2 [27.3] ng/mL) occurred in a mean time of 10.2 minutes (sd
2.0) after 0.1 mg/kg intranasal midazolam2 and 12 minutes after
0.2 mg/kg. Bioavailability was 0.55.3
BENZODIAZEPINES
The benzodiazepines (BZs) are lipid-soluble molecules that exert
their anxiolytic, sedative, and amnestic actions by binding to the
gamma-aminobutyric acid (GABA)BZ receptor complex.
Midazolam
Midazolam first synthesized in 1976, is water-soluble in an acidic
aqueous solution, and is highly lipid-soluble at physiologic pH. In
some markets, midazolam is available in a tablet form. The parenteral preparation is often administered via the oral, intranasal,
buccal, rectal, and I.M. routes. This preparation tastes bitter, and
its nasal administration is very irritating. Although 77% of children cried after oral, sublingual, intranasal, or rectal midazolam
administration, 75% accepted the face mask for induction of
anesthesia well after this premedicant.1
ORAL: Adolescents absorb oral midazolam more slowly than

children aged 2 to 12 years.4 Peak CP occurred 30 to 60 minutes
after oral administration in children younger than 12 years.5,6
Bioavailability was 0.27 to 0.36 after oral midazolam administration as a result of first-pass metabolism that is avoided with buccal
administration.5,7,8 Buccal midazolam has a mean time to clinical
response of 5 minutes in children with prolonged seizures.9
RECTAL: After 0.35 mg/kg and 0.5 mg/kg rectal midazolam, mean
peak CP (71 ng/mL and 246 ng/mL) were observed after 7.5 and
12.5 minutes, respectively. After 2 hours, the mean CP after
0.5 mg/kg was 120 ng/mL.10
Midazolam is hydroxylated (by cytochrome P450 [CYP]3A4)
in the liver to its less active metabolites, 1- and 4-OH midazolam;
the former is more important quantitatively and contributes
clinically to midazolams sedative effects.6 Both are glucuronidated
and excreted in the urine.11
Midazolam pharmacokinetics (PK) can be highly variable in
children, especially if they require extracorporeal membrane
oxygenation (ECMO), intensive care, or prolonged sedation or
have undergone major fluid shifts.1214 Its clearance (CL) is reduced
in preterm infants, with prolongation of elimination half-life
(T / ) and reduced 1-OH midazolam CP consequent to immature
CYP3A4 activity. CL increases when corrected for weight between
1 and 2 years of age (0.78 L/kg/h) and then declines exponentially
with body weight to adult values (0.380.66 L/kg/h).6 Elimination
t / was reported to be 0.5 to 3.5 hours and is age-dependent.36
1
Pharmacodynamics
Midazolam plasma concentrations correlate with clinical effect.
When both midazolam and 1-OH midazolam concentrations are
included, the sedation score can be predicted in 86% of children.6
Sedation and anxiolysis were maximal 20 minutes after intranasal
administration and 30 minutes after oral, sublingual, and rectal
administration consistent with the PK data just discussed.1,15 Sedation after intranasal midazolam was evident within 5 minutes.16
In a review of the published literature (19952006), oral midazolam 0.5 mg/kg reduced separation anxiety and distress at induction of anesthesia. Recovery times were not significantly delayed.
There was no consistent evidence suggesting reduced emergence
agitation. An oral dose of 0.5 mg/kg midazolam 20 to 30 minutes
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before surgery was recommended. Higher doses results in ataxia

and prolonged sedation.17
Two hours after 0.3 mg/kg rectal midazolam, 72% of children
were considered to be sedated.18 A recent review on procedural
sedation stated that the duration of oral midazolam is 60 to
90 minutes.19 This highlights an important point that relates to
duration of action. Absence of full recovery equates to some
sedation, but this does not reflect the duration of maximal (and
optimal) sedation. When the time course of sedation after oral
midazolam was investigated, 85% and 96% were satisfactorily
sedated at 15 and 30 minutes, respectively. A steady and rapid
decline was then observed such that 66% and 60% were sedated at
45 and 60 minutes, respectively.20
Paradoxical excitation occurs in some children soon after ingestion or at emergence. Flumazenil reduces emergence agitation
and the time to discharge.21 With increasing dose, delayed emergence from anesthesia is more likely.22
Lorazepam
Diazepam
Temazepam
Diazepam was synthesized in 1959. It is a highly lipophilic, lipidsoluble (but not water-soluble) BZ. Diazepam is available as a
tablet, an oral elixir, an I.V. lipid emulsion, and a clear fluid in
propylene glycol and alcohol. Less than half of children older than
4 years administered crushed diazepam tablets in raspberry syrup
as a premedicant found it unpalatable.23
Temazepam is rapidly absorbed from the gastrointestinal tract.

Mean time to peak CP is 1.4 hours in adults. It is metabolized
principally in the liver to temazepam glucuronide and excreted in
the urine. A small amount is demethylated to oxazepam and
eliminated as the glucuronide. The metabolites are inactive. Its
elimination T / is 10 hours.
Effective sedation was obtained in 93% of children who received oral temazepam 0.5 mg/kg.34 Increasing doses of temazepam elixir 0.5, 1.0, or 1.5 mg/kg administered to children
90 minutes before induction of anesthesia did not demonstrate
any clinical benefit. The sedation obtained was similar to that from
trimeprazine 3 mg/kg. Although more children receiving trimeprazine 4 mg/kg were either asleep or sedated compared with
those who received temazepam 1 mg/kg, no difference was observed in response to behavior during induction of anesthesia when
a parent accompanied the child. Recovery time was 1 hour shorter
in those who received temazepam.35
Pharmacokinetics
Diazepam is rapidly and completely absorbed. Peak CP occurs
within 2 hours after oral and within 30 minutes after rectal
(1 mg/kg) administration.24 Diazepam is metabolized in the liver
by N-demethylation to its active metabolite desmethyldiazepam
and by C-3-hydroxylation to N-methyloxazepam. Both are in turn
metabolized to oxazepam, which is conjugated with glucuronide
and excreted in the urine. Both diazepam and desmethyldiazepam
are metabolized slowly, accounting for diazepams long elimination
T / (2050 h) and low CL (0.20.5 mL/kg/min). Its distribution T /
is 30 to 40 minutes, explaining its shorter duration of action.11
There was no relationship between diazepam CP and recall at
induction in children.25
1
Pharmacodynamics
ORAL: Oral diazepam 0.25 mg/kg administered to children older
than 4 years a mean time of 84 minutes (sd 36) before the induction of anesthesia without a parent present was no better than
placebo, midazolam, or alprazolam with regards to preoperative
anxiolysis or behavior at induction.23 When the same dose was
given 2 hours prior, one third of children were assessed to have
unsatisfactory induction of anesthesia.26 Doubling the dose
(0.5 mg/kg) resulted in over 90% of children rated to have a
satisfactory reaction to induction.27 In other studies, oral diazepam
0.3 mg/kg sedated children but did not ease induction of anesthesia28 and 0.5 mg/kg 1 hour before induction of anesthesia
resulted in most children being asleep or awake and calm at induction, but was no more effective than placebo.29 Oral diazepam
before I.V. ketamine sedation for bone marrow aspiration resulted
in fewer bad dreams and more gradual onset and offset of sleep.30
RECTAL: Rectal diazepam 0.5 mg/kg produced sedation in 86% of

children on arrival at the operating room and 65% underwent
smooth induction.
Lorazepam, a 2chloro-substitution product of oxazepam, was

synthesized in 1971. It is less lipid-soluble than diazepam and
midazolam. This results in a longer onset time and duration of
action. Profound amnesia occurs. Lorazepam is well absorbed
orally and is conjugated in the liver to its inactive glucuronide and
excreted in the urine. Its elimination T / is 10 to 14 hours.11
Oral lorazepam 0.05 mg/kg was palatable and produced a cheerful demeanor preoperatively but was associated with restlessness, vomiting, and retrograde amnesia postoperatively.31 Oral
lorazepam 0.025 mg/kg the night before reconstructive burns
surgery in children resulted in less self-reported perioperative
anxiety.32 In a dose-finding study in children undergoing lumbar
puncture or bone marrow aspiration, premedication with oral
lorazepam 0.02 to 0.09 mg/kg produced adequate sedation for the
procedure.33
1
KETAMINE
The first clinical trials that investigated the utility of ketamine, an
N-methyl-D-aspartate (NMDA) receptor antagonist, were conducted in 1965. Its main advantages were its wide margin of safety,
hemodynamic stability, and the preservation of airway reflexes
while producing a dissociative state and analgesia. Vivid dreams
and hallucinations that were thought to be less marked in young
children were problematic at emergence.
Various formulations of racemic ketamine exist including a
transmucosal lollipop, an oral elixir, and a lozenge.36,37 The parenteral preparation was mixed with a sweet syrup in most studies to
disguise its unpleasant taste. A preservative-free formulation of
S(+) ketamine that has approximately twice the potency of the
racemate has superseded the racemic preparation in Europe.38 The
S(+) enantiomer is four times more potent than R() ketamine
while exhibiting less of the psychomimetic effects attributed to the
R() enantiomer.
Pharmacokinetics
Ketamine is metabolized mainly by N-demethylation to its lessactive metabolite norketamine, a process mediated by the CYP3A4
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Pharmacology of Premedication and Sedative Agents in Children 493
isoenzyme. Norketamine is subsequently hydroxylated to hydroxynorketamine, conjugated, and then excreted in urine. Peak
norketamine CP is reached 1 hour after I.V. administration. Norketamine has a shorter elimination T / (1.1 h) than ketamine.39
A two-compartment model best describes ketamine elimination. After I.V. bolus administration (11.5 mg/kg) in children,
almost all had a CP greater than 0.1 mg/L after 10 minutes, a level
associated with analgesia in adults. CL was estimated at 90 L/h/
70 kg.40
In adults, distribution T / is relatively slow (1116 min). Ketamine is very lipid-soluble, resulting in a large volume of distribution (3.1 L/kg). CL is high, accounting for ketamines short
elimination T / (23 h).41 Bioavailability by the oral and I.M. routes
was 0.16 and 0.93, respectively.42 In children, ketamine CP were
similar to those reported in adults except at later times. Absorption
after I.M. injection was more rapid in children and larger concentrations of norketamine were detected, suggesting that CL may
be greater in children when expressed as L/h/kg.43
After 3 or 9 mg/kg intranasal administration in children, mean
peak CP of 496 ng/mL and 2104 ng/mL were observed after 20 and
21 minutes, respectively. Bioavailabilty was 0.5.44
After 9 mg/kg rectal administration in children, a mean peak
CP of 632 ng/mL occurred after 42 minutes. Bioavailability was
0.25. Norketamine concentrations peaked earlier and were higher
than after intranasal administration of the same dose, reflecting
greater first-pass metabolism when ketamine is administered per
rectum.44
1
Pharmacodynamics
In an early study of nine children, plasma concentrations in children on awakening (0.84.0 g/mL) were higher than those found
in adults.43 A more recent study in 43 children demonstrated an
arousal median effective dose (EC50) of 0.52 mg/L, similar to that
for the ability to recall, suggesting that amnesia for events ceases
as the child wakes. Using the Childrens Hospital of Wisconsin
Sedation Scale, a CP of 1 mg/mL was associated with a sedation
level of 3 or less (arouses to consciousness with moderate tactile or
loud verbal stimulus) in 95% of children, whereas 1.5 mg/mL was
associated with a sedation score of 2 or less (rouses slowly to
consciousness with sustained painful stimulus) in 95% of children.45 Following the administration of 3 and 6 mg/kg of oral
ketamine, 17% and 9% were able to recall facemask application
for inhalation induction in one study,46 and 58% and 22% in
another,47 respectively. Administered intravenously, anesthesia is
achieved within 30 seconds and maximal effectiveness occurs
within 1 minute after rapid I.V. administration of 2 mg/kg. This is
consistent with an equilibration T / of 11 seconds found in
children.48
1
Ketamine for Premedication

Oral
Oral ketamine (6 mg/kg) produced effective sedation in most
children. In children with autism, 7 mg/kg was administered
30 minutes before induction of anesthesia with good effect in
86%. The mean time spent in the recovery room was 42 minutes
and the mean time to hospital discharge was 158 minutes.49
Increasing the dose from 4 to 8 mg/kg or from 3 to 6 mg/kg
afforded faster onset and less distress with parental separation, I.V.
cannulation, and facemask application.47,50
Intranasal
Intranasal ketamine 6 mg/kg 20 to 40 minutes before induction
was more effective than the combination of I.M. pethidine
1 mg/kg and promethazine 1 mg/kg and facilitated acceptance of
the facemask for inhalational induction in 78% of children.51
Intramuscular
I.M. ketamine 2 mg/kg was rapidly effective (mean time 2.7 min)
facilitating facemask acceptance in all children who were initially
uncooperative.52 Ketamine I.M. 2 to 3 mg/kg, produced rapid
sedation (within 16 min). After 5 mg/kg intramuscularly, 82% of
children were asleep and 15% separated calmly from their parents,
and 3% required restraint subsequently for facemask application
and insertion of an I.V. cannula.53
Rectal
Rectal ketamine produced dose-dependent sedation after
45 minutes, with 10 mg/kg facilitating separation from parents in
88% compared with 31% of those who received either 5 or 7 mg/
kg. None receiving the higher dose required restraint with facemask application, but time to spontaneous eye opening after the
cessation of anesthesia was prolonged.22 S(+) Ketamine 1.5 mg/
kg administered rectally resulted in only 30% of children being
tired or asleep after 20 minutes and 25% showed prolonged
excitation at the time of facemask application during inhalational
induction.15
Ketamine for Sedation and Analgesia

Oral
Oral ketamine 10 mg/kg provided good analgesia and sedation for
90% of children undergoing bone marrow aspiration and lumbar
puncture. After 30 and 45 minutes, 77% and 87% of children were
sedated, respectively. There was little improvement in sedation
beyond 45 minutes. Discharge within 2 hours occurred in 59%,
with the remainder needing up to 4 hours to recover.54
Intravenous
I.V. ketamine 1 or 1.5 mg/kg was used for sedation in the emergency department (ED) setting to facilitate fracture manipulation
and laceration repair. Plasma concentrations associated with
arousal occurred 10 minutes after the lower and 15 minutes after
the higher dose.45 The dose required for sedation decreases with
increasing age. A smaller initial bolus with a subsequent half-dose
top-up at 8 minutes achieved the same sedation level with earlier
recovery.48
Intramuscular
I.M. ketamine 2 or 2.5 mg/kg was used for sedation after analgesia
and distraction techniques had failed in children undergoing
minor procedures in an ED. A supplemental dose of 1 mg/kg was
needed in 5%.55 All children who received 4.5 mg/kg or greater
were adequately sedated for ED procedures.56 Children receiving
I.M. ketamine 4 mg/kg for orthopedic procedures reported less
pain, and observers less distress, than those receiving I.V. ketamine
1 mg/kg; however, the longer recovery times (median 129 min
vs 80 min) in the I.M. group led to the premature termination of
the study.57
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Intranasal
Intranasal ketamine 3 mg/kg provided adequate sedation for
dental procedures in children.58
Dose- and possibly route-dependent vomiting, nystamus,
hallucinations, excessive oral secretions, and tongue fasciculation
are common.46,47,50 A small number of children experienced severe
disorientation and hallucinations 10 to 20 minutes after oral ketamine 6 mg/kg.59,60 Hallucinations were reported in 12% of children
after 1 mg/kg intravenously but not after 3 mg/kg oral or rectal
administration.61 Less-frequent adverse effects include airway
obstruction, respiratory depression, rash, and laryngospasm that
in the ED setting are less common after ketamine than after midazolam and fentanyl combinations.55,62 Emergence reactions were
not observed in children receiving nasal ketamine 6 mg/kg.
Salivation was copious in 12% of children, similar to the control
group.51 Whereas nystagmus was frequently observed after I.M.
ketamine 2 mg/kg, salivation and emergence reactions were not
observed.47,52 After intranasal S(+) ketamine 1 to 2 mg/kg, excessive salivation was not observed.16 Concerns have been raised
regarding the potential for ketamine to cause neuronal apoptosis
in the developing brain.63
TABLE 30-1. Ketamine Characteristics

Sedation is dose dependent.
Time to maximal sedation is variable after oral administration.
There is a small but significant incidence of acute disorientation
in the first 20 min after oral ketamine administration.
Onset is faster with reduced likelihood of disorientation when
oral midazolam is co-administered with oral ketamine.
Intramuscular and intravenous administration result in rapid
onset of sedation.
Recovery times are longer with increasing dose.
Failure to achieve adequate sedation is more common with
lower doses.
Side effects including nystagmus and vomiting are dosedependent.
hydrate is detectable for several hours after the single administration of 50 mg/kg in neonates, infants, and toddlers. It is metabolized to dichloroacetic acid (DCA) and trichloroethanol (TCE).
TCE undergoes glucuronidation in the liver. It subsequently
undergoes enterohepatic circulation before conversion to trichloroacetic acid (TCA). In adults, this results in a long elimination
T / for its inactive metabolite TCA (8994 h),69 an effect that was
more pronounced when three 500 mg doses were administered at
48-hour intervals.70 In neonates, infants, and children, TCA CP
fails to decline up to 6 days after a single administration.71 Limited
data suggest that free TCE was positively correlated with serum
bilirubin, implying that individuals with impaired capacity for
glucuronidation may be very sensitive to the central nervous
system depressant effects of chloral hydrate that are attributed to
free-TCE CP.70 This has implications for neonates and young
infants in whom glucuronidation is immature especially with
repeat dosing. This risk is greatest in preterm neonates. The
elimination T / for TCE in preterm infants (3137 wk), full-term
neonates (3842 wk), and infants and young children (57(708 wk)
was 39.8 hours, 27.8 hours, and 9.7 hours, respectively.71
1
Combination Therapy
Oral ketamine 3 mg/kg in combination with oral midazolam
0.25 mg/kg produced shorter time to parental separation and
recovery compared with 6 mg/kg and 0.5 mg/kg of each drug alone,
respectively.64 This same drug combination in higher dose (oral
ketamine 6 mg/kg and oral midazolam 0.4 mg/kg 2030 min before
inhalational induction) resulted in all children aged 1.5 to 7 years
being calm or asleep, and 85% did not struggle with facemask application, whereas in the lower doses, 71% had good sedation and
79% did not require restraint during facemask application. Oral
ketamine 10 mg/kg in combination with oral trimeprazine 3 mg/kg
or midazolam 1 mg/kg produced effective premedication in
children with congenital heart disease.65 Conversely, oral ketamine
8 or 10 mg/kg in combination with diazepam 0.1 mg/kg provided
good conditions for dental procedures in only 28% and 44% of
anxious preschool children, respectively.66 The addition of oral
ketamine 3 mg/kg to oral midazolam 0.5 mg/kg premedication did
not prolong emergence after sevoflurane anesthesia.67
Premedication before anesthesia with 2 mg/kg intranasal S(+)
ketamine in combination with 0.2 mg/kg midazolam was more
effective than the same midazolam dose alone or with 1 mg/kg
S(+) ketamine in facilitating inhalational induction but not
separation from parents, 10 minutes after its administration.16
Rectal racemic ketamine 3 mg/kg or S(+) ketamine 1.5 mg/kg in
combination with midazolam has been used for premedication
with unimpressive results.15,68 Ketamine characteristics are summarized in Table 301.
CHLORAL HYDRATE
Chloral hydrate was first synthesized in 1832 and has been used as
a sedative or hypnotic since 1869. It tastes bitter.
Pharmacokinetics
Chloral hydrate is rapidly absorbed from the gastrointestinal tract
after oral and rectal administration. In contrast to adults, chloral
Pharmacodynamics
Onset time after oral chloral hydrate is summarized in Table
302. A recent study in which oral chloral hydrate 30 mg/kg was
administered to former preterm infants at term was terminated
early because of a significant increase in bradycardic events.72
These were more pronounced in neonates who had a lower gestational age at birth. Increased sedation was observed up to 12 hours
after administration.
No effect on CO2 chemoreceptor function was found 20 to
70 minutes after chloral hydrate 50 mg/kg was administered to
neonates and very young infants. Tidal volume fell in young
infants (mean age 21 wk),73 and in infants recovering from bronchiolitis, arterial oxygen desaturation has been reported. In cats
and rabbits, chloral hydrate depresses genioglossus activity but not
that of the diaphragm, suggesting that upper airway obstruction
may occur, especially in children with obstructive sleep apnea and
tracheo- and laryngomalacia.74
Common Uses
AUDIOLOGY: Middle ear pressure rises in infants and young
children with normal ears 40 to 60 minutes after chloral hydrate
administration.75
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TABLE 30-2. Onset Time After Oral Chloral Hydrate

Age
Neonates86
Infants85
Infants (mean
age 4.9 mo)84
Mean age 13.3 mo
(sd 9.3)200
Mean age 28.2 mo
(sd 18.1)87
Mean age 4.2 y
(sd 1.7)91
<3 y
Mean age 38 mo
(sd 31)80
Mean age 38 mo
(sd 31)80
Mean age 51.6 mo
[range 3675]
Range 0.3 mo4.3 y196
Chloral Hydrate
Dose, mg/kg
Onset Time, min,

mean (sd) [range]
50
50100
[940]
16 (11)
23.5 (13.4)
75100
25 (4.7) [550]
Mean 86.6
(sd 10.0)
Mean 71.9
(sd 11.1)
Mean 87
Mean 64 (sd 2)
39.1 (20.5)
28 (14)
25
28 (2)
Mean 93 (sd 2)
21 (1)
50
43.8
50100
29 (869)
sd = standard deviation.
DENTISTRY: Chloral hydrate 50 mg/kg provided sufficient sedation in combination with nitrous oxide to perform dental procedures of 40 minutes mean duration in children aged 3 to 6 years.
ELECTROENCEPHALOGRAPHY: Chloral hydrate has little effect on
the background electroencephalographic activity.76
MAGNETENCEPHALOGRAPHY: Chloral hydrate premedication did

not suppress interictal activity and localization of ictal activity on
magnetencephalographic scan.77
OPHTHALMOLOGIC EXAMINATION: Laser photocoagulation for

the treatment of retinopathy of prematurity in combination with
sub-Tenon block was successful.78 Visual evoked potentials can be
reliably obtained after chloral hydrate. Chloral hydrate (100 mg/kg
for the first 10 kg plus 50 mg/kg for each additional kg) administered to children younger than 6 years has no effect on intraocular
pressure in children with normal and high intraocular pressures.79
ECHOCARDIOGRAPHY: PREMEDICATION FOR ANESTHESIA. As a

premedicant before anesthesia, 75 mg/kg provided better
anxiolysis than 25 or 50 mg/kg in children younger than 5 years,
whereas in children older than 5 years, all doses provided good
anxiolysis.23
RADIOLOGY STUDIES.
Chloral hydrate has been used to provide

sedation for computed tomography (CT) and magnetic resonance
imaging (MRI). Adequate sedation for children undergoing MRI
was more likely after an initial dose of 100 mg/kg than 70 mg/kg,
with a faster rate of onset and no difference in the time to spontaneous awakening and adverse outcomes.80
Movement in the MRI scanner occurred in 22.5% of infants
receiving chloral hydrate (50100 mg/kg), with the result that the
scan was aborted (3.9%) continued after repositioning or bundling
(5.9%) or after additional or rescue sedation (11.7%).81 An incremental approach to dosing resulted in a 97% and a 100% success
rate for infants undergoing MRI scans and CT scans, respectively.82
The success rate for adequate sedation rose from 89% to 98% with
dose augmentation (mean total dose 78 mg/kg) after a mean initial

dose of 72 mg/kg. In another study, adequate sedation for MRI
was achieved in 64% and 87% of patients receiving a mean initial
dose of 70 mg/kg and 96 mg/kg, respectively; after dose augmentation, adequate sedation was achieved in 92% and 100%,
respectively.80
Failure after chloral hydrate administration for sedation for
MRI scanning is least likely in children aged younger than 1 year,83
although figures vary.81 Over half of children aged 1 to 5 years,
administered 80 mg/kg initially, required dose augmentation to a
total of 100 mg/kg. Scans were successfully completed in 91%.83
After 100 mg/kg of chloral hydrate, sedation was successful in 96%
of children younger than 4 years and 81% of children older than
4 years.84 Another study reported 30% failure in children older
than 5 years.83
Data from published studies regarding onset time for sedation
after oral administration are summarized in Table 301. After oral
administration, the duration of sedation was 61.2 minutes (sd
31.9)81 and 86 minutes (sd 36)85 in infants, and ranged from 5 to
240 minutes in neonates.86 Sedation time in children (mean age
28.2 mo [sd 18.1]) who received a mean dose of 86.6 mg/kg was
164.5 minutes (sd 85.9).87 Recovery occurred in 80.6 minutes (sd
15.6, range 35120) in children (mean age 13.3 mo [sd 9.3]) who
received 75 to 100 mg/kg.82 However, resedation or prolonged or
delayed sedation has been reported. Sedation has been observed
for up to 12 hours after 30 mg/kg oral chloral hydrate in ex
premature infants at term postconceptional age.72 In older infants
and children, drowsiness the day after 75 mg/kg single dosage has
been reported. Drowsiness lasted longer than 4 hours in 28% of
children who received a mean dose of 78 mg/kg, whereas normal
activity was resumed after 4 hours in 54%. After 50 mg/kg, 74%
and 94% of infants and children (6 mo5 y) fulfilled discharge
criteria within 3 and 6 hours of administration, respectively.88
After rectal administration of 75 mg/kg of chloral hydrate in
young children, 82% were effectively sedated within 15 minutes
and 94% within 30 minutes.89 The median duration of effective
sedation was 0.75 hour.89
Adverse effects may persist for 6 hours or longer and include
prolonged sedation,72,90 motor imbalance (1.668%).87,90 agitation
and hyperactivity (1.429%),84,87,90 vomiting (1.715%),84,87,91 respiratory obstruction (2.4%),87 and depression (4%).84,87 Paradoxical
excitement before sedation was reported in 18%. In former preterm neonates administered 30 mg/kg orally, sedation was observed for up to 12 hours after its administration, resulting in
reduced oral intake and more bradycardic events.72
Toxicity and Safety

Numerous publications report on the use of chloral hydrate in
combination with other drugs such as hydroxyzine, promethazine,
and nitrous oxide.82 The addition of a second drug to facilitate adequate sedation after poor initial response increased the likelihood
for adverse events.92
In an analysis of 95 case reports of adverse sedation-related
events, 20 were related to chloral hydrate. Thirteen of the chloral
hydraterelated cases resulted in death or permanent neurologic
damage and, of these, chloral hydrate was the sole sedative administered in 7 instances. Four patients received known overdoses,
2 received an unknown amount of drug, and the last received
60 mg/kg orally. It was unclear from the publication whether the
latter had other associated significant risk factors (8 of 13 did).93
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In 1095 children undergoing transthoracic echocardiography and

who received chloral hydrate (38% of whom were classified
American Society of Anesthesiologists [ASA] 3 or 4), minor intervention was required in 7% and major intervention in 0.5%. Age
younger than 6 months was the only predictor for adverse events.
Cyanosis, hospitalization, ASA class, oxygen requirement, and the
use of additional sedative medication were not. A 20% or more
reduction in heart rate (HR) or blood pressure (BP) was seen in
24% and 59% of patients, respectively. Apnea has been reported
in children with congenital heart disease. Supraventricular tachycardia after chloral hydrate administration has been reported in
children receiving inotropic drugs after surgical repair of complex
congenital heart disease.94 After overdosage, chloral hydrate has
been reported to cause arrhythmias95 and severe esophageal burn
in an 8-month-old infant.96
The majority of serious life-threatening or fatal adverse reports
after chloral hydrate administration have occurred in high-risk
children and, one could assume, poorly monitored environments,
because neither clinician supervision nor details of monitoring are
provided in the case reports.97 Children receiving chloral hydrate
experienced fewer cardiorespiratory problems than those who
received either pentobarbital or propofol for MRI sedation.81 In
the absence of cardiorespiratory disease and obstructive sleep
apnea, and with appropriate monitoring, chloral hydrate can be
safely administered in doses of 50 to 100 mg/kg for sedation. Table
303 summarizes chloral hydrate characteristics.
2 AGONISTS
When stimulated, 2 adrenoceptors inhibit the release of noradrenaline and sympathetic activity, decrease BP and HR, and produce
sedation, anxiolysis, and analgesia. They produce sedation by
binding to receptors in the locus coeruleus and analgesia by binding to spinal cord receptors located in the dorsal horn that are
present from early development.
Clonidine
Clonidine is a highly lipophilic drug that was first used as an
antihypertensive agent in 1966. Its affinity for 2 adrenoceptors is
220 times that for 1 adrenoceptors.
Pharmacokinetics
Pooled data from five studies undertaken on children with a mean
age of 4 years (sd 3.6 y, range 1 wk14 y) were combined for
population PK analysis. The absorption T / from the epidural
space (0.98 h) was slower than that from the rectum (0.26 h). The
relative bioavailability from both routes was unity. There was a lag
time of 2.3 minutes before absorption began in the rectum. The
mean time to peak CP (median 0.77 ng/mL) after rectal administration of 2.5 g/kg clonidine in children aged 14 to 48 months
occurred at 51 minutes (range 2970).99 CL at birth was 3.8 L/h/
70 kg and matured with a T / of 25.7 weeks to reach 82% of adult
CL by 1 year of age and is greatest between 1 and 5 years of age
using linear per-kilogram models. Distribution T / was 12 minutes
and elimination T / was 9 hours, similar to adult values. Contextsensitive T / was calculated for various ages after an infusion of
0.3 g/kg/h and ranged from 6.75 hours after a 10-hour infusion
at 10 years of age to 11.75 hours in a neonate and increased with
longer infusion duration because of return of drug from peripheral
compartments after infusion ceased.100 Transdermal patches are
not suitable as premedication agents because therapeutic clonidine
CP are not achieved for 2 to 3 days after application.
Between 40 and 60% of clonidine will undergo hepatic biotransformation after I.V. administration. CYP4502D6 is involved
in the formation of its major metabolite, p-OH clonidine. Approximately half is excreted unchanged by the kidneys but is subject to
considerable between-individual variation. Thus, renal immaturity or failure may extend the elimination T / of clonidine to
40 hours or more.
1
TRICLOFOS
Triclofos is the phosphoric ester of trichloroethanol and shares the

same active metabolite with chloral hydrate. It is more palatable
and less of a gastric irritant than chloral hydrate. In published
trials, the dose administered was 70 to 75 mg/kg. It did not inhibit
the Hering-Breuer reflex in healthy infants and had minimal effect
on respiratory rate, HR, and oxygen saturation in infants and
young children.98
TABLE 30-3. Chloral Hydrate Characteristics
Can result in prolonged sedation or resedation particularly in
sick and expremature neonates.
Most effective in producing adequate sedation in children
younger than 1 y.
Less effective in producing adequate sedation in children older
than 4 y.
Used primarily for painless procedures (e.g., MRI, CT,
transthoracic echocardiography).
Can be administered in doses ranging from 50 to 100 mg/kg
orally (maximum 2 g).
Onset time is variable:
Faster with higher dose.

Top-up doses can be given after 20 min if initial dose is low
and ineffective.
Offset time is variable.

Children receiving chloral hydrate should be monitored with
pulse oximetry, and those with congenital heart disease
should also have noninvasive blood pressure monitoring.
Should not be administered to children with obstructive sleep
apnea.
CT = computed tomography; MRI = magnetic resonance imaging.
Pharmacodynamics
SEDATION, ANALGESIA, AND AMNESIA: Sedation, analgesia, and
amnesia are dose-dependent.101 Satisfactory preoperative sedation
in children occurred with CP in the range of 0.3 to 0.8 g/L,102
whereas in adults, 1.5 to 2.0 g/L has been reported to result
in analgesia. In children aged 1 to 6 years, the mean time to
become drowsy or fall asleep after intranasal clonidine 4 g/kg
was 47.5 minutes (sd 19.4).103
CARDIOVASCULAR: A mean reduction in mean arterial BP of

26.3% (sd 13.6) was reported in children after the administration
of 2.5 g/kg intravenously. The time for 75% of the BP reduction
to occur was 21.3 minutes (sd 25.6).104 In children, oral clonidine
4 g/kg reduces the intraoperative lability of BP and HR. Although
oral clonidine premedication reduced HR and BP for up to
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10 hours postoperatively, no child had postoperative hypotension

or bradycardia that required treatment.
RESPIRATORY: Oral clonidine 4 g/kg did not attenuate the

increase in minute volume induced by hypercapnia in children
aged 3 to 13 years receiving sevoflurane.105 This is consistent with
the observation that epidural clonidine 1 g/kg did not induce an
increase in transcutaneous carbon dioxide pressure (PCO2) in
children aged 9 months to 7 years.106 Three case reports of apnea
after caudal epidural clonidine administration (1.252 g/kg) suggest that caution should be exercised in neonates.107109
Clonidine for Premedication

ORAL: After oral clonidine 4 g/kg was administered 60 to 90
minutes prior, 63% of children aged 7 to 12 years were either
drowsy or asleep.110 In children aged 1 to 6 years, the mean time to
become drowsy or fall asleep after the same dose was 38 minutes.
The mean time to peak sedative effect was 46.0 minutes (sd 15.7).
Steal induction, in which inhalational induction was performed
without waking the child who was cradled in a parents arms, was
successful in 60 to 66%. If children woke during transfer to the
theater, smooth induction was unlikely. In children with autism,
the mean time to adequate sedation for electroencephalographic
(EEG) study was 58 minutes (range 15135). No child was reported to have found the taste of oral clonidine unpleasant in two
studies in which the I.V. formulation was mixed with syrup.103,111
Emergence quality was reported in two studies. After clonidine
premedication, over 90% of children were calm on waking.103,111
Oral clonidine 4 g/kg, but not 2 g/kg, was effective in reducing
sevoflurane-induced agitation in children aged 1 to 6 years.112
The mean time to discharge from the postanesthesia care unit
was 53.7 minutes (sd 23.6) after oral clonidine 4 g/kg.113 The
mean time to hospital discharge after the same dose was 179
minutes (sd 52).114 When used for EEG sedation, the mean time
for return to baseline sedation score was 105 minutes (range 20
195) in children with autism.115
Table 304 summarizes clonidines characteristics. Additional
benefits from clonidine premedication include reduced postoperative nausea and vomiting after strabismus surgery; better
analgesia and reduced analgesic requirements; dose-dependent
reduction in minimum alveolar concentration (MAC) of sevoflurane for skin incision,116 tracheal intubation, tracheal extubation, and laryngeal mask insertion117 in children aged 2 to 11 years;
and attenuation of the surgical stress response118,119
Oral clonidine 4 g/kg blunted the increase in HR after I.V.
atropine in awake children aged 8 to 13 years120 but did not alter
the effectiveness of simulated epidural test dose using adrenaline
and isoprenaline in children aged 1 to 7 years receiving sevoflurane.121 In addition, it reduced lidocaine and monoethylglyTABLE 30-4. Clonidine Characteristics
Dose-dependent sedation.
Good oral and rectal bioavailability.
Reduces heart rate and blood pressure.
Apnea is a risk in neonates especially if expremature.
Optimal timing 3060 min prior.
Dose oral 4 g/kg.
Benefits include postoperative analgesia.
cinexylidide (MEGX) CP in children receiving continuous thoracic

epidural lidocaine.122
Clonidine for sedation

ELECTROENCEPHALOGRAPHY: Oral clonidine was used to successfully perform EEG studies in 85% of children aged 2.2 to
16.9 years (median 6) with autism, some of whom had previously
failed sedation with chloral hydrate.115
INTENSIVE CARE: Clonidine by continuous I.V. infusion (0.13.6

g/kg/h), with and without midazolam, has been used for sedation
in the intensive care unit after pediatric cardiac surgery.123,124 Oral
clonidine (35 g/kg q8h) was used in combination with morphine and lorazepam to achieve adequate sedation in children
undergoing mechanical ventilation for single-organ respiratory
failure.125 There were no adverse hemodynamic effects including
HR and rhythm, cardiac index, and BP.123125
Dexmedetomidine
Dexmedetomidine, the D-isomer of medetomidine used in veterinary medicine, is highly lipophilic and eight times more selective
for 2 than 1 adrenoreceptors than clonidine (1620:1 vs 220:1). It
is supplied as a clear, colorless, isotonic solution (100 g/mL) that
contains no preservatives, additives, or chemical stabilizers. Intranasal dexmedetomidine was well tolerated in children and adults.
None complained of smell, taste, local irritation, or pain.126,127
Pharmacokinetics
In adults, oral, buccal, and I.M. bioavailability was 16%, 82%, and
104%, respectively.128 Dexmedetomidine exhibits a rapid distribution phase (T / 6 min). It is over 90% protein-bound129 and undergoes extensive biotransformation in the liver that involves direct
glucuronidation and CYP2A6-mediated hydroxylation producing
inactive metabolites. Hepatic impairment reduces CL. Its terminal
elimination T / in children aged 2 to 12 years after a single I.V.
dose was 1.8 hours, similar to that in adults (2 h). There was no
evidence of dose-dependent PK.129 After a mean infusion duration
of 18.8 hours (range 824) at 0.2 to 0.7 g/kg/h in infants and
children (aged 4 mo7.9 y) terminal elimination T / was 2.65 hours
(sd 0.88).130 CL matured during the first year of life to reach 87% of
the adult value by 1 year.131
1
Pharmacodynamics
Dexmedetomidine has minimal respiratory depressant effects,
making it particularly useful when planning to extubate patients
in the intensive care setting.127,132138
Dexmedetomidine induces EEG activity similar to that seen in
natural sleep by reducing sympathetic activity and the level of
arousal. The sedation it produces is different from other sedative
drugs in that it is not GABAmimetic. After dexmedetomidine,
children are easily aroused, and one study noted that, despite satisfactory sedation to facilitate parental separation, some children
became distressed when they were aroused at induction of anesthesia.127 Adult patients receiving dexmedetomidine in the intensive care unit complained of awareness. It is unclear what dose of
dexmedetomidine produces anxiolysis or amnesia; although it
is used as a premedicant and administered intramuscularly in
adults, anxiolysis has been reported when higher doses were used.
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Increasing I.V. dosage is associated with increased sedation and

analgesia and decreased isoflurane requirements, amnesia, HR,
BP, and cardiac output.139,140
Dexmedetomidine reduces intraocular pressure. There is
evidence that, in rats, dexmedetomidine decreases the convulsive
potency of racemic bupivacaine and levobupivacaine.
Transient hypertension may occur secondary to initial vasoconstriction from stimulation of peripheral 2B receptors located
on vascular smooth muscle. To prevent this, the initial bolus dose
should be administered slowly over 10 minutes. Subsequently, the
activation of 2 receptors in the central nervous system leads to a
reduction in sympathetic outflow with possible peripheral ganglion blockade and a reduction in BP and bradycardia. Bradycardia may be more likely in neonates and young infants because
of their relatively unopposed high vagal tone. Although a reduction in BP and HR relative to baseline has been observed in older
children, clinically significant hypotension and bradycardia are
uncommon.
modine 2 to 3 g/kg was administered to children aged 4 months

to 19 years. After a mean of 28 minutes (range 1045), adequate
sedation to facilitate CT scan was achieved in only 65%.145
OTHER PROCEDURES: Dexmedetomidine has been used in conjunction with incremental doses of midazolam to provide sedation
for fiberoptic intubation in children. Propofol for rescue sedation
has been used in conjunction with dexmedetomidine to provide
sedation for children undergoing radiotherapy, cardiac catheterization, and awake craniotomy.138,146,147
OFFSET: After CT scan (mean duration 8.6 min [sd 5.4, range
136]), mean time spent in the recovery room was 27 minutes
(sd 16.2, range 4110).144 The mean recovery time after dexmedetomidine bolus 0.92 g/kg (sd 0.36) and infusion 0.69 g/kg/h
(sd 0.32) for procedures averaging less than 1 hours duration
was 84 minutes (sd 42).133 After 1 g/kg bolus and 0.5 to 0.7 g/
kg/h maintenance, the mean recovery time was 24 minutes
(sd 17.6) and the mean time to discharge was 32 minutes
(sd 20.1).136
Dexmedetomidine for Premedication

INTRANASAL: Intranasal dexmedetomidine 1 g/kg was more
effective than 0.5 g/kg in producing satisfactory sedation to

separate children (aged 212 y) from parents (75% vs 59%). Of
those who were sedated after the higher dose, 71% allowed I.V. or
inhalational induction without showing signs of distress or
awakening.127
ORAL: Oral dexmedetomidine (2.6 g/kg [sd 0.83]) in 13 children

aged 4 to 14 years produced effective sedation in 11 patients who
had failed in previous attempts to sedate. The time to effective
sedation for I.V. cannula insertion or parental separation ranged
from 30 to 62 minutes.141
TRANSMUCOSAL: Transmucosal dexmedetomidine 1 g/kg

45 minutes before induction in children 7 to 12 years was as effective as oral midazolam 0.5 mg/kg or clonidine 4 g/kg administered 30 and 90 minutes before induction, respectively.113 Children
who received dexmedetomidine were less sedated 30 minutes after
arrival into recovery. The mean time to discharge after arrival into
recovery was 41.4 minutes (sd 20.6).
Dexmedetomidine for Procedural Sedation

MAGNETIC RESONANCE IMAGING: I.V. dexmedetomidine produced insufficient sedation for MRI in one study,142 but a higher
dose (loading dose 23 g/kg and maintenance infusion rate 2
g/kg/h) provided adequate sedation in 97.6% of children (mean
age 4.5 y [sd 3.4, range 0.217.9]).143 In children aged 1 to 7 years,
I.V. dexmedetomidine (1 g/kg bolus and continuous infusion
0.50.7 g/kg/h) produced adequate sedation for MRI in 80% in
19 minutes (sd 8.2). When sedation was inadequate, a single dose
of midazolam 50 g/kg was sufficient to perform the MRI.136 Coinduction with ketamine and dexmedetomidine, followed by
dexmedetomidine infusion, provided adequate sedation for MRI
in children with trisomy 21 and obstructive sleep apnea.137
COMPUTED TOMOGRAPHY: Dexmedetomidine 2 to 4 g/kg bolus
intravenously and 1.0 g/kg/h by maintenance infusion was

sufficient for sedation in children undergoing CT scan,144 but a
single bolus of 2 to 3 g/kg was not.145 The mean time to achieve
adequate sedation was 10.5 minutes (sd 4.2). Buccal dexmedeto-
Dexmedetomidine for Intensive Care Sedation

Adequate postoperative sedation was achieved in spontaneously
breathing and mechanically ventilated children who had undergone cardiac and thoracic surgery with an initial dexmedetomidine bolus of 0.32 g/kg (sd 0.15) and continuous infusion
of 0.30 g/kg/h (sd 0.05). Children younger than 1 year required
more rescue boluses.134 In a randomized trial comparing midazolam and dexmedetomidine for sedation in children requiring mechanical ventilation, dexmedetomidine 0.5 g/kg/h was
superior and less effective in children younger than 1 year.148,149
Dexmedetomidine provided adequate sedation in 65 children
(aged 0.6(17 y) with burn injuries who had been inadequately
sedated with BZ and opioid infusions. The mean duration of
infusion was 11 days (range 250) with a maximum infusion rate
of 2 g/kg/h. No tachyphylaxis was observed.150 Dexmedetomidine has been used successfully to treat opioid and BZ
withdrawal in infants and children.149,151
Dexmedetomidine advantages are summarized in Table 305.
TABLE 30-5. Dexmedetomidine Has a Number of
Theoretical Advantages Over Other Sedative Agents
Minimal respiratory depression.
Elimination half-life is not prolonged and clearance is mature in
early infancy.
Mimics normal sleep EEG activity. Patients are easily aroused,
but may appear distressed.
Administered by the nasal, oral, and transmucosal routes for
premedication in children.
Used successfully to produce sedation for MRI, CT scan, and
cardiac catheterization, but may need supplementation with
other sedative agents.
Used successfully for intensive care sedation where more other
agents have failed and to treat opioid and benzodiazepine
withdrawal. It may have a place for use in children pending
extubation from mechanical ventilation because of its
minimal effect on ventilation.
CT = computed tomography; EEG = electroencephalographic; MRI = magnetic
resonance imaging.
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OPIOIDS
Fentanyl
Oral transmucosal fentanyl citrate (OTFC) has been studied extensively in children, leading to the U.S. Food and Drug Administrations (FDA) approving its use in children over 2 years and
10 kg in weight. The OTFC preparation is commercially available
in a lollipop form. Oral fentanyl solution is unpleasant, whereas
the OTFC is well accepted by children. Children took 20 minutes
to finish the prescribed dose.
Pharmacokinetics
Compared with adults, the bioavailability of OTFC in children
aged 3 to 10 years was lower (0.52 vs 0.36, respectively), suggesting
that children were more likely to swallow a larger proportion of
any given dose with a resultant increase in first-pass metabolism.
Peak CP was lower (adults 3.0 and children 1.0 ng/mL) and time
to mean peak CP longer (adults 22 min [sd 2.5], children 53 min
[sd 40]) and more variable in children.152 Peak CP was half and the
time taken to reach it double after ingestion of oral fentanyl solution compared with OTFC in adults. More variability was observed in children administered the oral fentanyl solution (mean
peak CP 1.8, sd 1.2 ng/mL; mean time to peak CP 1.7 h [sd 1.6]).153
An oral fentanyl buccal tablet preparation has been studied in
adults. Its advantage is greater bioavailability (F = 0.65) and more
rapid and complete absorption than OTFC. Its absorption characteristics are not affected by mucositis or buccal dwell time.154156
Pharmacodynamics
In children, the onset and depth of sedation is dose-dependent.
Time to peak sedation is 30 to 45 minutes.157 After 10 to 15 g/kg,
50% of children were sedated or asleep at this time. This percentage increased to 80% after 15 to 20 g/kg.158
OTFC produces preoperative anxiolysis, increased likelihood
of cooperation at induction, less emergence phenemona postoperatively, and delayed postanesthesia care unit discharge.157159
As a premedicant, OTFC 15 to 20 g/kg was as effective as oral
midazolam 0.5 mg/kg.158 The same dose produced sedation in 25%
of children undergoing bone marrow aspiration or lumbar puncture and effective analgesia within 30 minutes.
Pre- (830%) and postoperative (4080%) nausea and vomiting
are common.157,159 Pruritis (in up to 75%) occurs mainly preoperatively and is dose-dependent and mild.157,159 Postoperative
respiratory depression necessitating assisted ventilation and/
or naloxone after 10 to 15 g/kg was reported in one study.159
Ondansetron or droperidol did not reduce the incidence of
postoperative nausea or vomiting.157,159
Sufentanil
Sufentanils high lipid solubility results in a rapid onset of effect.
Over half the children aged 6 months to 7 years protested during
the administration over 15 to 20 seconds of intranasal sufentanil
in doses of 1.5, 3.0, and 4.5 g/kg. Within 10 minutes, most children were calm when separated from their parents; however, only
25% willingly accepted a facemask for induction of anesthesia.
Postoperative vomiting occurred in 25% or more in each group,
rising to 75% of those administered 4.5 g/kg. Chest wall stiffness
occurred in up to half of children and was marked in 25% receiving the higher dose.
When intranasal sufentanil 2 g/kg was compared with intranasal midazolam 0.2 mg/kg, 71% of the children receiving
midazolam cried compared with only 20% of those who were
administered sufentanil. Separation of children from their parents
was similar for both drugs; however, the sufentanil group was
more sedated, more cooperative during anesthesia induction, and
more likely to experience nausea and vomiting.
Pentazocine
Pentazocine is a mu opioid receptor antagonist and a kappa opioid
receptor agonist. It was thought less likely to cause opioid induced
respiratory depression. It was administered as an oral (2 mg/kg)
and I.M. premedicant (0.5 mg/kg) in children.
I.M. Opioids
I.M. pentazocine or morphine administered 45 minutes previously
produced dose-dependent sedation and anxiolysis such that 81%
and 60% of children were not crying during induction of anesthesia, respectively. Emergence agitation was uncommon. Nausea
and vomiting were uncommon preoperatively and more common
postoperatively (morphine 11.3% vs pentazocine 6.6%). I.M.
nalbuphine was similar to pentazocine. Papaveretum 0.4 mg/kg,
pethidine 1 to 2 mg/kg, or morphine 0.2 mg/kg was often combined with scopolamine and administered 1 hour preoperatively.
Although these agents produced effective sedation, children did
not like I.M. injections and half vomited after papaveretum and
scopolamine.28
Rectal Opioids
The mean bioavailability of 0.2 mg/kg rectal morphine administered to children preoperatively was 0.35 (range 0.180.59) with
a hydrogel formulation and 0.27 (range 0.060.93) when a parenteral solution was used. The hydrogel formulation is less painful on
administration.160
Dextromethorphan
Dextromethorphan is an isomer of the codeine analogue levorphanol. Its analgesic effects are mediated through noncompetitive
antagonism of NMDA receptors. It undergoes extensive first pass
metabolism and O-demethylation by CYP2D6. Poor and extensive
metabolizers have been identified. There is conflicting evidence
that dextromethorphan may reduce secondary but not primary
hyperalgesia; this effect may be delayed for up to 2 hours after peak
CP.161 In children undergoing tonsillectomy, oral dextromethorphan 1 mg/kg administered 30 to 60 minutes prior reduced intraoperative fentanyl administration, postoperative pain scores, and
morphine consumption compared with placebo in two studies162,163
but not in another.164
BARBITURATES
Barbiturates can be classified as long-, medium-, short-, and
ultrashort-acting. The latter act very briefly owing to rapid
redistribution that terminates their action. Elimination T / , however, are long. Their lipid solubility results in rapid onset of action,
whereas those with a short T / will have rapid offset of action.
1
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Methohexitone
Methohexitone is an ultrashort-acting barbituate that is rapidly
redistributed and metabolized and has little hangover effect. It was
administered rectally as a premedicant and induction agent,
rapidly inducing sleep before separating the child from their
parents in doses of 10 to 50 mg/kg. Bioavailability by the rectal
route has been estimated at 17% with a sixfold variation in
children. Elimination T / was 3.2 hours and CL 17.9 mL/min/kg.165
Methohexitone may induce seizures in children with epilepsy.
1
Methohexitone for Premedication

and Induction of Anesthesia
INTRAMUSCULAR: I.M. methohexitone 5.5 mg/kg was administered to 750 children younger than 15 years who may or may not
have received scopolamine or atropine. Spontaneous eye closure
occurred within 5 minutes of administration in 80% of children,
but did not occur at all in 9%. A vigorous struggle was described
in 8% at the time of facemask application. Eight percent of children made no attempt to clear their airway when it was obstructed,
limiting methohexitones utility as a premedicant.
RECTAL: Rectal administration and dosage were investigated in
one study of children aged 3 months to 7 years. The induction of
sleep was more rapid in those receiving 30 mg/kg (mean 6.7, sd
1.6 min) compared with those who received 20 or 25 mg/kg (mean
7.8, sd 2.2; and 7.2, sd 2.3 min, respectively). The percentage asleep
by 15 minutes were 93%, 84%, and 87% for the 30-, 25-, and
20-mg/kg doses, respectively. No hemodynamic or respiratory
complications were noted.
In another study, 25 mg/kg rectal methohexitone was administered to children aged 6 months to 5 years, inducing sleep in a mean
time of 8.6 minutes (range 422). One child did not fall asleep.
Hiccough was encountered in 8% and 1 patient required assisted
ventilation. Recovery times were similar to those who received I.V.
thiopentone without premedication for induction. Return of full
consciousness occurred between 30 and 60 minutes.166 Physostigmine postoperatively did not expedite discharge from the recovery
room (mean stay 34 min) after myringotomy.167
Methohexitone for Sedation

INTRAMUSCULAR: I.M. methohexitone 10 mg/kg was used for
CT scan sedation in children aged 2 months to 5 years. The mean
time to induce sleep was 3.3 minutes (sd 0.4). Arousal occurred
after 50 minutes and children were alert after 86 minutes.168
INTRAVENOUS: I.V. methohexitone (mean loading dose 2.3 [sd

0.7] mean total dose 6.1 [sd 3.3] mg/kg) was used for MRI
sedation. Hypoventilation and apnea were observed in a small
proportion and 5% moved, necessitating some MRI sequences to
be repeated. Discharge times were rapid (mean 3.5 min [range 0.6
40]).169 Methohexitone was used in combination with remifentanil
to provide sedation and analgesia for children undergoing brief
painful procedures. Time to discharge (geometric mean 5.0 min)
was shorter than when a propofol and fentanyl infusion was used
(geometric mean 16.2 min).170 Airway support was necessary in a
number of patients.
RECTAL: Rectal methohexitone 25 mg/kg was used for sedation
in children undergoing CT or MRI scans. The mean onset time
was 8 to 9 minutes.171 The mean sleep time was 46 minutes and
the mean time to discharge was 79.3 minutes (sd 30.9).171 Sedation
was most likely successful in children undergoing CT scan (97%)
compared with MRI (69%).
Secobarbitone (Quinalbarbitone)
Secobarbitone is a short-acting barbiturate that is well absorbed
from the gastrointestinal tract. It was commonly used to sedate
children for radiologic procedures. It is also thought to have
contributed to the deaths of Jimi Hendrix and Marilyn Monroe.
Onset time when administered rectally (57 mg/kg) for noninvasive diagnostic procedures was 10 to 15 minutes. Children
were fit for discharge 45 minutes after the procedure. It was
administered orally (7.5 mg/kg up to a maximum of 200 mg) with
a 10% failure rate for CT scanning. The mean time to effective
sedation was 27 minutes (range 1050). The mean time to discharge home was 212 minutes (range 30380).172 Secobarbitone
2 mg/kg intramuscularly was also used for premedication.11 It was
also used (4 mg/kg intramuscularly) as part of a cocktail that included pethidine (1 mg/kg), promethazine (1 mg/kg), and atropine (0.016 mg/kg). Mean time to induce sleep was 53 minutes.
Pentobarbitone
Pentobarbitone is a short-acting barbiturate with a relatively fast
onset of action that allows dose titration to response when administered intravenously.
Intramuscular
I.M. pentobarbitone 2 mg/kg was used for premedication.11 For
CT sedation, an initial dose of 5 to 6 mg/kg was administered,
supplemented by a further 1 to 3 mg/kg if required. Induction time
was 30 to 45 minutes, recovery time was 70 minutes, and there
was a 3% failure rate.
Intravenous
I.V. pentobarbitone produced effective sedation for MRI and CT
scaning (failure rate in children with I.V. titration < 1%).173 The
addition of midazolam to I.V. pentobarbitone 2 to 6 mg/kg was
not shown to reduce the failure rate and served only to prolong
time to discharge. The mean time to sedation after pentobarbitone
was 6.5 minutes (sd 4.4) and time to discharge was 106 minutes (sd
34).173 Mean time to discharge was reported as 55 minutes in a
cohort that included more children younger than 3 years. Adverse
effects included paradoxical reactions (1.614%), vomiting (0.6%),
and severe oxygen desaturation (<17.5%).91,173
Thiopentone
Rectal
Rectal thiopentone (2545 mg/kg) was administered for CT scan
sedation. The mean onset time was 8 minutes. A top-up dose was
required in 20% of children; effective sedation was not achieved in
3%. The mean duration of sedation was 2.75 hours.174 In another
study, rectal thiopentone 25 mg/kg was administered for CT,
nuclear medicine, and MRI scan sedation. Although the mean
time to scan was 12.2 minutes, an unstated number of children
received a second dose of 15 mg/kg if they were still awake
20 minutes after the first administration. Mean time to discharge
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was 71 minutes. Adverse effects included transient oxygen desaturation in 11%. Rectal irritation and discharge (20%), prolonged
drowsiness or ataxia (9%), and vomiting (5%) occurred after
discharge.175
ETOMIDATE
Etomidate is a carboxylated imidazole derivative that produces
rapid onset and offset of sleep, possesses a high therapeutic index,
and does not decrease systemic arterial pressure or cerebral
perfusion pressure.11 These features led to its use in the radiology
and ED settings for procedural sedation in children.176178 In these
studies, initial boluses of 0.1 to 0.3 mg/kg intravenously were used
with further boluses if required up to a total of 0.5 mg/kg.
In children (mean age 8.3 y [sd 3.7]) undergoing fracture reduction who received fentanyl 1 g/kg, the times taken for induction and recovery were shorter after etomidate 0.2 mg/kg (2 and
11.8 min, respectively) than after midazolam 0.1 mg/kg (4 and
24 min, respectively).178 More patients in the etomidate group were
adequately sedated (92% vs 36%). Pain on injection and myoclonus
were often noted. When etomidate in doses up to 0.4 mg/kg was
used for CT scan sedation, the failure rate was high (24%) when
compared to I.V. pentobarbitone. However, induction and sedation
times were shorter and more parents perceived their child to have
returned to baseline by discharge from hospital in the etomidate
group.177 Using a higher initial bolus dose (0.3 mg/kg) with up to
two 0.15-mg/kg boluses reduced the failure rate to less than 1%.176
ANTICHOLINERGICS
Anticholinergic drugs were often administered preoperatively.
Their I.V. administration at the time of induction or if and when
they should they be necessary is as effective.
Atropine
Atropine is a tertiary amine that crosses the blood-brain barrier.
It was used to prevent bradycardia and hypotension often seen in
infants receiving halothane, arrhythmias during cyclopropane
anesthesia, and for its antisialagogue properties, particularly in
infants and for surgery in the oropharynx. No sedation occurred
but palpitations were sometimes troublesome. It was thought to
protect against bradycardia secondary to vagal stimulation such
as that that occurred with traction on the spermatic cord and
extraocular muscles. Atropine was usually administered by I.M.
injection 30 minutes before induction of anesthesia in doses of 10
to 20 g/kg, after which peak CP was reached within 5 minutes.11
Oral atropine 20 g/kg was effective within 25 minutes in
infants and children aged 1 to 15 months in attenuating cardiovascular depression during halothane anesthesia. There was no
advantage in administering 40 g/kg.179 After rectal administration, atropine peak CP was reached after 15 minutes and was only
30% of that seen after I.M. administration of the same dose.11
Glycopyrrolate
Glycopyrrolate is a synthetic quaternary drug that crosses the
blood-brain barrier poorly. It is two to five times as potent an
antisialagogue compared with atropine.11 It protects against
bradycardia without causing tachycardia (5 g/kg intravenously),
and the oculocardiac reflex (7.5 g/kg intramuscularly).180,181 Oral

bioavailability is low (0.03),182 explaining its failure to attenuate
cardiovascular depression in infants receiving halothane after its
oral administration.183 Glycopyrrolate administration in children
resulted in lower gastric volumes and acidity compared with scopolamine or placebo.184 Given as premedication, it may increase
the likelihood for sore throat postoperatively.185
Scopolamine
Scopolamine (hyoscine), a tertiary amine, crosses the blood-brain
barrier causing amnesia, drowsiness, euphoria, and fatigue. It was
commonly used in combination with pethidine, papaveretum, or
morphine. Given alone, it sometimes caused delirium that was less
likely to occur with concomitant opioid administration and that
could be reversed with physostigmine. Its effect on the HR was
less pronounced than that of atropine.11
As a premedication agent (8 g/kg intramuscularly), scopolamines sedative, antisialagogue, and antiemetic effects were particularly useful when opioids were co-administered and when ether
was used. Rectal administration has been reported, although its
advantage was unclear. Transdermal scopolamine applied the
night before surgery reduced postoperative nausea and vomiting
in children undergoing strabismus surgery.
ANTIHISTAMINES
Hydroxyzine
Hydroxyzine is a derivative of both diphenylmethane and piperazine and chemically unrelated to phenothiazine. It is a central
nervous system depressant and was used primarily for its sedative,
anxiolytic, and antiemetic properties as a premedicant in preference to phenothiazine derivatives that were thought more likely
to induce extrapyramidal side effects. It is also an antihistamine.
Although there are multiple publications regarding its use as a
premedicant in children, poor study design prevents definitive
conclusions regarding its effectiveness. Hydroxyzine was almost
always used in combination with one or more other drugs including pentobarbitone, secobarbitone, chloral hydrate, pethidine,
atropine, scopolamine, midazolam, diazepam, and nitrous oxide.
Promethazine
Despite its widespread use, there are little pharmacologic data on
promethazine in children. Some unreferenced data are available
in textbooks. They state that promethazine is well absorbed after
oral administration and that its onset of action occurs within 30 to
60 minutes.
Promethazine is an H1 histamine receptor antagonist with antimuscarinic and antiemetic properties. Compared with trimeprazine, it is less sedating but may have a cumulative effect with
repeated administration. Promethazine 1 mg/kg each night for
3 nights led to central apneas and upper airway obstruction that
had not been present previous in infants.186 Sedation at induction
of anesthesia after promethazine 1 mg/kg was assessed as
inadequate in 61% of children, although the interval between
premedication and induction was highly variable.187
Children undergoing myringotomy receiving paracetamol
20 mg/kg or a combination of paracetamol 12 mg/kg, codeine
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0.5 mg/kg, and promethazine 0.65 mg/kg. Those who received the
promethazine-containing mixture took longer to open their eyes
and resume oral intake. Late sedation was observed, although
there was no difference in the time to discharge.188 A study comparing oral hydroxyzine 0.5 mg/kg, promethazine 0.5 mg/kg,
diazepam 0.1 mg/kg, and placebo administered for premedication
1 hour before induction did not detect any differences between
the groups with regards to anxiolysis, quality of induction, or
emergence time.189
trimeprazine took longer to wake but experienced less distress in

the recovery room and had half the incidence of vomiting than
the other groups.27
MELATONIN
The discovery that the phenothiazine chlorpromazine, although

having no intrinsic analgesic actions, enhanced opioid analgesia
and its use in neurolept analgesia and its antiemetic properties led
to its use alone and as part of the lytic cocktail.190 It also had
sympatholytic properties that were useful if surface cooling
hypothermia was employed. Little data exist in children regarding
its pharmacology or effectiveness as a premedicant. It is still used
as a sedative (0.51 mg/kg). In adults, chlorpromazine has a rapid
distribution T / (2 h) and a long elimination T / (30 h).11
Melatonin, a hormone secreted by the pineal gland, is important

in regulating the diurnal rhythm of sleep. Early reports suggested
that it may be effective to induce sleep for EEG and MRI scanning,
particularly in children who had been sleep deprived. Of children
administered 10 mg orally, 65% fell asleep within 35 minutes.194,195
More recently, melatonin 3 mg or 6 mg was not shown to contribute to sedation when given before chloral hydrate or a mixture
of temazepam and droperidol196 and was no more effective than
placebo after 3 or 0.5 mg/kg.197
As a premedicant in children aged 2 to 5 years, oral melatonin
0.25 or 0.5 mg/kg administered 1 hour prior facilitated separation
from parents and facemask acceptance while reducing postoperative excitement. Sleep disturbance in the 2 weeks after
surgery was less than in children who had received midazolam
premedication.198
Trimeprazine (Alimemazine)
COMBINATION PREMEDICATION
Trimeprazine is a H1 histamine receptor antagonist with antimuscarinic properties. Its sedative effects are more pronounced than
those of promethazine because of its central anticholinergic activity. It also antagonizes the effects of dopamine and noradrenaline.
After its oral administration in children, the elimination T / of
trimeprazine was estimated to be 6.8 hours.191
Trimeprazine enjoyed popularity as an oral premedicant and
sedative in children for some years after its introduction in 1959.
It produced good preoperative sedation, antiemesis, and amnesia.
Its major drawback was prolonged postoperative sedation, with
children taking 10 hours or more to regain normal functioning.
Case reports of unexplained hypotension, bradycardia, and respiratory depression within 30 to 80 minutes of its administration
in children with fever or upper respiratory tract infections were
also disturbing. Other side effects include extrapyramidal effects,
hypothermia, disturbing dreams, and hallucinations.
Administered 1.5 to 2 h before anesthesia, no difference was
found in distress at induction or recovery time when children were
administered 2 or 4 mg/kg. Trimeprazine 2 mg/kg administered
orally 90 minutes before induction was as effective as midazolam
0.5 mg/kg or placebo 30 minutes before induction.192 The same
doses of trimeprazine and midazolam were compared with diazepam 0.25 mg/kg with droperidol 0.25 mg/kg in older children, but
in this study, less attention was paid to the timing of premedicant
drug administration. A higher proportion of children who received trimeprazine experienced postoperative behavioral disturbance.193 Children receiving oral trimeprazine 3 mg/kg were
less likely to be asleep and more likely to be distressed at the induction of anesthesia than those given an oral mixture composed of
trimeprazine 1 mg/kg, droperidol 0.15 mg/kg, and methadone
0.08 mg/kg administered 2.5 hours prior. Administered 1 to more
than 2 hours prior, good preoperative and prolonged postoperative
sedation were reported after trimeprazine 3 mg/kg.187 In children
aged 1 to 10 years, oral trimeprazine 4 mg/kg administered 2 hours
before anesthesia was as effective as diazepam 0.5 mg/kg and pentobarbitone 3 mg/kg for preoperative sedation. Those receiving
Many of the premedicants described have been used in combination and administered by a variety of routes that precludes
further conclusion. Some were effective but not always, and it is
difficult to compare their efficacy and side effects in light of
modern anesthesia practice. An excellent review of the history of
the lytic cocktail that contained pethidine, promethazine, and
chlorpromazine and a critical appraisal of its use is highly recommended.199
Chlorpromazine
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131. Potts AL, Warman GR, Anderson BJ. Dexmedetomidine disposition in
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134. Chrysostomou C, Di Filippo S, Manrique AM, et al. Use of dexmedetomidine in children after cardiac and thoracic surgery. Pediatr Crit Care
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135. Hammer GB, Philip BM, Schroeder AR, et al. Prolonged infusion of
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136. Koroglu A, Demirbilek S, Teksan H, et al. Sedative, haemodynamic and
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137. Luscri N, Tobias JD. Monitored anesthesia care with a combination of
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138. Munro HM, Tirotta CF, Felix DE, et al. Initial experience with dexmedetomidine for diagnostic and interventional cardiac catheterization in
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140. Ebert TJ, Hall JE, Barney JA, et al. The effects of increasing plasma concentrations of dexmedetomidine in humans. Anesthesiology. 2000;93:
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141. Zub D, Berkenbosch JW, Tobias JD. Preliminary experience with oral
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142. Heard CM, Joshi P, Johnson K. Dexmedetomidine for pediatric MRI
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143. Mason KP, Zurakowski D, Zgleszewski SE, et al. High dose dexmedetomidine as the sole sedative for pediatric MRI. Paediatr Anaesth.
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144. Mason KP, Zgleszewski SE, Prescilla R, et al. Hemodynamic effects of
dexmedetomidine sedation for CT imaging studies. Paediatr Anaesth.
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145. Lami RO, Pereira AC. Transmucosal dexmedetomidine for computed
tomography sedation. Paediatr Anaesth. 2008;18:349378.
146. Shukry M, Ramadhyani U. Dexmedetomidine as the primary sedative
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147. Everett LL, van Rooyen IF, Warner MH, et al. Use of dexmedetomidine
in awake craniotomy in adolescents: report of two cases. Paediatr
Anaesth. 2006;16:338342.
148. Tobias JD, Berkenbosch JW. Sedation during mechanical ventilation in
infants and children: dexmedetomidine versus midazolam. South Med J.
2004;97:451455.
149. Tobias JD. Dexmedetomidine to treat opioid withdrawal in infants
following prolonged sedation in the pediatric ICU. J Opioid Manag.
2006;2:201205.
150. Walker J, Maccallum M, Fischer C, et al. Sedation using dexmedetomidine in pediatric burn patients. J Burn Care Res. 2006;27:206210.
151. Finkel JC, Elrefai A. The use of dexmedetomidine to facilitate opioid
and benzodiazepine detoxification in an infant. Anesth Analg. 2004;
98:16581659, table of contents.
152. Wheeler M, Birmingham PK, Dsida RM, et al. Uptake pharmacokinetics
of the Fentanyl Oralet in children scheduled for central venous access
removal: implications for the timing of initiating painful procedures.
153. Wheeler M, Birmingham PK, Lugo RA, et al. The pharmacokinetics of
the intravenous formulation of fentanyl citrate administered orally in
children undergoing general anesthesia. Anesth Analg. 2004;99:1347
1351; table of contents.
154. Darwish M, Kirby M, Jiang JG. Effect of buccal dwell time on the
pharmacokinetic profile of fentanyl buccal tablet. Expert Opin Pharmacother. 2007;8:20112016.
155. Darwish M, Kirby M, Robertson P, et al. Absorption of fentanyl from
fentanyl buccal tablet in cancer patients with or without oral mucositis:
a pilot study. Clin Drug Investig. 2007;27:605611.
156. Darwish M, Kirby M, Robertson P Jr, et al. Absolute and relative
bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl
citrate. J Clin Pharmacol. 2007;47:343350.
157. Ashburn MA, Streisand JB, Tarver SD, et al. Oral transmucosal fentanyl
citrate for premedication in paediatric outpatients. Can J Anaesth. 1990;
37:857866.
158. Howell TK, Smith S, Rushman SC, et al. A comparison of oral transmucosal fentanyl and oral midazolam for premedication in children.
Anaesthesia. 2002;57:798805.
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159. Binstock W, Rubin R, Bachman C, et al. The effect of premedication with

OTFC, with or without ondansetron, on postoperative agitation, and
nausea and vomiting in pediatric ambulatory patients. Paediatr Anaesth.
2004;14:759767.
160. Lundeberg S, Hatava P, Lagerkranser M, Olsson GL. Perception of pain
following rectal administration of morphine in children: a comparison
of a gel and a solution. Paediatr Anaesth. 2006;16:164169.
161. Duedahl TH, Dirks J, Petersen KB, et al. Intravenous dextromethorphan
to human volunteers: relationship between pharmacokinetics and antihyperalgesic effect. Pain. 2005;113:360368.
162. Dawson GS, Seidman P, Ramadan HH. Improved postoperative pain
control in pediatric adenotonsillectomy with dextromethorphan. Laryngoscope. 2001;111:12231226.
163. Hasan RA, Kartush JM, Thomas JD, Sigler DL. Oral dextromethorphan
reduces perioperative analgesic administration in children undergoing
tympanomastoid surgery. Otolaryngol Head Neck Surg. 2004;131:
711716.
164. Rose JB, Cuy R, Cohen DE, Schreiner MS. Preoperative oral dextromethorphan does not reduce pain or analgesic consumption in children
after adenotonsillectomy. Anesth Analg. 1999;88:749753.
165. Bjorkman S, Gabrielsson J, Quaynor H, Corbey M. Pharmacokinetics
of I.V. and rectal methohexitone in children. Br J Anaesth. 1987;59:
15411547.
166. Goresky GV, Steward DJ. Rectal methohexitone for induction of anaesthesia in children. Can Anaesth Soc J. 1979;26:213215.
167. Hannallah RS, Abramowitz MD, McGill WA, Epstein BS. Rectal
methohexitone induction in pediatric outpatients: physostigmine does
not enhance recovery. Can Anaesth Soc J. 1985;32:231234.
168. Varner PD, Ebert JP, McKay RD, et al. Methohexital sedation of children
undergoing CT scan. Anesth Analg. 1985;64:643645.
169. Kessler P, Alemdag Y, Hill M, et al. [Intravenous sedation of spontaneously breathing infants and small children before magnetic resonance
tomography. A comparison of propofol and methohexital] (German).
Anaesthesist. 1996;45:11581166.
170. Bauman LA, Cannon ML, McCloskey J, et al. Unconscious sedation in
children: a prospective multi-arm clinical trial. Paediatr Anaesth. 2002;
12:674679.
171. Pomeranz ES, Chudnofsky CR, Deegan TJ, et al. Rectal methohexital
sedation for computed tomography imaging of stable pediatric emergency department patients. Pediatrics. 2000;105:11101114.
172. Simpson JH, West CD, Law PJ. Paediatric sedation for CT scanning: the
safety and efficacy of quinalbarbitone in a district general hospital
setting. Br J Radiol. 2000;73:79.
173. Mason KP, Zurakowski D, Karian VE, et al. Sedatives used in pediatric
imaging: comparison of IV pentobarbital with IV pentobarbital with
midazolam added. AJR Am J Roentgenol. 2001;177:427430.
174. Burckart GJ, White TJ 3rd, Siegle RL, et al. Rectal thiopental versus an
intramuscular cocktail for sedating children before computerized
tomography. Am J Hosp Pharm. 1980;37:222224.
175. Glasier CM, Stark JE, Brown R, et al. Rectal thiopental sodium for
sedation of pediatric patients undergoing MR and other imaging studies.
AJNR Am J Neuroradiol. 1995;16:111114.
176. Baxter AL, Mallory MD, Spandorfer PR, et al. Etomidate versus pentobarbital for computed tomography sedations: report from the Pediatric
Sedation Research Consortium. Pediatr Emerg Care. 2007;23:690695.
177. Kienstra AJ, Ward MA, Sasan F, et al. Etomidate versus pentobarbital for
sedation of children for head and neck CT imaging. Pediatr Emerg Care.
2004;20:499506.
178. Di Liddo L, DAngelo A, Nguyen B, et al. Etomidate versus midazolam
for procedural sedation in pediatric outpatients: a randomized controlled trial. Ann Emerg Med. 2006;48:433440, 440 e431.
179. Miller BR, Friesen RH. Oral atropine premedication in infants attenuates
cardiovascular depression during halothane anesthesia. Anesth Analg.
1988;67:180185.
180. Mirakhur RK, Jones CJ, Dundee JW, Archer DB. I.M. or I.V. atropine or
glycopyrrolate for the prevention of oculocardiac reflex in children
undergoing squint surgery. Br J Anaesth. 1982;54:10591063.
181. Rautakorpi P, Ali-Melkkila T, Kaila T, et al. Pharmacokinetics of
glycopyrrolate in children. J Clin Anesth. 1994;6:217220.
182. Rautakorpi P, Manner T, Ali-Melkkila T, et al. Pharmacokinetics and
oral bioavailability of glycopyrrolate in children. Pharmacol Toxicol.
1998;83:132134.
183. Cartabuke RS, Davidson PJ, Warner LO. Is premedication with oral
glycopyrrolate as effective as oral atropine in attenuating cardiovascular
depression in infants receiving halothane for induction of anesthesia?
Anesth Analg. 1991;73:271274.
184. Salem MR, Wong AY, Mani M, et al. Premedicant drugs and gastric
juice pH and volume in pediatric patients. Anesthesiology. 1976;44:
216219.
185. Stratelak PA, White W, Wenzel D. The effect of glycopyrrolate premedication on postoperative sore throat. AANA J. 1996;64:545548.
186. Kahn A, Hasaerts D, Blum D. Phenothiazine-induced sleep apneas in
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187. Ong BC, Ng AS, Chew SL. Oral premedications in paediatric day
surgery. Singapore Med J. 1996;37:139142.
188. Ragg P, Davidson A. Comparison of the efficacy of paracetamol versus
paracetamol, codeine and promethazine (Painstop) for premedication
and analgesia for myringotomy in children. Anaesth Intensive Care.
1997;25:2932.
189. Desjardins R, Ansara S, Charest J. Pre-anaesthetic medication in paediatric day-care surgery. Can Anaesth Soc J. 1981;28:141148.
190. Schechter NL, Weisman SJ, Rosenblum M, et al. The use of oral transmucosal fentanyl citrate for painful procedures in children. Pediatrics.
1995;95:335339.
191. Sponheim S, Aune H, Gulliksen M, Morland J. Pharmacokinetics of
trimeprazine in children. Pharmacol Toxicol. 1990;67:243245.
192. Mitchell V, Grange C, Black A, Train J. A comparison of midazolam with
trimeprazine as an oral premedicant for children. Anaesthesia. 1997;52:
416421.
193. Patel D, Meakin G. Oral midazolam compared with diazepamdroperidol and trimeprazine as premedicants in children. Paediatr
Anaesth. 1997;7:287293.
194. Johnson K, Page A, Williams H, et al. The use of melatonin as an alternative to sedation in uncooperative children undergoing an MRI examination. Clin Radiol. 2002;57:502506.
195. Wassmer E, Carter PF, Quinn E, et al. Melatonin is useful for recording
sleep EEGs: a prospective audit of outcome. Dev Med Child Neurol.
2001;43:735738.
196. Sury MR, Fairweather K. The effect of melatonin on sedation of children
undergoing magnetic resonance imaging. Br J Anaesth. 2006;97:
220225.
197. Isik B, Baygin O, Bodur H. Premedication with melatonin vs midazolam
in anxious children. Paediatr Anaesth. 2008;18:635641.
198. Samarkandi A, Naguib M, Riad W, et al. Melatonin vs. midazolam
premedication in children: a double-blind, placebo-controlled study. Eur
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199. Reappraisal of lytic cocktail/demerol, phenergan, and thorazine (DPT)
for the sedation of children. American Academy of Pediatrics Committee on Drugs. Pediatrics. 1995;95:598602.
200. Wheeler DS, Jensen RA, Poss WB. A randomized, blinded comparison
of chloral hydrate and midazolam sedation in children undergoing
echocardiography. Clin Pediatr (Phila). 2001;40:381387.
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Pharmacology of Vagal Blockers

and Antagonist Agents
Martin Jhr
31
C H A P T E R
VAGAL BLOCKERS
Vagal blockers are mainly used as anticholinergic agents to prevent
vagal disorders in pediatric anesthesia (Table 311).
Years ago, they were considered as an inevitable premedicant in
children. Despite a trend to omit routine administration of vagal
blockers to adults,1 many authorities believe that they are useful for
infants and children, given as a premedicant or given intravenously
at induction. The vagal response is more intense in infants and
young children than in adults, and cardiac output is highly dependent on heart rate. The currently available anticholinergic agents
(Figure 311) have different preferences of action (Table 312).
Controversy on the Clinical Use of

Vagal Blockers in Pediatric Anesthesia
Scientific knowledge is clear with respect to the effects of anticholinergic agents on heart rate. Unclear, however, is the value of the
administration of atropine, glycopyrrolate, or scopolamine on a
routine basis to all pediatric patients.2 Overall, the use of anticholinergic medication is declining in pediatric anesthesia.3 Pediatric anesthetists essentially take two different positions.
TABLE 31-1. The Main Effects of Cholinergic
Stimulation and Inhibition
Cholinergic
Postganglionic
Fibers
Effects of
Cholinergic
Stimulation
Eye
Myosis
Heart
Bronchi
Bradycardia
Bronchoconstriction
Gastric/bowel
spasms
Ureter and
bladder spasm
Hypersudation
Digestive tract
Urinary tract
Sweating glands
(sympathetic
cholinergic fibers)
Salivary glands
Hypersalivation
Lower esophageal
Sphincter
sphincter
contraction
Figure 31-1. Chemical structure of vagolytic agents.
Effect of Atropine
Administration
Anticholinergic Agents Are Still a Standard

for All Pediatric Patients
Mydriasis and
increase in
intraocular
pressure
Tachycardia
Bronchodilation
Inhalational inductions are often performed in pediatric patients,

in whom dry mucous membranes may be advantageous and airway complications can be reduced.4 The vagal response is more
intense in infants and young children than in adults, and cardiac
output is highly dependent on heart rate. Atropine ensures a high
cardiac output, is usually not related to severe side effects, and
allows critical situations to be avoided. If bradycardia is already
present, the onset of even intravenous (I.V.) atropine is delayed.5
Even modern I.V. induction techniques, for example, propofol in
combination with remifentanil, can provoke severe bradycardia
and prophylactic atropine may be life-saving.
Decreases spasms
Decreases spasms
Inhibition of
sweating
Antisialogogue effect
Decreases sphincter
tone
Routine Use of Anticholinergic

Agents Is Not Essential
Although it was mandatory to block secretions and vagal reflexes
in the era of ether anesthesia, this is no longer necessary with
modern inhalational agents. Halothane, and especially sevoflurane,
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TABLE 31-2. Currently Available Anticholinergic Agents
Ammonium compound
Speed of onset
Duration of action
Oral or rectal administration
CNS effects
Tachycardia
Antisialogogue effect
Antiemetic effect
Effective in motion sickness
Atropine
Glycopyrrolate
Scopolamine (Hyoscine)
Tertiary
++
+
+
+ (Stimulation)
+++
+
Quaternary
+
+++
++
++
Tertiary
++
+
+
+++ (Sedation)
+
+++
++
++
allows a smooth inhalational induction without excessive secretions. Sevoflurane itself even promotes tachycardia without
atropine. The use of suxamethonium in pediatric anesthesia is
declining, for which the routine use of atropine has been advocated.6,7 The high incidence of bradycardia in pediatric patients is
most often related to the occurrence of hypoxemia, in which
oxygen and not atropine is the mainstay of treatment. Drying
mucous membranes makes them more friable, and mucociliary
clearance is reduced for several hours after a single dose of atropine.8 Furthermore, atropine interferes with temperature regulation and rapidly lowers the lower esophageal sphincter pressure in
infants and children.9 Scopolamine can be used as a sedative
premedication, but benzodiazepines (e.g., midazolam) or clonidine
is a more suitable drug. The anesthetic community has never
looked seriously at the side effects of anticholinergic agents: the dry
mouth that is very uncomfortable for the patient and the friable
mucous membranes.
Since the late 1980s, the author and other pediatric anesthesiologists have no longer administered anticholinergic agents
routinely, without any evidence of harm. From todays point of
view, anticholinergic agents, in common with other drugs, should
be used only when clearly indicated (Table 313). A vagal blocker,
preferably atropine, should, however, always be drawn up and
immediately available throughout anesthesia.
Atropine
DRUG CATEGORY: Atropine is an anticholinergic agent with parasympatholytic, antispasmodic, bronchodilatatory, and mydriatic
properties.
TABLE 31-3. Potential Indications for the Use
of Anticholinergic Agents
Clinical Situation
Intention
Difficult airway;
fiberoptic intubation
Reduced secretions,
improved view, of
unproven benefit
Reduced secretions,
improved view, of
unproven benefit
Reduced secretions
Reduced severity of the
oculocardiac reflex
Airway endoscopy
Ketamine anesthesia
Squint surgery
Reference
PHYSICOCHEMICAL PROPERTIES: Atropine is an ester of tropine,

an organic base (tertiary amine), and tropic acid, an aromatic acid.
Its molecular weight is 289 Da.
PHARMACOKINETIC PROPERTIES: Protein binding is 50%, and the

volume of distribution is 2 to 4 L/kg. Because of the increased
volume of distribution, the elimination half-life is twice as long
(6.9 h) in infants than in adult patients.14,15 Infants need a higher
dose to produce an increase in heart rate.16
METABOLISM: Metabolism is hepatic by N-demethylation followed by conjugation with glucuronic acid. The drug is partly metabolized and partly eliminated unchanged by the kidneys.17,18
MODE OF ACTION: Atropine antagonizes the muscarinic effects of

acetylcholine. Specific action is on muscarinic receptors, both
peripheral and central, mainly located in tissues supplied by postganglionic parasympathetic fibers. Atropine produces the most
effective cardiac vagal block and the least drying effects (see Table
312).
COMMERCIAL PRESENTATION: Atropine sulfate. Conservation at

ambient temperature (1530C). U.S. Food and Drug Administration (FDA) risk category C.
CLINICAL INDICATIONS: (1) Premedication (for its anticholinergic

properties; see Chapter 37), (2) prevention and treatment of
bradycardia (e.g., auriculoventricular block), (3) reversal of muscle
relaxants in conjunction with anticholinesterase agents, (4)
complementary treatment of bronchospasm, and (5) an antidote
against anitcholinesterase or organophosphate poisoning.
CONTRAINDICATIONS: Glaucoma, tachycardia, hyperthermia.
Careful use is advised in children with obstructive valvular heart
disease who may not tolerate tachycardia; in cases of paralytic
ileus, hemorrhagic proctocolitis, gastroesophageal reflux; and
in children with impaired mucociliary clearance (e.g., in cystic
fibrosis).
DOSAGE AND ROUTES OF ADMINISTRATION: The recommended
10
11
12, 13
dose (Table 314) is 20 g/kg intravenously; a minimum dose of

10 g/kg intravenously is needed to achieve one half the maximal
increase of heart rate and promote sinus rhythm.16 After intramuscular (I.M.) administration of 20 g/kg, the time to peak effect
is 25 minutes19; however, for most anesthesiologists, I.M. premedication is no longer acceptable. A much faster onset is provided
by I.M. injection into the tongue by the submental approach.20
Schematically, the oral dose should be at least twice the I.V. dose.
Oral atropine, 20 and 40 g/kg, was shown to attenuate halothane-
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TABLE 31-4. Clinically Used Doses of Atropine
Indication
Route of
Administration
Premedication
I.V., S.C., I.M.
(routine use,
Oral, rectal
(see Chapter 37)
Bradycardia
I.V.
I.M. submental
tracheally
Reversal of muscle
relaxants
Bronchospasm
Pharmacology of Vagal Blockers and Antagonist Agents 509
PHARMACOKINETICS AND METABOLISM: Distribution volume is
Commonly Used
Doses
0.2 L/kg. Only 10 to 25% of the total dose is absorbed from the
gastrointestinal tract.33 Glycopyrrolate is excreted unchanged in
both bile and urine.34
1020 g/kg
30 g/kg
CLINICAL USE AND DOSAGE: Glycopyrrolate is especially suitable
20 g/kg
20 g/kg
50100 g/kg
(emergency)
20 g/kg (together
with anticholinesterase agents)
Inhalation (rarely Children 50 g/kg
q46h
used, replaced
by ipratropium) Adolescents 25 g/kg
q46h
20 g/kg
I.V.
induced cardiovascular depression in infants,21 with the onset of

action occurring at approximately 25 minutes. However, atropine
30 g/kg orally was less reliable than 20 g/kg intramuscularly.19
Rectal administration of 30 g/kg atropine in conjunction with a
sedative drug is commonly used in pediatric practice.22,23 Atropine
50 g/kg given intratracheally rapidly increases heart rate in
anesthetized children,24 whereas after 20 g/kg, the onset of action
is delayed.25 Therefore, in emergency situations, 50 to 100 g/kg
should probably be used; however, the current American guidelines recommend only 30 g/kg.26 The maximum I.V. dose in children is 50 g/kg.
ADVERSE EFFECTS
AND OVERDOSE: Adverse effects are dosedependent (increasing order): (1) Mouth dryness, mydriasis,
accommodation paralysis, constipation, (2) tachycardia, headache,
hyperthermia, (3) irritability, facial erythema, urinary retention,
and (4) confusion, delirium, convulsion, coma. The side effects
are usually related to the vagolytic action. Small doses of atropine
can initially lower the pulse rate by a mechanism still under
debate.27 Because this phenomenon occurs also in vagotomized
animals, a central action may not be essential. Different affinities
to subtypes of muscarinic receptors may be important. In contrast
to adults,28 central nervous system (CNS) effects (e.g., agitation or
delirium) do not seem to be a clinical problem in children; however, overdosage29 and intoxication30,31 have been reported. True
allergies to atropine are extremely rare, if they exist at all. Transient
cutaneous reactions, however, after I.V. administration or local
reactions after ophthalmic use are occasionally seen.
DRUG INTERACTIONS: No major drug interactions occur provided atropine is not mixed with other agents in the same syringe.
The treatment of reflex bradycardia induced by vasoconstrictors
with atropine can result in severe hypertension.
Glycopyrrolate
DRUG CATEGORY: Glycopyrrolate is an anticholinergic agent with
pronounced antisialogogue activity.32 It is a quaternary ammonium
compound and penetrates the CNS poorly. Therefore, it antagonizes muscarinic effects of acetylcholine only outside the CNS.
for antagonizing parasympathomimetic side effects of neostigmine. The recommended dose is 10 g/kg intravenously, half the
dose of atropine, together with 50 g/kg of neostigmine. The drug
is as effective as atropine in preventing the oculocardiac reflex.35
For the treatment of acute bradycardia, however, atropine is still
the drug of choice.
Scopolamine (Hyoscine)
DRUG CATEGORY: Scopolamine is an anticholinergic agent. It is a
tertiary amine and has, by contrast to atropine, profound CNS
effects, such as sedation and amnesia. Scopolamine antagonizes
the muscarinic effects of acetylcholine. Furthermore, the drug has
moderate antiemetic activity. Scopolamine is less effective in
blocking the cardiac vagal response and has a greater drying effect
than atropine.
PHARMACOKINETICS AND METABOLISM: Scopolamine has a
distribution volume of 1.4 L/kg and undergoes enzymatic hydrolysis to scopine and tropic acid. The pharmacokinetics of scopolamine and especially their relation to clinical response are
poorly understood.18
CLINICAL USE AND DOSAGE: The drug has largely been used as
a sedative premedication (10 g/kg intramuscularly) in conjunction with I.M. morphine before cardiac surgery; resorption is
especially predictable after injection in the deltoid muscle.36 Rectal
administration of a slightly higher dose (25 g/kg) compares
favorably with I.M. application.37 The inclusion of morphinescopolamine in the premedication may be highly effective in
reducing arrhythmias during adenoidectomy38 but causes respiratory depression.39 In children with congenital heart disease, I.M.
morphine-scopolamine causes hypercarbia and desaturation to a
similar extent as oral midazolam,40 and therefore, monitoring
remains essential. Overall, the use of scopolamine as a sedative
premedication is declining, and in the authors opinion, benzodiazepines (e.g., midazolam) or clonidine is a more suitable drug.
A scopolamine patch can be used prophylactically for motion
sickness41 and postoperative vomiting4244 with moderate effectiveness.
ADVERSE EFFECTS AND OVERDOSE: Mydriasis owing to ocular

contamination41 as well as sedation44 and delirium45 may complicate the use of scopolamine, even after topical application.
DRUG INTERACTIONS: Sedative/hypnotic drugs may potentiate

the CNS depressant effects of scopolamine.
Ipratropium
Ipratropium is a quaternary ammonium compound and is, therefore, poorly absorbed when delivered via inhalation and has few
extrapulmonary effects46; but ocular contamination has also been
reported.47,48 Although 90% of the inhaled drug is swallowed, only
1% of the total dose is absorbed systemically. The drug is used in
the treatment of asthma and bronchospastic disorders in conjunction with topical steroids and stimulants.49,50 Unlike atropine,
ipatropium has no negative effects on mucociliary clearance.
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CHOLINESTERASE INHIBITORS
Anticholinesterases are mainly used to antagonize residual
neuromuscular blockade51 (neuromuscular blocking agents and their
reversal are discussed in Chapter 27). Inhibition of acetylcholinesterase prolongs the lifetime of acetylcholine competing with the
nondepolarizing relaxant; repeated occupation of the receptors by
acetylcholine occurs, leading to reopening of ion channels. The effect
of anticholinesterases is not restricted only to inhibition of
acetylcholinesterase but also includes prejunctional acetylcholine
releasing effects and some direct effects on the postjunctional
receptor. Neostigmine and pyridostigmine are themselves hydrolyzed by acetylcholinesterase similarly to acetylcholine, but much
more slowly, whereas edrophonium is not.
Successful and timely reversal of neuromuscular blockade with
actylcholinesterase inhibitors is possible only when plasma levels
of the curare compound are low; this indicates that some clinical
recovery has already occurred. Reversal is substantially more rapid
in younger age groups.5254 After administration of the anticholinesterase, reversal has to be reassessed using neuromuscular
monitoring in addition to clinical signs such as sustained head lift
in older children and adolescents55 or leg lift in neonates and infants
(Table 315).56
Neostigmine
DRUG CATEGORY: Neostigmine is a cholinesterase inhibitor,
mainly used to antagonize residual neuromuscular blockade. It
binds to the enzyme and is broken down similar to acetylcholine,
but much more slowly.
PHARMACOKINETICS AND METABOLISM: Neostigmine has a

distribution volume of 0.5 to 1.0 L/kg and is partly metabolized.
The elimination half-life of neostigmine is shorter in infants
(39 min standard deviation [sd] 5) and children (48 min sd 16)
than in adults (67 min sd 8), whereas distribution volumes are
similar.57 Renal failure delays plasma clearance of neostigmine and
edrophonium as much as or more than that of pancuronium.
CLINICAL INDICATIONS AND DOSAGE: Neostigmine 50 g/kg is
well established for the reversal of residual neuromuscular blockade. Neostigmine in smaller doses (e.g., 10 g/kg as a continuous
infusion over 30 minutes) may occasionally be used in postoperative paralytic ileus. Neostigmine, 10 to 40 g/kg intramuscularly or subcutaneously as needed, or orally (according to effect,
~2 mg/kg/d), is used in myasthenia gravis.58 For chronic treatment, however, oral pyridostigmine is the drug of choice.
Intrathecal neostigmine has been reported to produce spinally
mediated analgesia in a dose-dependent fashion.59,60 There have
1
2
been some reports on the neuraxial administration of neostigmine

to children6163; however, because of relevant side effects, this
approach is mainly of theoretical interest, and in the authors
opinion, there is no place for neuraxial neostigmine in pediatric
anesthesia.
Infants and children require a smaller dose (about two thirds)
to antagonize residual neuromuscular blockade than adults57
(Figure 312). There is, therefore, no justification for the excessive
doses of neostigmine formerly used in pediatric anesthesia.
Compared with edrophonium, neostigmine has been shown
to produce less variable and more complete recovery after
atracurium-induced blockade52; 50 g/kg neostigmine is, therefore, preferred for reversal in pediatric patients by most authorities.
ADVERSE EFFECTS: Signs of increased parasympathomimetic

stimulation may occur (e.g., bradycardia, atrioventricular block,
increased oral and bronchial secretions, or emesis and abdominal
cramps). The time course of action of neostigmine is suitably
matched by glycopyrrolate; simultaneous administration of both
drugs in a ratio of 1:5 results in a stable heart rate.
Edrophonium
TABLE 31-5. Cholinesterase Inhibitors
Onset of action
Duration of action
(clinical duration 12 h
with both drugs)
Usual dose
Vagolytic agent of choice
Elimination
T/
Figure 31-2. Dose-response curves for neostigmine in infants,

children, and adults. Reproduced with permission from
reference 57.
DRUG CATEGORY: Edrophonium is a cholinesterase inhibitor,
Neostigmine
Edrophonium
711 min
++
12 min
+
PHARMACOKINETIS AND METABOLISM: Edrophonium has a dis-
50 g/kg
Glycopyrrolate
50% renal
2080 min
1.0 mg/kg
Atropine
70% renal
30110 min
MODE OF ACTION: Edrophonium inhibits acetylcholinesterase.
mainly used to antagonize residual neuromuscular blockade.

tribution volume of 1.1 L/kg; in part, hepatic metabolism occurs
by conjugation with glucuronic acid. Elimination half-life and
distribution volumes of edrophonium are similar in infants,
children, and adults.64
Edrophonium has a more pronounced prejunctional effect than
neostigmine; however, the clinical importance of this finding is
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not completely understood. Edrophonium shows the greatest
selectivity between acetylcholinesterase and plasma cholinesterase,
the serum esterase that hydrolyzes succinylcholine and mivacurium. This is, however, not of clinical significance in the antagonism of a mivacurium-induced blockade because the difference
in selectivity is minimal at clinically reached concentrations.65
Furthermore, at the time when reversal is attempted, the plasma
concentrations of mivacurium are already very low, and in patients
with atypical cholinesterase, metabolism is minimal anyway.
CLINICAL INDICATIONS AND DOSAGE: Edrophonium is preferred

to neostigmine by some clinicians for reversing neuromuscular
blockade because of its faster onset of action and probably fewer
muscarinic side effects. Smaller doses of edrophonium (e.g., 0.03
0.1 mg/kg) may be used for diagnostic purposes in cases of myasthenia gravis. By contrast to neostigmine, infants and children
require equal or slightly higher doses than adults to antagonize
neuromuscular blockade.64 A dose of 1 mg/kg is usually recommended. Compared with neostigmine, edrophonium provides a
more rapid onset52,54 of reversal, but a less reliable final recovery.52
In particular, profound degrees of blockade are less reliably antagonized by edrophonium.66,67
ADVERSE EFFECTS: The time course of action of edrophonium
requires a rapid-acting vagolytic agent68; atropine 10 g/kg

30 seconds before edrophonium 1 mg/kg ensures minimal cardiovascular changes.64
glaucoma and convergent strabismus. Because the drug is systemically absorbed and inactivates plasma cholinesterase, prolonged
action of succinylcholine and probably mivacurium can occur.74
The drug is rarely used in children, however.
SELECTIVE RELAXANT
BINDING AGENTS
Selectively binding and encapsulating the active compound is a
new concept for reversing neuromuscular blockade.75,76 The first
drug of this class used in medicine is sugammadex, a modified
gamma-cyclodextrin that specifically encapsulates and binds the
aminosteroid neuromuscular blocking agents: Rocuronium
> vecuronium >> pancuronium. By contrast to cholinesterase inhibitors, sugammadex can successfully reverse even very profound
blockade (e.g., 3 min after the administration of rocuronium
1.2 mg/kg).77 High-dose rocuronium followed by sugammadex
could have a profile similar to that of succinylcholine.
Sugammadex
DRUG CATEGORY: Sugammadex (designation Org 25969) is a
modified gamma-cyclodextrin with a lipophilic core and a hydrophilic periphery (Figure 313). The molecular weight of sugammadex sodium salt is 2178 Da.
PHARMACOKINETICS AND METABOLISM: Sugammadex rapidly
Pyridostigmine
Pyridostigmine has a slightly slower onset of action than neostigmine. However, the drug is rarely used in pediatric anesthesia.
Oral pyridostigmine has a place in the treatment of myasthenia
gravis.69,70 It has to be given in up to 10 times higher doses compared with the I.V. route: 0.3 to 4 mg/kg orally every 4 to 6 hours
may be required. The treatment of myasthenia gravis requires the
expertise a pediatric neurologist.
binds rocuronium; equimolar doses should be sufficient to

antagonize the blockade (~4 mg sugammadex antagonizes 1 mg
rocuronium). Most sugammadex is excreted unchanged in the
urine. Sugammadex is biologically inactive, does not bind to
plasma proteins, and appears to be safe and well tolerated.
CLINICAL USE AND DOSAGE: The recommended doses depend

on the depth of the blockade (Table 316). At the time of this
Physostigmine
DRUG CATEGORY: Physostigmine, a cholinesterase inhibitor, is a
tertiary ammonium compound and, therefore, has profound CNS
effects.
PHARMACOKINETICS AND METABOLISM: The drug has an elimination half-life of 20 to 30 minutes. It is destroyed by hydrolysis at
the ester linkage.
CLINICAL USE AND DOSAGE: A dose of 10 to 30 g/kg intravenously (a typical initial pediatric dose is 0.5 mg) can be used to
treat unwanted CNS effects of scopolamine or atropine71; careful
monitoring for bradycardia is essential. Toxicity associated with
physostigmine consists mostly of seizures and cardiac arrhythmia
and occurs when used in the absence of anticholinergic symptoms.
In any case, its routine administration in case of emergence
delirium cannot be recommended.72 For intoxications with longacting compounds (e.g., biperidine), a continuous infusion with
30 g/kg/h may be suitable.73
Echothiopate Iodide
Echothiopate iodide (phospholine iodide), an irreversible cholinesterase inhibitor, is exclusively used topically for open-angle
Figure 31-3. Sugammadex, a gamma-cyclodextrin, is encapsulating rocurium. Reproduced with permission from Bom A,
Bradley M, Cameron K, et al. A novel concept of reversing
neuromuscular block: chemical encapsulation of rocuronium
bromide by a cyclodextrin-based synthetic host. Angew Chem
Int Ed Engl. 2002;41:266270. Copyright Wiley-VCH Verlag
GmbH & Co. KGaA.
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TABLE 31-6. Currently Used Doses of Sugammadex
TABLE 31-7. Dosage of Naloxone
Indication
Features
Routine reversal
Onto three twitches in

the train-of-four
Yes it is OK, Merci.
Early after rocuronium

up to 1.2 mg/kg
16
Profound blockade
Emergency reversal
Dose, mg/kg
Indication
Side Effects of Systemic
Opioids
Side Effects of Neuraxial
Morphine
writing, the clinical experience with sugammadex in children is

still very limited.
and somnolence
Urinary retention
OPIOID ANTAGONISTS
Pruritus
Naloxone
Nausea and vomiting
DRUG CATEGORY: Naloxone is a pure opioid antagonist with a

greater affinity for mu receptors than for delta or kappa receptors
(the partial antagonists, e.g., nalbuphine, are discussed in Chapter
25). The use of nalorphine, a less specific antagonist, is no longer
considered to be state-of-the-art.
AND METABOLISM: After I.V. administration, the onset of action is seen within 30 to 90 seconds. Naloxone
is metabolized primarily in the liver by conjugation with glucuronic
acid, with an elimination half-life of 60 to 90 minutes in adults and
over 3 hours in neonates. The duration of action is substantially
shorter than that of most opioid agonists. Naloxone can be given
intratracheally as well as intravenously or intramuscularly.
Suspected opioid
intoxication in the
emergency setting
Recommended Dose of Naloxone
12 g/kg, repeated q23min as

needed
14 g/kg, repeated q23min as
needed;
35 g/kg/h continuous infusion
12 g/kg; 35 g/kg/h continuous
infusion
12 g/kg; 0.51.0 g/kg/h
continuous infusion
0.51.0 g/kg/h continuous
infusion, limited efficacy
0.1 mg/kg for infants and children
20 kg or 5 y
2.0 mg for children > 20 kg or > 5 y
(titration using smaller doses
may be advantageous)
0.010.1 mg/kg intravenously,
intramuscularly, or intratracheally (emergency setting
0.1 mg/kg)
PHARMACOKINETICS
Neonatal resuscitation
CLINICAL USE AND DOSAGE: Naloxones indication is the reversal
in adults. This approach, however, has not entered clinical practice.

Nalmefene has a terminal half-life of 8.7 hours in children,87 which
is similar to that seen in adults. However, experience with these
drugs in pediatric patients is very limited. Naltrexone has been used
with moderate success in autistic children.88
of unwanted opioid effects such as respiratory depression, pruritus, and urinary retention. Careful titration is essential (Table
317) to restore adequate spontaneous ventilation without reversal
of analgesia. An initial dose of 1 to 2 g/kg intravenously, repeated
every 2 to 3 minutes as needed, is usually adequate. Substantially
higher doses are used for neonatal resuscitation or in the emergency
setting.26
The authors strong belief is that there is no place for routine
opioid antagonism in pediatric anesthesia. The drug may be
occasionally used, however, to antagonize side effects of neuraxial
opioids such as urinary retention or pruritus.78 Prophylactic
naloxone for this indication is not consistently effective; a high
incidence of urinary retention in children was still reported after
intrathecal morphine despite a prophylactic naloxone infusion.79
The co-administration of I.V. naloxone with I.V. morphine in
order to reduce the incidence of side effects was reported to be
beneficial in some8082 but not all83,84 studies. Despite encouraging
results in children,82 today, this concept is rarely used.
ADVERSE EFFECTS: The side effects are caused by the abrupt

cessation of the opioid effects. Therefore, severe pain and sympathetic activation with hypertension and tachycardia can result.
Naltrexone, Nalmefene
Naltrexone and nalmefene are both orally active, long-acting, pure
opioid antagonists with a greater affinity for mu-receptors than for
delta or kappa receptors. Oral naltrexone85 and nalmefene86 have
both been reported to reduce the side effects of epidural morphine
ANTAGONIST OF BENZODIAZEPINES
Flumazenil
DRUG CATEGORY: Flumazenil is a specific competitive antagonist at the benzodiazepine receptor, which is associated with
receptors for gamma-aminobutyric acid (GABA), the most
important inhibitory neurotransmitter in the CNS. Stimulation of
the GABA pathways produces anxiolysis, sedation, and muscle
relaxation. Flumazenil reverses these effects of benzodiazepines
(Table 318).
PHARMACOKINETICS
AND METABOLISM: Flumazenil has a

shorter duration of action than most benzodiazepines. The
volume of distribution is 0.77 to 1.6 L/kg, the elimination half-life
is 0.7 to 1.3 hours, and the drug is cleared rapidly by the liver,
metabolized, and excreted in the urine.90 Because the duration and
degree of reversal depend on the plasma concentration of benzodiazepine as well as the amount of flumazenil given, the sedative
and respiratory depressant effects of the benzodiazepine may last
longer than the antagonism produced by flumazenil.91
CLINICAL USE AND DOSAGE: Flumazenil is usually administered

intravenously. Rectal92,93 and sublingual administration is feasible,
but the onset of action is slower.94 After endotracheal administration of 1 mg flumazenil to adults, the peak plasma concentration
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TABLE 31-8. Reciprocal Dose Effects of Benzodiazepine
Agonists and Flumazenil
Effect
BZ Agonist
Flumazenil
Reversal
of the Effect
Anxiolysis
Low dose
needed
High dose
needed
Anticonvulsive
effect
Slight sedation
Reduced attention
Amnesia
Intense sedation
Muscle relaxation
Hypnosis
High dose
Postulated
Receptor
Occupancy, %
2030
2030
Low dose
2030
2030
50
50
6090
6090
is attained within 1 minute after administration.95 A dose of 10 g/

kg flumazenil intravenously may be effective after moderate doses
of midazolam; the rectal doses may be higher (e.g., 50 g/kg).
Although effective,96 antagonism of benzodiazepine effects
is rarely indicated. There is no place for routine antagonism
of bezodiazepine-induced sedation and anxiolysis in pediatric
anesthesia. Flumazenil, however, may be useful in certain circumstances (Table 319).
Paradoxical reactions to benzodiazepines occasionally occur.97,98
More common causes of agitation, however, are inadequate sedation and medical interventions in a frightened child. In true
paradoxical reactions, flumazenil can be successfully used.99,100
Even in delayed postoperative agitation after preoperative
midazolam, the use of flumazenil may be advantageous.101
Flumazenil-induced reversal of midazolam has been reported
for the wake-up test during scoliosis surgery.102,103
Flumazenil reverses benzodiazepine-induced airway obstruction.104,105 In the authors experience, in rare cases, this effect has
been helpful to ameliorate postoperative airway obstruction in
children with obstructive sleep apnea.
Although the use of flumazenil in comatose adult patients for
the diagnosis of drug overdose is being reexamined,106,107 there is
still a place for the empirical administration of both naloxone and
flumazenil in children.108 In comas not caused by benzodiazepines,
flumazenil was not consistently effective.109
ADVERSE EFFECTS: The main problems are inadequate sedation

and anxiety after acute benzodiazepine withdrawal. Seizures have
also been reported.110
TABLE 31-9. The Clinical Use of Flumazenil in
Paradoxical reactions to benzodiazepines

Wake-up test in scoliosis surgery
Benzodiazepine overdose
Diagnostic use in a comatose children
Postoperative airway obstruction after
benzodiazepine premedication
ANTAGONISTS OF
COAGULATION DISORDERS
Protamine
DRUG CATEGORY: Protamine sulfate is a polycationic, strongly
basic protein with a molecular weight of approximately 4500 Da.
It is extracted from the mature testes of fish of the family
Samonidae. Protamine combines ionically with heparin to form a
stable complex that is devoid of anticoagulant activity.
PHARMACOKINETICS AND METABOLISM: The antiheparin activity

starts 30 to 60 seconds after protamine administration and peaks
at about 5 minutes, with a clinical duration of approximately
2 hours. Protamine is eliminated by renal and hepatic pathways; in
animals, the half-life of the heparin-protamine complex was found
to be 24 minutes.
CLINICAL USE AND DOSAGE: Protamine is used to antagonize
BZ = benzodiazepine.
From reference 89.
Indications
Route of
Administration
I.V. or rectal
I.V.
I.V.
I.V.
I.V.
excess heparin after cardiopulmonary bypass or accidental heparin

overdose. Protamine has limited effectiveness against lowmolecular-weight heparin,111,112 and it is not active at all against
fondaparinux. One unit of protamine inactivates 1 unit of heparin;
however, the exact ratio depends on the type of heparin used.
Because heparin is eliminated with a dose-dependent half-life of
1 to 5 hours, the protamine dose may be reduced depending on the
timing of heparin administration (Table 3110). After high doses,
for example, after cardiopulmonary bypass, an identical number of
units of protamine as that of heparin is often administered,
although individualized dosing may be advantageous.113
ADVERSE EFFECTS AND OVERDOSE: Various side effects occur

(Table 3111).115 Rapid administration causes hypotension owing
to pulmonary vasoconstriction, myocardial depression, and
histamine release116118; anaphylactic or anaphylactoid reactions
may occur.119 Therefore, protamine should be given as a slow
infusion.120 Female sex, larger protamine dose, and smaller
heparin dose are each associated with increased risk.121 Despite
limited effectiveness,122 many protocols include the prophylactic
administration of histamine antagonists (e.g., clemastine 0.02 mg/
kg). An especially high incidence of anaphylactic reactions has
been reported in adult insulin-treated diabetics.123
In the absence of heparin, protamine interacts with platelets
and many proteins, including fibrinogen; these interactions may
account for its own anticoagulant activity.
Desmopressin
DRUG CATEGORY: Desmopressin (DDAVP) is a synthetic analogue
(1-desamino-8-D-arginine-vasopressin) of the natural hormone
vasopressin. The molecular changes produce prolonged antidiuretic
TABLE 31-10. Protamine Dosage in Relation to Time
of Heparin Administration
Delay After Heparin
Administration
Protamine Dosage
<30 min
3060 min
<2 h
1.0 unit protamine/1 unit heparin

From reference 114.
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TABLE 31-11. Side Effects of Protamine

Hypotension, Flush, Bradycardia
Respiratory system
Bronchoconstriction, dyspnea,
pulmonary hypertension
Anaphylactic or anaphylactoid
reactions
Increased bleeding
Allergic reactions
Overdose
activity and reduced cardiovascular effects compared with the original

substance, L-arginine-vasopressin. The vasopressin2 (V2) effect
stimulates endothelial cells to release von Willebrands factor,
tissue plasminogen activator (TPA), and certain prostaglandins.
PHARMACOKINETICS AND METABOLISM: DDAVP is
metabolized in the liver and different other sites with a terminal
half-life of 4 to 5 hours, independent of the way of administration.
CLINICAL USE
AND DOSAGE: DDAVP induces release of von

Willebrands factor, TPA and certain prostaglandins by the endothelial cells. It therefore ameliorates hemostasis in most patients
with von Willebrands disease (type I vWD),124,125 mild hemophilia
A (with a residual factor VIII activity > 10%),126 and a variety of
congenital and acquired thrombopathies.127,128 DDAVP has been
postulated to reduce bleeding in aspirin-pretreated adult cardiac
patients,129 but this is of questionable value.130
Specialized hematologic advice should be obtained in each
individual case; in type IIb vWD, DDAVP administration is
generally contraindicated, because thrombocytopenia may result.
In Glanzmanns thrombasthenia, the drug is not effective.
The usual I.V. dose of DDAVP to improve hemostasis is 0.4 g/
kg IV over 30 minutes, starting 1 to 1.5 hours before surgery. Intranasal administration of 300 g may be appropriate in adolescents
with vWD for minor surgery or dental extractions.131
When the drug is administered during or immediately before
surgery, the release of TPA and induction of fibrinolysis may
theoretically be a problem. However, the concentrations of TPA
tend to fall much more rapidly compared with Factor VIII levels
(Fig. 314). Co-administration of tranexamic acid or aminocaproic
acid has been recommended.
TABLE 31-12. Dosage of Desmopressin in the Treatment

of Diabetes Insipidus
Infants
Intravenously or
0.1 g as
intramuscularly
needed
Nasally
1.0 g as
needed
Orally
Children
Adolescents
0.41.0 g
12 daily
515 g
1-2 daily
0.10.2 mg
3 daily
14 g
12 daily
1040 g
12 daily
0.10.2 mg
3 daily
In general, in patients without a pre-existing bleeding disorder,

DDAVP is not considered effective for prevention of bleeding (e.g.,
during cardiac132136 or scoliosis137139 surgery). Reduced bleeding
has, however, been reported in one trial.140
For the treatment of diabetes insipidus, DDAVP can be administered by various routes: I.V., I.M., intranasal, or oral (Table
3112). Administration of DDAVP is part of some treatment
concepts for enuresis nocturna.141
ADVERSE EFFECTS AND OVERDOSE: The side effects after rapid

administration of large doses include flushing, hypotension, and
tachycardia. Especially in pediatric patients, careful observation
for water retention leading to hyponatremia and brain edema is
needed.142144 Regular monitoring of urine output, urine osmolarity, serum osmolarity, and serum concentrations of sodium and
potassium ise essential.
Aprotinin, Tranexamic Acid,

Aminocaproic Acid
These drugs inhibit proteinases and are used to reduce bleeding
thought to be caused by hyperfibrinolytic states (Table 3113),
most often in conjunction with cardiac surgery.145,146 For aprotinin,
prophylactic administration is essential; tranexamic acid and
aminocaproic acid can be used therapeutically. There is currently
a discussion concerning the safety of aprotinin; at the time of this
writing, this drug has been temporarily withdrawn from the
market.
Aprotinin
DRUG CATEGORY: Aprotinin, a highly basic polypeptide, is a
proteinase inhibitor that binds to a variety of enzymes (e.g.,
plasmin, trypsin, and kallikrein). Although the mechanism of
action has not yet been clearly established, it appears that aprotinin
has a protective effect on platelet function147 and an antifibrinolytic
activity via direct inhibition of plasmin and the kinin-kallikrein
system. Aprotinin may also partially inhibit the intrinsic coagulation pathway. Overall, evidence indicates that aprotinin attenuates
the systemic inflammatory response associated with cardiopulmonary bypass.148150
PHARMACOKINETICS AND METABOLISM: Aprotinin is of bovine
origin and is metabolized in peripheral cells to small metabolites.
Figure 31-4. Time course of release of Factor VIII, von Willebrand factor (vWf) and tissue plasminogen activator (tPA) after
the administration of 0.4 g/kg desmopressin. The plasma level
of tPA rapidly decreases. Reproduced with permission from reference 128.
CLINICAL USE AND DOSAGE: Aprotinin reduced blood loss after

pediatric cardiac surgery in some151153 but not all154 trials. It has
become a routine part of practice (Table 3114) in a large number
of pediatric heart centers155,156 and is recommended especially for
reoperations and complex surgery with multiple suture lines.
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TABLE 31-13. Comparison of Aprotinin and Tranexamic Acid and Aminocaproic Acid
Source
Costs
Elimination
Mechanism of action
Side effects
Cardiac surgery
Miscellaneous indications
Aprotinin
Tranexamic Acid and Aminocaproic Acid
Bovine
Very high
Peripheral metabolism
Multifactorial
Allergic reactions
Renal failure
Increased long-term mortality in adults
Clearly effective
Liver transplantation
Synthetic
Low
Renal elimination, unchanged
Inhibition of fibrinolysis
Rare, myopathy reported
Pediatric lung transplantation

Major orthopedic surgery
Aprotinin reduces blood loss157 and improves hemodynamic

stability158 in liver transplantation. Positive effects have also been
reported in pediatric lung transplantation159 and scoliosis surgery.160 In adults, decreased blood loss was shown after major
orthopedic surgery161 and in total hip162,163 and knee164 replacement. Improved hemostatis was not evident, however, after aortic
surgery.165
ADVERSE EFFECTS: The main drawbacks of aprotinin are the

potential for anaphylactic reactions166 and the substantial cost. The
drug should be administered by slow infusion; a test dose of 10,000
units some minutes in advance is recommended.
In adults, the use of aprotinin has been related to an increased
mortality in cardiac surgery167 and to a higher rate of renal failure
after cardiac168 or spine surgery.169 No adverse effects of aprotinin
on renal or hepatic function have been reported in pediatric
studies so far.155 The incidence of deep venous162,163 or arterial
graft170 thrombosis is not increased. In vitro coagulation is influenced by aprotinin: if kaolin is employed as an activator of the
activated clotting time (ACT), aprotinin is bound to this activator
and is, therefore, unable to develop its anticoagulatory properties
in vitro. The celite ACT produces reliable results.171
Moderately effective
Oral bleeding (especially in conjunction with
hemophilia or von Willebrands disease)
Bleeding from the lower urinary tract
Gastrointestinal bleeding
Hereditary angioneurotic edema
Bleeding during fibrinolytic treatment
fibrinolysis in renal bleeding, however, can lead to obstructive

uropathy, and the drug is therefore contraindicated.
Aminocaproic acid is theoretically capable of competitively
inhibiting thrombolytic agents such as streptokinase, urokinase,
and TPA. However, the profound hemostatic deficits after fibrinolytic therapy are a result of the interaction of circulating fibrin
and fibrinogen degradation products with the platelet surface and
with fibrinogen polymerization.
Aminocaproic acid has been used to reduce postoperative
cardiac surgical bleeding in adults168 and children.173 A loading
dose of 100 to 200 mg/kg is infused over 30 to 60 minutes, which
is followed by 30 mg/kg/h.174
Aminocaproic acid is administered in conjunction with
DDAVP or factor replacement therapy to reduce oral bleeding in
patients with hemophilia A, hemophilia B, or vWD. The drug is
also used to prevent exacerbations in patients with hereditary
angioneurotic edema.
ADVERSE EFFECTS: Severe side effects rarely occur, but hypotension, bradycardia, and arrhythmias have been reported following
rapid I.V. administration. With prolonged treatment, muscle pain
and rhabdomyolysis may occur. A reversible myopathy has been
described in a child.175
Aminocaproic Acid
DRUG CATEGORY: Aminocaproic acid (epsilon-aminocaproic acid
[EACA]), a synthetic lysine analogue, is a competitive inhibitor of
plasminogen and plasmin. Most of the drug is recovered unmetabolized in the urine.
CLINICAL USE AND DOSAGE: Aminocaproic acid is indicated in

the treatment of bleeding owing to primary fibrinolysis. Fibrinolysis associated with surgery of the lower genitourinary tract has
been successfully treated with aminocaproic acid.172 Inhibition of
TABLE 31-14. Dosage of Aprotinin for Cardiac Surgery
Before Sternotomy
30,000 units/kg
CPB priming dose

During surgery
30,000 units/kg
7000 units/kg/h continuous infusion
CPB = cardiopulmonary bypass.
Tranexamic Acid
DRUG CATEGORY: Tranexamic acid is a lysine analogue that
competitively binds to the lysine-binding sites of plasmin
and plasminogen. It inhibits fibrinolysis with a 6- to 10-fold
greater potency than aminocaproic acid and is used for similar
indications.
PHARMACOKINETICS: The drug is eliminated unchanged by the

kidneys with a terminal elimination half life of 1.9 to 2.7 hours in
adults.
CLINICAL USE AND DOSAGE: Tranexamic acid has been shown to

reduce blood loss after adult cardiac surgery.168 In pediatric
patients, a single dose of 50 mg/kg showed only a moderate effect
in subgroups.176 Efficacy is improved using higher doses followed
by a continuous infusion (Table 3115).177 Beneficial effects have
been shown in spine surgery as well.178
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TABLE 31-15. High-dose Treatment with Tranexamic

Acid for Repeat Cardiac Surgery
Before Sternotomy
100 mg/kg
CPB priming dose

During surgery
100 mg/kg
10 mg/kg/h continuous infusion
CPB = cardiopulmonary bypass.

From reference 177.
TABLE 31-16. Tranexamic Acid in Oral Bleeding in

Hemophilia Patients
Intravenous route
3 10 mg/kg, 3 1.0 g
Oral route
Mouth wash for
cooperative children
3 25 mg/kg (3 1.5 g)
5% prepared by diluting 10%
I.V. solution 1:1 with saline
Smaller doses of tranexamic acid (Table 3116) are effective in

conjunction with DDAVP or factor replacement therapy to reduce
oral bleeding in patients with hemophilia A, hemophilia B, or
vWD.126
ADVERSE EFFECTS: Severe side effects rarely occur, although

rhabdomyolysis and renal insufficiency have also been reported. Inhibition of fibrinolysis in renal bleeding can lead to
obstructive uropathy, and tranexamic acid is therefore contraindicated.
Figure 31-5. Schematic view of the coagulation pathway.
Factor VIII
DRUG CATEGORY: Coagulation factor, a plasma-derived or
recombinant protein, molecular weight 270 kDa, in lyophilized
form to be stored at 2 to 8C, and to be used within 3 hours after
reconstitution. The currently used plasma-derived products are
monoclonal antibodypurified and undergo a viral attenuation
process with a solvent detergent or by pasteurization.
PHARMACOKINETIC PROPERTIES: One unit of Factor VIII raises
Antihemophilic Factors
the plasma level by approximately 2% (0.02 U/mL). Its half-life in

the circulation is biphasic, averaging approximately 12 hours.
Congenital (e.g., hemophilia A and B) or acquired defects of the

coagulation pathway (Figure 315) may need factor replacement
therapy. It is important to specify that, even in case of mild forms
of hemophilia (Table 3117), in which spontaneous bleeding
rarely occurs, replacement therapy is crucial in case of major
trauma or surgery. Specialized hematologic advice should be
obtained in each individual case.
A variety of plasma-derived or recombinant products are
available throughout the different countries. The increase in
quality since about 2000 has markedly increased cost.
CLINICAL USE AND DOSAGE: Factor replacement therapy guidelines

for hemorrhage related to hemophilia are outlined in Table 3118.
In addition of factor replacement, antifibrinolytics are used in oral
bleeding (see Chapters 32 and 53), and prednisone, 1 to 2 mg/kg/d
for 5 to 7 days in case of hematuria.
Subsequent dosing usually includes 50% of the initial dose
every 8 to 12 hours for Factor VIII and every 12 to 24 hours for
Factor XI. In severe bleeding, continuous infusions may be
considered when high-purity preparations are available. Rigorous
daily laboratory monitoring of factor levels is mandatory.
TABLE 31-17. Laboratory and Clinical Manifestations of Hemophilia

Factor VIII/IX activity level
Normal 50150% (0.51 U/ml)
% of all hemophilia A
% of all hemophilia B
Bleeding Manifestations
Age of onset
Neonatal symptoms
Muscle/joint hemorrhage
CNS hemorrhage
Postsurgical hemorrhage without
prophylaxis
Oral hemorrhage after tooth extraction
Severe
< 1%
70
50
Moderate
15%
15
30
Mild
> 5%
5
20
<1 y
PCB usually
ICH occasionally
Spontaneous
High risk
Frank bleeding, severe
12 y
PCB usually
ICH uncommonly
Minor trauma
Moderate risk
Wound bleeding common
Usual
Common
2 yadult
PCB one
ICH rare
Major trauma
Rare
Wound bleeding with factor
< 3%
Often
CNS, central nervous system; ICH, intracranial hemorrhage; PCB, postcircumcision bleeding.
Adapted from Hathaway W, Goodnight S: Disorders of hemostasis and thrombosis, New York, McGraw-Hill, 1993.
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TABLE 31-18. Guidelines for Factor Replacement Therapy
for Hemorrhage in Hemophilia
Bleeding
Hemostatic
Factor
Level, %
Mild
1525
Low-risk site
Moderate
2550
Joint, muscle
Severe
>60
CNS bleeding
Mouth floor
or tongue
Trauma or surgery
Hemophilia
A Initial
Dose Factor
VIII, U/kg
Hemophilia
B Initial
Dose Factor
VIII, U/kg
1525
2530
2540
4060
5070
80100
PHARMACOKINETIC PROPERTIES: One unit of Factor IX raises the

plasma level by approximately 1% (0.01 U/mL), having a larger
volume of distribution than that of Factor VIII. Factor IX has a
plasma half-life averaging approximately 24 hours.
CLINICAL USE AND DOSAGE: Factor replacement therapy guidelines for hemorrhage related to hemophilia are outlined in Table 31
18, the guidelines for prophylactic substitution are in Table 3119.
Low-purity, Factor IXcontaining concentrates can be used to
replace all vitamin Kdependent factors in order to acutely
antagonize oral anticoagulation.
ADVERSE EFFECTS: As with Factor VIII, the risks of potential virus

transmission and inhibitor development exist (see Chapter 53). Lowpurity, Factor IXcontaining concentrates can contain significant
amounts of activated Factors VII and X and prothrombin; therefore,
these products have been implicated as causes of disseminated
intravascular coagulation and thrombosis.
Prophylactic factor replacement is proposed to reduce the

incidence of hemarthroses with subsequent irreversible joint
injury (Table 3119). Implanted central venous access devices may
be useful.
Recombinant or highly purified products do not contain von
Willebrand factor, which has a critical role in platelet function and
thrombus formation and is the carrier protein for Factor VIII in
plasma.
ADVERSE EFFECTS: During the early 1980s, high percentages of

patients with hemophilia were infected with HIV and hepatitis C.
Donor screening, as well as modern purifying and viral inactivation technologies, minimized these risks. Recombinant products
appear to be safe.
Development of polyclonal antibodies to Factor VIII or IX
that inhibit factor coagulant activity is one of the most lifethreatening complications. Inhibitors develop in 20 to 33% of persons with moderate to severe hemophilia A; however, inhibitors
occur only in 1 to 4% of persons with hemophilia B; inhibitors are
measured in Bethesda units (BUs). The treatment for bleeding in
the presence of an inhibitor can be challenging: in cases with low
Bethesda titers, replacement therapy with higher doses of factor
is feasible. Further options are activated Factor VII, temporary
removal of the antibody by plasmapheresis, or the use of porcine
Factor VIII or prothrombin complex concentrates.
Factor IX
DRUG CATEGORY: Coagulation factor, a plasma-derived glycoprotein, molecular weight 68 kDa, in lyophilized form to be stored
at 2 to 8C and to be used within 3 hours after reconstitution.
The currently used products are purified and undergo a viral
attenuation process.
TABLE 31-19. Guidelines for Prophylactic Factor
Replacement in Hemophilia
Hemophilia A
Hemophilia B
Dose, U/kg
Number of Doses
2030
3040
3 Doses weekly
2 Doses weekly
Factor VII
DRUG CATEGORY: Factor VII is plasma-derived coagulation factor
in lyophilized form to be stored at 2 to 8C, for immediate use
after reconstitution.
PHARMACOKINETIC PROPERTIES: One unit of Factor VII raises
the plasma level by approximately 2% (0.02 U/mL). The half-life
in the circulation averages 4 to 6 hours.
CLINICAL USE AND DOSAGE: The product is exclusively used in

the case of isolated Factor VII deficiency. Initial dosing is similar
to that for Factor VIII, but repeat doses have to be given more
often, every 6 to 8 hours.
Activated Factor VII

DRUG CATEGORY: Activated Factor VII is a recombinant activated coagulation factor, in lyophilized form to be stored at 2 to
8C, a glycoprotein, similar to the human plasmaderived compound.
PHARMACOKINETIC PROPERTIES: The half-life in the circulation
averages 3 hours.
CLINICAL USE AND DOSAGE: The product is indicated in normal

or hemophiliac patients with inhibitors against Factor VIII or
IX.179 The initial dosing is 60 to 120 g/kg as I.V. injection, repeated doses may be administered every 2 to 4 hours. It is being
increasingly used in uncontrollable hemorrhage of other origin in
adults and in children.180,181 The rationale for its use in hemorrhage
is that it will only induce coagulation at those sites where tissue
factor is also present and, therefore, initiates clot formation,
sealing the disrupted vessel.
Factor I, Fibrinogen
DRUG CATEGORY: Factor I, fibrinogen, is a plasma-derived coagulation factor in lyophilized form to be stored at 2 to 8C, for
immediate use after reconstitution. It is a glycoprotein with a
molecular weight of 340 kDA.
PHARMACOKINETIC PROPERTIES: The metabolic half-life averages
96 to 144 hours. Fibrinogen is an acute-phase protein, elevated in
any form of inflammation.
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CLINICAL USE AND DOSAGE: Sufficient amounts of fibrinogen

are needed to form a stable hemostatic plug or clot. The product
is indicated in acute bleeding when insufficient clot firmness is
suspected (e.g., by modified thrombelastography). The commonly
used initial dose is 30 mg/kg, given as a rapid I.V. infusion. The
perioperative treatment of congenital afibrinogenemia requires
specialized hematologic advice.182
ANTAGONIST OF
MALIGNANT HYPERTHERMIA
Dantrolene
DRUG CATEGORY: Dantrolene is a hydantoin drug initially used
for the treatment of spasticity. Its primary action is to reduce
sarcoplasmatic reticular release of calcium and thereby to lower
intramyoplasmatic calcium concentrations. This makes dantrolene
highly effective for the treatment of malignant hyperthermia
(MH).183 The management of malignant hyperthermia is discussed
in Chapter 81.
PHARMACOKINETICS
AND METABOLISM: Dantrolene is metabolized to 5-OH-dantrolene, which has 50% of the activity
of dantrolene. After a single dose of 2.4 mg/kg, whole blood concentrations have been reported to exceed 3 g/mL for approximately 6.5 hours. The concentrations decreases with an
elimination half-life of 10 hours.184 A significant placental transfer
occurs, the fetal-maternal ratio averages 0.4.185
COMMERCIAL PRESENTATION: Each vial contains 20 mg of

lyophilized dantrolene, sodium hydroxide, and 3 g of mannitol (to
make the solution isotonic). The drug has to stored protected from
light at ambient temperature (1525C). Reconstitution is timeconsuming and can be done only with sterile water.
CLINICAL USE AND DOSAGE: An I.V. dose of 2.5 mg/kg is the
mean effective dose for treating clinical MH episodes. Repeated
doses at 1 to 2 mg/kg may be given, as needed, up to 10 mg/kg.
Following initial control of the MH crisis, a continuous infusion
of 10 mg/kg/d is recommended by some authorities.183,186
The present consensus is that, in most instances, prophylactic
dantrolene is not needed in MH-susceptible patients. If used, the
dose is 2.5 mg/kg intravenously, given only just before induction,
because clinically significant muscle weakness is induced even
with oral dantrolene prophylaxis.187 On rare occasions, however,
trigger-free anesthesia may also be followed by MH reactions in
the immediate postoperative period.188
For the treatment of spasticity, dantrolene 1 to 2 mg/kg/d orally,
is occasionally used. Because fever of other origin is also lowered
by dantrolene,189 response to dantrolene cannot by itself confirm
the diagnosis of MH.
AND OVERDOSE: The side effects include
drowsiness, dizziness, and fatigue. Because dantrolene can cause
significant muscle weakness, leading to difficulty in swallowing
or even respiratory insufficiency,187 careful observation of the
patient is mandatory. Significant potentiation of neuromuscular
blocking drugs can be seen on mechanical recordings, but not
when electromyographic techniques are used. After repeated
infusions, thrombophlebitis is common. Liver toxicity, cholestasis,
may be a problem with long-term oral treatment.
TABLE 31-20. Dosage of N-Acetylcysteine as a

Mucolytic Drug
Infants
Children 27 y of age
Children > 7 y and adults
Intensive treatment, all pediatric
age groups
2 100 mg daily orally

23 300 mg intravenously
daily
ANTAGONIST OF ACETAMINOPHEN
(PARACETAMOL) TOXICITY
N-Acetylcysteine
DRUG CATEGORY: N-Acetylcysteine, a modified amino acid,
molecular weight 163.2 Da, is used for mucolysis and for treatment
of acetaminophen toxicity.
PHARMACOKINETICS AND METABOLISM: It is rapidly metabolized
to cysteine, a precursor of glutathione. Oral N-acetylcysteine is
rapidly absorbed; the peak plasma level occurs at about 1 hour.
The drug is eliminated with a half-life of 1 to 5 hours, in part by
renal excretion.
CLINICAL USE AND D OSAGE: N-Acetylcysteine has a free

sulfhydryl group that enables S-S bond in mucus to be split.
N-Acetylcysteine therefore has mucolytic properties, and can be
used systemically or by topical administration (Table 3120). A
4.8% solution is considered to be isotonic.
N-Acetylcysteine is the treatment of choice in acetaminophen
(paracetamol) poisoning and, when administered less than
16 hours and even up to 24 hours after acute ingestion, has a profound effect in lowering morbidity and mortality. N-Acetylcysteine
reduces the extent of acetaminophen-induced glutathione
depletion and thereby lessens the amount of toxic intermediate
metabolites (Fig. 316). The risk of hepatic damage can be assessed by correlating the time of ingestion with a single acetaminophen plasma estimation (Figure 317).190 As a rough guide,
ingestion of more than 150 mg/kg of acetaminophen should be
considered potentially toxic. Severe liver toxicity is probable after
250 mg/kg and certain after 350 mg/kg in adults. Little is known
about the toxic potential of the protracted administration of
repeated excessive doses of acetaminophen, the most common
ADVERSE EFFECTS
Figure 31-6. Metabolism of acetaminophen; N-acetylcysteine

restores glutathione and prevents toxicity.
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TABLE 31-22. Drug-Induced Methemoglobinemia
of Anesthetic Importance
Local anesthetics
Antimicrobial and
antiseptic agents
Vasodilatators
Analgesic-antipyretic
agents
Surface-acting agents
Miscellaneous
Prilocaine,203205 benzocaine,206,207
lidocaine208,209
Dapsone,210,211 chloroquine, sulfonamide
derivates, phenazopyridine
Amyl nitrate, nitroglycerine, sodium
nitroprusside
Acetanilid, p-aminosalicylic acid,
phenacetin
Silver nitrate, aniline dyes212
Nitric oxide213
From reference 202.
Figure 31-7. Acetaminophen toxicity nomogram. It is mainly

based on adult data, but is commonly applied to children too.
Redrawn after reference 190.
cause of toxicity in children.191194 If in doubt, treatment with
N-acetylcysteine should immediately be started (Table 3121).
With early initiation, oral treatment seems to be safe.195,196 With
delayed diagnosis and in severe cases, I.V. treatment is recommended.197 N-Acetylcysteine is an extremely safe drug and even
delayed administration will not worsen liver failure should it
develop. However, if liver function abnormalities are already
present, it is probably too late for N-acetylcysteine treatment to be
of any use.
ADVERSE EFFECTS: The most prominent side effect is often an

exorbitant amount of liquid secretions that may become difficult
for the patient to deal with. With I.V. administration, anaphylactoid
reactions occasionally occur, but treatment can usually be continued
after symptomatic medication.198 The high reductive potential of
N-acetylcysteine can cause instability of mixtures with other drugs
or leads to problems in case of contact with medical equipment.
ANTAGONISTS OF
METHEMOGLOBINEMIA
Methemoglobin (MetHb) is a derivative of normal hemoglobin in
which the iron of the heme complex has been oxidized from the
ferrous (Fe2+) to the ferric (Fe3+) form. It does not combine with
oxygen and, thus, does not take part in oxygen transport. Furthermore, the oxygen-binding curve is shifted to the left. In normal
red blood cells, MetHb is continually being formed, but it is
TABLE 31-21. N-Acetylcysteine in Acetaminophen
(Paracetamol) Overdose
I.V. administration
Oral administration
(if I.V. Nacetylcysteine
is not available)
150 mg/kg over 15 min

50 mg/kg over the next 4 h
100 mg/kg over the next 16 h
(infusions mixed in 5% dextrose)
140 mg/kg loading dose
70 mg/kg q4h (17 doses)
(A dose should be repeated if vomiting
occurs within 1 h of administration)
immediately reduced by two enzymatic systems, the nicotinamide

adenine dinucleotide, reduced form (NADH)methemoglobin
reductase and the nicotinamide adenine dinucleotide phosphate,
reduced form (NADPH)methemoglobin reductase. The concentration of MetHb under normal condition is therefore kept
under less than 1% of the total hemoglobin.
When MetHb rises to 10%, cyanosis is usually detectable clinically. Symptoms appear at concentrations above 20%, and concentrations exceeding 70% may be fatal. However, an elevated
MetHb concentration always reduces the margin of safety of the
oxygen carrying system and may put certain patients at risk
(e.g., small infants, children with cardiac or pulmonary disease).
Congenital methemoglobinemia is caused either by insufficient
production of the enzyme NADH-methemoglobin reductase or
by abnormal hemoglobin (Hb M) variants.
Acquired methemoglobinemia is most commonly induced in
young infants by nutritive factors, mainly nitrate-contaminated
water199 or inadequately stored vegetables,200,201 providing too
much oxidative stress to hemoglobin in the presence of a still
immature MetHb reductase system.
In addition, drug-induced methemoglobinemia has been associated with a number of agents (Table 3122).
In anesthetic practice, prilocaine is the most common cause of
methemoglobinemia. Because MetHb reductase reaches adult
activity only at the age of 3 months,203 severe methemoglobinemia
can occur in small infants even after moderate doses of prilocaine.203205 Methemoglobinemia has been also reported after topical use of prilocaine, EMLA (eutectic mixture of local anesthetics)
Cream205,214; but clinically relevant MetHb concentrations are
rarely reached212,215 (local anesthetics are discussed in Chapter 28).
Although lidocaine-induced methemoglobinemia has been
reported,208,216 it is unlikely to cause relevant MetHb concentrations in clinically used doses.209
Methemoglobinemia influences pulse oximeter (SpO2) readings; it has a high absorption of light at both currently used
wavelengths, 660 and 940 nm. Therefore, at moderate levels of
MetHb below 10%, SpO2 is reduced by approximately 1% for each
2% of MetHb; high MetHb concentrations will drive SpO2 toward
85% regardless of oxygen tension.217 Therefore, even with methemoglobinemia of known origin, MetHb has to be measured in case
of SpO2 readings below 90% (Figure 318).
Methylene Blue
DRUG CATEGORY: Methylene blue, a color dye, is used to mark
fistula tracts or as an antidote in case of methemoglobinemia.
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confusions have been reported after methylene blue 5 to 7.5 mg/kg
in order to stain the parathyroid glands.220222 The drug has the
potential for direct neurotoxicity and must not be administered
close to neural structures. Methylene blue causes intense coloration of all body fluids; the child and parents have to be warned in
advance.
Ascorbic Acid
Ascorbate and other antioxidant nutrients are presumed to play a
pivotal role in minimizing the damage from oxidative products,
including free radicals.223 In patients with acquired methemoglobinemia, ascorbic acid has only a modest activity224 and does
not reliably reduce methemoglobin levels.225 It is occasionally
given as a nutritive additive in patients with congenital methemoglobinemia226; however, reliable data on optimal dosing and
efficacy are not available.
Figure 31-8. Dependence of oxygen saturation of hemoglobin
(SaO2) and the pulse oximeter results (SpO2) on the methemoglobin concentration. Reproduced with permission from
reference 217.
PHYSICOCHEMICAL PROPERTIES: Soluble in water and ethanol,

the drug is usually commercialized as 1 to 2% aqueous solutions,
molecular weight 319.9 Da, maximal light absorbency at 668.6 nm.
During storage, the drug should be protected from heat and light.
PHARMACOKINETICS AND METABOLISM: Fifty-three to 97% of

the drug is absorbed from the gastrointestinal tract. Methylene
blue is reduced in peripheral tissues and undergoes slow renal
elimination. Overall, its pharmacokinetics are poorly understood.
CONTRAINDICATIONS: Methylene blue should not be given to

patients with glucose-6-phosphate dehydrogenase deficiency,
because the hexose monophosphate shunt regenerates NADPH.
With deficient NADPH regeneration, methylene blue may cause
hemolytic anemia. Methylene blue will also be ineffective in the
presence of Hb M variants. Exchange transfusion is effective in
such situations. The drug has been associated with jejunal atresia
after intra-amniotic injection during pregnancy.218
MODE OF ACTION: Methylene blue acts as an electron carrier for

the NADPH-methemoglobin reductase and causes a marked
increase in its normally insignificant activity; therefore, MetHb is
rapidly reduced.
CLINICAL USE AND DOSAGE: In case of symptomatic methemoglobinemia, methylene blue 1 to 2 mg/kg diluted with normal
saline is infused over 5 minutes. The delay of action is only a few
minutes; the maximal effect is reached at 1 hours. Additional
dosing, up to a total of 7 mg/kg, may necessary. In case of congenital disorders, oral treatment is theoretically feasible (11.5 mg/
kg/d), however, specialized hematologic advice should be obtained.
Further use of methylene blue involves viral attenuation in
blood products and cytoprotective effects in conjunction with
antineoplastic therapy.
ADVERSE EFFECTS
AND OVERDOSE: Rapid administration of

methylene blue leads to transient spurious readings with SpO2,217
as long as venous and arterial concentrations differ significantly.
High levels of methylene blue directly oxidize hemoglobin to
cause methemoglobinemia.219 Prolonged altered mental state and
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anaesthesia, a survey of their present position. Anaesthesia. 1978;33:
133138.
2. Jhr M. Is it time to question the routine use of anticholinergic agents in
paediatric anaesthesia? Paediatr Anaesth. 1999;9:99101.
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156. Groom RC, Akl BF, Albus R, et al. Pediatric cardiopulmonary bypass: a
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163. Murkin JM, Shannon NA, Bourne RB, et al. Aprotinin decreases blood
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166. Ryckwaert Y, Barthelet Y, Bonnet-Boyer MC, et al. Anaphylactic shock
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169. Okubadejo GO, Bridwell KH, Lenke LG, et al. Aprotinin may decrease
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170. Lemmer LH, Stanford W, Bonney SL, et al. Aprotinin for coronary
bypass opeations: efficacy, safety, and influence on early saphenous vein
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171. Dietrich W, Dilthey G, Spannagl M, et al. Influence of high-dose
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172. Osborne RW. Safety and efficacy of epsilon-aminocaproic acid in
postprostatectomy bleeding. Curr Ther Res. 1982;31:839.
173. Chauhan S, Das SN, Bisoi A, et al. Comparison of epsilon aminocaproic
acid and tranexamic acid in pediatric cardiac surgery. J Cardiothorac
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174. Bennett-Guerrero E, Sorohan JG, Canada AT, et al. -Aminocaproic acid
plasma levels during cardiopulmonary bypass. Anesth Analg. 1997;85:
248251.
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associated myopathy in a child. J Pediatr Hematol Oncol. 1995;17:5355.
176. Zonis Z, Seear M, Reichert C, et al. The effect of preoperative tranexamic
acid on blood loss after cardiac operations in children. J Thorac
177. Reid RW, Zimmerman AA, Laussen PC, et al. The efficacy of tranexamic
acid versus placebo in decreasing blood loss in pediatric patients
undergoing repeat cardiac surgery. Anesth Analg. 1997;84:990996.
178. Shapiro F, Zurakowski D, Sethna NF. Tranexamic acid diminishes
intraoperative blood loss and transfusion in spinal fusions for duchenne
muscular dystrophy scoliosis. Spine. 2007;32:22782283.
179. Konkle BA, Ebbesen LS, Erhardtsen E, et al. Randomized, prospective
clinical trial of recombinant factor VIIa for secondary prophylaxis
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19041913.
180. Agarwal HS, Bennett JE, Churchwell KB, et al. Recombinant factor seven
therapy for postoperative bleeding in neonatal and pediatric cardiac
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181. Mathew P. The use of rFVIIa in non-haemophilia bleeding conditions in
paediatrics. A systematic review. Thromb Haemost. 2004;92:738746.
182. Santacroce R, Cappucci F, Pisanelli D, et al. Inherited abnormalities of
fibrinogen: 10-year clinical experience of an Italian group. Blood Coagul
Fibrinolysis. 2006;17:235240.
183. Krause T, Gerbershagen MU, Fiege M, et al. Dantrolenea review of its
pharmacology, therapeutic use and new developments. Anaesthesia.
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184. Lerman J, McLeod ME, Strong HA. Pharmacokinetics of intravenous
dantrolene in children. Anesthesiology. 1989;70:625629.
185. Shime J, Gare D, Andrews J, et al. Dantrolene in pregnancy: lack of
adverse effects on the fetus and newborn infant. Am J Obstet Gynecol.
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186. Wappler F. Malignant hyperthermia. Eur J Anaesthesiol. 2001;18:
632652.
187. Watson CB, Reierson N, Norfleet EA. Clinically significant muscle
weakness induced by oral dantrolene sodium prophylaxis for malignant
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188. Carr AS, Lerman J, Cunliffe M, et al. Incidence of malignant hyperthermia reactions in 2,214 patients undergoing muscle biopsy. Can J
Anaesth. 1995;42:281286.
189. Inada H, Jinno S, Kohase H, et al. Postoperative hyperthermia of unknown origin treated with dantrolene sodium. Anesth Prog. 2005;52:
2123.
190. Rumack BH, Peterson RC, Koch GG, et al. Acetaminophen overdose.
662 cases with evaluation of oral acetylcysteine treatment. Arch Intern
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191. Mahadevan SB, McKiernan PJ, Davies P, et al. Paracetamol induced
hepatotoxicity. Arch Dis Child. 2006;91:598603.
192. Ranganathan SS, Sathiadas MG, Sumanasena S, et al. Fulminant hepatic
failure and paracetamol overuse with therapeutic intent in febrile
children. Indian J Pediatr. 2006;73:871875.
193. Bridger S, Henderson K, Glucksman E, et al. Deaths from low dose
paracetamol poisoning. BMJ. 1998;316:17241725.
194. Rivera-Penera T, Gugig R, Davis J, et al. Outcome of acetaminophen
overdose in pediatric patients and factors contributing to hepatotoxicity.
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195. Kanter MZ. Comparison of oral and I.V. acetylcysteine in the treatment of acetaminophen poisoning. Am J Health Syst Pharm. 2006;63:
18211827.
196. Betten DP, Cantrell FL, Thomas SC, et al. A prospective evaluation of
shortened course oral N-acetylcysteine for the treatment of acute
acetaminophen poisoning. Ann Emerg Med. 2007;50272279.
197. Whyte IM, Francis B, Dawson AH. Safety and efficacy of intravenous
N-acetylcysteine for acetaminophen overdose: analysis of the Hunter
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198. Bailey B, McGuigan MA. Management of anaphylactoid reactions to
intravenous N-acetylcysteine. Ann Emerg Med. 1998;31:710715.
199. Gupta SK, Gupta RC, Seth AK, et al. Methaemoglobinaemia in areas
with high nitrate concentration in drinking water. Natl Med J India.
2000;13:5861.
200. Sanchez-Echaniz J, Benito-Fernandez J, Mintegui-Raso S. Methemoglobinemia and consumption of vegetables in infants. Pediatrics. 2001;
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201. Murone AJ, Stucki P, Roback MG, et al. Severe methemoglobinemia

due to food intoxication in infants. Pediatr Emerg Care. 2005;21:
536538.
202. Chawla R, Kundra P, Bhattacharya A. Asymptomatic methaemoglobinaemia and its implications. Acta Anaesthesiol Scand. 1998;42:
736738.
203. Nilsson A, Engberg G, Henneberg S, et al. Inverse relationship between
age-dependent erythrocyte activity of methaemoglobin reductase and
prilocaine-induced methaemoglobinaemia during infancy. Br J Anaesth.
1990;64:7276.
204. Duncan PG, Kobrinsky N. Prilocaine-induced methemoglobinemia in
a newborn infant. Anesthesiology. 1983;59:7576.
205. Frayling IM, Addison GM, Chattergee K, et al. Methemoglobinemia in
children treated with prilocaine-lignocaine cream. Br Med J. 1990;301:
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206. Anderson ST, Hajduczek J, Barker SJ. Benzocaine-induced methemoglobinemia in an adult: accuracy of pulse oximetry with methemoglobinemia. Anesth Analg. 1988;67:10991101.
207. Seibert RW, Seibert JJ. Infantile methemoglobinemia induced by a
topical anesthetic, cetacaine. Laryngoscope. 1984;94:816817.
208. Burne D. Methaemoglobinaemia following lignocaine letter. Lancet.
1964;2:971.
209. Weiss LD, Generalovich T, Heller MB, et al. Methemoglobin levels
following intravenous lidocaine administration. Ann Emerg Med. 1987;
16:323325.
210. McDonald RD, McGuigan MA. Acute dapsone intoxication: a pediatric
case report. Pediatr Emerg Care. 1997;13:127129.
211. Trillo RA, Aukburg S. Dapsone-induced methemoglobinemia and pulse
oximetry. Anesthesiology. 1992;77:594596.
212. Hjelt K, Lund JT, Scherling B, et al. Methaemoglobinaemia among
neonates in a neonatal intensive care unit. Acta Paediatr. 1995;84:
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213. Hermon MM, Burda G, Golej J, et al. Methemoglobin formation in
children with congenital heart disease treated with inhaled nitric oxide
after cardiac surgery. Intensive Care Med. 2003;29:447452.
214. Kumar AR, Dunn N, Naqvi M. Methemoglobinemia associated with a
prilocaine-lidocaine cream. Clin Pediatr. 1997;36:239240.
215. Reinhold P, Storms FJ. Application of EMLA in term and preterm
neonatesMet-Hb-reductase-activity and methaemoglobinaemia. Acta
Anaesthesiol Scand. 1995;39(Suppl 105):176.
216. Neuhaeuser C, Weigand N, Schaaf H, et al. Postoperative methemoglobinemia following infiltrative lidocaine administration for combined
anesthesia in pediatric craniofacial surgery. Paediatr Anaesth. 2008;18:
125131.
217. Barker SJ, Tremper KK, Hyatt J. Effects of methemoglobinemia on
pulse oximetry and mixed venous oximetry. Anesthesiology. 1989;70:
112117.
218. Van Der Pol JG, Wolf H, Boer K, et al. Jejunal atresia related to the use
of methylene blue in genetic amniocentesis in twins. Br J Obstet
Gynaecol. 1992;99:141143.
219. Bilgin H, zcan B, Bilgin T. Methemoglobinemia induced by methylene
blue pertubation during laparoscopy. Acta Anaesthesiol Scand. 1998;42:
594595.
220. Ng BK, Cameron AJ, Liang R, et al. Serotonin syndrome following
methylene blue infusion during parathyroidectomy: a case report and
literature review. Can J Anaesth. 2008;55:3641.
221. Mihai R, Mitchell EW, Warwick J. Dose-response and postoperative
confusion following methylene blue infusion during parathyroidectomy.
Can J Anaesth. 2007;54:7981.
222. Bach KK, Lindsay FW, Berg LS, et al. Prolonged postoperative disorientation after methylene blue infusion during parathyroidectomy. Anesth
Analg. 2004;99:15731574.
223. Padh H. Vitamin C: newer insights into its biochemical functions. Nutr
Rev. 1991;49:6570.
224. Dotsch J, Demirakca S, Cryer A, et al. Reduction of NO-induced methemoglobinemia requires extremely high doses of ascorbic acid in vitro.
225. Kortgen A, Janneck U, Vetsch A, et al. [Methemoglobinemia due to prilocaine after plexus anesthesia. Reduction by prophylactic administration of ascorbic acid?] (German). Anaesthesist. 2003;52:10201026.
226. Da Silva SS, Sajan IS, Underwood JP III. Congenital methemoglobinemia: a rare cause of cyanosis in the newborna case report.
Pediatrics. 2003;112:e158e161.
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Anticoagulants
Gordon T. C. Wong
INTRODUCTION
Anticoagulation in the pediatric population lacks evidencebased treatment recommendations, particularly in the newborn.
Phase I and II studies usually include only consenting adults.
Difficulties performing clinical trials in this special population are
notorious1 with a low incidence of thromboembolic events in
children. Dosing regimes are extrapolated from adult studies
and therapies, despite differences in pediatric disease profiles and
ontogeny of the haemostatic system. Further, for those on longterm anticoagulation, changes in body weight, diet, treatment
compliance, and illness progression all influence response to
therapy. Consequently, close monitoring of coagulation status
is required.
OVERVIEW OF THE
COAGULATION PROCESS
The coagulation cascade involves a series of amplifying reactions.
Coagulation factors are proteins that function as either enzymes
or cofactors. Calcium is required for some reactions; it binds
the proteins to a phospholipid surface to form a quaternary
complex that speeds up the reactions. Negatively charged phospholipid surfaces bring the proteins closer together that further
improves the effectiveness of the cascade. The coagulation system is traditionally divided into an extrinsic and an intrinsic
Figure 32-1. Normally, blood constituents

are separated from the subendothelial
tissue by an intact endothelium.
32
C H A P T E R
pathway. The extrinsic pathway consists of the transmembrane

receptor tissue factor (TF) and plasma Factors VII and VIIa
(FVII/FVIIa). The intrinsic pathway, also known as the contact
pathway, consists of plasma Factors XI, IX, and VIII (FXI, FIX,
and FVIII). Although conceptually convenient, such a division
does not account for clinical observations of bleeding and
thrombotic disorders.
Current understanding recognizes the binding of FVII to TF
as the pivotal initiating step in clot formation. TF is constitutively
expressed in all cells except endothelium and circulating red blood
cells2,3 and can be considered as the cell surface receptor for FVII
(Figure 321). Emerging work points to a role of blood-borne
TF in the propagation of the clot.4 Small amount of circulating
FVII exists in its active form (FVIIa)5 and binds to TF when endothelium is breeched (Figure 322A). It is this TF-VIIa complex
that activates surrounding TF-VII complexes (see Figure 322B)
and TF-VIIa in turn converts FX to FXa and also FIX to FIXa with
minimal contribution from the contact pathway.6 The small
amount of thrombin generated then propagates the clot formation
(Figure 323).
Thrombin has roles as both a coagulation effector and a
regulator as well as a role in clot formation and lysis.7 It cleaves
fibrinogen into fibrin monomers and activates coagulation Factors
FV, FVIII, FXI, and FXIII, as well as platelets. It also activates
thrombin-activatable fibrinolysis inhibitor (TAFI), fibrinolysis,
and the naturally occurring anticoagulant protein C.
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NATURAL ANTICOAGULANT
SYSTEMS AND FIBRINOLYSIS
Several systems of naturally occurring proteins prevent uncontrollable clot propagation, mainly through direct or indirect
inhibition of thrombin generation or activity. Direct inhibitors of
thrombin include antithrombin (AT), 2 macroglobulin, and
Figure 32-2. A: Vessel injury leads to

formation of a platelet plug and exposes
tissue factor to circulating FVII/FVIIa.
B: Binding of FVIIa to tissue factor
increases its proteolytic activity and
TF-VIIa complexes activate nearby
TF-FVII complexes. TF = tissue factor.
heparin cofactor II (HCII). Indirect inhibitors include the protein
Cprotein Sthrombomodulin system. A third system involves
the protein tissue factor pathway inhibitor (TFPI).
AT is a serine protease inhibitor that cleaves a number of
enzymes in the coagulation cascade. This inhibition is strongly
potentiated by the glycosaminoglycans and naturally occurring or
exogenous heparins. 2 Macroglobulin also binds to and inhibits
Figure 32-3. TF-VIIa complex converts

FX to Xa and FIX into FIXa that, in turn,
generate small amount of thrombin,
thus initiating the coagulation process.
Thrombin then propagates the clot
via converting fibrinogen into fibrin
monomers and activating FV, FVIII, FXI,
FXIII, and platelets. TF = tissue factor.
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CHAPTER 32
serine proteases but quantitatively less compared with AT.
Likewise, HCII binds and neutralizes thrombin activity in a
stoichiometric 1:1 fashion.
Thrombomodulin is a cell surface receptor that binds thrombin.8 Bound thrombin lacks the ability to either cleave fibrinogen
or activate FV, FVIII, or platelets, but retains its ability to activate
protein C.9 Protein C is a vitamin Kdependent factor (VKDF)
and, when activated, is a serine protease that neutralizes FVa and
FVIIIa. This activity of active protein C is augmented by the
cofactor protein S, another VKDF.
TFPI is produced by endothelial cells10 and monocytes11
and binds the active site of FXa and together binds to and inhibits
TF-FVIIa complex to prevent further FIXa production. It is a more
potent antithrombotic than heparin or AT.
Fibrinolysis is a major feedback mechanism that prevents
excessive clot formation. Plasmin is a serine protease that lyses
clots by converting fibrin into fibrin degradation products. It
circulates as plasminogen, the inactive zymogen that becomes
activated after binding to fibrin. Activation is linked to FXIIa,
FXIa, kallikrein, tissue plasminogen activator, and urokinase.
There is also a number of naturally occurring plasmin inhibitors,
the primary one of which is 2 antiplasmin.
DEVELOPMENTAL HEMOSTASIS
The pediatric hemostatic system is functionally adequate at birth,
because neonates suffer from neither uncontrollable hemorrhage nor life-threatening clotting problems. The system at birth
is immature by adult standards and continues to evolve during
childhood. Coagulation factors first appear around 10 weeks of
gestational age and do not cross the placenta. The neonates ability
to generate thrombin is delayed, with a reduction in overall capacity, and remains at 26% less than adult levels throughout
childhood.12,13 At birth, the VKDFs (II, VII, IX, and X), the contact
factors (XII, XI, high-molecular-weight kininogen, and prekallikrein), and the four inhibitors (AT, HCII, protein C, and protein S)
are approximately half that of adult values.14 The pattern of
maturation in the postnatal period differs for different proteins.
FVII increases rapidly after birth in both premature and full-term
infants but remains remain less than adults for most of childhood15
as is the case with FII. However, even in early infancy, fibrinogen,
FV, FVIII, FXIII, 2 macroglobulin, 1AT, and C1 esterase inhibitor are similar to or increased above adult values.14 Other factors
increase toward adult concentrations at around 6 months of life,
where VKDFs and contact factors are within 80 to 90% of adult
values. AT concentrations approach adult values by 3 months
and remain relatively steady throughout childhood and decrease
to adult values at the third decade. Plasma concentrations of
thrombomodulin are increased during childhood but decrease to
adult concentrations during the teenage years.
Coagulation system components mature at different rates.
These differences confer upon the young an altered profile for
hemostatic disorders and response to therapy. For example, the
reduced rate and amount of thrombin generation during infancy
reduce the risk of thromboembolic but not necessarily hemorrhagic complications. The lower VKDFs at birth16 render them at
risk of hemorrhagic diseases of the newborn. The reduced vitamin
Kdependent enzyme metabolism in the immature liver may contribute to increased resistance to warfarin therapy.17 The response
to heparin may be lessened because AT concentrations at birth
Anticoagulants
527
TABLE 32-1. Common Indications for Anticoagulation in

the Pediatric Patient Population
Absolute Indication
Relative Indication
Thromboembolic complications
Myocardial infarction
Some forms of cerebrovascular accidents
Prophylaxis
Prosthetic heart valves
Cardiac catheterization
Indwelling central arterial
catheters
Other Indications
Kawasakis disease
Cardiomyopathy
Extracorporeal circuitry
Cardiopulmonary bypass
Extracorporeal membrane
oxygenation
Hemodialysis
Continuous extravascular
hemoperfusion techniques
Prophylaxis Likely
Endovascular stents
Blalock-Taussig or Glenn
shunts
Fontan circulation
Indwelling central venous
catheters
Atrial fibrillation
and in the first 3 months are reduced.18,19 The diminished activity

of AT and HCII from decreased plasma concentrations is counteracted by the increased inhibition of thrombin from higher
concentrations of 2 macroglobulin, resulting in only a small net
slower inhibition of thrombin.
INDICATIONS FOR
ANTICOAGULATION
The indications for anticoagulation are similar for adults and
children, but there are age-related differences in the frequency
of specific indications (Table 321). The risk of deep venous
thrombosis (DVT) and thromboembolism (TE) appear to increase
with age and are relatively rare in children.20,21 However, secondary
thrombosis in children with underlying health problems dominates thromboembolic complications and is overwhelmingly
related to the presence of indwelling vascular devices. The agerelated incidence of thrombosis may reflect the biphasic age
distribution of diseases that require long-term vascular devices.
Approximately half of infants younger than 6 months old and close
to a third of older children with venous TE have underlying
cardiac defects.22 Large devices in small-diameter vessels may
contribute to this peak. Upper limb venous thrombosis, although
rare in adults, is very common in the young. A thrombus can easily
extend into the heart and through the pulmonary valve, causing
obstruction to cardiac output. The higher incidence of malignancy
and the maturation of the coagulation system may account for the
second peak of TE around adolescence.
INDIVIDUAL AGENTS
Unfractionated Heparin
Heparin is a naturally occurring sulfated glycosaminoglycan
found predominantly in mast cells. Commercially available preparations are derived from porcine or bovine tissues, which are
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TABLE 32-2. Pharmacokinetic Data of Heparin

Gestational Age, wk
2528
2932
3336
Adult
41.6
81
35.5
73.3
35.5
57.8
63.3
36.6
1.49
1.43
1.37
0.43
Plasma T / , min
Volume of distribution,
mL/kg
Clearance, mL/kg/min
1
From reference 30.
homogenized and treated with proteolytic enzymes or extracted at

elevated pH and temperatures.23 The purified products have a
range of molecular weight from 3000 to 35,000 daltons (Da) with
a mean of around 12000 Da.
After intravenous (I.V.) injection, about a third of the heparin
binds to AT24,25 and causes a conformational change at its proteolytic site. This increases the natural anticoagulant activity of
AT by up to 1000 times. It is the inhibition of thrombin and FXa
that is primarily responsible for heparins anticoagulant activity.
Simultaneous binding of thrombin and AT by heparin is required
for thrombin inhibition but not for the FXa inhibition. At much
higher doses, heparin catalyzes thrombin inhibition by HCII.
Heparin also blocks platelet activation by thrombin in the presence
of AT26 and inhibits von Willebrands factor (vWf)dependent
platelet function.27,28 Clearance of heparin is dose-dependent,
involving a combination of a rapid saturable and a much slower
nonsaturable first-order mechanism, the latter of which is largely
renal.29 Age-dependent characteristics also play a role in its
clearance (Table 322).30
Systemic heparin is administered to pediatric patients using a
weight-based nomogram to achieve an adult therapeutic activated
partial thromboplastin time (aPTT) (Table 323).31 This Toronto
protocol was initially evaluated prospectively by Andrew and
coworkers.32 The original I.V. bolus of 50 U/kg achieved a therapeutic range in only 60% of the sample, increasing to 90% with a
bolus of 75 to 100 U/kg. The maintenance I.V. infusion rate is
determined according to age and weight, with the highest initial
dose used for infants (see Chapter 18). Complications from
bleeding were rare (2%) whereas recurrent thrombotic disease was
more common (7%) with this protocol. The measurement of aPTT
is most commonly used to monitor heparin therapy and the dose
Table 32-3. Recommendation for Heparin Doses
Most
Recent
aPTT, s
Bolus,
units/kg
Hold
Infusion
For, min
<50
5059
6085
8695
96120
>120
50
0
0
0
0
0
0
0
0
0
30
60
Adjust
Time After
Infusion
Rate Change for
Rate By, % Repeat aPTT, h
+10
+10
0
10
10
15
4
4
Next day
4
4
4
aPTT = activated partial thromboplastin time

This protocol recommends a loading dose of 75 U/kg and an initial maintenance
dose of 20 U/kg/h (>1 y) or 28 U/kg/h (<1 y). The therapeutic aPTT range is
between 60 to 85 seconds. A blood assay for aPTT four hours after every
infusion rate adjustment and a daily complete blood count plus aPTT once
target range is achieved are recommended.
is adjusted accordingly. Thromboelastography is also used in some

centers to gauge heparin activity.
Bleeding complications from heparinization are uncommon,
but this may reflect the low dose of heparin commonly used.32,33
Should bleeding occur, stopping the infusion is usually all that is
required owing to increased clearance in the young. If more urgent
reversal is required, protamine sulfate can be administered in a
concentration of 10 mg/mL at a rate not exceeding 5 mg/min.31
Cases of heparin-induced osteoporosis have been documented in
children.3436
Although rare, immune-mediated heparin-induced thrombocytopenia (HIT) is serious given the number of patients who get
exposed to this compound and its potential to develop lifethreatening complications. Even minute amounts of heparin
exposure, such as that used for maintaining catheter patency, can
trigger HIT.37 A paradoxical thrombotic state may develop from
immune complexmediated platelet activation and thrombin
generation. The reported incidence ranges from 0 to 2.3%.38 Two
groups are at most risk: newborns and infants younger than
4 years old undergoing cardiac surgery, and teenagers treated with
heparin for thrombosis.39 Both clinical and laboratory criteria have
to be satisfied for the confirmation of this condition. They include
the presence of a triggering agent, a substantial fall in platelet
count (usually 50%), the typical timing of the onset of thrombocytopenia with or without thromboembolic complications, and
the presence of heparin-dependent antibodies.38 Intermediate to
high probability of HIT requires immediate cessation of heparin and alternative anticoagulation by danaparoid, lepirudin, or
argatroban, with appropriate laboratory monitoring to prevent a
thrombotic or bleeding complication.40 Thrombotic complications
as well as the original indication for anticoagulation must be
addressed. Warfarin and other vitamin K antagonists should be
withheld initially until the platelet count normalizes.
Low-Molecular-Weight Heparin
Low-molecular-weight heparin (LMWH) or fractionated heparin
is prepared primarily from depolymerization of unfractionated
heparin (UFH), resulting in molecules with a range of molecular
weight from 3800 to 6000 Da.
Anti-FXa activity does not require simultaneous binding of AT
and thrombin and therefore predominates in LMWH. LMWH
preparations can contain molecules greater than 18 saccharide
units and therefore retain anti-FII activity. The ratio of anti-Xa to
anti-IIa activity ranges from approximately 2:1 to 4:1, depending
on the preparation (Table 324).
Potential advantages of LMWH use in children include its ease
of administration via the subcutaneous (S.C.) route, a minimal
requirement for laboratory monitoring and dose adjustments,
minimal drug or dietary interactions, and a reduction in the
incidence of HIT. It may reduce the risk of osteoporosis associated
with long-term UFH use. There may be less bleeding possibly
from reduced platelet, endothelium, and vWF binding.27,41,42
The lack of protein binding by LMWH confers a higher
bioavailability and more predictable anticoagulant activity than
UFH when administered in fixed doses. The half-life is generally
two- to fourfold longer than UFH and clearance is mainly via
the renal route. On the basis of target anti-FXa activity and every
12 hour administration of enoxaparin on a per-kilogram basis,
infants younger than 2 months required 50% more drug to achieve
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Anticoagulants
529
TABLE 32-4. Summary of Properties of Commercially Available Low-Molecular-Weight Heparins

DRUG
Average Molecular
Weight, Da
Defractionation and Preparation

Method (Species of Origin)
Ardeparin sodium
Certoparin sodium
Dalteparin sodium
Enoxaparin sodium
Nadroparin calcium
Parnaparin sodium
55006500
5600
56006400
4500
4300
45005000
Reviparin sodium
Tinzaparin sodium
4150
6500
Peroxidative depolymerization (porcine)

Amyl nitrate depolymerization (porcine)
Nitrous acid depolymerization (porcine)
Benzylation and alkaline depolymerization (porcine)
Nitrous acid depolymerization (porcine origin)
Cupric acid and hydrogen peroxide degradation
(porcine or bovine)
Nitrous oxide depolymerization (porcine)
Controlled enzymatic depolymerization (porcine)
Anti-Xa:IIa Ratio
1.8:1
2:1
2:1
2.7:1
3.2:1
3:1
3.5:1
1.9:1
Adapted from references 116 and 117.
the same end point than older children, the latter of which was
comparable with adults levels.43,44 Peak anti-FXa levels occurred
2 to 6 hours after dosing. Similarly, children under 5 kg required
50 IU/kg of reviparin, compared with 30 IU/kg required by their
heavier (and older) counterparts, to achieve similar target levels.45
Nohe and colleagues investigated the effectiveness and safety of
dalteparin using plasma anti-FXa activity for prophylaxis and
management of arterial and venous thrombosis in pediatric
patients (N = 48; age 31 wk gestation18 y). Prophylactic and
therapeutic anti-FXa levels were achieved with daily subcutaneous
dosages of 95 U/kg standard deviation (sd) 52 U/kg and 129 U/kg
sd 43, respectively.46
Children on long-term LMWHs are at higher risk of increased
concentrations owing to reduced clearance from the underlying
illness or unaccounted weight changes altering dose prediction,
and monitoring is therefore warranted. LMWHs have minimal
effect on aPTT, and monitoring of LMWH activity relies upon
anti-FXa assay. Protamine tends to reverse the anti-FIIa rather
than the anti-FXa activity47 and does not fully neutralize LMWH.
This differential reversal may be explained on the basis of reduced
sulfate charge in the lower-molecular-weight fractions.48 If protamine is to be used, the maximal dose is 1 mg/100 U if LMWH
was last administered within 3 to 4 hours.49
Danaparoid
Danaparoid sodium is a mixture of low-molecular-weight
heparinoid glycosaminoglycuronans that is purified from porcine
gut mucosa. The anticoagulant effect is mainly from FXa and FIIa
inhibition, at a ratio of greater than 20:1. It has minimal effect on
platelet function and low cross-reactivity with HIT antibodies
when compared with UFH and LMWH. It is the most reported
anticoagulant used for pediatric patients affected by HIT.50
Bioavailability after S.C. injection approaches 100%. Clearance
is through the kidneys. The half-lives of elimination of anti-FXa
and thrombin generationinhibiting activities are approximately
25 and 7 hours, respectively.51 There is no specific antidote for the
reversal of this agent. Danaparoid has little effect on aPTT or
prothrombin time (PT)52 and, therefore, should be monitored by
anti-FXa assays that are calibrated with danaparoid and not with
UFH or LMWH.53 An initial loading dose is 30 U/kg I.V. followed
by an infusion of 1.2 to 2.0 U/kg/h.54 Target anti-FXa levels are
0.4 to 0.6 IU/mL and 0.5 to 0.8 IU/mL for standard and high doses,
respectively.55
Warfarin
Warfarin is a coumarin derivative that remains the mainstay of
oral anticoagulation, despite disadvantages that include a narrow
therapeutic index, long onset and offset of action, and possible
prothrombotic tendency during start of therapy (owing to differential effects on VKDFs). Drug interactions with warfarin are
common.56 Altered absorption can occur with conditions such as
fat malabsorption or other diarrheal diseases, and metabolism can
be significantly changed with hepatic dysfunction. Warfarinized
patients must be cognizant of ingesting food containing vitamin
K1. Factors including an age-related dose response, the presence
of an underlying chronic illness that necessitated anticoagulation,
changes in weight and diet, along with compliance issues affect
predominantly the young. Concentrations of some VKDFs may
be only 50% of adult values at different stages of life.16,18,19 The
capacity of older children to generate thrombin is also decreased
to 75% compared with adults with similar International Normalized Ratio (INR).57
Warfarin interferes with the metabolism of vitamin K (ReVK),
which is required for the posttranslational carboxylation reaction
of glutamic residues on Factors II, VII, IX, X, protein S, and protein C. The activities of these VKDFs will then fall in accordance
to their plasma half-lives, those with shorter half-lives being
affected first.
Warfarin is a mixture of R and S enantiomers, the latter of
which is about five times more potent.58,59 Warfarin is essentially
completely absorbed enterally, reaching a maximum plasma
concentration between 2 and 6 hours in adults, and is extensively
protein-bound. It undergoes stereoselective metabolism by hepatic
microsomes, whereby the S isomer is oxidized and excreted in the
bile and the R isomer is metabolized to an inactive alcohol and
excreted in urine. The elimination half-life is about 36 to 42 hours
in adults.60 The terminal half-life of warfarin is about a week,
although the effective half-life is much shorter, in the range of
20 to 60 hours.
A pharmacodynamic model for the effect of warfarin on the
synthesis of clotting factors (prothrombin complex) is described in
Chapter 18. Prothrombin complex synthesis is inhibited 50% at a
warfarin concentration of about 1.5 mg/L in adults. Warfarin
concentrations associated with therapeutic anticoagulation are of
similar magnitude. The prothrombin complex synthesis rate is
about 5%/h/70 kg and the elimination half-life estimated from
changes in PT is approximately 17 hours in adults,61 but data in
children are few.
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TABLE 32-5. Protocol for Oral Anticoagulation for

Children to Maintain International Normalized Ratio
Between 2 and 3
Day 1
Days 24
Maintenance
therapy
Pentasaccharide-based compounds catalyze AT-mediated FXa

inhibition. Direct thrombin inhibitors bind directly to thrombin
to mediate effects. Compounds that can activate protein C cause
degradation of FVa and FVIIIa.
LD of 0.2 mg/kg on Day 1 if Baseline INR 1.01.3

INR
Action
1.11.3
1.41.9
2.03.0
3.13.5
>3.5
Repeat LD
Give 50% of LD
Give 50% of LD
Give 25% of LD
Withhold until INR < 3.5
and recommence at 50%
of previous dose
1.11.4
1.51.9
2.03.0
3.13.5
>3.5
Increase dose by 20%

Increase dose by 10%
No change
Decrease dose by 10%
Withhold until INR < 3.5
and recommence at 80%
of previous dose
INR = International Normalized Ratio; LD = loading dose.

The starting dose is 0.2 mg/kg, with subsequent dose adjustments made according to nomograms and therapeutic monitoring
(Table 325).31 With these typical regimes, 79% target INR are
achieved in less than 7 days, the actual time being age-dependent.
The median times to achieve INR are 2 to 5 days for infants and
3 days for teenagers.62 Because protein C has the shortest half-life
among the VKDFs, there could be a prothrombotic tendency
when starting warfarin without heparin or if the patient is loaded
too quickly, especially in those with protein C deficiency. The
maintenance doses for infants average approximately 0.32 mg/kg
and 0.09 mg/kg for teenagers.6367
The monitoring of warfarin effectiveness is based on measuring
the PT and INR. The recommended frequency of monitoring may
vary but is four times during the first week. Because the highest risk
of hemorrhage occurs during the first 6 to 12 weeks of therapy,
weekly monitoring is suggested for this period. Thereafter, the interval between monitoring should not exceed 4 to 6 weeks,31 bearing in
mind the relative difficulty in maintaining stability in children.
Reversing the effect of warfarin may be achieved with a
combination of exogenous vitamin K, fresh frozen plasma (FFP),
or prothrombin concentrate (PC), depending on the indication.31
For those with no bleeding who require rapid reversal, S.C. or I.V.
vitamin K can be given. Children not requiring anticoagulation
after reversal may be given 0.1 mg/kg (25 mg), whereas the dose
is reduced to 0.5 to 2 mg for those requiring anticoagulation
again in the near future. For those with nonlife-threatening but
significant bleeding that will not cause morbidity, 0.5 to 2 mg of
vitamin K along with 20 mL/kg of FFP should be given. For those
with life-threatening bleeding that will likely cause morbidity,
5 mg of vitamin K should be given and consideration should be
given along with PC at 50 U/kg instead of FFP 20 mL/kg.
NEWER ANTICOAGULANTS
Anticoagulants that interfere with specific parts of the coagulation system are under various stages of development.68,69
Pentasaccharides: Fondaparinux
and Idraparinux
Synthetic analogues of a specific five-residue sequence in heparin
can potentiate AT inhibition of FXa. The sequence is highly specific
for FXa inhibition because it is too short to link AT to thrombin.
It also has minimal plasma protein binding other than to AT. Both
fondaparinux and idraparinux can be given subcutaneously.
Fondaparinux is the first in this class of indirect selective FXa
inhibitors. It can be given on a daily basis (half-life 1320 h).
Maximal plasma concentration is reached 2 hours after S.C.
administration.70,71 It is almost exclusively excreted unchanged
from the kidney and should be used cautiously in those with renal
impairment and avoided in those with kidney failure. Routine
monitoring for dose adjustments is not required, but its anticoagulant effect can be measured by anti-FXa activity.
Fondaparinux binds to and causes a conformational change in
AT and increases its affinity to FXa.72 Irreversible complexes are
produced that inactivate FXa. Thereafter, the fondaparinux is
released from the complex unaltered, free for another reaction
with AT. The action of this drug is unaffected by protamine.
Rapid reversal for surgery or for significant bleeding may require
procoagulants such as recombinant FVIIa (rFVIIa). In healthy
volunteers, rFVIIa can normalize aPTT and PT and thrombin
generation during fondaparinux treatment.73 Fondaparinux has
been successfully reversed with rFVIIa in combination with
transexemic acid in a case of postoperative hemorrhagic shock.74
Fondaparinux does not interact with aspirin or warfarin, nor
does it bind to platelet or platelet factor 4 (PF4). It is nonreactive
to sera from HIT-affected patients.75 These factors suggest that
HIT is unlikely to occur with fondaparinux and may be considered
as an option for anticoagulation in HIT-affected patients.
Idraparinux is a more highly sulfated and, hence, negatively
charged derivative of fondaparinux. It has almost 10 times the
affinity for binding to AT compared with fondaparinux, and thus,
its plasma half-life mirrors that of AT of around 80 hours.76 The
dose-independent elimination half-life of idraparinux gives
potential for weekly dosing. However, major bleeding propensity
may increase with dose. Results of ongoing phase III trials have
not yet been published
Direct Thrombin Inhibitors: Recombinant

Hirudin and Synthetic Hirulogues
Direct thrombin inhibitor (DTI) binds directly onto thrombin
molecules to interfere with their enzymatic function, producing a
more predictable anticoagulant effect. They inactivate both fibrinbound and fluid-phase thrombin. Formation of fibrin is inhibited,
as well as thrombin-mediated feedback activation of FV, FVIII,
FXI, and thrombin-induced platelet aggregation. Further, they are
unaffected by the large amounts of PF4 present in the vicinity
of vascular injury and platelet-rich thrombi. Bivalent DTIs bind
to both the active (catalytic) and the fibrinogen-binding site
(exosite 1) of thrombin, whereas univalent DTIs bind only to the
active site.77
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Recombinant Hirudin: Lepirudin and Desirudin

Hirudin is a naturally occurring, potent thrombin inhibitor from
the blood-sucking leech Hirudo medicinalis.78 Recombinant technology has enabled this compound to be produced in sufficient
quantities for therapeutic use. It is a bivalent DTI that binds
thrombin in a ratio of 1:1, with high affinity and specificity.
Although the bond between thrombin and hirudin is noncovalent,
it is essentially irreversible owing to the high affinity. This is a
major limitation because there is no specific antidote. There are no
effects on platelets and plasma proteins.79 Currently, lepirudin and
desirudin are the two commercially available compounds, both
having small structural and pharmacologic differences from the
natural hirudin. After S.C. administration, plasma concentrations
peak at 90 to 180 minutes80 and redistribute into the extravascular
space. Redistribution back into plasma may occur after cessation
of prolonged use. It has a plasma half-life of 60 to 100 minutes.
Clearance of free hirudin and hirudin-thrombin complexes is
largely by glomerular filtration. The half-life is greatly increased
in patients with renal insufficiency81 and should best be avoided
in these patients. The activity of hirudin can be monitored
using escarin clotting time or chromogenic measurement of
lepirudin concentration. In the absence of availability of these
tests, laboratory-based, but not point-of-care aPTT measurements, can provide a reasonable guide to therapy.82
Lepirudin is licensed for treatment of HIT complicated by
arterial or venous thrombosis and as an alternative to heparin for
cardiopulmonary bypass in these patients. No formal dose-finding
studies are available for children. A regimen comprising an
omitted loading dose of 0.2 mg/kg followed by infusion of 0.03 to
0.05 mg/kg/h for neonates or 0.1 to 0.22 mg/kg/h for older
children is described.83 Favorable outcomes have been reported
in seven of eight pediatric cases using lepirudin in the treatment
of HIT.50 Antibodies are formed in up to 74% of those exposed to
recombinant hirudin, and re-exposure associated anaphylaxis has
been reported with lepirudin.84
Hirulogues: Bivalirudin and Argatroban

Bivalirudin is a 20-amino acid synthetic polypeptide analogue of
hirudin. This bivalent DTI binds to thrombin in a noncompetitive
nature. However, thrombin is able to cleave the polypeptide and
render the bivalirudin remnant susceptible to competition for
binding from other substrates, such as fibrinogen. Thrombin can
therefore regain its usual hemostatic activities. The plasma halflife is 25 minutes after I.V. infusion85 and clearance is decreased
by only 21% and 24% in moderate and severe renal failure,
respectively. Approximately 20% of unchanged drug is cleared via
the kidney, with the remainder presumably undergoing proteolysis
intracellularly.86 Activity may be monitored by activated clotting
time.87 A pilot dose-finding study has been conducted in infants
younger than 6 months.88 In this study, 37.5% of patients had
complete or partial resolution of their thrombosis by 48 to
72 hours; 2 of the 16 patients met the study criteria for major
bleeding, which resolved with a reduction in the drug infusion
rate. It has also been used successfully in an infant with AT deficiency undergoing cardiac stent placement to relieve a stenosed
conduit.89 It is currently licensed as an alternative to heparin
patients with or without HIT who require percutaneous coronary
interventions.
Argatroban is an L-arginine derivative, univalent DTI that
binds noncovalently to active site of thrombin in a competitive
Anticoagulants
531
fashion. It has a short plasma half-life of 45 minutes and undergoes mainly hepatobiliary metabolism.90 It is administered by
continuous I.V. infusion. The effect on aPTT is concentrationdependent, and this relationship is similar in pediatric patients
and healthy adults. For the pediatric population, an initial dose
of 0.75 g/kg/min is recommended with adjustment of 0.25 g/
kg/min every 2 to 4 hours, not exceeding 3.0 g/kg/min.91 aPTT
should be checked 2 hours after bolus administration or any dose
adjustment and at least once daily.92 Pediatric patients with hepatic
impairment or elevated bilirubin levels most likely secondary to
cardiac complications should be dosed at a quarter of the normal
dose. Activated clotting time may also be used for those receiving
larger doses, such as during cardiopulmonary bypass. It is approved for the treatment of HIT and should be considered for use
in this condition in those with renal insufficiency.
ANTIFIBRINOLYTICS
Agents in this class include the two synthetic derivatives of lysine,
aminocaproic acid (EACA) and tranexamic acid (TA), and the
serine protease inhibitor aprotinin. In addition to their use as a
part of blood conservation strategy in cardiac anesthesia, TA is
being used to reduce blood loss in corrective spinal surgery.9395
Specific pediatric pharmacokinetic data are scarce. Administration
regimens extrapolated from adults may over- or underestimate
actual pediatric requirements depending on age and maturation.96
TA and EACA competitively inhibit plasminogen and prevent
excessive plasmin formation by occupying the formers lysinebinding site. It also prevents the binding of plasminogen to fibrin.
Both agents appear equally effective in reducing postoperative
blood loss and blood product requirements in children with
cyanotic heart disease undergoing corrective surgery when
compared with controls.97 Aprotinin, conversely, is a nonspecific
serine protease inhibitor. It rapidly inactivates free plasmin but
has little effect on bound plasmin. Despite having different modes
of action, the combined use of these agents does confer additive
benefits.98
TA and EACA are both distributed throughout most body
tissues and are mainly excreted via the kidney, although there may
be extrarenal metabolism of EACA. Renal insufficiency reduces
their clearance.99 Aprotinin is entirely filtered by the kidneys and
undergoes metabolism in the proximal renal tubules.100
Pediatric dosing for antifibrinolytics remains poorly defined
owing to a lack of concentration-response data, along with developmental differences in hemostatic system and pharmacokinetic variables. Doses of 30,000 to 50,000 KIU/kg of aprotinin at
induction with a similar dose added to the pump prime have
been used in pediatric cardiac surgery.101,102 A loading dose of TA
of 100 mg/kg followed by 10 mg/kg/h reduces blood loss in both
acyanotic and cyanotic congenital heart disease patients. However,
doses as low as 10 to 50 mg/kg loading with repeat dosing has been
effective when compared with control.97,103 On a molar basis,
TA is at least seven times more potent than EACA.104 Pediatric
pharmacokinetic study of EACA suggests that a larger initial dose,
faster infusion rate, and an additional dose on cardiopulmonary
bypass are needed to maintain concentrations similar to that
of adults.105
Thrombotic complications with the use of antifibrinolytic
agents are an ever-present threat. Fortunately, reports of cases are
rare. Anaphylactic reactions to aprotinin are more frequently
reported and the risk is increased with re-exposure to the agent,
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especially if it occurs within 6 months.106 Concerns about renal

dysfunction after aprotonin use in adults107,108 may limit future
use, although these negative results have not been reported in
children.109
ANTIPLATELET AGENTS: ASPIRIN

Salicylic acid is a time-tested compound originally extracted
from natural plants such as willow and myrtle. Acetylsalicylic
acid, or aspirin, is widely used as an analgesic, antipyretic, antiinflammatory, and antiplatelet agent. Its therapeutic effect stems
from its irreversible inhibition of cyclooxygenase. This results in
inhibition of thromboxane A2 production such that platelet aggregation and release are impaired. New platelets are required for the
body to regain platelet function. Interestingly, neonatal platelets
are hyporeactive to thrombin, adenosine diphosphate/epinephrine,
and thromboxane A2,110 but bleeding times are shorter.111
When taken orally, 80 to 100% of the drug will be absorbed but
bioavailability is only around 70% owing to first-pass metabolism.
Salicylic acid is metabolized in the liver, with a plasma half-life of
2 to 4.5 hours. The metabolites are excreted in the urine. Renal
excretion of salicylic acid becomes increasingly important as the
metabolic pathways become saturated (zero-order metabolism)
with overdose.
Therapeutic antiplatelet effects can be achieved with doses as
low as 30 mg/d in adults.112 Aspirin in children may be prescribed
for Blalock-Taussig shunts or other endovascular stents, in doses
of 1 to 5 mg/kg/d.113 Higher doses of 6 to 20 mg/kg/d may be used
for mechanical prosthetic valves.111 Aspirin is used to prevent
thrombotic complications in Kawasakis disease and doses greater
than 80 mg/kg/d are used in the acute phase.114
CONCLUSIONS
Anticoagulation in the young is and will remain a challenging
proposition for the pediatric physician in the foreseeable future.
Practitioners must be vigilant for the threat of HIT with the use of
heparins. Newer anticoagulants, though having a more predictable
pharmacologic profile, are still not ideal for pediatric use. For
long-term use, the agent should be nonparental; be resilient to
changes in developmental hemostasis, diet, or body weight; be
readily reversible; and require minimal monitoring. In the acute or
perioperative setting, an agent should also be easily monitored,
nonallergenic, rapidly titratable, and reversible. The quest, therefore, continues.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
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Pharmacology of
Vasopressive Agents
Robert Whitty
33
C H A P T E R
INTRODUCTION
Vasopressors are pharmacologic agents that result in constriction
of vascular smooth muscle resulting in an increase in systemic
vascular resistance. The term vasopressor is often loosely used to
incorporate the inotropic agents that enhance cardiac contractility
and chronotropes that enhance heart rate. Both vasopressors and
inotropic/chronotropic agents work via receptors of the sympathetic nervous system (Table 331).
Vasopressors either directly or indirectly stimulate the sympathetic nervous system via its receptors. Direct-acting vasopressors
stimulate sympathetic receptors only. Indirect-acting vasopressors
promote the release of norepinephrine (noradrenaline).
maffin tissue and the central nervous system. Epinephrine is taken

up by storage vesicles and released by exocytosis (Figure 331).
During adrenergic nerve transmission, only a small proportion
of norepinephrine binds to adrenoreceptors. The majority is
actively transported back into the preganglionic nerve terminal
and returned to storage vesicles within the cytoplasm.
Catecholamine clearance form the blood is rapid. Epinephrine and norepinephrine have half-lives of 1 or 2 minutes. The
BIOSYNTHESIS AND
METABOLISM OF THE NATURALLY
OCCURRING CATECHOLAMINES
Dopamine, norepinephrine (noradrenline), and epinephrine
(adrenaline) are the naturally occurring catecholamines that are
manufactured in the adrenal medulla.
The amino acid tyrosine is the precursor in the biosynthetic
pathway of the naturally occurring catecholamines. Tyrosine is
hydroxylated to didroxyphenylalanine (DOPA). DOPA is converted to dopamine by the enzyme DOPA decarboxylase. Dopamine is then transported into storage vesicles in the sympathetic
nerve endings where dopamine beta-hydroxylase catalyzes the
addition of a beta-hydroxyl group, forming norepinephrine.
Norepinephrine is methylated to epinephrine by phenylethanolamine-N-methyl transferase (PNMT), which occurs in the
mainly in the adrenal medulla but also is in extra-adrenal chroTABLE 33-1. Principal Vasopressors and Their
Stimulated Receptors
Vasopressor
Receptor Stimulated
Norepinephrine
Epinephrine
Dopamine
Phenylephrine
Metaraminol
Ephedrine
Vasopressin
Dobutamine
Beta1, alpha1, alpha2

Beta1, beta2, alpha1, alpha2
Dopaminergic beta1, alpha1
Alpha1, alpha2
Beta1, beta2, alpha1, alpha2
Beta1, alpha1
V1, V2
Beta1, beta2, alpha1
Figure 33-1. Biosynthesis of the naturally occurring

catecholamines.
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catecholamines are metabolized by two enzymes, monoamineoxidase (MAO) and catechol-O-methyl transferase (COMT), which
are present in most tissues in the body but concentrated in
the liver, kidney, and intestines. MAO catalyzes the oxidative
deamination of catecholamines to aldehydes, which are then
oxidized to carboxylic acids and alcohols by aldehyde and alcohol
dehydrogenases.
The second major metabolic pathway is catalyzed by COMT.
Epinephrine and norepinephrine are methylated to normetanephrine and metanephrine, respectively. COMT converts these
metabolites to 3-metho-oxy-4-hydroxy-mandelic acid (VMA).
VMA is the principal end product of catecholamine metabolism
that is excreted in the urine.
striction of the systemic circulation is always much greater than

that of the pulmonary circulation even at the higher dose range.
This is because young infants and neonates have underdeveloped
sympathetic innervation and a reduced store of norepinephrine;
these require higher infusion doses than older children to achieve
the desired pharmacologic effect.11 However, in preterm neonates,
signs of cardiovascular alpha stimulation may occur at lower
doses than beta stimulation because beta receptor maturation
lags behind alpha receptor maturation in the development of
the adrenergic system. The preterm neonate also has immature
metabolic and elimination pathways, leading to an increased
dopamine concentration.1,3,12,13
DOPAMINE
Pharmacokinetics and Pharmacodynamics
Dopamine is a naturally occurring endogenous catecholamine

and a precursor of norepinephrine and epinephrine. It is widely
used in all pediatric age groups14 and is often the first-line vasopressor used by many clinicians for the treatment of fluid-resistant
hypotension in neonates.57
Cardiovascular Effects
Dopamine stimulates dopamine, serotonin, 1, 2, and 1 adrenergic receptors, and it should be used according to its pharmacologic effect rather than adhering to strict dosing regimens
(Table 332). Dopamine receptors are located in the central
nervous system and in the peripheral vasculature, adrenergic
nerve endings, and renal tubules. D1 dopamine receptors stimulation results in cerebral, renal, coronary, and mesenteric
vasodilatation.7,8
The pharmacologic effects of dopamine depend on the dose
infused. At a low infusion rate, dopamine receptors increase renal
blood flow and, hence, increase urinary output. At moderate doses,
beta receptors are stimulated, increasing cardiac output. When
infused at a high rate, dopamine caused peripheral vasoconstriction and a rise in systemic vascular resistance9 (Table 333).
Another vasopressor should be considered in addition to
or instead of dopamine when infusion rates greater than 20 g/
kg/min are required. Tachycardia and tachyarrhythmias may
occur at moderate doses in children10 but occur more commonly
in adults.
Dopamines effect on the pulmonary blood vessels is less well
understood. Dopaminergic receptors are present in the pulmonary
vasculature, and it is thought to cause pulmonary vasoconstriction
in preterm neonates. However, dopamine-induced vasocon-
Dopamine is considered to follow first-order kinetics with plasma

concentrations correlating with infusion rates.1417 However, considerable between-individual variability of plasma dopamine
concentrations with dopamine infusion has also been demonstrated,1820 particularly in children younger than 2 years in whom
plasma clearance is twice that of an adult.11,21,22 Dopamine is
metabolized by COMT and MAO and excreted as homovanillic
acid in the urine. Dopamine is also taken up by the sympathetic
nerve terminals and converted to norepinephrine or stored in
vesicles.23,24 Approximately 25% of infused dopamine is converted
to norepinephrine in the synaptic terminals.25
In addition to its hemodynamic effects, dopamine activates
the renin-angiotensin system and stimulates serotonin receptors.
It inhibits thyrotropin, gonadotropin, growth hormone, and
prolactin secretion. Prolactin secretion modulates antidiuretic
hormone (ADH) and aldosterone production,12,2630 increases
retention of sodium and water, and promotes natriuresis.
One advantage of dopamine over other vasopressor agents is
that, at lower doses, it may be infused peripherally over a short
period. However, extravasation may cause skin necrosis.
EPINEPHRINE
Epinephrine (adrenaline) is a naturally occurring catecholamine
and is synthesized in sympathetic nerve terminals and the adrenal
medulla from the amino acid phenylalanine.
Epinephrine stimulates 1 and 2 adrenergic receptors, resulting in
increased myocardial contractility and vasodilatation of blood
TABLE 33-2. Dosing Regimens for Principal Vasopressors

Drug
Infusion Concentration
Epinephrine
Norepinephrine
Dopamine
Vasopressin
Milronone
Dobutamine
0.3 mg/kg in 50 mL 5% dextrose or N/S

15 mg/kg in 50 mL 5% dextrose or N/S
15 mg/kg in 50 mL 5% dextrose or N/S
Range of Dose, g/kg/min
Range of Dose, mL/h
0.12.0
0.11.0
220
0.00010.002
0.330.99
220
120
110
0.44.0
120
13
0.44.0
N/S = normal saline.

The Handbook of Clinical Practice. Department of Critical Care Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada. 2001
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TABLE 33-3. Effects of Different Dopamine Infusion Rates
Infusion Rate, Receptors
g/kg/min
Stimulated
Physiologic
Effects
12
DA1
210
Beta1, beta2
>10
Alpha1
Increased renal blood flow and

urinary output
Increased cardiac contractility
and output
Increased peripheral vascular
resistance and blood pressure
DA = dopamine.
vessels supplying skeletal muscle.31,32 At low infusion rates (<0.01

g/kg/min), systemic vascular resistance in reduced or unchanged
but myocardial contractility in increased. At moderate doses
(0.040.10 g/kg/min), myocardial contractility and heart rate
increase with minimal effect on the peripheral vasculature. At
higher infusion doses (>2.0 g/kg/min), alpha effects become
prominent, causing a rise in peripheral vascular resistance.
Epinephrine dosing for cardiac arrest has been the subject of
much controversy.33,34 The dose for intravenous (I.V.) epinephrine
during cardiac arrest is 0.01 mg/kg and a high dose is considered
to be 0.1 mg/kg and above. The American Heart Association
recommends the use of a standard dose initially,35 but should there
be no response, then either a second standard dose or the high
dose may be used. There is high individual variability in response
to epinephrine,36 and although higher doses of epinephrine have
been associated with improved coronary and cerebral blood flow
during cardiopulmonary resuscitation (CPR),3739 doses greater
than 0.05 mg/kg maybe harmful during in-hospital CPR.40,41

Plasma concentration is linearly related to dose, and hence,
epinephrine follows first-order pharmacokinetics. As with many
infusions, there is between-individual variability, particularly in
critically ill children. Plasma half life is 2 to 3 minutes with steadystate plasma concentrations achieved after 10 to 15 minutes. The
principal pathway of metabolism of epinephrine by is O-methylation
to metanephrine by COMT. Deamination by MAO occurs at
multiple sites. Epinephrine is then excreted in the urine as VMA.
Its beta2 effects also result in relaxation of smooth muscle
in the bronchial tree. Epinephrine, because of its hydroxyl group
on the beta carbon atom of the side chain, is a more potent vasopressor than dopamine.42 It does, however, have more metabolic
adverse effects. Epinephrine infusions cause a rise in plasma
lactate.4348 Other metabolic effects include insulin suppression,
glycogenolysis, gluconeogenesis, and decreased clearance of
glucoseall of which collectively increase serum glucose.4952
Epinephrine-associated hypokalemia may also occur as a result
of beta2 receptor stimulation53,54 and may also cause central nervous system excitation that manifests as headache, tremor, and
agitation. Epinephrine directly accelerates the sinoatrial node,
hence, it has proarrhythmic properties.
Epinephrine is available for I.V. administration as 1:1000
(1 mg/mL) or 1:10,000 (100 g/mL) as an aqueous solution
of adrenaline hydrochloride.
Epinephrine may also be administered via the interosseous or
endotracheal (ET) route. When administered interosseously, the
Pharmacology of Vasopressive Agents 537
same dose of epinephrine is used as if it were being administered

intravenously. The ET route requires 10 times the I.V. dose to
achieve similar plasma concentrations.
Racemic epinephrine was traditionally nebulized for the treatment of laryngotracheobronchitis (croup) by stimulating alpha1
receptors that caused vasoconstriction and reduction of subglottic
mucosal swelling. The racemic mixture contained equal amounts
of D and L isomers. However, I.V. preparations of epinephrine are
equally effective when nebulized for croup. The typical nebulized
dose is 0.5 mL/kg of 1:1000 epinephrine (maximum dose 5 mL),
and it may be repeated every 15 minutes if required.
NOREPINEPHRINE
Norepinephrine (noradrenaline) is a naturally occurring catecholamine that is found in the brain and at the postganglionic
neurones of the sympathetic nervous system. It is secreted by the
adrenal medulla.
Norepinephrine stimulates alpha1, alpha2, and beta1 receptors with
minimal effect on beta2 receptors. The result of this is unopposed
vasoconstriction causing a rise in systolic and diastolic blood
pressure and a reflex slowing of the heart rate. The consequent
increase in afterload increases myocardial oxygen demand, which
may lower cardiac output.5557 Pulmonary vascular resistance is
also increased. Norepinephrine also causes vasoconstriction of the
renal and mesenteric vascular beds.5861 However, blood flow is
maintained because of the increased perfusion pressure. In fluidresuscitated hypotensive oliguric patients, norepinephrine caused
a rise in blood pressures that improved renal blood flow,6267
increased glomular filtration rate,6870 and a rise in urine output.
Norepinephrine, unlike dopamine, does not interfere with the
hypothalamic pituitary axis,64,71 but the combination of both may
be beneficial in resistant septic shock.72 It should not be infused
peripherally because extravasation may result in limb and digital
ischemia and skin necrosis.73,74
Norepinephrine has no effect on beta2 receptors and so its effect
on bronchial smooth muscle and smooth muscle elsewhere in the
body is minimal. It also produces less anxiety and agitation than
epinephrine because there is minimal stimulation of the cerebral
cortex.75

Norepinephrine infusion rates, when used within the recommended range, demonstrate a linear relationship with plasma
concentrations. This is consistent with single-compartment, firstorder elimination kinetics.76,77 The pharmacodynamic effects of
norepinephrine infusion do not follow such a linear path. This is
attributed to between-patient variability, adrenoreceptor downregulation, and adrenal suppression from sepsis and drugs.78,79
Norepinephrine is inactivated by oxidative deamination catalyzed by MAO and O-methylation carried out by COMT. The
two reactions occur in either order. The aldehyde products of
the MAO reaction are oxidized to their corresponding acids.
Epinephrine and norepinephrine are converted to vanillyl
mandelate, which is excreted in the urine.
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DOBUTAMINE
Cobutamine is a synthetic catecholamine derived from isoproterenol (isoprenaline). It is composed of a racemic mixture of
two isomers.
Dobutamine directly stimulates predominantly beta1 receptors.
It also has weaker 2 and alpha1 adrenoreceptor activity. The
L isomer acts on alpha receptors and the D isomer acts on both
beta receptors; beta1 stimulation by dobutamine results in
increased myocardial contractility. The weak beta2 activity results
in peripheral vasodilatation, inducing reduced afterload. The net
effect of both beta1, beta2, and alpha1 stimulation leads to increased
cardiac output, decreased left ventricular filling pressure,
decreased systemic vascular resistance, and either an increase or
a decrease in blood pressure. Although dobutamine is a strong
ionotropic agent it, has moderate chronotropic activity, and is not
associated with the tachycardia at doses less than 10 g/kg/min,
doses up to 20 g/kg/min may be used. Doses up to 20 g/kg/min
may be used, but as for all vasopressors, the dose should be titrated
to effect because of between-individual variability.
In the premature neonate, dobutamine raises blood pressure as
alpha1 receptor activity is more pronounced than beta receptor
activity because of the slower maturation of the beta receptor.80
Dobutamine may also lower pulmonary vascular resistance,
although the mechanism of this effect is not fully understood.
Septic patients with a high cardiac output and a high systemic
vascular resistance may benefit from dobutamine.72,81

There is conflicting evidence as to whether dobutamine follows
linear or nonlinear kinetics, and clearance in both critically ill and
noncritically ill children is variable.8285 Onset of action occurs
within 2 minutes with peak effect occurring within 10 minutes.
Plasma half-life is less that 3 minutes and is caused by redistribution and metabolism by COMT.
Dobutamine works on a cellular level through its action on
beta1 receptors by activating guanine nucleotide regulatory cascade
(via G proteins). This leads to increased adenylate cyclase activity
and increased conversion of adenosine triphosphate to cyclic
adenosine monophosphate (cAMP). Intracellular cAMP promotes
release of calcium from the sacroplasmic reticulum. Calcium is
used by contractile proteins to increase contractility. Dobutamine
maybe infused peripherally; inadvertent extravasation is unlikely
to produce significant cutaneous vasoconstriction or necrosis.
PHOSPHODIESTERASE
INHIBITORS (AMRINONE,
MILRINONE, ENOXIMONE)
Milrinone and enoximone are specific phosphodiesterase III
inhibitors (PDEIs) and are derivatives of amrinone. The use of
amrinone was curtailed because of its long context-sensitive halflife and its adverse effect profile that included thrombocytopenia
and gastrointestinal effects.86,87
Milronone is a bipyrinine inotrope/vasodilator that selectively
promotes cAMP levels in cardiac and vascular muscle. PDEIs
prevent the breakdown of cAMP by the isoenzyme phosphodiesterase. This, in turn, results in increased calcium availability
to cardiac muscle and improved cardiac contractility. The opposite occurs in the peripheral vascular smooth muscle where
a diminished availability of calcium leads to vascular smooth
muscle relaxation and consequent vasodilatation, hence the term
ionodilator.88
Milronone reduces preload and afterload and intracardiac filling
pressures,88,89 reducing myocardial oxygen consumption. PDEIs
act indirectly act on beta receptors and are not subject to tachyphylaxis or beta1 desensitization as is the case with other vasopressors.90,91 A major theoretical advantage of milrinone is that it
improves myocardial diastolic dysfunction and more readily
lowers pulmonary vascular resistance.88 It has also been shown to
improve cardiac output in neonates who have low cardiac output
states after cardiopulmonary bypass and in the treatment of
nonischemic heart failure that most commonly occurs in patients
with congenital heart defects. Hemodynamic effects are similar in
both adults and children.92
Although PDEIs may cause serious arrhythmias in adults, these
arrhythmias have not been observed in children.93
Milrinone has been used successfully in conjunction with other
vasopressors in septic shock,94 despite concerns that peripheral
vasodilator effects may be undesirable in hypotensive patients.
Milrinone is renally cleared, and dosing should be adjusted in
those with renal impairment. It has a longer half-life than other
vasopressors, greater than 2 hours in those with normal renal
function, and the effect is reduced when infusions are used for
longer than 48 hours. A clearance of 9 L/h/70 kg is reported in
adults with congestive heart failure. We might anticipate reduced
clearance in neonates in whom renal function is immature. This
has been confirmed in 26-week postmenstrual age infants who
had a clearance of 0.96 L/h/70 kg.95
Milronone has a larger volume of distribution and is more
rapidly cleared in children than in adults, and a larger loading
dose, and perhaps a greater initial infusion rate, may be necessary
in children to achieve serum concentrations within the desired
range and produce an optimal cardiovascular response.96
VASOPRESSIN
Vasopressin is an endogenous hormone produced by the posterior
pituitary gland and is also called ADH. Vasopressin and its synthetic analogue terlipressin have been widely used for the treatment of diabetes insipidus, variceal hemorrhage, and hepatorenal
syndrome.97,98 Vasopressin is released in response to a rise in
serum osmolality above 287 mOsm/kg.99 The osmoreceptors,
located peripherally in the portal system and centrally in the
third ventricle, detect rises in serum osmolality, which may be a
consequence of hypovolemia.
Because of its vasoactive properties, vasopressin has been studied
in relation to septic shock states and in resuscitation after cardiac
arrest. Vasopressin mediates its action via the V1 receptors located
in vascular smooth muscle in the splanchnic, renal, and coronary
circulations.100,101
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V2 and V3 receptors are less important and are located in the
nephron and anterior pituitary, respectively. They also respond
directly to vasopressin to stimulate water retention.
It has been shown that vasopressin concentrations are maintained and even rise in hypovolemic and cardiogenic shock
but drop dramatically in septic shock.102106 Hence, vasopressin
supplementation in septic shock states, particularly catecholamineresistant shock, became a focus for many studies.107113 In adults,
doses greater than 0.04 U/min (i.e., supraphysiologic doses) cause
critical increases in myocardial oxygen consumption, in addition
to intense renal, mesenteric, and pulmonary vasoconstriction.57
Vasopressin and terlipressin have been shown to be effective
adjunctive pressors in the management of norepinephrine and
refractory shock. The bolus dose for vasopressin is 0.01 to 0.3 U/
kg/min with an infusion range of 0.0002 to 0.002 U/kg/min.114
Terlipressin doses vary from 7 g/kg every 12 hours115 to 10 g/kg
given hourly.116 Larger children are given boluses of between
0.5 and 1 mg.117,118 Its role in pediatric septic shock has been less
well studied, although animal studies and case series reports
have been promising.119,120 There are no clear guidelines as to when
vasopressin infusions should be started in septic shock. A large
adult study56 and a small study on low-birthweight infants have
suggested commencing vasopressin infusions121 before norepinephrine has reached 0.6 g/kg/min. Neither vasopressin nor
terlipressin is recommended as first-line agents in the treatment of
septic shock but rather adjuncts should norepinephrine fail to
maintain blood pressure.
Vasopressin during resuscitation after cardiac arrest in adults
has been shown to improve short-term outcomes (survival to
hospital admission).122124 Wenzel and coworkers125 conducted a
large prospective study involving over 1000 adult patients comparing vasopressin 0.04 U and epinephrine 1 mg intravenously.
They reported similar outcomes in both the vasopressin- and the
epinephrine-treated patients after ventricular fibrillation and
pulseless electrical activity arrests. In patients who had asystolic
arrest, however, vasopressin improved survival rates. Vasopressin as
a resuscitative drug in pediatric cardiac arrests is less well studied.
Mann and colleagues case series suggested that vasopressin given
after epinephrine resulted in a return to spontaneous circulation
after prolonged cardiac arrest.126 Animal studies have demonstrated
a benefit of vasopressin used with epinephrine,127,128 but further
studies are needed to validate its use in pediatric patients. One
theoretical advantage of vasopressin over other vasopressors used
during cardiac arrest is that severe acidosis does not alter its
effectiveness.129 Vasopressin has also been shown to preserve renal
blood flow, creatinine clearance, and renal function better than
norepinephrine when used to maintain systemic vascular resistant in septic shock.130 Currently, American Heart Association
guidelines state that there is insufficient evidence to recommend
for or against the routine use of vasopressin during cardiac arrest
in children.131

Vasopressin is metabolized by tissue peptidases, 33% being eliminated by the kidney and renally excreted. It has an elimination
half-life of approximately 10 to 35 minutes. It can be administered
subcutaneously, intramuscularly, or intravenously. Its analogue
desmopressin is usually given intranasally as snuff or spray. Vasopressin increases renal lumen permeability to water. Vasopressin
secretion is enhanced by stimulation of the renin-angiotensin
mechanism. It also increases glycogen breakdown, stimulates the

release of corticotrophin from the anterior pituitary, and is a mild
stimulant of platelet aggregation.
ISOPRENALINE
Isoprenaline is a synthetic catecholamine with potent beta1 and 2
activity with no alpha activity.
Both myocardial contractility and heart rate are increased with
both systolic and diastolic pressures decreased. Blood supply is
diverted from vital organs to muscle and skin, and this can
potentiate myocardial ischemia and arrhythmias. Isoprenaline is
used therapeutically in torsades de pointes because it reduces the
QT interval.
Its inotropic effects occur at an infusion of 0.015 g/kg/min.
At rates greater than 0.02 g/kg/min, tachyarrhythmias and
ventricular irritability occur. Profound hypotension may also
occur because of the unopposed beta2 stimulation. Isoprenaline
has now been superseded by dopamine and dobutamine, which
have a lower incidence of malignant arrhythmias. However, it may
still be of use in the treatment of bradycardia unresponsive to
atropine, blocker overdose and atrioventricular conduction
block, particularly in denervated hearts. Other effects include
pulmonary vasodilatation and bronchodilatation.
DOPEXAMINE
Dopexamine is a synthetic analogue of dopamine that is about
60 times more potent. It has pronounced beta2 and DA1 activity
with minor beta1 and DA2 activity and no alpha activity. Dopexamine does decrease norepinephrine re-uptake, but its predominant effect is afterload reduction owing to renal and mesenteric
vasodilatation. Myocardial contractility is improved by virtue of its
potent beta2 activity.
Dopexamine also cause pulmonary vasodilatation and may
impair hypoxic vasoconstriction and, hence, may worsen pulmonary shunting. Infusion rates range between 0.5 and 6 g/kg/min.
Dopexamine has been associated with a rise in arterial pressure
and a rise in urine output in critically ill neonates.132 In older
children following surgery for congenital heart disease, dobutamine was associated with a significant rise in cardiac index and
heart rate.

Its pharmacokinetic profile has not been fully elucidated. Infusion
rates range between 0.5 and 6 g/kg/min and its plasma half-life
is 6 to 7 minutes. It is cleared from the circulation and taken up by
extraneuronal tissues and the liver where it is metabolized by
COMT and MAO.
PHENYLEPHRINE
Phenylephrine is a postsynaptic alpha1 adrenergic receptor agonist
with little beta activity, similar to norepinephrine. Aside from
its vasoconstrictive properties, it is most commonly used as a
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mydriatic and nasal decongestant. Parenteral administration of

phenylephrine causes a rise in systolic and diastolic pressures;
cardiac output is slightly decreased; and peripheral resistance is
considerably increased, which may cause a reflex bradycardia.
Most vascular beds are constricted; pulmonary, renal, splanchnic,
cutaneous, and limb blood flows are reduced, but coronary blood
flow is increased. The recommended bolus dose is 2 to 10 g/kg
and an infusion may run at 1 to 5 g/kg/min.
METARAMINOL
Metaraminol acts directly on postsynaptic alpha1 receptors and
indirectly to cause norepinephrine release from sympathetic nerve
terminals presynaptically. Metaraminol increases systolic and
diastolic blood pressure blood pressure as a result of its alpha1
stimulation but also causes a rise in cardiac output owing to its
stimulation of the beta1 receptors. Hence, reflex bradycardia is less
likely to occur with metaraminol than with phenylephrine.133 The
recommended dose is 10 g/kg.
EPHEDRINE
Ephedrine is a sympathomimetic amine that acts directly and
indirectly on the adrenergic beta1, beta2, and alpha1 receptors.
Direct stimulation occurs postsynaptically on the adrenergic
receptors and indirect stimulation promotes the release on
norepinephrine presynaptically. Consequently, it has chronotropic
and inotropic effects on the heart and increases peripheral vascular resistance. Ephedrine is also used as a bronchodilator because
of its beta2 effects and a nasal decongestant owing to its alpha
vasoconstrictive effects. Tachyphylaxis may occur owing to norepinephrine depletion.
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open heart surgery. Anesth Analg. 1998;86:283289.
97. Ioannou GN, Doust J, Rockey DC. Systematic review: terlipressin in
acute oesophageal variceal haemorrhage. Aliment Pharmacol Ther.
2003;17:5364.
98. Moreau R. Hepatorenal syndrome in patients with cirrhosis. J Gastroenterol
Hepatol. 2002;17:739747.
99. Antunes-Rodrigues J, de Castro M, Elias LL, et al. Neuroendocrine
control of body fluid metabolism. Physiol Rev. 2004;84:169208.
100. Share L. Role of vasopressin in cardiovascular regulation. Physiol Rev.
1988;68:12481284.
101. Altura BM. Dose-response relationships for arginine vasopressin and
synthetic analogs on three types of rat blood vessels: possible evidence
for regional differences in vasopressin receptor sites within a mammal.
102. Landry DW, Levin HR, Gallant EM, et al. Vasopressin deficiency contributes to the vasodilation of septic shock. Circulation. 1997;95:11221125.
103. Asfar P. Terlipressin in chronic hyperdynamic endotoxic shock: is it safe?
104. Lodha R, Vivekanandhan S, Sarthi M, Kabra SK. Serial circulating
vasopressin levels in children with septic shock. Pediatr Crit Care Med.
2006;7:220224.
105. Sharshar T, Blanchard A, Paillard M, et al. Circulating vasopressin levels
in septic shock. Crit Care Med. 2003;31:17521758.
106. Reid IA. Role of vasopressin deficiency in the vasodilation of septic
shock. Circulation. 1997;95:11081110.
107. Forrest P. Vasopressin and shock. Anaesth Intensive Care. 2001;29:
463472.
108. Tsuneyoshi I, Yamada H, Kakihana Y, et al. Hemodynamic and
metabolic effects of low-dose vasopressin infusions in vasodilatory septic
shock. Crit Care Med. 2001;29:487493.
109. Dunser MW, Mayr AJ, Ulmer H, et al. The effects of vasopressin on
systemic hemodynamics in catecholamine-resistant septic and postcardiotomy shock: a retrospective analysis. Anesth Analg. 2001;93:713.
110. Dunser MW, Mayr AJ, Ulmer H et al. Arginine vasopressin in advanced
vasodilatory shock: a prospective, randomized, controlled study.
Circulation. 2003; 107:23132319.
111. Patel BM, Chittock DR, Russell JA, Walley KR. Beneficial effects of shortterm vasopressin infusion during severe septic shock. Anesthesiology.
2002;96:576582.
112. Rosenzweig EB, Starc TJ, Chen JM, et al. Intravenous argininevasopressin in children with vasodilatory shock after cardiac surgery.
Circulation. 1999;100(19 Suppl):II182II186.
113. Malay MB, Ashton RC Jr, Landry DW, Townsend RN. Low-dose vasopressin in the treatment of vasodilatory septic shock. J Trauma. 1999;
47:699703.
114. Lechner E, Dickerson HA, Fraser CD Jr, Chang AC. Vasodilatory shock
after surgery for aortic valve endocarditis: use of low-dose vasopressin.
Pediatr Cardiol. 2004;25:558561.
115. Matok I, Leibovitch L, Vardi A, et al. Terlipressin as rescue therapy for

intractable hypotension during neonatal septic shock. Pediatr Crit Care
Med. 2004;5:116118.
116. Zeballos G, Lopez-Herce J, Fernandez C, et al. Rescue therapy with
terlipressin by continuous infusion in a child with catecholamineresistant septic shock. Resuscitation. 2006;68:151153.
117. Salluh JI, Martins GA, Santino MS, et al. Early use of terlipressin in
catecholamine-resistant shock improves cerebral perfusion pressure
in severe traumatic brain injury. Acta Anaesthesiol Scand. 2007;51:
505508.
118. Peters MJ, Booth RA, Petros AJ. Terlipressin bolus induces systemic
vasoconstriction in septic shock. Pediatr Crit Care Med. 2004;5:112115.
119. Rodriguez-Nunez A, Fernandez-Sanmartin M, Martinon-Torres F, et al.
Terlipressin for catecholamine-resistant septic shock in children. Intensive
Care Med. 2004;30:477480.
120. Westphal M, Bone HG, Van AH, Sielenkamper AW. Terlipressin for
haemodynamic support in septic patients: a double-edged sword?
Lancet. 2002;360:12501251.
121. Meyer S, Gottschling S, Baghai A, et al. Arginine-vasopressin in
catecholamine-refractory septic versus non-septic shock in extremely
low birth weight infants with acute renal injury. Crit Care. 2006;10:R71.
122. Stiell IG, Hebert PC, Wells GA, et al. Vasopressin versus epinephrine for
inhospital cardiac arrest: a randomised controlled trial. Lancet. 2001;
358:105109.
123. Lindner KH, Dirks B, Strohmenger HU, et al. Randomised comparison
of epinephrine and vasopressin in patients with out-of-hospital
ventricular fibrillation. Lancet. 1997;349:535537.
124. Guyette FX, Guimond GE, Hostler D, Callaway CW. Vasopressin
administered with epinephrine is associated with a return of a pulse in
out-of-hospital cardiac arrest. Resuscitation. 2004;63:277282.
125. Wenzel V, Krismer AC, Arntz HR, et al. A comparison of vasopressin
and epinephrine for out-of-hospital cardiopulmonary resuscitation.
N Engl J Med. 2004;350:105113.
126. Mann K, Berg RA, Nadkarni V. Beneficial effects of vasopressin in
prolonged pediatric cardiac arrest: a case series. Resuscitation. 2002;52:
149156.
127. Voelckel WG, Lurie KG, McKnite S, et al. Effects of epinephrine and
vasopressin in a piglet model of prolonged ventricular fibrillation and
cardiopulmonary resuscitation. Crit Care Med. 2002;30:957962.
128. Voelckel WG, Lindner KH, Wenzel V, et al. Effects of vasopressin and
epinephrine on splanchnic blood flow and renal function during and
after cardiopulmonary resuscitation in pigs. Crit Care Med. 2000;28:
10831088.
129. Eichinger MR, Walker BR. Enhanced pulmonary arterial dilation to
arginine vasopressin in chronically hypoxic rats. Am J Physiol. 1994;
267:H2413H2419.
130. Guzman JA, Rosado AE, Kruse JA. Vasopressin vs norepinephrine in
endotoxic shock: systemic, renal, and splanchnic hemodynamic and
oxygen transport effects. J Appl Physiol. 2003;95:803809.
131. American Heart Association. Pediatric Basic and Advanced Life
Support. Circulation. 2005;112:III-73III-90.
132. Kawczynski P, Piotrowski A. Circulatory and diuretic effects of
dopexamine infusion in low-birth-weight infants with respiratory failure.
133. Drugdex editorial staff. Metaraminol (Drug Evaluation). In: Hutchison TA,
Shahan DR, eds. Drugdex System. Greenwood Village, Colorado, Micromedex,
2001.
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Mario J. da Coneicao
INTRODUCTION
Postoperative vomiting (POV) continues to be a frequent and
important cause of morbidity in children. It is important to define
the meanings of nausea, retching, and vomiting: nausea is a
subjective sensation, vomiting is expulsion of stomach contents,
and retching is the expulsive effort. The feature that distinguishes
retching from vomiting is the expulsion of stomach contents.
Retching and vomiting can be grouped together under the common term emetic episode.1 Vomiting is a complex behavior that
presumably conveys a survival advantage in that it promotes the
rapid expulsion of ingested toxins.
POV is more commonly studied in children than postoperative
nausea because of a childs inability to effectively express subjective
sensations and distress after experiencing nausea. POV is one of
the leading postoperative complaints from parents and the leading
cause of unplanned readmission to the hospital after day surgery.1
POV occurs twice as frequently in children as in adults. The
incidence increases until puberty and then decreases to adult rates.
Gender differences are not seen before puberty. Severe vomiting
can be associated with dehydration, postoperative bleeding, pulmonary aspiration, and wound dehiscence. Although children
have an increased potential for dehydration and the resulting physiologic impairments, other associated results such as a delay in
hospital discharge or an overnight or longer hospital admission
also must be considered.2 Adequate POV control adds significant
improvement in patients and parents satisfaction.3 The cause of
POV is multifactorial with differing contributions depending
upon the clinical situation.
HOW DO POSTOPERATIVE NAUSEA

AND VOMITING OCCUR?
If nausea and vomiting could be considered natural responses,
making up components of the bodys defense system against
ingested toxins, why then should anesthesia and surgery induce
nausea and vomiting? Are there particular special features about
anesthesia and surgery that relate to this disturbing problem? The
reason is that some feature of anesthesia and surgery activates
triggers for the emetic system. We do not have a satisfactory answer to the question proposed as the heading to this section, even
though it is possible to identify several of the likely explanations.
The question could perhaps be addressed in a different way: how
do various components of anesthesia and surgery that contribute
to POV trigger detection systems developed primarily to detect
ingested toxins? It is unclear whether the emetic effects of anesthetics relate to anesthetic action or to a side effect such as opioid
receptor activation, although the evidences suggest that emesis is

most likely a side effect (or an indirect effect) of these agents and
does not relate to their anesthetic action. The high incidence of
POV after throat and middle ear surgery is unsurprising considering the activation of the vestibular afferent pathways involved
in motion sickness and of the auricular vagus branch, which
supplies the tympanum. The surgical trauma to the pharynx after
tonsillectomy causes edema and sensitization of the glossopharyngeal afferents contributing to observed POV. It is easy to
understand that similar processes may be induced by the presence
of an orotracheal tube even after the tube is removed. Manipulation, displacement, and traction of gut and mesentery during
abdominal surgery stimulate vagal afferents supplying the upper
gut and release of 5-hydroxytryptamine (5-HT) from the enterochromaffin cells. 5-HT release can cause both direct activation of
the afferents and produce long-lasting sensitization to other
stimuli.
The mechanisms of emesis can be divided into three components (Figures 341 and 342):
1. Afferent inputs go to the central nervous system (CNS),
relaying the signals of emetic stimuli.
2. These signals are received, recognized, and centrally processed.
They then form integrated emetic efferent signals coming from
the CNS.
3. These motor and chemical efferent pathways relay signals that
lead to the coordinate respiratory gastrointestinal and abdominal muscle expulsive actions of vomiting.
Abdominal Visceral Afferents

Gut afferents may be viewed as the second line of defense against
poisoning from food once first-line defenses of vision, taste, and
smell have been circumvented.4 Contrary to popular belief, the
stomach alone does not actively expel its contents during vomiting. The stomach, esophagus, and their relevant sphincters are all
relaxed during vomiting. Contraction of the diaphragm and the
abdominal muscles generates most of the force that expels gastric
contents. The vagus is the major nerve involved in the detection of
emetic stimuli; its abdominal course contains 80 to 90% afferent
fibers. Electrical stimulation of the vagal afferents is capable of
inducing emesis within 20 seconds and confirms the potential
of this pathway for rapid ejection of gastric contents.5 Two types of
vagal afferent fibers are involved in emetic response. These mechanoreceptors are located in the muscular wall of the gut and activated by both contraction and distention. Overeating, causing
distention of the gastric antrum or intestinal obstruction, may
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545
Area Postrema
Application of chemicals to the dorsal surface of the brainstem
can induce emesis, and it was assumed that this was through direct
stimulation of the vomiting center located in this region. However,
it has been demonstrated that stimuli were detected by cells of
the area postrema, a U-shaped structure a few millimeters long
located in the caudal part of the fourth ventricle in the region of
the obex.7 This region is termed the chemoreceptor trigger zone
(CTZ) for emesis.8 It is assumed that all chemicals in the circulation may induce emesis by this route.
Vestibular System
Figure 34-1. The vomiting mechanism.

induce vomit by stimulation of these afferents. The chemoreceptors
located in the mucosa of the upper gut are responsible for the
monitoring of several intraluminal stimuli. They respond, for
example, to acid, alkali, and hypertonic solutions and mucosal
stroking. Vagotomy reduces or even abolishes emesis induced by
irritants such as hypertonic sodium solution.6
Figure 34-2. Peripheral and central mechanisms in the control

of emesis.
The vestibular labyrinthine system is essential for induction of

emesis by motion. There is limited evidence that the vestibular
system could be involved directly in the emetic response to some
drugs. However, motion sickness appears to be a predictor of both
PONV and the response to antiemetic prophylaxis.9 Although its
predictive value was fairly low, there is a strong association
between motion sickness and POV in pediatric populations.10 It is
recognized that higher cerebral influences also have a role in the
motor components of the emetic reflex, although the precise role
remains unclear. Input from the brainstem (e.g., limbic system)
can induce nausea and vomiting. These higher inputs appear to
have a mainly facilitatory role in modulating the sensitivity of the
brainstem emetic mechanism rather than acting as primary
detectors of the stimuli.
THE VOMITING REFLEX

The vagal motor neurons supplying the gut and heart, the dorsal
and ventral respiratory groups regulating the phrenic nerve output, and the presympathetic neurons that maintain sympathetic
tone to the heart and blood vessel all contribute to the well-known
vomiting pattern.11 This vomiting reflex is complex (Figure
343), and no single brainstem nuclei that could be in charge of
output coordination has been identified.
Figure 34-3. Motor components of the vomiting reflex.
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RISK FACTORS FOR POV IN CHILDREN

Age, a history of POV with anesthesia, and particular types of
surgery have been identified as risk factors for POV in children
(Table 341).12 Although efforts have been made to develop and
validate a risk score that predicts the probability of POV in pediatric patients, controversial and unresolved issues remain.13 An
evaluation of a score for predicting POV in children (POVOC
score) had sufficient accuracy comparable with results in adult
patients, but strabismus surgery, a major risk factor, was not
included.14 The evaluation has indicated that, even in the absence
of strabismus surgery, the POVOC score allows estimation of the
risk of POV in pediatric patients. In order to ensure that the
POVOC score is valid for all types of surgery, a further evaluation
in a large-scale survey with rigorous assessment of emetic symptoms would be helpful. The introduction into daily practice of
predictive score could decrease POV incidence, enhance the
effectiveness of treatment, discriminate which children needs
prophylaxis, and improve antiemetic trial design.15
Consensus guidelines for managing postoperative nausea and
vomiting (PONV) are inadequate for children, although a number
of patient characteristics, anesthesia, and surgery-related factors
have been identified as important in deciding those children most
likely to suffer from POV.9 A history of previous POV, strabismus
surgery, long-duration anesthesia, age older than 5 years, and
opioid use are important factors increasing the risk of POV.
Motion sickness in adults appears to be a predictor of PONV,
responding to antiemetic prophylaxis.9 A correlation between
motion sickness in children and POV is reported, although the
positive predictive value was only 64%.9 A history of previous
motion sickness is insufficiently precise to be recommended as
the sole basis for a clinical decision-making. When children were
given halothane or sevoflurane anesthesia for inguinal surgery,
those with a history of motion sickness (MS+) vomited more than
those without such a history (MS) regardless of the inhalation
anesthetic used. However, MS children displayed a higher incidence of vomiting when halothane rather than sevoflurane was
used.16 According to currently available evidence, there are no
clinically important differences in the incidence of POV with the
use of sevoflurane, desflurane, or isoflurane for maintenance of
anesthesia. There is general agreement, however, that the incidence of POV is higher with volatile agents when compared with
intravenous anesthesia (e.g., propofol).17 Studies in both children
and adults have shown that the incidence of POV is decreased with
the use of propofol. The use of propofol for induction alone has no
clinically relevant effect on POV. Infusions of propofol for maintenance of anesthesia showed better reduction of POV in highTABLE 34-1. Important Factors for Postoperative
Vomiting in Children
In children, POV is better described than nausea.
Gender is not important before puberty.
Risk decreases after puberty.
Specific operations increase the risk consistently.
Motion sicknesspositive children are more than twice as likely
to vomit.
Vomiting incidence is twice as frequent among children as
among adults.
Risk scores remain controversial,
POV = postoperative vomiting.
risk pediatric patients. The antiemetic mechanism of propofol is

still unclear, and it does not appear related to blockade of dopaminergic receptors.
The two most common emetic surgical procedures in children
are strabismus repair and tonsillectomy with or without adenoidectomy. Ear, nose, and throat (ENT) operations, particularly,
remain one of the most frequently performed pediatric surgical
procedures worldwide.18 POV is one of the most common postoperative complications associated with these procedures.19 Trigeminal nerve stimulation, swallowed blood causing gastrointestinal
irritation, and the use of diathermy are all contributing factors
peculiar to ENT operations that increase POV. Tracheal intubation
and the use of opioids or nitrous oxide have all been implicated as
anesthetic factors increasing the rate of POV.20
POV after strabismus surgery remains a common and distressing problem with a high incidence and increased morbidity after
such surgery. Emesis occurs because of eye manipulation or pain.
A number of drugs and strategies have been used with some
success including the use of peribulbar block. Success found with
the regional anesthesia could be caused by the inhibition of the
afferent pathway of the occuloemetic reflex.21
Pain, sight, smell, taste, and emotion are sensations leading to
information sent to the higher centers in the brain, stimulating
and activating the vomiting reflex via neurotransmitters that
include acetylcholine. Opioids are well recognized as a cause of
vomiting that act through stimulation of trigger zones, increased
vestibular sensitivity, gastric stasis, or impaired intestinal motility
and constipation.22 Nitrous oxide causes vomiting, and the avoidance of nitrous oxide reduces the risk of PONV by an average of
28% in adults.23 The diffusion of nitrous oxide into the middle ear
with stimulation of the vestibular apparatus and bowel distention
with serotonin release are among possible mechanisms. Most of
these data come from adult studies, and it is suggested that there
is similar action in children. By contrast, there is no decrease in
POV after pediatric tonsillectomy attributable to omission of
nitrous oxide in children.24 Children undergoing chemotherapy
and radiotherapy are more likely to suffer from POV. The cytotoxic drugs cause mobilization of serotonin (5-HT) from mucosal
enterochromaffin cells that excites 5-hydroxytryptamine3 (5-HT3)
on mucosal vagal afferents and possibly centrally in the area
postrema, inducing POV. The severity of the problem varies with
the chemotherapeutic drug cocktail administered; antiemetic
treatment is successful for most of these patients.25 Ingested toxic
substances can induce PONV that may be life-saving. Mediators,
or even the circulating substance, act directly on trigger zones,
leading to induction of PONV. The routine use of cholinesterase
inhibitors to antagonize residual neuromuscular block may be
associated with increased postoperative emesis in children.
Edrophonium may offer advantages over the use of neostigmine
for antagonism of neuromuscular block.26
The duration of surgery and anesthesia also increases the
incidence of POV. The reasons remain unclear but can possibly be
related to increased accumulation of emetogenic anesthetic agents.
It has been documented that 48% of pediatric patients experienced
POV when surgery duration was greater than 30 minutes compared with 34% when surgery duration was less than 30 minutes.27
ANTIEMETIC AGENTS
The use of antiemetic agents in infants and children without a clear
purpose is not recommended. There are only few situations in which
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antiemetic agents are indicated and possibly effective, and these include
POV. Several types of antiemetics could be used in the management
of POV: gastrointestinal prokinetic drugs, which enhance gastric and
upper intestinal motility with antido paminergic actions
(metoclopramide; phenothiazines as perphenazine); butyrophenones
(droperidol), and 5-HT3 antagonists (ondansetron or tropisetron).
There are also reports of an association between antiemetic activity
and central anticholinergic agents (hyoscine and atropine) and
some antihistamine receptor type 1 antagonists (cyclizine). These
drugs are all reported in children, although their efficacy in fully
stopping POV is undetermined. Other gastrointestinal prokinetic drugs such as cisapride or domperidone are not frequently
used in children because of adverse effects.26 A single dose of
dexamethasone has been reported to be effective for PONV
prophylaxis without evidence of significant side effects. It has also
been suggested that dexamethasone might be especially effective
against late POV.27
Dopaminergic Antagonists
The receptor in the CTZ most closely associated with POV is the
dopamine2 receptor (D2). This explains the antiemetic effect of
D2 receptor antagonists like butyrophenones, metoclopramide,
and domperidone. Under normal conditions, dopamine inhibits
the release of acetylcholine in the myenteric plexus by acting at
presynaptic D2 dopaminergic receptors. D2 receptor antagonists
such as metoclopramide also have prokinetic effects, enhancing
the release of acetylcholine.28
Metoclopramide
Structurally related to procainamide (2-methoxy-5chloroprocainamide), metoclopramide has been used extensively
since the earlyh 1980s in the treatment and prevention of PONV
by oral intramuscular, and intravenous routes in both children and
adults. The pharmacokinetics are described for neonates.29
Metoclopramide acts primarily as a dopamine antagonist in the CNS,
specifically at the CTZ. It has selective peripheral cholinergic
stimulant effects on the proximal gastrointestinal tract, although
the real role of its direct action on the gastrointestinal tract and
consequent antiemetic effect still remains unclear. Some of its
antiemetic activity could be account for by its effect at the 5-HT3
receptor, particularly at high doses.30 At high doses, above 0.5
mg/kg/d, metoclopramide blocks not only D2 receptors but also the
central and local receptors for serotonin. This antiserotinergic action
in children may possibly cause greater clinical effect.31 However, the
use of metoclopramide is strongly associated with extrapyramidal
reactions, especially in young patients. It is important to note that
most of studies employing metoclopramide in children neglect to
mention that children, especially females, are at increased risk of
acute dystonic reactions such as extrapyramidal syndromes,
although the incidence of this adverse event has never been
established.32 Sedation and delayed recovery from anesthesia are
reported for adult patients.33
Butyrophenones
Butyrophenones are potent neuroleptics, and from this class of drugs,
droperidol is most familiar to anesthesiologists. In adults, droperidols
distribution half-life is approximately 10 minutes, the elimination
half-life is 2 hours, and plasma clearance approximately 15 mL/
Antiemetic Agents
547
min/kg.34,35 Like metoclopramide, droperidol can be administered

by oral, intramuscular, or intravenous routes. Droperidol was
more effective than placebo in the prevention of POV in children.36
It has a good antinausea effect and a less pronounced antiemetic effect.
Pediatric studies focus on the antiemetic effect.37 This may explain
why ondansetron has been shown to be a better drug for prophylaxis
of POV in children but not in adults.38 The doses employed range
from 40 to 80 g/kg, and the effectiveness increases with dose.
Droperidol causes sedation or even drowsiness in the recovery period,
which can be accompanied of dysphoria and extrapyramidal
effects. A warning from the U.S. Food and Drug Administration
(FDA) emphasizes that the use of droperidol, according to some
reports, causes serious electrocardiogram rhythm changes.
Considering this current status, droperidol should be used for POV
prevention and treatment in children only in selected cases.
Curiously, the drug has been used safely since the late 1970s. Similar
warning from FDA alerts for increasing risk of prolonged QT
syndrome after use of benzodiazepines, volatile anesthetics, and
opioids. Domperidone, unlike metoclopramide, does not pass the
blood-brain barrier and CNS side effects are rare. Because the CTZ
is outside the blood-brain barrier, domperidone does have an
antiemetic effect here. Domperidone raises lower esophageal
sphincter pressure, increases the amplitude of gastric and duodenal
contractions, and accelerates small intestinal transit. In children, it
seems domperidone is quite effective in the treatment of gastroparesis.
Its use in POV is not as common because of adverse effects like extrapyramidal symptoms and possible interference with cardiac rhythm.
Phenothiazines
Phenothiazines also exert their antiemetic effect at the D2 chemoreceptors in the CTZ. Promethazine is administered in doses
ranging from 0.25 to 0.5 mg/kg to a maximum of 25 mg,
and perphenazine has been shown to be effective for POV prophylaxis in children at doses of 0.7 mg/kg with minimal sedative
effects.
5-HT3 Antagonists
This class of drugs is thought to act by highly selective and efficient
antagonism of 5-HT3 receptors located in the brain with a high
density occurring in the area postrema and the nucleus tratus
solitarius. Ondansetron, granisetron, tropisetron, and dolasetron
are the most known drugs from this class. They can be administered by oral or intravenous routes. In addition to having a central
site of action, they may act peripherally in the gastrointestinal
tract, stimulating afferent vagal fibers that, in turn, cause 5-HT
release in the area postrema.39 The peak plasma concentration
after 8 mg orally in adults occurs at about 1.5 hours. Ondansetron
is bound to plasma proteins to a moderate extent (75%) with a
volume of distribution of approximately 160 L. Its terminal plasma
half-life is approximately 3 hours, with 5% excreted renally.
Hydroxylation followed by glucuronide or sulfate conjugation in
the liver is the major route of excretion. Clearance is 541 mL/min.
Normally, the intravenous preparation is an isotonic aqueous
solution compatible with 0.9% sodium chloride, 5% glucose, and
Ringers lactate solution.40 Clinically, some studies have reported
ondansetron 0.1 mg/kg to be a superior drug to metoclopramide
0.5 mg/kg for the prophylactic control of POV in children undergoing tonsillectomy.32
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Although it is assumed that the major site of action of the

selective serotonin antagonists is the CTZ, a major effect of 5-HT3
receptor antagonists is at the enteric level, where they block receptors in the peripheral ends of vagal afferents, thus blocking
serotonin-stimulated vagal afferent input to the central pattern
generator and reducing the perception of emetic stimuli.
Side effects with this class of drug are rare and may include
headache, flushing at the intravenous site of administration, and
headedness. In adults, there are reports of prolongation of the QRS
complex and PR interval, although no change in heart rhythm or
hemodynamics was documented in children.
Steroids
Dexamethasone 150 g/kg, as well as other glucocorticoids like
methylprednisolone, is also associated with prevention of early and
late vomiting. The exact mechanism of action is unknown. It is
supposed to be consequence of the decreased enteric prostaglandin
synthesis. However, steroids are better combined with other
antiemetic drugs for synergistic effect rather than as the sole agent.
Dimenhydramine
Dimenhydrinate is available for use as a theoclate salt of diphenhydramine that can be administered orally, intravenously, and as a
suppository. Dimenhydrinate 0.5 mg/kg was found to be as clinically effective as ondansetron with few serious adverse effects.
Although it was synthesized to avoid the sedative effects of
diphenhydramine, sedation and dry mouth as well as other muscarinic effects do occur. Some evidence support the use of
dimenhydrinate as prophylaxis in children at moderate and high
risk of POV.41 It has been used as an agent for rescue therapy in
established POV in children.
ALGORITHMS, PROPHYLAXIS,
AND TREATMENT
of POV should take into account resources, patients and parents

preferences, surgical setting, and risk factors.44 Prophylaxis appears to be different from treatment. In the treatment approach,
only children who actually deserve antiemetic drugs will eventually receive those antiemetics, reducing the risk of drug-induced
harm.45 At the other extreme, the strategy most likely to achieve
the lowest incidence of POV would be to administer all antiemetic
interventions to all patients without any risk stratification, increasing acquisition costs and needlessly exposing patients who
have no propensity for POV. Further, the efficacy of some antiemetic drugs that have been used for decades is unreported.
Vomiting is a common symptom of many disease states. The
differential diagnosis of the child with vomiting varies with the
age of the patient. Congenital anatomic, genetic, or metabolic
disorders are more frequent in neonatal period, whereas peptic,
infectious, and psychogenic problems are more commonly seen
with increasing age. In preoperative evaluation, the anesthesiologist must remain alert to these problems, especially gastroesophageal reflux, because of the high risk for POV.
Hypovolemia has been associated with increased postoperative
PONV attributable to gut mucosal hypoperfusion.46,47 Gut ischemia results in release of 5-HT, which is a potent trigger of PONV.
Although the mechanism of hydration in reduction of PONV is
not clear, intravenous fluid therapy contributed to reduced POV
after pediatric strabismus surgery.48,49
Some proposed steps to a successful POV management strategy
are shown in Figure 344. Unfortunately, this kind of algorithm
may be satisfactory only when applied to specific patient populations. It is suggested that the single most important factor reducing
POV is the number of antiemetic interventions administered.41
Without prophylaxis, there is a high incidence of POV (73%)
after high-risk surgical procedures such as tonsillectomy,50 and
this adverse event is the most common cause of delayed discharge
or overnight admission in day case tonsillectomy. POV is also
associated with increased bleeding, aspiration of gastric contents,
dehydration, and electrolyte disturbance.51 Among the prophylactic measures described for high-risk patient groups, the 5-HT3
receptor antagonists and dexamethasone are consistently at the
The identification of risk factors is an important step toward

improved control of POV. Patients with risk factors are thought to
benefit most from a prophylactic anti-POV strategy.42 Countering
known risk factors reduced POV (Table 342). Most algorithms
for the prevention of PONV are adult-based and reliability in
children is uncertain. Stepwise18,43 or dichotomous44 models for
emetic control suggest that a combination of antiemetic interventions increases effectiveness, although a gold standard algorithm
for adults or children remains elusive. The rational management
TABLE 34-2. How to Reduce Baseline Risk
If NMBD reversal is required, use edophronium instead of
neostigmine.
Avoid or minimize the opioid perioperative use.
Avoid postoperative use of morphine.
Avoid nitrous oxide especially in ENT or strabismus surgeries.
Avoid. if possible. volatile anesthetic agents.
Use propofol for induction and maintenance, if indicated.
Use regional anesthesia, if indicated.
Do not neglect hydration.
ENT = ear, nose, and throat; NMBD = neuromuscular blocking drug.
Figure 34-4. Algorithm for prevention of postoperative vomiting.
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Antiemetic Agents
549
TABLE 34-3. Antiemetic Drugs Used in Postoperative Vomiting: Dose and Possible Mechanism of Action
Drug
Receptor
Mechanism
Dose
Metoclopramide
D2
(5-HT3)
5-HT3
5-HT3
5-HT3
D2
D2
D2
D2
H1
D2 blockade at the CTZ and enteric nervous system. In high dose,

has 5-HT3 activity enterically.
5-HT3 receptor blockade most important at the enteric level but
possibly some effect at the CTZ.
0.250.5 mg/kg
Ondansetron
Granisetron
Tropisetron
Droperidol
Dexamethasone
Domperidone
Promethazine
Perphenazine
Dimenhydrinate
D2 receptor blockade at the CTZ. Central anxiolysis and sedation.

Unknown, decreased enteric prostaglandin synthesis.
D2 receptor blockade at enteric nervous system.
D2 receptor blockade at the CTZ.
Antagonist
0.10.3 mg/kg
0.40.5 mg/kg
0.10.2 mg/kg
5080 g/kg
11.5 mg/kg
50 g/kg
0.250.5 mg/kg
0.7 mg/kg
0.5 mg/kg
CTZ = chemoreceptor trigger zone; D2 = dopamine2 receptor; 5-HT3 = 5-hydroxytryptamine3.

From references 12 and 38.
forefront.52,53 Dexamethasone with ondasentron is a useful combination53,54 because ondansetron is most effective against early
vomiting54 whereas dexamethasone is effective against both early
and late nausea and vomiting.37,55 The sole use of 5-HT3 receptor
antagonists is not as efficient as when they are combined with
dexamethasone.18 There were no differences among the combination of dexamethasone 2 mg or 4 mg with ondasentron 2 mg
or 4 mg in adult prophylaxis.52 Optimal combinations of dexamethasone with 5-HT3 antagonists in children require investigation.37,52,54,55 The prophylactic antiemetic doses recommended for
children at risk for POV are shown in Table 343.
The use of opioids, especially morphine, for treatment of postoperative pain contributes to POV in high-risk surgical procedures, although the use of ondasentron could minimize this
problem.56 Some authors propose the use of alternative postoperative pain control techniques, rendering the use of morphine
in conjunction with 5-HT3 antagonists unnecessary.57
Ondasentron and tropisetron have been studied extensively for
POV prophylaxis in children at doses ranging from 50 to 100 g/
kg. The class of 5-HT3 antagonists is effective in preventing
vomiting and is commonly used as antiemetics of first choice in
children. There is a consensus that the evidence supports the
administration of 5-HT3 antagonists at the end of surgery rather
than before induction.
Droperidol has a role in the prophylaxis of POV, although lowdose droperidol in children has not been explored. However, the
risk of extrapyramidal symptoms, high level of sedation, and
electrocardiogram rhythm changes found with droperidol restrict
its use for patients who have failed all other therapies. 12
Metoclopramide has been used extensively since the early 1980s in
the treatment and prevention of PONV for adult patients. The effectiveness of this drug is now in doubt. When it was used in
standard clinical doses, or even larger doses, it was ineffective for
both PONV prophylaxis and treatment.42,58 Although adult studies
demonstrated metoclopramide 20 mg to be comparable with
ondansetron 8 mg, metoclopramide showed no worthwhile effect
in children.59 There is no unanimous agreement among authors
about the use of metoclopramide for POV prophylaxis.17,60 Evidence
for the effectiveness of midazolam and perphenazine is still
controversial, and the results for dimenhydrinate, droperidol,
gastric aspiration, and acupuncture deserve better understanding
and reliable clinical trials to verify their effectiveness. Propofol has
gained a reputation as the intravenous anesthetic agent least likely
to cause POV. Studies comparing propofol with other anesthetics
suggest that propofol has an emetic effect.61 When propofol was used
along with nitrous oxide, rather than halothane for pediatric
tonsillectomy, there was no differences in end points such as
unplanned admissions or discharge times.62
Midazolam used in subhypnotic dose has been effective in
decreasing PONV incidence without untoward sedative effect in
adult studies.55 Although there are no available studies for children, treatment using ondansetron 4 mg compared with midazolam
2 mg given intravenously before the end of surgery did not provide
superior benefit in decreasing the incidence of PONV in female
adult patients, whereas midazolam was effective in decreasing the
incidence of PONV without increasing recovery time or level of
sedation.63
Combination of Antiemetics
There has been a growing interest of combining antiemetics from
different classes for POV prophylaxis and treatment. In addition
to enhancing efficacy, a synergistic interaction between combinations of two or more antiemetics might also permit a reduction
in total dose, thereby reducing side effects. The physiologic basis
for combining different antiemetics is based in the multimodal
aspects of vomiting and the major receptor systems involved in its
etiology: dopaminergic, serotonergic, histaminergic, and cholinergic. The neurokinin-1 (NK-1) receptor could also be involved with
the triggering of vomiting. The mainstay of POV management
today is to employ antagonists at these receptors. However, the
antiemetic prophylaxis or treatment with a combination of agents
still is controversial.64
The evidence collected for pediatric patients shows that combination therapy should be the approach planned for children at
high risk of POV. The most common choice is a 5-HT3 antagonist
and a second drug, usually dexamethasone, with an acceptable
side effect profile. Antiemetic rescue therapy should be administered to patients who have an emetic episode after surgery. When
POV occurs within the first 6 hours, it is not recommended to
administer a repeat dose of the prophylactic antiemetic. After
6 hours, any of the drugs used for prophylaxis, except dexamethasone, could be used.
Nonpharmacologic Approach
A variety of different nonpharmacologic options aredescribed in
order to prevent or treat POV in children. However, the data are
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Pharmacology
still insufficient to allow any definite conclusion about this subject.

When compared with placebo, the nonpharmacologic alternatives
were more effective in preventing PONV, although no benefit was
found within the pediatric population.65
The best promise in this field looks to be the stimulation of the
so-called P6 acupuncture point. The stimulation of the P6 acupuncture point (acupressure, acupuncture, or electrical-laser
stimulation) compared with antiemetic drugs in preventing
PONV was found to be equally effective in adults. The P6 point is
located in the wrist, and when stimulated in children, it was also
found to be of some benefit in reducing the incidence of POV.66
Acupuncture was found more effective than acupressure or electrical stimulation. The current status supports acustimulation of P6
as a promising method of preventing POV in children, and it
could be considered as an alternative treatment to antiemetic
medications for pediatric high-risk POV patients.
WHAT IS LACKING ABOUT POV?

Robust data for antiemetic treatment in established PONV for
adults or children are lacking. Evidence-based treatment strategies
that take into account all possible antiemetic interventions have
not yet been established.36, 62 There are few trials that report both
short and long postoperative observation periods. Report of a
delay until the antiemetic treatment shows effect would be also
useful. Few studies show the impact of antiemetic administration
timing on either the incidence or the appearance of POV during
the first 24 or 48 hours postoperatively in children undergoing
high-risk surgical procedures. This information is fundamental
for establishing additional prophylactic measures to reduce POV.
There is a lack of reliable documentation about the adverse drug
reactions as well.
The experience with 5-HT3 receptor antagonists used singly or
in combination with dexamethasone or droperidol in both prevention and treatment of POV is encouraging mainly in high-risk
patients. Propofol and midazolam used perioperatively could be
good alternatives for induction and maintenance of anesthesia,
decreasing the incidence of POV.
The importance of controlling POV has increased with the
current emphasis on rapid postoperative discharge in day cases
surgeries. The decreased use of preoperative opioids, attention to
speed in operative procedures, care with perioperative hydration,
adequate postoperative pain management, and POV prophylaxis,
among others, are important factors decreasing the incidence of
POV. Despite these improvements, POV still remains a problem
for children, particularly those at high risk after tonsillectomy or
strabismus surgery.
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19. Ewah BN, Robb PJ, Raw M. Postoperative pain, nausea and vomiting
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20. Gupta N, Kumar R, Kumar S, et al. A prospective randomised double
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25. Watcha MF, Safavi FZ, McCulloch DA, et al. Effect of antagonism of
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27. Fozard JR. Neuronal 5-HT receptors in the periphery. Neuropharmacology. 1984;23:14731486.
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29. Kearns GL, van den Anker JN, Reed MD, Blumer JL. Pharmacokinetics
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30. Baines DB. Postoperative nausea and vomiting in children. Paediatr
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32. Bolton CM, Myles PS, Carlin JB, Nolan T. Randomized, double-blind
study comparing the efficacy of moderate-dose metoclopramide and
ondansetron for the prophylactic control of postoperative vomiting in
children after tonsillectomy. Br J Anaesth. 2007;99:699703.
33. Pang WW, Wu HS, Lin CH, et al. Metoclopramide decreases emesis but
increases sedation in tramadol patient-controlled analgesia. Can J
Anaesth. 2002;49:10291033.
34. Fischler M, Bonnet F, Trang H, et al. The pharmacokinetics of droperidol
in anesthetized patients. Anesthesiology. 1986;64:486489.
35. Stead SW, Beatie CD, Keyes MA, Isenberg SJ. Effects of droperidol dosage
on postoperative emetic symptoms following pediatric strabismus
surgery. J Clin Anesth. 2004;16:3439.
36. Watcha MF. Management of postoperative vomiting in pediatric patients.
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37. Tramer MR. A rational approach to the control of postoperative nausea
and vomiting: evidence from systematic reviews. Part I. Efficacy and harm
of antiemetic interventions, and methodological issues. Acta Anaesthesiol
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38. Kranke P, Eberhart LH, Gan TJ, et al. Algorithms for the prevention of
postoperative nausea and vomiting: an efficacy and efficiency simulation.
39. Gore S, Gilmore IT, Haigh CG, et al. Colonic transit in man is slowed
by ondansetron (GR38032F), a selective 5-hydroxytryptamine receptor
(type 3) antagonist. Aliment Pharmacol Ther. 1990;4:139144.
40. Russell D, Kenny GN. 5-HT3 antagonists in postoperative nausea and
vomiting. Br J Anaesth. 1992;69(7 Suppl 1):63S68S.
41. McCall JE, Stubbs K, Saylors S, et al. The search for cost-effective prevention of postoperative nausea and vomiting in the child undergoing
reconstructive burn surgery: ondansetron versus dimenhydrinate. J Burn
Care Rehabil. 1999;20:309315.
42. Apfel CC, Kranke P, Katz MH, et al. Volatile anaesthetics may be the
main cause of early but not delayed postoperative vomiting: a randomized controlled trial of factorial design. Br J Anaesth. 2002;88:
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43. Drake R, Anderson BJ, Persson MA, Thompson JM. Impact of an antiemetic protocol on postoperative nausea and vomiting in children.
44. Tramer MR. Rational control of PONVthe rule of three. Can J Anaesth.
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45. Wagner DS, Yap JM, Bradley KM, Voepel-Lewis T. Assessing parents
preferences for the avoidance of undesirable anesthesia side effects in their
children undergoing surgical procedures. Paediatr Anaesth. 2007;17:
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46. Kazemi-Kjellberg F, Henzi I, Tramer MR. Treatment of established postoperative nausea and vomiting: a quantitative systematic review. BMC
47. Gan TJ, Mythen MG, Glass PS. Intraoperative gut hypoperfusion may be
a risk factor for postoperative nausea and vomiting. Br J Anaesth. 1997;
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48. Gan TJ, Mythen MG. Does perioperative gut-mucosa hypoperfusion
cause postoperative nausea and vomiting? Lancet. 1995;345:11231124.
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49. Gan TJ. Postoperative nausea and vomitingcan it be eliminated? JAMA.

2002;287:12331236.
50. Goodarzi M, Matar MM, Shafa M, et al. A prospective randomized
blinded study of the effect of intravenous fluid therapy on postoperative
nausea and vomiting in children undergoing strabismus surgery. Paediatr
Anaesth. 2006;16:4953.
51. Dillier CM, Weiss M, Gerber AC. [Tropisetron for prevention of nausea
and vomiting in children undergoing tonsillectomy and/or adenoidectomy] (German). Anaesthesist. 2000;49:275278.
52. Rose JB, Watcha MF. Postoperative nausea and vomiting in paediatric
53. Paech MJ, Rucklidge MW, Lain J, et al. Ondansetron and dexamethasone
dose combinations for prophylaxis against postoperative nausea and
vomiting. Anesth Analg. 2007;104:808814.
54. Kim MS, Cote CJ, Cristoloveanu C, et al. There is no dose-escalation
response to dexamethasone (0.06251.0 mg/kg) in pediatric tonsillectomy
or adenotonsillectomy patients for preventing vomiting, reducing pain,
shortening time to first liquid intake, or the incidence of voice change.
Anesth Analg. 2007;104:10521058, tables of contents.
55. Tramer MR. A rational approach to the control of postoperative nausea
and vomiting: evidence from systematic reviews. Part II. Recommendations for prevention and treatment, and research agenda. Acta Anaesthesiol Scand. 2001;45:1419.
56. Henzi I, Walder B, Tramer MR. Dexamethasone for the prevention of
postoperative nausea and vomiting: a quantitative systematic review.
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57. Anderson BJ, Ralph CJ, Stewart AW, et al. The dose-effect relationship for
morphine and vomiting after day-stay tonsillectomy in children. Anaesth
58. White MC, Nolan JA. An evaluation of pain and postoperative nausea
and vomiting following the introduction of guidelines for tonsillectomy.
59. Polati E, Verlato G, Finco G, et al. Ondansetron versus metoclopramide
in the treatment of postoperative nausea and vomiting. Anesth Analg.
1997;85:395399.
60. Quaynor H, Raeder JC. Incidence and severity of postoperative nausea
and vomiting are similar after metoclopramide 20 mg and ondansetron
8 mg given by the end of laparoscopic cholecystectomies. Acta Anaesthesiol Scand. 2002;46:109113.
61. Balli P. The use of propofol as antiemetic. Int Anesthesiol Clin. 2003;41:
6677.
62. Ved SA, Walden TL, Montana J, et al. Vomiting and recovery after
outpatient tonsillectomy and adenoidectomy in children. Comparison of
four anesthetic techniques using nitrous oxide with halothane or propofol.
63. Unlugenc H, Guler T, Gunes Y, Isik G. Comparative study of the antiemetic efficacy of ondansetron, propofol and midazolam in the early
postoperative period. Eur J Anaesthesiol. 2004;21:6065.
64. Lee Y, Wang JJ, Yang YL, et al. Midazolam vs ondansetron for preventing
postoperative nausea and vomiting: a randomised controlled trial. Anaesthesia. 2007;62:1822.
65. Habib AS, Gan TJ. Combination antiemetics: what is the evidence? Int
Anesthesiol Clin. 2003;41:119144.
66. Lee A, Done ML. The use of nonpharmacologic techniques to prevent
postoperative nausea and vomiting: a meta-analysis. Anesth Analg. 1999;
88:13621369.
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Craig Sims
INTRODUCTION
Resuscitation agents are the drugs and fluids required in the management of the acutely ill child before, during, or after anesthesia
and surgery. They may be required in either the operating room
or the intensive care unit. They are often needed urgently, yet they
may be an unfamiliar group of drugs because of infrequent use.
The catecholamines and other adrenergic agonists form the
backbone of this group of drugs. The catecholamines all share a
common chemical structure that includes a benzene ring hydroxylated at positions 3 and 4 and an ethylamine side chain with a
terminal amine group. Epinephrine, norepinephrine, and dopamine are the endogenous catecholamines, and dobutamine,
dopexamine, and isoproterenol are synthetic catecholamines. They
all exert their effects via adrenergic receptors, and all increase
myocardial contractility, oxygen consumption, and heart rate, as
well as increasing the propensity to develop arrhythmias.
ADRENERGIC RECEPTORS
AND AGONISTS
The catecholamines, sympathomimetic amines, and related agents
are among the most important drugs for the resuscitation of
critically ill children. They are administered to increase perfusion
pressure, increase cardiac output and oxygen delivery, and manipulate regional vascular resistance. These actions are mediated by
a mechanism involving adrenergic receptors that are members
of a superfamily of over 1500 G proteincoupled receptors. At least
10 adrenergic and dopaminergic receptor subtypes have been
identified using molecular biology techniques. They are all characterized by the presence of seven transmembrane domains that form
loops and binding sites. The functions of many of these receptor
subtypes are still not clear, and clinically they remain classified on
the basis of their physiologic and biochemical responses into alpha1
and alpha2, beta1 and beta2, and dopaminergic D1 and D2.
Adrenergic receptors on the cell surface are the first part
of a cascade that amplifies the binding of a single molecule of
agonist. They are part of a complex of three interacting proteins: adrenergic receptor, guanine nucleotide binding protein
(G protein), and effector enzymes or ion channels. The cascade of
events after alpha and beta receptor binding has been described
in detail.13 After an agonist binds, the adrenergic receptor undergoes a conformational change allowing interaction with a
G protein. There are three types of G protein: stimulatory (Gs),
inhibitory (Gi) and a third, Gq. Beta receptors are associated with
a Gs protein, and after receptor activation, the cascade results in
enzyme phosphorylation, increased calcium entry into the cytosol,
Figure 35-1. Schematic diagram showing the cascade of intracellular events following binding of an agonist to a beta receptor.
AC = adenylyl cyclase; Gs = stimulatory G protein.
and positive inotropy and lusitropy (Figure 351). Chronic beta1
stimulation also affects gene transcription, cell growth, and cell
death. Alpha receptors also act through a cascade, though they use
the Gi protein that results in either a reduction in adenylyl cyclase
activity or the hydrolysis of membrane-bound phospholipids to
form other compounds, including those leading to increased entry
of calcium into the cell.
All parts of the cardiovascular system have both alpha and beta
receptors. Adrenergic receptors on the myocardium include beta1
(80%), a significant number of beta2, and some alpha receptors
that are not associated with any nerve terminals. Alpha receptors
mediating vasoconstriction predominate in the peripheral
circulation, but there are also beta2 and dopaminergic receptors
mediating vasodilatation. Although each of the catecholamines
has varying degrees of specificity for the different receptor
subtypes dependent on its plasma concentration, this distinction
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TABLE 35-1. Receptor Activity During Infusions of Adrenergic Agonists

Receptor Activity
Epinephrine
Norepinephrine
Dopamine
Dobutamine
Isoproterenol
Infusion Dose, g/kg/min
Alpha
Beta1
Beta2
0.050.1
0.10.2
0.050.1
<5
510
>10
2.515
0.051
+
+++
++++
+
+++
+
+++
++
++
+
++
++
+++
++++
++
++
+/
+
+
+
++
+++
is of limited clinical use (Table 351). There is no consistent

relationship between the plasma concentration of catecholamine
and its clinical effect because the pharmacokinetics and the bodys
reflex cardiovascular responses change during illness. For these
reasons, their effects during resuscitation will differ from those
seen under healthy conditions. Continuous titration of dose
against clinical response is the appropriate technique of administration. All of the catecholamines have a short half-life, and steadystate concentrations are reached within 5 to 10 minutes of starting
a continuous infusion. All potent, vasoactive agents should be
given by a linear piston syringe pump rather than a peristaltic
pump, especially if flow rates lower than 5 ml/h are being used.
Delivery should be as close to the patient as possible, with small
volume extensions.
Developmental Changes in
Adrenergic Receptors and the Myocardium
Sympathetic innervation is incomplete in the newborn, but
parasympathetic innervation is intact at birth. The parasympathetic predominance gradually decreases until around 6 months
of age. Adrenergic receptors are present and functional from an
early gestational age, but the number of beta receptors increases
and the number of alpha receptors decreases with development.
Approximately 80% of ventricular adrenoceptors are beta1, and
this proportion of beta1 and beta2 receptors probably stays constant with maturation. However, neonatal animal models suggest
that the function of the receptors may change with maturation.
The role of the beta receptors in neonatal animal models is
different from that in adultsbeta2 receptor stimulation results
in intracellular changes similar to that seen after beta1 stimulation in adults, and hence beta2 stimulation plays a much greater
role in mediating the response to catecholamines in the neonate.
Also, there may be changes in the function of alpha receptors
such that stimulation in the neonate results in tachycardia rather
than the bradycardia seen later in development. Whether these
changes in alpha and beta receptor function also occur in humans
is not clear.4
The myocardium of the neonate and infant is different from the
older child (Table 352). The myofibrils are poorly organized with
a random orientation rather than the parallel and well-organized
arrangement seen in the adult. The neonatal myocardium develops
less tension per gram than adult hearts, and it is less compliant,
relying more on heart rate to maintain or augment cardiac output.
At birth and over the weeks after birth, high levels of endogenous
catecholamines support the transitional circulation. The neonatal
Dopaminergic
+++
myocardium has less reserve to respond to exogenous catecholamines. However, there is enhanced response to intracellular levels
of calcium, and animal studies suggest this may be caused by
increased amounts of the different isoforms of myosin light chains,
and of troponin I and T. Finally, the extracellular collagen matrix
of the heart develops over the first 6 months with increasingly
efficient transfer of the contractile force of the myofibrils to the
blood within the ventricles.4
Changes in Adrenergic Receptors

With Disease and Catecholamine Use
The number and distribution of adrenergic receptors change
in response to disease and catecholamine administration, significantly limiting the effectiveness of catecholamine therapy.
Heart failure is associated with elevated endogenous catecholamine levels and results in receptor changes similar to those seen
with the use of exogenous catecholamines. The most rapid of
these changes occurs within minutes of therapy and is receptor
desensitization.2,4 G proteincoupled receptor kinase (GCRK)
phosphorylates occupied beta receptors, causing them to be
TABLE 35-2. Summary of Major Differences Between
Neonatal and Mature Hearts
Contractility
Heart rate
dependence
Innervation
Predominant site
of calcium flux
Dependence on
normal intracellular calcium
Adrenergic
receptors
Myocardial
structure
Neonatal
Mature
Limited
High
Normal
Low
Parasympathetic pre- Complete

dominates Sympathetic incomplete
Sarcolemma
Sarcoplasmic
reticulum
High
Lower
Down-regulated
Insensitive
80% beta1, beta2
behavior similar to
beta1
Disorganized
myofibrils
Normal
80% beta1, beta2
different mechanism to beta1
Organized
myofibrils
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internalized and degraded. Slower, but also important, is a fall in

the number of beta1 receptors resulting in a lower receptor density
on the cell surface with nearly equal proportions of beta1 and beta2
receptors. As a result, less cyclic adenosine monophosphate
(cAMP) and downstream signaling effectors are formed within
the myofibril. Interestingly, animal work suggests the opposite
may occur in neonates, with an enhanced response to beta receptor stimulation than would normally cause desensitization in
the adult.4,5
POSITIVE INOTROPIC AGENTS

The catecholamines improve inotropy by enhancing the release
of Ca2+ from the sarcoplasmic reticulum, increasing the intracellular calcium concentration. Although this leads to positive
inotropy in the short term, intracellular calcium plays a critical
role in cell death and apoptosis, and increased calcium concentration appears to be detrimental in the long term. Beta1
agonists and phosphodiesterase-3 inhibitors have been found
detrimental during the long-term treatment of heart failure
because they contribute to the development of malignant ventricular tachyarrhythmias and increase the incidence of sudden
cardiac death.68 Other positive inotropic drugs work through
different mechanisms and are discussed separately (Table 353).
Epinephrine (Adrenaline)
Epinephrine is the single most important drug in both adult and
pediatric cardiac resuscitation. It is used to treat asystole, severe
bradycardia, ventricular fibrillation (VF), electromechanical
dissociation, and anaphylaxis. Epinephrine is released primarily
by the adrenal medulla and, unlike norepinephrine, functions as
a circulating hormone. At physiologic concentrations, epinephrine
acts on beta1 and beta2 receptors to improve myocardial performance and dilate blood vessels supplying skeletal muscle. At
the much higher concentrations achieved during intravenous
(I.V.) infusions, it continues to act on beta1 receptors, but also
causes vasoconstriction via alpha stimulation in the peripheral
circulation. Epinephrine stimulates beta2 receptors on bronchial
smooth muscle, which results in bronchodilatation and inhibition of mast cell degranulation. The other effects of epinephrine
outside the cardiovascular system are summarized in Table 354.
Epinephrine increases the blood sugar level by the activation
of hepatic glycogen phosphorylase and conversion of glycogen
to glucose. It simultaneously inhibits the further synthesis of
glycogen. Epinephrine has a molecular weight of 183.2 Da, and is
very slightly soluble in water. Its solutions are acidic, and it must
not be mixed with alkaline solutions.
TABLE 35-4. Noncardiovascular Effects of

Epinephrine Infusions
Effect
Mechanism
Metabolic
Increased glucose and Insulin resistance,

free fatty acids
increased glucagons
Increased lactate
and cortisol
Reduced plasma potas- Increased glycogenolysium, magnesium,
sis
calcium, phosphate Transcellular shift
Increased oxygen
consumption
ImmunomoDecreased neutrophil
dulatory
adherence, chemotaxis, and phagocytic
capacity; increased
platelet aggregation;
Reduced tumor necrosis factor release
from monocytes
Pharmacokinetics
Epinephrine follows first-order kinetics, and plasma concentration
is linearly related to the infused dose.9 Endogenous concentrations
of epinephrine vary widely with disease and activity, but range
between 50 and 400 ng/L. Concentrations reached in children
during I.V. infusion rates of 0.03 to 0.2 g/k/min are 670 to 9430
pg/mL.10 Healthy, resting adults have concentrations less than
100 pg/mL, and sick adults 200 to 1200 pg/mL. There is substantial
between-individual variability, particularly in critically ill patients,
and therefore, the infusion rate must be titrated against effect.
Epinephrine is methylated by catechol-O-methyl transferase
(COMT) and deaminated by monoamine oxidase (MAO) at
multiple sites. Clearance is 15.6 to 79.2 mL/min/kg (similar to
dobutamine and dopamine). Plasma half-life is 2 to 2.5 minutes.
Epinephrine in Cardiac Arrest

Epinephrine is the mainstay of advanced pediatric life support
because of its beneficial effects on cerebral and myocardial blood
flow. During external cardiac massage, myocardial perfusion
occurs during the relaxation cycle of chest compression. Coronary
perfusion pressure during this time depends on the difference
between the aortic diastolic pressure and the right atrial diastolic
pressure (or central venous pressure). A coronary perfusion pressure of at least 30 mmHg is required, and return to spontaneous
circulation is unlikely if this is not achieved. Chest compression
alone cannot give a high enough coronary perfusion pressure
TABLE 35-3. Classification of Positive Inotropic Agents

Agent
Effector Site
Molecular Mechanism
Effect on Intracellular [Ca2+]
Catecholamines
Phosphodiesterase inhibitors
Digoxin
1 Adrenergic receptor
Phosphodiesterase
Sarcolemmal Na+-K+-ATPase
Increases
Increases
Increases
Calcium sensitizers
Troponin CCa2+ complex
Increases cAMP
Increases cAMP
Increases Ca2+ stored in
sarcoplasmic reticulum
Increases sensitivity myofilament
to Ca2+
cAMP = cyclic adenosine monophosphate.
No effect
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beyond the first few minutes because of the peripheral vasodilatation that rapidly occurs during cardiac arrest. Exogenously
administered epinephrine acts on alpha receptors near the vascular lumen to cause vasoconstriction.11 Blood is shunted from
skeletal and splanchnic beds to the heart and brain. Aortic diastolic pressure increases markedly with only a minor increase in
central venous pressure and results in a coronary perfusion
pressure of 25 to 30 mmHg during both systole and diastole.
Epinephrine must be given early, when peripheral vessels are
still responsive and before local metabolic vasodilator effects
predominate, and then repeatedly, to increase the aortic diastolic
and coronary perfusion pressures.12,13 Although there is a massive
rise in endogenous catecholamines during cardiac arrest, their
effect on the circulation is inadequate.
Other vasopressors have been studied for use in cardiac arrest.
In adults, pure alpha agonists are attractive because of the avoidance of the potentially deleterious effects of postarrest tachycardia and increased myocardial oxygen consumption resulting
from beta stimulation. However, the lack of effectiveness of the
pure alpha agonists methoxamine and phenylephrine suggests
that beta effects are important, although the mechanism is unknown. Norepinephrine may be an alternative to epinephrine
because of its effects on alpha and beta1 receptors. It has been
found effective in resuscitation from arrest in VF but not asphyxial
arrest.14,15 Vasopressin is of interest and is discussed separately. In
children, however, epinephrine firmly remains the agent of choice
because its deleterious effects are believed to be less of a problem
than in adults.
DOSE OF EPINEPHRINE DURING CARDIAC ARREST: The dose of

epinephrine during cardiac arrest is 10 g/kg, repeated every few
minutes16,17 (Table 355). High-dose epinephrine (100 g/kg) was
initially thought to be of potential benefit in children and to be
better tolerated postarrest than in adults. However, it is now
known that high-dose epinephrine may cause a hyperadrenergic
state after the return to spontaneous circulation and a worse
24-hour survival rate. High doses may be considered in exceptional circumstances such as blocker overdose.
ROUTES
OF ADMINISTRATION: Drugs can be administered by

three different routes during resuscitation. The I.V. and intra-
TABLE 35-5. Epinephrine and Other Resuscitation Drug

Doses for Cardiac Arrest in Children
Drug
Dose
Epinephrine
First-line drug for

I.V. or I.O.: 10 g/
cardiac arrest
kg, q3min
ETT: 100 g/kg
I.V. or I.O.: 5 mg/kg First-line antiarrhythmic for VF or
pulseless VT
I.V. or I.O.: 0.02 mg/ For bradycardia
unresponsive to
kg
ventilation and
ETT 0.03 mg/kg
circulatory support
I.V. or I.O.: 1 mg/kg Use if amiodarone not
available
ETT: 23 mg/kg
Consider for prolonged
1 mL/kg of 8.4%
arrest
solution
Amiodarone
Atropine
Lidocaine
Sodium
bicarbonate
Role
ETT, = endotracheal tube;VF = ventricular fibrillation; VT = ventricular

tachycardia.
555
osseous (I.O.) routes are the preferred means of administering

drugs. A saline flush helps peripherally administered drugs behave
like they were administered centrally. The endotracheal route is a
poor alternative, and the intracardiac route is no longer used.
INTRAVENOUS: I.V. administration is safe and simple and is the
first choice of route. During external cardiac massage in adults,
epinephrine given intravenously via the antecubital fossa reaches
a peak arterial concentration at 1.5 to 3 minutes,18 and this is
shortened by 40% if the epinephrine is followed by a 0.25-mL/kg
flush.19 Central venous administration of drug results in a faster
onset, higher peak concentration, and more potent effect than
peripheral administration, but this is not usually recommended
because of the practical difficulties and complications of insertion.18 In adults, I.V. access should be obtained in vessels above
the diaphragm, where venous return during external cardiac
massage is better. In infants and small children, cardiac output and
perfusion pressure during external cardiac massage are higher and
any site is acceptable.
INTRAOSSEOUS:
I.O. administration can be quickly and

successfully used for a wide variety of drugs and resuscitation
fluids in children of any age, including neonates.20 Drug delivery
to the central circulation is similar to peripheral or central I.V.
administration, and no dose adjustment is required.21,22
TRACHEAL: Tracheal administration may be used for epinephrine,
lidocaine, atropine, midazolam, and vasopressin, but not for
calcium or sodium bicarbonate.23,24 Epinephrine is the drug most
likely to be administered by the tracheal route. Plasma concentrations of epinephrine after tracheal administration to animals
are about one tenth of those after I.V. administration. This may
result in transient beta effects rather than alpha effects with
detrimental effects on blood pressure and outcome. Increasing
the dose by a factor of 10 gives similar plasma concentrations
to I.V. epinephrine, but there is also a depot effect owing to local
vasoconstriction and lymphatic storage. The result of this is a
lower peak and slower plasma concentration decline after endotracheal epinephrine (Figure 352). Trapping of epinephrine in
the lungs can also act as a reservoir after resuscitation and cause
severe hypertension, particularly in adults.
The site of absorption after endotracheal administration
includes the alveolar capillary network and the mucosa of the trachea and bronchi.18 Epinephrine must be diluted before administration to improve absorption. Various models and techniques
have been used in studies of ETT administration. There are
probably no important clinical differences in effect between the
different techniques, particularly because the overall efficacy
of the route is poor. Absorption is faster if water is used as the
diluent, possibly because water is hypotonic and moves faster from
alveoli into the vascular space.25 The most practical method is to
use 100 g/kg epinephrine (0.1 mL/kg of 1:1000 solution) mixed
with an equal volume of water or saline (Table 356). This is a
poor alternative to the I.V. and I.O. routes, and drugs given by the
ENDOTRACHEAL route should be re-administered when
vascular access is obtained.26
INTRAMUSCULAR AND SUBCUTANEOUS:
Anaphylactic reactions
in the community are treated with epinephrine from an
autoinjector. Plasma epinephrine concentrations are higher and
achieved earlier after intramuscular (I.M.) injection than after
subcutaneous (S.C.) injection. The plasma concentration after 0.01
mg/kg reaches approximately 2100 pg/mL 8 minutes after I.M.
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TABLE 35-7. Nebulized Epinephrine Doses and Dilutions
Agent
Dose
Racemic epinephrine
2.25%
L-Isomer epinephrine
1% nebulizer solution
Epinephrine 1:1000
(I.V. preparation)
0.05 mL/kg diluted with normal

saline to 45 mL
0.05 mL/kg diluted with normal
saline to 4 mL
0.5 mL/kg (maximum 5 mL), use
undiluted in nebulizer bowl
Nebulized Epinephrine
Figure 35-2. Plasma concentrations after intravenous and

tracheal epinephrine in dogs. Ten times the intravenous dose of
epinephrine must be given via the endotracheal tube (ETT) to
achieve similar plasma concentrations, but the high ETT dose
also has a prolonged effect that may be problematic after resuscitation. Data from Schttler J, Hrnchen U, Stoeckel H, Hahn N.
[Endobrachial administration of adrenaline in cardiopulmonary
resuscitation: pharmacokinetic and dynamic studies in the dog]
(German). Langenbecks Arch Chir. 1987;370:119127.
injection, compared with 1800 pg/mL 34 minutes after S.C.

injection. Furthermore, most children given I.M. injections reach
the peak concentration by 5 minutes.27
Therapeutic Use
Epinephrine is also indicated for treatment of the hypotensive, bradycardic child who has been unresponsive to ventilation
and fluid loading. Adult work has shown that there is little
difference between epinephrine and norepinephrine in septic
shock.2830 Epinephrine is prepared as an infusion of 0.3 mg/kg
made up to 50 mL, so that 1 mL/h equals 0.1 g/kg/min. The
infusion is usually started at 0.05 to 0.1 g/kg/min and increased
as required. Epinephrine is often used when other inotropic
agents have not been effective. It is not compatible with sodium
bicarbonate.
Both the I.V. preparations and the endogenous forms of epinephrine and norepinephrine are L-isomers, and this form is suitable
for nebulization. Racemic epinephrine contains equal amounts
of D and L isomers and is used for nebulization in croup. It was
historically chosen in preference to L-epinephrine because it was
incorrectly believed to cause fewer cardiovascular problems.31,32
Nebulized epinephrine stimulates adrenergic receptors and
reduces mucosal swelling by vasoconstriction. The doses are
given in Table 357. Onset is immediate, and it can be given as
frequently as every 15 minutes if indicated clinically. Continuous
nebulized epinephrine can be delivered in the intensive care unit
by mixing 5 mg/kg (0.5 mL/kg of the 1% solution) in 500 mL of
saline delivered by a pump into the nebulizer chamber at 20 mL/h.
Toxicity and Precautions

The effects of epinephrine infusions on regional blood flow are of
concern in children. Pulmonary vascular resistance (PVR) and
pulmonary blood flow are affected by the pre-existing PVR,
coexisting hypoxia, and epinephrine dose and duration. At low
doses, PVR falls, pulmonary blood flow increases,
and there may
. .
be worsening of ventilation-perfusion (V/Q) mismatch. Higher
doses increase the PVR.
Epinephrine is a potent renal vasoconstrictor. Vasoconstriction
is mediated by alpha receptors and is relatively unopposed by the
few beta2 receptors in the renal vascular bed. However, restoration
of renal perfusion pressure is more important than isolated effects
on the vasculature, and urine output often increases because of
increased cardiac output. Nevertheless, renal vasoconstriction is a
major reason for a reluctance to use epinephrine as a first-line
therapy for shock. Epinephrine interacts with volatile anesthetics
and, in particular, halothane in hypercarbic patients to produce arrhythmias. Doses of epinephrine as high as 10 g/kg are
acceptable in children, although patients studied were given
epinephrine in conjunction with lidocaine.
Norepinephrine
TABLE 35-6. Volume of Water to Be Added to
Epinephrine 0.1 mg/kg for Tracheal Administration
During Cardiac Arrest
Age
Newborn
Infant
Small child
Large child
Volume of Water Added to

Epinephrine 0.1 mg/kg
0.7 mL
12 mL
25 mL
510 mL
Norepinephrine is a naturally occurring catecholamine released

from adrenergic nerve terminals. Endogenous norepinephrine is
taken up into sympathetic neurones after its release, and there is
very little circulating in the plasma. Exogenous norepinephrine
has a plasma half-life of 2 to 2.5 minutes, and the clearance is
24 to 40 mL/min/kg in adults.9 It is broken down by COMT and
MAO and removed from the plasma by neuronal and nonneuronal tissue uptake. Norepinephrine has a molecular weight
of 169.2 Da, and because it is strongly acidic in solution, it cannot
be mixed with alkaline solutions.
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TABLE 35-8. Summary of Inotrope Pharmacokinetics in
Children Compared With Adults
Drug
Adrenergic Agonists
Epinephrine
Dobutamine
Dopaminergic Agents
Dopamine
Pharmacokinetics
Probably reduced clearance in
children compared with adults
Large variability in clearance
Increased clearance in children
<2y
Phosphodiesterase inhibitors
Amrinone
Reduced clearance, prolonged
half-life in neonates
Enoximone
Similar to adults
Milrinone
Increased volume of distribution, increased clearance
Calcium Sensitizers
Levosimendan
Similar to adults
Norepinephrine acts primarily on and 1 adrenergic receptors and has little effect on beta2 receptors. Doses over 0.1 g/
kg/min increase systemic vascular resistance (SVR) and blood
pressure and reduce renal blood flow. Heart rate is either
unchanged, or there is a reflex slowing. PVR increases and cardiac
output is unchanged or decreases. It is used to increase SVR in
spinal cord shock and, in association with other agents, for the
treatment of septic shock. Although norepinephrine is often used
in the treatment of septic shock in adults, children with septic
shock more often have an increased SVR and a low cardiac output,
and thus, dopamine is frequently used for treatment (Table 358).
Norepinephrine is given as an infusion commencing at 0.05 to
0.1 g/kg/min and increased up to 0.5 to 1 g/kg/min. Although
hyperglycemia and other metabolic effects can occur, they are
much less pronounced during norepinephrine than during
epinephrine therapy.
Dopamine
Dopamine is the biosynthetic precursor of norepinephrine and is
released from peripheral and central neurones. Its hemodynamic
effects result from actions at specific dopaminergic receptors, from
direct and indirect actions on and adrenergic receptors, and
from causing the release of endogenous norepinephrine from
nerve terminals. The latter is responsible for up to 50% of its
effects, particularly at higher doses.33 In higher doses, actions on
the specific dopaminergic receptors are overshadowed by effects
resulting from and adrenergic receptor stimulation (see Table
351). The predominant cardiovascular effects of dopamine at
normal plasma concentrations relate its actions on beta1 receptors.
Cardiac output and PVR increase. Heart rate increases are dosedependent, and tachycardia contributes to the increase in cardiac
output at infusion rates above 7.5 g/kg/min.
There are at least five subtypes of dopaminergic receptors,
though they are functionally divided into subclasses D1 and
D2. Stimulation of D1 receptors causes vasodilatation of renal
(particularly cortical), cerebral, coronary, and splanchnic blood
557
vessels. Salt and water excretion is increased, with the increase

in sodium excretion being greater than the increase in renal
blood flow. Dopamine also exhibits significant endocrine effects
independent of its cardiovascular actions. The release of thyroidstimulating hormone is reduced, and even low doses of dopamine block the rise in serum prolactin seen as part of the stress
response.34 Dopamine is acidic in solution and has a molecular
weight of 189.6 Da.
Pharmacokinetics
Dopamine has a redistribution half-life of less than 2 minutes and
an elimination half-life of 7 minutes.9 About 25% of exogenous
dopamine is taken up into presynaptic neurones by a dopamine
transporter and converted to norepinephrine, although the
proportion taken up varies owing to polymorphism of the gene
controlling beta-hydoxylase. The remainder is either sulfated by
the enzyme phenol sulfotransferase or broken down by MAO
and COMT. Clearance in children younger than 2 years is twice
that of older children and adults, though there is a great amount
of between-individual variation. At steady state, the plasma concentration may vary fourfold among patients receiving the same
infusion rate.35,36 Neonates and young infants also have reduced
myocardial sensitivity to dopamine, resulting from incomplete
sympathetic innervation and reduced norepinephrine stores. For
these reasons, children younger than 12 months, and especially
those younger than 6 months, may be less responsive to dopamine
and need higher infusion rates to achieve the same effect as older
children and adults.36 Clearance may be reduced in children with
marked renal or hepatic disease37 and increased during concomitant dobutamine infusion. MAO inhibitors not only block the
breakdown of dopamine but also increase the neuronal stores of
norepinephrine released by dopamine.
Therapeutic Use
Dopamine is used as an inotropic and vasopressor agent in
critically ill neonates, infants, and children, in whom it is less likely
to cause severe tachycardia or arrhythmias than epinephrine.
At lower doses, it increases contractility and cardiac output, and
at higher doses, it increases heart rate and SVR. Dopamine can
be used as the first line of inotropic support in neonates and
children.3840 However, children younger than 12 months, and
especially younger than 6 months, may be less responsive to dopamine because of reduced epinephrine stores in nerve terminals
that can be released. Epinephrine should be used if there is a poor
response to dopamine or perhaps as a first line for cold hypodynamic shock. A low-dose dopamine infusion increases urine
output during critical illness, but it is doubtful that there is any
renal protective effect.41,42 Dopamine infusions can be prepared
using 15 mg/kg diluted to 50 mL (1 mL/h = 5 /kg/min),
commencing at 5 g/kg/min for shock states. The usual upper
dose limit is 10 to 20 g/kg/min, but there is some evidence for
higher doses in neonates.43

Low infusion rates of dopamine can be given temporarily through
a peripheral I.V. line. However, extravasation can result in skin
necrosis.44 If this occurs, it should be treated with either local
infiltration of a phentolamine solution (2 mg in 5 mL saline) or
topical glyceryl trinitrate. Infusion rates of 7.5 g/kg/min or
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greater increase PVR in the absence of concomitant pulmonary

vasodilators,45 and other catecholamines should be used in
patients with pre-existing pulmonary hypertension. Dopamine
increases myocardial oxygen demand, decreases ventricular
compliance, and increases end-diastolic pressure and afterload.
Tachycardia and tachyarrhythmias can limit the dose able to
be given.
Dobutamine
Dobutamine is an inodilator and acts by direct stimulation of
cardiac beta and alpha receptors to give a positive inotropic effect
with variable chronotropic and peripheral vascular effects. It is a
racemic mixture (molecular weight 337.8 Da), with the () isomer
acting as a partial alpha1 agonist, and the (+) isomer stimulating
beta1 and beta2 receptors. The advantages of dobutamine over
dopamine are (1) it has limited chronotropic effect; (2) it is
relatively cardioselective and does not increase SVR; and (3) it does
not depend on endogenous stores of norepinephrine for its
actions.38 It is a more titratable inodilator than either levosimendan or the phosphodiesterase inhibitors. Dobutamine increases
cardiac output by increasing stroke volume. The heart rate remains
fairly stable at infusions less than 10 g/kg/min but can increase
more markedly even at low doses in some patients.46 SVR most
commonly falls, but may remain unchanged or even increased,
and so there is an unpredictable effect on blood pressure. PVR
decreases at low doses.
Pharmacokinetics
Dobutamine has redistribution and elimination half-lives of 2 and
26 minutes, respectively, and a volume of distribution (Vd) of 0.2
L/kg. The reported clearance in children is extremely variable, and
it is not even clear whether its pharmacokinetics follow linear or
nonlinear kinetics.47,48 This finding may reflect the very large
between-individual variability in its pharmacokinetics. The wide
variability in hemodynamic responses and clearance kinetics
indicates that dobutamine infusions must be titrated individually.
Metabolism is by COMT, hepatic glucuronidation, and extraneuronal uptake.
Therapeutic Use
Dobutamine is suitable for patients with low cardiac output but
normal or high SVR (e.g., after cardiac bypass, cardiomyopathy, or
newborns with primary myocardial dysfunction). Dobutamine
does not usually cause vasoconstriction, and it is not suitable as a
first-line agent to treat hypotension from septic shock. Dopamine
has been shown to be better than dobutamine in treating hypotension in neonates.40 An infusion of dobutamine is prepared by
using 15 mg/kg of dobutamine diluted to a total of 50 mL (1 mL/h
= 5 g/kg/min). The infusion is commenced at 2.5 to 5 g/kg/
min and increased as necessary to 20 g/kg/min. Although a
higher dose can be used, changing to another agent should
be considered.

Tachycardia may be a problem with dobutamine and is an indication to reduce the dose or change to another agent. Arrhythmias
can occur, but less commonly than with dopamine. Dobutamine
increases myocardial oxygen demand, but supply is also increased
if there is no coronary artery obstruction and blood pressure is

maintained.
Isoproterenol (Isoprenaline)
Isoproterenol is a synthetic catecholamine that is a nonspecific
beta receptor agonist and possesses inotropic, chronotropic, and
vasodilatory properties. Its molecular weight is 211.3 Da. It is the
most arrhythmogenic of the catecholamines, a problem that
significantly restricts its use. Because it increases heart rate and
reduces blood pressure, myocardial oxygen delivery may be
reduced.49 It is also a bronchodilator, but the specific beta2 agonist
albuterol is a safer alternative. Other catecholamines are inotropic
with less tachycardia, and isoproterenol is now used primarily for
bradyarrhythmias, and complete heart block when transvenous
pacing is not immediately practical. Isoproterenol increases
conduction velocity, shortens atrioventricular (AV) node conduction time, and directly stimulates the sinoatrial node. Isoproterenol is broken down by COMT and taken up by nonneuronal
tissue. It has a plasma half-life of 1.5 to 4.2 minutes. The dose is
1 g/kg as a bolus if required, and the infusion dose is 0.05 to
0.5 g/kg/min.9
Phosphodiesterase Inhibitors
The phosphodiesterase (PDE) inhibitors amrinone, milrinone,
and enoximone improve contractility and reduce peripheral
vascular resistance and PVR. They are termed inodilators.
Although they increase mortality in chronic heart failure, they
remain useful agents in the acute setting because they have a
positive inotropic action independent of the beta receptor
complex. They may also have some anti-inflammatory effects in
septic shock. However, their use is limited by the side effects
of hypotension, thrombocytopenia, and their long duration of
action. The enzyme PDE ends the actions of cAMP by converting
it to adenosine monophosphate (AMP) (Figure 353). There are
five families of PDEs, and at least 25 different isoenzymes.
Theophylline is a nonspecific inhibitor of PDE. These inodilators
affect the isoenzyme peak III (PDE III) and act on the heart
and peripheral and pulmonary circulations, with lesser effects
elsewhere. The isoenzyme PDE V is found in high concentrations in the pulmonary vasculature and is inhibited by sildenafil,
which is useful in the treatment of pulmonary hypertension in
neonates.50
The PDE inhibitors bypass adrenergic receptors; a particularly advantageous trait in patients with longstanding congestive cardiac failure in which beta receptor down-regulation has
occurred. Their mechanism may also be synergistic with drugs
acting at adrenergic receptors, leading to lower-dose catecholamine requirements. A loading dose of the PDE inhibitor is
required because they all have long elimination half-lives. Changes
in infusion rates are slow to take effect, and it may be difficult to
titrate therapy. Cardiac output increases through a combination
of positive inotropy and changes in the loading conditions of the
myocardium. Blood pressure, PVR and SVR, and filling pressures
all decrease. PDE inhibitors are less arrhythmogenic, cause less
tachycardia than catecholamines, and do not increase myocardial
oxygen demand. Only milrinone can be diluted with glucosecontaining solutions, but all PDE inhibitors can be administered
into a line that is infusing dextrose.
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559
5.2 hours and undergoes oxidation in the liver. Hepatic disease

increases the Vd and reduces clearance. Severe hepatic dysfunction
is a contraindication to its use. Enoximone is of benefit after pediatric cardiac surgery and in infants and children with septic shock
not responsive to beta receptor agonist therapy.56 The loading dose
is 1 mg/kg if given during cardiopulmonary bypass, or otherwise
0.5 mg/kg over 1 hour. The maintenance infusion is 10 g/kg/min.
The infusion is prepared using enoximone 15 mg/kg in 50 mL
saline or water (do not mix with any other solution and avoid
contact with glass). A rate of 1 mL/h corresponds to 5 g/kg/min.
Adverse effects include hypotension with high infusion doses
or inadequate volume loading and ventricular arrhythmias.
Thrombocytopenia does not appear to be a problem with its use.
Enoximone is manufactured and dissolved in a propylene glycol
and alcohol vehicle, and hyperosmolality should be checked by
measuring the osmolal gap if treatment continues for 3 days
or more.57
Milrinone
Figure 35-3. Schematic diagram showing phosphodiesterase

inhibition preventing the breakdown of cyclic adenosine
monophosphate (cAMP) and increasing Ca2+ release from sarcoplasmic reticulum. AC = adenylyl cyclase; Gs = stimulatory
G protein.
Amrinone
Amrinone was the first available PDE inhibitor and is a bypiridine
derivative with a molecular weight of 187.2 Da. It is metabolized
at a much slower rate in neonates. It has a half-life in adults of
3.6 hours, infants and children 6.8 hours, and neonates 22.2 hours.
The Vd in children is 1 to 1.7 L/kg and is larger than in adults.
Elimination is by glucuronidation and acetylation, although 10 to
40% is excreted unchanged in urine.51 The rate of acetylation is
affected by acetylator phenotype. Slow acetylators have about 45%
the rate of metabolism of fast acetylators. Approximately 20% of
administered amrinone binds to cardiopulmonary bypass tubing.
A total loading dose of 2 to 4.5 mg/kg is divided into two or three
boluses over 3 to 5 minutes, given 10 minutes apart, with close
observation of blood pressure and volume status. The infusion
rate in children is 5 to 10 g/kg/min, with a maximum dose of
10 mg/kg/d. The infusion rate in neonates is lower, at 2.5 to
5 g/kg/min.5254 Reversible thrombocytopenia occurs in 2 to 4%
of patients. This is caused by a nonimmune, peripheral destruction
of platelets, through an unknown mechanism. It is not related to
dose or duration of treatment and has limited the use of amrinone,
increasing interest in other agents.
Enoximone
Enoximone is an imidazole derivative with a molecular weight
248.3 Da. It has pharmacokinetics that are similar in adults and
infants.55 Its Vd in neonates and infants is 3.8 L/kg and clearance
is approximately 10 mL/kg/min. It has an elimination half-life of
Milrinone has a shorter half-life, is more potent, and is less likely

to cause thrombocytopenia than amrinone. It has a molecular
weight of 211.2 Da and is 70% protein bound. The pharmacokinetics of milrinone have been well studied, albeit with different
modeling techniques in different studies. It has a larger Vd at
steady state and faster clearance in children than in adults. Steadystate concentrations in children are lower than in adults given
similar doses. Vd is small and stays fairly constant over the pediatric age range (Table 359). However, the clearance in neonates
is lower than infants and children and dosage adjustment is
required.58,59 The majority of milrinone (8085%) is excreted
unchanged in the urine during the first 24 hours, making it the
best PDE inhibitor to use if there is severe hepatic dysfunction.
The loading dose of 50 to 75 g/kg is given undiluted over 20 to
60 minutes, followed by an infusion at 0.25 to 0.5 g/kg/min. A
lower bolus and infusion rate has been suggested for preterm
neonates.60 It does not bind to bypass circuitry. The prophylactic
use of milrinone reduces the incidence of low cardiac output
syndrome after cardiac surgery in children from 26 to 12%,61 and
it may be of benefit in neonates with pulmonary hypertension not
responsive to inhaled nitric oxide.62 The main adverse effects are
hypotension, tachyarrhythmias, and thrombocytopenia after 12
to 24 hours of treatment.59 Also of concern is the reliance on renal
function for its excretion, and the infusion dose should be reduced
in patients with renal failure.
Levosimendan
Levosimendan is a myofilament calcium sensitizer with positive
inotropic and vasodilatory properties. Calcium sensitizers increase
TABLE 35-9. Pharmacokinetic Parameters for Milrinone
in Different Pediatric Age Groups
Preterm neonate
Neonate
Infant
Child
Volume of
Distribution,
L/kg
Clearance,
mL/kg/min
Elimination
Half-life, h
0.6
0.5
0.9
0.7
0.6
1.6
3.8
5.9
10.3
3.7
3.2
1.9
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contractility by increasing the sensitivity of myofilaments to

calcium. They differ from catecholamines and PDE inhibitors in
that they do not increase calcium concentration in the myofibril.
This difference is of importance. Although increased calcium
concentration leads to positive inotropy in the short term, it
appears to be detrimental in the long term, with an increased
mortality owing to sudden cardiac death in adults.7 Increased
calcium concentration is also the final step in cellular apoptosis
and death. Levosimendan also does not adversely affect the
myocardial oxygen supply-to-demand relationship or predispose
to arrhythmias.
The mechanism of action of levosimendan within the
myofilaments has been described in detail.6 Levosimendan binds
to cardiac troponin C during systole, stabilizing the troponin CCa2+ complex and prolonging the interaction of actin and myosin
filaments (Figure 354). The binding of levosimendan to troponin
C is dependent on calcium concentration, such that levosimendan releases from the troponin C-Ca2+ complex when the calcium
concentration falls during diastole. Levosimendan is also a
potassium channel agonist. Vasodilatation of peripheral, pulmonary, and coronary vessels occurs via the opening of several
types of K+ channels (including voltage-dependent, adenosine
triphosphate [ATP]sensitive, and Ca2+-activated forms).63 Finally,
it inhibits PDE III in vitro, but this effect is not clinically
significant.
Levosimendan is 97% protein bound and has a small Vd. It is
eliminated by metabolism, with a terminal elimination half-life
after I.V. administration of about 1 hour. Most is conjugated with
glutathione to inactive metabolites. Approximately 5% is reduced
by bacteria in the intestinal lumen to produce an inactive
intermediate OR 1855. It is absorbed from the intestine and
acetylated to produce the active metabolite OR 1896. The amount
of OR 1896 produced depends on the acetylator status of the
patient, with fast acetylators having higher levels of the active
metabolite. This active metabolite has hemodynamic properties
TABLE 35-10. Pharmacokinetics of Levosimendan

in Children
Age
36 Mo
>6 Mo
Adults
T / elimination
Vdss
Clearance
2.3 h
0.43 L/kg
3.8 mL/
min/kg
1.6 h
0.35 L/kg
3.6 mL/
min/kg
1.11.4 h
0.330.39 L/kg
33.6 mL/
min/kg
Vdss = volume of distribution at steady state.
similar to those of the parent drug. Both of these metabolites have

long half-lives of around 80 hours in adults, resulting in a prolonged therapeutic effect from a 24-hour infusion of levosimendan. The pharmacokinetics of levosimendan have been studied in
children after a single dose of 12 g/kg during cardiac catheterisation.64 The pharmacokinetic profile in children is broadly similar
to that in adults, but children aged younger than 6 months have a
longer elimination half-life than older children (Table 3510).
Levosimendan produces a dose-dependent increase in heart rate
and may slightly decrease blood pressure owing to peripheral
vasodilatation. It has a proarrhythmic potential, but this does not
seem to be a common problem in practice. Early, published experience in children is limited to those with severe heart failure.65 The
use of levosimendan allows for substantial reduction or cessation
of catecholamine infusions. Levosimendan is likely to become
widely used in children after cardiac surgery and in pediatric
intensive care. It is an alternative or adjunct to beta1 agonists in
children with heart failure. It may replace catecholamines or allow
a period of treatment without catecholamines to reduce the
likelihood of desensitization. However, it is difficult to titrate
against effect, and this limits its role in acutely unstable patients.
Dosage is an initial bolus of 6 to 12 g/kg over 10 minutes, then a
24-hour infusion at 0.05 to 0.2 g/kg/min.6,65
SODIUM BICARBONATE
Figure 35-4. Schematic diagram showing intracellular binding

of levosimendan to cardiac troponin C within the myofibril.
Sodium bicarbonate is the most controversial resuscitation

drug. Arterial, venous, and intracellular hypercapnia and acidosis develop rapidly during cardiac arrest. Arterial carbon dioxide
pressure (PaCO2) is corrected, or even overcorrected, because
of effective ventilation in the presence of poor pulmonary blood
flow during cardiac massage. Therefore, arterial blood gases often
show normocapnia, or even hypocapnia. However, the venous and
intracellular blood gases remain hypercapnic and severely acidotic.
Cerebral and myocardial intracellular acidosis occurs rapidly
because of the accumulation of carbon dioxide, as well as the
production of lactic acid and the hydrolysis of ATP from anaerobic
metabolism. During cardiopulmonary resuscitation, the PaCO2 in
myocardial cells is greater than 300 mmHg (40 kPa) and pH is less
than 6.5.66 This severe acidosis impairs myocardial contractility
and automaticity and opposes the effects of catecholamines and
defibrillation. Sodium bicarbonate administration is aimed
at correcting the acidosis during cardiac arrest and improving
the effectiveness of catecholamines and defibrillation. However,
problems exist when large doses are used (Table 3511), and it
does not improve outcome in adults.
One major concern is that sodium bicarbonate may paradoxically increase the intracellular PaCO2 by the reaction:
HCO3HH2CO3H2OCO2
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TABLE 35-11. Adverse Effects and Problems After
Intravenous Sodium Bicarbonate Infusion
Hypernatremia
Hyperosmolarity
Extracellular fluid overload
Overshoot alkalosis
Hypocalcemia
Left shift of O2 dissociation curve
Hypokalemia
Venous hypercapnia, paradoxical intracellular acidosis, CSF
acidosis
Cerebral vasodilation, raised ICP, peri- and intraventricular
hemorrhage
Hemodynamic changes
CSF = cerebrospinal fluid; ICP = intracranial pressure.
One mmol/kg of sodium bicarbonate forms 22.4 mL/kg of

carbon dioxide (compared with the normal production of 46
mL/kg/min) which must be eliminated.66 The carbon dioxide is
formed within the plasma and quickly enters cells to form H+ ions.
The resultant intracellular acidosis is one of the main arguments
against the use of sodium bicarbonate, but its severity and duration
are disputed.67,68
Sodium bicarbonate is not recommended in adult cardiac
arrest. However, there are several differences between adult and
pediatric cardiac arrest. First, children are often hypoxic and
acidotic before arresting. Second, cardiac massage in children
results in better pulmonary blood flow than in adults, and lastly,
there is no evidence that sodium bicarbonate use worsens outcome
in children. For these reasons, sodium bicarbonate is often used
in prolonged pediatric cardiac arrest.69 However, the evidence
supporting its use in children and neonates is not strong,70,71 and
it should be used only after effective ventilation epinephrine has
failed to restore spontaneous circulation. The dose is 1 mmol/kg
(the 8.4% solution is 1 mmol/mL), repeated after 10 minutes. This
hyperosmolar solution should be given slowly in premature
neonates to reduce the risk of intracranial hemorrhage.
Sodium bicarbonate is also used for the treatment of metabolic
acidosis and low plasma bicarbonate concentration occurring in
shock and severe diarrheal or biliary bicarbonate loss. Although
the kidneys can contribute to the replacement of bicarbonate, this
may take several days. Exogenous alkali is therefore often used to
rapidly correct severe acidosis (pH < 7.1 or base deficits > 10),
even if the cause of the acidosis can be reversed.72 The dose should
be modest, given slowly, and guided by arterial blood gas values
before and after use. The dose can be an empirical 1 mmol/kg, or
according to the half-correction formula:
Number of mmol required =
[body weight (kg) 0.3 base deficit]/2.
Infants less than 5 kg have a larger extracellular fluid volume,
and the correction constant of 0.5 rather than 0.3 is used in the
formula. A continuous infusion may be necessary if bolus therapy
is not effective. Total doses approaching or exceeding 10 mmol/kg
should be considered very large and adverse effects such as those
in Table 3511 watched for carefully.
Although sodium bicarbonate has a limited and unproven
place in the management of cardiac arrest, it has several other
more defined uses. Sodium bicarbonate can be given to alkalinize
561
the plasma in the management of hyperkalemia, tricyclic overdose, and pulmonary hypertensive crises. It can also be used for
the treatment of symptomatic hyponatremia. The dose is calculated based on the difference between the measured and desired
sodium concentration and the total body water volume. Once the
sodium concentration is above 120 mmol/L, further correction
should depend on the cause and whether the hyponatremia is
acute or chronic.
CALCIUM
Calcium is important for excitation, contraction coupling, and AV
node conduction. It increases blood pressure by increasing the
SVR and improves inotropic function of the heart in the presence
of hypocalcemia. Cardiac output may actually fall when calcium
is given in the presence of normal serum calcium. It is attractive
as a resuscitation agent because many inotropic agents act by
increasing intracellular calcium. However, it is no longer used in
the management of asystole because of lack of evidence to support
its use and concerns about it being part of the pathway leading to
apoptosis and cell death.7 Calcium has a plasma concentration of
2.1 to 2.6 mmol/L and is bound to albumin (45%) and complexed
to citrate and phosphate (10%). The normal total calcium level is
lower in neonates because of low albumin concentrations. The
remaining ionized calcium is physiologically active and has a
normal range of 1.12 to 1.32 mmol/L. Calcium concentrations are
increased with acidosis and decreased with infused albumin and
blood. Calcium chloride is commonly used in children for the
correction of hypocalcemia and may have greater bioavailability
than calcium gluconate.73 Calcium can cause skin and muscle
necrosis if it extravasates, but necrosis can also occur if there has
been no extravasation.74 The risk of tissue injury can be reduced
by central venous administration, perhaps by diluting before
administration and using calcium gluconate rather than chloride.
The doses of calcium are shown in Table 3512, and administration must be slow to prevent bradycardia and peripheral vasodilatation.75
MAGNESIUM SULFATE
Magnesium is the second most plentiful intracellular cation after
potassium, with less than 1% of the total body store found in the
serum.76 The ionized fraction is physiologically active and is
important in a host of vital enzymatic reactions, neuromuscular
function, and conformation of macromolecules such as DNA. A
low serum level of magnesium is common in seriously ill children,
but it is not known whether it results in any consequences or is
instead a reflection of the childrens physiologically stressed state.77
Furthermore, low serum magnesium may not indicate total body
TABLE 35-12. Calcium Chloride and Gluconate Contain
Different Amounts of Elemental Calcium and Require
Different Doses
Elemental
calcium
Dose
Calcium Chloride 10%
Calcium Gluconate 10%
27.2 mg/mL (0.7

mmol/mL)
0.10.2 mL/kg
(maximum 10 mL)
9.0 mg/mL (0.22

mmol/mL)
0.20.5 mL/kg
(maximum 20 mL)
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depletion, because several agents, including epinephrine infusions,

promote intracellular shift. Alkalosis and hypoalbuminemia
reduce the measured level of magnesium. If magnesium is low,
Na+/K+-ATPase activity is reduced and there is loss of potassium
from the intracellular space with subsequent renal potassium loss.
Replacement with potassium will be ineffective until magnesium
is replenished. Magnesium should be given for hypomagnesemia
and torsades de pointes VT, but there is insufficient evidence to
recommend for or against its routine use in cardiac arrest.17
Magnesium acts as a bronchodilator by inhibiting the release of
calcium from the sarcoplasmic reticulum. There is good evidence
that I.V. magnesium is of benefit in children with acute severe
asthma who have not responded to albuterol (salbutamol) and
anticholinergic agents.78,79 The dose is 25 to 75 mg/kg (maximum 2 g; 0.10.3 mmol/kg), given over 20 minutes. Nebulized
magnesium (2.5 mL of 6.3% solution) has the advantage of faster
administration but appears to have no benefit over nebulized
albuterol.
Magnesium sulfate 1 g is equivalent to 4 mmol, 8 mEq, or
98 mg of elemental magnesium. Hypotension, bradycardia, or
asystole may occur if it is administered too quickly. Plasma levels
over 2.5 mmol/L or loss of deep tendon reflexes is an indication
to stop magnesium therapy. Patients with renal disease are at
particular risk of hypermagnesemia during therapy.
ANTIARRHYTHMIC DRUGS
Antiarrhythmic drugs are relatively toxic and can either cause new
arrhythmias or worsen existing arrhythmias (proarrhythmia). For
this reason, it is always important to be confident that the arrhythmia present actually needs treatment. It should be a potentially
life-threatening arrhythmia, associated with hemodynamic instability or disabling symptoms.
Adenosine
Adenosine is a purine nucleoside that is used as first-line
treatment of supraventricular tachycardia (SVT) in children and
adults.8082 Adenosine is an endogenous molecule that acts by
binding to specific adenosine receptors in the atrium, sinus node,
and AV node. Receptor binding initiates an intracellular cascade
involving G proteins and slows the sinus rate and AV conduction
velocity. This slowing of conduction velocity is only transient but
terminates the re-entry wave responsible for SVT.
dose is 100 g/kg in children and 150 to -200 g/kg in infants,

followed by 200 to 300 g/kg if not successful. All doses should be
halved if given into a central vein. The maximum single dose is
500 g/kg or 6 mg in children and 300 g/kg in neonates, though
this dose can be repeated if required.83,84 Major side effects are
uncommon and short-lived. They include transient hypotension and bradycardia and brief asystole. Awake patients report
dyspnea, chest pain, and nausea as well as facial flushing. Adenosine may result in a brief sympathetic rebound that can accelerate
a tachyarrhythmia that is not converted. Another problem is the
re-initiation of SVT soon after reversion to sinus rhythm. Bronchospasm outlasting the adenosine can also sometimes occur in
patients with or without pre-existing asthma.

The dose should be halved in patients taking dipyridamole (which
inhibits the uptake of adenosine into red blood cells) and doubled
if taking theophylline (which is a competitive inhibitor of the
A1 adenosine receptor). It should be used cautiously, if at all, in
patients with asthma.
Esmolol
Esmolol is an ultrashort-acting 1 adrenergic blocker administered
intravenously for the acute control of narrow-complex tachycardia, for the treatment and prevention of hypercyanotic spells
in children with tetralogy of Fallot, and for the treatment of
hypertension during and after various types of surgery.85,86 It is
broken down by esterases in red blood cells, which are not blocked
by cholinesterase inhibitors such as neostigmine. As with other
blockers, esmolol exerts most of its antiarrhythmic activity by
delaying conduction through the AV node.
Esmolol has a very short half-life that permits titration of
blockade in acute situations and also limits the duration of any
adverse effects. Distribution and terminal elimination half-lives
are 1 to 2 and 9 minutes, respectively. Its Vd is less in children
(2 L/kg) than in adults (3.5 L/kg).86,87 Onset of activity is within
2 minutes, with 90% of steady-state blockade reached within
5 minutes. There is full recovery from blockade within 18 to
30 minutes after stopping the infusion. Therapy is started with a
loading dose of 500 g/kg over 1 minute, followed by an infusion
of 25 to 100 g/kg/min. If this is not successful, the 500-g/kg
bolus can be repeated and the infusion increased until a maximum
rate of 200 g/kg/min is reached. Doses higher than this are
unlikely to be effective.
Pharmacokinetics
Adenosine has a serum half-life of less than 10 seconds owing to
its rapid uptake by red blood cells and the endothelial system. It is
totally cleared from the plasma in less than 30 seconds but has a
duration of action of 1 to 2 minutes.
Therapeutic Use
Adenosine is the drug of choice for SVT because of its rapid effect,
successful conversion to sinus rhythm in greater than 75% of
patients, and relative lack of adverse effects. It can also be used to
help differentiate between the ventricular and the supraventricular
causes of broad-complex tachycardia. It is not effective in the
treatment of VT, atrial flutter, or fibrillation. A rapid bolus is given
through a large vein, or preferably, a central venous line. The initial
Amiodarone
Amiodarone is an iodine derivative of benzofurane (molecular
weight 681.8 Da) that is effective for serious ventricular and
supraventricular arrhythmias.88,89 Although it has many side
effects, particularly with chronic administration, amiodarone has
the advantage of a low negative inotropic effect. It causes diffuse
slowing of conduction through complex electrophysiologic
effects. I.V. amiodarone causes blockade and slows conduction
through the AV node. Sodium or potassium channel blockade
is also partly responsible for the antiarrhythmic effects after
chronic oral administration, and possibly after I.V. administration.
Amiodarone is extremely lipophilic, with a Vd greater than 60 to
100 L/kg in adults. After a single I.V. dose, the plasma level falls
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over 4 hours owing to redistribution. Its elimination half-life is
long and variable at 1 to 2 weeks90 and is dependent on the duration of therapy. Therapeutic plasma levels range from 1 to 2.5 g/
mL. Although rate slowing may occur sooner, reversion of arrhythmias often takes many hours. Amiodarone undergoes hepatic
metabolism to an active metabolite, but this does not accumulate
sufficiently after I.V. amiodarone to have a significant effect.
The main role of amiodarone as a resuscitation agent is for the
treatment of shock-refractory or recurrent VT or ventricular
fibrillation (VF), in which it can be used as an alternative to
lidocaine. Evidence extrapolated from studies in adults17,91 and
children92 shows increased survival to hospital admission (but
not discharge) when amiodarone is compared with placebo or
lidocaine for shock-resistant VF. It can also be used for the
treatment of SVT as a second-line agent after adenosine. In acute
situations, a loading dose of 5 mg/kg is given rapidly intravenously
or intraosseously in cardiac arrest or over 20 to 60 minutes in
perfusing tachycardias. Transient hypotension during the loading dose is the most frequent adverse event reported with I.V.
amiodarone and can be treated with fluid infusion. Hypotension
is not as common in children as in adults. It has been attributed to
the vasoactive solvents of the standard formulation and is not
dose-related but is related to the rate of infusion. A new aqueous
formulation does not contain vasoactive excipients and may
be administered safely by rapid administration without hypotension. A continuous infusion of 5 to 15 g/kg/min is given after
the loading dose. Amiodarone should not be used with procainamide or lidocaine because all of these agents can prolong the
QT interval. Caution is needed in patients receiving blockers
and calcium channel blockers, because amiodarone causes
additive suppression of the sinus and AV nodes. I.V. amiodarone
causes peripheral vasodilatation, sinus bradycardia, and negative
inotropy from noncompetitive blockade of and adrenergic
receptors. It may also cause AV block and ventricular arrhythmias. Pulmonary toxicity has occurred after only a few days of
treatment, and care should be taken if there is serious pre-existing
pulmonary disease. There is minimal antithyroid action after
I.V. amiodarone.
Lidocaine
Lidocaine is a sodium channel blocking agent useful for the
treatment of serious ventricular arrhythmias. It decreases
automaticity, increases the VF threshold, and exhibits only weak
myocardial depressant and proarrhythmic properties. However,
lidocaine increases the defibrillation threshold and increases the
energy required for defibrillation during acidosis. It may be
effective more by preventing the immediate recurrence of VF than
by facilitating defibrillation.18,93 There is little evidence to show
that it promotes the conversion of VT or VF to sinus rhythm in
any setting, and amiodarone has replaced it in adult cardiac arrest
protocols.91
Lidocaine redistributes rapidly after I.V. administration and is
extensively metabolized in the liver. Neonates have an increased Vd
(2.8 L/kg, adult 1.1 L/kg), and longer elimination half-life (3.2 h,
adult 1.8 h). Clearance is similar in both age groups. The dose of
lidocaine is 1 to 2 mg/kg followed by an infusion of 10 to 50
g/kg/min. The therapeutic plasma level is 2 to 6 g/mLl. Adverse
effects include conduction abnormalities and central nervous
system effects of drowsiness, disorientation, tinnitus, twitching,
and seizures.
563
VASODILATORS
Vasodilators are nonselective and act on the systemic and
pulmonary circulations. When given systemically, oxygenation
may deteriorate because of an increase in blood flow to poorly
ventilated lung units and worsening of intrapulmonary shunt.
When given as pulmonary vasodilators, systemic hypotension and
hemodynamic instability may result. Inhaled nitric oxide and
inhaled or parenteral prostaglandins are increasingly used when
pulmonary vasodilatation is required.
Sodium Nitroprusside
Sodium nitroprusside is a potent vasodilator that acts on venous
and arterial vessels.94 It is converted by glutathione and other
reducing agents in smooth muscle cells to its active metabolite
nitric oxide. Nitroprusside is easily titratable because it has
immediate onset, a short half-life, and effects that disappear 2 to
4 minutes after it is stopped. Cardiac output is either unchanged
or increased if preload is adequate. The initial infusion dose is
0.3 to 0.5 g/kg/min, and it is usually effective at doses under
3 g/kg/min. Doses greater than this should be used only briefly
and not exceed 10 g/kg/min. Concurrent therapy with esmolol
200 to 400 g/kg/min reduces the nitroprusside requirement and
prevents a reflex increase in plasma catecholamines and renin,
which work against achieving a stable, lower blood pressure.95
Other agents should be considered if the infusion is not rapidly
effective or if tachyphylaxis occurs. Nitroprusside is best diluted
with dextrose and should be protected from light during infusion.
Cyanide and thiocyanate toxicity are particularly likely in patients
with hepatic compromise, renal failure, or poor nutritional state.
Rebound hypertension and dose-dependent alterations in platelet
aggregation are other problems with its use.
Nitroglycerin
Nitroglycerin (molecular weight 227.1 Da) is predominantly
a venodilator but also acts on arterial vessels at doses used
to induce hypotension. It is thought to act by generating nitric
oxide but may work by stimulating soluble guanylate cyclase
and forming cyclic guanosine monophosphate (cGMP).96 Nitroglycerin is broken down in the liver, with a half-life of 2 to
3 minutes. Polyethylene-lined (not polyvinylchloride) syringes
and tubing should be used. The initial dose is 0.5 to -1 g/kg/
min, increased as necessary by the same amount every few
minutes to a maximum of 10 g/kg/min. It has a slower, less
abrupt onset than nitroprusside, and tolerance to its effects
develops within 24 hours.
Hydralazine
Hydralazine (molecular weight 196.6 Da) has a modest
antihypertensive effect if used alone because of reflex tachycardia,
increased stroke volume, and fluid retention. Metabolism after I.V.
administration is by various hepatic pathways, resulting in a halflife of 1 hour, which is not affected by fast or slow acetylator status,
as is the case with chronic oral use. The I.V. dose is a bolus of 0.1
to 0.2 mg/kg (maximum 10 mg), repeated after 20 minutes if
required. Onset is 5 to 20 minutes, and duration of action is up to
5 hours.
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VASOCONSTRICTORS
Vasopressin and Terlipressin
Vasopressin (arginine vasopressin, antidiuretic hormone) is a
nonopeptide released from the posterior pituitary gland in
response to increased osmolarity and hypovolemia.9799 During
resuscitation, it is given as a vasoconstrictor. Desmopressin
(DDAVP) is a synthetic analogue of vasopressin that has antidiuretic activity but minimal pressor effect. It is used to treat
diabetes insipidus and to increase Factor VIIIc activity and
the level of von Willebrand factor. Terlipressin (triglycyl-lysine
vasopressin) is a prodrug that is converted to lysine vasopressin
in the circulation. It has a similar pharmacodynamic profile but a
significantly longer half-life than vasopressin.
Vasopressin acts via a receptor with three subtypes, each
coupled to a G protein. V1 receptors are vascular and result in
vasoconstriction through a mechanism involving Gq, phospholipase C, and increased intracellular calcium. V2 receptors are
renal and mediate an antidiuretic effect and also mediate release
of von Willebrand factor from vascular endothelium. V3 receptors
are responsible for the actions of vasopressin on the central nervous system. Under physiologic conditions, the role of vasopressin
is the regulation of water balance, with normal concentrations less
than 4 pg/mL. Vasopressin does not increase blood pressure in
health but does in septic shock both through direct vasoconstriction and by restoring vascular sensitivity to catecholamines.
Exogenously administered vasopressin is not protein-bound and,
in adults, has a Vd of 140 mL/kg. It undergoes renal elimination
(65%) and metabolism by peptidases (35%), with a half-life of
24 minutes. Terlipressin has an elimination half-life of 50 minutes
and effect half-life of 6 hours in adults.
Vasopressin plasma concentrations increase 10-fold in shock
states but fall back toward normal after 24 hours in hemorrhagic
and septic shock. Septic shock is associated with vasopressin
deficiency but markedly increased sensitivity to low doses of exogenous vasopressin. In patients who have catcholamine-resistant
septic shock, rescue treatment with vasopressin may reduce
catecholamine requirements and increase blood pressure.100 It
may also have a role in the treatment of shock owing to vasodilatation after cardiopulmonary bypass.97,101 Vasopressin is attractive as a vasoconstrictor in cardiac arrest because it increases
cerebral and myocardial blood flow more than epinephrine and
has a longer half-life. Studies in adults have shown inconsistent
efficacy,102 and a series of pediatric cases has been reported.103
However, it neither improves nor worsens survival from cardiac
arrest and is currently suggested as a second-line agent after
epinephrine has failed.17 Terlipressin has also been studied as an
adjunct to epinephrine in prolonged pediatric resuscitation, but
its role is not yet clear.104
The adverse effects of vasopressin mostly relate to ischemia,
although most reports are from patients who were also at risk of
ischemia from their illness. Intestinal and peripheral limb
ischemia have been reported, and skin necrosis occurs both with
and without extravasation.105 The dose of vasopressin in cardiac
arrest in adults is most commonly 40 U and 0.5 to 0.8 U/kg in
children. The dose in septic shock ranges from 0.001 to 0.1
U/kg/h, perhaps with 0.01 to 0.04 U/kg/h being more common.
Titration to achieve a blood pressure may increase coronary,
mesenteric, and skin ischemia compared with use of a low,
constant infusion.98 There is no difference in 28-day mortality in
adults with septic shock treated with low-dose vasopressin or lowdose norepinephrine.106
Phenylephrine
Phenylephrine is a sympathomimetic thath acts selectively on
alpha1 receptors in the systemic and pulmonary circulations. It
causes vasoconstriction, increased SVR and blood pressure, and
reflex slowing of the heart rate. Pulmonary vascular resistance also
increases, but to a lesser extent than in the systemic circulation.
Because it is not a catecholamine, phenylephrine is not broken
down by COMT and has a long half-life of 2.5 hours. It is used to
treat hypotension, to increase SVR, and to reduce intracardiac
shunting (e.g., during hypercyanotic spells in tetralogy of Fallot).
A bolus dose of 40 to 100 g/kg lasts 5 to 10 minutes and can be
followed by an infusion of 2 to 5 g/kg/min. Pulmonary edema is
reported after phenylephrine ocular drops in children.
Metaraminol
Metaraminol has a direct action on and adrenoreceptors
(predominately the former) and also enters nerve terminals where
it displaces norepinephrine. It can eventually act as a false neurotransmitter. A dose of 10 g/kg has a duration of 20 minutes.
BRONCHODILATORS
Inhaler Devices
Adrenergic agonists are administered as an aerosol, formed by
either a small-volume nebulizer or a metered-dose inhaler (MDI).
Particles sized 1 to -5 m reach the smooth muscle of the distal
bronchi, particles 5 to 10 m only reach the first six generations of
airway, and particles 10 to 15 m deposit in the mouth. In smalldose nebulizers, a jet of oxygen at 6 to 8 L/min creates a Bernoulli
effect and pulls medication from the reservoir and a baffle in front
of the jet stream removes larger particles.107,108 The medication
is diluted with saline to 3 to 4 mL and administration takes 10 to
15 minutes. Children older than 6 months have a peak inspiratory
flow higher than 6 L/min and entrain room air that dilutes the
nebulized agent during inspiration. The dose inhaled by these
older children is independent of body size, and the dose inhaled
per kilogram of body weight gradually reduces as they grow.
Children younger than 6 months have low peak inspiratory flows
and inhale more concentrated nebulized agent (Figure 355).
They receive a much larger dose than adults when compared as
dose per kilogram. However, they automatically adjust the size of
their own doses because smaller infants have smaller tidal volumes
than larger infants.109 Only 9 to 12% of the total nebulized dose
reaches the patient and much less reaches the bronchi. During
endotracheal intubation and positive-pressure ventilation,
most of the dose nebulized into the circuit is deposited in the
endotracheal tube, and only 2 to 3% reaches the lung. MDIs give
particles mostly 2 to 5 m in diameter. They are very effective
when used with a spacer or other valved holding chamber devices
that hold the particles for up to 20 secound and allow inhalation
over several breaths.110 Only 6 to 9% of the dose enters the lung.
MDIs have five to seven times the potency of nebulizers, so that
4 puffs of albuterol (0.36 mg) via a large-volume spacer is equivalent to 2.5 mg nebulized. MDIs can also be used in intubated
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565
Figure 35-5. Effect of air entrainment on inhaled dose from nebuliser. Children, but not infants, entrain air during inspiration
while receiving nebulized drugs. Inspiratory flow exceeds nebulizer flow in children, and room air is entrained. In infants, inspiratory flow does not exceed nebulizer flow, and a smaller mass of undiluted drug is inhaled. Modified from reference 109.
patients, with about 2% of the dose entering the lungs.111 They
should be connected to the inspiratory limb of the circuit and
actuated at the onset of inspiration. Humidification should
be stopped for a few minutes beforehand. MDIs are increasingly
used instead of nebulizers in patients with severe asthma, though
they have yet to be evaluated in patients requiring intensive care
therapy for their asthma.
Adrenergic Agonists
Adrenergic agonists have a rapid onset and large therapeuticto-toxic ratio, and their inhalation is the preferred treatment for
bronchoconstriction. They cause bronchodilatation by stimulation
of beta2 receptors on the smooth muscle membrane of bronchi,
inhibit mast cell degranulation, reduce mucous gland secretion,
increase mucociliary clearance, and improve intrinsic respiratory
muscle contractility.112 Beta2 agonists have been characterized as
those that directly activate the receptor (albuterol), those that are
taken up into a membrane depot (formoterol), and those that
interact with a receptor-specific auxiliary binding site (salmeterol).
These differences in mechanism of action are reflected in the
kinetics of airway smooth muscle relaxation and bronchodilatation in patients with asthma.113 The response to albuterol is
affected by genetic polymorphisms in the gene for the beta
adrenoceptor, notably the presence of arginine residues at the 16th
position of the receptor (Arg/Arg).114 Approximately 16% of the
population has the Arg/Arg genotype and has diminished asthma
control with regular albuterol.
after 30 minutes, and last 2 to 5 hours. Its Vd is 156 L, and its renal
clearance is 290 mL/min. It undergoes extensive metabolism in
the liver and is also excreted unchanged in the urine, with an
elimination half-life of 2.7 to 5 hours.115
In acute severe asthma, larger and more frequent doses of beta
agonist are required because the bioavailability and duration of
action are markedly affected by the degree of bronchoconstriction. Undertreatment with beta agonists is a bigger problem
than catecholamine toxicity. Younger children and infants need
larger doses than older children.116 In severe asthma, albuterol is
nebulized undiluted (5 mg/mLl) at frequent intervals with cardiac
monitoring in intensive care. Continuously nebulized albuterol
can be used as an alternative to nebulizer doses more frequent
than every half hour.117 Albuterol 6 mg/kg is added to a 500-mL
bag of normal saline and pumped into the nebulizer chamber at
20 mL/h. This gives a dose of 4 g/kg/min and is equivalent to a
half-hourly nebulized dose. I.V. albuterol can be used if there is a
poor response to high-dose nebulized beta2 agonist, or if it is
thought that the drug is not reaching the lower airway because of
severe bronchospasm or mucous plugging. The dose is a 5-g/kg
bolus over 10 minutes, then an infusion at 1 to 5 g/kg/min.
A single I.V. bolus of 15 g/kg of albuterol improved the subsequent treatment of children with asthma in the emergency
department.118 The dose of both inhaled and I.V. albuterol is
frequently limited by tachycardia and tremor and occasionally
by tachyarrythmia. Beta2 agonists can also cause hypokalemia
through intracellular shifts.
Anticholinergics
Albuterol (Salbutamol)
Albuterol (molecular weight 239 Da) is the most widely used beta2
agonist in children. Its effects begin within 5 to 15 minutes, peak
Ipratoprium is a quaternary anticholinergic that is nebulized and

acts on more proximal airways than beta agonists. It has a slower
onset but longer duration of action. It is less effective alone than
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TABLE 35-13. Plasma Elimination Half-lives for

Theophylline During Growth
Age
Elimination
half-life, h
Premature
Neonate Neonate 1 Mo1 Y 115 Y Adult
1458
2035
5.6
1.48
3.58
Based on data from reference 122.
albuterol, but albuterol given with ipratoprium is more effective

than albuterol alone.119 However, it is not known whether there is
any benefit to continuing the combination of ipratoprium and
albuterol beyond the first few nebulizations. The dose is 0.5 mg
every 4 to 6 hours. Nebulized atropine causes many systemic side
effects and is not recommended.
Aminophylline and Theophylline

Aminophylline is the soluble salt of theophylline with ethylenediamine. Aminophylline 100 mg is approximately equivalent
to 80 mg of theophylline. Aminophylline is given intravenously
as a bronchodilator and to prevent apnea in preterm infants.
Theophylline is a methylxanthine that relaxes bronchial smooth
muscle; increases myocardial and skeletal muscle (particularly
diaphragmatic) contractility, heart rate, and urine output; and
stimulates the central nervous system. It is a nonspecific PDE inhibitor and an adenosine antagonist. It also has anti-inflammatory
actions.120 Theophylline is 60% protein-bound and has a Vd of
0.4 to 0.6 L/kg. Neonates have less protein binding and a higher Vd
than older children and adults. The metabolism of theophylline
varies with age. Hepatic demethylation in term neonates is
poor but increases markedly during the first year of life. It then
gradually decreases again to reach adult levels around 16 years of
age. In preterm neonates, about 50% of theophylline is excreted
unchanged in the urine, but a significant amount is converted
to caffeine. These changes in metabolism are reflected in the
changing clearance and half-life during growth (Table 3513).
When plasma concentrations are in the therapeutic range,
theophylline metabolism is first order. In patients who have theophylline overdose, metabolism is zero order because metabolic
pathways become saturated. In this situation, the plasma concentration falls linearly with time, and reduction to nontoxic
concentrations is slowed. The concentration at which pathways
become saturated is lower in children (~32 mg/L) than in adults
(67 mg/L).121
I.V. aminophylline continues to have a place in the management of acute severe asthma in children when inhaled adrenergic agonists are not effective alone.123 The loading dose is
9 mg/kg (maximum 500 mg) over 1 hour, then a maintenance
dose in children 1 to 9 years of 1.1 mg/kg/min and 0.7 mg/kg/min
in children older than 9 years. Therapeutic plasma concentrations
are 55 to 110 mol/L (1020 mg/L) when used as a bronchodilator.

A bolus dose of aminophylline 1 mg/kg increases the plasma
theophylline concentration by 10 mol/L (2 mg/L). If the plasma
level is measured 20 minutes after the loading dose and 4 to
6 hours into the maintenance infusion, it can be used to assess
clearance and adjust the infusion rate.124 Adverse effects such as
nausea and vomiting, restlessness, and tachycardia frequently
restrict the use of aminophylline in the treatment of acute severe
asthma.
CORTICOSTEROIDS
All corticosteroids are chemical modifications of natural
glucocorticoids and are used for their glucocorticoid (antiinflammatory) and mineralocorticoid (salt-retaining) properties.
They have direct effects on metabolic and other functions of tissues
and also facilitate the actions of other hormones.125,126 Steroids
increase vascular reactivity to catecholamines and other vasoactive substances, probably by increased expression of adrenergic
receptors in the vascular wall. They also inhibit non-neuronal
norepinephrine reuptake. Cortisol is the naturally occurring,
endogenous glucocorticoid, and hydrocortisone sodium succinate is the pharmaceutical preparation of cortisol. Cortisol
binds to intracellular glucocorticoid receptors, which then enter
the cell nucleus and affects gene expression and protein synthesis. Although most of its effects are slow in onset (several hours),
there may also be some immediate effects via membrane-bound
glucocorticoid receptors. Cortisol circulates in free, active form
(~5%) and a protein-bound form (predominantly to cortisolbinding globulin). Apart from dexamethasone, synthetic glucocorticoids also bind to cortisol-binding globulin. All are metabolized
in the liver.
Therapeutic Use
The dosage and effects of the three commonly used I.V. steroids
are given in Table 3514. Hydrocortisone is used for replacement
therapy in patients with adrenal insufficiency, but its high
mineralocorticoid activity limits its role in anti-inflammatory
therapy. The physiologic replacement dose is 0.2 mg/kg every
8 hours intravenously. Corticosteroids have been studied in
patients with septic shock, because this condition is often complicated by adrenal insufficiency and steroids improve vascular
reactivity. It seems likely that children also have this state of
relative adrenal insufficiency during septic shock.127 A metaanalysis suggests that low-dose corticosteroids for 5 to 11 days
reduces mortality in adults with septic shock.128
Methylprednisolone has an intermediate duration of action,
high anti-inflammatory activity, and relatively low mineralocorticoid activity and is used for the treatment of conditions requiring
some mineralocorticoid activity in addition to anti-inflammatory
TABLE 35-14. Relative Potencies and Effects of Parenteral Corticosteroids

Agent
Hydrocortisone
Methylprednisolone
Dexamethasone
Anti-inflammatory
Potency
1
5
25
Salt-Retaining
Potency
Plasma
Half-life, h
1
0.5
0
1.5
2.3
3
Duration
of Action
Short
Intermediate
Long
Equivalent
Dose, mg
20
4
0.75
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effects, such as severe asthma. The I.V. dose is 0.5 to 1 mg/kg
(maximum 120 mg) every 6 hours. Methylprednisolone (I.V.
bolus of 30 mg/kg followed by 5.4 mg/kg/h for 23 h) may improve
neurologic outcome when given in the first 8 hours after spinal
cord injury. Although still commonly used in this setting, its
benefit is at best modest, and its role is being increasingly questioned. The treatment carries risks including infection, myopathy,
avascular necrosis, and death.129
Dexamethasone has minimal mineralocorticoid activity,
high anti-inflammatory action, and a long duration of action.
It is best when maximum anti-inflammatory activity alone
is needed, such as in edema associated with upper airway problems and brain tumors. The I.V. dose is 0.1 to 0.25 mg/kg every
6 hours and 0.6 mg/kg (maximum 12 mg) as a stat dose for upper
airway edema.

Short-term I.V. use of steroids is generally safe, although problems
have been reported. Hyperglycemia and hypokalemia are common. Therapy for approximately 2 weeks or more will result in the
many metabolic problems associated with chronic steroid use.
DIURETICS
Mannitol
Mannitol is an osmotic diuretic commonly used to reduce
intracranial pressure and to prevent or treat acute renal failure. It
most likely reduces intracranial pressure by increasing plasma
osmolarity and drawing water from the brain. However, it is
difficult to demonstrate that clinically effective doses alter the
water content of the brain, and other, less plausible mechanisms of
action have also been proposed. Although a damaged blood-brain
barrier reduces the effective tonicity of mannitol, it also increases
the hydraulic conductance of the blood-brain barrier, which
enhances removal of water from the brain. Therefore, it is difficult
to predict the net effectiveness of mannitol when the blood-brain
barrier is damaged.130
Mannitol is not metabolized by the body but is filtered at the
glomerulus; there is no tubular reabsorption. It is eliminated in
the urine with a half-life of 0.25 to 1.7 hours in adults and 4 hours
in children with raised intracranial pressure.131 Renal failure
greatly prolongs the half-life. The dose is 0.25 to 1 g/kg, which
reduces intracranial pressure within minutes, and has a maximal
effect after 20 to 40 minutes. Doses of 1.4 g/kg have been reported,
but the dose-response relationship for mannitol and intracranial
pressure is not known.132 Mannitol induces a urine volume five
times greater than its own volume. It also reduces blood viscosity
by reducing hematocrit and altering red blood cell membrane
properties and acts as a scavenger of oxygen free radicals. Side
effects include hypotension secondary to peripheral vasodilatation
and release of histamine from pulmonary basophils if administered too quickly, rebound increases in intracranial pressure after
prolonged therapy, and dilutional hyponatremia in acute renal
failure owing to accumulation.
567
loop of Henle, increasing sodium, potassium, and calcium in the

tubular fluid. This nephron site normally reabsorbs approximately
20% of filtered sodium, but furosemide can cause excretion of up
to 20%. However, the effectiveness of furosemide depends on the
amount of sodium being filtered, and if this is reduced because
of disease, effectiveness is reduced. I.V. furosemide takes 5 to
10 minutes to work and lasts 2 hours. Plasma half-life is 28.6 hours
in preterm neonates, 8.6 hours in neonates, and only 0.7 to
1.5 hours in adults.133 The I.V. dose is 0.5 to 1 mg/kg every 6 to
12 hours (daily in preterm neonates). An infusion of 0.1 to 1 mg/
kg/h can be used to reduce fluctuations in diuresis that occurs with
bolus dosing. Most adverse effects relate to abnormalities of fluid
and electrolyte balance, although ototoxicity can occur with rapid
I.V. administration.
ANTICONVULSANTS
Generalized tonic-clonic status epilepticus is a medical emergency
that carries a significant risk of mortality and permanent brain
damage.134 Although status epilepticus is defined as generalized
convulsions lasting 30 minutes or more, tonic-clonic contractions
persisting beyond 4 or 5 minutes may not stop spontaneously and
can become prolonged. The longer the duration of the seizure, the
more difficult it is to terminate.135 Benzodiazepines, phenytoin,
and phenobarbital are the three main drugs for initial seizure
control, though there is little published comparison of them
(Table 3515).
Benzodiazepines
The benzodiazepines act on gamma-aminobutyric acid
A (GABAA) receptors to potentiate synaptic inhibition136 and are
very commonly used because of their rapid onset and wide safety
margin. The onset of action after I.V. administration is less than
3 minutes, but the duration of action is also short because of
redistribution from the brain, particularly after diazepam.
Although lorazepam is more lipid-soluble than diazepam and
enters the brain more slowly, its onset time is similar to that
of diazepam. Lorazepam is long-acting and is usually effective for
12 to 24 hours. It may cause less respiratory depression than
diazepam. Respiratory depression occurs particularly with clonazepam, or if other central nervous system depressant drugs
are used. Benzodiazepines are often used as a first step to stop
TABLE 35-15. Antiepileptic Treatment of Status Epilepticus
Initial treatment
Then if seizures persist
after 10 min
after 10 more min
after 20 more min
Furosemide
If no IV access
Furosemide (molecular weight 330.8 Da) is secreted into the

tubular fluid and blocks chloride transport in the thick ascending
Based on references 134 and 137.
Lorazepam 0.1 mg/kg or diazepam

0.20.4 mg/kg
Repeat lorazepam or diazepam
Phenytoin 18 mg/kg (or phenobarbitone 20 mg/kg if already on
phenytoin) and rectal paraldehyde 0.4 mL/kg with olive oil
Thiopentone 4 mg/kg with rapidsequence induction of
anesthesia and intubation
Buccal midazolam 0.5 mg/kg or
rectal diazepam 0.5 mg/kg
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seizures, followed by a loading dose of phenytoin. The I.V. doses

are given in Table 3515. Repeat doses can be given after several
minutes, although subsequent doses are less effective and recovery
is delayed because of accumulation of the drug or its metabolites.
Diazepam can be given rectally (0.5 mg/kg diluted with saline),
although midazolam 0.5 mg/kg given bucally between the
gum and the cheeks may be more effective.137,138 Lorazepam and
midazolam can be given intramuscularly.
and arrhythmias. If seizures persist 20 to 30 minutes after this

dose, another 3- to 5-mg/kg dose can be given once or twice at
20-minute intervals. Doses greater than 20 mg/kg in neonates
may necessitate mechanical ventilation. Maintenance doses
are started after 12 to 24 hours, and the therapeutic range is 60 to
120 mol/L (1530 mg/L)
Phenytoin and Fosphenytoin
Paraldehyde is a second-line anticonvulsant, used when the other

three drugs have failed to stop seizures. It is only given rectally
and in a dose of 0.4 mL/kg of the 5% solution, mixed with an equal
volume of olive oil. Onset is 10 to 20 minutes, and the dose can
be repeated after 2 to 4 hours, a maximum of four to six times in
24 hours. It should not be left in plastic syringes for longer than a
few minutes.
Phenytoin prolongs the inactivation of sodium channels, reducing

the ability of neurones to fire at high frequencies. It is effective
against most forms of seizures and does not depress respiration or
conscious state. However, phenytoin has limited aqueous solubility
and contains propylene glycol, which contributes to infusion site
reactions, hypotension and arrhythmias, and precipitation after
mixture with dextrose or I.M. injection. Phenytoin is 90% proteinbound, and the free fraction enters the central nervous system
and is responsible for its efficacy and toxicity. It has a Vd of 0.6
L/kg, but the unbound drug is much more extensively distributed.
Protein binding is reduced in neonates, who thus have therapeutic
free concentrations at lower total phenytoin concentrations than
older children. The metabolic pathways for phenytoin in the liver
are saturated at plasma concentrations above 10 mg/L, resulting
in zero-order kinetics. The half-life at low concentrations is 6 to
24 hours, but at therapeutic concentrations, half-life increases
to 20 to 60 hours. Small increases in dose will cause large increases
in plasma concentration. The therapeutic plasma range is 10
to 20 mg/L (4080 mol/L). A loading dose of 15 to 20 mg/kg
(maximum 1.5 g) diluted with saline is given over 20 minutes
and has an onset of 20 to 25 minutes. Administration should
be slowed if hypotension, bradycardia, arrhythmias, or QT prolongation occurs. If seizures stop during the loading dose, the rate
should be slowed to reduce the risk of toxicity. Phenytoin remains
effective for 24 hours, at which time the maintenance dose is
begun. Fosphenytoin is a water-soluble replacement for phenytoin.139 It is a prodrug with a formation half-life of 8 to 15 minutes
and is converted completely by tissue phosphatases to phenytoin
(because of differences in molecular weight, 150 mg of fosphenytoin yields 100 mg of phenytoin) Because it does not contain
propylene glycol, it can be given faster than phenytoin, at the
equivalent of 1.5 to 3 mg/kg/min of phenytoin. Administration
may be associated with parasthesia or pruritus. Onset time is
similar to that of phenytoin, but it causes less local and systemic
reactions.
Phenobarbital
Phenobarbital stops seizures by the same mechanism as
benzodiazepines and is the first-line treatment of seizures in
neonates and infants. Although it is not as sedating as other
barbiturates, phenobarbital is still very sedating compared with
other anticonvulsants.134 It reaches peak levels in the brain after
60 minutes, but seizure control is usually within 10 to 20 minutes.
It is 40 to 60% bound to plasma and tissue proteins and has
a Vd of 0.5 L/kg. It is metabolized in the liver and also excreted
unchanged in the urine. The half-life is 100 hours in adults,
longer in neonates, but only 40 to 70 hours in children. A loading
dose of 20 to 30 mg/kg is given slowly to avoid hypotension
Paraldehyde
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81. Bink-Boelkens MT. Pharmacologic management of arrhythmias. Pediatr
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82. Manole MD, Saladino RA. Emergency department management of the
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83. Dixon J, Foster K, Wylie J, Wren C. Guidelines and adenosine dosing in
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84. Rosenthal E. Pitfalls in the use of adenosine. Arch Dis Child. 2006;91:451.
85. Weist D. Esmolol: a review of its therapeutic efficacy and pharmacokinetic characteristics. Clin Pharmacokinet. 1995;28:190202.
86. Weist DB. Pharmacokinetics of esmolol in children, Clin Pharmacol
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87. Adamson PC, Rhodes LA, Saul JP, et al. The pharmacokinetics of
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88. McKee M. Amiodaronean old drug with new recommendations.
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89. Burri S, Hug MI, Bauersfeld U. Efficacy and safety of intravenous
amiodarone for incessant tachycardias in infants. Eur J Pediatr. 2003;
162:880884.
90. Saul JP, Scott WA, Brown S, et al. Intravenous amiodarone for incessant
tachyarrhythmias in children. Circulation. 2005;112:34703477.
91. Thompson A, Balser JR. Perioperative cardiac arrhythmias. Br J Anaesth.
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92. Perry JC, Fenrich AL, Hulse JE, et al. Pediatric use of intravenous
amiodarone: efficacy and safety in critically ill patients from a
multicenter protocol. J Am Coll Cardiol. 1996;27:1246 50.
93. Bossaert LL. Fibrillation and defibrillation of the heart. Br J Anaesth.
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94. Friederich JA, Butterworth JF. Sodium nitroprusside: twenty years and
counting. Anesth Analg. 1995;81:152162.
95. Edmondson R, Del Valle O, Shah N, et al. Esmolol for potentiation of
nitroprusside-induced hypotension: impact on cardiovascular, adrenergic and renin-angiotensin systems in man. Anesth Analg. 1989;69:
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96. Kleschyov AL, Oelze M, Daiber A, et al. Does nitric oxide mediate the
vasodilator activity of nitroglycerin? Circ Res. 2003;93:e104e112.
97. Kam P, Williams S, Yoong F. Vasopressin and terlipressin: pharmacology
and its clinical relevance. Anaesthesia. 2004;59:9931001.
98. Barrett L, Singer M, Clapp L. Vasopressin: mechanisms of action on the
vasculature in health and in septic shock. Crit Care Med. 2007;35:3340.
99. Wolf A. Vasopressin in paediatric practice. Pediatr Anesth. 2008;18:579
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100. Meyer S, Gortner L, McGuire W, et al. Vasopressin in catecholaminerefractory shock in children. Anaesthesia. 2008;63:228234.
101. Lechner E, Hofer A, Mair R, et al. Arginine-vasopressin in neonates with
vasodilatory shock after cardiopulmonary bypass. Eur J Pediatr.
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102. Aung K, Htay T. Vasopressin for cardiac arrest: a systematic review and
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103. Mann K, Berg R, Nadkarni V. Beneficial effects of vasopressin in
prolonged pediatric cardiac arrest: a case series. Resuscitation. 2002;
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104. Matok I, Vardi A, Augarten A, et al. Beneficial effects of terlipressin in
prolonged pediatric cardiopulmonary resuscitation: a case series. Crit
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105. Inui D, Ohto J, Nishimura M. Massive melena due to argininevasopressin for septic shock in two pediatric patients. Paediatr Anaesth.
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106. Russell JA, Walley KR, Singer J, et al. Vasopressin versus norepinephrine
infusion in patients with septic shock. N Engl J Med. 2008;358:877887.
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entrainment in children. Lancet. 1990;336:341343.
110. Amirav I, Newhouse M. Metered dose inhaler accessory devices in acute
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111. ODoherty MJ. Thomas SHL. Nebuliser therapy in the intensive care
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112. Nelson HS. Beta-Adrenergic bronchodilators. N Engl J Med. 1998;333:
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113. Johnson M. The beta-adrenoceptor. Am J Respir Crit Care Med. 1998;
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114. Foroughi S, Thyagarajan, Stone KD. Advances in pediatric asthma and
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115. Taburet AM, Schmit B. Pharmacokinetic optimisation of asthma
treatment. Clin Pharmacokinet. 1994;26:396418.
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responsiveness. Pediatr Pulmonol. 1993;15:98104.
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nebulization in children with severe status asthmaticus. Pediatr Emerg
Care. 1996;12:15.
118. Browne GJ, Penna AS, Phung X, Soo M. Randomised trial of intravenous
salbutamol in early management of acute severe asthma in children.
Lancet. 1997;349:301305.
119. Ward MJ. Nebulisers for asthma. Thorax. 1997;52:S45S48.
120. Aubier M, Barnes PJ. Theophylline and phosphodiesterase inhibitors.
Eur Respir J. 1995;8:347348.
121. Anderson BJ, Holford NHG, Woolard GA. Aspects of theophylline
clearance in children. Anaesth Intensive Care. 1997;25:497501.
122. Walson PD: Paediatric clinical pharmacology and therapeutics. In:
Speight TM, Holford NHG, editors. Averys Drug Treatment. 4th ed. New
Zealand, Adis International; 1997. p. 134. Adis Press International,
Auckland, New Zealand.
123. Mitra A, Bassler D, Watts K, et al. Intravenous aminophylline for acute
severe asthma in children over two years receiving inhaled bronchodilators. Cochrane Database Syst Rev. 2005;2:CD001276
124. Holford NHG, Tett S. Therapeutic drug monitoring: the strategy of
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1997. p. 247. Adis Press International, Auckland, New Zealand.
125. Jung C, Inder WJ. Management of adrenal insufficiency during the stress
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126. Shulman DI, Palmert MR, Kemp SF. Adrenal insufficiency: still a cause
of morbidity and death in childhood. Pediatrics. 2007;119:e485e494.
127. Carcillo JA. Whats new in pediatric intensive care. Crit Care Med.
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128. Annane D, Bellissant E, Bollaert PE, et al. Corticosteroids for severe
sepsis and septic shock: a systematic review and meta-analysis. BMJ.
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129. Hurlbert RJ. Strategies of medical intervention in the management of
acute spinal cord injury. Spine. 2006;31(11 Suppl):S16S21.
130. Paczynski RP. Osmotherapy. Crit Care Clin. 1997;13:105129.
131. MacDonald JT, Uden DL. Intravenous glycerol and mannitol therapy in
children with intracranial hypertension. Neurology. 1982;32:437.
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intracranial pressure: a meta-analysis. J Neurosurg. 2008;108:8087.
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134. Friedman MJ, Sharieff GQ. Seizures in children. Pediatr Clin North Am.
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135. The Status Epilepticus Working Party. The treatment of convulsive status
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137. McIntyre J, Robertson S, Norris E, et al. Safety and efficacy of buccal
midazolam versus rectal diazepam for emergency treatment of seizures
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138. Wiznitzer M. Buccal midazolam for seizures. Lancet. 2005;366:182183.
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and Techniques
36
C H A P T E R
III
P A R T
Preoperative Evaluation, Laboratory

Testing, and Preparation for
Anesthesia and Surgery
Robin G. Cox
INTRODUCTION
As with adult practice, patterns of surgical and interventional
treatment for children have evolved over the years, requiring that
the anesthesiologist adapt to new models of health care delivery.
Pediatric anesthesiologists have been leaders in the provision of
ambulatory care, and the specialty continues to push the limits of
what can be achieved on an outpatient basis. At the Alberta
Childrens Hospital, Calgary, Canada, 80% of elective pediatric
surgical cases are carried out as day procedures (2006/2007 data).
Even when medically complex patients require a postoperative stay,
they are rarely admitted preoperatively. This means that systems
have to be developed to ensure that the preoperative interaction
between child, family, and anesthesiologist can still occur in a
thorough, yet unhurried fashion. If the preoperative assessment
process is comprehensive, this may minimize the need for lastminute cancellations because of unrecognized medical concerns.1,2
Quite apart from the trend toward ambulatory care, there are
other changes in practice that affect the preoperative evaluation
process. The number of anesthetic procedures for children outside
of the operating room continues to expand. Initially, this was
largely confined to oncology procedures and some radiologic
investigations, notably magnetic resonance imaging (MRI).
Countless other types of interventions now demand the services of
the anesthesiologist, for example, radiotherapy, diagnostic and
interventional cardiac catheterization, magnetoencephalography,
endoscopies, as well as a variety of other noninvasive radiologic
procedures. Brief painful procedures, such as chest tube removal
and burn dressings, may warrant specialized anesthetic care.
Often, the children receiving treatment in remote sites have
medically complex cases and anxiety issues, making the need for
thorough preanesthetic evaluation all the more important.
In addition to the trend toward ambulatory care in a hospital
setting, there is also the move in some countries toward more
procedures being done in an office setting or nonhospital surgical

facility. The need for a meaningful preoperative assessment and
interaction with the child and family is crucial in such environments, because there is sometimes little in the way of medical
backup should a complication occur. Patient selection for officebased procedures is therefore critical.
Increasingly, children are undergoing more complex procedures. Minimally invasive techniques, performed in either
interventional radiology suites or specialized operating rooms, are
becoming routine. Fetal surgery3 and EXIT4 procedures continue
to be explored (See Chapter 120), and robotic surgery is likely the
way of the future. Surgery is also being performed with MRI
present in the operating room, either throughout the case or
episodically with a mobile magnet.5 All such procedures have
implications for anesthetic care that will affect the evaluation and
informed consent process.
There are four main purposes of the preanesthetic interaction
with the child and the family. These are
1. To conduct an appropriate medical evaluation of the child that
will guide the anesthetic plan, including optimization of the
childs condition preoperatively.
2. To aid with anxiolysis for both child and family.
3. To provide information, education, and preoperative instructions for the family.
4. To obtain informed consent and assent when appropriate.
These goals are explored in further detail.
PREANESTHETIC EVALUATION
Models of Evaluation
The days when children were admitted the night before surgery and assessed by the anesthesiologist are largely over.
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Anesthesiologists have, therefore, developed models of evaluation

to accommodate this change. There is no one perfect system of
evaluation, although a face-to-face interview with the anesthesiologist is still the cornerstone of the assessment. Generally, the
first knowledge that the family will have of the proposed procedure will be gained at the treating physicians office, whether this
is a surgeon, pediatrician, or other specialist. This provides an
opportunity for some patient evaluation by a physician other than
the anesthesiologist. In the case of healthy children undergoing
minor procedures, this does not often add much to what the anesthesiologist will determine in due course, but with more complex
children, this assessment can be invaluable. As an example, when
a cardiologist schedules a child for interventional cardiac catheterization, full details of the anatomy and physiologic status of the
child can be identified, together with a recent echocardiogram. In
many institutions, a history and physical examination must be
completed and documented before anesthesia, and this is usually
supplementary to the anesthesiologists assessment.
Preoperative telephone evaluations can be invaluable in
pediatric practice. The distance from home to the facility may be
significant, and the telephone interview becomes a useful tool to
gather data as well as an opportunity to provide instructions
and answer questions. Most often, such interviews are conducted
by a nurse, and the information is recorded either on paper or
electronically for the attention of the anesthesiologist. Telephone
interviews have been shown to reduce the number of lastminute cancellations because of illness, failure to adhere to diet
instructions, and failure to attend.1,2 Unexpected admission rates
are also lower in cases in which a telephone screening process is
used.1,2 There is also some evidence that a history obtained by
a suitably trained nurse may be superior to that obtained by a
medical resident.6
Various software programs can be used to process information
obtained at the time of the telephone interview. At the Alberta
Childrens Hospital, Calgary, Canada, the preanesthetic clinic
uses CareSuite Preop Manager (PICIS, Wakefield, MA) when
conducting the telephone interview. This program provides an
electronic record and is linked to CareSuite Anesthesia Manager
(PICIS, Wakefield, MA), the intraoperative automated anesthesia
record and database. Anesthesiologists have the ability to view any
preoperative record from an appropriate workstation.
Hospitals vary considerably in the proportion of children who
will attend a formal face-to-face preanesthetic clinic. Some will
see virtually every child at a separate visit, whereas others are
highly selective and will see only more complex patients for a
formal anesthesia consultation. There are clearly pros and cons to
these two approaches. There may be other options also.
Our pediatric surgical colleagues have already explored the
utility of telehealth as a tool for evaluating children in remote
locations. This involves the child and family being interviewed
and evaluated via a remote audiovisual link. The initial experience
with these methods has been positive, with a high level of patient
satisfaction and no demonstrable untoward outcomes in the small
numbers studied to date.7,8 There is no reason why anesthesiologists could not explore the same methods in selected cases, which
can include such technology as tale-auscultation. Whether such
interactions would be required routinely versus an evaluation on
the day of surgery is still open to question.
Whichever system of assessment is chosen, the traditional
components of history taking, physical examination, and further
investigations are still the foundations of the evaluation, and these

are now discussed in more depth.
Routine Evaluation of the Healthy Child

The routine evaluation of the healthy child requires that the
anesthesiologist approach the child and family in an unhurried,
empathetic manner, interacting with the child as much as possible
in the circumstances. It is useful to review the patients medical
record in advance, so that basic information such as the age of the
child, the procedure to be performed, and significant past medical
issues are identified. It does not inspire much confidence if the
anesthesiologist is unclear on such information when approaching
the family. Before delving into the history, it is worth tactfully
clarifying who is present with the child. All varieties of family
structure exist, and it is not always clear who is the parent or legal
guardian. Sometimes relatives, friends, or translators may be
present, but large crowds should be discouraged. Ideally, the
evaluation should be conducted in a private, quiet area, but this
is not always easy in some facilities. If possible, the family and
anesthesiologist should be seated to reinforce the unrushed
nature of the encounter and for the anesthesiologist to appear less
intimidating to the child. Interruptions from surgical residents
and others should also be discouraged.
The content of the history can be focused to a large degree, but
it is often wise to begin with some open-ended questions,9 for
example, How are you feeling today? Do you have any particular concerns? or How did the anesthetic go last time? Such
questions often reveal important information and also allow the
child and family to mention things that they feel are important.
As a minimum, the history should include the age of the child, any
past surgical or anesthetic experiences, any past or current medical
conditions (requiring a visit or admission to hospital), medications
(prescribed, nonprescribed, and alternative), allergies, family
history of anesthetic problems, and any history of intercurrent
illness (particularly respiratory tract infection). The younger
the child, the more relevant the birth history and neonatal
period become.
Physical examination begins the moment the anesthesiologist lays eyes on the child. Much can be learned from astute
observation during the interview. Features such as the demeanor,
nutritional status, and activity are noted. Physical signs such as the
presence of a small mandible, respiratory tract infection, pallor,
tachypnea, or malaise, may be apparent. The admitting nurse will
often obtain the vital signs; however, these may have been taken
with an agitated child and usually may need to be repeated.
Temperature estimation is important, especially in the presence
of a respiratory tract infection. Infrared (IR) thermometers have
largely replaced older technology and are generally well tolerated
by children. The tympanic IR thermometer has been shown to be
reasonably reliable,10 although some expertise is required in its
use; ideally, the ear canal should be free of wax for accurate
readings. The temporal artery IR thermometer is easy to use and
has been shown to be more accurate than the tympanic one11;
however, both routes are less sensitive than the rectal route for
detecting fever.12
Oxygen saturation measurement is becoming a routine
vital sign conducted preoperatively, and a low saturation in the
presence of a respiratory infection is an important red flag that
there may be significant lower respiratory tract disease.
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Physical examination is conducted at the most opportune

moment. In toddlers, if the child is quiet and settled in the parents
lap, this is often a good time to examine the heart and lungs.
Auscultation is best performed first, because this is the best chance
of having a quiet child. Lungs should be auscultated anteriorly,
laterally, and posteriorly, because findings may be confined to one
lobe. If a cardiac murmur is heard, the child will need to be
examined in both the supine and the upright positions. Palpation
of the precordium is a valuable part of the examination, because
cardiac hyperactivity and/or thrills point to organic disease.
There may be external clues that the airway may be difficult,
notably a high-arched palate or small mandible on lateral inspection. It is not always easy to get a small child to open the mouth,
but this should be attempted. The presence of loose teeth should
be determined, particularly in children of ages 6 to 10 years.
Syndromes known to be associated with a difficult airway (e.g.,
hemifacial microsomia) may be evaluated by more formal scoring
systems, such as that proposed by Uezono and coworkers.13
Preoperative physical examination remains an important
process and provides an opportunity to screen the child for
unknown disease. There are reports of significant abnormalities
being detected by the anesthesiologist before elective surgery.14
Interviewing a teenager poses certain challenges. Teenagers
vary considerably in their attitude toward their parent/guardian
and authority in general, so some flexibility is required. Teenagers
may be particularly concerned with their body image and privacy
is essential. It may be that the patient wishes to disclose something without the parent/guardian present, such as a history of
smoking,15 alcohol or recreational drug use, or possible pregnancy.
Although it is not standard to routinely interview the teenager
separately, circumstances may require this on occasion.
Once the history and physical examination are complete,
the anesthesiologist is able to assign an American Society of
Anesthesiologists (ASA) Physical Status Grade (Table 361).16 This
is widely used in pediatric circles, but moderate to poor interrater
reliability has been shown.17,18 Even though this grading system is
not perfect, it is used to drive local policies, such as selection of
patients for ambulatory care or early discharge from recovery
rooms. A specific grading system for pediatric use has been
proposed, but this is not available at present.18
Evaluation of Emergency and Urgent Cases

Evaluation of emergency and urgent cases demands special attention. The nature of the proposed procedure and the underlying
TABLE 36-1. American Society of Anesthesiologists
Physical Status Classification
1. A normal healthy patient
2. A patient with mild systemic disease
3. A patient with severe systemic disease that limits activity,
but is not incapacitating
4. A patient with an incapacitating systemic disease that is a
constant threat to life
5. A moribund patient not expected to survive 24 hours with or
without operation
In the event of emergency operation, precede the number
with an E
From reference 16.
573
pathology are key. As an example, appendectomy is one of the

more com-mon surgical procedures carried out on an emergency
basis in children. When the patient is a teenager with a short
history of pain (2448 h), it is unlikely that there will be features
of severe sepsis present. In younger children, however, and with
longer histories, the chance of perforation, generalized peritonitis,
and associated sepsis is more likely.19 An evaluation of the airway
is particularly important in emergency cases, particularly if a
rapid-sequence induction is planned.
The fasting status is determined, as with elective cases, but in
the emergency scenario, the history may be uncertain, and the
child who is in pain, on narcotics, or systemically unwell should be
assumed to have full stomach.20,21
It is particularly important to evaluate the childs hemodynamic
status in emergency cases. Hemodynamic instability may be
related to hemorrhage, sepsis, or third-space losses. In a child, an
apparently minor injury, such as a scalp laceration, may lead to
significant hemorrhage. Children have a remarkable ability
to maintain a normal blood pressure in the earlier phases of
compensated shock. When frank hypotension occurs, the child
may have progressed to uncompensated shock, which can rapidly
become irreversible. The early signs of shock must, therefore,
be looked for carefully. These include tachycardia and, most
important, decreased peripheral perfusioncommonly reported
as capillary refill time in seconds. Toes or fingertips are convenient
places to evaluate perfusion. Other important signs of impending
shock are thirst, pallor (from vasoconstriction), oliguria, and
altered mental state, such as confusion or irritability.
Evaluation of the Child With Comorbidity

ExPremature Infants
Prematurity is defined as a birth occurring before 37 weeks of
postconceptional age (PCA). Although many expremature babies
encounter no medical complications, there are others who may
have a host of medical sequelae; in general, these are more
significant the earlier the PCA. As examples, the baby may have
developed intraventricular hemorrhage, bronchopulmonary
dysplasia, patent ductus arteriosus, acute renal failure, necrotizing
enterocolitis, or retinopathy of prematurity (ROP). Even those
who are apparently healthy are still considered at risk for postoperative apnea for a period as long as 60 weeks PCA.22,23 Ex
premature babies often present for inguinal hernia repair,24
or treatment of ROP, at an age when they are still at risk for
postoperative apnea. There is some urgency with both of these
surgical procedures, because the hernia may incarcerate25 or vision
may deteriorate if surgery is delayed.
Preoperative evaluation of the expremature baby requires
a detailed assessment of comorbidities. It should be remembered
that the baby may have undergone a long and difficult time in
the neonatal intensive care unit and that there may have been
difficulties conceiving and supporting the pregnancy. Parents
of such infants are generally very knowledgeable about their
childs condition and understandably protective of their childs
interests. As well, the neonatologists who have been involved
in the babys care may have strong views on such matters as
avoidance of intubation, particularly if it was previously difficult
to extubate the child. These are important perspectives to
consider.
In conducting the preoperative evaluation, it is crucial to
determine the gestational age (GA) at birth, the PCA, and the
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current hemoglobin level. Cot and colleagues combined analysis

is still the best evidence that we have concerning risk factors for
postoperative apnea in expremature infants.26 They determined
that the three most important predictors for the occurrence
of postoperative apnea are GA, PCA, and anemia.26,27 There is no
absolute PCA at which the apnea risk becomes zero, and institutions vary in their policies for postoperative admission. The
most conservative admit and monitor all expremature infants
younger than 60 weeks PCA. When discussing the perioperative
plan with families, it is worth discussing the measures that might
be considered, for example., a regional technique28 and the use
of caffeine.29 There is no clear evidence that blood transfusion
reduces the incidence of postoperative apnea in expremature
infants; however, a reduction in spontaneous apneic episodes has
been shown in anemic expremature infants after transfusion.30
If anemia is significant, therefore, there is an argument for
preoperative transfusion. The evidence for apnea risk in full-term
babies is weaker than for expremature infants, but there are
sufficient case reports to warrant admitting and monitoring these
babies before 44 weeks PCA.31,32
Respiratory Disorders
One of the most common comorbidities encountered in pediatric
anesthesia is the presence of an upper respiratory infection
(URI).23,33,34 A runny nose, however, does not always signify
infection, so the history must be structured to differentiate
infection from allergy. In the presence of a likely viral infection,
the anesthesiologist must address two issues, namely, whether to
proceed with anesthesia and how to minimize complications
if anesthesia is undertaken. Numerous studies have pointed to a
higher incidence of adverse events associated with anesthesia
in children with URIs3540; however, serious sequelae are rare.33
Independent risk factors for adverse respiratory events in children
with active URIs include use of an endotracheal tube (ETT) in
a child younger than 5 years old, prematurity, reactive airway
disease, paternal smoking, airway surgery, copious secretions, and
nasal congestion.4143 Although it has not been formally studied, it
would seem reasonable to assume that a low preoperative oxygen
saturation points to lower respiratory disease and that this would
be an additional risk factor.
The decision to proceed must take into account the urgency of
the surgery, the severity of symptoms, the nature of the procedure
and type of anesthesia required, presence of comorbidities, and
other social and geographic factors. It is no longer tenable to
simply postpone all children with a URI.44,45 Children may
experience six to eight URIs per year, and although these are
mainly self-limited viral infections, there may be evidence of
airway hyperreactivity for several weeks following the infection.33
Particularly over the winter months, therefore, many children
either have a URI or are in the recovery period from one. Most
anesthesiologists are prepared to anesthetize at least some children
with URIs45; one reasonable approach is nicely illustrated in an
algorithm suggested by Tait and Malviya (Figure 361).33
If the decision is made to proceed with anesthesia in a child
with a URI, can any measures minimize the risk of adverse events?
It has been shown that endotracheal intubation is associated with
more adverse events and that the laryngeal mask, if practical, is
associated with fewer complications.46 Preoperative bronchodilation (albuterol or ipratropium) has not been shown to be effective
in reducing adverse respiratory events.47 The routine use of
glycopyrrolate in children with URIs does not appear to reduce

the incidence of perioperative respiratory adverse events.48
Choice of anesthetic agent may be important. Sevoflurane appears
to be satisfactory in the presence of a URI, but it has only been
compared in this context with halothane.49 It would make sense
to avoid more irritating agents, such as desflurane or isoflurane.
Children with reactive airway disease are a significant concern
for the anesthesiologist. Most of these have documented asthma;
however, some children may be undiagnosed, and a history of a
chronic nocturnal cough may be the only clue that there is airway
reactivity.50 It is important to remember that the child who
wheezes may in fact have other pathology, such as a foreign body,
tracheal stenosis, or tracheomalacia.51 Infants with bronchiolitis
present with similar issues to the asthmatic child, although they
are best delayed unless the surgery is urgent.52 The expremature
infant and the baby recovering from bronchiolitis may exhibit
airway reactivity for a prolonged period.53
In evaluating the child with asthma, it is important to note
whether the disease has ever lead to hospital admissions, intensive
care unit admissions, or even mechanical ventilation. The degree
of compliance with medications, and the amount of agonist use
are key points. Unless the procedure is urgent, the presence of
wheezes on auscultation is an indication to postpone surgery.
Regarding preoperative management, it is wise to continue the
childs regular inhaled asthma medications up to the time of
surgery. If the parent has omitted the childs usual medications,
they can be given on arrival to the surgical facility. It has been
shown in asthmatics that tracheal intubation is associated with
an increase in respiratory system resistance54,55; this effect can be
prevented by the use of preanesthetic inhaled salbutamol.5658 In
addition, it has been shown that propofol causes less wheezing
than thiobarbiturates in patients with asthma59 and that the
laryngeal mask airway causes less bronchoconstriction than tracheal intubation.54 The anesthetic plan should take these various
findings into account.
An increasing number of children presenting for anesthesia
have overt or occult obstructive sleep apnea syndrome (OSAS).60
Younger children with OSAS generally have adenotonsillar
hypertrophy; whereas in older children, OSAS is more often
related to obesity (See Chapter 62). A subset of children with
OSAS have craniofacial anomalies or Down syndrome. Children
with OSAS are at significant risk of perioperative respiratory and
cardiovascular complications, with a reported incidence up to
20%.61 Those at highest risk are the very young (<2 y) and those
with significant comorbidity.61,62
Younger children differ from adults in terms of OSAS
symptoms. Daytime somnolence and obesity, common with adult
OSAS, are rare features in young children. Young children may
present with failure to thrive, behavioral problems, and poor
school performance.63 Symptoms are not reliable predictors of
the severity of OSAS; snoring is present in 10 to 15% of children,
but OSAS is prevalent in only 1 to 3% children.62 Investigations
such as polysomnography are not routinely available in all
centers. Overnight oximetry provides evidence as to the severity
of OSAS and is a cheaper option than a full polysomnogram.64
A preoperative oxygen saturation nadir of 80% is a predictor for
postoperative respiratory complications after adenotonsillectomy in 50% of children with OSAS.65 A preoperative apnea and
hypopnea index of greater than five events per hour is also
predictive of such complications.65 There is also a high incidence
of postoperative complications in children who undergo urgent
adenotonsillectomy.66 The anesthetic plan for the child with OSAS
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575
Figure 36-1. Suggested algorithm for the

assessment and anesthetic management
of the child with an upper respiratory
infection. ETT = endotracheal tube; Hx =
history; LMA = laryngeal mask airway;
URI = upper respiratory infection. From
reference 33.
should include scheduling the child early in the day,67 very cautious
use of opiates,6870 and postoperative admission and monitoring.71
Cystic fibrosis is another respiratory condition worth considering.72,73 The key with this condition is close collaboration
between the family, the various pediatric services involved, and
the anesthesiologist. Preoperative preparation is crucial and
should include chest physiotherapy, antibiotics, and bronchodilators. Inhalational induction may be prolonged and complicated
by vigorous episodes of coughing; therefore, it is reasonable to
consider an intravenous induction for most of these children.
Cardiac Disorders
Children with known congenital heart disease (CHD) present
particular challenges for the anesthesiologist. Far more commonly,
however, a child presents with a previously undetected cardiac

murmur. Innocent murmurs have been reported with an incidence
varying between 8 and 96%.74 The incidence of true CHD in
children lies closer to 0.5%, and most of these children are already
diagnosed when they present for anesthesia. The chances of
a newly heard murmur being related to organic heart disease are,
therefore, slim. Nevertheless, the anesthesiologist should be aware
of the features of the three most common innocent murmurs,
Stills murmur, pulmonary flow murmur, and venous hum
(Table 362), as well as the features of a clearly pathologic murmur.
Red flags pointing to organic disease include diastolic,
pansystolic, or late systolic murmurs, thrills, murmurs in infancy,
and associated cardiac signs. Unfortunately, many murmurs
are not clearly innocent or pathologic. For instance, it may be
impossible clinically to differentiate an innocent pulmonary flow
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TABLE 36-2. Innocent Murmurs in Childhood

Murmur
Location
Features
Stills murmur
Lower left sternal

edge, radiating
to apex
Vibratory, early systolic,

medium to low
pitched, grade 13,
loudest supine,
changes or diminishes
when upright
Blowing, midsystolic,
grade 13, loudest
supine, changes or
diminishes when
upright, normal
second heart sound
Whirring, continuous,
variable intensity,
sound, loudest sitting,
changes or diminishes
when supine
Pulmonary flow Left sternal border

murmur
at two to three
interspace
Venous hum
Supra- and/or
infraclavicular,
louder on right
murmur from that of an atrial septal defect.75 The anesthesiologist

must then decide whether it is safe to proceed with anesthesia or
delay the surgery, pending a cardiology opinion. In general, if the
surgery is minor and the child is asymptomatic with no signs of
cardiac compromise, it is acceptable to proceed with appropriate
precautions, including antibiotic prophylaxis when indicated. In
such cases, the parents should be advised to seek further followup with their regular physician.
The child with CHD merits special attention. The spectrum of
disease is wide and includes those who are uncorrected, who have
had surgical correction, or who may have just had a palliative or
part of a staged procedure. There is good evidence that the anesthetic risk in some children with CHD is significant, particularly
those with hypoplastic left heart syndrome.7678 These risks should
be properly disclosed to the family, and close communication with
the childs cardiologist is crucial, particularly for the more complex
cases. With known or suspected CHD, the anesthesiologist should
ask about symptoms of cardiac failure, such as rapid breathing,
failure to thrive, sweating, and feeding difficulties. Clinical signs
of cardiac failure in infancy include tachypnea, tachycardia,
cardiomegaly, hepatomegaly, and truncal edema. In considering
the child with CHD, the three key questions to be addressed are
1. What is the precise anatomy? This includes the structure of the
heart and any subsequent surgical corrections.
2. Is there a significant shunt, and if so, in what direction?
3. Is there evidence of complicationscardiac failure, ventricular
dysfunction, pulmonary hypertension, or arrhythmia?
Frequently, the best information to answer these questions
comes from a recent echocardiogram, but some patients may have
angiographic or MRI studies that will clarify the situation further.
The question of antibiotic prophylaxis must also be addressed; and
the reader is referred to the latest guidelines from the American
Heart Association.79
Neurologic and Musculoskeletal Disorders

Infants and children with neurologic handicap frequently present
for diagnostic and surgical procedures requiring anesthesia. It is
important to review the general health of the child as well as

impairment of motor function, intellectual function, and seizure
potential. A child with severe cerebral palsy may have normal or
high intelligence, so it is important always to assume a high level
of intellectual functioning when addressing the child, unless the
record indicates otherwise. Pain may be difficult to assess in the
child with cerebral palsy, but the family or care provider may be
particularly helpful in describing how the child expresses pain.
New tools of pain assessment for children with cerebral palsy have
also been developed.80
Certain muscular disorders are of particular interest to the
anesthesiologist. The group of disorders known as dystrophinopathies (e.g., Duchenne and Becker muscular dystrophy) have
the potential to develop sudden hyperkalemia in the presence
of volatile agents or succinylcholine.81,82 At the preanesthetic visit,
a trigger-free anesthetic should be planned.82 These children often
develop cardiomyopathies as they grow older,81 so a recent echocardiogram to evaluate ventricular function is useful. Pulmonary
function testing is also essential in more advanced cases.
Many previously obscure diseases are being recognized as
variants of mitochondrial myopathy. These conditions require a
thorough preoperative assessment of functional organ system
reserve,83 and it has been suggested that parental presence at
induction may be helpful in cases with sensory deprivation and
that excessive preoperative fasting should be avoided.83
Autistic children can present special challenges for families
and caregivers alike.84 Generally, these children are physically
well and their main problems are behavioral. Attention to detail,
such as minimizing auditory stimuli, tailoring the experience
to the individuals needs and characteristics, planning for an early
discharge, and judicious premedication are useful measures.
Some autistic children react in a paradoxical way to midazolam;
severely autistic children may fare better with oral ketamine for
premedication.84
Children with known or suspected malignant hyperthermia
sensitivity (MHS) present little difficulty with modern anesthesia.
A trigger-free anesthetic is planned. It must be remembered that
some of the newer anesthetic machines need longer flushing times
than older machines. It is wise to schedule these patients first in
the day to allow for adequate preparation. Oral midazolam, topical
anesthetic cream over suitable veins, and nitrous oxide will facilitate an intravenous induction in anxious children. It has been
shown that MHS children need to be monitored for only 4 hours
in the hospital after a minor procedure.85
Children with seizure disorders may be at risk if their
seizure control is poor or if they are on multiple anticonvulsants.
Anesthesia may have a somewhat unpredictable effect on seizure
control, and anesthetic drugs may interact with anticonvulsants,
causing oversedation. Conversely, enzyme induction from seizure
medications may increase anesthetic needs. It is prudent to
arrange for monitoring of these children until they have fully
recovered from the effects of anesthesia, to re-establish their
regular anticonvulsant regime as soon as possible, and to involve
their neurologist as required.
Metabolic and Endocrine Disorders

Diabetes mellitus (DM) is increasing in incidence in North
American children, with type 1 DM accounting for the majority of
cases. Children tend to be prone to instability in their glycemic
control, and many are treated with complex regimes. The principles of perioperative management are simple, however:
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1.
2.
3.
4.
5.
To optimize the childs preoperative state.

To ensure as rapid return as possible to the preanesthetic state.
To avoid hypoglycemia.
To avoid extreme hyperglycemia and/or ketosis.
To adequately treat pain and postoperative nausea and vomiting,
because these may compromise glycemic control.
The anesthesiologist should be aware of the various regimes of

insulin therapy that are in common use in children. These include
combinations of intermediate- and short-acting insulins; longacting insulin supplemented with short-acting insulin at meal
times; or subcutaneous insulin infusions.86,87 Newer modalities of
insulin administration (e.g., inhaled or orally absorbed insulin)
are the subject of investigation. Regimes are evolving rapidly, so it
is wise to seek the assistance of the childs regular endocrinologist
or pediatrician when planning perianesthetic care. One question
that sometimes arises concerns the use of dexamethasone in
diabetic children. Although a glucocorticoid might lead to hyperglycemia,88 the antiemetic and anti-inflammatory benefits of
dexamethasone may outweigh this concern in selected cases (e.g.,
with tonsillectomy or eighth molar extractions).
There appears to be a current epidemic of obesity in children,
particularly in North America, and some of these children develop
type 2 DM. Obesity may also be a feature of syndromes such
as Prader-Willi; however, these children are usually identified by
the pediatrician. Prader-Willi syndrome has many implications
for the anesthesiologist, notably the risk of sleep apnea and
postoperative respiratory failure.89
Countless other metabolic disorders may have implications
for the anesthesiologist, particularly those involving the urea
cycle. The keys to managing such children are the avoidance of
dehydration, hypoglycemia, and hyperammonemia. The choice
of intraoperative fluids is important. Avoiding lactate and providing glucose may be particularly important in some situations.
Close liaison with the metabolic specialists is essential, because
there may be specific regimes that are useful for particular conditions (e.g., sodium benzoate, arginine, citrulline, and sodium
phenylbutyrate regimes in cases of ornithine transcarbamylase
deficiency).90
Oncologic, Immunologic,
and Hematologic Disorders
Malignancy is encountered fairly frequently in the pediatric population, and many of these patients require repeated procedures
under anesthesia. The family of a child newly diagnosed with
cancer must be approached with compassion because this may
represent one of the most challenging situations that they will have
faced in their lives. The anesthesiologist can do much to make the
childs experiences with procedures as comfortable and stress-free
as possible. Judicious use of premedication, avoidance of parental
separation, close attention to pain control, and postoperative
nausea and vomiting (PONV) prevention are all measures that
will help to alleviate the stress that the child and, hence, the family
will experience. Children who are frequent flyers for minor
oncologic procedures (e.g., lumbar puncture or radiotherapy)
often develop a close rapport with a sympathetic anesthesiologist,
whom they may see on a regular basis.
Certain oncologic conditions are associated with increased risk
for complications, notably those with an anterior mediastinal
mass.91,92 It would appear that children who present with orthopnea, upper body edema, great vessel compression, mainstem
577
bronchus compression, pleural effusion, or tracheal compression

are at the greatest risk.92 The problem is that the cause of some
of these effects may require sedation or anesthesia to allow appropriate evaluation and investigation. A suitable algorithm should,
therefore, be agreed upon in each institution dealing with these
patients.91
Children with HIV infection present many challenges for
the anesthesiologist.93 The preoperative process should follow
traditional lines, with particular attention paid to the possible
involvement of multiple organ systems, tuberculosis comorbidity,
adverse reactions and drug interactions of antiretroviral agents,
pain evaluation, and plans to prevent HIV transmission within the
facility. As with all patients, confidentiality must be maintained
with these patients.
The child with sickle cell disease requires careful evaluation
preoperatively. The most crucial factors to assess are dehydration,
hypoxemia, vascular stasis, hypothermia, acidosis, and infection.94
Symptoms and signs of end-organ damage, such as respiratory
compromise from previous episodes of acute chest syndrome,
should be sought. Although a preoperative hemoglobin and
hemoglobin S level should be obtained, it remains unclear whether
there is a benefit to preoperative blood transfusion, particularly
for minor procedures.9496 It should be remembered that children
with sickle cell disease often have a history of painful crises and
they may be tolerant of opiate analgesics. Because opiate requirement may vary considerably between patients with sickle cell
disease, patient-controlled analgesia or a regional technique is
often a reasonable approach to discuss with the family.97
Syndromes (Trisomy 21 As an Example)

Countless syndromes have implications and challenges for the
anesthesiologist.98,99 Examples include urticaria pigmentosa,
epidermolysis bullosa, and familial dysautonomia. Anesthesiologists should have access to material, either text or web-based,
that will serve to rapidly identify all the key features of all such
syndromes and their implications for anesthesia.
Trisomy-21 (Down syndrome) is described as one example of
a common syndrome with abnormalities of all body systems,
many of these influencing anesthetic care.100,101 The most crucial
systems for the anesthesiologist to evaluate in these children are
respiratory, cardiovascular, and musculoskeletal. It is important
to realize that the degree of cognitive challenge is very variable in
children with Down syndrome. Many of these children are highly
functional, and it is wise to assume that they will understand much
of what is happening to them; they should be spoken with directly,
just as with any other child.
Preoperative evidence of respiratory tract infection has been
found in up to 23% of cases102 and should be sought; a history of
recurrent croup will alert the anesthesiologist to the possibility of
subglottic stenosis. Particular attention should be paid to the
airway; the degree of macroglossia present and the presence
of stridor should be noted. Subglottic stenosis is likely to be
undetectable unless very severe.
Children with Down syndrome have a high incidence of OSAS.
One study of 53 children with Down syndrome demonstrated
abnormal nap polysomnograms in 77% and abnormal overnight
polysomnograms in 100%.103 Interestingly, in this study, 57% of
children did not have a history suggestive of OSAS.
CHD is found in approximately 40% of children with Down
syndrome.99 Often, this is well documented and details of previous
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cardiac surgery, medications, and recent cardiologic evaluations

with echocardiographic reports are available. Children with
Down syndrome are particularly prone to develop pulmonary
hypertension, related to either a left-to-right shunt, impaired
development of alveoli and pulmonary vasculature, and/or arterial
hypoxemia owing to chronic upper airway obstruction.99 Evidence
of residual anatomic defects, cardiac failure, or pulmonary hypertension should be evaluated preoperatively. It has been known for
years that children with Down syndrome may have a poorly
developed sympathetic nervous system,104 and this makes them
particularly prone to bradycardia with anesthesia.105 The resting
heart rate should, therefore, be noted. Down syndrome children
respond normally to atropine106; this drug should be available
at induction.
Children with Down syndrome have been shown to have
atlantoaxial instability (AAI) in 7 to 36% of cases.107 Despite this
high incidence, the incidence of anesthesia-related complications
related to this is exceedingly rare.107 It is important to structure
the history and physical examination to identify children with
neurologic findings, but in the absence of significant symptoms
or signs, the need for routine radiographic evaluation remains
controversial. In one survey, 171 North American members of the
Society for Pediatric Anesthesia, only 18% reported routinely
obtaining radiographs in asymptomatic children.108 It would seem
prudent, however, to obtain radiographs109 in any case with signs
or symptoms or in which the head will be in a nonneutral position.
Signs of AAI on radiographs are an indication for further surgical
evaluation preoperatively. This topic is well covered in a review
article.107
Investigations
At one time, it was routine practice to obtain a complete blood
count (CBC) and urinalysis (UA) before anesthesia. It has been
shown conclusively that this is not required.110113 In children with
no abnormalities in the history or physical signs, anemia is rare,
and mild even if present. Some children, however, do require a
CBC. The premature baby may be more at risk for postoperative
apnea if anemic,26,27 so a CBC is useful to help quantify the apnea
risk. Children who have significant comorbidity and/or who
are undergoing major procedures merit a preoperative CBC, at
least to determine their baseline status. There is very little value in
routine preoperative UA analysis in otherwise healthy children.110
Routine testing for sickle cell disease (SCD) is commonly
performed in so-called at-risk populations. This practice has been
called into question recently.114 The population at risk is essentially
any ethnic group whose origins arose in malaria-infected areas.
This includes those of African, Hispanic, Mediterranean, Middle
Eastern, and Asian Indian heritage. Of note, in 12 to 17% of infants
diagnosed with SCD, neither parent was of African ancestry.114,115
With the increasing number of children of blended racial origin,
the number of patients to potentially screen is huge, and to what
benefit? There is very little of clinical significance in those
with sickle cell trait, so identification of this condition does not
generally aid in anesthetic management. In a study from a large
pediatric institution, which reviewed 1906 children of African
ancestry who were screened for SCD, only 1 case of SCD was
identified in a child who had a negative family history.114 That
child had SCD, with a hemoglobin of 112 g/L. The message seems
to be that preoperative screening for SCD should be undertaken
selectively; this might include those with a positive or unknown
family history, those with known or suspected anemia, those with

sickle symptomatology, and those undergoing high-risk procedures involving hypothermia or interference with the circulation
(e.g., tourniquets).114
Coagulation testing should be reserved for children with
possible coagulopathy identified by history, physical examination,
or family history; or for those undergoing major surgery. Some
centers, however, demand that children undergoing adenotonsillectomy undergo routine preoperative coagulation testing.
This has been shown to provide low sensitivity and to be a poor
predictor of perioperative bleeding.116
The issue of preoperative pregnancy testing in children is
controversial. There is little doubt that some teenagers may be
pregnant when presenting for surgery. Studies of female adolescents screened preoperatively for pregnancy have revealed a 0.9
to 1.2% incidence of positive testing.117,118 Several authors have
proposed that routine pregnancy testing be made mandatory,
and some hospitals have introduced such policies. This, however,
is an ethical and logistical minefield, and as Duncan and Pope
point out we must maintain an awareness of the impact of our
decisions on the overall cost to the healthcare system and ensure
that policies required for access to our services are both ethical
and responsible within a societal context.119
Children undergoing highly complex procedures clearly
require comprehensive investigations. As an example, a teenager
scheduled to undergo surgical correction of scoliosis may require:
blood work (CBC, electrolytes, UA, creatinine, coagulation tests,
blood group, and cross-match), UA, radiographs (chest anteroposterior and lateral), pulmonary function tests, electrocardiogram, and echocardiogram. In all likelihood, this patient will have
had extensive imaging studies (computed tomography [CT] or
MRI), and these may be available on-line for the anesthesiologist
to review.
ANXIOLYSIS
Anxiety is common whenever a child requires anesthesia.
This anxiety is not limited to the child; the family is often just as
anxious, if not more so, than the child. High anxiety at induction
has been shown in at least half of children.120 Risk factors for
anxiety include younger age, behavioral problems with previous
health care attendances, longer procedures, more than five previous admissions, and anxious parents.120 Anxiety is unpleasant
for the child and may have other adverse effects, such as a higher
requirement for postoperative analgesia and a higher incidence of
emergence delirium or postoperative anxiety.121,122
Apart from the presence of a calm, confident, friendly, and
approachable anesthesiologist, several specific strategies may help
to decrease the incidence of anxiety that can be planned at the
preanesthetic visit. Perhaps the most effective intervention is the
use of premedication. There is no doubt that oral midazolam
effectively reduces anxiety at induction of anesthesia.123 Other
sedatives (e.g., clonidine, ketamine) have their advocates.124,125 See
Chapter 37
Other strategies to reduce anxiety include hypnosis,126 music,127
acupuncture,128 clowns,129 and orientation programs.130 These nonpharmacologic approaches have had some success; however, they
generally require resources and expertise. Acupuncture been
shown to reduce anxiety in the parent; however, it seems that
the children also demonstrate less anxiety at induction when
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the parent receives acupuncture.128 Orientation programs vary

widely in their content130 and, hence, their benefit. It is being increasingly recognized, however, that an intensive, family-centered,
behaviorally oriented preoperative program can be more effective
at reducing anxiety than other, simpler, cheaper orientation
methods.131,132
Perhaps the most questionable anxiolytic intervention is
parental presence at induction of anesthesia (PPIA).133 Numerous
studies have evaluated PPIA over the years, and the majority do
not seem to show an overall benefit in terms of anxiety reduction.134,135 It does appear though that children older than 4 years
and those with nonanxious parents derive some benefit from
PPIA.134 Irrespective of whether it actually helps the child or not,
most parents wish to be present at induction.134,136 Interestingly, in
one study, 90% of parents rated themselves as being helpful to their
child at induction, whereas only 12% were rated as being helpful
by the anesthesiologist.134 Finally, there is some evidence that
PPIA, in combination with oral midazolam premedication, may
reduce the incidence of emergence delirium.137
Most anesthesiologists have adopted a flexible approach to
PPIA.138 There are certainly some children, such as those with
special needs or language barriers, the very anxious child, and
the repeatedly hospitalized child, who seem to benefit from
PPIA. Because parents seem to appreciate the chance to be with
their child at induction, it can be assumed that the practice will
continue to increase.139 It would make sense, however, that PPIA
be accompanied by a formal educational program for the parents,
so that they at least know what to expect and how they can be
helpful to their child.133 There is evidence that such programs
reduce anxiety in the parent,140 so presumably the child might
benefit also.
PREOPERATIVE INSTRUCTIONS
AND INFORMATION SHARING
Fasting Instructions
Fasting instructions need to be very clear and leave no room
for confusion. Standard fasting intervals for children are provided in Table 363, and the topic is covered in more detail in
Chapter 37. Essentially, based on extensive research, it is safe
to allow clear fluids up to 2 hours preinduction in elective
patients.141146 Furthermore, prolonged fasting may be deleterious, particularly in infants.147 Even with liberalization of preoperative fluid intake, it appears that the incidence of aspiration
in children undergoing anesthesia is very low.148 There is scant
evidence, however, to support a definite fasting period for
solid food and much depends on the nature and quantity of the
food ingested.
TABLE 36-3. Fasting Guidelines for Elective Surgery
in Children
Substance
Clear fluid
Breast milk
Formula or nonhuman milk
Solid food
From reference 141.
Minimum Fasting Period, h

2
4
6
8
579
The issue of chewing gum in the preoperative period has been

the subject of some debate. Adult studies have found conflicting
results in terms of the effect of gum-chewing on gastric fluid
volumes and pH.149,150 A recent pediatric study, however, did show
larger gastric fluid volumes in children who chewed gum before
anesthesia.151 Reassuringly, the gastric pH was higher in the gumchewing subjects. There was no difference between sugared and
sugar-free gum. An additional hazard of gum is that it may remain
undetected in the oral cavity and lead to subsequent aspiration.
It is important, therefore, to include gum in the list of items to
avoid on the day of surgery. If a child does arrive chewing gum, the
effects should be similar to ingesting clear fluids, so a delay of
2 hours would seem to be justifiable.
Preoperative Medications
Children who are on regular medications should generally
continue taking these up to the time of surgery. This is particularly
important with cardiac medications, bronchodilators, and anticonvulsants. Children who are on oral anticoagulants may need
to be switched to heparin; this is done in consultation with a
hematologist.
Apart from the childs regular medications and sedative premedicants, some other preoperative drugs may be considered. It is
common practice in many centers to administer acetaminophen
orally to children in the preoperative period. There have been
conflicting results of this therapy before myringotomy152,153;
however, there is some evidence of a morphine-sparing effect
in children who might be predicted to require opiates.154 This
latter study showed a clear dose response, with doses of rectal
acetaminophen in the 40- to 60-mg/kg being superior to 20 mg/kg
or placebo.154 It is known that the relative bioavailability of rectal
versus oral acetaminophen is 0.54,155 and some authors have
recommended rectal loading doses of 40 m/kg to account for
this.156 It must be remembered, however, that the therapeutic
window for acetaminophen is narrow. Care must be taken to avoid
acetaminophen overdose.157 Even in a child with no risk factors
for hepatotoxicity; the maximum 24-hour dose is 90 mg/kg, by
whatever route, to a maximum of 4 g.
The use of anticholinergic agents before induction of anesthesia is controversial158 and has waned with the advent of modern
inhalational agents. Most anesthesiologists do not administer an
anticholinergic routinely but reserve it for selected indications
(e.g., strabismus repair,159 Down syndrome,105,106 before succinylcholine,160,161 and during bronchoscopy). A prudent anesthesiologist, however, has atropine (and succinylcholine) drawn up
when anesthetizing children, unless contraindicated.160
Information Sharing
The preanesthetic visit is an opportunity for the anesthesiologist
to address any concerns that the child or parent may have. There
should always be an invitation for the family to ask questions
about the anesthetic in an unhurried manner. Even if the family
has few questions, the anesthesiologist should outline the plan for
anesthetic care that the child will receive. A brief description of
the type of anesthesia is appropriate, and the method of induction
may be a matter of negotiation (children often appreciate having
some control over what is happening to them). The requirement
for invasive lines or regional blocks can be discussed at this time.
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Much of the information to be provided pertains to postoperative

care. The plan for pain control,162 emergence delirium,163 and
PONV prevention164,165 needs to be outlined.
CONSENT AND ASSENT

The preoperative interaction concludes with the anesthesiologist
obtaining consent from the parent or legal guardian and assent
from the child when appropriate. The information sharing process
should mean that families are aware of what will take place and
the anticipated benefits and risks of these interventions. Specific
interventions, such as invasive lines, blood transfusion, and
regional blocks, should be identified and explained as part of the
consent process. The child may have questions too, and these
should be answered truthfully in an age-appropriate fashion.
Families are often concerned about the risk of anesthesia.
Specific questions often concern morbidity, mortality, awareness,
blood component transfusion, and regional techniques, particularly epidural or spinal anesthesia. Families should be made
aware that the risk for each child varies, depending on the age and
condition of the child, as well as the surgical procedure to be
performed. If numerical indicators of risk are requested by the
family, these can be provided with the caveat that these are average
numbers only (Table 364).166172
Although the focus should be on anesthetic risk, inevitably this
is influenced by surgical decisions. For example, a surgeon may
opt to perform a pyloromyotomy laparoscopically, despite some
evidence that open pyloromyotomy is associated with fewer complications than the laparoscopic procedure173 and that the anesthetic concerns may be greater with the laparoscopic approach.
In this situation, the anesthesiologist must disclose all the anesthetic risks to the family but should avoid commenting on specific
surgical risks that are the domain of the surgeon.
Assent implies the agreement of the child as to what is about
to occur. This becomes more relevant the older the child. Most
anesthesiologists are very uncomfortable forcing anesthesia
on an unwilling teenager for elective surgery.174 Both consent and
assent for anesthesia-related research purposes are topics unto
themselves and are beyond the scope of this chapter.175178
CONCLUSION
When considering the preanesthetic evaluation and preparation
process, it becomes clear that the key to good outcomes is excellent
communication between the family and all the care providers
involved, as well as excellent communication between the various
TABLE 36-4. Quantification of Anesthesia-Related
Risks in Children
Complication
Risk
Reference
Anesthesia-related mortality
Permanent neurologic damage
from epidural anesthesia
Awareness
HIV infection per unit transfused
Hepatitis B infection per unit
transfused
Hepatitis C infection per unit
transfused
00.36:10,000
1:10,000
166169
170
0.81.2:100
1:4,000,000
1:31,000
171
172
172
1:3,000,000
172
health care providers.179,180 One aspect of communication that is

sometimes overlooked is the ability of the family and the child to
provide feedback on their overall experience. Many centers are
now incorporating such programs into their practice or have
evaluated parental preferences181183; this can only aid in improving
our outcomes after anesthesia in children.
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children: hypnosis versus midazolam. Paediatr Anaesth. 2005;15:
275281.
127. Kain ZN, Caldwell-Andrews AA, Krivutza DM, et al. Interactive music
therapy as a treatment for preoperative anxiety in children: a randomized controlled trial. Anesth Analg. 2004;98:12601266.
128. Wang SM, Maranets I, Weinberg ME, et al. Parental auricular
acupuncture as an adjunct for parental presence during induction of
129. Vagnoli L, Caprilli S, Robiglio A, et al. Clown doctors as a treatment for
preoperative anxiety in children: a randomized, prospective study.
Pediatrics. 2005;116:e563e567.
130. OByrne KK, Peterson L, Saldana L. Survey of pediatric hospitals
preparation programs: evidence of the impact of health psychology
research. Health Psychol. 1997;16:147154.
131. Kain ZN, Caldwell-Andrews AA, Mayes LC, et al. Family-centered
preparation for surgery improves perioperative outcomes in children: a
randomized controlled trial. Anesthesiology. 2007;106:6574.
132. Maclaren J, Kain ZN. Pediatric preoperative preparation: a call for
evidence-based practice. Paediatr Anaesth. 2007;17:10191020.
133. Lerman J. Anxiolysisby the parent or for the parent? Anesthesiology.
2000;92:925927.
134. Kain ZN, Mayes LC, Caramico LA, et al. Parental presence during
induction of anesthesia. A randomized controlled trial. Anesthesiology.
1996;84:10601067.
135. Kain ZN, Mayes LC, Wang SM, et al. Parental presence during induction
of anesthesia versus sedative premedication: which intervention is more
effective? Anesthesiology. 1998;89:11471156.
136. Kain ZN, Caldwell-Andrews AA, Wang SM, et al. Parental intervention
choices for children undergoing repeated surgeries. Anesth Analg.
2003;96:970975.
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CHAPTER 36
137. Arai YC, Ito H, Kandatsu N, et al. Parental presence during induction
enhances the effect of oral midazolam on emergence behavior of
children undergoing general anesthesia. Acta Anaesthesiol Scand.
2007;51:858861.
138. Kain ZN, Caldwell-Andrews AA, Krivutza DM, et al. Trends in the
practice of parental presence during induction of anesthesia and the
use of preoperative sedative premedication in the United States, 1995
2002: results of a follow-up national survey. Anesth Analg. 2004;98:
12521259.
139. Kain ZN, Mayes LC, Wang SM, et al. Parental presence and a sedative
premedicant for children undergoing surgery: a hierarchical study.
140. McEwen A, Moorthy C, Quantock C, et al. The effect of videotaped
preoperative information on parental anxiety during anesthesia
induction for elective procedures. Paediatr Anaesth. 2007;17:534539.
141. Cot CJ, Goudsouzian NG, Liu LM, et al. Assessment of risk factors
related to the acid aspiration syndrome in pediatric patientsgastric pH
and residual volume. Anesthesiology. 1982;56:7072.
142. Splinter WM, Schaefer JD, Zunder IH. Clear fluids three hours before
surgery do not affect the gastric fluid contents of children. Can J Anaesth.
1990;37:498501.
143. Schreiner MS, Triebwasser A, Keon TP. Ingestion of liquids compared
with preoperative fasting in pediatric outpatients. Anesthesiology.
1990;72:593597.
144. Schwartz DA, Connelly NR, Theroux CA, et al. Gastric contents in
children presenting for upper endoscopy. Anesth Analg. 1998;87:
757760.
145. Schreiner MS. Gastric fluid volume: is it really a risk factor for
pulmonary aspiration? Anesth Analg. 1998;87:754756.
146. Ferrari LR, Rooney FM, Rockoff MA. Preoperative fasting practices in
pediatrics. Anesthesiology. 1999;90:978980.
147. Friesen RH, Wurl JL, Friesen RM. Duration of preoperative fast
correlates with arterial blood pressure response to halothane in infants.
Anesth Analg. 2002;95:15721576.
148. Warner MA, Warner ME, Warner DO, et al. Perioperative pulmonary
aspiration in infants and children. Anesthesiology. 1999;90:6671.
149. Dubin SA, Jense HG, McCranie JM, et al. Sugarless gum chewing before
surgery does not increase gastric fluid volume or acidity. Can J Anaesth.
1994;41:603606.
150. Sreide E, Holst-Larsen H, Veel T, et al. The effects of chewing gum on
gastric content prior to induction of general anesthesia. Anesth Analg.
1995;80:985989.
151. Schoenfelder RC, Ponnamma CM, Freyle D, et al. Residual gastric
fluid volume and chewing gum before surgery. Anesth Analg. 2006;
102:415417.
152. Bennie RE, Boehringer LA, McMahon S, et al. Postoperative analgesia
with preoperative oral ibuprofen or acetaminophen in children
undergoing myringotomy. Paediatr Anaesth. 1997;7:399403.
153. Bhananker SM, Azavedo L, MacCormick J, et al. Topical lidocaine and
oral acetaminophen provide similar analgesia for myringotomy and tube
placement in children. Can J Anaesth. 2006;53:11111116.
154. Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of
acetaminophen in pediatric day-case surgery. Anesthesiology. 1999;91:
442447.
155. Anderson BJ, Holford NH, Woollard GA, et al. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology.
1999;90:411421.
156. Birmingham PK, Tobin MJ, Fisher DM, et al. Initial and subsequent
dosing of rectal acetaminophen in children: a 24-hour pharmacokinetic
study of new dose recommendations. Anesthesiology. 2001;94:385389.
157. Heubi JE, Barbacci MB, Zimmerman HJ. Therapeutic misadventures
with acetaminophen:hepatoxicity after multiple doses in children.
J Pediatr. 1998;132:2227.
158. Jhr M. Is it time to question the routine use of anticholinergic agents in
paediatric anaesthesia? Paediatr Anaesth. 1999;9:99101.
159. Mirakhur RK, Jones CJ, Dundee JW, et al. I.M. or I.V. atropine or
glycopyrrolate for the prevention of oculocardiac reflex in children
undergoing squint surgery. Br J Anaesth. 1982;54:10591063.
583

paediatric anaesthesia. Can J Anaesth. 1995;42:17.
161. Shorten GD, Bissonnette B, Hartley E, et al. It is not necessary to
administer more than 10 micrograms kg1 of atropine to older children
before succinylcholine. Can J Anaesth. 1995;42:811.
162. Wolf AR. Tears at bedtime: a pitfall of extending paediatric day-case
surgery without extending analgesia. Br J Anaesth. 1999;82:319320.
163. Vlajkovic GP, Sindjelic RP. Emergence delirium in children: many
questions, few answers. Anesth Analg. 2007;104:8491.
164. Bolton CM, Myles PS, Nolan T, et al. Prophylaxis of postoperative
vomiting in children undergoing tonsillectomy: a systemic review and
meta-analysis. Br J Anaesth. 2006;97:593604.
165. Goodarzi M, Matar MM, Shafa M, et al. A prospective randomized
blinded study of the effect of intravenous fluid therapy on postoperative
nausea and vomiting in children undergoing strabismus surgery.
166. Morray JP, Geiduschek JM, Ramamoorthy C, et al. Anesthesia-related
cardiac arrest in children: initial findings of the Pediatric Perioperative
Cardiac Arrest (POCA) Registry. Anesthesiology. 2000;93:614.
167. Tay CL, Tan GM, Ng SB. Critical incidents in paediatric anaesthesia: an
audit of 10,000 anaesthetics in Singapore. Paediatr Anaesth. 2001;
11:711718.
168. Murat I, Constant I, Maudhuy H. Perioperative anaesthetic morbidity in
children: a database of 24,165 anaesthetics over a 30-month period.
169. Bhananker SM, Ramamoorthy C, Geiduschek JM, et al. Anesthesiarelated cardiac arrest in children: update from the Pediatric Perioperative
Cardiac Arrest Registry. Anesth Analg. 2007;105:344350.
170. Llewellyn N, Moriarty A. The national pediatric epidural audit. Paediatr
Anaesth. 2007;17:520533.
171. Davidson AJ, Huang GH, Czarnecki C, et al. Awareness during
anesthesia in children: a prospective cohort study. Anesth Analg.
2005;100:653661.
172. Kleinman S, Chan P, Robillard P. Risks associated with transfusion
of cellular blood components in Canada. Transfus Med Rev. 2003;17:
120162.
173. Hall NJ, Van Der Zee J, Tan HL, Pierro A. Meta-analysis of laparoscopic
versus open pyloromyotomy. Ann Surg. 2004;240:774778.
174. Lewis I, Burke C, Voepel-Lewis T, et al. Children who refuse anesthesia
or sedation: a survey of anesthesiologists. Paediatr Anaesth. 2007;
17:11341142.
175. Tait AR, Voepel-Lewis T, Malviya S. Do they understand? (Part I):
parental consent for children participating in clinical anesthesia and
surgery research. Anesthesiology. 2003;98:603608.
176. Tait AR, Voepel-Lewis T, Malviya S. Do they understand? (Part II):
assent of children participating in clinical anesthesia and surgery
research. Anesthesiology. 2003;98:609614.
177. Denham EJ, Nelson RM. Self-determination is not an appropriate model
for understanding parental permission and child assent. Anesth Analg.
2002;94:10491051.
178. Erb TO, Schulman SR, Sugarman J. Permission and assent for clinical
research in pediatric anesthesia. Anesth Analg. 2002;94:11551160.
179. American Academy of Pediatrics. Section on Anesthesiology. Evaluation
and preparation of pediatric patients undergoing anesthesia. Pediatrics.
1996;98:502508.
180. Maxwell LG. Age-associated issues in preoperative evaluation, testing,
and planning: pediatrics. Anesthesiol Clin North Am. 2004;22:2743.
181. Le T, Drolet J, Parayno E, Rosmus C, et al. Follow-up phone calls after
pediatric ambulatory surgery for tonsillectomy: what can we learn from
families? J Perianesth Nurs. 2007;22:256264.
182. Jones DT, Yoon MJ, Licameli G. Effectiveness of postoperative follow-up
telephone interviews for patients who underwent adenotonsillectomy:
a retrospective study. Arch Otolaryngol Head Neck Surg. 2007;133:
10911095.
183. Gidman W, Elliott R, Payne K, et al. A comparison of parents and
pediatric anesthesiologists preferences for attributes of child daycase
surgery: a discrete choice experiment. Paediatr Anaesth. 2007;17:
10431052.
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Premedication, Sedation,
and Preoperative Fasting
William M. Splinter and Jarmila Kim
PREOPERATIVE SEDATION
OF CHILDREN
Children undergoing anesthesia and surgery can experience
significant anxiety and distress during the preoperative period. Up
to 50% of children undergoing surgery are reported to exhibit
significant anxiety preoperatively.1,2 Preoperative sedation, or the
commonly simplified term premedication, is often administered
to children to allay this anxiety. Factors that may increase anxiety
include separation from the family, anticipation of postoperative
pain, fear of surgery and/or anesthesia, loss of independence,
and fear of death.3,4 This anxiety can be of minor importance and
intervention is not indicated, but in other situations, the parent(s)
and/or child may become quite dysfunctional and a variety of
anxiolytic interventions may be beneficial.
Anxiety can be divided into state-anxiety and trait-anxiety.
State-anxiety is a transitory emotional condition that consists
of feelings of tension, apprehension, nervousness, and worry. This
state fluctuates in intensity over time. Trait-anxiety refers to
individual differences in anxiety proneness, being a personality
trait that remains relatively stable over time.5 High state-anxiety
scores indicate high levels of anxiety at the time of evaluation,
whereas high levels of trait-anxiety indicate an anxious personality
disposition.6
Preoperative anxiety is exhibited in several ways. Depending
upon the age of the child, this anxiety may be exhibited verbally
and/or behaviorally. Crying, silence, pallor, agitation, deep breathing,
trembling, urinary retention, violent actions, tense muscles, and
other activities may be signs and symptoms of the anxious child.
This stress usually peaks at the time of induction of anesthesia.7
Interventions currently available to treat and/or prevent
preoperative anxiety fall into three major categories: (1) providing
hospital-based preparation programs before surgery, (2) administration of sedatives and anxiolytics before surgery, and (3) parental
presence at induction of anesthesia. Preoperative preparation
programs have been in existence since the early 1960s, and initially,
the programs were exclusively information-oriented. Evidencebased recommendations for such programs suggest that (1) information on both procedural and sensory aspects of the procedure
should be included, (2) coping skills should be taught via a peer
model, (3) written materials alone are not effective and preparation
should be provided at least 5 days in advance for children older
than 6 years and no more than a week in advance for children
younger than 6 years.8 A survey of 34 childrens hospitals and
24 community hospitals with pediatric surgery revealed that most
preoperative programs do not meet evidence-based criteria mainly
because of cost and time constraints.9
Advanced, family-centered preoperative preparation programs

not only are as effective as oral midazolam for preoperative anxiety
reduction but also reduce the incidence of emergence delirium
and analgesics requirements in the recovery area.10
Although the presence of parents at the induction of anesthesia
has become commonplace in some centers, the incidence and
attitude toward it vary widely. In a 1996 survey, 58% of American
anesthesiologists allowed parental presence in fewer than 5% of
cases, whereas 84% of British anesthesiologists allowed parental
presence in more than 75% of cases.11 This discrepancy may be
attributable to the availability of induction rooms and cultural,
anesthetic, medicolegal, economic, and resource-based differences
and not necessarily evidence-based factors. There has been limited
study of factors surrounding this issue. Although the majority of
parents prefer to accompany their children during induction of
anesthesia or minor medical procedures, parental presence is not
always effective.11 Kain and coworkers studied some of these issues
when they divided parents and their children preoperatively into
three groups: a control group, a parental-presence group, and a
premedication group (oral midazolam 0.5 mg/kg).12 The parent
and child in the premedication group demonstrated the least
amount of anxiety at critical points (separation and induction of
anesthesia) during the preoperative period.12 Children were also
found to be calmer if they were older than 4 years, if their temperament had lower levels of activity and impulsivity, or if they
had parental presence.13,14 Parent satisfaction ratings are very
high with parental presence and nearly all parents (>97%) feel they
help their child during induction of anesthesia and judge their
presence during this time as positive. However, some parents
become distraught at the sight of their child at induction. With
the current information available, parental presence at induction
of anesthesia should be considered a therapeutic option but
should be used at the discretion of the attending anesthesiologist
and not the parent.12
The aims of premedication vary among individual anesthesiologists, parents, and children. The goals should include decreased
psychological stress of both patient and parent(s) by allaying
apprehension, uncertainty, fear, or excitement and should facilitate
separation of the child from the parent. Other desirable properties
include a rapid and predictable onset and offset, select amnestic
properties, ease of administration, low cost, facilitation of induction
of anesthesia, analgesic and antiemetic properties and minimal
adverse interactions with other medication, and patient physiology.
The large quantity of literature published on premedication for
children suggests that the ideal agent has yet to be produced.
Generally, the following are accepted indications for premedication:
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TABLE 37-1. Children Who Should Be Carefully
Assessed Before and Monitored After Administration
of Sedative Premedication
1. Children with central or obstructive apnea syndrome.131
2. Children with adenotonsillar hypertrophy.
3. Children with functional macroglossia, for example,
hypertrophy of the tongue (Down syndrome, BeckwithWeideman syndrome) or relative micrognathism (PierreRobin syndrome).
4. Children with neurologic impairment, including
gastroesophageal reflux, dysphagia, or impaired cough.
5. Children with muscular dystrophy.
6. Infants less than 10 kg.
7. Children with cyanotic heart disease (they may become more
cyanotic or develop hypercarbia).
1. Children who have had previous surgical experiences, because
they are generally aware of the discomforts related to the
upcoming surgery.15
2. Children who will not separate from their parents easily.
3. Children for whom the anesthesiologist is of the opinion that
parental presence at the time of induction would not be of
benefit.15
4. Children with neurologic or developmental disabilities and
mental health issues causing behavioral disorders, autism, or
other personality disorders.
5. Children who require a smooth anesthetic induction with
minimal crying or struggling (e.g., children with cyanotic heart
disease).
6. Adolescents who show significant degrees of anxiety.
(Adolescents in particular are often fearful of loss of control,
loss of body image, and dying under anesthesia and may be
quite anxious despite outward attempts of bravado.)
The risks of preoperative premedication include respiratory
depression, loss of protective reflex control, and a paradoxical
response to the drug. The physical status, age, and underlying
surgical pathology may modify the risks. For example, emergency
surgery, a full stomach, head injury, and abdominal trauma may
markedly affect the need for premedication. In a normal healthy
child, these risks are minimal, but when complications arise,
they are usually caused by a relative overdosage. However, some
children who are at increased risk and discretion should be
used with premedication (Table 371). These patients, especially
those with a history of obstructive sleep apnea, require very close
observation after receiving premedication.
Incredibly, there is still no consensus on the benefits of premedication in children, especially infants. That said, a sedated,
cooperative child invariably reduces the anxiety level in those
parents whose own anxiety and fears may be contributing significantly to the preoperative behavior of the child. Parents and
patients, therefore, obtain different potential benefits from premedication. These include amnesia, anxiolysis (patient and parent),
analgesia, and increased cooperation.
SEDATIVE PREMEDICATIONS
Sedative premedication can be administered by various routes that
will determine the doses and the onset times (Table 372). Oral
and rectal routes are most commonly used. Although popular,

the efficacy of drugs administered by these routes is not always
predictable because of marked fluctuations in bioavailability and
a substantial first-pass effect.1519
Oral
Oral is usually the most acceptable route.20,21 Issues of concern
include medication palatability, volume required, onset, duration
of action, behavior during recovery, interaction with other
medications, and side effects.
Midazolam
A large-scale U.S. survey indicated that oral midazolam is the
preoperative sedative of choice for children in 90% of cases.22
A dose of 0.5 mg/kg to a maximum of 15 to 20 mg produces consistent preoperative anxiolysis with a wide margin of safety.23
Increasing the dose above 0.5 mg/kg typically does not enhance
its sedative and anxiolytic effects.24 Infants and children undergoing cardiovascular surgery, however, had decreased agitation
on induction, improved sedation, and increased SpO2 (oxygen
saturation of hemoglobin monitored with pulse oximetry) after
1.5 mg/kg versus 0.5 mg/kg.25
Sedation and anxiolysis can be observed 10 minutes after
administration26 and within 20 minutes in the majority of
children.23 The onset of sedation can be reduced by 4 minutes with
the addition of antacids (sodium citrate) to the oral midazolam.27
The peak effect is seen at 30 minutes, and by 45 minutes, the
incidence of satisfactory separation scores begins to decline.28
Anxiolysis and light sedation can still be present up to 2 hours
after administration.16,29
Awakening times appear to be minimally delayed by midazolam. There is inconsistent evidence that discharge times are
increased by midazolam premedication.28,3033 In a recent review,
it was concluded that oral midazolam reduces both separation
and induction anxiety in healthy children and has minimal effect
on recovery times.34 Given that the sedative, amnestic and anxiolytic properties of midazolam are relatively brief and begin to
wane after 45 to 60 minutes, the timing of its administration is
important. In order to avoid disruptions in the operating room
schedule, the specific timing of premedication administration
should ideally be determined by the anesthesiologist assigned to
the case. If given too early and the child is no longer adequately
sedated on arrival in the operating room, consideration should be
given to repeating the oral midazolam using a reduced dosage
(~0.25 mg/kg) and, if warranted, reorganizing the operating room
schedule to accommodate this.
The major problem with midazolam is its bitter taste, even
when mixed with flavored syrup. The commercially prepared
midazolam syrup, introduced in 1998, has an improved taste and
a lower pH than the intravenous preparation.35 This lowered pH
increases its bioavailability, but the dose may be unpredictable if a
crystalline precipitate is present.36 From time to time, a child may
expectorate an unpalatable oral premedicant. Although an attempt
can be made to repeat the oral dose, this will probably be futile,
and an alternative route of administration should be considered.
In a recent survey of members of the Society for Pediatric Anesthesia in the United States, 45% of the respondents had cancelled
1 or more cases during their career because the child had refused
to take the premedication.37 These rare events affect operating
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TABLE 37-2. Premedicant Drugs

Agent
Route
Dose
Onset, min
Common Adverse Effects
Oral
Nasal
Rectal
Oral
0.30.7 mg/kg (max. 15 mg)

0.10.2 mg/kg (max. 3.010.0 mg)
0.51.0 mg/kg
0.10.3 mg/kg (max. 10 mg)
1530
510
1530
3060
Postoperative excitation
Oral
Nasal
I.M.
Rectal
38 mg/kg
35 mg/kg
25 mg/kg (max. 150 mg)
0.30.5 mg/kg
1015
Secretions
Increased blood pressure
Increased intracranial pressure
Opioids
Morphine
Meperidine
I.M.
I.M.
0.10.2 mg/kg (max. 5.0 mg)

0.51.0 mg/kg (max. 5.0 mg)
1530
1530
Fentanyl (lollipops)
Oral
1015 mg/kg (max. 250 mg)
515
Sufentanil
Nasal
1.53.0 mg/kg (max. 50 mg)
510
Dexmedetomidine
Oral
Rectal
Oral/nasal
24 g/kg
25 g/kg
14 g/kg
Barbiturates
Pentobarbital
Oral
3.0 mg/kg (max. 30 mg)
60
510
Pentothal
Rectal (10%
solution)
Rectal (510%)
510
Prolonged duration
Postoperative excitation
Rectal irritation
Prolonged duration
Others
Melatonin
Oral
0.250.5 mg/kg
3060
None reported
Benzodiazepines
Midazolam
Diazepam
Dissociative
Ketamine
2 Agonists
Clonidine
Methohexital
room efficiency and may have consequences related to delayed

surgery and treatment.
Although midazolam usually provides effective preoperative
anxiolysis, many clinicians are aware that some children still
exhibit significant distress despite premedication. Satisfactory
anxiolysis occurs in 97.5% of children receiving midazolam,
whereas only 86% have a satisfactory anxiety rating at facemask
application.24 There appears to be a subgroup of children that are
midazolam nonresponders. This group tends to be younger,
more anxious preoperatively, and higher on the emotionality
subscale of the EASI (Emotionality, Activity, Sociability, and
Impulsivity) Instrument of Child Temperament.38,39
Midazolam may also have adverse effects postoperatively.
Preoperative oral midazolam has been noted to increase or have
no effect on postoperative emergence delirium or agitation.33,40
The data addressing behavioral outcomes, such as nightmares,
temper tantrums, and bed wetting, in the first few weeks postoperatively are inconsistent.34 Doses exceeding 0.5 mg/kg or
associated with more side effects in the recovery period, including
loss of balance and head control, blurred vision, and dysphoric
25
Excitation
Pruritus
Prolonged duration
Itching
Itching
Prolonged sedation
Transient hypotension and
bradycardia
reactions.40 Abnormal postoperative behavior as the result of a

relative overdose of midazolam can be rapidly reversed with
flumazenil using 10-g/kg increments to a maximum of 1 mg
intravenously.
Midazolam has been compared with other pharmacologic
agents. When compared with oral chloral hydrate, both preoperative and postoperative behaviors were considered better
in the midazolam group.41 Oral midazolam is similar to rectal
methohexital with respect to separation at induction, sedation,
and recovery scores.42 When compared with zolpidem, a shortacting nonbenzodiazepine hypnotic, both provided equally
effective sedation and anxiolysis.43 Oral etomidate 1.3 mg/kg was
compared with midazolam and sedation was similar, but recovery and discharge times after etomidate were decreased.44 Oral
ketamine 5 mg/kg had similar onset time and sedative effect, but
delayed recovery.45 Rectal thiopentone 35 mg/kg led to better
sedation and lower anxiety scores but prolonged recovery times.46
When compared with trimeprazine 2 mg/kg and to diazepamdroperidol both 0.25 mg/kg, sedation and anxiolysis were
improved after midazolam.47
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Fentanyl
Oral transmucosal fentanyl citrate (OTFC or fentanyl lollipop)
is a formulation of fentanyl citrate embedded in a sweetened
matrix that dissolves in a childs mouth. It has been used by some
with success as a premedicant.4851 Fentanyl readily crosses the
mucosal barrier of the oral cavity and peak blood levels are usually
achieved 15 to 30 minutes after sucking is initiated.52 It loses
efficacy and bioavailability when chewed or swallowed. OTFC
was similar to that of an oral solution of meperidine, diazepam,
and atropine.49 Overall, it does not appear to be cost-effective or
beneficial, given its side effects of respiratory depression, pruritus,
and vomiting.48,50,53,54 Some anesthesiologists have ethical concerns
delivering a premedicant sedative in lollipop form.
Ketamine
Oral ketamine is a popular alternative to oral benzodiazepines but
has a high hepatic first-pass effect.55 A dose of 6 mg/kg is well
tolerated and predictably provided sedation by 20 to 25 minutes,
leading to a calm separation from parent and good induction
conditions.56 Oral ketamine was not associated with respiratory
depression, tachycardia, or emergence phenomena,56 but adverse
events (oxygen desaturations, laryngospasm, and hallucinations)
are common.57 Ketamine 5 to 6 mg/kg has also been successfully
administered in lollipop form.58
of compensatory homeostatic reflexes is highly desirable in pediatric anesthesia. Although clonidine can induce hypotension
and bradycardia, no serious adverse effects, such as pronounced
hypotension and bradycardia, have been reported in children
when using doses of clonidine less than 10 g/kg.62
Dexmedetomidine is an imidazole 2 agonist that is similar to
clonidine but with an even higher 2/1 specificity ratio of 1600:1
(compared with clonidine 200:1). Its elimination half-life is 1.5 to
3 hours. Given its unique mechanism of action and limited effects
on cardiorespiratory function, it may offer specific advantages
as a premedicant for oral administration. Data in children are
limited, although preliminary experience suggests that an oral or
transmucosal dose of 1 to 4 g/kg may be a useful alternative.70
Children who received intranasal dexmedetomidine 2 g/kg were
more likely to be asleep before entering the operating than those
who received oral midazolam.71 Both medications were similar in
effectiveness during induction and emergence of anesthesia. Oral
midazolam 0.5 mg/kg, oral clonidine 4 g/kg, or transmucosal
dexmedetomidine 1 g/kg regimens are all comparable in terms of
reducing preoperative anxiety; however, the 2 agonists were
associated with less perioperative sympathetic stimulation and
less postoperative pain.72 Further prospective trials are needed to
more clearly define the effective dose as well as to compare oral
dexmedetomidine with other premedicants.
Melatonin
Pentobarbital
Barbiturates were used for many years as oral premedicants before
the advent of midazolam. Their onset of action is slow and their
duration is long. Pentobarbital 3 mg/kg to a maximum of 30 mg
has an onset time of 1 hour and duration of action of over
6 hours.59 The clear disadvantage is prolonged sedation, restricting
its use to in-patient surgery. Conversely, the long duration of
action ensures that the patient is adequately premedicated for an
extended time period, an advantage in the event that a surgical
case be delayed for any reason.
Melatonin is a hormone involved in the diurnal rhythm of sleep

and is a potentially useful oral natural-sleep agent. The sleepinducing properties of melatonin differ from those of benzodiazepines. It does not suppress rapid eye movement sleep and
does not induce hangover effects. In a recent dose-finding study,
melatonin 0.25 and 0.5 mg/kg orally was as effective as midazolam
in alleviating preoperative anxiety in children and had a tendency
toward faster recovery and a lower incidence of excitement
postoperatively.73 Melatonin, like other premedications, decreased
the induction dose of propofol and thiopental.74
2 Agonists
Nasal
Recently, oral 2 adrenoreceptor agonists, such as clonidine

and dexmedetomidine, have been used as oral premedicants in
children.60 Clonidine provides effective anxiolysis and sedation
with a high degree of parent satisfaction.6065 Oral clonidine in
doses ranging from 1 to 4 g/kg produces postoperative analgesia,
less postoperative vomiting, perioperative hemodynamic stability,
and fewer requirements for intraoperative inhalation agents.
A lower incidence of emergence agitation has been reported in
children premedicated with clonidine.66 When compared with
midazolam, it has a significantly better taste and, thus, minimal
refusal to swallow the drug. Clonidine lacks the psychotropic
quality of benzodiazepines and will cause a state of sedation more
similar to normal tiredness-sleepiness in which the patient can
easily be awoken to perform various tests.67,68 Unfortunately, the
onset is delayed up to 90 minutes and the offset may extend well
into the postanesthetic recovery period. Many anesthesiologists
may be willing to accept its slow onset of sedation if clinical
advantages are provided during the perioperative period. It has
been suggested that it may enhance the antiemetic effect of
propofol after strabismus surgery.69 The ability of 2 agonists to
decrease sympathetic nervous system activity without inhibition
Premedicants administered intranasally include midazolam,

opioids, and ketamine. Side effects, such as respiratory depression,
may develop rapidly with intranasal administration, mandating
that this route should be used only in an environment in which
personnel and equipment are immediately available to intervene
when necessary.
Intranasal premedication can be administered by two
methods:75 intranasal drops or intranasal spray. Accurate dosage
is necessary, and rapid onset is achieved when the nasal route is
used.76,77 However, the patients experience, although short-lived,
is usually unpleasant and may also cause apprehension and
fear.7579 For many, the discomfort associated with intranasal
administration of some medications is similar to that with intramuscular administration.
Several studies have compared intranasal administration of
premedicants. When 100 g/kg intranasal midazolam was compared with 10 g/kg intranasal alfentanil, the sedation was similar
but there was no nasal burning among the children receiving
alfentanil whereas 70% of the midazolam-treated children noted
nasal burning.43 Intranasal sufentanil in a dose of 1.5 to 3 g/kg
was compared with intranasal midazolam 0.1 to 0.3 mg/kg.
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Intranasal midazolam was associated with improved sedation,

higher oxygen saturations, improved chest wall compliance, and
less vomiting.8083
Ketamine is another alternative intranasal premedicant.8486
Effective doses include 3, 4, 6, and 8 mg/kg.8486 When compared
with the combination of intramuscular promethazine and meperidine, intranasal ketamine 6 mg/kg provided better sedation
whereas the recovery patterns were similar.84 When compared
with placebo, the ketamine-treated children were rapidly sedated
(15 min), tolerated the administration well, had easier separation,
and were more cooperative in the operating room. Postanesthetic
recovery and discharge were not delayed.85
Intranasal clonidine has also been studied in children.
Although 4 g/kg produces sedation and anxiolysis, the onset of
clinical effects was significantly slower than with oral clonidine
(i.e., 48 min vs 38 min).71
Rectal
Rectal premedication was perhaps the route of choice for preoperative sedation before the advent of the more predictable
oral regimes.87 Its use varies among individual anesthesiologists,
centers, regions, and countries.1 Mode of administration also
varies markedly. Although rectal administration, using a variety
of agents, has been reported in continental Europe, its popularity
and acceptance elsewhere have been limited.
Methohexital 30 mg/kg is the rectal drug of choice, having a
relatively predictable onset, short duration, and lack of complications.88,89 About 85% of children fall asleep after this dose with
an average onset time of 6 minutes. Of those who do not sleep,
only 4% are not adequately sedated.89 Hiccups (13%) and
defecation (10%) are the most common side effects.89 Oxygen
desaturation and airway obstruction are uncommon, but may be
life-threatening.89 Rectal thiopentone 30 mg/kg has a relatively
predictable onset, but it is associated with more prolonged duration of action.90 Both drugs may produce respiratory depression
and significant rectal mucosal irritation. At the present time, their
use is limited to children younger than 5 years in whom oral
premedication has failed. After administration, all children given
rectal premedicant drugs should be carefully monitored for
respiratory depression. When rectal methohexital was compared
with rectal pentobarbital premedication, the efficacy was similar
but emergence delirium or agitation after pentobarbital was
a concern.91
Ketamine and the benzodiazepines may also be given rectally
to achieve sedation,92 but their effect by this route is less predictable. Midazolam may be given rectally at doses of 0.15 to
5 mg/kg.19,93 The recommended dose to achieve adequate sedation and acceptance of the facemask was 0.35 mg/kg,93 whereas
the 1 mg/kg resulted in effective sedation with negligible effects
on postanesthesia care unit discharge times.94 Beebe and colleagues compared four groups, placebo, rectal midazolam (0.5 mg/
kg), rectal ketamine (3mg/kg), and both midazolam and ketamine.94 The midazolam-treated patients, especially in the combination group, were better sedated, but they had a prolonged
recovery.94 Premedication with rectal midazolam 0.3 mg/kg was
compared with rectal clonidine 5 g/kg in patients undergoing
adenotonsillectomy.67 Immediate postoperative analgesia was
enhanced in the clonidine group; postoperative sedation was
increased for the first 24 hours, which was preferred by a majority
of parents when compared with an alert and ambulating child.67
Rectal clonidine despite a very high bioavailability, a slow time to

peak (52 min), and a long elimination half-life (12.5 h).95
Rectal administration has been compared with other modes of
delivery. Rectal midazolam was compared with oral midazolam.96
Both modes were effective, but rectal administration was much
better tolerated. Rectal administration is not an option in older
children for aesthetic reasons and the large volume required to
deliver the requisite dose.
Intramuscular/Subcutaneous/Biojector
Needle phobia and the increased efficacy of the alternate routes
of administration have reduced intramuscular or subcutaneous
administration of premedicant drugs to those rare circumstances
in which other routes of administration are not possible such as in
the noncompliant combative adolescent, the mentally deranged
patient, or the extremely upset and otherwise unmanageable child.
In this situation, intramuscular ketamine 2 to 10 mg/kg, which
has a relatively rapid onset of 3 to 10 minutes, is useful. The larger
doses may delay recovery.90 When a difficult child refuses the mask
and when intravenous induction of anesthesia is not practical, a
small, 2-mg/kg, sedating dose of intramuscular ketamine has been
shown to be effective.97
Intramuscular midazolam 0.1 to 0.2 mg/kg combined with
intramuscular ketamine 1 to 2 mg/kg in children undergoing
bilateral myringotomies significantly prolonged recovery and
delayed discharge times.98
Historically, a mixture of opioids and an antisialogogue
given intramuscularly has been used Onset was 30 to 60 minutes
and the duration long. These combinations produced anxiolysis,
sedation, amnesia, and analgesia in a predictable fashion.
The biojector jet injection needleless system has been recently
introduced. This device was studied in 40 children who received
midazolam doses ranging from 0.05 to 0.3 mg/kg.99 Sedation was
achievable at doses starting at 0.1 mg/kg, but crying on injection
was common and a major downside of this approach. Complete
patient cooperation is not required and its uses overcome the
problem of children who refuse premedication, expectorate their
premedicant, or expel rectally administered medication.
Sublingual
Although more rapid in onset than oral or rectal administration,
the sublingual route has not gained popularity in the younger
pediatric age groups. It may be suitable, however, for the older,
more inherently cooperative child. Sublingual midazolam induces
more rapid (by 15 min), effective sedation with a dose of at least
0.5 mg/kg.100
Drug Combinations
It is advantageous, where possible, to use only one drug to produce
preoperative sedation. However, no single premedication has
universal acceptance. In those situations in which a previous
premedicant has failed or it is essential that the premedication
is successful, a combination of drugs can be highly effective.
For example, Warner and associates reported a 100% successful
parental separation after midazolam plus ketamine, whereas
midazolam alone was associated with only a 75% success rate at
parental separation.101 They reported a similar improvement in
successful mask induction.
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CHAPTER 37
TABLE 37-3. Combinations of Sedative and Anxiolytic
Premedications Used Prior to Induction of Anesthesia
1. Pentobarbital 3 mg/kg orally 2 h preoperatively, plus
morphine 0.1 mg/kg I.M. 1 h preoperatively, and
scopolamine 0.01 mg/kg I.M. 1 h preoperatively132
2. Ketamine 4 mg/kg plus midazolam 0.4 mg/kg p.o.101
3. Ketamine 3 mg/kg plus midazolam 0.5 mg/kg p.o.133,134
4. Ketamine 2.5 mg/kg plus midazolam 0.25 mg/kg p.o.135
5. Ketamine 12 mg/kg plus midazolam 0.10.2 mg/kg I.M.98
6. Meperidine 1.2 mg/kg, atropine 16 g/kg, and diazepam
120 g/kg p.o.136
7. Ketamine 3 mg/kg plus midazolam 0.5 mg/kg p.o.137
Some medications are not very effective when used solely, but
when combined with other medications, the effect is synergistic
with improved efficacy. The classic combination was the so-called
lytic cocktail, a mixture of pethidine, promethazine, and chlorpromazine.102 Combinations of drugs that have been used with
success are included in Table 373.
Multiple studies have addressed combining oral ketamine and
oral midazolam in smaller than usual doses in order to improve
success and minimize the side effects and improve postanesthesia
care unit discharge times. When compared with either ketamine
or midazolam alone, faster onset time, faster time to maximum
sedation, earlier parental separation, and faster recovery times
were noted when the combination was used.
Combinations may be considered in children who have had a
traumatic experience with their previous surgery or in children
with congenital cyanotic heart disease.
High-risk children have been studied only to a limited extent,
and generally, premedication has been well tolerated and good
results have been obtained.103 Comparing oral 0.5 mg/kg midazolam and atropine with the combination of oral meperidine
3 mg/kg, pentobarbital 4 mg/kg, and atropine resulted in similar
vital signs and onset of action, but there was less sedation in the
midazolam-treated children before cardiac surgery.104 Levine
and coworkers, comparing oral midazolam (0.75 mg/kg) and a
combination of pentobarbitone, morphine, and atropine in
children with cyanotic congenital heart disease,105 found that the
oral midazolam-treated patients did very well and concluded
that oral midazolam was safe and effective and avoided oxygen
desaturations associated with intramuscular injections. When
oral transmucosal fentanyl citrate was compared with the oral
combination of meperidine, diazepam, and atropine, the combination was considered superior to the fentanyl lollipop among
children with congenital heart disease.106
RECOVERY
Recovery from premedication is not always without complication
or additional benefits. Premedication may delay recovery from
anesthesia and discharge from the hospital.28,3032
Studies on the effect of premedication on postoperative
behavior have yielded mixed results. Benefits include improved
quality of sleep the first night after surgery.31,107 McGraw and
Kendrick observed improved behavior oral midazolam but
only preoperatively. In the postoperative period, more of the
midazolam-treated children had behavioral problems such as
night terrors, nightmares, food rejection, fussiness, anxiety, and
negativism.108 A more elaborate study by Kain and colleagues

observed the opposite.109 In their study, postoperative behavior
was better in the midazolam group (0.5 mg/kg) during days 1 to
7 postoperatively. Payne and associates have had results similar
to those of Kain and colleagues, more specifically, midazolam
premedication was associated with a lower incidence of night-time
crying and awakening.107 The likelihood of negative postoperative
behaviors increases if the child is anxious during induction.110
A lower incidence of apathy/withdrawn behavior was observed
after a temazepam or trimeprazine premedication.111 Trimeprazine premedication was associated with less restlessness and
decreased vomiting in the recovery period when compared with
oral lorazepam.112
In summary, children often require premedication before
anesthesia to alleviate patient and parental anxiety, to provide
analgesia and/or amnesia, and to facilitate separation from parents
before induction of anesthesia. The benefits and risks of each drug
should be balanced against to the childs personality, the severity
of disease, the type of surgery, and the monitoring available.
A variety of drugs is available and may be used alone or in combination to achieve the desired response with minimal adverse
effects. In addition, nonpharmacologic approaches are often
beneficial and should be applied where appropriate.
PREOPERATIVE FASTING
Originally, the importance of preoperative fasting was not
appreciated, but after several reports of regurgitation and reflux
of gastric contents, the value of having gastric contents (both
liquid and solid components) at a nadir before anesthesia was
appreciated. The minimal fast was rapidly replaced by an allinclusive, extensive fast. This resulted in a reduction of gastric
contents, but at the cost of a dehydrated, thirsty, hungry, and unhappy patient and distressed parents. In debilitated, chronically
malnourished patients, fasting may also lead to hypoglycemia
and ketosis. It is clearly not desirable to have children, especially
neonates and young infants, undergo a prolonged period of fasting
before general anesthesia
Gastric contents can be split into two constituents: solid and
liquid. Each has a specific gastric-emptying time. Solids empty
from the stomach quite slowly, unaltered by liquids, and follow
zero-order kinetics113 (Table 374). Normally, liquids empty quickly
from the stomach because they follow first-order kinetics.114,115
Isotonic solutions, such as normal saline, do not interact with
duodenum osmotic receptors and rapidly empty from the stomach
(see Table 374). Aqueous solutions containing glucose and proteins do interact with receptors in the duodenum and have gastric
half-lives of approximately 10 minutes.
TABLE 37-4. Gastric Emptying Times for
Healthy Individuals
Gastric Contents
Gastric Half-life
Clear isotonic liquids

Clear liquids containing
protein, lipids, and glucose
Full meal
35 min
10 min
Light snack (e.g., cracker)
Average 8 h to empty; 1030%

remains after 68 h
12 h
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After a routine fast, the volume of gastric contents is not

dependent on ingested food, but rather on the residual from oral
and gastric secretions. These secretions are produced at a rate of
0.4 to 2 mL/kg/h, and the nadir gastric volume present at steady
state varies from patient to patient.
Several large, well-controlled studies of perioperative fasting
were performed after anesthetists became more aware of the
physiology of gastric emptying.116126 Studies in infants, children,
and youths have demonstrated that unlimited, clear, aqueous fluids
may be ingested by healthy patients up to 2 hours before elective
surgery, without increasing residual gastric contents. Investigations
of solid food ingestion are generally inadequate. Gastric emptying
of solid food can be assessed by aspiration plus gastroscopy or
by radiolabeling. Based upon the investigations of the gastric
emptying of small meals, one would expect that a minimal meal
(e.g., a cracker) would require less than 2 hours to be evacuated
from the stomach of a healthy patient. By contrast, a very large
meal would often require approximately 8 hours to empty.
Formula, cows milk, and breast milk represent a conundrum.
Formula and cows milk are generally treated as a solid food,
whereas breast milk is mostly a clear liquid and the solid food
component empties relatively rapidly from the stomach. Thus,
breast milk requires a fast somewhere between a full solid meal
and a clear fluid. One can either empirically fast these children
from breast milk for 4 hours or individualize treatment and follow
the infants feeding pattern (i.e., if the baby feeds by breast every
3 h, then a 3-h fast before elective surgery is appropriate).
Patients with significant debilitating disease undergoing
elective surgery have not been studied extensively. Many of these
patients, including patients with symptomatic heart disease,
gastrointestinal disease, or increased intracranial pressure, have
been noted to delay gastric emptying. The fasting guidelines for
this group of patients should optimally be on an individual basis
or, alternatively, conservative guidelines should be used.
The appropriate duration of the preoperative fast for patients
undergoing emergent and urgent surgery is determined after
assessing many issues, such as the type of food ingested before
and after the injury, time from food ingestion to time of injury,
severity and location of the injury, time from injury to induction of anesthesia, and medication given to the patient after the
injury.127,128
In summary, several preoperative fasting guidelines have been
proposed,123126,129,130 and these guidelines are summarized in Table
375. A 2-hour fast from clear fluids is acceptable for healthy
TABLE 37-5. Recommendations for Preoperative Fast
State
Recommendation
Fluids
Healthy patient
Ill patient
Emergency surgery
Minimum 2 h
Minimum 4 h
Individualized care
Milk
Breast milk
Nonhuman milk
Minimum 4 h
Minimum 6 h
Solids
Elective surgery
Emergency surgery
No solids on day of surgery (minor

deviations need individual care)
Individualized care
children. In practice, it is simpler to extend these guidelines to

3 hours in order to facilitate rescheduling of operations. The solidfood fast should be prolonged when compared with the clear-fluid
fast. The historic no-solids-after-midnight has a proven safety
record and is practical. Similarly, a 4-hour fast for breast milk and
a 6-hour fast for nonhuman milk have a proven safety record and
are easily complied with.
CONCLUSION
There are multiple arguments for and against the use of premedication in children.138 Sedative medications offer proper conditions
to minimize the psychological impact associated with anesthesia
and surgery, although its practice has been largely influenced by
several factors such as cultural beliefs and hospital practices over
time. Furthermore, the nature of expectations and responses for
both parent and child vary greatly in different environments
around the world.138
In contrary, preoperative fasting has evolved considerably over
the years and offers clear guidelines in regards to the optimal
practice in children. This approach has contributed to significantly
reduce the stress associated with long periods of deprivation of
fluids before anesthesia and surgery.
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reduces minimum alveolar concentration of sevoflurane for tracheal
62. Nishina K, Mikawa K, Shiga M, et al. Clonidine in paediatric anaesthesia.
63. Nishina K, Mikawa K, Maekawa N, et al. Oral clonidine premedication
blunts the heart rate response to intravenous atropine in awake children.
64. Nishina K, Mikawa K, Maekawa N, et al. Clonidine decreases the dose of
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65. Reimer EJ, Dunn GS, Montgomery CJ, et al. The effectiveness of clonidine
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66. Constant I, Leport Y, Richard P, et al. Agitation and changes of Bispectral
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67. Bergendahl HT, Lonnqvist PA, Eksborg S, et al. Clonidine versus midazolam as premedication in children undergoing adeno-tonsillectomy: a
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71. Almenrader N, Passariello M, Coccetti B, et al. Steal induction after
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74. Naguib M, Samarkandi AH, Moniem MA, et al. The effects of melatonin
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75. Griffith N, Howell S, Mason DG. Intranasal midazolam for premedication
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81:865869.
76. Davis PJ, Tome JA, McGowan FX, et al. Preanesthetic medication with
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77. Lejus C, Renaudin M, Testa S, et al. Midazolam for premedication in
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78. Karl HW, Rosenberger JL, Larach MG, et al. Transmucosal administration
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nasal and sublingual routes. Anesthesiology. 1993;78:885891.
79. Fishbein M, Lugo RA, Woodland J, et al. Evaluation of intranasal midazolam in children undergoing esophagogastroduodenoscopy. J Pediatr
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80. Henderson JM, Brodsky, DA, Fisher DM, et al.: Pre-induction of anaesthesia in paediatric patients with nasally administered sufentanil.
81. Karl HW, Keifer AT, Rosenberger JL, et al.: Comparison of the safety and
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82. Wilton NCT, Leigh J, Rosen D, et al. Preanesthetic sedation of preschool
children using intranasal midazolam. Anesthesiology. 1988;69:972975.
83. Zedie N, Amory DW, Wagner BKJ, et al. Comparison of intranasal midazolam and sufentanil premedication in pediatric outpatients. Clin
84. Weksler N, Ovadia L, Muati G, et al. Nasal ketamine for paediatric
premedication. Can J Anaesth. 1993;40:119121.
85. Diaz JH. Intranasal ketamine preinduction of paediatric outpatients.
86. Diaz JH, Guarisco JL, Buhrman WC, et al. Intranasal ketamine premedication of infant outpatients: a blinded, controlled study. Anesthesiology. 1993;79:A1140.
87. Goresky GV, Steward DJ: Rectal methohexatone for induction of
anaesthesia in children. Can Anaesth Soc J. 1979;26:213215.
88. Barry CT, Lawson R, Davidson DG. Recovery from methohexitone and
thiopentone. Anaesthesia. 1967;22:228234.
89. Audenhart SM, Montgomery CL, Thompson DE, et al. A prospective
study of rectal methohexital: efficacy and side effects in 648 cases. Anesth
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90. Ryhanen P, Kangas T, Rantakyla S. Premedication for outpatient adenoidectomy: comparison between ketamine and pethidine. Laryngoscope.
1980;90:494500.
91. Christensen PA, Balslev T, Hasellstrom L. Comparison of methohexital
and pentobarbital for premedication in children. Acta Anaesthesiol Scand.
1990;34:478481.
92. Malinovsky J-M, Lejus C, Servin F, et al. Plasma concentrations of
midazolam after I.V., nasal or rectal administration in children. Br J
Anaesth. 1993;70:617620.
93. Saint-Maurice C, Esteve C, Holzer J, et al. Premedication par le midazolam
intrarectal. Recherche de la dose efficace en anesthesie pediatrique. Ann Fr
Anesth Reanim. 1984;3:181184.
94. Beebe DS, Belani KG, Chang P-N, et al. Effectiveness of preoperative
sedation with rectal midazolam, ketamine, or their combination in
young children. Anesth Analg. 1992;75:880884.
95. Lonnqvist PA, Bergendahl HTG, Eksborg S. Pharmacokinetics of
clonidine after rectal administration in children. Anesthesiology. 1994;
81:10971101.
96. Khazin V, Ezra S. Comparison of rectal to intranasal administration of
midazolam for premedication in children. Mil Med. 1995;160:579581.
98. Verghese ST, Hannallah RS, Patel RI, et al. Ketamine and midazolam is
an inappropriate preinduction combination in uncooperative children
undergoing brief ambulatory procedures. Paediatr Anaesth. 2003;13:
228232.
99. Greenberg RS, Maxwell LG, Zahurak M, et al. Preanesthetic medication
of children with midazolam using the biojector jet injector. Anesthesiology. 1995;83:264269.
100. Khalil S, Philbrook L, Rabb M, et al. Sublingual midazolam premedication in children: a dose response study. Paediatr Anaesth. 1998;8:
461465.
101. Warner DL, Cabaret J, Velling D. Ketamine plus midazolam, a most
effective paediatric oral premedicant. Paediatr Anaesth. 1995;5:293295.
102. Laub M, Sjogren P, Holm-Knudsen R, et al. Lytic cocktail in children.
Anaesthesia. 1990;45:110112.
103. Burnett YL. Midazolam preop. effects on sedation, ventilation, and
oxygen saturation in higher risk children. Anesth Analg. 1993;76:S30.
104. Grunwald Z, Froese N, Nicolson SC, et al. Oral midazolam is not an
acceptable preanesthetic medication for children undergoing cardiac
surgery. Anesth Analg. 1994;78:S142.
105. Levine MF, Hartley EJ, MacPherson BA, et al. Oral midazolam
premedication for children with congenital cyanotic heart disease
undergoing cardiac surgery: a comparative study. Can J Anaesth. 1993;
40:934938.
106. Goldstein-Dresner MC, Davis PJ, Kretchman E, et al. Double-blind
comparison of oral transmucosal fentanyl citrate with oral meperidine,
diazepam, and atropine as preanesthetic medication in children with
congenital heart disease. Anesthesiology. 1991;74:2833.
107. Payne KA, Coetzee AR, Mattheyse FJ, et al. Behavioural changes in
children following minor surgeryis premedication beneficial? Acta
Anaesth Belg. 1992;43:173179.
108. McGraw TT, Kendrick A. Oral midazolam premedication and
postoperative behaviour in children. Paediatr Anaesth. 1998;8:117121.
109. Kain ZN, Mayes LC, Wang S-M, et al. Postoperative behavioural outcomes in children. Effects of sedative premedication. Anesthesiology.
1999;90:758765.
110. Kain ZN, Wang SM, Mayes LC, et al. Distress during the induction of
anesthesia and postoperative behavioral outcomes. Anesth Analg.
1999;88:10421047.
111. Padfield NL, Twohig MM, Fraser ACL. Temazepam and trimeprazine
compared with placebo as premedication in children. Br J Anaesth.
1986;58:487493.
112. Peters CG, Brunton JT. Comparative study of lorazepam and trimeprazine
for oral premedication in paediatric anaesthesia. Br J Anaesth. 1982;54:
623628.
113. Moore JG, Christian PE, Coleman RE. Gastric emptying of varying meal
weight and composition in man: evaluation by dual liquid- and solidphase isotopic method. Dig Dis Sci. 1981;26:1622.
114. Minami H, McCallum RW. The physiology and pathophysiology of
gastric emptying in humans. Gastroenterology. 1984;86:15921610.
115. Erskine L, Hunt JN. The gastric emptying of small volumes given in
quick succession. J Physiol. 1981;313:335341.
116. Maltby JR, Lewis P, Martin A, et al. Gastric fluid volume and pH in
elective patients following unrestricted oral fluid until three hours before
surgery. Can J Anaesth. 1991;38:425429.
117. Splinter WM, Schaefer JD. Ingestion of clear fluids is safe for adolescents
up to 3 hours before anaesthesia. Br J Anaesth. 1991;66:4852.
118. Splinter WM, Schaefer JD. Unlimited clear fluid ingestion two hours
before surgery in children does not affect volume or pH of stomach
contents. Anaesth Intensive Care. 1990;18:522526.
119. van der Walt JH, Carter JA. The effect of different preoperative feeding
regimens on plasma glucose and gastric volume and pH in infancy.
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120. Miller BR, Tharp JA, Issacs WB. Gastric residual volume in infants and
children following a 3-hour fast. J Clin Anesth. 1990;2:301305.
121. Phillips S, Hutchison S, Davidson T. Preoperative drinking does not
affect gastric contents. Br J Anaesth. 1993;70:69.
122. van der Walt JH, Foate JA, Murrell et al. A study of preoperative fasting
in infants aged less than three months. Anaesth Intensive Care. 1990;
18:527531.
123. Cot CJ. NPO after midnight for childrena reappraisal. Anesthesiology.
1990;72:589592.
124. Goresky GV, Maltby JR. Fasting guidelines for elective surgical patients.
Can J Anaesth. 1990;37:493495.
125. Miller DC. Why are children starved? Br J Anaesth. 1990;64:409410.
126. Strunin L. How long should patients fast before surgery? Time for new
guidelines. Br J Anaesth. 1993;70:13.
127. Bricker SRW, McLuckie A, Nightingale DA. Gastric aspirates after
trauma in children. Anaesthesia. 1989;44:721724.
128. Schurizek BA, Rybro L, Boggild-Madsen NB, et al. Gastric volume and
pH in children for emergency surgery. Acta Anaesthesiol Scand.
1986;30:404408.
129. Brady M, Kinn S, Ness V, et al. Preoperative fasting for preventing
preoperative complications in children. Cochrane Database Syst Rev.
2009;4:CD005285.
130. The Royal College of Nursing. Perioperative fasting in adults and
children. A national guideline. Available at: Rcn.org.uk/resources/
guidelines Accessed July 2, 2010.
131. Litman R. Airway obstruction after oral midazolam. Anesthesiology.

1996; 85:12171218.
132. Shearer WM: The evolution of premedication. Br J Anaesth. 1960;32:
5462.
133. Funk W, Riedl T, Schickendantz J, et al. Low dose oral ketamine
augments midazolam premedication in paediatric patients. Br J Anaesth.
1998;80:A489.
134. Lin YC, Moynihan RJ, Hackel A. A comparison of oral midazolam,
oral ketamine, and oral midazolam combined with ketamine as
preanesthetic medication for pediatric outpatients. Anesthesiology. 1993;
79:A1177.
135. Ghai B, Grandhe RP, Kumar A, et al. Comparative evaluation of
midazolam and ketamine with midazolam alone as oral premedication.
136. Pywell CA, Hung Y-J, Hagelhout J. Oral midazolam versus meperidine, atropine, and diazepam: a comparison of premedicants
in pediatric outpatients. J Am Assoc Nurs Anesth. 1995;63:124
130.
137. Funk W, Jakob W, Riedl T, et al. Oral preanaesthetic medication for
children: double-blind randomized study of a combination of midazolam and ketamine vs midazolam or ketamine alone. Br J Anaesth.
2000;84:335340.
138. Rosenbaum A, Kain ZN, Larsson P, et al. The place of premedication in
pediatric practice. Paediatr Anaesth. 2009;19:817829.
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Anesthesia Equipment
Francis Veyckemans
INTRODUCTION
Anesthesia providers need to understand the functioning of the
equipment (e.g., breathing system, ventilator) to avoid misuse.
They should also know the specific physiologic and technical
limitations of the monitoring devices in use (e.g., pulse oximetry,
capnography) to avoid incorrect interpretation of the information
provided. These monitors and equipment should be not only
checked before use but also regularly maintained to prevent
dysfunction. Moreover, for the sake of safety, the information
given by a monitor and the functioning of any equipment should
be regularly double-checked using clinical examination of the
patient and information provided by other devices: for example,
auscultation, SpO2 oxygen saturation of hemoglobin monitored
with pulse oximetry), PETCO2 (end-tidal carbon dioxide pressure),
and PIP (peak inspiratory pressure) to ensure that the child is
adequately ventilated by the anesthesia machine.
Last, elementary rules of hygiene should be observed when
manipulating these devices to reduce the risk of contamination
and/or nosocomial infections.
The purpose of this chapter is to give the reader up-to-date
information concerning monitors and equipment used in children during either standard general anesthesia or more complex
procedures. The equipment used to perform regional anesthesia in
pediatric patients is described in Chapters 44 through 51. Many
brands of equipment are quoted as examples, but neither the
author nor the editors have any conflict of interest concerning the
devices described.
For a more detailed description of some equipment, the reader
is invited to read more elaborate reference such as Dorsch and
Dorschs Understanding Anesthesia Equipment, 5th edition, edited
by Dorsch JA and Dorsch SE (Wolters Kluwer, Lippincott Williams
& Wilkins; 2008).
Moreover, in addition to the cart containing the anesthetic

drugs and the equipment needed for airway management and,
intravascular access material as described earlier, the operating
room should be equipped with two smaller carts:
Standard Equipment
TABLE 38-1. Standard Equipment of the Airway Cart
A pediatric operating room should be equipped with
A cart containing all drugs and devices necessary to achieve safe

anesthesia (e.g., vascular access device, airways and tracheal
tubes, anesthetic drugs, and fluids).
An anesthesia ventilator and a manual resuscitator adapted to
the childs size to allow emergency ventilation in case of failure
of the ventilator.
A suction apparatus.
One cart for the equipment to be used to control the airway

(Table 381).
One cart for the equipment to be used to obtain vascular access
(Table 382).
Care should be taken to avoid restocking contaminated

equipment (e.g., a used but not yet disinfected laryngoscope blade)
ORGANIZATION OF THE
OPERATING ROOM1
A monitoring apparatus with at least electrocardiogram (ECG),

SpO2, PETCO2, noninvasive blood pressure (NIBP) monitor, and
a temperature probe.
Means to prevent hypothermia: air-conditioning, an overhead
radiant warmer, a warming mattress, a forced-air and/or a fluidwarming device.
Blankets to cover the childs body during induction and awakening.
At least one infusion pump.
An emergency call button to obtain immediate help in case of need.
A telephone in order to be able to contact the ward or the central laboratory without leaving the room.
Facemask adapted to the childs face.

3 TTs: the size calculated according to the childs age + one
size larger and one size smaller.
1 LMA, according the childs body weight or size (if
overweight): it is either the foreseen airway device or a rescue
in case of unforeseen difficult intubation and/or ventilation.
1 laryngoscope with blades (straight and/or curved) adapted
to the childs size.
1 Magills forceps.
1 malleable stylet or bougie.
1 silicone spray to lubricate the TT.
Cuff pressure-monitoring device if a cuffed TT or a cuffed
supraglottic will be used.
Precut tape or gauze string to fix the TT or LMA.
Lidocaine solution to be sprayed on the childs cords or
lidocaine jelly to be applied on the outer surface of the distal
end of the TT or LMA (optional).
Recipient (e.g., kidney basin) to collect used items and to keep
them separated from clean or sterile equipment.
LMA = laryngeal mask airway; TT = tracheal tube.
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TABLE 38-2. Standard Equipment of the Intravascular
Access Cart
Intravascular cannulas of different sizes.

Alcohol, chlorhexidine, or povidone-iodine (Betadine) swabs
for skin disinfection.
Tourniquet.
Gauze swabs (disinfection, dressing) and tape (dressing).
Special container for sharps disposal.
Small roll (e.g., made with gauze swabs or a roll of tape)
adapted to the size of the childs wrist to stabilize it in
hyperextension to cannulate the radial or ulnar artery.
19-Gauge needles to make a hole in the skin before
intravenous or intra-arterial catheterization (optional).
Syringes filled with well-identified anesthetic drugs (type and
dilution adapted to the individual patient).
on these carts. Proper rules must be followed: for example, the

immediate storage of any contaminated equipment in a dedicated
kidney dish placed on the cart. A functional laryngoscope
should always be available during induction, maintenance,
and recovery whatever the technique used to control the upper
airway.
If a regional anesthesia technique is foreseen, a separate cart
should be used in order to prevent accidental contamination and
avoid errors during injections caused by syringes containing other
medications than local anesthetics.
Special Equipment
Special equipments that cannot be stored in each operating room
because of its cost or size should be available in a special place near
a group of operating rooms, in order to be quickly available in case
of need, including
1. A small operating room automatic laboratory to measure blood
electrolytes, glycemia, and hematocrit.
2. A difficult intubation trolley, with supraglottic airways and a
range of devices that can be used in case of difficult intubation
(see the section Equipment for Difficult Intubation (Except
Supraglottic Airways, later).
3. A cardiac defibrillator with pediatric pads, usually kept in the
operating room for heart surgery.
4. A malignant hyperthermia trolley stocked with dantrolene (see
Chapter 81). For the sake of safety, this equipment should be
checked daily and/or after each use.
5. A refrigerator allowing storage of blood, blood products as well
as ice and iced saline bags must be available.
Anesthetic Records
The anesthesia records must be a legible and complete report of
preoperative evaluation; all accurate events occurring during
induction, maintenance, and recovery; as well as the postanesthesia
care with postoperative orders. Electronic chart recording has
become widely used, ensuring better recording, quality control
evaluations, research, and medicolegal purposes.
The anesthesia record should document all aspects of anesthetic care:
1. Preuse check of the anesthesia equipment, identification of
anesthesiologists and surgeons, time of starting the case.
Anesthesia Equipment 595
2. Notes on airway management (mask, supraglottic airway,

tracheal tube size, quality of intubation), intravascular access
(intravenous [I.V.], intra-arterial, central venous, size of
cannula, number of attempts, and complications), and regional
anesthesia technique.
3. Type of breathing system and/or ventilator used, including
settings (fresh gas flow [FGF], fractional concentration of
oxygen in inspired gas [FIO2], and rate).
4. Drugs, doses, and composition of I.V. fluids administered.
5. Record of vital signs. This is important because it provides
trends of information. Handwritten records are recorded every
5 minutes, which limits the accuracy because it is completed
after the event (e.g., laryngospasm) has occurred. Automated
record-keeping improves accuracy and completeness of the
perioperative data, but it is costly and also records artifacts.
The postanesthesia care chart should include
1. A summary of relevant information regarding the childs health,
procedure performed, drugs and I.V. fluids administered, type
and size of airway used, and intraoperative events.
2. Precise orders for pain management, antiemesis, fluid administration.
3. Records of vital signs, pain and sedation scores, recovery score,
drugs and fluids administered, and any event occurring during
the recovery period.
Precise orders for the ward or ambulatory unit nurses at the
time of discharge must include analgesics, timing of first oral
intake, I.V. fluids rate and composition, antiemetics, among other
things.
Maintenance of Equipment
All equipment should be checked regularly (between cases, e.g.,
laryngoscope, suction) or at the beginning of the procedure (e.g.,
anesthesia machine; Table 383) and maintained according to the
TABLE 38-3. Main Points of the Anesthetic
Pre-Use Checklist
1. Emergency ventilation equipment (e.g., Ambu bag)
available and functioning.
2. Central and cylinder O2, air, and N2O supplies: present and
correctly connected.
3. Functioning of the flowmeters and of the emergency O2
bypass.
4. Vaporizer(s): filling level, connection, filler cap closed.
5. Electrical supply to the anesthesia machine and monitors:
switch on.
6. Calibration of FIo2 monitor.
7. Calibration of all monitoring devices (e.g., PETCO2).
8. CO2 absorbent: color, freshness, and humidity.
9. Leak test of the anesthesia machine and breathing system,
including the low-pressure system.
10. Scavenging system: correct assembly and functioning,
absence of obstruction.
11. Correct functioning of the anesthesia machine and
breathing system in the controlled ventilation mode (to be
adapted to the particular ventilator/breathing system used).
12. Correct functioning of the suction apparatus.
FIo2 = fractional concentration of oxygen in inspired gas; PETCO2 = end-tidal CO2.
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manufacturers specifications. Moreover, proper documentation

of regular inspections and repairs is important for both safety and
medicolegal reasons.
Hygiene
The operating room is a zone at high risk for nosocomial infection,
especially for more susceptible patients such as neonates or
immunocompromised (posttransplant, cancer, HIV) and members
of the health care team. Guidelines must be used to ensure proper
hygienic principles in daily practice.
Hands should be washed before starting a new case, performing invasive procedures and manipulating blood, body fluids,
secretions, contaminated items, and other situations whether or
not gloves are worn. Alcoholic handwashing solutions must be
available in the operating room. Anesthesiologists should wear
gloves when handling equipment that has been or will come in
contact with the patients blood, saliva, or secretions. These gloves
should be removed before handling other items (e.g., ventilator,
monitors, drugs) in order to minimize contamination. Work surfaces (anesthesia machine, carts, trolley, operating room table)
should be cleaned with a detergent between cases, and any blood
or other secretions spills should be wiped up as soon as possible.
It is important to separate all used equipment from those that are
still sterile or clean. The most efficient way to achieve this is to
establish a routine whereby used equipment is placed in a special
receptacle (e.g., a kidney basin) physically separate from the
clean area.
The recommended cleaning or disinfection methods are
described for each equipment.
PREPARATION OF THE
OPERATING ROOM
As a rule, everything must be ready for use before the child enters
the operating room:
Adequate equipment for airway and intravascular access.

Drugs appropriate to the childs size (see Tables 381 and
382).
The anesthetic machine, breathing system, and monitoring have
been checked using a checklist (see Table 383). However, local
modifications of these checklists are sometimes necessary to
adapt to specific types of equipment: for example, the test to detect a leak in the low-pressure part (i.e., the vaporizer and its
connections) should be adapted to the design of the anesthesia
machine.2 The full checklist should be completed daily before
starting the first anesthesia, and an abbreviated form of it should
also be used between cases in order to verify the parts of equipment that have been changed.
The operating room is adequately warmed, and equipment
used to prevent the occurrence of accidental hypothermia during induction of anesthesia must be functional and turned on.
MONITORING
Monitoring devices are used in anesthesia to detect deviations
from normal values and unexpected life-threatening events
(safety monitors) and to help maintain proper anesthetic care
(management monitors).
Clinical Observation
Whatever the accuracy and sensitivity of the monitoring in use,
there is no substitute for the continuous presence of a well-trained
and vigilant anesthesiologist. Interpretation of the numbers and
curves displayed on the screen must be assessed in accordance
with the childs physical status and in function of the interfering
events. Physical signs not provided by the monitoring equipment are
Signs of pending airway obstruction: retractions, paradoxical

chest and abdominal wall movement, stridor that most often
precedes any physiologic value changes on the monitor.
Eyes (size of pupils, divergence of gaze, lacrimation) to estimate
the depth of anesthesia.
Capillary refill time to evaluate the childs peripheral circulation
and intravascular volume.
Color, temperature, and dryness of the skin and mucosa.
Palpation of a peripheral pulse, the strength of which may
change despite sustained normal invasive blood pressure (BP)
measurements.
Pulsatility of the mesenteric vessels provide a qualitative assessment of splanchnic perfusion during laparotomy.
Palpation of the fontanelle in the neonate and small infant to
estimate the patients volemia or intracranial pressure.
Volume and color of urine during bladder catheterization.
Knowing the stage of the procedure undertaken and observing

the surgical field are also important because these may explain
major hemodynamic changes that may be anticipated or rapidly
reversed: for example, bradycardia caused by traction on the
extraocular muscles during strabismus surgery, or systemic
hypotension caused by compression of the inferior vena cava
during major abdominal surgery.
Stethoscope
The use of a stethoscope, whether precordial or esophageal,
is a cheap, safe, and continuous way to easily monitor circulation and ventilation. Chest auscultation allows confirmation of
tracheal intubation (except in the premature infant and small
infant in whom it must be correlated with chest expansion), the
diagnosis of cardiac (murmur, air emboli) or pulmonary (bronchospasm, bronchial intubation) pathologies, and the assessment of heart rate and sounds. Although 35% of British pediatric
anesthesiologists never use a precordial or esophageal stethoscope
in their practice because they feel that its role has been superseded
by other monitors,3 this is not the opinion of the main author of
this book.
Indications
In addition to its use for cardiopulmonary auscultation, a
stethoscope is useful at the beginning of an inhalation induction
because it is quick and easy to place and does not frighten the
child; during patient transport, when other portable monitors
are unavailable or may fail; or to monitor ventilation in awake
neonates undergoing locoregional anesthesia.
Limits
However, in clinical practice, the accuracy of the information
given by either a precordial or an esophageal stethoscope is often
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limited because (1) changes in heart rate are quantitative: whether
it increases or decreases, an ECG trace is necessary to know the
exact cardiac rhythm present; (2) changes in heart sounds may
occur rapidly during inhalation induction with halothane,4 but
can be difficult to hear or interpret in the noisy environment
of the operating room; and (3) it always depends on the level of
attention of the anesthesiologist, which may vary during long
procedures.
Precordial Stethoscope
In order to monitor both ventilation and circulation, the precordial stethoscope should be positioned over the left sternal
border, at the second or third intercostal space. However, it must
be displaced to distinguish between esophageal, tracheal, or
bronchial intubation. The chest piece can be fixed to the skin with
a piece of tape or an adhesive ring (e.g., Double-Stick disks).
Esophageal Stethoscope
The esophageal stethoscope should be used in patients only
when the trachea is intubated. It consists of a disposable soft
catheter with holes in its distal 2 to 3 cm. These holes are covered
with a cuff. More sophisticated models have been designed in
which a thermistor or an ECG lead is incorporated. It is positioned
in the mid-esophagus, where breath and heart sounds are best
transmitted and of maximum intensity.
An esophageal stethoscope should not be used in case of
esophageal atresia; neck dissection because it may confer a firmer
feel to the esophagus that might then be mistaken for the trachea;
laser surgery of the airway because of its inflammability.
Complications have occasionally been reported when using
an esophageal stethoscope: esophageal burns caused by current
leakage in esophageal stethoscopes incorporating an ECG or
temperature lead; airway obstruction following insertion of
the esophageal stethoscope into the trachea, beside the tracheal
tube5; and hypoxemia owing to compression of aortopulmonary
collateral vessels in an infant with complex cyanotic heart disease.6
Electrocardiography
Goal and Limits
Electrocardiography is the most accurate method to measure heart
rate and diagnose dysrhythmias. However, it may give a false sense
of security, especially in neonates and infants, because a normal
ECG may still be present in spite of a significant fall of cardiac
output particularly when halothane is used.7 Therefore, an ECG is
not a substitute for other monitors of tissue perfusion and BP such
as a stethoscope, palpation of a peripheral pulse, pulse oximetry,

and BP measurement.
Description
The normal pediatric ECG tracing changes with age and shows
several differences from the adult: as a rule, heart rate decreases
whereas the intervals (PR, QT) and duration (QRS) increase with
increasing age. The right ventricle predominates in early infancy
owing to the dominant right ventricular mass, and the T-wave is
larger in infants because the electrodes are closer to the heart. This
larger T-wave can lead to erroneous double-counting of the heart
rate if both QRS and T are interpreted as a cardiac complex by the
monitor. The presence of an adjustable gain on the cardiac
monitor is useful to eliminate this artifact. Lead II gives the best
P-wave configuration and is, therefore, most useful to diagnose
rhythm abnormalities. Cardiac dysrhythmias are rare in children,
their occurrence should always alert the anesthesiologist who
should rule out:
Hypoxia (bradycardia) and/or hypercapnia (atrial or ventricular ectopics).

Too light anesthesia (bradycardia, tachycardia).
An overdose of halogenated agents (nodal rhythm) or local
anesthetic.
An unsuspected intracardiac conduction defect (e.g., WolffParkinson-White or long Q-T syndrome).
A malignant hyperthermia crisis or rhabdomyolysis (ventricular ectopics, asystole).
Conversely, it is very important to note that potentially

dangerous levels of hypercapnia or hypoxia can be achieved without being accompanied with dysrhythmias until cardiovascular
collapse occurs!
Indications
An ECG monitoring should be used for every pediatric anesthesia
in order to provide a beat-to-beat measurement of heart rate and
to allow for the immediate diagnosis of any dysrhythmia. The
analysis of the ECG signal can give useful clinical information
such as
Prominent T-wave and ST-segment changes in case of accidental I.V. injection of an epinephrine-containing local anesthetic
solution8 (Figure 381).
Prominent T-waves in case of hyperkalemia caused by
rhabdomyolysis after the administration of succinylcholine
and/or halogenated agents in children with unsuspected dystrophinopathy (e.g., Duchennes muscular dystrophy) or susceptibility to malignant hyperthermia (see Chapter 81), by
Figure 38-1. Modification of the electrocardiogram (ECG; huge T-wave) following accidental administration of 0.10.2 mL/kg of
levobupivacaine with epinephrine 1/400,000 during performance of a caudal block in a 4-kg baby under sevoflurane anesthesia
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TABLE 38-4. Practical Aspects of Intraoperative

Electrocardiography in Children
1. Snap the electrodes on the leads before applying them on the
childs skin.
2. In small infants, use small, flexible, and adhesive electrodes.
3. In small infants, place the electrodes on the proximal part of
the limbs in order to lessen the baseline drift caused by the
movements of the thorax.
4. Do not apply electrodes on the nipples.
5. Check the path of the electrocardiographic leads to make
sure there is no risk of pressure necrosis.
6. Adjust the gain of the monitor in order to obtain an easily
interpretable tracing (P-wave) and to avoid double-counting
of QRS and T.
massive transfusion, or occurring at the time of reperfusion during organ transplantation.

ST segment changes in case of cardiac ischemia caused by insufficient coronary perfusion9,10 or myocardial hypertrophy
(e.g., glycogenesis II, mucopolysaccharidosis).
A prolonged QT interval in case of hypocalcemia.
Practical points concerning the application of ECG electrodes

are given in Table 384.
Artifacts
The large number of electrical equipments in the operating
room and pediatric intensive care unit (PICU) increases the risk
of interference with the ECG. To name few, possible sources of
artifacts are evoked potentials monitoring, electrostimulation,
hemodialysis machine, high-frequency oscillation (HFO), magnetic resonance imaging (MRI), electrical current leakage from
fluid administration or warming devices, and extracorporeal
shock wave lithotrypsy. These artifacts can mimic supraventricular
or ventricular arrhythmia and must be confirmed using clinical
examination (a palpable pulse), comparison with the information
from other monitoring devices (e.g., SpO2), and the on-off test
of the suspected cause of artifact.11
Pulse Oximetry
Goal and Indication
Continuous pulse oximetry gives a beat-to-beat measurement of
the oxygen saturation of hemoglobin, a physiologic criterion that
is difficult to evaluate clinically because cyanosis is a late and not
a reliable sign of hypoxemia. It should be used whenever a patient
undergoes anesthesia or sedation. However, situations exist in
which pulse oximetry may give misleading or inaccurate information; its basic principles must, therefore, be understood to
correctly interpret the readings displayed.
Description
Briefly, pulse oximetry measures the absorption of two wavelengths of light (660 and 940 nm) between a light source and a
photodetector. The pulsatile expansion of the arteriolar bed
interposed between the source and the detector produces a pulseadded increase in the path length of the light beam and, thus, an
increase of its absorbance. Because only two wavelengths are used,
pulse oximeters can measure only two forms of hemoglobin that,

according to the absorption spectra of those wavelengths, are
oxyhemoglobin (HbO2) and deoxyhemoglobin (Hb). At each
wavelength, both the nonpulsatile and the pulse-added absorbance are measured and allow the calculation of a ratio, R, that has
been empirically related to oxygen saturation (SaO2) measured in
arterial blood of healthy nonsmoking adult volunteers: a ratio
of 1 corresponds to an SpO2 of 85%. Good functioning of all pulse
oximeters is, therefore, based on the two assumptions that
1. The only pulsatile absorbance present is that of arterial blood.
2. The patient has normal hemoglobin A and no dyshemoglobins
in his or her blood.
Pulse oximeters measure what is called functional saturation (i.e., HbO2/HbO2 + Hb). By contrast, the co-oximeters used in
the blood gas laboratory use more wavelengths of light and are,
thus, able to measure all sorts of hemoglobin present in the patients
blood. They measure what is called fractional saturation, HbO2/
HbO2 + Hb + dysHb, where dysHb mainly represents carboxy(COHb) and methemoglobin (MetHb).The normal percentage of
dyshemoglobin is less than 2%. The most recent pulse oximeters
(e.g., Rad-57 by Masimo) uses up to 12 wavelengths of light and
are able to measure both SpCO (very close to COHb), SpMet (close
to MetHb) and even SpHb (total Hb).12 Their availability will
improve the noninvasive diagnosis and management of CO
poisoning (acute burns), methemoglobinemia,13 and anemia. It
should, however, be kept in mind that, despite that major technologic progress, SpO2 readings from those 8- to 12-wavelengths
pulse oximeters are still obtained according to the classic
2-wavelengths algorithm and, therefore, subject to the same errors
as described under Physiologic Limitations, later: interpreting
SpO2 taking into account SpCO and SpMet is mandatory.12 The
mean difference (error) between SpO2 and HbO2 measured by a
co-oximeter is called bias, whereas the standard deviation of this
difference is called precision. Although most manufacturers claim
that their pulse oximeter is accurate to within 3% of the line of
identity between SpO2 and HbO2, bias and precision values are
often greater. A monitor integrating in the same low-pressure ear
probe a pulse oximeter and a transcutaneous CO2 Severinghaus
electrode (see Special Monitoring, later) (e.g., Tosca) can be used
in children, even neonates14 (Figure 382).
A technology similar to classic or transmission pulse goniometry is called reflectance or surface sensor goniometry. The
source of multiple wavelengths of red and infrared light is placed
beside and very close to the detector, which measures light that
is reflected from the underlying tissues to determine HbO2.
Nonhomogeneity of the optical path between emission and
measurement, as well as the rather weak signal reflected, limits
the precision of the measure. The underlying tissue must be
well perfused to avoid loss of the signal. The probe is flat and
can be placed on flat surfaces such as the forehead or small infant
chest or cheek. The skin of the lower forehead, just above the
eyebrows, is a good location because its blood supply comes
from the supraorbital artery and this area is less sensitive to
vasoconstrictive stimuli such as cold. The results of transmission
and surface pulse oximetry are usually similar but care must be
taken to avoid placing the probe over a vein or artery. The same
technology is used in a miniature pediatric esophageal pulse
oximetry probe that has been successfully tested in a few patients.15
Near-infrared spectroscopy is an optical technology that measures
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CHAPTER 38
Figure 38-2. A: Combined SpO2 (oxygen saturation of hemoglobin monitored with pulse oximetry) and PtcCO2 (transcutaneous
partial pressure of carbon dioxide) sensor (Tosca) placed at the right ear of a 2.4-kg prematurely born infant undergoing laser therapy for retinopathy of prematurity under sedation. A small catheter is also inserted in the nasal O2 prongs to obtain a capnogram
and check upper airway patency. B: Monitor shows the measured values.
tissue oxygenation and is described under Neurophysiologic
Monitoring, later.
Physiologic Limitations
The first limitation of pulse oximetry is linked to the sigmoid
shape of the HbO2 dissociation curve, which plateaus once arterial
oxygen pressure (PaO2) is greater than 80 mmHg. Pulse oximetry
is, therefore, not a monitor of hyperoxia because, above that level,
important changes in PaO2 may occur with only small changes
in HbO2 (Table 385). In the same way, SpO2 can be used as an
indirect monitor of ventilation (e.g., in the postoperative period)
only if the patient is breathing room air. In case of hypoventilation,
arterial carbon dioxide pressure (PaCO2) and alveolar carbon
dioxide pressure (PACO2) rise and, according to the alveolar
gas equation, PAO2 and thus PaO2 fall, leading to hemoglobin
desaturation. However, in the presence of an increased FIO2, N2 is
washed out and PAO2 will rise even if PACO2 increases and the
monitoring of SpO2 will fail to detect hypoventilation until it is
very severe.16
Fetal hemoglobin (HbF) constitutes 50 to 80% of total
hemoglobin at birth and decreases to adult levels after 5 months
of age. The absorption spectra of HbF and adult hemoglobin
(HbA) are very close and the presence of HbF, therefore, does not
interfere with SpO2 measurement. However, the HbFO2
dissociation curve is shifted to the left, which means that, for a
similar SpO2 reading, the actual PaO2 is lower. Moreover, a COHb
level higher than 2 to 3% may be present during the first week of
life because of physiologic hemolysis. This also interferes with the
measurement of SpO2. The combination of a variable percentage
of HbF, the leftward shift of its oxyhemoglobin dissociation curve,
and the possible presence of COHb do not support the statement
that, in preterm infants, it is safe to maintain SpO2 below 95%17 or
93%18 to avoid hyperoxemia and prevent the development of
retinopathy of prematurity. Although those upper limits of SpO2
will indeed identify the majority of episodes of hyperoxemia, SpO2
readings in the normal range can also be associated with a very
low PaO2 in that population. Intermittent comparison of SpO2
TABLE 38-5. Physiologic Limitations of Pulse Oximetry

1. Oxyhemoglobin dissociation curve
Plateau poor monitoring of hyperoxia
poor monitoring of hypoventilation once supplemental
O2 is given
HbF, beta-thalassemia shift to the left: lower PaO for
2
same SpO2!
Acidosis, HbSS shift to the right
2. Abnormal absorption spectrum of hemoglobin: extremely
rare, e.g., Hb Kln, Hb Milwaukee
3. Anemia: no problem as long as Hb > 5 g/dL
4. Presence of dyshemoglobin
COHb: overestimation of SpO by an amount close to
2
COHb %
MetHb: if < 20%, SpO decreases by about half of MetHb %
2
If > 20%, SpO = 85%
2
5. Reduced perfusion
Hypothermia: no problem if core temperature > 30C
Hypovolemia:
Increased variability of plethysmogram with IPPV
(see text)
Loss of signal (but presence of signal adequate
perfusion!)
6. Dyes
Bilirubin: no influence except if acute hemolysis ( COHb)
Nail polish: effect variable position probe sideways
Meconium staining of the skin: possible falsely low SpO
2
Intravenous methylene blue, indigo carmine, indocyanine
green: short-lived low SpO2
Subcutaneous Isosulfan or patent blue: progressive
spurious decrease in SpO2
7. Venous pulsations: e.g., tricuspid regurgitation: falsely low
SpO2
COHb = carboxyhemoglobin; Hb = hemoglobin; HbSS = hemoglobin SS; IPPV =
intermittent positive-pressure ventilation; MetHb = methemoglobin; PaO2 =
arterial oxygen pressure; SpO2 = percutaneous oxygen hemoglobin saturation as
read with a pulse oximeter.
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with arterial PaO2 and HbO2, or measurements of transcutaneous

arterial oxygen pressure (PtCO2) are safer to avoid hyperoxemia.
One should be cautious when comparing SpO2 with the HbO2
measured by a co-oximeter because part of HbF is measured as
COHb by some co-oximeters. To avoid this pitfall, the laboratory
should be informed of the presence of HbF in the blood sample in
order to use an algorithm compensating for it. Lastly, when
comparing SpO2 and HbO2 in neonates and infants, it is important
to check whether the measurements are made on the same side of
the ductus arteriosus. If not, the discrepancy could be caused by
right-to-left shunting at the ductal level.
In case of shift to the right of the oxyhemoglobin dissociation
curve (increased 2,3-diphosphoglycerate [2,3DPG] levels as
during infancy to compensate for so-called physiologic anemia,
hemoglobin SS (HbSS), acidosis, hyperthermia, or other problems),
the PaO2 that can be inferred from SpO2 is higher than usual.
Some hemoglobins have an abnormal absorption spectrum,
and pulse oximeter readings are affected in these cases.19 The
presence of anemia does not interfere with pulse oximetry as long
as the total hemoglobin level is greater than 5g/dL, but it should be
borne in mind that a normal SpO2 does not reflect the patients
O2-carrying capacity.
COHb levels in excess of 2% are present in cases of CO
poisoning (e.g., victims of flame burns) and of acute hemolysis
because the metabolism of hemoglobin produces equimolar
amounts of bilirubin and CO. COHb is read by pulse oximeters
as if it was HbO2, and SpO2 is, therefore, overestimated by an
amount close to but usually somewhat less than the percentage of
HbCO.12
MetHb, whether congenital (e.g., HbM Boston) or acquired, is
a rarer cause of dysfunction of pulse oximetry. MetHb strongly
absorbs light at both wavelengths used to measure SpO2 and its
influence is, therefore, concentration-dependent: if less than
20% MetHb is present, the SpO2 is decreased by about half the
percentage of MetHb; if more than 20% MetHb is present, SpO2 is
85% regardless of the actual HbO2 because the absorption ratio is
equal to 1.12 However, in case of Hemoglobin M (Milwaukee), in
which methemoglobin level ranges between 15 and 30%, pulse

oximetry is unreliable because this hemoglobin has a decreased
oxygen affinity.20
Reduced peripheral perfusion affects the performance of pulse
oximetry. Although the disappearance of the plethysmographic
signal is a sign of poor peripheral perfusion, the presence of an
oximeter waveform and the measurement of an SpO2 do not imply
adequate tissue blood flow. Conversely, when using a pulse
oximeter that does not automatically normalize the gain of its
plethysmographic display, increased variation of the peaks of the
pulse waveform and/or intermittent dysfunction of the pulse
oximeter during positive-pressure ventilation is a sign of hypovolemia (Figure 383).21 In adults undergoing volume-controlled
ventilation in the operating room or intensive care unit, respiratory variations in pulse oximeter waveform (i.e., variations in
local blood volume) can be used to evaluate ventilation-induced
cyclic changes in left ventricular stroke volume and thus preload
and predict responsiveness to fluid loading in case of hypotension.
The latest models of pulse oximeters (e.g., Masimo Radical 7)
provide the automatic and continuous measurement of the
dynamic changes in perfusion index during a complete respirator
cycle: this is called the plethysmography variation index (PVI). It is
calculated from
[PImax PImin/PImax] 100
where PI is the perfusion index. For each PI calculation, the
variable amount of light absorption of the infrared signal (AC) is
indexed against its constant nonpulsatile absorption (CD) and
expressed as a percentage:
PI = AC/DC 100
For PVI, a threshold value of 11.5 to14% has been proposed in
adults, but it should be interpreted with caution because changes
in vasomotor tone or the use of vasoconstricting agents could
affect it.21 Moreover, interpretation of PVI should take into
account that tidal volume (VT), level of positive end-expiratory
pressure (PEEP), and respiratory rate modify ventilation-induced
Figure 38-3. Simultaneous variations

of the plethysmographic waveform of
the pulse oximeter (lower tracing) and
the invasive arterial blood pressure
(radial artery, upper tracing) during
controlled ventilation in an infant with
moderate hypovolemia.
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cyclic changes in left ventricular stroke volume. The use of PVI
to evaluate fluid responsiveness is still under investigation in
pediatric animal models.22
In dark-skinned patients, pulse oximeters tend to overestimate
HbO2 in case of hypoxia.23 In case of hypothermia, SpO2 underestimates HbO2 when core temperature becomes less than 30C.
Because its absorption spectrum peaks below 600 nm, bilirubin
has no effect on the measurement of SpO2.24 However, in case of
hemolytic jaundice, the presence of high levels of COHb interferes
with SpO2 measurement. Moreover, the presence of bilirubin levels
greater than 20 mg/dL affects the good functioning of some
co-oximeters.24 In these cases, the laboratory should be informed
of the presence of hyperbilirubinemia in order to correct the
co-oximeter readings accordingly. Otherwise, spuriously high
levels of COHb and MetHb will be reported.
Although nail polish should theoretically have no influence
on pulse oximetry because its absorbance is continuous and
nonpulsatile, some colored nail polishes cause an underestimation
of saturation. It is recommended to place the oximeter probe
sideways on the finger if colored nail polish is present.
In the same way, meconium staining of the neonates skin could
produce low SpO2 readings.25 Because of their light absorption
characteristics, the I.V. injection of dyes such as methylene blue,
indigo carmine, indocyanine green, or fluorescein causes erroneously low SpO2 readings. Fortunately, because of the rapid
dilution and distribution of the dye in the body, this effect is very
short-lived. A blood sample for in vitro measurement should
not be taken within a few minutes of the injection because cooximeters are subjected to the same interference. In the same
way, the subcutaneous injection of isosulfan blue or patent blue
(to map pathologic lymph nodes or lymphatic vessels) produces a
progressive decrease in SpO2 during 5 to 40 minutes and a falsely
elevated methemoglobinemia on co-oximetry. PaO2 should be
checked if there is any doubt about the patients oxygenation.26
The presence of venous pulsations, such as in case of tricuspid
regurgitation, produces falsely low SpO2 readings. Unfortunately,
the degree of interference cannot be predicted from the peak
central venous pressure (CVP) value measured.27
Technical Limitations
Before an SpO2 reading is interpreted, the quality of the signal
received by the probe should be confirmed by a good plethysmographic waveform and/or a heart rate similar to the one
measured with the ECG (Table 386). Moreover, the measured
SpO2 is only as accurate as the empirical calibration curve included
in the pulse oximeter software. There are small differences
between the measurements obtained with different brands of pulse
oximeters. All pulse oximeters become more inaccurate when
HbO2 is lower than 75 to 80%.
The response time to both desaturation and resaturation also
varies according to the brand of the pulse oximeter and to the site
of measurement. In children as in adults, both saturation and
desaturation are detected 50 to 60% earlier by sensors placed
centrally (ear, cheek, and tongue) than in those placed peripherally
(finger, toe).28 The response time also depends on the averaging
time used in the pulse oximeter. The shortest one should be
selected, although this usually increases the sensitivity to motion
artifact.
The performance of pulse oximeters is affected by motion. To
reduce motion artifact, which is the most common cause of failure
TABLE 38-6. Technical Limitations of Pulse Oximetry

1. Calibration and accuracy
Quality of the signal: waveform and/or heart rate similar
to ECG
Inaccuracy increases when SaO < 80% (e.g., cyanotic
2
congenital heart disease)
2. Delay of response
Response time faster if probe centrally placed
Depends on averaging time chosen
3. Motion artifact
4. Interference of other light sources
Fluctuating light sources: shield the probe
Neuronavigation: shield the probe with aluminum foil
Incorrectly placed probe (optical shunt): visual control of
the probe
5. Electrical or magnetic interferences
ECG = electrocardiogram; SaO2 = arterial oxygen saturation.
or false alarm in awake patients, several brands of pulse oximeters

are equipped with new algorithms canceling the noise signal that
is common to both wavelengths and improving detection of true
hypoxemic events.29
Ambient light should have no influence because it is measured
when the light-emitting diodes in the probe are off and its effect
is subtracted during light transmission by the probe. However,
fluctuating light sources such as fluorescent or xenon lights
can cause problems because they are flickering at frequencies
similar to the harmonics of the light-emitting diodes. The probe
should be shielded with cloth or opaque material. The infrared
pulse waves of the frameless stereotactic neurosurgical positioning systems (neuronavigation) reduce the accuracy of pulse
oximetry. This can be prevented by shielding the probe with
aluminum foil.30
A more insidious cause of error is malpositioning of the probe.
This produces an optical shunt or penumbra effect because part of
the light is transmitted without any tissue absorption. This is more
likely in children in whom too large a probe is used. Barker and
coworkers tested the response to hypoxemia of different brands
of pulse oximeters with probes malpositioned in such a way that
heart rate measurement was still correct and that no error message
was displayed on the monitor screen.31 The results varied greatly
depending on the actual HbO2, brand, and model. They concluded
that, to prevent this potential cause of error, the probe in use
should always be visible to the user.
Electrocautery is another annoying cause of failure of pulse
oximetry. When using pulse oximetry in the MRI suite, care
should be taken to use specially designed equipment in order to
avoid interference with SpO2 measurement and/or imaging or
even skin burns.32
Possible Complications
Skin burns have been reported when using probes during MRI,32
either probes with small defects or probes from another brand of
oximeter.33 Burns are also reported during perioperative photodynamic chemotherapy owing to photosensitivity to red light. In
this situation, the probe should be used for only few minutes and
at rotating sites.34
Pressure necrosis can also occur if the probe is left in place on
a single site for a long period of time, especially during hypo-
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TABLE 38-7. Rules for the Optimal Use of Pulse Oximetry

1. Verify probe integrity before use.
2. Avoid mixing of probes and monitors of different brands.
3. Do not use clip-on ear probe on the extremities of children
< 10 kg (risk of pressure necrosis).
4. Check the quality of the signal received by the probe
Good waveform and heart rate similar to ECG monitor.
5. Direct visual control of probe position.
6. Remember pulse oximeter measures SpO2 not PaO2.
7. In case of doubt: check the patients condition before blaming
the equipment.
8. In case of control with arterial blood gases: inform the
laboratory if
Presence of HbF.
Presence of bilirubin levels > 20 mg/dL.
ECG = electrocardiogram; HbF = fetal hemoglobin; PaO2 = arterial oxygen
pressure; SaO2 = arterial oxygen saturation; SpO2 = percutaneous oxygen
hemoglobin saturation as read with a pulse oximeter.
thermia. The probe should be checked frequently and changed if

necessary during long-lasting procedures. Cliplike ear probes
should not be used in children weighing less than 10 kg because
the pressure applied to the skin is excessive and often exceeds the
infants mean arterial pressure, resulting in the loss of signal, often
simulating desaturation.35 Proper rules when using pulse oximetry
are summarized in Table 387.
Respiratory Gas Monitoring

The measurement of inspired and expired O2, CO2, and volatile
agent concentration enables the anesthesiologist to continuously
check the good functioning of the ventilatory equipment and
evaluate noninvasively the adequacy of the patients ventilation
(PETCO2).
Capnography
Carbon dioxide monitoring measures breath-to-breath partial
pressure of inspired and expired CO2. Capnometry is the measurement of CO2 partial pressure and capnography is the continuous
graphic display of this measurement. If the graphic display is
calibrated, capnography includes capnometry. In practice,
capnography usually refers to both capnometry and capnography.
Analysis of the capnographic waveform is essential to verify the
adequacy of gas sampling and to interpret capnometry. PETCO2 is
the partial pressure of exhaled CO2 measured at the end of each
tidal breath.
PHYSIOLOGY: The two working principles when measuring

PETCO2 are (1) the end-tidal gas sample is composed mostly of
alveolar gas and (2) the concentration of CO2 in the alveolar gas is
very close to PaCO2 and can be used to noninvasively estimate
its value.
However, the degree to which PETCO2 approximates PaCO2 is
subject to many variables that are either physiologic or technical.
Physiologically, the difference between PaCO2 and PETCO2
is usually slightly positive (05 mmHg) and increases when
deadspace ventilation increases, for instance, in the presence
of lung disease or cyanotic congenital heart problem. This
difference remains usually stable intraoperatively, except in case
of cyanotic heart disease,36 if the childs position is changed or

during laparoscopy. The PaCO2-PETCO2 difference is sometimes
negative in healthy children,37 namely in the presence of minimal
alveolar deadspace, or in some cases of laparoscopic surgery38 (see
Chapter 60).
The technical variables are the site of sampling, the FGF, the
type of breathing circuit, the respiratory rate, and in case of
sidestream capnometry, the aspiration flow rate. The smaller the
child, the more important these technical variables are.
INDICATIONS: Capnography is included in the standards of

monitoring during anesthesia. It allows
Confirmation of the correct placement of the tracheal tube (TT)

or supraglottic airway.
Assessment of the adequacy of ventilation.
Recognition of metabolic (e.g., malignant hyperthermia),
hemodynamic (e.g., embolism, cardiac arrest), or respiratory
(e.g., bronchospasm, residual muscular blockade) events.
Monitoring of airway equipment patency: disconnection,
exhausted CO2 absorber, malfunction of a valve.
For research.
DESCRIPTION: Gas for analysis of CO2 may be aspirated from the

airway and transported to the analyzing chamber (sidestream or
aspirating capnography) or analyzed as it passes through a sensor
placed into the breathing circuit (mainstream or flow-through
capnography). The advantages and disadvantages of both techniques are summarized in Table 388. The CO2 can be measured
using either infrared analysis, mass spectrometry, acoustic
spectrometry, or Raman scattering. If PETCO2 is measured at the
connection of the breathing circuit, it is called proximal PETCO2;
if it is measured in the TT or supraglottic airway, that is, distal to
the connection with the breathing circuit, it is called distal
PETCO2.
TABLE 38-8. Comparison of Mainstream and Sidestream
Capnography Advantages and Disadvantages
Mainstream
No response delay
Delicate sensor close to the patient
Kinking? disconnection? burn?
Deadspace (! in infants)
Interferences in presence of blood, water or secretions in
the cuvette
Accurate even at rapid-cleaning of cuvette between cases
Respiratory ratesnot usable in nonintubated patient
No scavenging neededno measurement of other gases
Sidestream
Light adaptertransport time to sensor causes response
delay
Distal sampling easysampling site critical for accuracy
Evacuation of expired gases
OK in nonintubated patientrisk of obstruction of sampling
tube
Measurement of other gasesrisk of leaks in the connections
Accurate zeroingrisk of distortion of the expired gas wave
during aspiration to sensor
Accuracy affected by rapid respiratory rate (>40 breaths/min)
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Figure 38-4. A: Sampling of expired air at the nostril of a high-risk expremature infant undergoing inguinal hernia repair under
awake caudal blockade. B: Capnogram obtained.
MAINSTREAM CAPNOMETRY: The main advantage of mainstream capnometry is the absence of response delay even at rapid
ventilation rates.39 Although the latest pediatric sensors present
a small deadspace, the sensor is close to the childs face, causing
a risk of disconnection, kinking, and pressure or burn injury
because the sensor is heated to prevent water condensation. The
main disadvantages of mainstream capnography are
It is not usable in nonintubated patients.

The sensor needs to be cleaned and disinfected between cases.
It measures only CO2, not O2 nor volatile anesthetics.
SIDESTREAM CAPNOMETRY: The main advantages of sidestream

capnometry are the possible simultaneous sampling and measurement of inspired/expired volatile anesthetics and the multiple
possibilities of remote sampling. For example, the sampling tube
can be taped adjacent to the external nares to monitor breathing
in unsedated infants undergoing surgery under regional anesthesia (Figure 384) or in children in the recovery room. It can also
be connected to nasal oxygen cannulas to monitor ventilation in
children receiving supplemental O2 undergoing deep sedation or
in the recovery room.40 Sidestream spirometry can be combined
with capnography to measure ventilatory parameters such as
compliance and resistance and display volume-pressure and flowvolume waveforms.
The site of sampling is critical to obtain accurate PETCO2
measurements. The optimal site of sampling varies with the
airway device and the breathing system used. As a rule of thumb,
the more distal the sampling site, the more accurate PETCO2 is to
PaCO2 (Table 389). When using a facemask and a T-piece system
during inhalation anesthesia, the difference between PaCO2
and PETCO2 is smaller when expired gas sampling is performed
through a few-centimeters-long cannula inserted through a
sampling port into the elbow connector between the circuit and
the mask than when it is obtained at the elbow connector.37 The
PETCO2 obtained under those conditions should be interpreted
cautiously because high FGF can result in an artificially low
PETCO2 owing to mixing with the expired gases. Last but not
least, partial upper airway obstruction can result in an apparently
normal to low PETCO2 and hypoventilation can go unnoticed until
the obstruction is relieved.41 Clinical signs of hypoventilation (slow

and/or shallow breathing) or upper airway obstruction (stridor
and/or retractions) should help in interpreting the displayed
PETCO2.
When using a TT, sampling can be performed with a catheter
inserted through the wall of the TT, via the sampling port of the
elbow connector, or via a specially designed TT connector or the
sampling line of specially designed TTs. If the TT is connected to
a Mapleson D circuit, sampling distal to the point at which the
tracheal tube connector narrows to the diameter of the TT is
necessary to avoid mixing of expired gases with inspired gas flow.42
When using a laryngeal mask airway (LMA) with a circle
circuit and spontaneous or controlled ventilation, sampling at
the elbow connector gives accurate results in children43 and in
infants less than 10 kg.44 If an LMA is used in children breathing
spontaneously through a nonrebreathing circuit, expired gas
should be sampled at the distal end of the shaft of the LMA. Even
TABLE 38-9. Ideal Site for End-tidal Gases Sampling
According to the Airway Control Device and Breathing
System in Use
Facemask
Spontaneous ventilation special cannula through elbow
connector
TT
Sampling distal to the TT connector
Supraglottic Airways
Spontaneous ventilation and connected to a nonrebreathing
circuit
Special cannula inserted into the shaft of the LMA
Controlled ventilation and connected to a circle system:
Elbow connector between circuit and patient
If an HME has been placed, sampling should be performed
either in it or distal to it, i.e., between the patient and
the HME.
HME = heat and moisture exchanger; LMA = laryngeal mask airway; TT =
tracheal tube.
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TABLE 38-10. Interpretation of the Capnogram
Sudden disappearance: disconnection, obstruction, cardiac
arrest, embolism, or automatic zeroing of the device?
Gradual decrease of PETCO : hypoventilation, decreased
2
cardiac output?
Slow increase of PETCO : hypoventilation, fever, exhausted
2
CO2 absorbent?
Increase of PICO : rebreathing, artifact caused by rapid
2
respiratory rate?
Rapid increase of PETCO : malignant hyperthermia?
2
Transient and short-lived increase in PETCO : injection of
2
blood or NaHCO3?
Gradual increase of PETCO and/or PICO : faulty
2
2
unidirectional valve?
Sharp upstroke of the plateau: bronchospasm, kinking
of TT?
Curare cleft: residual curarization?
Cardiac oscillations: slow respiratory rate respiratory
depression?
In case of esophageal intubation, there is either no PETCO2
waveform or only a few small humps of decreasing height if
some CO2 was present in the childs stomach after induction
of anesthesia. Bronchial intubation may present with either
decreased or increased PETCO2.
Figure 38-5. Sidestream capnography via a connector included

in a heat and moisture exchanger (HME).
so, although the PaCO2-PETCO2 difference is low (2.02
6.9 mmHg), the correlation with PaCO2 remains poor (r2 = 0.5).
This is probably caused by the shaft of the LMA being larger than
the TT and the presence of the pharyngeal cavity is bypassed in
case of tracheal intubation.45
Conversely, whatever the airway device used, if an HME or
bacterial filter is inserted in the breathing system, the PETCO2
measured at the machine side of the filter is lower than at the
patient side (Figure 385). This difference is caused by an increased
deadspace, which is larger during spontaneous than controlled
ventilation.46
Last, the monitor sampling rate should be the same as for
adults, that is, between 100 and 240 mL/min, ideally 150 mL/min,
because lower flow rates may not capture the peak expired CO2,
giving unreliable measurements and a blunted capnogram falsely
suggesting rebreathing. Although these high sampling rates were
initially thought to extract large volumes of gas from the lungs
of small infants, their safety has been demonstrated. Sampling
150 mL/min in a 4-kg infant breathing at 25 breaths/min with an
inspiration-to-expiration (I:E) ratio of 1:1 aspirates 6 mL from the
VT at each breath, which represents 15% of the volume (4 10 mL).
The loss of VT decreases at lower I:E ratios as well as in larger
children and increases if sampling rate increases. The expired gases
sampled can be re-injected into the ventilator circuit, eliminated
via the scavenging system, or eliminated in the operating room
atmosphere. In case of low-flow anesthesia, the volume of gas
aspirated should be compensated for if it is not returned to the
breathing circuit.
The disadvantages of sidestream capnometry are
The risk of obstruction of the sampling tube with water or secretions.

The presence of some transport delay, that is, the time required
to suction the gas sample into the analyzer cuvette. It varies from
1.6 to 5.2 seconds and becomes longer as the length of the sampling line increases. It also delays the dynamic response of the
capnometer (i.e., rise time of the measured signal once the gas
sample reaches the cuvette), which may affect accuracy in case
of rapid respiratory rate.47 When using sidestream capnography,
one should always bear in mind that both the PETCO2 and the
capnogram signal are delayed. This transport delay could lead to
an incorrect diagnosis of esophageal intubation.
PETCO2 = end-tidal CO2; PICO2 = inspired concentration of CO2; TT =

tracheal tube.
INTERPRETATION OF DATA: In infants and children ventilated with

a circle circuit, the normal capnogram has the same waveform as in
adults, that is, a sharp upstroke at the beginning of expiration
followed by a slightly ascending plateau phase interrupted by
the next inspiration. The information obtained is similar and
summarized in Table 3810.
It should be kept in mind that the presence of a plateau does not
always mean that PETCO2 accurately reflects PaCO2. A plateau can
be present despite a large PaCO2-PETCO2 difference in case of
Proximal sampling in infants less than 10 kg.

Increased deadspace ventilation (lung disease).
Shunting of pulmonary circulation (cyanotic congenital heart
disease).
Conversely, in infants and because of the rapid respiratory rates

used, PETCO2 is sometimes close to PaCO2 even in the absence
of a flat plateau phase on the capnogram. In these cases, the
difference between PaCO2 and PETCO2 should be measured with
an arterial or central venous blood sample.
The capnographic baseline can be erroneously elevated in
the presence of very high respiratory rates (>40 breaths/min).
The inspired concentration of carbon dioxide (PICO2) increases
progressively with respiratory rate when sidestream capnography
is used during controlled ventilation with a circle circuit.39 This
artifactual elevation of the PICO2 is partly caused by the parabolic
distortion of the CO2 sample as it travels through the sampling
line. Because of laminar flow, gas near the wall of the catheter
moves more slowly than gas in the middle of it. This mechanical
phenomenon may lead to partial fusion of the beginning of one
sample with the end of the previous one and, thus, to elevation
of the baseline without actual rebreathing. Conversely, if the
capnometer response time (transport delay + dynamic response)
exceeds the time for one breath, the analyzer will measure
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inappropriately low PETCO2 and elevated PICO2. Both parabolic
distortion and capnometer response time are minimized when
using short sampling lines.
Lastly, in the presence of a large leak around the TT, PETCO2 is
inaccurate, with both mainstream and sidestream capnometry,
because there is a loss of expired gas.
PORTABLE COLORIMETRIC PETco2 Detectors: Portable devices
allow detection and estimation of expired CO2. They can be used

in emergency situations when a capnograph is not readily available
(e.g., prehospital setting) or during transport of the patient.
The Statcap (Nellcor) is a small, battery-operated capnograph
that provides a semiquantitative measurement of PETCO2 using
colored bars that range from purple (PETCO2 06 mmHg) to
yellow (>20 mmHg). The device is not designed for use in children
younger than 3 years or weighing less than 10 kg. Its disposable
airway sensor has a deadspace of 4 mL.
The Pedi-cap (Nellcor) is a 5-gauge clear plastic device to be
connected between the TT and the breathing system. It contains
filter paper impregnated with a pH-sensitive chemical indicator
the color of which changes on exposure to CO2. It provides a
breath-to-breath estimation of PETCO2 through a range of colors
from purple (<4 mmHg) to yellow (1538 mmHg). Because of its
small deadspace volume (3 mL), it can be used in children less
than 15 kg. For bigger children, another version of the same
device, called Easy-capII (deadspace 25 mL), is used. All these
devices are, however, easily damaged by excessive humidity
(e.g., humidified gases, pulmonary edema, drugs administered
intratracheally), which can result in permanent color changes.
Measurement of Volatile Anesthetics

The measurement of volatile anesthetics is useful to assess the
function of the vaporizer in use, detect agent error, and perform
low-flow anesthesia. The technology and the limits are the same as
for sidestream capnometry. Potential sources of transient erroneous
measurements when mass spectrometry or infrared analysis are
used are
The presence of ethanol, as in some fruit-flavored extracts used

to scent facemasks.48
The presence of halogenated propellants, when metered-dose
bronchodilators are introduced into the breathing circuit.49
Inspired and End-Tidal Oximetry

The measurement of inspired and expired O2 concentration is
achieved either with two different sensors (one being placed on
the inspiratory limb of the anesthesia machine) or using the same
sampling system and technology as that used to measure volatile
agents concentration. This second approach is especially useful
when the FGF outlet used to supply the breathing circuit (e.g.,
Mapleson D or F) does not pass through the oximeter of the
anesthesia machine.
A less known application of the measurement of expired
O2 (FEO2) is the accurate assessment of preoxygenation before
induction of anesthesia in clinical situations at high risk for
hypoxia such as rapid-sequence induction, anticipated difficult
intubation, pulmonary disease, obesity, or high altitude. This is
provided that a snug mask seal is obtained to prevent entrainment
of ambient air.50 The aim is to obtain an FEO2 of 0.9 because the
remaining 0.1 of exhaled gas consists of CO2 and N2.51
Blood Pressure
BP should be measured during anesthesia to ensure adequate perfusion of all organs. The most accurate method of BP
measurement is continuous invasive measurement following
catheterization of a peripheral artery. However, because of the
risks involved, especially in small children, this procedure is
reserved for critically ill patients or major surgical procedures.
Noninvasive methods are used during routine procedures.
Normal values for BP according to age should be known in order
to correctly interpret the measured data (see Chapter 7).
NIBP Measurement
DESCRIPTION: Many noninvasive techniques are available to
measure BP using a BP cuff. Selection of a BP cuff of appropriate
size is critical to obtain reliable results. Too narrow a BP cuff results
in overestimation of BP whereas a too large cuff underestimates
it. As a rule, the width of the inflatable bladder of the cuff should
be approximately 40% of the arm circumference. This usually
corresponds to a BP cuff that is two thirds or three fourths of the
distance between the childs axilla and the antecubital fossa.
But, in fact, when using the upper arm length criterion, one usually
chooses a BP cuff that is larger than when using the arm circumference criterion. Commercially available BP cuffs rarely correspond to the chosen criterion for an individual child. As a rule, there
is a mild underestimation of systolic BP when compared with a
radial arterial line if BP is measured with a cuff chosen according
to the childs arm length.52 The basic working principle is observing
the return of arterial flow during deflation of the BP cuff. The
pressure at which flow reappears is considered as systolic BP.
The various methods are (1) observation of a flush of the limb or
(2) palpation, auscultation, or Doppler location of the pulse distal
to the cuff. The major drawback of all these methods is that they
are dependent on the speed of cuff deflation. The use of the
Doppler method is difficult in the operating room because it
depends on the accurate placement of the probe and is subject to
motion and electrosurgical interferences.
Conversely, automated oscillometry allows the measurement
of systolic, diastolic, and mean BP. Monitors using the oscillometric principle are easy to use and accurate and are, therefore,
the most popular nowadays. The cuff of the automated oscillometry monitors (e.g., Dinamap) NIBP acts as the actuator and
transducer. Because the whole cuff acts as a signal sensor, placement of the cuff directly over an artery is not necessary, although
strongly recommended. The cuff is automatically inflated above
systolic pressure and slowly deflated in steps by a microprocessor.
At each stage, both mean cuff pressure and oscillations resulting
from the arterial pulse wave in the limb are sensed and stored.
Systolic BP corresponds to the cuff pressure where the oscillations
rapidly increase, mean BP to the lowest cuff pressure at which
maximum oscillations are recorded, and diastolic BP to the cuff
pressure where the oscillations fade. A specific artifact rejection
strategy requires that identical oscillations are measured at
two consecutive times at each deflation step before the monitor deflates the cuff to the next step. In case of motion artifact
potentially caused by the patient, surgeon, nurse, and/or leak in
the tubings, dysrhythmias, important variations of BP with
respiration or poor peripheral perfusion, determination of BP will
be slower or even unreliable because successive cardiac pulsations
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will be compared until the rejection criterion is no longer met.

Many studies have shown a good correlation of systolic and mean
BP measured with NIBP with the same measurements made
invasively. However, diastolic BP is much less precise. In neonates
and premature infants, noninvasive systolic BP is falsely elevated
if mean BP is less than 40 mmHg. When BP is measured in the
lower limb (BP cuff placed on the calf with its upper edge at the
level of the tibial tuberosity), in children younger than 4 years
old the mean BP is lower (mean 10 mmHg) than the pressure
measured in the upper limb.53
QUALITY CONTROL: Guidelines to obtain accurate results when

using NIBP to measure BP are summarized in Table 3811.
Because NIBP devices provide discontinuous data and are mainly
accurate as trend recorders, the anesthetic management should
not be modified only on the basis of a single measurement. In case
of difficulty with NIBP, the measurement should be repeated after
verifying that the patients condition is not deteriorating (presence
of a good peripheral pulse), that there are no leaks in the tubing
and connections, and that the cuff is correctly applied. Because
the presence of residual air in the BP cuff causes damping of the
oscillations and thus spurious low BP measurements, all air should
be squeezed out of the cuff before positioning on the childs arm.
Care should be taken to use tubing and cuffs that are adapted
to the specific NIBP monitor in use, otherwise improper functioning of the internal monitor algorithms could ensue.54 If the
NIBP and ECG are measured with independent devices, the BP
measurements are valid if the heart rates displayed by both devices
are similar.
POSSIBLE COMPLICATIONS: During placement of the BP cuff, care
should be taken to ensure that its tubing and cuff do not compress
a nerve path and the skin is properly protected. Care should be
taken to avoid pinching the skin when closing the cuff, which
could result in skin avulsion.
TABLE 38-11. Guidelines to Obtain Accurate Data With
an NIBP Device
1. Use a BP cuff of proper size, i.e., it covers at least two thirds
of the distance between the axilla and the antecubital fossa.
2. Squeeze all the residual air out of the BP cuff before
connecting it to the tubings
3. Wrap the BP cuff snugly around the limb.
4. Keep the BP cuff and heart at the same horizontal level.
5. If the NIBP and ECG are measured with independent
devices, the BP measurements are valid if the heart rates
displayed by both devices are similar.
6. In case of malfunction of the apparatus, check the childs
condition first!
Peripheral pulse: shock? pulsus paradoxus?
Hypovolemia causing major respiratory variations in BP?
ECG: dysrhythmias?
7. Common causes of malfunction are
BP cuff of inappropriate size.
Leak in the cuff, tubings, or connections.
Extrinsic (surgeon, nurse) or intrinsic (movement) cuff
compression.
BP = blood pressure; ECG = electrocardiogram; NIBP = noninvasive blood
pressure.
Finger Blood Pressure and Arterial Tonometry

Some devices were designed to monitor BP continuously in a
noninvasive way.
FINGER BLOOD PRESSURE: The Finapress device uses a small

pneumatically inflated cuff applied to the middle phalanx of a
finger. This cuff contains an infrared photoplethysmograph the
wavelength of which is absorbed by hemoglobin, allowing arterial
pulsations to be sensed. The finger-cuff pressure is continuously
adjusted by a servocontrolled loop to keep the infrared signal and,
hence, the finger blood volume constant over the arterial pressure
cycle. The fluctuations of pressure in the cuff are the same as in the
patients artery, which allows a continuous reading of BP. Accuracy
and reliability of data vary widely in adult studies; although the
mean difference between Finapress and oscillometric or intraarterial data is small, there is a large variability in the difference
between individual values.55 This device is, therefore, not a reliable
alternative to direct BP monitoring. Although part of these
differences is caused by difficult application of the cuff, variable
levels of peripheral vasoconstriction explain the reduction
of accuracy related to time. The use of this device is limited to
children older than 5 years. A prototype pediatric finger cuff
and software are currently under investigation. There is a large
bias between finger arterial pressure and invasive BPs, but it gives
results similar to NIBP.56
NONOCCLUSIVE ARTERIAL TONOMETRY: When using arterial

tonometry (Vasotrac), the tonometer sensor is positioned over
the skin and produces cyclical nonocclusive compression and
decompression of the radial artery between the sensor and the
radius bone. Some variables are measured over three beats at a
time and BP is calculated using an algorithm. If used in a continuous mode, the device provides an arterial BP reading every
12 to 15 beats. In stable cardiac children in whom an adult sensor
was used, mean differences between systolic and diastolic BP as
measured invasively and with tonometry was 4.0 4 mmHg and
3.4 3.2 mmHg, respectively.57 Further studies are necessary to
evaluate the accuracy and reliability of these devices in small
children and infants.
Intra-arterial Measurement
INDICATIONS: Intra-arterial BP measurement gives precise and
instantaneous information about BP changes; it allows sampling
blood to measure parameters such as arterial blood gases,
electrolytes, and blood glucose. Indications are the same as in
adults undergoing similar procedures and are mainly based on
hemodynamic or pulmonary considerations, taking into account
the childs preoperative condition, the invasiveness of the planned
procedure, and the importance of the anticipated changes in blood
volume or fluid shifts. In small infants and neonates, the technical
feasibility and the risk/benefit ratio of the technique should be
evaluated on an individual basis. The techniques of insertion of a
catheter into an artery and the analysis of the hemodynamic
information provided are described in Sites of Measurements.
Computerized analysis of the pulse pressure contour (PiCCO)
allows the continuous measurement of cardiac output through a
4-French arterial thermodilution catheter inserted in the femoral
artery (see Monitoring Mechanical Ventilation, later).
A few cases of deliberate intra-arterial injection of anesthetic
drugs have been published. In all cases, a femoral artery had been
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inadvertently punctured in infants with no venous access and
only drugs in an aqueous solvent (e.g., fentanyl, midazolam,
vecuronium) or normal saline were used. Although those reports
are reassuring, this route of administration is risky and is not
recommended.58
SITES OF MEASUREMENT: Virtually all peripheral arteries can be

used for intra-arterial monitoring. However, the use of the
temporal artery is no longer recommended because it carries a
risk of cerebral embolization during flushing of the line. The radial
and femoral arteries are the most commonly used. Cannulation
of the ulnar artery should be avoided when cannulation of the
radial artery has already been attempted on the same wrist because
this could result in total occlusion of the arterial supply to the
hand. Although it is recommended to perform Allens test to check
the collateral circulation to the hand before attempting to insert a
catheter in the radial or ulnar artery,59 this is often difficult to
perform in small children. Although its catheterization in a large
series of cardiac neonates and infants was not associated with
more complications than the radial artery, the brachial artery
should be used with caution because there is no collateral blood
flow at its level and the median nerve runs close to it.60 The axillary
artery can be used because there is collateral flow at this level, but
because it is surrounded by terminal nerves of the brachial plexus,
it must be used with caution. The femoral artery is usually easy to
locate and cannulate. Although there is a theoretical increased risk
of contamination owing to the proximity of the perineum, the
incidence of infection is no greater than with radial catheters but
the incidence of perfusion-related complications is greater.61 When
using one of the pedal arteries, one should keep in mind that
because of pressure-wave amplification in the vascular tree, peak
systolic pressure may exceed aortic values. The umbilical artery is
accessible for monitoring purpose during the first 3 days of life.
The position of the catheter tip should be monitored by x-ray to
make sure it is either below the origin of the renal arteries or in the
midthoracic aorta. The use of an umbilical catheter is not suitable
in cases of intra-abdominal surgery because it will be mobilized
during the procedure. In surgery in which it is critical to know the
brain perfusion pressure (neurosurgery) or the preductal PaO2 to
prevent retinopathy of prematurity or assess shunting through a
patent ductus arteriosus (diaphragmatic hernia repair), preductal
placement (into the right upper limb) of the arterial catheter is
necessary.
DESCRIPTION: Small-gauge nontapered over-the-needle cannulas

are used to catheterize peripheral arteries. They are 24 gauge for
infants weighing less than 3 kg, 22 gauge for infants 3 to 20 kg,
and 20 gauge for bigger children. These cannulas are made of
Teflon or polyurethane. The latter are less rigid and potentially
less traumatic but sometimes more difficult to insert. Catheters
with a built-in atraumatic guidewire (e.g., BD Insyte-A) that can
be introduced into the arterial lumen as soon as blood flows back
into the needle are available. The fluid used to maintain arterial
line patency is a heparinized solution of normal saline, 0.45%
saline, or 5% dextrose. The saline solutions have the advantage of
allowing blood glucose measurements and to be less susceptible to
bacterial growth in case of contamination. The concentration of
heparin is 0.5 (neonates) or 1 IU/mL. The heparinized solution
is flushed at a constant rate through an automatic disposable
pressurized system at a rate of 1 (neonates) to 3 mL/h (children
and adults). The pressurized system consists of a syringe pump
(neonates) or an externally pressurized infusion bag connected to
a flow-regulating device. An adult flow-regulating device requires

that the solution be pressurized at 300 mmHg to provide a continuous flow of approximately 3 mL/h. However, large differences in
the infusion pressure effectively delivered to the flow-regulating
device are observed. This pressure is influenced by the volume of
the infusion bag (less if 250 mL compared with 500 mL) and by
the vertical position of the pressurized infusion according to the
flow-regulating device. The pressure increases when the bag is
above the device and vice versa.62 These variations in pressure can
have important consequences because the flow rate and the fast
bolus flush performed through the flow-regulating device are
closely correlated. Insufficient flow can lead to catheter obstruction, whereas excessive flow can produce fluid overload or
retrograde embolization of flush solution in small infants. The
tubing connecting the cannula to the transducer should be rigid
and as short as possible to avoid discrepancies caused by highfrequency harmonics and resonance within the tubing.
PRACTICAL ASPECTS: Before inserting an arterial catheter, the

tubing and transducer are carefully flushed with the heparinized
solution, taking care to eliminate any bubble of air. The pressure
transducer is placed level with the childs midaxillary line and
zeroed. In case of procedures in a head-up or sitting position
(e.g., neurosurgery), the transducer should be placed at the level
of the brain (i.e., outer canthus of the eye) to allow more precise
measurement of brain perfusion pressure. During use of the
arterial monitoring, the position of the zero baseline of the
transducer should be checked regularly because a slow drift
sometimes occurs.
The limb in which the catheter will be inserted is gently
immobilized. This will make arterial puncture and catheterization
easier and probably less traumatic. Strict asepsis is essential to
avoid infectious complications. To avoid damaging the tip of the
catheter when piercing the skin, make a small nick in the skin with
a 19-gauge needle before inserting the arterial catheter In neonates
and small infants, in whom precise localization of the artery by
palpation alone is difficult, the peripheral arteries can be located
using a Doppler probe, transillumination with a cold fiberoptic
light, or ultrasound.63 Three different techniques can be used
to catheterize the artery: direct catheterization, transfixion, or
Seldinger technique.
Once inserted into the artery, the cannula is carefully fixed in
order to avoid both accidental removal and kinking at the skin
entry site. Connections should be secure in order to avoid blood
loss by disconnection. In neonates and small infants, the dressing
should allow visual control of the skin proximal and distal to the
catheter in order to detect its blanching or cyanotic discoloration
as soon as possible. These are considered early signs of a thrombotic complication. The stopcocks of the arterial line should be
clearly identified in order to avoid the accidental intra-arterial
injection of anesthetic agents, antibiotics, and other agents.
Blood sampling should be performed slowly to avoid collapsing
the vessel and damaging its endothelium. After blood sampling,
the tubing should be flushed gently, especially in neonates and
infants. Too rapid or forceful flushing results in blanching of the
skin proximal to the cannula and transmission of the iatrogenic
pressure wave to distal sites such as the cerebral or splanchnic
circulation. Flushing no more than 0.5 mL with a syringe over
a period of 5 seconds is recommended in neonates. In case of
damping of the arterial waveform, the tubing and stopcocks
should be inspected to eliminate bubbles of air; however, gentle
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flushing is sometimes necessary to obtain a satisfactory waveform

from a partially blocked cannula.
POSSIBLE COMPLICATIONS: The most common complication of

arterial cannulation is a local hematoma that usually resolves
quickly. The incidence of arterial thrombosis varies according to
the childs age. One prospective study in which the radial artery
was cannulated with a Teflon cannula and Doppler flow measurement was used to assess vessel patency is worth mentioning. In
60 children, the incidence of total arterial thrombosis was of 7.4%
but recanalization usually occurred within the following days.64 The
most important predisposing factors were a cannulatoartery
diameter ratio in excess of 0.7, transfixion of the artery during
insertion, and presence of a hematoma at the site of cannulation.
Partly because of a greater cannula-to-artery ratio, thrombosis was
more common in neonates. Although permanent ischemic damage
after arterial catheterization is rare, removal of the cannula using
negative pressure to aspirate as much of the thrombus as possible
is recommended in case of increasing difficulties with blood sampling or appearance of cyanotic discoloration of the skin distal to
the entry site. Ischemic damage is more likely in case of low cardiac
output and/or use of vasopressors agents and can lead to dramatic
consequences such as amputation.65
Embolization can occur distally or proximally. Distal embolization results from propagation of a thrombus formed near the
cannula; proximal embolization of air or debris occurs in case of
aggressive flushing. Careful inspection of the skin proximal and
distal to the cannula entry site and gentle flushing by hand are
mandatory to avoid these complications.
Local infection is rare if the rules of asepsis are observed and if
the cannula is left in place less than 4 days. However, colonization
of the cannula is more frequent when multiple attempts have been
required for its insertion. This is probably caused by unnoticed
breaks in the rules of asepsis when dealing with technical difficulties. Other complications described include nerve damage
by the exploring needle or by a compressive hematoma, tendon
sheath injury,66 accidental intra-arterial injection of anesthetic
drugs, formation of an arteriovenous fistula, and occurrence of a
compartment syndrome.67
Temperature Monitoring68
Goal and Indications
Intraoperative monitoring of body temperature is necessary to
detect hypo- and hyperthermia, manipulate body temperature
(e.g., to provide brain protection during hypothermic cardiac
surgery), and prevent complications associated with variations
from normal. It is mandatory during pediatric anesthesia because
the mechanisms of thermoregulation are less efficacious. Both
hypothermia and hyperthermia are more frequently observed in
children than in adults. Body temperature should be monitored
during any anesthetic lasting more than 30 minutes.68
Technology
The temperature probes used in the operating room are either
thermistors, thermocouples, infrared sensors, or liquid crystals. A
thermistor is a metal semiconductor, the resistance of which varies
with temperature. Placed at the tip of the probe, it is generally
incorporated in soft plastic tubing, an esophageal stethoscope, or
urinary catheter. It has a quick response time and is sensitive to
small changes in temperature. A thermocouple is an electrical

circuit made of two different metals welded at their ends. The
end in contact with the body area produces a voltage difference
proportional to temperature of the site of measurement. It is
accurate with a quick response time and is sensitive to small
changes in temperature. The energy radiated from an object is
proportional to its temperature. Infrared sensors measure the
infrared radiation emitted by any surface without touching it.
Liquid crystal thermometers are adhesive strips attached to the
patients skin. The liquid crystals change in color with changes
in skin temperature. It measures only skin temperature and is
sensitive to humidity, air movement, or external sources of heat
(e.g., heating lamps).
Sites of Measurement
The interpretation of the temperature measured depends on the
site of measurement: rectal temperature is usually 0.5 to 1.0C
greater than oral temperature, which is 0.5 to 1.0C greater than
axillary temperature. These differences are not constant and
depend on various factors such as environmental temperature, local blood supply, and rate of change in temperature.69 In
anesthetized infants and children undergoing superficial surgery,
there is no significant difference between tympanic membrane
and esophageal, rectal, or axillary temperature measurements.70
Conversely, in children undergoing cardiac surgery, esophageal
temperature readings are the closest to those in the pulmonary
artery (mean difference 0.1C 0.5C) compared with tympanic
(mean difference 0.6 C 1.0C), rectal (mean difference 0.7C
1.7C), bladder (mean difference 0.9C 1.4C), and axillary
temperature (1.3C 1.3C).69 Similarly, nasopharyngeal temperature measurements show the most rapid response during cooling
and rewarming, whereas tympanic measurements vary in an
unpredictable way and rectal measurements lag behind.71
The site for the intraoperative measurement of temperature
should be chosen according to the childs age and the procedure
undertaken. For example, core temperature can be monitored with
good accuracy in the distal esophagus, nasopharynx, or tympanic
membrane for superficial procedures, but measuring temperature
at two sites, usually esophageal and rectal or vesical, is critical
during procedures in which large and/or rapid changes in temperature occur (e.g., cardiac bypass, trauma, spinal instrumentation)
because large gradients are indicative of nonuniform heat
distribution or poor cardiac output. The specific advantages and
disadvantages of each site are described hereafter and summarized
in Table 3812.
T YMPANIC MEMBRANE: Tympanic membrane temperature as

measured with a thermistor or thermocouple placed in contact
the tympanic membrane is very close to core temperature because
the tympanic membrane is vascularized through a branch
of the internal carotid artery. Correct placement of the probe is
sometimes difficult (risk of bending into the aural canal),
and some authors recommend otoscopic examination before
insertion. Cases of tympanic perforation have been described.
After placement of the probe, it is important to block the aural
canal with some cotton wool to prevent cooling of the probe by
air movement. The infrared tympanic thermometer allows only
intermittent measurement of temperature. The disposable cover
of these portable otoscope-like probes is large and can be entered
only a few millimeters into the aural canal. The temperature
recorded can be influenced by improper positioning of the probe
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TABLE 38-12. Sites of Temperature Monitoring

Site
Advantages
Disadvantages
Tympanic membrane
Nasopharyngeal
Closest to hypothalamus
Close to internal carotid artery
Esophageal
Close to great vessels and heart
Rectal
Traditional
Bladder
Oral
Axillary
Better reflector of central temperature

than rectal
Convenient
Convenient
Rare: risk of perforation via internal carotid artery

Affected by temperature of inspired gases
Risk of epistaxis
Affected by temperature of inspired gases if placed in distal
third! if thoracic surgery
Inaccurate if temperature changes are rapid
Guide to uniform rewarming affected by feces, peritoneal after
induced hypothermia lavage, cystoscopy.
Risk of perforation in infants
High urine output necessary
Skin
Useful to indicate temperature
Swan-Ganz catheter
Measures mixed venous
and the temperature of the aural canal. It is atraumatic and is

often used in the recovery room. A tug on the ear and application
of gentle pressure on the probe during the measurement could
improve the correlation with core temperature.
NASOPHARYNX: Nasopharyngeal measurement is close to hypothalamic temperature when the probe is placed in the nasopharynx. It is influenced by the temperature of inspired gases if
there is a leak around the TT or supraglottic airway and there is a
risk of epistaxis during its insertion.
ESOPHAGUS: Esophageal measurement (e.g., within an esophageal
stethoscope or with a temperature probe) rapidly reflects changes
in core temperature if it is located in the distal third of the
esophagus, between the heart and the great vessels. There is a
small influence of the inspired gases temperature because it is
approximately 0.25C lower than tympanic temperature in the
absence of humidification and 0.35C higher when inspired gases
are actively or passively humidified and warmed.70
RECTUM: Although a good index of core temperature, rectal
temperature measurement may show some delay in case of rapid
changes in temperature because the rectum is less well vascularized than the other central sites of measurement. It is often
considered as an intermediate site of measurement.69 The presence
of feces may insulate the probe and the temperature of the fluids
used during peritoneal lavage or cystoscopy may interfere with
the measurement. Because of fear of trauma or perforation, a rectal
probe should not be inserted in small infants nor in children who
have undergone previous anorectal surgery.
BLADDER: Bladder temperature measurement, through a probe
incorporated in the urinary catheter (e.g., silicone Foley catheters
with a thermocouple), could be a better index of core temperature
than rectal measurement, but its performance depends on the
presence of a high urine output.
AXILLA: Axillary measurement is easy, but placement of the probe

is critical. It should be placed directly over the axillary artery with
Probe must be placed over axillary artery; affected by blood

pressure cuff and ipsilateral I.V. infusion
Needs 1015 min equilibration time
Affected by peripheral perfusion, gradient between core and
vasoconstriction, sweating, and periphery environmental
temperature
Affected by cardiac bypass blood temperature or thoracic
surgery
the arm tightly adducted. It requires a few minutes of equilibration
before giving accurate results. In order to avoid displacement
of the probe, the BP cuff should not be placed on the same arm.
No fluids should be administered intravenously in the same limb
because their temperature affects the performance of the probe. It
is a commonly used site of measurement in nonintubated children
undergoing short procedures.
SKIN: Because skin temperature is under the influence of many

factors such as cardiac output, anesthetic technique, environmental temperature and, therefore, shows great variability in
correlation with core temperature, its intraoperative monitoring
is of little use during anesthesia. The core-to-forehead temperature
gradient is rather stable when ambient temperature varies between
18 and 26C. Core temperature can be inferred from forehead
skin temperature as long as a correction factor of +2C is added.68
TEMPORAL ARTERY: The temporal artery infrared skin temperature probe records the highest temperature across the forehead
including the site of the temporal artery. The temporal artery
temperature is theoretically very close to core temperature,
but this monitoring is not sufficiently accurate in clinical circumstances.72
PULMONARY ARTERY: The temperature of mixed venous blood,
as measured with a probe incorporated in a pulmonary artery
catheter, is the closest to core temperature and is used to measure
cardiac output by thermodilution.
The probe should be checked before use to detect any defect in its
insulation because this could lead to local electrical burns during
the use of diathermy. In order to avoid cross-contamination
between patients, the reusable temperature probe should be
covered with a plastic protective sleeve before insertion into the
patient. In case of nasopharyngeal probes, care should be taken
to retrieve the sleeve before extubating the patient. A case of
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postoperative airway obstruction caused by a sheath lost in the

patients nasopharynx has been described. Intraoperative airway
obstruction caused by inadvertent intratracheal insertion of
an esophageal probe has also been described.73 Last, a case of accidental extubation when removing an oropharyngeal temperature
probe has also been described.74
Urine Output
Goal and Indications
The presence of an adequate urine output is a sign of good renal
perfusion and an indirect sign of adequate volume loading and
peripheral perfusion of the patient. Urine output should be
measured during procedures in which large shifts of fluids are
anticipated. Cardiopulmonary bypass, transplant surgery, neurosurgery, anticipated blood loss in excess of 1 effective blood
volume are good examples. Bladder drainage is also performed
before long procedures to prevent bladder distention, for anorectal
or urogenital surgery to avoid intra- and postoperative surgical
wound contamination by urine, or to ensure vesical emptiness
during some laparoscopic surgery.
Description
Either a urinary Foley catheter or a percutaneous cystostomy
catheter can be used. In both cases, great care should be taken to
avoid trauma to the fragile urethral mucosa or the neighboring
organs, respectively. The catheter should be connected to a drainage system allowing the precise measurement of the hourly urine
output. The color of the urine produced should also be noted, for
example, the apparition of red or brown urine should alert for the
presence of hematuria, myoglobinuria, or hemolysis.
Limits and Caution

Beyond the neonatal period, a urine output of 0.5 to 1 mL/kg/h
indicates adequate renal perfusion. However, it should be interpreted cautiously in case of use of diuretics (mannitol, dopamine,
and I.V. contrast media) or in the presence of glycosuria. Large
amounts of diluted urine are produced in case of diabetes insipidus
(see Chapter 93), postobstructive diuresis, salt-losing nephropathy,
or metabolic disorder (e.g., absence of or resistance to aldosterone).
Conversely, the patency of the urinary catheter and/or the absence
of a huge bladder should be checked before establishing the
diagnosis of anuria or oliguria. In neonates younger than 1 week,
urine output alone is not a good index of changes in intravascular
volume or cardiac output because the neonatal kidney has a limited
capacity to concentrate and dilute urine.
Central Venous Pressure

CVP is the venous BP measured at the junction of the right atrium
and the vena cavae, and it represents the filling pressure of the
right ventricle. The type of catheters used is described later in
this chapter, whereas the routes of insertion and the possible
complications are described in Chapter 70.
Indications
The indications of CVP measurement are the same as for insertion
of a central venous line: major surgery involving massive fluid
shifts or blood loss (scoliosis repair, organ transplantation, and

major laparotomy), cardiac surgery, and procedures carrying a
high risk of venous air embolism (neurosurgery) or in which the
infusion of inotropes could be necessary.
Normal CVP is approximately 2 to 6 mmHg (312 cmH2O). In
children with normal right ventricle function, its value is well
correlated with intravascular volume and left ventricle preload.
However, as in adults, the trend of successive measurements is
more useful in therapeutic management than an absolute value.
The CVP value is rarely the sole basis of therapeutic action. It
should be interpreted in accordance with the other hemodynamic
parameters and interfering events such as compression of the
inferior vena cava by retractors or cross-clamping by the surgeon.
Quality Control
The pressure transducer should be at a level with the childs
midaxillary line and the position of the zero baseline of the
transducer should be checked regularly because a slow drift
sometimes occurs. The measurement should ideally be made at the
end of expiration to avoid any respiratory interference and after
verifying that a CVP waveform is present on the monitoring screen.
In case of difficult access to the childs neck or contraindication to
the catheterization of the superior vena cava, the venous pressure
measured in the abdominal inferior vena cava or common iliac
vein is identical with CVP, provided the measurement is made
at end-expiration and there is no obstruction to flow from the
inferior vena cava to the right atrium such as in patients presenting with an abdominal tumor.75 In the same way, there is a good
correlation between CVP and pressure from a peripheral I.V.
catheter (peripheral venous pressure [PVP]) (mean difference 2
1 mmHg), provided there is a continuity with the central venous
compartment as shown by an increase in PVP in response to a
Valsalva maneuver or following occlusion of the limb above the site
of the catheter.76 However, the measurement is less valid if PVP is
measured through an I.V. catheter placed on the dorsum of the
hand or the lateral aspect of the foot.77
Neuromuscular Block
Neuromuscular blockade (NMB) following the administration of
a muscle relaxant varies in both depth and duration, especially in
neonates and infants. It is important to monitor not only the depth
of NMB but also, most importantly, recovery from it whenever a
muscle relaxant is administered. The pharmacology and clinical
use of NMB are described in Chapter 27.
Description and Limits

The basic principle of neuromuscular monitoring is to stimulate a
peripheral motor nerve and to observe/measure the resultant
motor response of the corresponding muscle. This method is
independent of the patients effort, unlike head lift or eye opening,
but is dependent on many other factors such as the pattern of
stimulation used, the sensitivity of the muscle tested, the age and
body temperature of the patient, the method used to assess the
evoked muscular response, and the pharmacodynamic properties
of the muscle relaxant administered. Most of these factors are
considered later. Moreover, when evaluating recovery from NMB,
one should always bear in mind that incomplete recovery is
possible despite normal evoked motor responses and ventilatory
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movements and that the upper airway muscles are more sensitive
to the muscle relaxants than the muscle tested. The following
clinical indices of recovery should also be present when spontaneous breathing has resumed and before extubating the child:
Absence of a rocking pattern of breathing (i.e., upward movement of the abdominal wall and sinking of the chest during inspiration, owing to the contraction of the diaphragm in the
presence of residual paralysis of the other respiratory muscles).
Sustained wide opening of the eyes.
Lifting both legs (in neonates and infants).78
Swallowing.
Protrusion of the tongue.
Ability to perform purposeful movements (e.g., catching the nasogastric tube).
Neuromuscular monitoring is not widely used in routine

pediatric anesthesia owing to the complexity of setting up the
monitoring devices available at present in small patients. Because
of immaturity of their neuromuscular junction, neonates may
show abnormal evoked responses to nerve stimulation in the
absence of any NMB.79,80
Equipment
Accurate monitoring of NMB requires the precise and constant
delivery of the minimum current that produces supramaximal
nerve stimulation. A reliable peripheral nerve stimulator and
carefully placed stimulating electrodes are necessary.81 The
peripheral nerve stimulator must have the characteristics described
in Table 3813.
Most peripheral nerve stimulators available at present have
the characteristics just discussed. Neuromuscular transmission
monitors that include both a stimulating and a recording system
(e.g., TOF-Guard; TOF-Watch, Relaxograph) also carry most of
those features. The stimulating electrodes are pediatric ECG
silver/silver chloride electrodes. Their small size allows accurate
anatomic positioning and increases the current density in the
TABLE 38-13. Ideal Properties of a Nerve Stimulator Used
to Monitor Neuromuscular Blockade
Delivery of a monophasic square wave of 0.20.3 ms
Longer stimulation time favors repetitive nerve stimulation
and direct muscle stimulation.
Shorter stimulation time depolarizes only part of the nerve
and could lead to overestimation of the NMB.
Delivery of a constant current despite a varying impedance
(drying of electrodes, cooling of the limb): if stimulation of
the nerve becomes submaximal, changes in the muscular
response are observed that are not caused by NMB.
Adjustable current output with a digital readout of the current
delivered.
Digital readout of the current delivered to detect a weak battery
or a bad contact with the skin.
Clearly labeled output polarity to avoid errors when connecting
the electrodes.
Audible pulse indicator to warn when stimuli are delivered.
Possibility of delivering all stimulus patterns: single-twitch, TOF,
tetanus, DBS.
DBS = double-burst stimulation; NMB = neuromuscular blockade; TOF = train
of four.
underlying tissue while decreasing the risk of direct muscle

stimulation. The negative electrode should be placed closest to
the nerve to be stimulated and distally. This reduces the current
required to depolarize the nerve.81 Careful attention to the details
listed herein can significantly reduce the skin-electrode impedance
and allow supramaximal stimulation to be achieved at a lower
current:
Cleaning the skin with an alcohol swab.

Sealing the edges of the electrode before applying pressure to its
central area. Otherwise, gel will be lost and the quality of current
conduction will deteriorate,
Avoiding contact between electrodes, which is sometimes difficult to achieve in neonates and small infants.
Needles are almost never used as stimulating electrodes in

children.
Sites of Stimulation: Pharmacologic Differences

Several nerve-muscle units can be used to monitor NMB. The
ulnar nerve + adductor pollicis (thumb), the posterior tibial nerve
+ flexor hallucis brevis (big toe), and the facial nerve + corrugator
supercilii (eye) are the most commonly used because these motor
nerves are superficially placed and their evoked muscular response
is easily observable. However, differences in sensitivity to NMB
exist between the muscle evaluated by the monitor and the
muscles that are of special interest to the anesthesiologist (i.e., the
diaphragm, intercostal, laryngeal, and upper airway muscles).
Muscles that are the most resistant to nondepolarizing muscle
relaxants are the diaphragm, the vocal cords and abdominal wall
muscles, and the corrugator supercilii.82 The muscles that are more
sensitive to muscle relaxants are the upper airway muscles (tongue,
pharynx), masseter, adductor pollicis, and flexor hallucis brevis.
Thus, stimulation of the facial nerve to observe the response of
the corrugator supercilii is most useful to monitor the relaxation
of the laryngeal muscles and the diaphragm (e.g., before intubation), whereas stimulation of the ulnar or posterior tibial nerve
allows the evaluation of the relaxation of the upper airway muscles
(e.g., during recovery).
The time course of NMB is not simultaneous in all muscles: in
children, onset of blockade is faster at the masseter than at the
adductor pollicis.83 This is probably because the masseter muscles
are closer to the central circulation and receive a larger blood flow
than the muscles of the hand and because of small differences in
muscle composition.
Modes of Stimulation
SINGLE-TWITCH STIMULATION: Single-twitch stimulation of the
motor nerve at a frequency of 0.1 to 1 Hz is of limited usefulness
during pediatric anesthesia because the size of the evoked
response must be compared with a control response obtained
before the administration of any muscle relaxant. Sufficient
accuracy is achieved if the response is precisely measured (see
Modes of Evaluation of the Motor Response, later).
TRAIN OF FOUR: The train of four (TOF) is the sequence of four

equal stimulations at 2.0 Hz. This allows an easy identification of
the individual responses and measurement of fading of the fourth
response. Successive TOF stimuli should be separated by at least
a 12-second interval to avoid fade of one sequence interfering with
the following sequence. The evoked response can be quantified
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either as the number of muscular twitches obtained (TOF count)

or as the ratio of the force of the fourth and the first responses
(TOF ratio). A TOF ratio less than 0.5 is an indicator of important
residual NMB, whereas a TOF ratio greater than 0.9 indicates
adequate monitored (as opposed to clinical) recovery. However,
a TOF ratio greater than 0.9 was associated with some visual
disturbance in adult volunteers who had received mivacurium.84
In neonates, the fourth response to TOF is lower even in the
absence of NMB.79 If a depolarizing muscle relaxant (succinylcholine) is used, the responses after TOF stimulation remain
equal in height and the appearance of some fade is associated with
the appearance of a phase II block. This mode of stimulation has
become the gold standard in NMB monitoring because of its
simplicity and ease of interpretation. It is not necessary to establish
a control response, and failure to deliver supramaximal nerve
stimulation does not affect the monitoring of the TOF ratio
because all responses are affected proportionally.
TETANUS: Tetanus consists of a repetitive high-frequency

stimulation in which the responses to individual stimuli summate
and produce a sustained muscle contraction. A rate of stimulation
of 50 Hz during 5 seconds is considered as the maximum physiologic rate because the evoked muscle response is similar to the
maximal tension developed during voluntary muscle contraction.
The response to tetanic stimulation (i.e., the presence or absence of
fading of the contraction obtained) is mainly used to assess the
adequacy of recovery. Tetanic stimulation is painful and should
not be performed in awake patients. Following tetanic stimulation
in the presence of a nondepolarizing muscle relaxant, increased
mobilization and release of acetylcholine occur at the neuromuscular junctions tested. This causes posttetanic facilitation (i.e.,
an increased response to the following stimulus). To avoid this
conditioning effect of previous tetanic stimulation from interfering
with the assessment of NMB recovery, it is necessary to delay any
type of stimulation for 2 minutes after a tetanic stimulation.
POSTTETANIC COUNT: Posttetanic count (PTC) stimulation takes
advantage of posttetanic facilitation to evaluate a deep level of
NMB, when responses to single-twitch and TOF have been
abolished. PTC is the number of responses to 1 Hz stimulation
starting 3 seconds after 5-second 50-Hz tetanus. The number of
posttetanic responses is inversely related to the depth of NMB. The
deeper the block, the smaller the PTC. However, to avoid any
conditioning effect from the preceding tetanic stimulation, this
stimulus pattern should not be repeated more often than every
6 minutes!
DOUBLE-BURST STIMULATION: Double-burst stimulation (DBS)
consists of two short bursts of 60 ms, 50-Hz tetanus separated
by 0.75 second. This time interval allows the muscle to relax
completely between the tetanic stimuli, so that the responses
are perceived as two twitches. These tetanic bursts fatigue the
neuromuscular junction more than single twitches, so that fade
is exaggerated. This type of stimulation is mainly used to detect
residual NMB. An interval of at least 12 to 15 seconds should
separate DBS to avoid any conditioning effect from previous
stimulation. The DBS ratio (i.e., the ratio of the height of the
second response to that of the first) is numerically similar to the
TOF ratio. The DBS is more sensitive than TOF for the clinical
assessment of recovery from NMB in children. With the TOF ratio
measured with mechanomyography (see Modes of Evaluation of
the Motor Response) as the control value, the clinical fade was no
longer detected by TOF when the TOF ratio was 0.44 0.03, but
remained detectable by DBS until the TOF ratio was 0.67 0.04
(P = .00002).85 This is because the two DBS-elicited contractions
are stronger and probably easier to compare than the first and
fourth responses to TOF.
Modes of Evaluation of the Motor Response

VISUAL OR TACTILE EVALUATION: Although commonly used to
assess the evoked motor response, both visual and tactile
evaluations usually overestimate recovery of NMB even when
using DBS.85 In the same way, when visual evaluation of the
response to TOF stimulation was compared with accelerography
or electromyography (EMG) in children, full recovery by clinical
evaluation alone was reported, although a TOF ratio of 0.4 was
still measured.86 Visual and tactile evaluations are most useful only
when they detect fade because this indicates the presence of
significant residual NMB.
MECHANICAL RECORDING: The motor response of the thumb can

be accurately measured using a force transducer. Both the hand
and the forearm are immobilized on an armboard and the thumb
is attached to the force transducer that is preloaded with 100 to
300 g of tension. Although this system is the gold standard for
research purposes, it is very cumbersome to use in everyday
practice.
ELECTROMYOGRAPHY: EMG measures the electrical activity of

the muscle. The biphasic action potentials obtained in response
to nerve stimulation are summated as a single compound action
potential recorded between an electrode placed on the belly of the
muscle studied, a reference electrode placed on the tendon of
the same muscle, and a ground electrode. The most widely used
device is the Relaxograph that delivers only TOF stimuli and
automatically calibrates current output to obtain supramaximal
stimulation. It also displays TOF ratio, TOF count, and the height
of the first twitch as a percentage of the control value. In children,
a good-quality EMG recording can be obtained when the recording electrode is placed on the adductor pollicis or the hypothenar
muscles and the ground electrode is placed on the second or
fifth finger.87 The hypothenar muscles are probably best avoided
in infants and small children because the onset latency between
the stimulus and the compound action potential is often shorter
than the 3 ms internal delay from the stimulus used in the
Relaxograph to avoid stimulus artifact.87 Careful positioning of
the electrodes and immobilization of the limb on a splint, with the
hand in the open position, is very important to obtain successful
recordings. The initial calibration sequence is painful and should
be done after induction of anesthesia in children. Difficulties
with calibration are unfortunately not uncommon. A drift of the
baseline recording or a progressive decrease of the height of
the first twitch in the absence of NMB is also not uncommon. The
final baseline of the EMG trace can be used to calculate recovery
times from NMB,88 and it does not affect calculation of the
TOF ratio.
ACCELEROGRAPHY: Accelerography measures the acceleration produced by the evoked muscle contraction using a small
piezoelectric wafer with electrodes on both sides placed on the
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TABLE 38-14. Monitoring of Neuromuscular Blockade
With a Nondepolarizing Agent
1. Before intubation: first choice TOF count 0 at the
orbicularis oculi
Otherwise: TOF count 0 at the ulnar nerve, but
diaphragm and vocal cords are more resistant!
2. During maintenance: deep block: posttetanic count < 10 at
the ulnar nerve
Moderate block: TOF count 1 3
3. During recovery: first choice: adductor pollicis
Orbicularis oculi may underestimate residual block
Either TOF ratio or DBS ratio
Measurement: visual but absence of fade is unreliable!
Electromyography
Accelerography
DBS = double-burst stimulation; TOF = train of four.
distal phalanx of the thumb or big toe. The setup is easy because
the only requirement is that the thumb or toe must be able to move
freely and no preload is required. Both the TOF-Guard and the
NMT Monitor use this technology. Very small acceleration
transducers (0.5 1 cm, weighing only 20 g) are available that can
be placed on an infants thumb or big toe.89 In children, when using
TOF stimulation, accelerography provides similar estimations
of recovery of NMB as observed with EMG but is easier to use.86
When determining the dose-response curve of rocuronium in
children, the curve determined by accelerography was steeper and
shifted to the right compared with that obtained with mechanomyography.90 The neuromuscular block was consistently underestimated by accelerometry with a bias of 25%!
A summary of the best choice of stimulation and evaluation
techniques according to whether curarization or decurarization is
evaluated is proposed in Table 3814.
Monitoring Mechanical Ventilation

The latest ventilators are equipped with electronic devices and
screens to monitor real-time values of respiratory mechanics
during anesthesia and in the PICU. This helps not only monitor
the adequacy of ventilation but also minimize lung injury (baroand volutrauma) and prevent atelectasis. The following respiratory
parameters and gas values can be displayed on the anesthetic
machine monitor:
Peak Inspiratory Pressure

The PIP is of special significance in pediatric anesthesia because
the potential leak around the tracheal tube and high compliance
of standard breathing systems dictate the use of pressurecontrolled ventilation. The PIP must initially be set at a value that
ensures an adequate VT (e.g., 20 cmH2O) or chest expansion. After
this, it can be adjusted with reference to the upper inflection
point (UIP) of the pressure-volume (PV) loop and the dynamic
compliance.
Plateau Pressure
The plateau pressure is the end-inspiratory pressure (i.e., the
distending pressure of the lungs used to calculate dynamic
compliance).
Positive End-Expiratory Pressure

PEEP is used to prevent atelectasis. PEEP is set at a value just
greater than the lower inflection point of the PV loop and/or with
reference to the dynamic compliance (see Chapter 42).
I:E Ratio
The I:E ratio must allow adequate time for the lungs to deflate or
air-trapping will occur. The typical adult (and default) value is 1:2.
In neonates and infants, values of 1:1 to 1:1.5 are often used.
VT, Minute Volume, and Respiratory Rate

Inspiratory and expiratory VTs are obtained by integrating the flow
signal with time. A difference between the inspiratory and the
expiratory VTs indicates a leak around the TT or in the breathing
system. Expiratory minute volume is obtained by multiplying the
expired VT by the respiratory rate.
Respiratory Rate
The respiratory rate is greater in infants and children than in
adults because of their increased metabolic rate per kilogram.
Typical values are 10 to 12 breaths/min for adults, 12 to 20 for
children, and 20 to 30 for infants.
Compliance
Dynamic compliance reflects the distensibility of the lung-thoracic
system. It is calculated as
Compliance = Expired VT (mL)/
Plateau pressure PEEP (cmH2O)
Care should be taken to avoid pressure injury from the electrodes
or their leads when setting up the neuromuscular monitor device.
Typical values during mechanical ventilation are 5 to 15 mL/

cmH2O for infants, 15 to 50 for children, and 50 to 100 for adults.
A decreased compliance may indicate suboptimal values of
PEEP or PIP, increased intra-abdominal pressure (e.g., during
laparoscopy), or decreasing neuromuscular blockade. When
compliance decreases, the slope of the PV loop moves toward the
horizontal axis and more pressure is needed to maintain constant
lung inflation.
Resistance
Airway resistance expresses the relationship between the pressure
difference across the airway (i.e., between the mouth and the
alveoli) and the rate at which gas is flowing through the airway.
An increase in airway resistance (e.g., because of a kinked tracheal
tube, bronchospasm, or airway secretions) is most easily detected
as a reduction in the size of the flow-volume loop.
Pressure-Volume and Flow-Volume Loops

PV and flow-volume loops illustrate on-line the relationship
between pressure and volume and flow and volume, respectively
(Figure 386). It allows changes in these relationships to be
directly visualized and thus easier to perceive than using numbers
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those monitors in clinical practice. Both CO2 and O2 consumption increase with age and body weight but actually decrease
if indexed according to body weight or surface. This makes interpretation of data even more delicate. The measurement made
should be interpreted according to the childs clinical status and
to other parameters such as BP, hemoglobin level, and SpO2. Their
changes according to therapy are probably more relevant to
clinical care than their absolute value.
Pulmonary Artery Pressure and

Central Venous O2 Saturation
Figure 38-6. Pressure-volume loop measured in a 9-kg child

undergoing pressure-controlled ventilation with a laryngeal
mask airway (LMA).
or pressure or flow versus time curves. Loop recognition is helpful
for an early diagnosis of several adverse events such as TT kinking,
bronchospasm, bronchial intubation, and reduced compliance.
It helps to detect the development of auto-PEEP (e.g., when ventilation frequency is too high) when the expiratory loop no longer
reaches the baseline. Moreover, analysis of the PV waveform can
be used to optimize patient ventilation.
Special Hemodynamic Monitoring:

Measurement of Cardiac Output and
Related Parameters
Different monitoring tools are available to measure cardiac output
in children. Thermodilution or dye dilution or applying the Fick
principle to O2 metabolism is considered the gold standard. The
different tools usable are based on different physiologic principles
and technologies (Table 3815). The latter should be understood
to ensure the safe, effective, and appropriate use of the results of
In children as in adults, insertion of a pulmonary artery catheter allows measurement of right atrial, right ventricular, and
pulmonary pressures, and when occluding a distal pulmonary
artery during balloon inflation, the measurement of the pulmonary
wedge pressure. If the compliance of the left ventricle is normal,
there is no mitral valve disease, the pulmonary and tricuspid valves
as well as right ventricule function are normal, pulmonary wedge
pressure is close to left atrial pressure and reflects left ventricular
preload. The insertion of a flow-directed pulmonary catheter (PC)
is indicated in the presence or anticipation of left ventricular
dysfunction, to monitor pulmonary artery pressure (e.g., after
corrective cardiac surgery or to make the diagnosis of cardiac vs.
noncardiac pulmonary edema), to monitor mixed venous oxygen
saturation (SvO2) or to measure cardiac output either by thermodilution or by using the Fick principle (via measure of SvO2).
Guidelines for adequate catheter size according to the childs body
weight are given in Table 3816.
In the authors experience, the occlusion pressure measured
with a PC in an infant or small child often overestimates left atrial
pressure because the fast heart rate does not allow enough time
for equilibration of the pressures across the pulmonary bed.
Regarding cardiac output measurement, interpretation of the
data is also difficult because it varies with age and it is influenced
by associated pathologies such as presence of an intracardiac
defect or end-stage liver disease. SvO2 is measured by withdrawing
a blood sample through the nonwedged pulmonary artery catheter
or by fiberoptic oximetry. In the absence of cyanotic cardiac
disease, the normal value is close to 75%. The risks and contrain-
TABLE 38-15. Devices to Assess Carbon Monoxide in Children

Invasiveness
Reliability
in children
TPTD + APCCO
+++
+++
TPLD + APCCO
++
+++
Flowtrac/Vigileo
Edwards, US)
Cardio QP
(Deltex, UK)
APCCO
Esophageal Doppler
+/
NICO (Respironics, NL)
CO2 Fick
rebreathing)
Electrical (impedance)
cardiometry
+/
+/
Name (Manufacturer)
Technology
PiCCO (Pulsion,
Germany)
LidCO (LidCO, UK)
Aesculon (Cardiotronic,
Germany)
Remarks
Multiple hemodynamic parameters,
continuous, gold standard in children.
Continuous, requires injection of lithium,
not for young children.
Uses existing arterial catheter, continuous,
calibration not possible.
No intravascular catheters needed, velocity
in descending aorta.
Difficult in small children.
Noninvasive, only in intubated patients with
VT > 300 mL.
Noninvasive, continuous, no calibration.
APCCO = arterial pressurebased continuous cardiac output; TPLD = lithium dilution; TPTD = transpulmonary thermodilution; USTD = transpulmonary
ultrasound dilution; VT = tidal volume.
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TABLE 38-16. Pediatric Pulmonary Artery Catheters:
Recommended Sizes
Weight, kg
<15
1540
>40
Introducer
Size, Fr
5
6
8.5
Catheter
Size, Fr
4
5
7
Distance From
Right Atrium
Port to Tip, cm
10
10 or 15
20
dications are similar to those for to the placement of any central

venous catheter (see Chapter 70). There are, however, specific
complications of the insertion of a PC:
Pulmonary artery rupture or thrombosis.

Pulmonary infarction.
Dysrhythmias: ventricular or supraventricular arrhythmias,
rarely acute right bundle-branch block.
Cardiac valve damage.
Intracardiac knotting.
Thrombocytopenia..
The risk-benefit ratio of the technique should be carefully

evaluated on an individual basis.
Because of all those risks and limitations, noninvasive techniques such as transesophageal/transthoracic echocardiography/
Doppler are, therefore, increasingly used to monitor cardiac
output, heart function, and filling in children. Central venous
oxygen saturation (ScvO2) in the superior vena cava reflects O2
extraction from the upper part of the body and can be used as a
surrogate for SvO2. In the absence of cardiac pathology, its normal
value is 70 to 85%. A multilumen central venous catheter allowing
continuous ScvO2 (one lumen contains a fiberoptic filament) is
now available in pediatric sizes (Pediasat Oximetry catheter): two
lumens 4.5 French (5 or 8 cm) and three lumens 5.5 French (8 and
15 cm). It needs in vivo calibration (blood sample analyzed with
a co-oximeter) after insertion and includes a signal quality index
from 1 to 4; a value of 4 means unreliable measure.91
Changes in SvO2/ScvO2 usually precede modifications of other
hemodynamic parameters and excellent tools to evaluate the
adequacy of cardiac output and tissue perfusion. They are very
useful in the management of congenital heart disease, shock, and
resuscitation.
line should be checked regularly because a slow drift sometimes

occurs. The waveform displayed should be regularly checked
to ensure that the PC is not permanently wedging. It reduces
pulmonary perfusion in small children and is a significant risk
factor for pulmonary infarction or pulmonary artery perforation.
If thermodilution is used to measure cardiac output, the volume of
cold injectate used should be measured to avoid fluid overload.
Pulse Contour Analysis

The basic principle of pulse contour analysis is that the area under
the curve of the arterial waveform correlates with cardiac stroke
volume (Figure 387). However, the arterial waveform is the
combination of an incident pressure wave (proportional to stroke
volume) and a reflected wave created by the reflection of the
preceding pressure wave from the periphery, which is influenced
by arterial compliance and systemic resistances. Pulse contour
analysis should be used to estimate changes in stroke volume and
cardiac output rather than to measure them precisely.
The PiCCO system incorporates both a transpulmonary
thermodilution (through a thermistor at the tip of the catheter) and
a computerized analysis of the pulse pressure contour to continuously measure the cardiac output. It is a 3- (7 cm) or 4-French
(8 cm) catheter inserted in the femoral artery (or radial artery in
older children and adolescents). Transpulmonary thermodilution is
used first to calibrate the system by injecting cold saline in a central
venous catheter (515 mL depending on the patients weight) and
pulse contour analysis is used to measure stroke volume and
calculate cardiac output, cardiac function index, intrathoracic
blood volume, and extravascular lung water. The system has to be
recalibrated every 4 hours (or earlier in case of brisk hypovolemia
or hypotension). Pulse contour analysis is much more reliable in
children without intracardiac shunts92 than in the presence of
unrepaired congenital heart disease.93
Another equipment using pulse contour analysis is the FloTrac
sensor, which has to be used with a Vigileo monitor. The sensor is
connected to a peripheral arterial catheter and the cardiac output
is continuously calculated using a secret algorithm without any
need for calibration. It has been designed for adults; its reliability
in children is not established.
Quality Control
To prevent air embolism, all the ports of the PC should be carefully
flushed with saline before insertion. Fluoroscopy is useful during
insertion of the PC because it allows proper orientation of the
balloon tip, which helps accurate placement and reduces insertion
time. The tip of the PC should be placed in an area of the lung
where pulmonary venous pressure exceeds pulmonary alveolar
pressure (i.e., in a dependent part of the lung [West zone 3]).
Otherwise, the pressure measured in the PC, whether pulmonary
or occlusion pressure, will be influenced by airway pressure.
The measurement should be made at the end of expiration to
avoid any respiratory interference. When using a 5-French PC to
measure cardiac output, the distance between the atrial and the
distal ports should be adapted to the childs height to obtain
reliable results. The pressure transducer should be at a level with
the childs midaxillary line and the position of the zero base-
Figure 38-7. PICCO tracing (and derived hemodynamic values)

obtained from a 20-gauge catheter inserted in the femoral artery
of a 12-kg child.
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Esophageal Doppler (CardioQP)
Partial CO2 Rebreathing
Esophageal Doppler measures beat-to-beat blood flow velocity in

the descending aorta via a Doppler transducer at the tip of a flexible
probe introduced in the esophagus. The probe should be greased
with lubricant jelly before being carefully inserted in the esophagus.
It should be rotated in order to obtain the best Doppler signal
possible. Aortic blood flow is calculated from the product of flow
(average of five cycles) times the aortic diameter as obtained from
a normogram based on age, weight, and height. Blood flow in
the descending aorta is only about 70% of total cardiac output: a
correction factor of 30% is automatically added to the measured
value. Cardiac output can be calculated from the area under the
velocity-time waveform (called stroke distance, i.e., the distance
traveled by a column of blood during one systole). By multiplying
stroke-distance by heart rate, one obtains minute-distance. Multiplying the latter times the aortic diameter as obtained from a
normogram based on age, weight, and height gives an estimation
of cardiac output. Recent research suggests that measuring the
childs aortic diameter or cross-sectional area in M mode instead
of using the normogram would improve the accuracy of the
measurements.94
Systolic flow time corrected for heart rate reflects preload
(it is shorter in case of hypovolemia) but is also influenced
by systemic vascular resistances whereas peak velocity is an index
of left ventricular contractility. This monitor is relatively easy
to use and should be use to follow the trends in cardiac output
or other derived values rather than to accurately measure
cardiac output.
The NICO (Novametrix Medical Systems) is a noninvasive

monitor that uses partial rebreathing of CO2 to determine cardiac
output via the Fick principle in mechanically ventilated patients.
The monitor includes a mainstream CO2 sensor, a special valve
able to direct the flow of expired gas to a rebreathing tubing added
to the ventilator circuit, an airflow sensor (to measure minute
ventilation), and a pulse oximeter. The change in PETCO2 is measured during a short period of rebreathing and is used to estimate
the change in PaCO2. It is assumed that cardiac output, carbon
dioxide production (VCO2), and physiologic deadspace remain
the same during the measurement period: thus cardiac output =
VCO2/PETCO2. The pulmonary shunt fraction is calculated to
correct the measurement.
NICO has been validated in adults but the correlation with
thermodilution becomes poor when cardiac output is high. A
pediatric study has shown that NICO, using the shortest position
of the rebreathing tubing (125 mL), provides clinically acceptable
results (mean percentage difference between NICO and thermodilution: 3, 2% 17.2%) in children with no intracardiac shunt
lesions nor pulmonary hypertension, a body surface area greater
than 0.6 m2 and a VT greater than 300 mL.97 The system is difficult
to use in the operating room.
Echocardiography
The indications and use of transesophageal echocardiography
are described in Chapter 73. In addition to the visualization of the
cardiac chambers, valves, and flows, echocardiography can be used
to measure cardiac output. The operator needs to measure the
diameter of the ascending aorta. Its surface (in square centimeters)
can be calculated and cardiac output is estimated by multiplying
this surface by the blood velocity (in centimeters per second)
measured in the ascending aorta using the Doppler function of
the monitor. The main advantage of echocardiography, whether
transthoracic or esophageal, in the context of cardiac output evaluation is that it also allows direct visualization of cardiac contractility and preload. It should be kept in mind that interpretation of
echocardiography needs training and experience and that transesophageal echocardiography (the easiest to use in the operating
room) can cause complications such as tracheal, bronchial, or
great vessel compression and esophageal injury.95
Electrical Velocimetry
This noninvasive technique uses the changes in electrical
conductivity of aortic blood flow in the thorax, as measured via
skin electrodes, to calculate stroke volume and cardiac output.
Standard ECG electrodes are placed side to side in a vertical
direction (two at the left middle and lower neck level and two on
the thorax, on the midaxillary line and at the level of the xyphoid
process). The signal is correct if an ECG signal and an impedance
waveform are seen on the monitor. This system does not correlate
well with thermodilution in cardiac children but can be used to
evaluate changes in cardiac output.96
Neurophysiologic Monitoring
Electroencephalography Monitoring
The electroencephalogram (EEG) recorded from the scalp is
generated by electrical activity in the cerebral cortex (see Chapter
74). Subcortical activity is not recorded by surface EEG. EEG
consists of waves of various frequencies and amplitudes. The
frequencies are divided in four categories: (813 Hz), 1 (1330
Hz), (48 Hz), and (0.54 Hz). To facilitate its quick interpretation by nonspecialists, EEG is mathematically transformed by
Fourier analysis. The latter is based on the hypothesis that each
waveform of the raw EEG is the summation of various sinus waves
with different frequencies and amplitudes. The EEG can be
analyzed by spectral analysis and displayed as a power spectrum of
the four categories of frequencies. By definition, median frequency
divides the power spectrum (i.e., area under the curve on a graph
with frequency in Hz on the x-axis and power in V2 on the y-axis)
in half and spectral edge frequency (SEF) is the frequency under
which 95% of the EEG is registered (Figure 388).
Different devices using continuous EEG monitoring are
currently used to measure depth of anesthesia. However, because
the EEG measures only the cortical activity, only the hypnotic
component of general anesthesia or sedation is evaluated. EEG
monitoring is unable to predict the absence of motor response to
a noxious stimulus that is mediated by subcortical and spinal
structures. The relationship between EEG under anesthesia and
consciousness is imprecise and drug-dependent. Some anesthesiarelated influences on EEG are reported in Table 3817. Last, there
are age-related differences in EEG: for example, the dominant
frequency is 5 Hz at 6 months, 6 to 7 Hz from 9 to 18 months,
7 to 8 Hz at 2 years, and 9 Hz at 7 years and reaches the adult value
of 10 Hz around 15 years.98,99 Finally, the relationship between
arousal and consciousness as well as the transition from the awake
to the asleep state are very different in infants. All the EEG-derived
monitors can be reliably used in children older than 2 years, but
their use in infants cannot be recommended at present.
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TABLE 38-17. Factors Influencing Electroencephalography

and Bispectral Index Under Anesthesia
Agent or Environmental
Change
Halogenated agents
N2O
Propofol
Opiates
Ketamine
Xenon
Hypocapnia
Hypothermia
Figure 38-8. Power spectrum of the awake electroencephalogram

(EEG). Median frequency and SEF are shown on the graph with
frequency in Herz on the x-axis and power in V2 on the y-axis.
BISPECTRAL INDEX MONITOR: The bispectral index (BIS) monitor

uses an algorithm based on changes of EEG in adults undergoing
sedation. This algorithm is regularly adapted according to ongoing
research. A one-channel EEG undergoes Fourier transformation
and bispectral analysis to give a single number called BIS. It ranges
from 0 (isoelectric EEG) to 100 (awake). A value between 40 and
60 is considered satisfactory for general anesthesia (sedation
6585). The monitor provides the BIS value, the real-time unprocessed EEG waveform (to enable the user to detect burst suppression
or electric silence), the amount of EEG suppression (suppression ratio: percentage of time over the last 60 s when EEG was
isoelectric), a facial electromyogram in decibels (a potential source
of artifact), and a signal quality index (SQI bar graph) to give an
indication of the amount of interference from EMG as a bar graph
(Figure 389). The adult disposable sensor presents with four
electrodes, and the pediatric sensor has only three electrodes. Some
Effect on BIS
BIS higher under halothane than
under equipotent doses of
isoflurane or sevoflurane
Moderate increase (70%)
Dose-dependent diminution
No influence except in very high
doses
Increases BIS
Unreliable
Increases total EEG power
Decreases brain metabolism and,
thus, EEG and BIS
BIS = bispectral index; EEG = electroencephalogram.
hydrogel is present on the electrodes to reduce impedance. When

placed on the skin, each electrode needs to be pressed with the
finger for 5 seconds to ensure optimal conductance. The electrodes
are applied as follows: the first in the center of the forehead, the
second above the eyebrow, and the last on the temple. They are
connected to a recording system in which the signal is processed.
The device requires no calibration but is subject to interference
from electric equipment present in the operating room.
The underlying pathology of the child and its treatment must
be kept in mind when interpreting BIS. For example, although
BIS monitoring changes during anesthesia were similar, absolute BIS values were lower than in normal children in profoundly delayed noncommunicating children with quadriplegic
cerebral palsy under antiepileptic therapy.100 In the same way, even
awake low BIS values are not unexpected in the presence of
an abnormal cerebral cortex.101 The pharmacology of the EEG
effects of sevoflurane also explains the paradoxical increase
in BIS during induction with sevoflurane.102 In children, BIS is
probably more useful to avoid too deep maintenance of general
Figure 38-9. A: Pediatric bispectral index (BIS) electrodes. B: Signal obtained during induction. Note that the BIS value increased
when the child was switched from a Mapleson D circuit to the circle circuit. This short period of time is at risk for awareness because
the alveolar concentration of the halogenated agent decreases transiently.
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TABLE 38-18. Narcotrend Stages and Index

Level of
Consciousness
Narcotrend
Stage
Narcotrend EEG
Index
Activity
Awake
Sedated
Light anesthesia
General anesthesia
Deep general
anesthesia
General anesthesia
with burst
suppression
A
B0B2
C0C2
D2D2
E0E2
10095
9480
7965
6437
3613
F0F1
120
Isoelectric,
suppression
burst
EEG = electroencephalogram.
anesthesia (BIS < 20) and to avoid awareness in at-risk situations103

(see Chapter 77).
NARCOTREND: Narcotrend is an automatic EEG analysis system

using an algorithm based partially on a sleep classification. This
algorithm includes age-related changes of the EEG and helps
differentiate 6 EEG stages (AF) and 15 substages (Table 3818).
It provides a Narcotrend index ranging from 100 (awake) to 0.
Other EEG parameters are provided such as power spectrum,
relative power (percentage) of frequencies of waveforms, and SEF.
The system uses a single-channel lead with three standard ECG
electrodes placed on the patients forehead (two lateral and one
central reference electrode). Comparative studies in adults have
shown that, although BIS and Narcotrend index are very close,
both measures are not linearly scaled and equal numbers do not
represent similar hypnotic states. Pediatric studies have shown
a negative correlation between end-tidal halogenated agent
and Narcotrend index.104 However, even if the Narcotrend index
follows changes in sedation level, there is such a high probability
of incorrect prediction of changes that its clinical usefulness in
pediatric patients is still doubtful.105
SPECTRAL ENTROPY: Spectral Entropy is a measure of the degree

of disorder in the EEG (see Chapter 75). It quantifies the
randomness of distribution of the frequencies of the EEG after
removing artifacts, normalizing amplitudes, and applying Fourier
transformation. The working principle is that frequency disorder
decreases with increasing depth of anesthesia. The Datex-Ohmeda
Entropy module measures state entropy (091), a slow response to
changes computing the EEG-dominant frequencies (0.832 Hz),
and response entropy (0100), a quicker response to changes
computing the EMG-dominant frequencies (0.847 Hz). If there
is no electromyographic activity, both values are the same.
Adequate depth of anesthesia is achieved when both parameters
vary from 40 to 60. Because it is independent of amplitude and
frequency, this monitoring could be less age-specific than the
other EEG processing monitors. Preliminary studies have shown
that, in the same way as BIS, it is less reliable in infants.106
Monitoring Brain Oxygenation

This monitoring is mostly used during cardiac surgery to monitor
brain oxygenation during surgery and in the PICU (Figure 38
10). There are two main systems.
The INVOS by Somanetics uses two wavelengths of nearinfrared light to measure the brain concentrations of HbO2 and Hb
and calculate the SaO2 of the part of the brain (frontal cortex)
under the electrodes. The numerical value displayed (called rSO2i
[regional cerebral saturation index]) is the ratio of HbO2 to total
Hb (1595%) measured in the electrode light path. The INVOS
probe is placed on the forehead, below the hairline. The probe
contains one diode emitting 15 times/s two wavelengths of nearinfrared (730 and 810 nm) light that passes through a small part of
brain tissue before being detected by two detectors placed 3 and
4 cm from the emitting diode. The proximal detector measures
light absorbed by extracranial tissue and the distal one light absorbed by all tissues. The algorithm subtracts proximal absorption
from distal absorption to obtain cranial tissue absorption and
calculates rSO2i on the mean of 50 consecutive measures. The
INVOS 5100 model can be used in children 4 to 40 kg. It uses a
Figure 38-10. A: INVOS electrodes on the infants forehead. This infant undergoing open heart surgery is also equipped with a
transesophageal echocardiography probe and a 4.5-Fr ScvO2 (central venous oxygen saturation) catheter (Pediasat) inserted in the
right internal jugular vein (dressing removed for picture). B: Monitor and values measured.
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specific algorithm taking into account the thinner skull and
extracranial tissues present at that age.
The NIRO300 by Hamamatsu measures absolute values
of HbO2 and Hbtot by spatially resolved spectrophotometry. Laseremitting diodes generate light at 775, 825, 850, and 904 nm.
Absorption of those wavelengths is measured by detectors placed
at a distance of 4 cm, and a specific algorithm allows the measurement of absolute concentrations of HbO2, Hbtot and calculation of
a tissue oxygenation index (TOI).
Because they measure tissue oxygenation, both rSO2i and TOI
correlate only moderately with either venous bulb saturation
(venous blood drainage from the brain) or ScvO2 (total venous
drainage).107 No standard values are available. Ideally, these
monitors should be placed on the childs forehead when awake
and used as a trend monitoring of brain oxygenation. For example,
when using the INVOS system, normal rSO2i values of 68% 10%
are obtained in healthy children but are much lower in case of
cyanotic cardiac disease (57% 12% in tetralogy of Fallot). This
individual reference value can be used to determine a threshold
value that is usually a decrease of 20% or more of the initial rSO2i
or an rSO2i lower than 50%. Ideally, one probe should be placed
over each cerebral hemisphere. This allows detecting quickly bad
positioning of an arterial or venous bypass cannula.108
The INVOS device is also used to monitor splanchnic (kidney,
liver) tissue oxygenation in infants. The probe is positioned on the
skin surface closest to the organ (lumbar area for the kidney).
Splanchnic oxygenation is normally 10 to 20% higher than the
cerebral one. It seems that a difference of less than 10% between
splanchnic and cerebral rSO2i is a predictive sign of tissue
hypoperfusion and an increase in anaerobic metabolism. It could
thus be used to quickly detect hypoperfusion and low cardiac
output.109 The latest version of INVOS includes this simultaneous
multisite monitoring option.
Monitoring Brain Perfusion: Transcranial Doppler

A 2-MHz pulsed-wave ultrasound probe (different sizes are
available) placed at the level of the temporal window (i.e., above the
zygoma just anterior to the tragus of the ear) can be used to measure
cerebral blood flow velocity in the middle cerebral artery in realtime. This measurement can also be made through the anterior
fontanelle in small infants. The monitor displays and measures peak
systolic velocity and mean flow velocity (in centimeters per second).
Moreover, it calculates the pulsatility index:
Peak systolic velocity Peak diastolic velocity/mean velocity
Normal values in awake children are given in Table 3819.110
When interpreting these measurements, keep in mind that
transcranial Doppler measures velocity, not flow. Although velocity
and flow are generally correlated, the status of the cerebral vascular
resistances (e.g., according to PaCO2) must be taken into account.
Auditory Evoked Potentials

Only the middle latency evoked potentials (MLAEPS) are briefly
described here: sensory and motor evoked potentials as used
during scoliosis surgery are described in Chapter 76. The
MLAEPS are extracted from the EEG 10 to 100 ms after an
auditory signal delivered through headphones. They represent the
earliest cortical response to this stimulus. It is an active measure of
brain activity, contrary to the previously described EEG monitoring devices. Both their amplitude and their latency are influenced
by anesthesia. Different algorithms have been elaborated but
even the latest one (AAI-1.6 of the AEP Monitor by Danmeter
Neurosensor) is a poor predictor of sevoflurane concentration in
infants and children.111
Special Monitoring
Blood Chemistry112
The presence of an arterial or central venous catheter allows
sampling of blood to measure blood gases, electrolytes, and
glucose level as well as coagulation tests.
Continuous intra-arterial blood-gas monitoring is presently
available. The Paratrend 7+ is a 0.48-mm diameter heparin-coated
sensing element that can be introduced in a 20gauge arterial
cannula without interfering with the invasive measurement of BP.
The sensor in fact consists of three separate optodes to measure
PaO2, PaCO2, and pH and a thermocouple to measure temperature.
A pediatric version (Neotrend) can be inserted via the femoral or
umbilical artery. No interference from anesthetic agents (halogenated agents, propofol) has been described so far. It should be kept
in mind that the measurement system becomes unreliable if
blood flow around the catheter decreases or stops (vasospasm,
resuscitation) and that the sensing probe should be inserted for a
sufficient distance (10 cm in children and adults, 23 mm in
neonates and infants) over the distal end of the arterial cannula to
avoid contamination with the arterial flush solution. Both the
monitor and the disposable sensor are very expensive. The use of
this monitoring device is reserved for situations in which the
patients clinical condition can change rapidly (acute respiratory
failure, major acidosis). The system requires 30 minutes warm-up
time for calibration before being used.
Nitric Oxide and Its Byproducts

GOAL AND INDICATIONS113: Nitric oxide (NO) is sometimes used
in the operating room or cardiac catheterization unit to continue
TABLE 38-19. Normal Transcranial Velocities in Awake Infants and Children

Age
Depth, mm
03 mo
312 mo
13 y
36 y
610 y
1018 y
25
30
3545
4045
4550
4550
From reference 100.
Mean Velocity,
cm/s
Peak Systolic
Velocity, cm/s
2442 10
74 14
85 10
94 10
97 9
81 11
4675 15
114 20
124 10
147 17
143 13
129 17
End-diastolic
Velocity, cm/s
1224 8
46 9
65 11
65 9
72 9
60 8
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a therapy initiated in the PICU (e.g., in neonates with pulmonary

hypertension or congenital diaphragmatic hernia) or to allow
weaning from cardiopulmonary bypass in infants with complex
cardiac pathologies. NO delivery is more complicated with anesthesia machines than with PICU ventilators because some rebreathing of exhaled gases occurs. The true inspired concentration
of NO depends on the NO concentration added to the system, the
FGF, the I:E ratio, the patients minute ventilation, and NO uptake.
NO can be delivered accurately with an anesthesia machine using
either a nitrous oxide (N2O) flowmeter or a special device (e.g.,
INOvent, INOmax, OPTI-NO), provided FGF is greater than the
patients minute volume. It is important to accurately measure inspired NO but also nitrogen dioxide (NO2), which is produced in
the presence of O2 and can cause pulmonary edema. The concentration unit used to measure NO is parts per million in volume
(1 ppm = 1 mol NO/106 mol gas) or even parts per billion (1 ppb
= 1 mol NO/109 mol gas).
DESCRIPTION: Mass spectrometry, electrochemical sensing, or

chemoluminescence reaction devices can be used to measure NO.
NO and NO2 levels are measured in the inspiratory limb of the
ventilator.
The electrochemical analyzer (e.g., Noxbox) consists of
analyzing gases through an oxidoreduction reaction. The potential
difference produced by the transfer of electrons is proportional to
the each gas concentration. Separate cells measure NO and NO2.
These devices are mainly used as security sensors to warn when
NO or NO2 concentrations are above a fixed limit or when the NO
cylinder is empty.
Chemoluminescence is based on the reaction of NO with ozone
in a chamber. This produces energized NO2 molecules which emit
photons. The amount of light emitted is proportional to the
concentrations of NO + NO2 initially present in the chamber. To
measure the original NO2 level, a molybdenum converter reduces
NO2 to NO in a parallel system. This allows the exact measurement of NO concentration by subtracting NO2 of the parallel
system from (NO + NO2) measured in the chamber. Although
widely used in the clinical setting, this method is susceptible to
several artifacts such as
The presence of a high O2 concentration.

The presence of water (3.5% of the signal is lost for each percent of humidity present); a water trap or a heated sampling line
is thus mandatory.
The presence of halogenated agents. NO2 monitoring is temporarily affected by a sudden change in inspired concentration
of a halogenated agent.114
The composition of the tubing used to sample the gas. Depending in part on its nature and in part on the NO concentration present in the tubing, molecules of NO may be either
absorbed or released and the measurement will be affected
accordingly.
POSSIBLE COMPLICATION: Because NO therapy can cause

methemoglobinemia, MetHb levels should be checked regularly
when NO is administered.
Transcutaneous Blood Gas Measurement115

GOAL: Transcutaneous monitoring is used to measure skinsurface PtcO2 and transcutaneous arterial carbon dioxide pressure
(PtcCO2) and to estimate PaO2 and PaCO2. It is mostly used in
neonatal intensive care in conjunction with SpO2 and arterial

blood gases when available. However, better design of electrodes
nowadays permits their use in children and even adults.
DESCRIPTION AND LIMITS: Heating of the skin between 42 and

44C induces local hyperperfusion. PtcO2 is measured with a
miniaturized Clark electrode whereas PtcCO2 is measured with a
modified Severinghaus electrode (pH-sensitive glass electrode).
Both measurements are under the influence of all variables that
affect skin perfusion such as
Skin thickness. They are, therefore, more often used in neonates

(less keratinized skin). The presence of edema impedes the diffusion of O2.
Peripheral perfusion: for example, hypovolemia, hypothermia,
increased peripheral vascular resistance, hyperventilation, and
vasoactive drugs.
Electrode temperature, but are also appropriate for use by
experienced personnel:
Careful calibration and maintenance of the electrode (intact
membrane).
Proper placement of the probe on the skin.
Avoidance of air bubbles being trapped between the membrane
and the skin.
Transcutaneous measurements should be regularly validated

against an arterial sample. Other technical limitations make this
equipment difficult to use in the operating room:
Warm-up time of 5 to 10 minutes.

Need for calibration (510 min).
A low response time. It is of little usefulness in acute situations.
Interference of electrosurgical apparatus.
Halothane and N2O can produce falsely high PtcO2 values unless
a Teflon membrane or an electrode with a low polarization voltage is used.
POSSIBLE COMPLICATIONS: Care should also be taken to change

the measuring site regularly to avoid local skin injury (erythema,
blisters, burns).
PTCo2: Ptco2 is an indirect measurement of PaO2 and does not
reflect O2 delivery nor O2 content. Their assessment requires the

measurement of hemoglobin and its saturation. Although PtcO2
monitoring is usually recommended in premature infants to avoid
hyperoxemia and lessen the risk of retinopathy of prematurity, the
correlation between PaO2 and PtcO2 becomes less good when PaO2
is greater than 100 mmHg.
PTCco2: The PtcCO2 is usually slightly higher than PaCO2 owing
to local skin metabolism producing CO2. In the presence of an increased deadspace and/or shunt fraction, which increase the difference between PaCO2 and PETCO2 (e.g., infants with respiratory
failure), PtcCO2 provides a more accurate estimation of PaCO2 than
does PETCO2.115 A monitor integrating in the same ear probe a
pulse oximeter and a PtcCO2 Severinghaus electrode (Tosca monitor) is successfully used in children14 and very low birthweight
infants116 (see Figure 382). It can be used to evaluate PaCO2 when
PETCO2 is unreliable or unmeasurable (e.g., during laparoscopic
surgery, high-frequency jet ventilation [HFJV],117 noninvasive
ventilation, or sedation). However, it is not substitute for PETCO2
monitoring because the latter has a shorter response time, can
act as a deconnection alarm in intubated patients, and helps to
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diagnose pulmonary embolism. The analysis of the capnogram
gives useful information.
Peripheral I.V. Cannulas

Access to the venous circulation should be obtained for every
anesthesia. The techniques and sites of venous access are described
in Chapter 69.
Description
Nontapered Teflon or polyurethane over-the-needle cannulas are
currently available. The diameter of the I.V. cannula is related to
the childs size, chosen vein, and the importance of the procedure
to be performed: 22-gauge cannulas can be used from the neonatal
period up to 4 to 5 years, whereas 24-gauge cannulas are used in
premature infants, and 26 gauge in very small premature infants.
The design of these cannulas is still improving. For example,
Vialon cannulas have a thinner wall and are able to deliver greater
fluid flow than Teflon cannulas of the same gauge size. These
cannulas are better fitted on their inner needle, which results in a
lesser incidence of cannula damage when puncturing the skin.
Some cannulas are designed with a build-in silicone injection valve
(e.g., Venflon or Adsyte).
Whenever a medication (e.g., a muscle relaxant) is injected,
care should be taken to flush the injection site and catheter in
order to avoid the retention of part of the dose and its delayed
administration when another injection is performed.118 In order
to prevent needlestick injuries, I.V. cannulas are now designed
with either a spring-loaded mechanism (e.g., Insyte or Angiocath
Autoguard; pushing a button retracts the needle into a plastic
safety barrel when it is taken out of the cannula) or a protective
shield that automatically (no active maneuver needed) retracts the
needle point when it is withdrawn from the catheter (Introcan
Safety). The efficient use of these catheters needs some experience
and training. Although the number of needlesticks is dramatically
reduced, an increased incidence of blood splashes of the environment can be observed, especially with the active systems.119 Some
devices are designed to improve peripheral vein visualization and
cannulation. For example,
Transillumination with a portable light source and a light-emitting diode (LED; e.g., Vein-Locator-Universal, Wee Sight).120
Using a movable system that includes a near-infrared light
source, a digital video camera, and a digital image projector. It
provides a real-time image of the subcutaneous veins onto the
surface of the overlying skin (Veinviewer).
seconds instead of advancing the catheter farther will allow blood

to appear at the needle hub. A good trick to detect immediate
entering the vein in children whose veins are poorly filled is
to prime the catheter with some saline. Red blood cells will be
seen running up to the catheter hub as soon as the vein wall is
pierced.
Small polyurethane cannulas sometimes adhere to their needle,
which can make venous catheterization difficult. Gentle mobilization before the use of the cannula over the needle is useful. To
avoid damaging the cannula or peelback of its tip when entering
the skin, a small nick in the skin can be made with a 19-gauge
needle before inserting the venous catheter is useful. Because there
is a risk of shearing or piercing the shaft of the catheter, the needle
should not be re-inserted into the cannula blindly, that is., beyond
the point of entry in the skin. The cannula should be carefully
fixed to the skin in order to avoid losing venous access at critical
moments (e.g., in case of agitation during recovery) or to have to
stick the child again.
Complications
In addition to a small tender hematoma at the site of skin
penetration, the main possible complications of peripheral venous
cannulation are phlebitis and extravasation. Phlebitis is caused by
mechanical and chemical irritation of the venous endothelium.
It depends on the material of the cannula (polyurethane is less
phlebogenic than Teflon), the duration of catheterization, the
nature of the solution injected (pH, tonicity, composition), and
the site of insertion (veins of the upper limb are less prone to
phlebitis than the lower limb).
Delayed diagnosis of extravasation can have dramatic consequences: for example, skin necrosis (Figure 3811), compartment
syndrome, and delayed limb deformation.121 It should be prevented by a careful insertion technique and surveillance of the
peripheral venous line. At the time of insertion of the catheter, it
is sometimes difficult, in the absence of blood return, to make sure
the cannula is truly in the vein. A simple way to confirm the I.V.
placement of the cannula is to allow the infusion to drip by gravity
alone. The obtained flow rate is observed and compared with the
flow rate obtained when the anesthesiologists hand occludes the
limb (like a tourniquet) well above the tip of the I.V. cannula. If
the flow stops quickly, the cannula is in the lumen of the vein; if the
flow does not change, extravascular placement of the cannula
should be strongly suspected.122
Practical Aspects
Strict asepsis should be observed during venous cannulation.
Because the inner needle of the catheter is slightly longer than the
cannula, it may be located in the vein (with blood running back in
its hub) while the cannula is still outside it. Therefore, as soon as
a venous flashback is observed at the needle hub, which means
that it is in the vein, the needle should be advanced a few
millimeters farther to make sure the cannula has also entered the
venous lumen. The needle is then slightly withdrawn and kept
immobile while the cannula is gently advanced over it into the
vein. However, the venous flashback is sometimes not immediate.
Some experience is required to recognize entering the vein by
feeling a click when the venous wall is pierced. Waiting a few
Figure 38-11. Extravasation of I.V. fluids in the lower right leg.
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I.V. Administration Sets

The amount of I.V. fluids administered during the perioperative
period needs to be carefully measured. The use of a microdrip
infusion set (e.g., 150-mL Burette or Soluset) allows the accurate
delivery of small volumes of infusate and also prevents accidental
volume overload if care is taken to fill it with a volume of fluid not
exceeding the calculated hourly infusion rate. Conversely, for
procedures in which the rapid administration of fluid is necessary (e.g., major abdominal surgery), it is wise to place a large
(adult) extension between the stopcock and the I.V. cannula to
lessen the resistance to injection. A standard adult infusion set is
used in children older than 10 years. Extension tubing is often
necessary, especially if the I.V. cannula has been placed in the foot.
Many textbooks recommend using a short T-connector as the last
extension, to reduce the deadspace to be flushed. However, using
this injection port carries a risk of embolization of part of its
material (latex or elastomere) and of needle injury to the caregiver.
The author prefers using short Luer-Lok extension tubing (10 cm
long, 0.1 mL capacity). The use of nonLuer-Lok fitting extension
carries a risk of accidental and possibly unnoticed disconnection
with its risks of hemorrhage or air embolism.
The whole I.V. administration set should be carefully flushed to
eliminate any bubble of air both when prepared and immediately
before connection to the I.V. cannula. Cases of air embolism
caused by the presence of air in the I.V. administration set do
occur.123 and even small bubbles should be eliminated because
there is a risk of paradoxical embolism in children with any
intracardiac shunt or a patent foramen ovale. An air filter can be
added in the I.V. fluid administration set but it increases resistance to injection, which may be deleterious when rapid volume
loading is necessary. When blood is administered, a standard
adult-type 170-m filter is sufficient to trap leucocytes microaggregates, and the use of smaller pore (2040 m) filters is no
longer recommended.
If an I.V. patient-controlled analgesia (PCA) device or a
continuous infusion of an opiate is used to control postoperative
pain, a special I.V. administration set, equipped with an antisiphon
and antireflux valve, should be connected to the I.V. administration
set in order to avoid the retrograde accumulation of the infused
drug in case of occlusion of the I.V. cannula. If no such valve is
used, the occlusion will be detected at a later time and the drug
accumulated in the I.V. set will be rapidly administered when the
occlusion is relieved.
Infusion Devices
Mechanical Devices
These simple systems function by gravity alone and with an
adjustable mechanical occlusion system; the user must control the
rate of infusion by drop counting. More controllable systems such
as Dosicair or Dial-a-Flo have been calibrated under very precise
conditions of use and are, therefore, reliable only if:
The I.V. fluid container is approximately 80 cm above the midaxillary line of the patient.
The I.V. cannula is larger than 21 gauge.
The fluid infused is a normal parenteral solution and does not
contain blood or blood products, lipid emulsion, or glucose in
a concentration above 10%.
TABLE 38-20. Properties of a volumetric infusion device.

Ideal Properties of a Volumetric Pump for Pediatric Use
1. Accuracy of flow rate: <5% difference at 25 mL/h
2. Detection of air in the tubing
3. Time to alarm after occlusion: <10 min at 5mL/h
4. Volume of bolus administered after relief of occlusion:
<0.9 mL
Ideal Properties of a Syringe Pump for Pediatric Use
1. Accuracy of flow rate: <5% difference at 5 mL/h
2. Effective delivery of syringe content < 1 min after starting
(without priming)
3. Time to alarm after occlusion: <10 min at 2 mL/h
4. Volume of bolus administered after relief of occlusion:
<0.5 mL
5. Alarm to warn that the syringe is nearly empty
6. Firm grip on the syringe plunger to prevent undesired
movements of it (risk of siphoning, see text)
7. Simple to operate, lightweight, operating with chargeable
batteries (for transport)
These mechanical systems should not be used for the administration of potent agents such as vasopressors or opiates.
Volumetric Pumps
A photoelectric drop-counting system is combined with a
microprocessor controlling the intermittent occlusion of the
infusion tubing. The system is usually able to detect air in the
tubing and occlusion of the infusion line. The ideal properties of
a volumetric infusion device for use in children are summarized
in Table 3820. If a peristaltic pump is used to run the infusion,
special, more expensive, precision silicone tubing is necessary.
These pumps are appropriate to administer large volumes of fluids
(e.g., maintenance fluids), but syringe pumps perform better if
small volumes of potent medications are to be administered.
Syringe Pumps
Syringe pumps are often used in pediatric anesthesia because they
allow the continuous administration of small volumes of I.V. fluids
or a local anesthetic solution. However, owing to the potential
dramatic consequences of accidental over- or underdosage of
potent medications (e.g., inotropes, vasopressors, opiates) in small
children, the syringe pump should have the properties summarized
in Table 3820.124 Most problems of accidental bolus or delayed
drug administration are caused by the overall compliance of the
syringe, connecting tubing, and syringe-pump combination. As a
rule of thumb,
The time to trigger the occlusion alarm is shorter when using

small syringes and/or high infusion rates.
The volume of the bolus injected when the occlusion is released
increases with the infusion rate and the compliance of the administration system.125
These problems should be prevented by establishing operating

procedures. For example, when a slow infusion rate (e.g., 1 mL/h)
is foreseen, a small-size syringe with low-compressibility plunger
should be preferred to avoid start-up delays that can be clinically
important (e.g., 3.6 0.9 min with a 10-mL BD syringe at 1 mL/h
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with a Alaris Asena syringe pump) and the time required to
achieve steady-state flow.126 In practice, flushing an initial bolus
of 2 mL before actually connecting the infusion line to the patient
reduces the delay in effective fluid delivery.127
The height of the pump should not be changed relative to the
patient. For example, when the infusion rate is 1 mL/h, elevating
the syringe pump 1 m above the child results in a bolus administration of 0.19 to 2.28 mL in less than 1 minute (depending on
the model of the pump and on the size of the syringe) and
returning the pump to its original level results in the aspiration
of 0.06 to 0.34 mL into the syringe!125 After such an up-down
maneuver, the syringe pump does not actually deliver any volume
at all during the following 8 to 105 minutes. This is caused by the
presence of the small gap that facilitates fitting the syringe wings
onto the pump. This gap allows some internal motion between
the plunger and the syringe cylinder and some siphoning to
occur by gravity alone. Only the syringe(s) recommended by the
manufacturer of the pump should be used to avoid problems with
calibration of the pump.
Very sophisticated electronic syringe pumps are currently
available that make the use of target-controlled total intravenous
anesthesia (TIVA) reliable in children (see Chapter 41).
STANDARD AIRWAY EQUIPMENT

The various techniques of airway management is described in
Chapter 72.
The Pediatric Facemask

Description
The two most common types of pediatric masks used currently
are the Rendell-Baker-Soucek (RBS) mask and a variety of
cushioned masks. The RBS masks have a low-deadspace, and the
cushioned masks have a cushion rim inflatable with air that makes
achieving a good seal easier. The larger deadspace created by the
presence of the cushion is clinically of little consequence. Pediatric
masks may be scented with the childs preferred flavor. In case of
application of fruit-flavored extracts onto the inside surface of the
mask, transient erroneous measurement of end-tidal vapors may
be observed if ethanol is added in these extracts (see Respiratory
Gas Monitoring).128 When selecting a facemask for a child,
consider its dead space and the ease of its application to the childs
face to fit over the bridge of the nose, cheeks, and chin. It should
be transparent to facilitate detection of cyanosis, secretions, or
regurgitated material.
Indications
The facemask is used to perform inhalation induction of
anesthesia, preoxygenate the patient before rapid-sequence
I.V. induction, assist or control ventilation, and administer O2 at
any time during anesthesia. A special double-mask has been
developed to allow scavenging of gases leaking around the inner
mask (see Scavenging, later). The housing for the connection
to the breathing circuit and the exhaust tube is unfortunately
large and heavy, and this system did not achieve much popularity.
Several endoscopic masks have been designed to allow fiberoptic intubation in an anesthetized patient breathing spontaneously
or receiving positive-pressure ventilation by mask.
Figure 38-12. Transesophageal echocardiography through the

central movable opening of an airway endoscopy mask. The
breathing circuit is connected to the flexible lateral extension.
The Patil-Syracuse mask has an endoscopic port with a silicone

diaphragm. In small children, a similar system may be created
by connecting a swivel bronchoscopy adapter to the appropriately sized facemask. The fiberoptic bronchoscope is passed
through the suction port of the adapter.
The airway endoscopy mask.129 The center of a regular facemask
is removed and replaced by a removable distensible silicone
membrane. The latter is equipped with a movable opening allowing direct access of the fiberoptic bronchoscope to the nares
or mouth. An airtight flexible extension is inserted in a second
hole in the lateral part of the mask and connected to the anesthesia circuit. It can also be used for upper airway or esophagogastric endoscopy or transesophageal echocardiography.
When a TT has been inserted into the trachea over the bronchoscope, the silicone membrane is pushed inside to allow removal of the mask over the TT. This device is available in three
sizes and may be used in newborns (airway endoscopy mask,
VBM) (Figure 3812). However, handling of the fiberoptic
bronchoscope in the oropharynx is somewhat impaired and
may lead to an increased intubation time when compared with
fiberoptic intubation without a facemask.
When holding a facemask in neonates and small children, care

should be taken to avoid digital pressure in the submental triangle
because this could push the childs tongue on its palate and aggravate airway obstruction. Care should also be taken to avoid eye
injury (e.g., corneal abrasion) or compression with the rim of the
mask. During mask ventilation, it is sometimes easier to maintain
a good airway by tilting the childs head slightly on one side. This
moves the tongue laterally and usually provides a clear airway with
less jaw-thrust.
Cleaning and Sterilization

Reusable facemasks are usually made from different materials
(rubber, silicone, plastic) that deteriorate rapidly when autoclaved
in high-pressure steam. Fortunately, decontamination and highlevel disinfection are sufficient to avoid cross-contamination. The
masks should be immersed in a soap solution immediately after
use. They may be cleaned automatically in a washing machine or
soaked in a liquid chemical. Phenolic compounds should not be
used because they are absorbed by many materials and could result
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in dermatitis in the area of contact between the childs face and

the mask. Whatever the cleaning method used, the masks should
be thoroughly rinsed and carefully dried before being used in
another patient.
Oral and Nasopharyngeal Airways

Oral Airways
forward with a Magill forceps while the airway is inserted in the

mouth and advanced into the pharynx. The classic method, in
which the airway is inserted with its concave side toward the upper
lip and rotated 180 degrees when its tip has passed the uvula,
should be avoided in children to prevent trauma to the oral tissue.
When using an oral airway, take care to avoid the avulsion of loose
or decayed teeth or to catch the childs lip between the airway and
the childs teeth.
Oral airways are used either to maintain an open oropharyngeal

airway (as during induction of anesthesia) or to prevent a patient
from biting and occluding an orally inserted TT. Choosing its
appropriate size is crucial. If the airway is too small, it will push the
tongue backward and obstruct the oropharynx. If it is too large, it
could push the epiglottis down into the laryngeal inlet. The correct
size is estimated by placing the oral airway along the childs
face. When the flange is at the childs lips, the tip should be at the
angle of the mandible (Figure 3813). Using MRI to measure the
distance between the teeth or lips and the prevertebral tissues, it
was found that the distance varies with age, weight, and gender
and that the location of the tip of the epiglottis varies widely as
well.130 Standards for manufacturing oral airways probably need
to be adapted accordingly. The most commonly used oral airways
are the Guedel airway (with a central lumen) and the Berman
airway that consists of two horizontal plates joined by a median
ridge. A suction catheter can be passed down either side of the
ridge. These oral airways may be modified to facilitate oral fiberoptic intubation. They help keep the fiberscope in the midline,
maintain an open airway, and expose the laryngeal opening while
preventing the patient from biting the fiberscope. The Guedel
airway can be modified by cutting out a strip of its convex surface;
however, in order to allow adequate visualization of the hypopharynx, it is recommended to use an airway device slightly smaller
than if it had been used only to maintain the airway patent. The
median ridge of the original model of the Berman airway is
displaced to one side, providing a longitudinal opening on the
other side. These modified oral airways are rarely used since the
LMA became available.
To avoid laryngospasm or vomiting, pharyngeal and laryngeal
reflexes should be depressed before attempting the insertion of an
oral airway. Various methods of insertion have been described.
The tongue may be depressed with a tongue blade or gently pulled
A nasopharyngeal airway is used to provide a conduit for gas

flow between the tongue and the posterior pharyngeal wall. Its
pharyngeal end should be above the epiglottis and below the base
of the tongue. It offers an alternative to an oral airway and is better
tolerated in awake or semiawake patients. It can be used only in a
spontaneously breathing patient. Either the Robertazzi nasal
airway (Rsh) or the Wendl nasal airway (with an adjustable flange
at its nasal end) may be used. Although nasal airways are available
in 12- to 36-French sizes (ID in millimeters), they can be made
from a cut TT. A safety pin or a tube connector should be inserted
at the nasal end of the airway to prevent its migration into the
nasopharynx. The proper diameter of the nasal airway is usually
the same or even 0.5 mm larger than the TT that is appropriate
for the childs age (see Standard Tracheal Tubes, later). The
proper length of the nasal airway is estimated by measuring the
distance between the nose tip and the tragus of the ear (Figure
3814). However, especially in cases of orofacial dysmorphism,
the actual length of a nasal airway is the one that provides good
entry of air without stridor and/or a capnogram. The indications
for insertion of a nasopharyngeal airway are listed in Table
3821.131 Contraindications to the use of a nasopharyngeal airway
include hemorrhagic disorders, a basilar skull fracture, and any
pathology of the nose or nasopharynx. The nasal airway is
lubricated with water, a local anesthetic ointment, or a silicone
spray and gently inserted through a nostril in a posterior direction,
perpendicular to the coronal plane along the floor of the nasopharynx. During insertion, it is sometimes necessary to turn or
twist the airway to follow the path of least resistance, but the
passage should never be forced to avoid mucosal damage and/
or epistaxis. The patency of the small nasopharyngeal airways
Figure 38-13. Estimation of the correct size of an oral airway.

When the flange is at the childs lips, the tip should be at the
angle of the mandible.
Figure 38-14. Estimation of the length of a nasopharyngeal

airway by measuring the distance between the tip of the nose
and the tragus of the ear.
Nasopharyngeal Airways
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TABLE 38-21. Indications of Nasopharyngeal Airway
To provide some postoperative CPAP

To maintain a patent airway in neonates and infants with
obstructive apnea (e.g., Pierre Robin anomalad, TreacherCollins syndrome, sleep apnea syndrome)
To maintain a patent airway following cleft palate,
palatopharyngeal, or choanal atresia surgery
To allow insufflation of O2 and halogenated agents during
upper airway endoscopy (e.g., fiberoptic intubation, laser
surgery on the larynx)
To allow insufflation of O2 and halogenated agents during
chair dental anesthesia.
CPAP = continuous positive airway pressure.
should be checked frequently because they can easily become

obstructed by blood or secretions. Possible complications of the
use of a nasopharyngeal airway are epistaxis and submucosal
insertion. Gentle insertion is mandatory. It produces sometimes
hypersalivation.
Standard Tracheal Tubes

Description
The TTs in common use today are made of polyvinylchloride
(PVC) and disposable. They should bear markings showing that
they comply with the American Society for Testing and Materials
standards, such as IT or Z79, that specifies that the material has
not shown tissue toxicity both in vivo and in vitro. They are
calibrated according to their ID (millimeters), outer diameter
(OD; mm), and length (cm), and are beveled 40 degrees off to
the left when viewed with the tube curved up. Most TTs contain a
radio-opaque line in their wall that allows easy evaluation of their
position by x-ray. Some TTs are designed with a hole in their wall
on the side opposite to the bevel and just above the tipthey are
called Murphy-type tubes, in contrast to the others, which are
called Magill-type. The purpose of the Murphy hole is to provide
an alternate pathway for airflow if the bevel becomes occluded or
the TT is inserted too far into the trachea, but it makes pulmonary auscultation less reliable to detect bronchial intubation.132
Although the TTs are categorized according to their ID, their wall
thickness and also their OD vary from one manufacturer to
another. For example, the OD of a 4.5-ID TT is 6.0, 6.2, 6.2, or
6.6 mm when it is made by Mallinckrodt, Rsch, Sheridan, or
Portex-Sims, respectively. The smallest uncuffed TT available is
2.0-mm ID. TTs are usually supplied from the manufacturer with
their connector loosely attached. Care should be taken to insert
the connector tightly into the tube before its use to minimize the
risk of accidental disconnection. Conversely, the connector should
be inserted gently, especially if the TT has been cut, taking care to
avoid buckling it. Any inward deformation of the connector can
result in total or partial occlusion of the TT.133
Size
When choosing a TT for use in a child, consider its influence on
airway deadspace,134 resistance during spontaneous breathing,135
and potential tracheal or laryngeal injury136 (see Chapter 43).
Tracheal intubation actually decreases the deadspace of the natural
extrathoracic airway but dramatically increases resistance to
breathing. If the air flow is laminar, resistance is proportional to

the length of the tube and inversely proportional to the fourth
power of its radius (Hagen-Poiseuille law). For example, resistance
to airflow increases by 50% when the ID of the TT decreases from
3.5 to 3.0 mm. Luminal changes between the 15-mm connector
and the TT favor turbulent flow, which further increases resistance. These considerations led the anesthesiologist to use the
largest TT possible that will enter the childs larynx (cricoid ring)
without force and without compressing the tracheal mucosa.
Additional reasons to use a large TT are
The lesser likelihood of its occlusion by secretions.

The ability to use a larger suction catheter if suction is necessary.
A relative protection against regurgitation of foreign material
into the lungs.
Less leakage around the TT, which has implications for the quality of ventilation and monitoring of PETCO2 and halogenated
agents as well as for the use of closed circle ventilation.
Conversely, whereas resistance to breathing is linked to the ID

and length of the TT, the potential for laryngeal or tracheal injury
is related to its OD, the gentleness applied during its insertion, and
the duration of intubation. Mild trauma to the airway causing as
little as 1 mm edema can result in significant airway narrowing at
the level of the cricoid cartilage in infants137: avoiding traumatic
intubation is essential. Ischemia of the tracheal mucosa occurs
when the pressure from the TT exceeds the capillary pressure of
the tracheal mucosa. In the absence of pediatric data in the
literature, this pressure is unknown but believed to be close to
25 to 35 mmHg or 20 to 25 cmH2O, as in adults. Until recently,
uncuffed TTs were almost exclusively used in pediatric patients
up to 8 to 10 years of age, essentially because it was believed, based
on cadaver studies, that the childs larynx was funnel-shaped with
its apex (i.e., smallest portion) at the level of the round cricoid ring
and, subsequently, that a TT whose OD is close to the ID of the
cricoid would seal the trachea without applying dangerous pressure on the tracheal mucosa. In fact, both MRI138 and videobronchoscopy139 have demonstrated that the glottis is the narrowest
portion of the pediatric airway and that the trachea as an elliptic
section at the cricoid level. However, the vocal cords are mobile
and can distend when a TT is inserted through them. This
explains damage to the vocal cords after traumatic or prolonged
intubation and the cricoid ring remains functionally the narrowest
part of the larynx.
When using an uncuffed TT, the pressure applied against the
tracheal wall by the tube can be estimated by slowly inflating the
breathing bag of the anesthetic circuit and listening for a leak over
the neck (stethoscope) or mouth. A properly sized TT is the one
that, once in place, allows leakage at an insufflation pressure
ranging from around 18 to 20 cmH2O. However, many other
factors may affect the pressure at which the leak occurs and should
be borne in mind when performing the leak test. For example, the
depth of insertion of the TT and the FGF do not influence leak
pressure, but measuring the leak when the childs head is turned
to one side or when she or he is not paralyzed increases the
pressure required to cause the leak.140 This could lead to a leak
occurring at a much lower pressure, with a risk of hypoventilation,
when the childs head is straight or when she or he is paralyzed.
Last, most data on postoperative croup were collected at a time
when rubber reusable TTs were used. They were confirmed in
a study with modern PVC TTs.141 Children who had no leak at
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TABLE 38-22. Recommended Uncuffed Tracheal Tube Sizes

Age
Size, mm ID
premature < 1000 g

>1000 g
Term neonate 3 mo
39 mo
918 mo
>2 y
2
2.5
3.03.5
3.54.0
4.04.5
Age + 16
4
25 cmH2O pressure presented with 2.8 times more adverse respiratory events than those with an audible leak. But it also highlighted the role of trauma because intubation by an inexperience
anesthesiologist increased the risk of adverse events 3.7 times.141
Several methods are available to aid selecting the appropriate TT.
Measuring the diameter of the external nares, the distal joint of
the index finger, or the tip of the little finger or even the childs
height (Broselow tape) have been proposed.142 The most accurate
estimation can usually be obtained by using an age-based
formula143,144 and results in the recommendations shown in Table
3822. However, they represent estimates that should be confirmed in each patient by testing the leak pressure. They are not
usable with ticker-walled TTs such as reinforced TTs. In practice,
three sizes of TT should always be available during induction of
anesthesia: the size calculated from the formula, one size larger,
and one size smaller.
The depth to which the TT should be advanced past the glottis
varies with the length of the trachea (i.e., the childs age). Many
uncuffed TTs have a black area or a line printed near their tracheal
end. The aim is that advancing the tube through the cords up to
the line or the end of the black area places the tip of the TT
approximately in the midtrachea. However, the length of this black
area varies from one manufacturer to another. For example, it is
2.5 cm long in the 4.5 to 6.0 ID Portex Ivory TT and the 3.5 to 6.5
ID Vygon plain TT, whereas it increases progressively with tube
size in the Sheridan TT.145 Several formulas are available to
calculate the approximate length at which a TT can be inserted
into the trachea with a low risk of unexpected extubation or
bronchial intubation, However, they are accurate only in children
whose airway dimensions do not differ significantly from those
of children of the same age or size (e.g., not in children with
dwarfism). The approximate length at which an oral uncuffed TT
has to be at the alveolar ridge to have its tip in the midtrachea is
Length (cm) = 3 ID (mm)
or
Length (cm) =
Age (y) + 13 older than1 year of age146

2
For a nasal tube, the formulas are

Length (cm) = 3 ID (mm) + 2147
or
=
Age (y) + 15 older than 1 year of age146

2
or, more practically, setting the following mark at the level of

the cords: 3 cm for the 3 and 3.5 ID TT, 4 cm for the 4 and 4.5 ID
TT, and 5 cm for the 5 and 5.5 TT.148
Figure 38-15. Palpation of the tip of the tracheal tube in the

suprasternal notch.
Other methods to position the TT in the mid-trachea are
1. Suprasternal palpation of the tip of the tube. With the childs
head in the neutral position and his or her neck mildly
hyperextended with a roll under the shoulders, the pad of
the palpators index finger may feel the TT when it is gently
moved in the trachea and position its tip just within the
suprasternal notch. This should be done gently to avoid local
trauma and stimulating the lower airway (Figure 3815).
Palpation of the TT tip in the suprasternal notch is very reliable
in children between 2 and 8 years of age to prevent accidental
extubation and endobronchial intubation during neck
movement.149
2. Deliberate gentle bronchial intubation followed by withdrawal
of the TT until breath sounds become symmetrical (i.e., near
the carina). The TT is withdrawn a further 2 cm.150 This technique carries a risk of bronchospasm and is not recommended.
Whatever the method or formula used, the correct positioning
of the TT should be verified by careful auscultation of all the
lung fields. The position of the TT should be verified each time
the patients head is moved because the distal tip of the tube
moves toward the carina during flexion and toward the vocal
cords during extension of the neck.151
We recommend disconnecting the TT from the breathing
circuit each time the childs position is changed in order to prevent
both accidental extubation and laryngotracheal trauma. The TT
should be secured using tape or a gauze band. Many different
techniques can be used to achieve this goal. If the TT has been
inserted nasally, care should be taken to avoid applying too
much pressure on the alae nasi or septum to prevent pressure
necrosis. If the TT has been inserted orally, an oropharyngeal
airway is placed along it (except in case of oral surgery!) to prevent occlusion (e.g., the child biting on her or his TT during
awakening) or displacement in the oropharynx. Before performing nasotracheal intubation, a suction catheter should be inserted
into the TT to avoid plugging it with secretions or debris accumulated during its passage through the nasopharynx. A closefitting suction catheter is carefully lubricated with a silicone
spray and placed in the TT. They are inserted together through the
nares and carefully slipped into the posterior pharynx; the suction
catheter is then withdrawn from the TT, which is introduced into
the trachea.
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CHAPTER 38
Cuffed Pediatric Endotracheal Tubes

Description
The design of pediatric TTs with low pressure-high volume cuffs
led to their use in infants and children with poor lung compliance
in order to maintain adequate ventilation (see Chapter 43). In
several series, there was no increased incidence of postintubation
stridor in children intubated with a cuffed TT, but they were
intubated with a TT 0.5-mm ID smaller than calculated with
the usual formulas and a minimal leak was maintained at the
current PIP needed by the child.152,153 However, most TTs with a
PVC cuff available at present are poorly designed for use in
pediatric patients. Their OD varies considerably for the same ID,
most of these cuffs do truly show low-pressure, high-volume
properties when tested, and, the length and position of their cuff
are inadequate. If the tip of the TT is in the middle of the trachea,
the cuff of most TTs less than 5 mm ID lies in the subglottic area
or between the cords. Conversely, if the cuff is adequately placed
in the trachea, endobronchial intubation ensues.154 TTs specially
designed for pediatric use with a low-compliance, thin-walled,
short polyurethane cuff placed distally and marks allowing
positioning their tip in the middle of the trachea and their cuff
at the tracheal level (to avoid any pressure on the subglottic
mucosa) are now available (Microcuff) (Figure 3816). The major
companies will probably adapt their products accordingly. In
vitro studies using a tracheal model in which parietal pressure
measurements were made have demonstrated that, regardless of
whether the cuff had a low or high compliance when tested in an
unrestricted environment, cuff compliance decreased considerably
when placed in the model. More important, this study also showed
that tracheal wall pressure increased with cuff pressure if the latter
was sufficiently large when inflated to drape the inner tracheal
wall. Accordingly, even the use of high-volume, low-pressure cuffs
does not avoid high intratracheal pressures being generated,
and cuff pressure monitoring (and limitation to 20 cmH2O) is,
therefore, mandatory.155
Last, the incidence of postintubation stridor is not a good

indicator of the presence and severity of airway injury. Stridor can
indeed be a sign of early benign edema or severe obstruction, but
large areas of mucosal necrosis do not cause stridor until later,
when scarring narrows the airway by more than 50%.156 The pilot
balloon of cuffed TTs usually contains a stainless steel spring that
may cause signal interference during MRI.157
Precautions
The use of cuffed TTs in small children is becoming a more
common practice in the operating room, especially when
prevention of aspiration or possible intraoperative changes in lung
compliance is of concern. Other advantages of using cuffed TTs in
children are a more reliable monitoring of end-tidal gases and
expired volumes, a reduction in contamination of the operating
room atmospheres, and a lesser need for repeated laryngoscopy
(and its own traumatic risk) to replace an initially too small TT.153
The following points should, however, be kept in mind when using
a cuffed TT in a pediatric patient:
1. The presence of a cuff, especially a high-volume, low-pressure
cuff, increases the OD of the tube by approximately 0.5 mm.158
A TT 0.5 mm smaller than calculated with the usual formulas
should be inserted or the following rule should be used:
ID (mm) = age (y)/4 +3 or 3.5.153,159
An air leak should be present at 20 cmH2O around the TT with
its cuff uninflated. If not, a smaller TT should be inserted.156,160
Table 3823 shows the size recommendations for the Microcuff
TT. The ensuing reduced ID of all cuffed TTs increases both
airway resistance and the work of breathing during spontaneous
ventilation.
2. Cuff pressure should be monitored, even if no N2O is used, to
avoid tracheal mucosa damage. The increase in temperature of
the air used to inflate the cuff will raise the pressure within it
and may be responsible for tracheal edema.
3. Active deflation of the cuff must be avoided (except during the
process of tracheal intubation and extubation) because it
usually results in sharp folds and edges at the external surface
of the cuff and leads to mucosal damage.156,160
4. The cuff should be carefully positioned below the cricoid area
because the majority of endoscopy-proven postintubation
laryngeal injuries were caused by folds and malposition of
the cuff.156
TABLE 38-23. Recommended Size of Microcuff Tracheal
Tube According to Age
ID of the Cuffed TT, mm
Figure 38-16. Comparison of the distal part of a Microcuff tracheal tube with a Mallinckrodt tube of the same size. The cuff of
the Microcuff tube is shorter, cylindrical, closer to the tip, and
made of polyurethane. When the large black mark is at the level
of the vocal cords, the cuff is theoretically in the middle of the
trachea, below the cricoid area.
3.0
3.5
4.0
4.5
5.0
5.5
6.0
6.5
7.0
Childs Body Weight or Age

Term 3 kg to <8 mo
8 mo to <2 y
2 to <4 y
4 to <6 y
6 to <8 y
8 to <10 y
10 to <12 y
12 to <14 y
14 to <16 y
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Preformed Tubes
TTs with a special configuration may be useful during certain
surgical procedures. The most commonly used are the RAE tubes
(designed by Ring, Adair, and Elwyn) for cleft palate surgery and
any head and neck surgery in which the surgeon needs to have
intraoral access. The preformed tubes are made of PVC and
available in oral and nasal versions. The oral version is bent toward
the concavity of the curve of the tube so that, when in place, it rests
on the patients chin. The nasal version is bent away from the
curvature of the tube and rests on the patients forehead when
in place. These acute nasal or oral curves make tracheal suction
difficult. Uncuffed preformed TTs are available from 3.0 to
7.0 mm ID. Most uncuffed preformed TTs have two Murphy holes
(distal lateral wall orifices). However, in neonates and small infants,
the presence of a Murphy hole can make the diagnosis of bronchial
intubation more difficult or even hinder adequate ventilation if it
encroaches into the glottis following head movement. The main
disadvantage of the preformed TTs is that their flexion point (bend)
is fixed. Their intratracheal length may be inappropriate in children
whose cricoid diameter is larger or smaller than usual for their age
and results in either bronchial intubation,161 especially when a
mouth gag is inserted, or accidental extubation. An easy way to
prevent bronchial intubation if the TT is too long is to place a pad
(e.g., piece of gauze) between the chin and the tube. If the bend is
placed inside or outside the oral cavity, kinking of the TT is more
likely after insertion of a mouth gag.
Oral cuffed TTs range in size from 4.0 to 9.0 mm ID and the
nasal cuffed TTs from 6.0 to 8.0 mm ID. Their design, especially
the bendtotracheal tube tip distance, varies according to
the manufacturer.161 Even with the newly designed oral cuffed
pediatric TTs (high-volume, low-pressure polyurethane cuff close
to the TT tip), it is not unusual that the cuff moves toward the
cricoid area during head extension.162 Whatever the type of TT
used, insertion of a mouth gag moves it caudally and auscultation
should be checked afterward.
Supraglottic Airways
Based on their shape and presence of a sealing device, supraglottic
airways can be classified as
Cuffed perilaryngeal sealers: all LMAs.

Cuffed pharyngeal sealers: laryngeal tube, CobraPLA.
Uncuffed preshaped sealer: Igel.
Some of them are equipped with a drain tube to allow escape of

gastric fluid and gases. Their common indications and contraindications are reported in Tables 3824 and 3825. The nasopharyngeal airway is in fact an uncuffed nonsealer supraglottic
airway.
The LMAs
Initially designed to be an alternative to the face mask and the TT,
the LMA quickly became an essential tool in the management of
the difficult airway.
DESCRIPTION: The classic laryngeal mask airway (CLMA)

consists of a bowl-shaped mask with an inflatable cuff, connected
to a large-bore tube attached to the back of the mask. It provides
a low-pressure seal around the laryngeal inlet. Vertical bars at the
TABLE 38-24. Supraglottic Airways: Indications

In place of a facemask: any peripheral or superficial surgery
Laser treatment of the face
In place of a TT: ophthalmic examination or surgery
ENT, anterior dental surgery
Neonatal resuscitation, administration of surfactant
For remote control of the airway: radiotherapy
MRI
For diagnostic examination of the airway: fiberoptic
laryngoscopy or bronchoscopy
For difficult intubation: as the sole airway or to help
endotracheal intubation (introduction of fiberoptic
laryngoscope or bougie)
ENT = ear, nose, and throat; MRI = magnetic resonance imaging; TT = tracheal
tube.
distal end of the tube prevent the epiglottis from obstructing the
lumen. When the CLMA is correctly placed, its tip rests against
the upper esophageal sphincter, the sides of the cuff face the
pyriform fossae, and the epiglottis and esophagus are outside the
bowl. A black line along the posterior aspect of the tube is used to
ensure proper positioning of the LMA. When this black line is in
the midline and facing cephalad, the mask faces the larynx.
Fiberoptic bronchoscopy performed through a clinically wellpositioned CLMA revealed a clear laryngeal opening in only 27%
of children and the epiglottis was either impinged in the bars of
the CLMA 1 or downfolded by the CLMA 2 in 57% and 38% of
children, respectively.163 In other words, clinical airway patency
does not guarantee ideal anatomic positioning of the CLMA in
infants and children. The cuff around the mask is inflated via a
pilot balloon and a valve. Reusable CLMAs are made of silicone
(and are thus latex-free) and, therefore, able to withstand autoclaving and repeated use. Because careful washing and sterilization
do not eliminate protein deposits from reusable LMAs,164 singleuse PVC LMAs should be preferred. Different companies produce LMAs (e.g., Portex Soft Seal, Intersurgical Solus, or Ambu
AuraOnce). They vary slightly in shape, tube diameter, maximum
volume of inflation, presence of bars, and flexibility, which can
influence their easiest mode of insertion165
The Flexible reinforced version of the LMA allows its use for
head, neck, and oral surgery. The mask is connected to a flexoTABLE 38-25. Contraindications to the Use of a
Supraglottic Airway
Increased risk of aspiration/regurgitation (except Proseal LMA,
Supreme, LTD, Igel, which are equipped with a gastric drain
tube)
Any full stomach situation
Presence of a gastroesophageal reflux disease
Obesity
Upper abdominal surgery
Laparoscopic surgery
Need for high inflation pressures: lungs with low compliance,
thoracotomy
Oral, laryngeal, or pharyngeal pathology
Difficult control of the airway in case of dislodgment: e.g., prone
position
Too small mouth opening
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CHAPTER 38
TABLE 38-26. Specifications of the Laryngeal Mask Airways
Size, #
Patients
Weight, kg
1
1.5
2
2.5
3
4
5
>5
510
1020
2030
>30
Adult
Large adult
Max. Cuff Volume

Max. Pressure,
60 cmH2O, mL
<4
<7
<10
<14
<20
<30
<40
ID, mm,
Standard/
Reinforced
5.3
6.1
7.0/5.1
8.4/6.1
10.0/7.6
10.0/7.6
11.5/8.7
Largest Fiberoptic
Bronchoscope Usable,
mm, With Reusable LMA
2.7
3.0
4.7
5.3
7.3
7.3
8.7
Largest Gastric
Tube in
Proseal LMA
NA
10 Fr
10 Fr
14 Fr
16 Fr
16 Fr
18 Fr
ID = inner diameter; LMA = laryngeal mask airway.
metallic tube that can be bent without kinking. In the reinforced

version, the mask and the ID of the tube are smaller, and the tube
is longer, than in the standard version (Table 3826). It is available
in sizes 2 to 4 only.
The Proseal laryngeal mask airway (PLMA) is a single-use
LMA to which an esophageal drain tube is added. This tube passes
parallel to the flexible wirereinforced airway tube and across the
floor of the mask to open at its distal end, at the level of the upper
esophageal sphincter. The drain tube gives access to the digestive
tract and allows escape of gastric fluid and gases. This tube can
also be used to place a temperature probe or even a small gastroscope or a transesophageal echocardiography probe.166 The airway
tube of the PLMA is 0.6 mm smaller than the conduit of the
CLMA of the same size and its cuff is different in sizes greater than
2. It does not contain distal bars, and a rear part has been added
to improve the seal at the pharyngeal level. The different sizes of
PLMA available and the sizes of gastric tube insertable in their
drain tube are reported in Table 3826. The PLMA can be inserted
using the operators finger, a special introducer tool, a gum elastic
bougie placed in the drain tube (the distal extremity of the bougie
protruding out of the distal end of the tube is introduced in the
esophageal inlet during direct pharyngoscopy before railroading
the PLMA over it),167 or a Trachlight placed in the drain tube.168
The LMA Supreme is similar to the PLMA, but its shaft is
more curved, which makes it easier to insert.169 The smallest
model available is #3 for children weighing more than 30 kg.
An intubating laryngeal mask (Fastrach) has been designed
to allow blind tracheal intubation through it. It consists of an
anatomically curved stainless steel tube bonded to a standard LMA
cuff (sizes 3, 4, or 5) and a handle. This allows manipulation of the
device within the patients airway. Moreover, the ID of the airway
tube is larger and the tube is shorter than that of the CLMA,
whereas the distal bars are replaced by an epiglottic elevating bar to
keep the epiglottis from obstructing the glottic opening. The size 3
Fastrach can be used in children weighing more than 25 kg.170 The
LMACTrach is equipped with a small video camera that allows
visual control of correct positioning of the airway tube in front of
the glottis and intubation through it.
The air-Q ILA intubating LMA is specially designed to facilitate
intubation using fiberoptic laryngobronchoscopy. It has a shorter,
more curved shaft than a CLMA, a removable airway adapter, and
no grills in the bowl. It can be removed when the TT is in place
without the need a stabilizing device. It is available in single-use
(14.5) and reusable (24.5) models. Their size is based on the
same weights as the CLMA. Sizes 1, 1.5, 2, and 2.5 can be used to
intubate the trachea with cuffed TTs up to 4.0, 5.0, and 5.5 mm ID,
respectively.171 Although the sizes of all models are recommended

according to the childs body weight, in case of malnutrition or
obesity, another method can be used. The childs hand is extended
with the palm facing up and the three middle fingers kept together.
An LMA with its cuff inflated with the maximum volume recommended is placed with its anterior aspect facing the palmar side of
the childs three middle fingers. The widest part of the LMA that
matches the widest part of those three fingers is the most appropriate size for the child.172
Both the silicone-made classic and the reinforced version of the
LMA have been shown to be more resistant to a CO2, KTP
(potassium titanyl phosphate), or Nd:YAG (neodymium:yttriumaluminum-garnet) laser beam than PVC TT. The most vulnerable
parts are the black marks on the shaft, the places where the LMA
is blood-stained, the metal wires of the reinforced LMA, and the
cuff, but filling the latter with saline has a protective effect.173
When compared with the TT that could be inserted in the same
child, a CLMA has a lower resistance to flow. A reinforced LMA
has a similar resistance to flow. Spontaneous ventilation through
a CLMA is associated with a high incidence of hypercarbia. It is
better to use controlled ventilation, and in this setting, pressurecontrolled ventilation is more efficient than volume-controlled
ventilation,174 unless pressure-support ventilation is available.175
PRESSURES IN AND AROUND THE LMA CUFF: The LMA sealing

or leak pressure is the pressure measured in the breathing system
when air can first be heard to escape around the LMA. It usually
varies between 15 and 25 cmH2O. The leak pressure is usually
higher around a PLMA than around the same size CLMA. This
makes the PLMA more suitable for controlled ventilation.176
The LMA cuff inflation pressure or intracuff pressure is measured by connecting a pressure transducer to the LMA pilot balloon
valve. Measurement of cuff inflation pressure gives only indirect
information about the pressure applied by the LMA to the pharyngeal mucosa because the latter is determined by cuff pressure
and volume, the muscular activity and/or elasticity of the pharyngeal wall, and the elastic recoil from the curved tube. Using strain
gauge microchip sensors placed between the LMA and the
pharyngeal mucosa, Brimacombe and Keller were able to directly
measure pharyngeal mucosal pressures in anesthetized adults.
They found that mucosal pressure increases with increasing
intracuff pressure and cuff volume,177 and there is no correlation
between mucosal pressures and leak pressure. Pharyngeal damage
caused by excessive mucosal pressure is unlikely if intracuff
pressure is kept below 60 cmH2O. The maximum volumes of air to
be injected according to CLMA size are given in Table 3826,
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keeping in mind that intracuff pressure should not exceed 60 cm

H2O. In vitro studies have shown that injecting the maximum
recommended cuff filling volumes in pediatric LMAs, as is usually
done by many teams, results in hyperinflation in almost all models
tested.178 This has been confirmed by measuring their cuff PV
relationship in vivo; injecting approximately 50% of the maximum
volume recommended resulted in intracuff pressure in excess
of 60 cmH2O.179 Because a higher intracuff pressure can result
in pharyngeal morbidity and increased leakage of air around the
LMA, monitoring intracuff is now strongly recommended.180
Diffusion of N2O into an air-filled LMA cuff causes a significant increase in intracuff pressure and much more if the cuff is in
silicone rather than in PVC.181 To minimize the risk of cuff
overinflation of the LMA cuff, we recommend
1. Careful inspection of the LMA cuff before each use.
2. Inflating the cuff with the lowest effective volume and measuring intracuff pressure; if volumes of air greater than 50% of
those indicated in Table 3826 or an intracuff pressure greater
than 60 cmH2O are needed to obtain a leak pressure of
10 cmH2O or lower, the LMA should be re-inserted or a larger
size used.
3. If N2O is used, periodic measurement of intracuff pressure
should be performed.
is maintained. Bronchoalveolar lavage and fiberoptic removal of

bronchial foreign bodies can also be performed while securing the
upper airway with an LMA. In adults, tracheal or pharyngeal laser
surgery has been performed while airway patency was secured
with an LMA.
Finally, any model of LMA is an important tool in the management of the difficult airway and during the cannot intubate, cannot
ventilate situation, in which it is a safe alternative to cricothyrotomy. It is usually inserted after induction of anesthesia, but it can
be inserted in awake infants with an abnormal upper airway186 or
to administer surfactant in neonates.187 Although blind passage of
the TT or a bougie through the CLMA has been described in adults
and children,188 it is not recommended. A fiberoptic bronchoscope
should be used to confirm proper position of the epiglottis within
the LMA and/or to guide the TT into the trachea either directly or
after inserting a guide under direct vision.189
CONTRAINDICATIONS: The contraindications to the use of an

LMA are (see Table 3825)
INDICATIONS: The indications for the use of LMAs are summarized in Table 3824. LMAs can be used in place of a facemask
for any peripheral or superficial surgery. They free the hands of
the anesthesiologist and reduce environmental pollution with
inhaled agents. For example, in case of laser treatment of facial
port-wine stains, the O2 concentrations measured around the
lips in children breathing spontaneously 100% O2 were lower than
when a facemask was used.182 The reinforced LMA can be used
instead of a TT to perform ophthalmic surgery or examination
under anesthesia because the insertion of an LMA does not
increase intraocular pressure as is often observed with a facemask.183 The reinforced LMA is an alternative to tracheal
intubation in children undergoing adenotonsillectomy. When
compared with an oral Ring-Adair-Elwyn (the name of the
inventors [RAE]) preformed TT, it provides as good surgical
access and no more postoperative complications. Care should be
taken when the surgeon inserts and opens the mouth gag because
this could displace or obstruct the LMA. The LMA seems to
protect the lower airway better than an uncuffed TT against
inhalation of blood. Minor oral and dental surgery can also be
performed using a reinforced LMA. The LMA is also useful when
remote control of the airway is necessary, such as during
radiotherapy, avoiding repeated tracheal intubation in children
undergoing daily anesthetics for several weeks, and MRI or CT
scan. When the LMA is used for MRI, care should be taken to
place the LMA valve away from the coil because it generally
contains a metallic spring that interferes with the quality of the
image.184 Only a few companies (e.g., Medis) produce LMAs with
an MRI-compatible nonferrous valve. A reusable LMA should
not be used for 13C spectroscopy of the head because siliconecontaining material has a resonance similar to that of the surrounding tissue.185 The LMA is also useful when performing
diagnostic fiberoptic examination of the larynx, trachea, and
bronchi. It provides effective oxygenation and ventilation while
providing excellent views of these structures and allowing their
examination under dynamic conditions if spontaneous ventilation
Except for the Proseal and the Supreme versions, any situation in which there is an increased risk for aspiration or
regurgitation (emergency, obesity) because the seal between the
larynx and the LMA is not watertight and does not protect the
patient from aspirating gastric contents. In children with no
esophagogastric pathology, use of the LMA could be associated
with a greater incidence of gastroesophageal reflux up to the
middle third of the esophagus, especially at the time of its
removal and during the following 30 minutes.190 This could be
caused by lowering of the lower esophageal sphincter pressure
by the presence of the LMA cuff in the pharynx. Last but not
least, the esophagus is within the lumen of the LMA in up to
10% of the cases!
In patients with a low-compliance respiratory system when positive airway pressures greater than 20 cmH2O are required to
ventilate the lungs, major air leak and/or gastric inflation can
occur.
The presence of an oral, laryngeal, or pharyngeal pathology, although the airway of children with mild or severe subglottic
stenosis can be successfully managed with an LMA.191
Situations in which the airway would be difficult to control
quickly if the LMA becomes dislodged (e.g., prone position,
complex oral surgery).
A small mouth opening that hinders the introduction of the
LMA into the mouth.
Quality Control
The LMA should be checked before each use for discoloration
(yellow), kinking when flexed to 180 degrees, or any damage of its
outer aspect. The cuff should be inflated with a volume of air 50%
greater than the maximum volume recommended (see Table 38
26) to check whether there is any herniation or leak either at the
cuff or at the valve level. The cuff should be fully deflated and, if
spontaneous re-inflation occurs, it indicates failure of the valve.
The connection between the mask and the cuff should be inspected
to detect any disconnection. The inside of the LMA should be
inspected to make sure it does not contain a foreign body and that
the distal bars are intact. Last, whatever the technique of insertion
of the LMA used, only its posterior aspect should be lubricated,
taking care to avoid using silicone-containing solution if the cuff is
made of silicone.
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CLEANING AND STERILIZATION: Careful washing and sterilization

do not eliminate protein deposits from reusable LMAs.164 If a
single-use LMA is unavailable, the following steps should be taken
to ensure the safest possible repeated use of a reusable LMA. The
LMA is washed immediately after use with warm water and a mild
detergent. Glutaraldehyde should not be used because any residue
could cause supraglottic edema. Ethylene oxide, formaldehyde,
iodine-containing solutions, or even chlorhexidine should be
avoided because they may damage the LMA. After cleaning, the
LMA is sterilized in an autoclave at a temperature of maximum
134C for 18 minutes. The cuff and the pilot tube should be
completely deflated before autoclaving to prevent damage to the
cuff and the inflation valve.
PRACTICAL POINTS: The different techniques of insertion of

the different versions of the LMA in a child are described in
Chapter 72. However, some points related to the safe use of the
LMA need to be emphasized.
During insertion of the LMA, the patient should be deeply anesthetized in order to avoid coughing, laryngospasm, and vomiting.
Whatever the technique used (standard, rotational, lateral), the insertion should be performed gently to avoid pharyngeal trauma.192
If the LMA has to be placed in a child in whom cricoid pressure is
applied, for example, in a cannot intubate and full stomach situation, cricoid pressure could hinder correct positioning of the
LMA and should be temporarily relieved during its insertion.
The shaft of the LMA should not be held during inflation of the
cuff because this will prevent the slight outward movement that
usually occurs at that time and could result in misplacement of
the LMA. This could result in a higher incidence of regurgitation because stretching of the upper esophageal sphincter by
the tip of the LMA decreases the tone of the lower esophageal
sphincter. Inflation of the cuff above 60 cmH2O should be
avoided because it increases both leak pressure and morbidity.180
Cases of lingual edema could have been caused by prolonged
use of an overinflated LMA obstructing the lingual venous
drainage.193 The position of the LMA in the middle of the mouth
should be secured by using two lateral bite blocks (e.g., rolledup gauze swabs). To prevent dislodgment of the LMA, it should
be disconnected from the breathing circuit each time the patients position is changed, and unnecessary traction from
breathing systems should be avoided. Whether the LMA should
be removed with the child fully awake or still deeply anesthetized and with the cuff inflated or deflated are matters of controversy (see Chapter 58).
Figure 38-17. Reusable laryngeal tube size 1 with two cuffs

fully inflated.
drainage tube. Different sizes are available: 0 for neonates and
infants less than 5 kg, 1 from 5 to 12 kg, 2 from 15 to 25 kg, and 3
for small adults (<155 cm tall). The device is available as a silicone
autoclavable model (LT and LTS II) or as a PVC single-use model
(LTD and LTSD).
The LT should be lubricated and its cuffs fully deflated before
insertion. It is introduced into the mouth with the flat edge of its
tip placed against the hard palate. It is slid along the palate in the
midline of the pharynx until some resistance is felt or the depth
marker on the tube is at the level of the upper teeth. The company
recommends deflating the tubes before removing the LT.
The ventilation orifices of the pediatric LTS II are small, and a
fiberoptic bronchoscope cannot be inserted through them in case
of difficult intubation. A case has nevertheless been published in
which a flexible bronchoscope introduced nasally was passed
alongside the LTS to intubate an infant.195 The insertion success
rate of the LT II version (with no drainage tube) is similar to that
of the LMA, but its leak pressure is higher than that of a CLMA.196
The CobraPLA
The CobraPLA is a cuffed, disposable, and latex-free pharyngeal
sealing supraglottic airway (Figure 3818). It is available in eight
sizes (Table 3827) and presents three parts:
1. a silicone distal part that broadens distally into the shape of the
head of a cobra snake. It is equipped with slotted openings to
allow the passage of air and to keep soft tissues and the
epiglottis away from the glottic opening. This part is flatter and
larger than the distal part of the cuff of an LMA.
2. A circumferential low-pressure pharyngeal at the junction of
the distal one fourth and the proximal three fourths of the
The Laryngeal Tube

The laryngeal tube (LT) is a short J-shaped tube equipped with
two low-pressure cuffs separated with two ventilation holes
oriented toward the laryngeal aperture (Figure 3817). The
proximal cuff is bigger and designed to stabilize the tube in the
pharynx and to achieve proper seal. The distal cuff is smaller and
intended to block the esophageal inlet. Both cuffs are inflated via
a single inflation tube; a maximum intracuff pressure of 60 cmH2O
is recommended. Sealing pressure should be checked when the
childs head position is modified. Neck flexion has been shown to
compromise ventilation with the LTS II.194 The latest version (LTS
II or LTS D) is longer than the first ones, has a more ovoid distal
cuff, and is equipped with a posteriorly placed esophageal
Figure 38-18. CobraPLA size 11/2 supraglottic airway with its

pharyngeal cuff fully inflated.
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TABLE 38-27. Sizes of Pediatric CobraPLA
Size
Childs Age
Patient
Weight, kg
Neonate
Infant
Child
Child
2.57.5
7.515
1630
3160
/2
1
11/2
2
Tube ID, mm
Max. Volume of
Air Injectable
in the Cuff, mL
5
6
6
1.5
<8
<10
<25
<40
Max. ID of Uncuffed
TT Insertable
Through CobraPLA
3
4.5
4.5
6.5
ID = inner diameter; TT = tracheal tube.
breathing tube. It is inflated with air to a cuff pressure that

should not exceed 40 cmH2O.
3. A breathing tube, the distal part of which is curved anteriorly
(toward the base of the tongue) to avoid kinking. It is larger
than the breathing tube of an LMA and can be connected to a
standard 15-mm ID connector.
To insert this device, slightly extend the childs head. Lubricate
the head and cuff of the CobraPLA. Open the mouth with the
nondominant hand and advance the CobraPLA with its cuff
totally deflated into the pharynx until moderate resistance is met.
Pull back slightly before inflating the cuff. The cuff should not be
visible in the mouth after proper insertion. The CobraPLA
provides a higher airway seal pressure and a better endoscopic
view of the glottis and is more stable during anesthesia than
a single-use LMA.197 A new model, CobraPLAPLUS, is equipped
with a thermistor temperature probe on the posterolateral part of
the cuff (to measure hypopharyngeal temperature) and a gas
sampling line. Video assessment of the airway through the initial
(not bent) version of the CobraPLA showed that the laryngeal
view was nearly or completely obstructed in 76.9% of the children
weighing 10 kg or less. It was caused by downfolding of the epiglottis. The bars of the grill were apposed against the supraglottic
structures. It is recommended to remove the CobraPLA under
deep anesthesia to avoid laryngospasm.198 If the glottic opening is
not obstructed by the epiglottis, a TT can be inserted through the
CobraPLA (see Table 3827).197
Uncuffed Preshaped Sealer: Igel

Igel, a single-use supraglottic airway, contains an airway and an
esophageal drainage tube equipped with a noninflatable cuff made
in a gel-like thermoplastic elastomer that softens when warming
to body temperature. There are no bars inside the distal part of
the airway tube, but a small ridge is present at the proximal end of
the bowl to prevent epiglottis downfolding. The posterior part
of the device should be well lubricated before insertion. Place the
childs head in the sniffing position and introduce the device,
grasped at the level of its integral bite block, into the mouth against
the hard palate until resistance is felt. Correct position is confirmed by adequate chest expansion when ventilation is assisted,
the presence of a capnogram, absence of gastric insufflation, and
the presence of an air leak. At the time of writing, the pediatric
experience with this new device is limited.199 The size 3 Igel can be
used in children weighing more than 30 kg.
Laryngoscopes and Blades

The choice of pediatric laryngoscope blades is extensive and their
selection is largely a matter of user preference and familiarity.
There are straight and curved blades; most textbooks recommend

using a straight blade in neonates and infants and a curved blade
in children and adolescents. In theory, a straight blade is used
to lift the epiglottis anteriorly to see the vocal cords and a curved
blade is placed in the vallecula, anterior to the epiglottis. In
practice, however, a straight blade can be used in the same way as
a curved blade.
Description
The Miller blade is straight with a slight curve near the tip,
whereas the Wisconsin, Wis-Foregger, and Wis-Hipple blades
have no curve at all. In cross-section, as seen from the handle
connection, they are C-shaped, which gives enough room to
perform oral intubation but does not always prevent the childs
tongue from slipping underneath the spatula. The Robertshaw
blade is curved near the tip, but its cross-section presents a
C-shape, which is extended to the left (as seen by the intubator) to
give more room to use a Magill forceps.
Other straight blades have a reverse-Z shaped cross-section,
which keeps the patients tongue away and facilitates the use a
Magill forceps. They are easier to use during nasotracheal intubation. They are the Soper (straight) and the Seward, Cardiff,200 or
Heine (curve near the tip) blades. The Macintosh blade is the only
curved blade. In cross-section, as seen from its handle connection,
it has a reverse-Z shape. In the improved vision modification of the
Macintosh blade, the midportion of the spatula of the blade is
concave. One disadvantage of the small Macintosh blades equipped
with a light bulb is the excessive height of their connection to the
handle, which is smaller in the fiberoptic curved blades.
The McCoy levering laryngoscope allows mechanical
manipulation of the blade tip in order to improve the glottic view
without applying excessive force on the pharyngeal structures.
A pediatric levering laryngoscope with a Seward blade (size 1
or 2) has been introduced in practice, but it does not provide any
advantage over the classic Miller blade.201
By contrast to a fiberoptic laryngoscope, a light bulb laryngoscope blade can fall out during laryngoscopy202 and can reach
temperatures that could result in burns to the oropharynx.
It should be switched on for less than 1 minute before use or
its temperature should be checked with the hand before use.203
Both the Miller and the Macintosh blades have a built-in tube
that allows administration of oxygen or anesthetic gases during
laryngoscopy and intubation: they are called oxiport versions. They
are both also available in plastic, single-use, fiberoptic versions
that are especially useful in infected cases. Their quality (flexibility,
brightness, and direction of light) varies according to the manufacturer.204 They usually make laryngoscopic view a little worse
than a reusable blade of the same size and shape.
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TABLE 38-28. Disinfection of Airway Equipment After

Use in a Patient With Known or Suspected Prion Disease
Whenever possible, use disposable equipment, which should be
destroyed after use for reusable items:
1. Aluminum- or zinc-containing tools: chemical disinfection
with sodium hypochlorite for 1 h
2. Stainless steel tools: chemical disinfection with sodium
hydroxide 1 N for 1 h followed, in both cases, by autoclaving
at 134C for 1 h (or two cycles of 18 min each at 134C)
suggested that the light output should be at least 700 lux at a
distance of 20 mm for a minimum of 10 minutes, but this level of
illumination seemed too bright in a study.207
Figure 38-19. Correct way to hold the laryngoscope handle
during laryngoscopy in neonates and infants. Hold it at the level
of the hook-on connection to allow the intubator to use the little
finger to push on the childs trachea and improve the vision of
the glottic aperture.
Laryngoscope blades of different shapes and sizes should be
available before induction of anesthesia. Usually, the blade is
introduced at the right side of the mouth and passed on the side
of the tongue to displace it to the left and reach the vallecula.
A modified technique, the retromolar or paraglossal approach,
is useful in case of micrognathia. The straight blade is inserted
through the corner of the mouth, posterior to the molar teeth, and
directed in the groove between the tongue and the ipsilateral tonsil
until the epiglottis is seen. The endotracehal is then inserted
through the ipsilateral corner of the mouth and directed into the
glottis with the help of external laryngeal manipulation and a stylet
or an intubation guide.205,206 During laryngoscopy, care should be
taken to avoid crushing the childs lip between the blade and the
teeth and to avoid applying force on the neonates upper gum
because this could result in damage to future teeth. In case of cleft
lip and palate, inserting a roll of gauze into the gap in the gum
helps prevent the laryngoscope blade from slipping into it, which
prolongs laryngoscopy and could result in tissue damage. Laryngoscope handles are also available in several sizes: a lightweight
narrow handle is useful in neonates and infants. In this population,
the laryngoscope should be held at the level of the hook-on
connection instead of at the handle itself to allow the intubator to
use his or her left little finger to push on the cricoid cartilage and
bring the glottis into view without applying too much force on the
infants mandible (Figure 3819) (see Chapter 86).
Cleaning and Sterilization

The laryngoscope blade should be considered as contaminated
after use and stored away from clean surfaces to avoid contamination of other items. Because laryngoscopy and insertion of any
airway device can cause mucosal abrasion and bleeding, increasing
the risk of spread of blood-borne pathogens, the reusable blades
should be washed and scrubbed between cases before undergoing
autoclaving (which progressively damages fiberoptic bundles), gas
sterilization, or immersion in a disinfectant solution (e.g., 70%
alcohol solution). Although transmission of prion disease by blood
or airway secretions is unlikely, the patients tonsils are a possible
source. Because of the high resistance of this infectious agent to
ordinary sterilizing procedures, the use of a disposable laryngoscope or special sterilization techniques is recommended. Five
minutes immersion in a potassium permanganate solution
(8 mg/L) at 50C to remove all protein deposits208 (Table 3828) is
suggested.209 The laryngoscope handle must be considered as
a potential source of contamination and should be cleaned
between cases.
Aids for Intubation

This is equipment designed to make oral or nasal intubation easier.
Bougies or Intubation Guides

Bougies or intubation guides are used as an atraumatic guide over
which the TT is advanced
Quality Control
The blade is equipped with a light bulb, a fiberoptic bundle, or
LEDs that transmit light from a source in the handle. The position
of this light should be near the tip of the blade. If it is too proximal,
the pharyngeal soft tissues or the distal part of the tongue can
come in front of it and obstruct the light. The light bulb is screwed
into a socket with a metallic contact. This area is subject to soiling
and oxidation, which can affect the quality of the light; the
adequate screwing of the bulb to its socket should be verified
before each use. The brightness and steadiness of the light as well
as the proper contact between handle and blade should be checked
before use by placing the blade in working position. It has been
When the tip of the TT cannot be directed easily into the glottis during direct laryngoscopy.
To facilitate the insertion of a Flexible LMA, but their tip
should not protrude beyond the distal extremity of the airway
tube.
When oral intubation is difficult but an LMA has already been
inserted.210
During retrograde intubation after the guidewire has been
passed in the oropharynx.
When an already placed TT has to be changed in difficult
circumstances or when mobilization of the neck has to be
avoided.
The following devices can be used for those purposes:
An exchange catheter such as the Cook airway exchanger (four

sizes, the smallest being usable with endotracheal tubes of
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ID 3 mm), the Sheridan T.T.X., and Tracheal tube guide, both

available in 5-French size).
A suction catheter.
A nasogastric tube can also be used for that purpose.
The use of a hollow device allows the delivery of O2 during the

procedure and/or the measurement of CO2 to confirm its
intratracheal position before inserting the TT over it. Tracheal
trauma is possible when using a bougie, especially in neonates and
infants. It should be used very gently and force should never be
applied if any resistance is met.
Stylets
Stylets are pliable but firm devices (usually plastic-coated metal
rods) used to modify the curvature of the TT and impose a
predetermined shape to it. This is mandatory when using the
retromolar approach or most videolaryngoscopes (Glidescope or
Airtraq). They are often used for routine intubation. The stylet
should resist chipping and breaking, and its distal end should be
smooth to avoid trauma to the pharyngeal and laryngeal tissues.
Before inserting the stylet into the TT, it should be well lubricated
with silicone or another water-soluble lubricant and the TT
connector should be removed to make withdrawal of the stylet
easier. The stylet is inserted into the TT until its distal end is just
inside the tip of the TT. Bending the stylet at the proximal end of
the TT or an adjustable stop should prevent the stylet from
advancing past the end of the TT during the intubation procedure.
The stylet and TT are bent to the desired shape, usually a hockeystick configuration (distal end bent sharply). The laryngeal inlet
is exposed with a laryngoscope or videolaryngoscope and the
styletted TT is directed into it. The stylet should be removed as
soon as the extremity of the TT has passed the vocal cords.
Possible complications are difficult removal of the stylet after
intubation, shearing off of part of the stylet during its difficult
removal and subsequent TT obstruction,211 and tracheal trauma.
Many brands and sizes of stylets are available that can be used in
TTs as small as 2 mm ID. If reused, stylets should be washed and
scrubbed between cases before undergoing autoclaving, gas
sterilization, or immersion in a disinfectant solution.
Forceps
The Magill forceps can be used to guide a TT in the trachea or a
nasogastric tube in the esophagus, to pull out the patients tongue,
or to retrieve foreign objects from the pharynx or larynx. During
endotracheal intubation, the forceps is used to place the distal part
of the TT between the arytenoids. It should not be used to further
advance the TT into the trachea because the feel of the force
applied to it is less precise and forceful insertion could result in
laryngeal trauma. Care should also be taken to avoid traumatizing
the uvula when picking up the TT or a nasogastric tube in the
nasopharynx. When intubating with a cuffed TT, care should be
taken to avoid picking it up at the cuff level because this could
result in cuff damage. The Magill forceps is available in a small
size to be used in neonates and infants.
The Magill forceps should be cleaned in the same way as the
laryngoscope blade.
Teeth Protector
The presence of loose deciduous teeth is not uncommon in
children 4 to 11 years old. To prevent their dislodgment during
intraoral maneuvers (intubation, insertion of an oral or supraglottic airway or a rigid bronchoscope), a single-use PVC
device can be inserted (e.g., Ortho Plus Junior). This will either
support and protect a loose tooth or bridge the gap of an already
lost one.
Topical Anesthesia of the Upper Airway

Topical application of a lidocaine solution (benzocaine should be
avoided to prevent methemoglobinemia) to the larynx and trachea
is used before endoscopy of the upper airway or even before
routine endotracheal intubation. When deep inhalational
induction is used, this allows the evaluation of the depth of
anesthesia before intubation and reduces the incidence of
laryngospasm, coughing, and bucking after intubation. Either a
multiuse sprayer with disposable nozzles or a needle connected to
a Luer-Lok syringe (to avoid dropping the needle into the pharynx
or trachea) can be used. The use of a needle carries a risk of injury
to the oral and pharyngeal mucosa. Because its absorption from
mucosal surfaces is rapid and may lead to high blood levels, the
dose of lidocaine should not exceed 3 mg/kg.212
ANESTHETIC CIRCUITS
Numerous anesthetic breathing systems are described in the
literature and large differences of practice exist around the world,
based more on local habits, imprinting by initial teaching, and
local availability of components than on scientific grounds.
A simple and easily understandable functional classification of the
breathing systems usable in children is based on the presence or
absence of a CO2 absorption device and on the direction of flow
in the system (bidirectional vs. unidirectional)213:
The nonabsorber bidirectional circuit: Mapleson classification.

The unidirectional circuits: presence of a nonrebreathing
valve.
The absorber unidirectional circuit: the circle system.
A detailed description of all these circuits can be found in

Understanding Anesthesia Equipment (5th edition by Dorsch JA &
Dorsch SE, published by Wolters Kluwer, Lippincott, Williams &
Wilkins 2008).
Nonabsorber Bidirectional Circuits

(e.g., Maplesons Circuits)
The Mapleson circuits were invented to reduce deadspace and
work of breathing. These circuits have no unidirectional valves
and no CO2 absorber, but a high FGF is needed to flush the
expired CO2 out of the circuit and avoid rebreathing. They
are listed from A to F (Figure 3820) in order of increased
requirement of FGF to prevent rebreathing during spontaneous
ventilation and described according to the place of the reservoir
bag and of an adjustable pressure-limiting (APL) valve. The major
advantages of these circuits are a low compression volume and
allowance of rapid changes in the inspired gas concentration.
Their common drawbacks are loss of heat and humidity, waste of
anesthetic gases, and difficult scavenging, leading to increased
pollution of the working environment. They are mainly used for
induction and emergence of anesthesia, but also for transport, in
neonates and small infants.
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Mapleson C
In the Mapleson C circuit, there is almost no corrugated tubing
between the FGF inlet and the reservoir bag (see Figure 3820C).
This allows complete mixing of FGF and exhaled gases during
expiration. An FGF of three times the patients minute ventilation
is necessary to prevent rebreathing.
Reusable systems are commercially available that combine an
FGF inlet and an APL valve connected to a scavenging tubing.
These systems, which can be used in the Mapleson B or C configuration, are cumbersome to use during surgery and carry a risk of
reverse connection of the FGF and scavenging tubing.
Mapleson D, E, and F
Figure 38-20. Maplesons classification of nonabsorber bidirectional breathing systems: A = Magill circuit; A = coaxial version
of Lack circuit; A = parallel version of Lack circuit; D = coaxial
version of D = Bain circuit; E = Ayres T-piece; F = Jackson-Rees
modification of Ayres T piece; F = Kuhns circuit (lateral hole in
the reservoir bag).
Adapted from Cazala JB, Murat I, Servin F, et al. Pour ou contre
les circuits anesthsiques accessoires: arguments pour leur utilisation. Ann Fr Anesth Ranim 1998;17:372384, with permission
of the authors and publishers.
Mapleson A
In the Mapleson A (or Magill) circuit, FGF enters the circuit near
the reservoir bag and the APL valve is placed close to the patients
face. This system is very efficient during spontaneous ventilation,
because the FGF needs to be only 0.7 to 1.0 times the patients
minute ventilation (~150 mL/kg/min in children) to avoid
rebreathing. It is less efficient in case of rapid respiratory rate (such
as in small children) because the end-expiratory pause that allows
the elimination of the alveolar gas that has entered the tubing
during exhalation becomes too short. It is even less efficient during
controlled ventilation, because an FGF of two or more times the
patients minute ventilation is necessary to avoid rebreathing.
Close proximity of the APL valve to the patients face is inconvenient during surgery. A version of the Mapleson A circuit exists
in which the APL valve is away from the patients face. It is called
the Lack circuit and exists in coaxial and parallel versions (see
Figure 3820A and A). The Magill circuit should not be used
in children less than 20 kg because of the important apparatus deadspace (40 mL without the facemask). The Lack and
Humphrey A Hybrid Systems circuits deliver FGF much closer to
the patients airway and are therefore more efficient (deadspace of
apparatus 1.8 mL).
Mapleson B
The FGF enters the circuit close to the patient, just distal to the
APL valve (see Figure 3820B). During expiration, both FGF and
exhaled gases accumulate in the reservoir tubing and bag to the
point at which the pressure in the circuit is sufficient to open the
APL valve. The patient inhales FGF and a mixture of retained FGF
and exhaled gases. FGF greater than twice the patients minute
volume is necessary to reduce rebreathing to acceptable levels
during both spontaneous and controlled ventilation. It is seldom
used today.
In the Mapleson D circuit, the FGF inlet is close to the patients

airway and the APL valve is placed just before the reservoir bag
(see Figure 3820D). It also exists in a coaxial version, the Bain
circuit (see Figure 3820D), in which the FGF supply runs inside
the corrugated tubing through which expired gases are eliminated.
This is supposed to allow heating of FGF. The major drawback
of this coaxial circuit is that major rebreathing occurs if the
inspiratory tubing disconnects or cracks within the expiratory
limb, which can be difficult to detect during the preanesthetic
check. The Mapleson E circuit is the Ayres T-piece, in which
neither a reservoir bag nor an APL valve is present. The Mapleson
F circuit is the Jackson-Rees modification of Ayres T-piece; a
double-ended reservoir bag is added to the end of the reservoir
limb. To control ventilation manually, the open end of the
reservoir can be squeezed between two fingers or partially closed
with a tap. Another version, Kuhns circuit (see Figure 3820F), is
available in Western Europe. The reservoir bag has no open end
but a lateral hole that can be occluded with one finger to control
ventilation. In fact, the Mapleson D, E, and F circuits are functionally the same because the same factors influence the gas
content of the expired limb and, thus, of the inspired gas mixture
of the subsequent inspiration. They are
1. The patients CO2 production, which is related to both body
size and metabolic status (body temperature, catabolism).
2. The capacity of the reservoir limb. Its volume should be greater
than the patients tidal volume to avoid entrainment of air
during inspiration if FGF is low. If a reservoir bag is present,
its volume should be similar to the childs vital capacity (i.e.,
0.5 L in neonates, 1 L in infants, and 2 L in children).
3. The respiratory rate. If the expiratory pause is too short, such
as during rapid ventilation, time is insufficient for FGF to flush
alveolar gas out of the reservoir limb, unless FGF is increased.
4. The VT. If the VT increases, the volume of alveolar gas filling
the reservoir limb increases. Therefore, if the FGF or the
expiratory pause is insufficient to flush it, rebreathing will
occur and PaCO2 may not change, although minute ventilation
increases.
5. The FGF. As soon as FGF is sufficient to flush alveolar gas from
the reservoir limb, any further increase in FGF does not change
PaCO2. Conversely, if FGF is too low, rebreathing increases
with respiratory rate and PaCO2 remains stable despite
increased minute ventilation. Different formulas have been
recommended for FGF and minute ventilation when using
Mapleson D, E, or F circuits for spontaneous or controlled
ventilation in children. However, whatever the formula used,
the safest and most accurate means to determine the FGF and
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minute ventilation requirements is to continuously monitor

PETCO2,214 bearing in mind the limitations described in
Capnography, earlier.
For spontaneous ventilation:
FGF (mL/min) = 15 weight (kg)
respiratory rate (breaths/min)
e.g.: 10 kg FGF is 4500 mL/min if RR is 30 breaths/min
FGF (mL/min) = 2.5 to 3 times the childs theoretical
minute ventilation
(~150 mL/kg/min)
For controlled ventilation:
FGF (mL/min) = 1000 + (200 weight in kg)215
if a VT of 10 mL/kg and a respiratory rate of 20 breaths/min
are chosen and the expiratory limb of the T-piece is connected to
a Nuffield Ventilator 200 with a Newton valve
e.g.: 10 kg FGF is 3000 mL/min
FGF (mL/min) = 250 mL/kg/min
If a PETCO2 of 38 mmHg is aimed at and the expiratory limb of
a Mapleson F circuit is connected to a Sechrist ventilator (expired
VT of 1015 mL/kg, I:E ratio of 1:2, PIP 1525 mmHg)214
e.g.: 10 kg FGF is 2500 mL/min
FGF (mL/min) = 1000 mL/min + 100 mL/kg/min216
and minute ventilation is set at twice the FGF
e.g.: 10 kg FGF is 2000 mL/min and
minute ventilation is 4000 mL/min
The D, E, and F circuits are more efficient during controlled
than during spontaneous ventilation. The shape of the FGF inlet,
the T-piece, is important, especially for neonates and infants. If it
is at an angle pointing toward the patient rather than at right
angles to the inspiratory and expiratory limbs, it provides some
continuous positive airway pressure (CPAP) during expiration,
which could be beneficial in reducing the fall in functional
residual capacity during anesthesia. The good functioning of these
breathing systems (especially the expiratory valve) should be
checked before each use, and care should be taken to avoid any
obstruction of the expiratory limb because this may cause
barotrauma.217
Hybrid Systems
Some hybrid breathing systems have been proposed as the
universal breathing system because they incorporate the features
of the Mapleson A, D, and E circuits. The most recent is the
Humphrey ADE circuit. It consists of a manifold that has to be
connected to the FGF outlet of the anesthesia machine. A lever
switch rotates a cylinder within the manifold and converts
the system from the A (Lack version) to the D/E mode. The
Humphrey system can be used for spontaneous ventilation in the
A mode (lever up) and for controlled ventilation in the D/E mode
(lever down) and is connected to a mechanical bag-squeezer
ventilator. It is easy to scavenge from the manifold. A version
supplied with 15 mm smooth-bore nonkinking breathing hose
and a low-resistance special APL valve has been evaluated in
children larger than 8 kg.218 It is very efficient during spontaneous

ventilation in the A mode and allows an FGF of 3 L/min to be used
with no rebreathing in children less than 25 kg. During controlled
ventilation in the E mode, it behaves similar to a T-piece circuit.
Despite its advantages, this system has not gained much popularity
in pediatric anesthesia.
Nonabsorber Unidirectional Circuits

(Nonrebreathing Valves)
These breathing systems are those in which the inspired and
expired gases are completely separated by a nonrebreathing (oneway) valve. The expired gases are directly eliminated to the
atmosphere. Various valves are available that can be used for that
purpose: for example, the Ruben valve, the Ambu valve, the
Laerdal valve, and the Digby-Leigh valve. The valve is inserted
between the patient and the reservoir bag into which the FGF inlet
is connected. Controlled ventilation is achieved either by
occluding the expiratory port of the valve (Digby-Leigh) or by
squeezing the reservoir bag (Ruben, Ambu). These valves may also
be used with a self-inflating reservoir bag for resuscitation or
transport, for the administration of 50% N2O in O2 (Entonox,
Kalinox) for conscious sedation, or as part of a draw-over circuit
(see Chapter 56). Because there is no mixing of inspired and
expired gases, the exact composition of the inspiratory gases
is known but FGF needs to be much greater than the patients
minute ventilation to keep the reservoir bag filled during both
spontaneous and controlled ventilation. This results in loss of heat
and humidification and in a waste of anesthetic gases. Although
the nonrebreathing valves used have a low resistance, they increase
apparatus deadspace (e.g., 7 mL, 9 mL, and 0.8 mL for the DigbyLeigh, Ruben, and Ambu Paedi valves, respectively), which
can result in significant hypercarbia in spontaneously breathing
small infants. The risks associated with the use of nonrebreathing
valves are219
Bad connection or misassembly after cleaning. They should be

checked before each use.
Overdistention of the reservoir bag, causing barotrauma, if the
valve becomes blocked by moisture or if FGF is too high.
Hypoventilation and rebreathing in case of malfunction of the
valve. The easiest way to check the good functioning of a nonrebreathing valve before use is to breathe oneself through it
while wearing a mask or through a bacterial filter.
Absorber Unidirectional Circuits (Circle)

Description
The circle circuit incorporates unidirectional valves, a CO2
absorber, an FGF inlet, a reservoir bag, an APL valve, and a
Y-piece to connect its inspiratory and expiratory limbs to the
patient. All those components are part of the modern ventilators.
Although all these components increase the volume of the circuit,
its resistance during spontaneous ventilation, and the risk of leaks,
circle systems are increasingly used in pediatric anesthesia in order
to decrease operating room pollution, because scavenging is easy;
minimize loss of heat and water through the respiratory system;
reduce the consumption of anesthetic vapors by using less FGF;
and standardize the equipment used by pediatric and adult
anesthesiologists.
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Although the circle system is usually presented with two parallel
limbs joining at the Y-piece, coaxial versions have also been
designed (Universal F or PedF2, especially for children 30 kg,
Mera F)220 in which the inspiratory gases are delivered through the
inner tubing. As with any coaxial circuit, care should be taken to
avoid kinking or obstruction of the inner tube, reverse attachment
of the inspiratory and expiratory limbs to the absorber, and
displacement of the inner tube into the outer one, which results in
increased deadspace. Another breathing circuit that can be adapted
to a circle system is the Limb-. It is made of one corrugated tube,
22 mm in diameter, with a septum extruded down its middle separating the inspiratory from the expiratory passage. Its compliance
and its expiratory resistance are less than with the Universal F2
coaxial circuit; it can be used in children down to 5 kg body weight.
Stand-alone disposable circle circuits are available at present
(Universal F, PedF2, Clear Flo Circle) that can be connected to the
inspiratory outflow of the anesthesia machine or used during
transport or in remote locations anesthesia.
Quality Control
The adequate functioning of the unidirectional valves is
mandatory when using a circle system. The presence of moisture,
electrostatic charges, or foreign material can impair normal
seating of the disk of the valve and allow reverse flow through it.
For example:
An expiratory valve that does not close properly at the end of exhalation causes reverse flow in the expiratory limb during inspiration and thus rebreathing, which can be detected by
capnography.
A leaking inspiratory valve allows reverse flow in the inspiratory limb during exhalation and rebreathing during the beginning of the next inspiration, which is difficult to detect.
An inspiratory valve that does not open easily increases the
childs work of breathing and can result in the absence of ventilation if it remains stuck in the closed position.
If the expiratory valve is stuck in the closed position, exhalation
is impossible, leading to lung overinflation and barotrauma.
The circuit should be checked carefully for leaks and for correct
functioning of its unidirectional valves before use. A simple way to
check the valves is to breathe while wearing a mask through the
circuit or through each limb of it separately and to observe the
movement of the valves and the reservoir bag during inhalation
and exhalation.
concentrations of CO and a significant rise in absorbent

temperature. Those with calcium hydroxide-based CO2
absorbents such as Amsorb do not produce CO. The anesthetic
agent used may, at equipotent concentrations, show a different degree of degradation and production of CO. Desflurane
and enflurane produce more CO than isoflurane, whereas
halothane and sevoflurane produce negligible amounts. The
higher the absorbent temperature, the greater the production
of CO.
3. Compounds A and B are produced when sevoflurane passes
through soda lime. Compound A is a known nephrotoxic agent
in rats, but its toxic threshold in human beings is not known.
The use of low-flow sevoflurane anesthesia (FGF 600 mL/min),
with soda lime as CO2 absorbent, is safe in healthy pediatric
patients because the mean highest concentration of compound
A obtained after up to 7 hours of anesthesia is only 12.2
3.8 ppm.222 The calcium hydroxide-based CO2 absorbent
(Amsorb) produces no compound A when in contact with
volatile anesthetic agents. The exhaustion of the absorbent is
indicated by the color change of the indicator added to it.
However, the color may revert back to its pre-exhaustion status
if the absorbent is left to stand for a few hours because
exchange of hydroxide ions coming from the inside of the
absorber occurs. The color of an already used absorber is not
a reliable index of its efficacy except if Amsorb is in use.
For all these reasons, it is safer to use an absorber with no KOH.
Circle Circuit for Spontaneous Ventilation

Pediatric circle circuits (i.e., made of 15-mm diameter tubings
connected to a standard adult CO2 absorber) have been shown to
be efficient for spontaneously breathing infants and children.223
These studies were done with equipment less efficient than
currently available and their results are difficult to compare. In
brief, expiratory resistance increases with FGF in both systems.
This should be borne in mind during inhalational induction of
anesthesia, when a high FGF is used in the circle circuit to increase
the uptake of volatile anesthetics. When using an FGF of 6 L/min,
the Jackson-Rees circuit is more efficient in terms of work of
breathing than the pediatric circle circuit, which is more efficient
than the coaxial Mera F circuit (Table 3829).220 However, the use
of higher than usual FGF in both circle circuits might have
influenced the observed differences. In conclusion, there is no
great problem letting an infant or child breathe spontaneously
through a circle system for a limited period of time, except perhaps
for the coaxial version that increases the work of breathing.
The CO2 Absorber

Although often considered as an inert part of the circle circuit,
the absorbent used to remove the CO2 from the re-inhaled gases
has possible interactions with the volatile anesthetic used.221
1. the CO2 absorbent can absorb the volatile anesthetic at the
beginning of inhalational induction. This occurs when the
absorbent is very dry, the absorber is placed between the FGF
inlet and the patient, and FGF is low. This can result in a slow
inhalation induction.
2. Carbon monoxide (CO) can be produced from the degradation
of volatile anesthetics by the CO2 absorbent. The importance of
CO production depends upon the type of absorbent, that
is, those containing high amounts of potassium hydroxide
(KOH) and or lye (NaOH) can produce clinically important
Circle Circuit for Controlled Ventilation:

The Compression Volume Issue
During positive-pressure ventilation, whether mechanical or
manual, with a circle system, pressure increases within the circuit
and leads to important changes to its gas content.224 A reduction
in ventilation actually delivered to the patient may result from
Compression of the gas in the circuit, which is directly related

to the volume of the circuit, is called the compression volume.
Distention of the breathing circuit itself, which is influenced by
the material of the tubing, is called the compliance volume.
These volumes are usually combined and called compression

volume. This lost volume of ventilation, which does not enter or
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TABLE 38-29. Comparison of the Jackson-Rees circuit, the Pediatric Circle Circuit, and the MERA F Coaxial Breathing
System in Spontaneously Breathing Childrena
Criterion
Jackson-Rees
Pediatric Circle
MERA F
Minute ventilation
Respiratory rate (breaths/min)
Inspired airway resistance (cmH2O/L/s)
Expired airway resistance (cmH2O/L/s)
Work of breathing (J/L)
PaCO2 (mmHg)
226 50 mL/kg
39 9
27.7 10.4
14.8 6.0
0.48 0.16
35.0 3.5
213 58
39 9
31.8 10.5b
23.0 6.6b
0.52 0.14b
42.9 5.9b
239 70
39 8
30.5 8.4c
22.6 6.1c
0.56 0.16b,c
42.1 3.7b
PaCO2 = arterial carbon dioxide pressure; sd = standard deviation.

a
Values are mean sd.
b
P < .05 vs Jackson-Rees Circuit.
c
P < .05 vs pediatric circle.
leave the patients airway, is a function of airway pressures and may

be quite large. Its effects are comparatively more important in
small patients. For example,
To deliver a 10-mL/kg VT to a 5-kg infant with a PIP of

18 cmH2O using an adult circle circuit with adult bellows
(compression volume 4 mL/cmH2O), 122 mL will have to be delivered within the circuit (72 mL for the circuit + 50 mL for the
patient),
Conversely, if a low-compliance pediatric circle circuit (compression volume 0.7 mL/cmH2O) is used; only 63 mL will have
to be delivered within the circuit (13 mL for the circuit only).
If the child weighs 20 kg, 272 mL and 213 mL will have to be
delivered within the adult and pediatric circuits, respectively.
The compression volume of a circuit can be estimated as

follows:
1. occlude the patients end of the circuit and fill the reservoir bag
with some fresh gas.
2. Stop the FGF and compress of the reservoir bag up to a
predetermined pressure (e.g., 20 cmH2O).
3. Release the reservoir bag and measure the volume of gas
displaced within the circuit with a spirometer connected on the
expiratory limb of the circle circuit.
4. Divide the volume so measured by the predetermined pressure
obtained. It gives the compliance of the breathing system.
Usual values are 0.78, 0.74, 2, and 1.6 mL/cmH2O for the
pediatric circle, pediatric coaxial, adult circle, and adult
coaxial systems, respectively, but values up to 5 mL/cmH2O are
considered acceptable with the ventilators that compensate for
circuit compliance.
illustrated clinically in infants with normally compliant lungs who

were adequately ventilated using an Ohmeda 7800 ventilator, the
VT being set to provide appropriate chest expansion and PIP.226
The safe use of circle circuits with a large compression volume is
easier and safer with modern ventilators that measure their own
total compliance during their pressure test and have a system of
continuous compensation of compression losses and changes in
FGF. Last, whenever possible, small-bore noncompliant tubing
and a small reservoir bag should be used when using a circle
circuit for controlled ventilation in small infants.
The majority of children can be anesthetized using a standard
adult circle circuit, with modification of the size of the reservoir
bag and, if possible, of the connecting tubing in order to reduce as
much as possible the volume of the circuit. Even a neonate can be
anesthetized with an adult circle system provided the anesthesiologist understands how its PV characteristics (compression
volume) alter the clinical estimation of the adequacy of ventilation,
ventilation is controlled, and adequate monitoring (PETCO2, SpO2,
and PIP) is used.
Scavenging227
Occupational exposure to waste anesthetic gases is more important during pediatric anesthesia than in adults because of the
frequent use of mask or steal induction, uncuffed TTs, supraglottic
airways, and breathing systems requiring high FGF and that are
difficult to scavenge.228 Effective scavenging of excess gases, nonrecirculating air-conditioning, and the use of low-flow anesthesia
can reduce pollution.
The optimal scavenging system is made of five components:
In an in vitro study, the Mapleson D circuits had the smallest

compression volume and were more efficient than all the circle
circuits tested.224 The addition of a humidifier to any circle system
(pediatric or adult, rubber or plastic) increased their compression
volume further. More recent studies have been performed to better
understand which ventilator setup parameters are required when
using an adult circle system during infant anesthesia.225 They
demonstrated that, when an adult circle is used for controlled
ventilation in infants and small children, the PIP achieved,
the respiratory rate chosen, and the compliance of the infants
lungs are the main determinants of the ventilation delivered.
But in infants with poorly compliant lungs, a very high PIP may
be needed to provide an adequate VT. This concept has been
A gas collecting assembly: a 30- or 19-mm connection to the

APL valve of the breathing system or to the ventilator pressure
relief valve.
A transfer tubing: a wide-bore, kink-resistant tubing that can be
easily disconnected in case of malfunction and that should be as
short as possible to avoid it being crushed by the wheels of the
anesthesia machine.
An interface that acts as a reservoir to accommodate for changes
in flow rate and to prevent pressure changes in the scavenging
system from being transmitted into the breathing system.
It contains either pressure-relief valves (closed interface) or a
system allowing escape of excess gases in case of overpressure
and air entrainment in case of excessive negative pressure (open
interface).
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A gas disposal tubing.

A gas disposal assembly that is either passive (pressure is raised
above atmospheric by the patients expiratory flow or by the ventilator) or active (suction from the hospital vacuum system generates a small negative pressure in the tubing).
An absorption system made of activated charcoal stored in

special canisters can be used instead of the gas disposal assembly
in nonventilated remote locations. This system is expensive, does
not absorb N2O, and is effective for only a limited period of time.
Nonrecirculating air-conditioning is another way to reduce
personnel exposure to waste gases. A frequency of air change of
20 cycles/h reduces high concentrations of anesthetic vapors in
10 minutes. Some devices have been designed to scavenge the
pediatric breathing systems, especially during facemask induction.
For example, scavenging around the facemask with a double
facemask (Medicvent) is designed to evacuate gases leaking
around the silicone inner mask through a slot between it and a
rigid plastic outer mask.229 The inner mask is connected to any
breathing system, whereas the gas escaping between the two masks
is evacuated through a housing connected to a fan unit that
aspirates 25 to 40 L/min. The same coupling housing could also be
connected to an uncuffed TT to scavenge gas escaping around it.
Another system to scavenge gases around an uncuffed TT is to
place a gas-impermeable plastic bag around the childs face. Its
exhaust port is connected to a vacuum source via multiperforated
suction tubing placed inside into this flexible hood.227
In fact, scavenging of waste anesthetic gases is rather easy
as soon as an APL valve is present in the breathing circuit, as in
the circle, Mapleson A, B, C, and D systems. The 19- or 30-mm
collecting assembly system can be connected to it. However, this
often makes the Mapleson A, B, C, and D systems more awkward
to use. Many home-made systems have been designed to scavenge
the Mapleson F system in which no APL valve is present. For
example,
Scavenging through the reservoir limb. A second T-piece is

placed proximal to the reservoir bag and is connected to a large
tubing leading the expired gases to a control valve on the anesthesia machine and so to the collecting system.230
Scavenging at the bag level. For example, different valves to be
fixed at the open tail of the bag,231,232 a silicone tail placed
through the end of the bag,233 and a big bag enclosing the reservoir bag.234
Unfortunately, all these devices make the Mapleson F system

more awkward to use and can result in overinflation of the
reservoir bag, and barotrauma, if the outflow becomes obstructed.
Even when appropriate equipment is used, scavenging is difficult
during mask induction in children. Chronic exposure of the
personnel to sevoflurane in excess of 2 ppm is important, especially when working outside the operating room, in a poorly
ventilated postanesthesia care unit (PACU) or when performing
facemask induction or rigid bronchoscopy.228
and the circuit. Although disposable breathing circuits are available, their cost is high. The best way to achieve a more costeffective acceptable standard of hygiene with breathing systems is
a subject of research.
The filters currently available are classified into two groups. The
pleated hydrophobic filters are made of an extremely compact fiber
matrix membrane with very small pores. Resistance to airflow is
significant but is compensated for by pleating that increases the
exchange surface. The electrostatic or electret filters have a small
flat surface and incorporate a feltlike material with a high polarity.
Their network of fibers is less dense and they have a greater pore
size. The use of filters is controversial in pediatric anesthesia
because they tend to have a poorer filtration performance than
filters used for adults. They increase work of breathing by adding
deadspace and resistance to flow. The ideal pediatric breathing
filter should have a good filtration performance, a low-pressure
drop when gases flow through it, and a small internal volume. In
vitro studies have shown that
The filtration performance of pleated filters is generally better

but pressure drop across them is greater.
The greater the gas flow through the filter, the more particles
pass through it. This can be a concern because flow can be
greater than 15 L/min during cough.235
Desflurane reduces the filtration performance of some filters
when administered at 2 minimum alveolar concentration
(MAC) during at least 1 hour.236
The solutions usable for each type of breathing circuit are

described hereafter.
Bacterial/Viral Precautions When Using a

Nonabsorber Bidirectional Circuit (Mapleson)
Use a disposable breathing system for each patient.

Wash-disinfection (pasteurization) of a reusable circuit after
each use. The treated equipment must be dried and packaged,
and its adequate functioning should be rechecked before use
Insert a filter at the circuit connector. This increases resistance
in the inspiratory limb and diverts some FGF into the expiratory
limb. In the presence of a filter, the FGF actually delivered
through the inspiratory limb of a T-piece in which the FGF inlet
is at right angles to the inspiratory and expiratory limbs is 50%
less than the total FGF dialed on the rotameters.237 Once a tight
fit with the facemask is achieved, the childs inspiratory effort
can inhale gas from the expiratory limb, but this is obviously
not possible for neonates and infants. If a filter has to be used,
these authors recommend closing the open tail of the Mapleson
F circuit as long as no tight fit with the facemask is obtained, in
order to direct all the FGF to the inspiratory limb. In children in
whom the trachea is intubated, weighing 3 to 8 kg, adding a dry
12-mL HME between the TT and a Mapleson D circuit increased their work of breathing by a median of 43% (95% confidence interval [CI] 25138%).238 This should be kept in mind
when anesthetizing spontaneously breathing infants.
Cleaning and Disinfection

Breathing systems can become contaminated and act as a reservoir
for a wide variety of infectious agents. Possible solutions to prevent
patient cross-contamination are complete replacement of the
breathing circuit between cases or introducing a mechanical
barrier such as a bacterial/viral filter between the patients airway
Bacterial/Viral Precautions When

Using a Nonabsorber Unidirectional
Circuit (Nonrebreathing Valves)
The whole circuit (including the valve) should be disinfected
except if a filter has been placed on the TT or mask connector
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(which is not recommended in case of spontaneous breathing

because it increases deadspace and resistance to breathing).
Bacterial/Viral Precautions When Using an

Absorber Unidirectional Circuit (Circle)
Use a disposable circuit.

Place a filter either at the Y-piece connection or on both the inlet
and the outlet valves of the circle. The outlet filter also prevents
soda lime dust from entering the circuit. The parts of the circuit that are placed between the bacterial filter and the patient
should be disposable or disinfected between cases. It should be
kept in mind that, in a clinical study, 9% of filters were contaminated on the machine side after use. The breathing circuit
should be changed if there were episodes of coughing while the
filter was in use.239
VENTILATORS
Only the working principles of the different types of ventilators
available at present and the essential points that need to be understood when using them in pediatric patients are described hereafter. For more details, the reader is invited to consult specialized
textbooks (e.g., Al-Shaikh B, Stacey S. Essentials of Anaesthetic
Equipment. 3rd edition, Churchill Livingstone/Elsevier; 2007; or
Dorsch JA, Dorsch SE: Understanding Anesthesia Equipment, 5th
ed. Baltimore, Wolters Kluwer and Lippincott Williams & Wilkins;
2008) and the instruction manual of the ventilator(s) in use in your
hospital. The principles and modes of mechanical ventilation are
described in Chapter 42. The ideal properties of the pediatric
anesthesia ventilator are summarized in Table 3830.
Manual Resuscitators (Self-inflating Bag)

Manual resuscitators are used for patient transport, for emergency
resuscitation, or as a part of draw-over anesthesia. A manual
resuscitator should be immediately available in every place where
anesthesia is administered to allow emergency ventilation in case
of failure of the breathing system, accidental intravascular
injection of local anesthetics in awaken patients, and other
situations. They have three components:
TABLE 38-30. Ideal Properties of a Pediatric
Anesthesia Ventilator
1. Easy and quick change-over to manual ventilation.
2. Ability to deliver tidal volumes ranging from 20 to 500 mL
in the volume or pressure-controlled mode.
3. Ability to deliver respiratory rates ranging from 10 to
60 breaths/min.
4. Ability to deliver PEEP.
5. Ability to provide pressure-support ventilation.
6. Adjustable I:E ratio.
7. Ability to deliver an air/O2 mixture.
8. Accurate pressure and volume monitoring and alarms.
9. Compensation of the compression volume of the breathing
circuit.
10. Interruption or buffering of FGF during inspiration.
FGF = fresh gas flow; I:E ratio = inspired-to-expired ratio; PEEP = positive
end-expiratory pressure.
A self-inflating bag that is expanded in the resting state and contains a bag refill valve.
A fresh gas inlet for O2, with or without a reservoir at one end.
A nonrebreathing valve (Ambu, Ruben, Laerdal) at the
patient end.
These manual resuscitators should always be used with a

reservoir, which is either long tubing or a large-capacity bag, because
it stores O2 that cannot enter the self-inflating bag during its
compression and provides a greater FIO2 during the next filling cycle.
If a reservoir bag is used, it should be equipped with an overpressure
and an entrainment valve to avoid both barotrauma (excessive O2
supply, inspiratory jamming of the nonrebreathing valve) and
collapse of the bag (interruption of O2 supply). Many pediatric
manual resuscitators are also equipped with an overpressure safety
valve fitted on the nonrebreathing valve. This safety valve has an
opening pressure at 30 or 45 cmH2O, but it can be overridden by
placing a finger on it when higher inflation pressures are needed.
Care must be taken not to use these resuscitators in a spontaneously
breathing child, because they increase deadspace and because the
inspired gas may come from the exhalation port as well as from the
self-inflating bag, depending on the design of the nonrebreathing
valve and on the relative resistance of its inspiratory and expiratory
limbs. The proper functioning of the bag and the nonrebreathing
valve should be carefully checked every day in the morning and
before use.219 The whole manual resuscitator should be carefully
disinfected after each use.
Mechanical Ventilators
Many classifications of the mechanical ventilators have been
proposed. In pediatric anesthesia, the two main working principles
used are (1) the intermittent occlusion of the expiratory limb of a
T-piece: the mechanical thumb and (2) squeezing the reservoir
bag, the mechanical or pneumatic bag squeezer. The latter is
more frequently used.
Mechanical Thumbs
The most popular ventilators of this type are the Sechrist, Babylog,
and Bear Cub. The ventilator is connected to the expiratory limb
of the T-piece and the FGF enters the anesthesia breathing system
at the usual place. Cycling of the intermittent occlusion of the
expiratory limb of the T-piece is determined by the settings of the
ventilator control panel, which adjusts PIP, respiratory rate, I:E
ratio, and PEEP. In some cases (e.g., Sechrist 100 and 200), the
FGF coming from the anesthesia machine can be connected
directly to the inspiratory limb of the ventilator in place of the
air/O2 mixture as when used in intensive care. Because the FGF is
diverted to the infants/childs lung, it must be equal to the
inspiratory flow rate. The calculation of FGF is described in
Mapleson D, E, and F, earlier. This results in very high FGF
requirements in large patients; this mode of ventilation is usually
restricted to children less than 20 kg.
A similar ventilation system is very popular in the United
Kingdom and among UK-trained pediatric anesthesiologists. It is
the Penlon Nuffield 200 ventilator connected to the expiratory
limb of a T-piece via the Newton valve.240 This valve has four ports:
An input port, connected to the outlet of the low-compliance

ventilator. Inspiratory time, expiratory time, and flow rate are
determined on the ventilator control panel.
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A fixed-orifice gas outlet.

A patient port, connected to the expiratory limb of the T-piece
in place of the reservoir bag.
A safety pressure relief valve set at 40 cmH2O.
alarm and could result in the patient being not ventilated, underventilated, or ventilated with a mixture of circuit gas and entrained room air. However, it is important to mention that the
falling bellows is also an early warning sign of disconnection.
The FGF is set as recommended for controlled ventilation with

a T-piece (see Mapleson D, E, and F, earlier). The system actually
functions as a partial thumb occluder if the ventilator gas flow is
lower than FGF, as a thumb occluder if ventilator gas flow is equal
to FGF and as a bag squeezer if ventilator gas flow exceeds FGF. In
order to avoid dilution of the inspired anesthetic gases by the
ventilator driving gas (usually O2), the ventilator circuit deadspace
(i.e., volume of tubing interposed between the patient port of the
valve and the expired limb of the T-piece + internal volume of the
last) should be at least equal to the delivered VT. The pressurelimited nature of the ventilation provided by these mechanical
thumbs is potentially dangerous in the operating room where
events may lead to a fall in VT or even in the absence of ventilation
without any changes in the ventilator display unless volume and
pressure alarms are added close to the patient. These events are
The mechanical bag squeezers use a motor or a piston to

mobilize the bellows. These ventilators usually have a lower
compliance than the pneumatic bag squeezers and, thus, more
accurately deliver very small VTs. Most of these anesthesia ventilators use the portion of FGF coming into the breathing circuit
when the inspiratory valve is open and add it to the VT delivered
by the ventilator bellows. Changes in FGF may modify the
delivered VT even if no change is made to the ventilator settings.241
This may have serious consequences in small patients. For example,
if the ventilator is set to provide a 2-L/min minute ventilation with
an I:E ratio of 1:2 and an FGF of 6 L/min, the child actually receives
a VE of 2 L/min + 1/3 6 L/min = 4 L/min. If the FGF is reduced to
2 L/min, the child receives a VE of 2 L/min + 1/3 2 L/min = 2.7
L/min, that is, a reduction of 32% of delivered minute ventilation
(VE)! Careful monitoring of oxygenation, ventilation, and PIP, and
adaptation of the ventilator settings, is mandatory when FGF is
altered in order to avoid both hypo- and hyperventilation. This
effect of FGF on delivered VT is no longer present in modern
ventilators in which changes in FGF are electronically compensated
by its interruption or storage in a reservoir bag during inspiration.
For example, when using the Ohmeda 7900 ventilator, inspired and
expired minute ventilation as well as PETCO2 are not affected by
changes in FGF from 1.5 to 6 L/min.242
All these ventilators are equipped with pressure and volume
alarms. However, it is very important to correlate the monitor
information with the clinical patient observation (i.e., chest
movement, auscultation, oximetry, and capnography). For
example, if a large leak is present around the TT, insufficient
expired volume goes back to the ventilator, which leads to
sounding of the low-volume alarm despite adequate ventilation.
The low-pressure alarm may not be triggered in case of accidental
extubation when small infants are ventilated with an adult-size
ventilator and a large FGF because small TTs add a great resistance
to the circuit.243 A bacterial filter should be placed either at
the inlet and outlet valve connectors of the circle circuit or at the
patient connection (Y-piece) to prevent contamination of the
ventilator and cross-contamination between patients. The parts of
the breathing system that are not isolated from the patient should
be either single-use or disinfected between cases.
Brisk intraoperative changes in lung compliance caused by retractors, the surgeon leaning on the infants thorax, pneumothorax, bronchospasm, and other factors.
Kinking or blockade of the TT.
Obstruction of the expiratory limb of the T-piece.
Disconnection of the anesthesia system or interruption of FGF.
Continuous monitoring of ventilation (chest movement,

stethoscope, PETCO2, and SpO2) is mandatory. As far as cleaning
and disinfection is concerned, only the T-piece, its expiratory limb,
and the connection to the ventilator (e.g., the Newton valve) have
to be changed between cases unless a bacterial filter has been placed
on the TT connection. The availability of electronic ventilators able
to more precisely ventilate small infants makes the use of those
ventilators less and less popular in the operating room.
Bag Squeezers
Most of these ventilators use semiclosed circuit anesthesia
(i.e., they include a circle breathing system and re-administer the
expired gases to the patients).
The pneumatic bag squeezers use a double-circuit system in
which a separate gas supply (O2, air, or a mixture of both) provides
the driving pressure to compress the reservoir bag (bag-in bottle)
or the bellows of the breathing system. When the bellows are
compressed, these ventilators are further classified according to
the direction of bellows movement during expiration: descending
(or hanging) bellows fall during expiration whereas ascending (or
standing) bellows rise during expiration. Ideally, the movement of
the bellows should be visible so that any abnormality (e.g.,
insufficient FGF) can be rapidly detected.
The descending bellows design has potentially two disadvantages
The effect of gravity creates a negative pressure that can be

transmitted to the breathing circuit and to the patient. At the
beginning of expiration, this is prevented in the most recent
ventilators by adding a reservoir bag into which FGF is stored
during inspiration or by providing FGF during expiration only.
In case of disconnection in the breathing circuit, the bellow falls
with gravity and room air is entrained through the disconnection site. This may hinder triggering of the lowairway pressure
Electronically Controlled Ventilators

The most recent ventilators are bag squeezers (pneumatic:
Smartvent 7900, Aisys, Julian, Titus, Kion; or mechanical: Primus,
Apollo, Zeus) equipped with electronic sensors and microprocessors. Two main techniques are used to match the VT actually
delivered to the lungs with the desired VT during volumecontrolled ventilation:
1. The total compliance of the breathing system is measured
during the preuse test and provides continuous compensation
of FGF (which is either stored in a reservoir or interrupted
during inspiration) and of volume losses caused by compression and leaks.
2. A special flow sensor placed between the TT and the
Y-connector of the breathing circuit compares the delivered VT
to the desired VT and adjust the difference (caused by leaks and
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TABLE 38-31. Usual Settings for Pressure-Support

Ventilation in Children
PEEP: +3 cmH2O
Flow: 2.5 L/min
Trigger: 2 cmH2O decrease in airway pressure
Max PIP: 10 cmH2O above PEEP
Rescue breathing rate: according to age
PEEP = positive end-expiratory pressure; PIP = peak inspiratory pressure.
changes in FGF) within the following 5 to 6 breaths.242 Control

and safety functions are fully integrated in those ventilators,
enabling them to ventilate small infants (VT < 20 mL) in the
volume- and pressure-controlled mode244 and to provide lowflow anesthesia.
The Zeus ventilator is a closed circuit machine equipped with
a servocontrolled valve system to control different ventilation and
FGF feedback modes and a compressor turbine in the inspiratory
limb. It can be used as a conventional ventilator (fresh gas control
mode: anesthetic vapor is mixed with the fresh gas before injection
in the circuit), in the autocontrol mode (fresh gas and vapors are
injected separately aiming at a target end-tidal concentration), or
in the uptake mode (same as autocontrol but with feedback control
of FGF, FIO2, and anesthetic delivery). The latter mode is the most
economical.245
The most recent ventilators are able to provide pressuresupport ventilation175 (Table 3831). Some teams even use the
pressure-support mode to perform target-controlled inhalation
induction in infants and children.246 The recommendations
regarding the prevention of contamination of the ventilator are
similar to those given in Bag Squeezers, earlier. The preuse test,
which calculates the compliance of the breathing circuit, should be
performed after connection of the bacterial filters.
High-frequency Ventilators
High-frequency ventilation refers to the different modes of ventilation characterized by supraphysiologic ventilatory frequencies
and low VTs (less than or equal to physiologic dead space). The
main advantage is that it ensures adequate transport of CO2 with
small VTs at a near-constant airway pressure, avoiding both high
and low extremes of lung volumes. When using such ventilators in
the operating room, the different problems are
Inhalational agents are not usable because special vaporizers

are not available. The Venturi effect produced by the jet ventilators has a diluting effect. A total I.V. anesthesia technique is
mandatory.
Measurement of expired volumes is not possible.
Monitoring PETCO2 is not possible unless a special port is used
and connected to a sidestream capnometer.247 Measuring PtcCO2
is a good alternative.117,248
To avoid necrotizing tracheitis, a special humidification system,
usually adapted to the ventilator, must be used during utilization
lasting more than 3 hours.
High-frequency Positive-Pressure Ventilation

(Frequency: 60100 Breaths/min)
A conventional pressure-controlled ventilator with lowcompliance tubing is used to produce these high respiratory rates.
There is no entrainment of gas; the FIO2 delivered is the same as the

FIO2 provided by the ventilator.
HFJVs (Frequency: 100150 Breaths/min)

HFJVs are used in the PICU for the treatment of acute respiratory
distress syndrome (ARDS) or the management of an air leak (e.g.,
pulmonary interstitial emphysema, bronchopleural fistula); and in
the operating room for laryngotracheal surgery, bronchoscopy, or
laser surgery of the airway, or as an alternative to one-lung
ventilation during thoracic surgery.249 Short bursts of a highvelocity jet of fresh gas are delivered in the airway using a TT with
a special port or through a special cannula used either alone250,251 or
within a laryngoscope or rigid bronchoscope. During bronchoscopy, intermittent jet ventilation can be performed through the
suction channel of a fiberoptic bronchoscope. Because of the
Venturi effect, a large volume of air or gas contained in a parallel
continuous-flow circuit is entrained. The jet is produced with a
special ventilator (e.g., Mistral, Monsoon ) or, for short cases, with
a manual system (e.g., the Manujet III by VBM). Because expiration
is passive, relying on the passive recoil of the lungs and chest wall,
there should be no obstruction to expiration. Expired airway
pressure is monitored in all jet ventilators to avoid barotrauma and
the jet is automatically interrupted as soon as a threshold endexpiratory pressure is achieved. As a rule, oxygenation depends on
mean airway pressure, which is a function of driving pressure and
I:E ratio and on FIO2, whereas ventilation depends on VT, which is
also a function of driving pressure and I:E ratio but is inversely
related to respiratory rate. In clinical practice, the following
parameters are adapted to the patients response:
Driving pressure. In infants and children with normal lung

compliance, the starting pressure should be 0.1 bar (= 1.5 psi =
10 kPa). Increasing the driving pressure (maximum 3.5 bar in
adults) increases VT and, thus, both CO2 elimination and oxygenation. The usual value in children is between 0.5 and 1 bar
Respiratory rate. Increasing the respiratory rate reduces VT and
CO2 elimination. PaCO2 usually increases above 150 breaths/min.
I:E ratio. The I:E ratio is usually set between 25 and 33%, in
order to avoid gas trapping and barotraumas.
FIO2. No more than 40% should be administered if CO2 laser
is used.
If a multilumen central venous catheter or a special tube is used
to deliver jet ventilation, one of its lumens can be connected to
a sidestream capnometer to monitor PETCO2 and FEO2 when
ventilation is temporarily slowed to more physiologic rates.
If a manual jet injector system is used, a high-pressure source

of gas is connected to a reducing valve, a pressure gauge, and a
manual on-off trigger valve. The anesthesiologist controls the
duration of the injection with the manual valve by watching the
movement of the chest. Care should be taken to avoid barotrauma
by using a purpose-made device such as the Manujet III (by VBM
with color-coded range of insufflation pressures according to
childs size). The Enk O2 Flow Modulation set can also be used. It
is a short connector with five side holes, a distal Luer-Lok fitting,
and a side syringe connector (for nebulizing drugs) placed
between the O2 tubing and the airway connection. It can be totally
or partially occluded by the operators fingers during bursts
of insufflation. However, it has been experimentally shown that
it should be totally occluded to allow effective insufflation.252
Whatever the manual injector system used, an I:E ratio of 1/3 to 1/4
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should be used along with a slow ventilation rate (12 breaths/min)
to avoid overinsufflation and barotrauma. Whatever the injection
system used, the peak inflation pressures produced in the childs
lung are influenced not only by the driving pressure and the
diameter of the jet injector but also by the diameter and shape of
the device in which jet ventilation is performed, that is, much
higher inflation pressures are measured when the jet injector
enters 3 to 5 mm Storz bronchoscopes at an angle of 20 degrees
than when it is placed coaxially in same-size Pilling bronchoscopes.253 Partial obstruction of the lumen of these bronchoscopes
by instruments (e.g., forceps, aspiration) will further increase
the inflation pressure. Manual jet injection should be used very
cautiously in pediatric patients because small changes in the
system can produce large changes in the patient.254
HFOs255 (Frequency: 4002400 Breaths/min)

HFOs are mainly used in neonatal intensive care for the treatment
of respiratory failure (e.g., hyaline membrane disease, meconium
aspiration syndrome) and the preoperative stabilization of congenital diaphragmatic hernia (see Chapter 86). Gas is delivered to
the patient by the to-and-fro movement of a reciprocating piston
or diaphragm that moves the same volume of fresh gas into a
standard TT. Expiration is active, which is an important
characteristic of HFOs, but air trapping may still occur. V T and
CO2 elimination are adjusted by changing the peak-to-peak
pressure generated by the piston, whereas oxygenation is
controlled with the FIO2 and the mean airway pressure. If
ventilation is interrupted (e.g., for patient transport), the alveoli
collapse and a sustained inflation (a sigh) are necessary to recruit
them and reestablish adequate ventilation. The most popular HFO
in use is the Sensormedics 3100A,256 but it lacks the means to provide a conventional mode of ventilation when weaning from HFO.
Other oscillatory-type ventilators are the Baby Log 8000 and the
Humming V, which are able to provide conventional ventilation
either alone or superimposed on oscillations. According to a
comparative study in rabbits, the mean airway pressure displayed
on the control screen of neonatal oscillators can be lower, similar,
or higher than the mean alveolar pressure in the lung, depending
on the oscillator used. The mean pressure dial should be adjusted
to achieve the desired degree of alveolar recruitment on the chest
x-ray and according to arterial blood gas measurements.
DEVICES DESIGNED TO
MAINTAIN NORMOTHERMIA
These devices are used either to maintain normothermia or to
warm up a hypothermic patient. Their use is mandatory in
anesthetized neonates and infants because their heat balance is
more affected by environmental factors than that of older children
and adults, because of their higher surface areatoweight ratio,
their increased thermal conductance (thin skin and subcutaneous
tissue), and their thermoregulatory mechanisms being more
affected by general anesthesia (see Chapter 14). In order to maintain perioperative normothermia, all mechanisms of heat loss (i.e.,
radiation, convection, evaporation, and conduction) must be
addressed. Approximately 90% of metabolic heat is lost via the skin
surface and less than 10% is lost via the respiratory system.
Radiation and convection are the main mechanisms of heat loss,
accounting for approximately 60% and 25%, respectively, but the
contribution of evaporation increases dramatically when a large
wound (peritoneum, small bowel) is exposed to air. The different
methods to prevent hypothermia are summarized in Table 3832.
Cutaneous Warming
Cutaneous warming may be obtained by several methods.
TABLE 38-32. Prevention of hypothermia
SUCTION APPARATUS
A good functioning suction apparatus is essential to the safe
practice of anesthesia. It is used to clear mucus, blood, secretions,
or debris from the pharynx, trachea, main bronchi, or stomach.
The power source that generates the necessary subatmospheric
pressure may be an electric motor or a pneumatically driven
pump, which usually uses the Venturi principle and is driven by
compressed air, O2, or water, or even human energy (hand- or
foot-operated spring-loaded bellows with unidirectional valves).

The suction nozzle or catheter should include a limiting pressure
valve that admits air and reduces the vacuum when opened (e.g.,
the Yankauer handheld suction to clear pharyngeal secretions)
and/or have two or more holes at its end to avoid performing a
mucosal suction biopsy. The shape of the tip of these suction
catheters should be smooth to prevent tissue damage. When
performing tracheal suctioning, take care to minimize the negative
pressure generated within the tracheobronchial tree by using a
suction catheter the diameter of which does not exceed the two
thirds of the ID of the TT. For the same purposes, suction should
not be applied when the suction catheter is introduced in the
TT but only during its withdrawal. Vacuum should, however,
be maintained until the suction catheter has been completely
removed in order to retrieve solid debris that cannot pass through
the lumen of the catheter.
High-frequency Flow Interrupters

The Infant Star and Infant Star 950 are not true oscillators
because they use a mechanical valve to very frequently interrupt
a continuous flow of gas into a low-compression delivery system.
This produces low VTs at high rates. They are able to produce
the entire range of respiratory rates used in high-frequency
ventilation.
Keep operating room warm (>21C in children, 24C for

neonates and small infants).
Use an overhead radiant warmer until completion of skin
preparation.
Use warmed skin preparation solution and irrigation fluids
(e.g., cystoscopy, open abdominal surgery).
Cover as much as possible of the childs body surface with a
warmed cotton blanket (before surgery) or sterile drapes, and
put a hat on the neonates and infants head.
Use an HME.
Use a forced-air warming device.
Use a fluid warming device if large volumes of I.V. fluids or
blood is to be administered.
Monitor body temperature to avoid both hypothermia and
overheating.
HME = heat and moisture exchanger.
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Increasing the Operating Room Temperature

Ideally, this temperature should be close to the neutral temperature
(i.e., the temperature at which the childs O2 consumption and
metabolic rate are minimal, related to the childs age and/or
birthweight). For a newborn baby lying naked in a draught-free
incubator with 50% relative humidity, neutral temperature is
33C at term and36C if preterm or low birthweight. This
temperature range is lower and wider if the newborn is covered
with a layer of clothing. The recommended optimal operating
room temperature during induction of anesthesia varies with the
childs age and is 24 to 26C for a newborn or small infant and 21C
for an older child. Maintaining the operating room warm until
skin preparation is completed will prevent the drop in temperature observed after induction of anesthesia (see Chapter 14).
In addition, this initial heat loss can be prevented or lessened by
Using a overhead radiant warmer during both induction and

recovery reduces cutaneous heat loss by 77%.257
Covering the child with a warmed blanket.
Using prewarmed skin preparation fluids.
Using waterproof paper drapes.
The use of an overhead radiant-warmer is mandatory when

anesthetizing children in situations in which the room temperature cannot be controlled (e.g., the radiology suite). Ideally, the
overhead radiant-warmer should be servocontrolled with a skin
probe placed on the child to avoid skin burns. However, ambient
temperatures greater than 21C and radiant warmers are uncomfortable for the operating personnel and are rarely maintained
during surgery. Other means should be used to maintain
intraoperative normothermia.
Covering the Skin with Passive Insulators

Insulation of the skin with cotton blankets, drapes, plastic composites, or even aluminum foil can decrease heat loss by approximately 30%. Differences among insulators are minimal, the most
important factor being the amount of surface isolated to reduce
heat loss. Cotton-made wrapping may become counterproductive
if it becomes wet with surgical preparation or irrigation fluid.
In neonates and infants, in whom the head is a great proportion of
total body surface area, covering their head with cotton or foil hat
significantly reduces heat loss.
weighing more than 30 kg, pressure-heat lesions or skin burns can

occur where the patient is lying on the warming area.259 Thermal
injuries have been described owing to malfunction or a fault in
the insulation.260
Using Forced-air Warming Devices

Forced-air warming devices are a very effective method of preventing intraoperative hypothermia because they provide convective warming by passing heat over the skin. This heat is
transferred from the warmed skin surface to the body core by
convection. Environmental air entrained through a microbial filter
is heated and blown through a detachable hose into a specialized
disposable cover with perforations. Special pediatric covers have
been designed in a tubular configuration to allow easy access to
the child while providing sufficient contact with the body surface
for heat transfer. In fact, the covers designed to direct the warm air
stream mainly toward body areas where major blood vessels are
close to the skin (chest, abdomen, axilla) are more efficacious than
the others. In practice and for economical reasons, these devices
are frequently used without their cover with warm air blowing
directly onto the patient, under the surgical drapes. This practice
is not recommended because it carries a risk of burn if the patients
skin is to close to the exit of warm air.261
Airway Heating and Humidification

Airway heating and humidification is more effective in infants and
small children than in adults because of their higher minute
ventilation per kilogram of body weight. Humidification of the
inspired gases is more important than heating because 65 to 85%
of the respiratory heat loss is insensible and caused by the high
latent heat of vaporization of water. Only a small amount of heat
is needed to warm gases from ambient to body temperature, and
maintaining a relative humidity of at least 50% in the respiratory
system is sufficient to maintain normal cilia function in the
trachea.262 Airway heating and humidification may be active
or passive.
Using a Warming Mattress,

either Electric or Circulating Hot Water
The old models used to reduce conductive heat loss were
poorly effective to warm the patient owing to the small area of the
body they were in contact with. New systems (e.g., Thermowrap
by Allon, Thermamed, Klimamed, or Kimberly-Clark Patient
Warming System) consist of a microprocessor heating/cooling
unit connected to a modular and flexible garment or gel pads
placed on the nonoperated parts of the patient. One or two body
temperature sensors (nasopharyngeal or rectal and cutaneous
temperature) provide feedback data to the microprocessor,
which is preset to the desired body temperature.258 The surface
temperature should not exceed 39C in order to avoid burnlike
tissue injuries caused by the combination of heat and pressure.
The risk of injury is increased when skin preparation fluid is
allowed to run between the patients skin and the mattress. In case
of intense cutaneous vasoconstriction, especially in a patient
Active heater-humidifiers warm and humidify inspired gases

using a water bath with a controlled temperature. They are expensive and bulky and are sometimes difficult to clean and sterilize, which increases the risk of bacterial contamination. There
is a risk of overhydration or overheating if the airway temperature probe is either misplaced or omitted. Water condensation
in the inspired gases tubing requires regular drainage or installation of a water trap to avoid obstruction of gas flow or patient
aspiration. Last, adding a humidifier may change the breathing
system compression volume.
Passive HMEs conserve some of the water and heat of the
expired gases and return them to the inspired gases. Their
efficiency is reduced in the presence of a large leak around the
TT. They should be placed as close to the patients airway as
possible. Ideally, respiratory gases should be sampled between
the breathing circuit and the HME in order to prevent ingress
of water and infectious agents into the sampling system, but
sampling on the machine side of the HME results in an underestimation of PETCO2.263 End-tidal gases are, therefore, best
sampled distal to or within the HME (Figure 3821; see also
Figure 385). When used with nonabsorber breathing circuits,
the HMEs provide 50% relative humidity after a few minutes
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the blood bag is immersed in a 37C water bath.268 Most in-line

fluid warmers incorporate an optional gas eliminator at the patient
end to eliminate microbubbles. Care should be taken when a gas
eliminator is not in use because the decreasing solubility of gases
in liquid as they warm leads to the formation of bubbles that are
a potential source of air embolism.269 Unfortunately, both the
warming device and its disposable tubing are expensive.
Warming of Irrigation Fluids

Using a cold irrigation fluid to wash the wound, peritoneum, or
thorax or to perform a cystoscopy may cause rapid hypothermia,
especially in infants and small children. All these fluids should be
prewarmed to body temperature before use. The use of cold gas to
inflate the abdomen or thorax during laparoscopic surgery also
exposes the child to the risk of hypothermia in case of prolonged
surgery.
Figure 38-21. Special infant capnometry connector placed
between the HME and the tracheal tube in a 3-kg neonate.
of use and become nearly as effective as active systems in terms
of relative humidification after 80 minutes of use262 even though
the absolute inspired humidity achieved does not meet the requirements of the International Standards Organization (i.e., 30
mgH2O/L). They are useful even in short-lasting procedures.264
An HME is less expensive than active systems and most of them
are also efficient bacterial and viral filters. Their main disadvantage is the increase in deadspace and in resistance to respiration when used in small children breathing spontaneously.
The use a circle anesthetic circuit is another way to humidify
and rewarm inspired gases.
Warming During Transportation

Transportation to and from the operating theater is another
opportunity to lose heat, especially in neonates and small infants.
Neonates should be transported in a prewarmed transport
incubator and infants well covered with a warm blanket.
FRAMES USED TO
POSITION THE PATIENT
Patient positioning for anesthesia and surgery is described in
detail in Chapter 80. The basic equipment for child positioning is
Warming of I.V. Fluids and Blood

Heat loss caused by the administration of large amounts of cold
I.V. fluids or blood can be prevented by using an I.V. warming
device. Conventional devices warming the solution by circulating
it through a sleeve or coil in contact with a heat exchanger perform
poorly in children because, at slow infusion rates, the warmed
fluid cools to room temperature because of heat loss from the
tubing connecting the warmer and the patient.265 They have a high
resistance to flow and warm inadequately at high flow rates.
A similar method to warm I.V. fluids consists of placing the tubing
around a special holder into the hose of a forced-air warming
device (241 Fluid warming set for Bair Hugger). The immersion of
the tubing of the bottle of albumin solution or of the bag of blood
in a container filled with warm water or placing most of the I.V.
tubing under a warming mattress are frequently used to warm
fluids.266 The efficacy of the former method is variable, depending
on the volume of fluid present in the immersed part of the tubing
and on the gradient of temperature between the two solutions,
and carries a risk of contamination. In-line warming devices, in
which warm water circulates around the delivery tubing, deliver
adequately warmed I.V. fluids or blood at rates ranging from
10 to 6000 mL/h (e.g., Hotline, System 250, Medi-Temp II,
Thermocyl, or Ranger).267 When using the Hotline, 20 mL of 4C
packed red blood cells injected over 60 seconds reaches an average
temperature of 34.6C at the patients end of the tubing, whereas
it needs 15 minutes to obtain a mean temperature of 32.7C when
A roll to be placed underneath the childs shoulders to help

maintain airway patency during induction of anesthesia and recovery, especially in cases in which positioning the childs large
head in a neutral position would result in flexion of the neck
(e.g., premature infants, neonates, and those with hydrocephaly
or macrocephaly), increasing the risk of upper airway obstruction. The height of the roll should be adapted to the childs size
to avoid hyperextension of the neck. It is, however, often useful
to remove the shoulder roll for laryngoscopy in neonates and
small infants. Similarly, the roll must be placed under the iliac
spines and the thorax to avoid abdominal compression when
the child is placed in the prone position.
A head ring to stabilize the childs head when lying supine or in
the lateral position. In the latter case, the hollow part of the ring
provides free space to the childs downside ear and prevents
its compression. This sort of device can be used to position
neonates with meningomyelocele to protect their fragile zone
of defect during induction of anesthesia (see Chapter 93). This
device can be homemade with short remnants of disposable
ventilator tubing covered with foam padding or tissue, but soft
models made of a viscoelastic polymer or carboxyvinyl are commercially available.
Sandbags to maintain positioning (e.g., lateral decubitus position).
Different sizes of foam padding to protect potential pressure
points (e.g., heels, elbows, head of fibula).
Small and adaptable armboards and stirrups.
A very useful tool during pediatric anesthesia is the anesthetic

screen. It divides the operating table into two areas, a sterile
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working area for the surgeon and a clean working area for the
anesthesiologist. Ideally, the anesthetic screen should be rigid
enough to support the surgical drapes and the surgeons elbow
but flexible enough to adapt to the procedure and to the childs
size. During any positioning maneuver, the TT or supraglottic
airway should always be disconnected from the breathing system
to prevent accidental tracheal extubation and/or mucosal trauma
caused by movement of the artificial airway.
SPECIAL CONSIDERATIONS
Special I.V. Access Devices
Central Venous Catheters
The indications, technique of insertion, and early complications of
central venous catheters are described in Chapter 70.
PERCUTANEOUSLY INSERTED CENTRAL VENOUS CATHETERS:

Central venous catheters are polyurethane or silicone single or
multiple-lumen catheters. Polyurethane softens at body temperature and becomes more flexible, which reduces the risk of perforation. They are inserted in a central vein using the Seldinger
technique. The metallic guidewire should be atraumatic and
equipped with a J-tip. In neonates and infants, the radius of
curvature of the J-tip is close to the size of or larger than the vessel
to be cannulated. It is important, in those cases, to use a relatively
stiff introducing catheter rather than a needle to enter the vein
and to introduce it completely into the vein before using the J-wire
for the Seldinger technique.270 Ideally, these catheters should
be radio-opaque, making x-ray visualization easier. Also, they
should provide length marks that help to diagnose an eventual
decannulation or partial embolization. The tip of the catheter
should be atraumatic and slightly tapered to facilitate its insertion
through tissue and vein wall. The catheter fixation system should
be secured and easy to handle in order to prevent both premature
exit and kinking of the catheter. Adjustable wings that can be fixed
to the catheter and to the skin are probably the best system. The
size of the catheter should be adapted to the childs size: 22 gauge
(or 2 French) if body weight is less than 2 kg and 20 gauge (or 3 or
4 French) when it is above 2 kg. Over 10 kg body weight, 18 gauge
(or 5 French) catheters can be used. New equipment for central
venous catheterization that uses adjunct technologies to facilitate
either localization of the vein or precise positioning of the catheter
without x-ray is available:
1. A portable two-dimensional ultrasound machine with a
7.5- or 9-MHz probe that allows high-resolution imaging
of structures up to 40 mm deep to the skin surface before
(screening the vascular anatomy, vessel position and patency)
and/or during the procedure.271 Its use results in a higher success rate for internal jugular vein cannulation and a lower
incidence of complications than the classic landmark techniques.272 It can also be used to catheterize the femoral and
subclavian vein, deep brachial veins, and the axillary vein.
Ultrasound imaging allows quick diagnosis of early complications such a hemo- or pneumothorax. Its learning requires
supervision and training to correctly interpret the ultrasound
images and to coordinate the hand movement with the twodimensional pictures on the screen.273
2. An endocavitary ECG (with a special connection of the
guidewire to the ECG monitor via an adapter). In order to be
in the superior vena cava, the catheter is withdrawn 2 to 3 cm

from the place where the size of P-wave started to increase. This
system does not work in case of dysrhythmias or if the
guidewire has followed an aberrant intravascular pathway.
3. The use of a Doppler system connected to a special exploratory
needle (e.g., 22-, 20-, or 18-gauge SmartNeedle) is not easy to
use because the exploratory needle needs to be flushed regularly
(air bubbles or particulate matter result in loss of Doppler
signal) and because the presence of the probe into the needle
slows the return of blood flow.274
IMPLANTABLE CATHETERS (HICKMAN, BROVIAC, IMPLANTABLE

PORT): Implantable catheters are polyurethane or silicone
catheters that are either fixed to the subcutaneous tissue with a
Dacron cuff or equipped with a clampable reinforced extravascular
section or connected to a subcutaneous implanted injection
chamber. They are inserted for long-term but intermittent use,
mainly chemotherapy or parenteral nutrition. They are usually
inserted surgically. The childs parents should be carefully informed
about the care of the catheter injection site; a specific protocol
for catheter flushing with a heparin or saline solution should be
followed. These catheters can also be used for anesthesia, but strict
asepsis should be observed to avoid bacterial contamination.
PERIPHERALLY INSERTED CENTRAL VENOUS CATHETERS: To

avoid the immediate complications associated with the insertion
of a central venous catheter (e.g., pneumothorax, arterial puncture,
and hematoma), these especially designed venous catheters are
inserted in a peripheral vein (upper or lower limb) to gain access
to the central circulation. They are rarely used for surgical procedures. Their main indications are access for prolonged I.V.
therapy (e.g., antibiotics, parenteral nutrition). Cases of cardiac
dysrhythmias,275 myocardial perforation and tamponade have
been described with these devices because movements of the arm
affect the position of the tip of the catheter (e.g., the tip of a catheter
inserted in the basilic or axillary vein migrates toward the heart
when the arm is adducted).276 The catheter tip should be positioned
outside the pericardial reflection line (i.e., above the second
thoracic rib on the chest x-ray while the arm is in the position that
leads to the maximum migration toward the heart). When the
catheter is inserted in the cephalic vein, abduction of the arm will
advance the catheter toward the heart whereas adduction will cause
the same displacement when the basilic or axillary vein is used.
Cases of pleural effusion or catheter rupture with migration into a
pulmonary artery with subsequent hemorrhage have also been
reported.277 The peripherally inserted central venous catheters
(PICCs) are made of polyurethane, silicone, or Silastic. They are
either radio-opaque or provided with a radio-opaque guidewire to
facilitate insertion and radiologic control of the position of their
distal tip. Their length can be adapted to the patients size. They
either are through-the-needle catheters (with a metallic split-able
introductory needle) or can be placed under echographic control
using the Seldinger technique.
PICCs are used in small premature infants in place of centrally
inserted venous catheters. They are also used in ambulatory
patients with cystic fibrosis for prolonged antibiotic treatments.
Their lumen is narrow, which makes rapid infusion of fluid
difficult and withdrawal of blood often problematic. There is a
risk of rupture and intravascular migration of the distal part of
the catheter: 11 cases were observed in a series of 1650 PICCs.
Forceful attempts to flush a blocked line (e.g., with a syringe
< 5 mL) is an important risk factor for rupture.278
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CHAPTER 38
Intraosseous Needles279
The intraosseous access is a last resort for vascular access to be
used in life-saving circumstances, when no other venous access is
possible and only as a temporary measure. Although it can be used
in adults, this access is usually used only in children younger than
5 to 6 years because later the bone becomes too hard to allow
insertion. The preferred insertion sites are the proximal or distal
end of the tibia and the distal end of the femur. Any bone marrow
aspiration needle can be used, but special needles have been
designed that are shorter, preventing deep insertion, and easier
to secure. They are available with different lengths (2.5, 3.0, or
4.0 cm), different needle design (lancet, trochar, or pencil-point
end), or even lateral sideports near the distal tip of the needle to
ensure flow in case the distal end is obstructed (Dieckmann modification). Other models of intraosseous needles are the SussmanRaszynski needle, which includes a fine screw needle cannula tip
to facilitate needle insertion and stabilization, and the Sur-Fast
needle, which is shorter and includes both a screw needle cannula
and lateral sideports. Some brands have an adjustable flange to
allow better control of needle insertion depth.
The Bone Injection Gun is a small trochar needle (18 gauge
for children < 6 y) that is incorporated in a specially designed
insertion device. The depth of insertion is predetermined and
insertion is automatic after triggering a spring-loaded system.
The EZ-I0 (Vidacare) device is a 15-gauge stainless steel needle
(pink,15 mm long for patients 339 kg; blue, 25 mm long for those
weighing = 40 kg; and yellow, 45 mm long for adults) adapted to
a battery-powered driver that allows the insertion of the needle in
less than 30 seconds. The needle is equipped with a Luer-Lok
connection and can be adapted to any I.V. line (Figure 3822). It
can be easily removed by connecting the hub to a Luer-Lok syringe
moved counterclockwise.
Possible complications of the intraosseous route are cellulitis,
osteomyelitis, bone fracture, fat or bone marrow embolism, and
extravasation of fluid into the extraosseous tissue that can lead to
compartment syndrome if not recognized early. To avoid extra-
vasation, the intraosseous route should not be attempted in a

broken bone or after previous intraosseous administration in the
same bone. The needle should be properly secured and its site of
insertion regularly inspected.
Intraoperative Autotransfusion Devices

Indications and Contraindications
The salvage and re-infusion of blood lost during major surgery is
the most common form of autologous blood transfusion in
children because predeposited autologous blood transfusion is
often difficult for technical and organizational reasons. Blood
salvage techniques are used in surgical procedures known to be
associated with important blood loss such as scoliosis surgery,
cardiac surgery, or liver transplantation. Even in these circumstances, the main indication for the use of a blood cell processor in
a child larger than 10 kg is an anticipated blood loss greater than
20% of its estimated blood volume. Blood salvage techniques are
rarely used in children less than 10 kg because a minimum of 100
to 300 mL of shed blood is needed to fill the currently available
pediatric-size centrifuge bowls (e.g., 55 mL bowl of Dideco
Compact A, 100 mL bowl of HaemoLite 2 Plus, 70 mL for CellSaver
5) before the processing phase. Homologous blood transfusion is
unavoidable in these cases, and most of the advantages of autotransfusion are then lost. In the authors experience, the centrifugation and washing system of the autotransfusion apparatus can
be successfully used to avoid hyperkalemia during massive
transfusion (see Chapter 54), especially in small children and
infants. The blood bank blood is processed through the autotransfusion system, as if it was shed blood, before being warmed and
administered to the patient. The contraindications to intraoperative
blood salvage are
Suspected or confirmed contact with bowel contents.

Suspected or confirmed contamination with malignant cells.
Shed blood from an infected wound.
Shed blood from a wound irrigated with a wound-sterilizing
solution or in which hemostatic substances have been used (e.g.,
thrombin, microfibrillar collagen glue).
Hemolysis.
Some teams use intraoperative blood salvage in patients with

sickle cell disease.
Description
Figure 38-22. EZ-10 intraosseous access device.
Most autotransfusion devices are discontinuous systems in which

shed blood is aspirated from the surgical field through a doublelumen suction designed to allow immediate mixing with an
anticoagulant solution (usually acid-citrate-dextrose [ACD] or
citrate-phosphate-dextrose [CPD] solution) and stored in a special
reservoir until a sufficient amount has been collected. Shed
blood is pumped into a spinning centrifuge bowl that separates
blood components on the basis of their density. Red blood cells
accumulate progressively in the bowl, starting from its base,
whereas all other components are evacuated into a waste container.
When the bowl is totally filled with red blood cells, a washing cycle
rinses away all contaminants and residual anticoagulants before
resuspending the washed red blood cells in a normal saline
solution. The final hematocrit varies from 50 to 70%. It should be
kept in mind that the centrifugation process virtually eliminates
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all the plasma components of the salvaged blood. Its potassium

content is very low but plasma proteins, including coagulation
factors, and platelets are eliminated. When large volumes of
salvaged blood are re-infused, dilutional coagulopathy can occur.
Another autotransfusion system has recently been designed
that allows continuous washing and separation of collected blood
(C.A.T.S.). It is based on the principle of the separation chamber
used in cell separators or plasmapheresis devices. Shed blood
and normal saline directly enter the rotating separation chamber
(1530 mL volume) so that the red blood cells are washed during
the centrifugation/separation process. An optical sensor guarantees that the washed red blood cells do not leave the chamber
before a hematocrit of at least 65% is reached. This continuous
processing system is preferable for intraoperative autotransfusion
in pediatric surgery because it guarantees a hematocrit level
greater than 60% independent of the volume of shed blood to be
processed.280 Some of these autologous transfusion systems
(e.g., BRAT 2 or C.A.T.S.) are equipped with a special plasma
sequestration program, which allows the separation of the
patients blood taken before the start of surgery into plasma, red
cells, and platelets.
Devices for Laser Airway Surgery

During laser endoscopic surgery, the anesthesiologist shares the
airway with the surgeon and must ensure optimal operators view
and proper laser beam path. All equipment in contact with the
laser beam must be nonflammable, and the gas mixture should
not support combustion. The other safety aspects of endoscopic
laser surgery, such as avoidance of N2O, aspiration of smoke, eye
protection of the patient and all the personnel present in the
operating room, must be done.
Ultrafiltration281
In case of cardiac surgery, a hemofilter can be added to the
extracorporeal circuit to remove excess circulating blood volume
at the end of bypass. Ultrafiltration is a technique in which fluids
pass through a semipermeable membrane filter. Water, electrolytes,
and other substances of small molecular weight (depending on
the size of the pores in the membrane) are removed following
transmembrane pressure gradient. Red blood cells from the extracorporeal circuit can then be concentrated to the desired hematocrit without losing platelets or plasma proteins but at the expense
of increased plasma free hemoglobin concentration (hemolysis
caused by bypass) and prolonged activated clotting time (recirculation of heparin).
Special Airway Equipment

Reinforced or Anode Tubes
Most standard PVC TTs kink when they are bent at an acute angle
or when compressed. In situations when this could occur, for
example, during intraoral or neurosurgery, kinking-resistant tubes
should be used. They are made by embedding a reinforcing spiral
of metal or nylon into the wall of the tube, which is often made of
material that is more elastic than usual (silicone, rubber; e.g.:
Safety-Flex, Spiral-Flex). These TTs are flexible and more difficult
to insert without the use of a stylet. They are also more susceptible
to accidental extubation. The TT with a metallic spiral should not
be used for MRI.
Tubes With Additional Lumens

The PVC uncuffed TTs have been developed with one or more
additional small channels to allow tracheal administration of gases
(high-frequency ventilation) or drugs (e.g., surfactant), or airway
monitoring (pressure and/or PETCO2; Boussignac, Edgar tube,
Sheridan EtCO2; all starting from size 2.0 ID). The OD of these
TTs is larger than the standard TTs of the same ID. These small
sampling channels are easily obstructed by secretion.
Apneic ventilation, in which the TT is removed at regular

intervals.
Spontaneous ventilation with a nasopharyngeal airway.
Positioning a metal (e.g., the Andrews anterior commissure
retractor or a Benjamin proximal injection cannula by Storz)282
or Teflon cannula above the glottis through a suspension laryngoscope or a bronchoscope. Either spontaneous ventilation or
Venturi jet ventilation may be used. If jet ventilation is used,
care should be taken to maintain the cannula aligned in the
laryngotracheal axis at a proper distance above the glottis to
avoid gastric inflation and barotrauma.
Positioning a metal cannula into the trachea (e.g., stainless steel
Holinger aspiration cannula # 507055, 3 mm OD and 1.5 mm
ID283 or pediatric cannula 2.5 mm OD and 1.7 mm ID250)
through the surgeons microlaryngeal laryngoscope and using
HFJV. Proper alignment with the tracheal axis and free egress of
expired gas are mandatory.
Positioning a Teflon double-lumen tube (Hunsaker Mon Jet
ventilation tube) into the trachea. One lumen (3.5 mm OD) is
used for HFJV and the other (1 mm ID) for end-tidal gases or
pressure monitoring. When the inner stylet is removed from the
tube, distal flanges open out and maintain the tube in a central
position in the trachea, avoiding any lashing of the tube caused
by HFJV. This tube is very flexible and nonflammable, even in
100% ambient O2, when struck with a CO2, KTP, or Nd:YAG
laser beam. However, because of its size, this device is usable
only in big children and adolescents.284 The author nevertheless
uses it routinely in infants after cutting off the distal flanges of
the device (Figure 3823).
Transtracheal ventilation through a radio-opaque Teflon
transtracheal catheter (Ravussin 16 gauge, ID 0.8 mm, length
37 mm, VBM), which can be used in neonates and children up
to 12 years of age.251 The catheter is inserted percutaneously
through the cricothyroid membrane and its correct position is
verified by endoscopy. The cannula has two lateral holes at its
distal end, and two lateral attachments allow its secure fixation
around the neck with a Velcro band. Care must be taken to avoid
damage to the tracheal wall and the esophagus.
A TT can also be used:
A standard rubber or PVC TT wrapped with an adhesive

laminate of silver foil and sponge material (Merocel LaserGuard). This adhesive material, which adds almost 2.5 mm to
the OD of the TT, has to be carefully applied around it and
soaked with water or saline. The smallest TT that can be covered
with Merocel Laser Guard is 5.0 mm ID. If this special material
is not available, either an aluminum #425 (3M) or a copper Venture foil (Venture Tape) tape may be used to wrap the TT.285
However, foil wrapping reflects only the energy of the laser
beam and does not protect a combustible TT from indirect
combustion owing to sparks or high temperature owing to tis-
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CHAPTER 38
TABLE 38-33. Internal and External Diameter of the

Smallest Laser Tracheal Tubes
Tube
Xomed Laser-Shield II
Laser-Trach cuffed
Laser-Flex uncuffed
Cuffed
Bivona Laser tube
Lasertubus
Figure 38-23. High-frequency jet ventilation in a 4-year-old
child. Suspension laryngoscopy is used and the Hunsaker is
connected to the high-frequency jet ventilation source.
sue combustion. Lastly, if a cuff if present, it cannot be wrapped

with the protective foil and should be covered by wet cottonoids.
A silicone-made TT with an overlapping spiral aluminum wrap
and a smooth Teflon outer coating of the Laser-Shield II series.
There is 1 cm of unprotected silicone proximal to the cuff that
has to be protected by wet cottonoids during the procedure. The
smallest tube available has an ID of 4.0 mm.
A metallic tube with a silicone covering (Bivona Laser tube).
This tube is also equipped with a polyurethane self-inflating
foam cuff from which air has to be actively aspirated before its
insertion into or removal from the larynx. The pilot tube of the
cuff is located at the outer surface of the tube and is susceptible
to damage by the laser beam. This could result in the cuff being
undeflatable and laryngeal damage during removal of the TT.
This tube may ignite when high-power laser is applied.
A stainless-steel flexible tube (Laser-Flex). Pediatric uncuffed
Laserflex tubes are available from 3.0 mm ID (OD 5.2 mm). The
smallest cuffed version is 4.5 mm ID. It has two PVC cuffs that
are inflated by separate inflation tubes, so that the distal cuff can
be used if the proximal one is damaged by the laser beam. It is
compatible with CO2 and KTP but not with Nd:YAG lasers.
A red rubber TT covered with an embossed copper foil and
overwrapped with Teflon (Laser-Trach). The smallest version is
4.0 mm ID and cuffed. It has to be soaked with water or saline
before use but may ignite if an Nd:YAG laser is used.
A rubber foam (Merocel) and silver foilwrapped Lasertubus.
Before use, it has to be soaked in water or saline to help absorb
the laser energy. It has a Murphy hole and a double cuff (one
inside the other). The smallest ID available is 4.0 mm.
All those special laser tubes are laser-resistant, not laser-proof.

They can ignite if laser intensity is high or if they are directly
exposed to the beam for a prolonged period of time.
The cuffs of the TT used for laser surgery should be filled with
methylene bluetinged saline to give an immediate visual
ID, mm
OD, mm
4.0
4.5
5.0
5.5
4.0
5.0
3.0
3.5
4.0
4.5
5.0
5.5
3.0
4.0
5.0
4.0
6.6
7.3
8.0
8.6
8.2
9.5
5.2
5.7
6.1
7.0
7.5
7.9
5.5
6.5
7.5
8.0 (wrapped area)
indication of cuff rupture and to extinguish any small ignition.

Care should be taken to avoid overfilling the cuff with saline
because this could cause a dramatic increase in tracheal mucosal
pressure. Because of the special composition of their wall, all
laser-tubes have an outer diameter that is greater than the
standard TT of the same ID (Table 3833). If the child has already
a tracheostomy tube in place before surgery, this should be
replaced with a metal cannula before using the laser. Special
standard PVC TTs can be used for microlaryngeal surgery when
no laser is used. They are available with an ID of 4, 5, and 6 mm
but with the same length and cuff as a standard 8-mm ID tube.
Devices for One-lung Ventilation

In children, one-lung ventilation is used either to prevent the
contamination of one lung by blood, pus, or secretions coming
from the other or to improve surgical access during thoracotomy
or thoracoscopic procedures (see Chapters 96 and 97).
DOUBLE-LUMEN TTS: In children older than 8 to 10 years, 26-,

28-, or 32-French double-lumen TTs may be used (Table 3834
provides sizes). As a rule, the largest double-lumen tube that can
be introduced atraumatically through the glottis and passed into
the appropriate bronchus should be used. Less air is required to
seal the bronchial airway, and this reduces the risk of mucosal
trauma from overinflation and bronchial cuff herniation into the
carina. Whether the dependent or the operated lung should be
selectively intubated is a matter of controversy.
For neonates and infants, a special uncuffed double-lumen tube
initially designed by Marraro for separate lung ventilation can be
used.286 It consists of two separate radio-opaque Portex blue line
PVC tubes, of different length and attached laterally to each other.
The bronchial tube is longer and usually larger than the tracheal
one; has a bevel and a Murphy hole, which both face outward; and
is bent at an angle of5 degrees a few millimeters proximal to the
Murphy hole to facilitate bronchial entry. The Marraro Paediatric
Bilumen tube is inserted orally and rotated to the right or the left
after passing the vocal cords, according to the bronchus to be
intubated. A tricky aspect of the use of this tube is its connection
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TABLE 38-34. Tracheal Tube Dimensions of Devices

Used for One-lung Ventilation
Devicea
ID of Each
Lumen, mm
Total OD, mm
26 Ch Bronchopart
28 Ch Bronchopart
Broncho-Cathb
32 Ch Broncho-Cathb
35 Ch Bronchopart
Broncho-Cathb
Univent 3.5
Univent 4.5
Univent 6.0
Univent 6.5
Univent 7.0
3.4
3.7
3.55.4
3.86.7
4.2
4.78.7
3.5
4.5
6.0
6.5
7.0
9.08.0
10.28.6
9.3
10.7
12.510.8
11.7
7.58.0
8.59.0
1011
10.511.5
1112
TABLE 38-36. Characteristics of Fogarty Thru-Lumen

(Baxter) Arterial Embolectomy Catheters
Catheter size, Fr
Diameter of inflated balloon, mm
Max. liquid capacity, mL
Max. gas capacity, mL
BRONCHIAL BLOCKERS: Selective mainstem bronchial intubation

of the nonoperative lung with a standard288 or slightly modified289
TT can ensure one-lung ventilation. The appropriate TT is usually
ID 0.5 mm smaller than would normally be used for tracheal
intubation. To perform selective bronchial intubation, the childs
head should be turned to the side opposite to the bronchus to be
intubated. The orientation of the bevel of the TT seems critical.
Ideally, the TT should be turned so that its bevel faces the
bronchus opposite to the one to be intubated to guide the tip of the
tube down into the bronchus.288 If a cuffed TT is used, the distance
from the tip of the TT to the proximal edge of the cuff must be
shorter than the length of the mainstem bronchus to ensure that
the cuff will be entirely in the bronchus.
Another way to achieve one-lung ventilation in children is
to perform tracheal or selective bronchial intubation and to
block the mainstem bronchus of the operated lung. Several
devices have been described to achieve bronchial blockade290 and
consist of
Balloon-tipped catheters (Fogarty arterial embolectomy catheters).291 However, only the Thru-lumen Fogarty has an internal
TABLE 38-35. Marraro Pediatric Bilumen Tube
Age
Premature 14002500 g
Neonate 25004000 g
1 mo
6 mo
12 mo
Tracheal ID
2
2
2.5
2.5
2.5
3.0
Bronchial ID
2
2.5
2.5
2.5
3.0
3.5
ID = inner diameter; OD = outer diameter.

According to Marraro G. Selective endobronchial intubation in paediatrics: the
Marraro Paediatric Bilumen tube. Paediatr Anaesth. 1994;4:255258.
4
9
0.5
1.2
5
11
0.9
1.7
6
13
1.4
2.3
According to the manufacturers data sheet.

a
Bronchopart by Rsch; Broncho-Cath by Mallinckrodt; Univent by Fuji/Vitaid.
b
For the Broncho-Cath: both lumens are D-shaped and the dimensions given are
the largest and the smallest width for each lumen.
to two breathing systems. The recommended sizes are shown in

Table 3835. Recently, the use of a homemade assembly of two
small cuffed TTs connected together via the Y-connector of a
standard double-lumen TT has been described to perform lung
lavage in a child.287
3
5
0.15
0.4
lumen that allows suctioning or administration of O2 to the

blocked lung. They are equipped with a stylet that allows gentle
curving of the catheter about 2 cm from the tip to facilitate its
introduction into the mainstem bronchus. However, the high
pressures generated in these balloons when they are inflated
above the recommended volume to completely occlude the
bronchial lumen might induce localized ischemic damage to the
airway or even bronchial rupture.292 The balloon should be carefully inflated according to the manufacturers recommendations.
The characteristics of the 3-, 4-, 5-, and 6-French Fogarty
catheters made by Baxter are given in Table 41.36. The 3-French
Fogarty catheter is used in infants weighing 5 to 10 kg, whereas
the 4 French is used in 11- to 15-kg children.
Balloon atrioseptostomy catheters. their tip is angled at 35 degrees, which may help manipulation into the bronchus, and have
a central lumen for suction or administration of O2 to the
blocked lung.291 A 5-French Edwards atrioseptostomy catheter
has a 19-mm diameter when fully inflated with 4 mL of fluid.
Swan-Ganz pulmonary artery flotation catheters. These are easy
to insert and have a central lumen for suction or administration
of O2 to the blocked lung. No more than the recommended volume of air should be injected in the balloon.
All these devices may be inserted either inside or outside the

standard TT. It is usually better to insert them outside the
TT because this makes fiberoptic confirmation of position
and fixing easier. It also eliminates the risk of leaks across the
swivel connector. If fibroscopy is not used, the position should be
controlled by x-ray (if necessary with contrast dye in the catheter
balloon). To prevent bronchial injury, the largest balloon whose
catheter will pass beside the TT at the cricoid level should be used
and the balloon should be inflated to the smallest volume that seals
the bronchus, under bronchoscopic control.292
The best bronchial blocker is the pediatric version of the
Arndt catheter. It consists of a 50-cm-long 5-French double-lumen
catheter (ID 0.7 mm; maximum OD 2.5 mm) with a high-volume,
low-pressure elliptical silicone balloon (maximum capacity 3 mL;
length 1 cm) near the end. One lumen allows inflation of the
balloon. A nylon guideloop is inserted through the second
lumen and exits at the end of the blocker (Figure 3824). The tip
of a pediatric fiberoptic bronchoscope is passed into this loop
to help insert the blocker into the bronchus. When the guide is
withdrawn, this lumen can be used for suction or administration
of O2. A special multiport airway adapter, with a bronchoscopy
port, a ventilation port, and a blocker port, needs to be connected
to the TT. This system can be used in children older than
2 years.293 In infants, the blocker can be placed within the TT
under fibroscopic control if the connector is slightly modified or
fluoroscopic guidance can be used to place it into the selected
bronchus before tracheal intubation. In the latter case, the blocker
is placed outside the TT.294,295
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easy and quick to perform because the cricothyroid membrane is

immediately under the skin and its landmarks are easily identified.
Cricothyrotomy is much more dangerous in infants and small
children because their trachea and larynx are smaller and the
landmarks difficult to identify. Because this material must be used
in a life-threatening situation, it should be available in all locations
where anesthesia is provided and in the emergency room.
The key for success is the accurate placement of an intratracheal
needle in the middle of the cricothyroid membrane or between two
tracheal rings. The exploring needle should be connected to a
syringe filled with saline and advanced perpendicularly to the skin
in all planes while negative pressure is applied to the plunger. Easy
aspiration of air indicates the intratracheal position of the needle.
Cricothyrotomy can be performed with
Figure 38-24. Arndt bronchial blocker.

Pediatric versions of the Univent tube have been developed.
They consist of a conventional TT with an additional small lumen
inside which is a thin tube (OD 2 mm) that can be advanced past
the large lumen into the bronchus to be blocked.296 The bronchus
is blocked by inflation of the balloon. Because a large volume of
air is usually needed to inflate the bronchial balloon, ischemic
damage to the airway is possible. Fiberoptic bronchoscopy is
useful for accurate placement of the blocker. Two pediatric sizes of
the Univent tube are available, a 3.5-mm (uncuffed, OD similar
to uncuffed 5.5-mm ID TT) and a 4.5-mm (cuffed, OD similar to
uncuffed 6.5-mm ID TT) ID (Table 3837; see also Table 3834).
They may be used instead of a 26- or 28-Ch double-lumen tube or
a balloon-tipped bronchial blocker.296 Unfortunately, the 3.5-mm
size has no lumen inside the blocking tube to allow suction or
administration of O2 to the blocked lung. Whatever the device
used to block a bronchus, it should be carefully secured after its
insertion to avoid its accidental dislodgment into the tracheal
lumen. This will cause hypoxemia and increased airway pressure
owing to herniation or obstruction of the tracheal lumen. This can
be easily solved by evacuating the air from the cuff.
Needles for Cricothyrotomy297

Cricothyrotomy is used when upper airway obstruction cannot be
relieved by facemask ventilation, insertion of a supraglottic airway,
or tracheal intubation and the obstruction is located above the
level of the cricoid cartilage. In adults, this procedure is usually
A 18-gauge (neonate), 16-gauge (infant), or 14-gauge I.V. cannula,

to which the connector of a standard 3.5-mm ID TT is connected
after removal of the needle.298
The emergency transtracheal airway catheter (15-gauge needle,
ID 2 mm) (Cook) or the 16-gauge (infant) or 14-gauge (child)
Ravussin Teflon catheter, already described for laser surgery in
the section : Devices for Laser Airway Surgery.251
The Melker or Arndt kit, which includes a guidewire (to use a
Seldinger technique once the needle is in the trachea), a scalpel,
and a dilator over which the cannula is introduced into the
trachea. The smallest sizes available are 3.0-, 3.5-, and 4-mm ID
with an 18-gauge needle.
The Patil (ID 2 or 3 mm), Pertrach (ID 3 mm), or QuickTrach
(ID 2 or 4 mm) kits consist of a needle, introducer, and cricothyrotomy catheter inserted together.
The proximal end of all the commercially available cricothyrotomy sets have a Luer-Lok connection for connection to a highpressure gas supply, as well as a 15-mm ISO male connector for
attachment to a standard breathing system. Those commercially
available cricothyrotomy sets have rarely been used in small
children and their use is not recommended in neonates and
infants because their cricothyroid membrane is barely palpable.
All these devices can provide oxygenation in a spontaneously
breathing child but hypercapnia and fatigue will ensue. To control
ventilation, different systems can be used:
Jet ventilation. For example, Manujet III by VBM with colorcoded range of insufflation pressures according to the childs size.
A Y-connector interposed to the tubing connected to a high- or
low-pressure source of O2. Its free end can be occluded by one
TABLE 38-37. One-lung Ventilation in Children: Recommended Equipment According to Age

Age, y
Endobronchial
TT ID, mm
0.51
12
24
46
68
810
1012
1214
14 16
3.54
44.5
4.55
55.5
5.56
6 + cuff
6.5 + cuff
6.57 + cuff
7+ cuff
Fogarty, Fr
Swan-Ganz, Fr
23
3
5
5
6
6
6
6
7
4
5
5
5
5
7
7
7
7
Arndt, Fr
5?
5
5
5
5
9
9
Univent
3.5
3.5
4.5
4.5
6
DLT, Fr
26
2628
32
35
DLT = double-lumen tube; ID = inner diameter; TT = tracheal tube.

Modified from Hammer GA, Fitzmaurice BG, Brodsky JB. Methods for single-lung ventilation in pediatric patients. Anesth Analg. 1999;89:14261429.
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finger during 1 second to insufflate the childs lungs. Using a

three-way stopcock instead of a large Y-connector results in
dangerous insufflation pressures.299
The Enk O2 Flow Modulation set is a short connector with
five side holes, a distal Luer-Lok fitting, and a side syringe
connector (for nebulizing drugs) placed between the O2 tubing
and the tracheal access; the side holes can be totally or partially
occluded by the operators fingers to provide bursts of insufflation. However, total occlusion is necessary to provide effective
insufflation.252
Whatever the system used, care should be taken to avoid

barotraumas. To allow safe and effective ventilation, the Advanced
Pediatric Life Support (APLS) guidelines should be followed, that
is, starting with setting O2 flow at 1 L/min/y of age and assessing
chest movement during periods of 1-second occlusion or
injection. Gas flow is titrated by adding 1 L/min to obtain
satisfactory chest excursion. A slow ventilation rate is necessary, as
well as a long expiration time (I:E ratio of 1:3 to 1:4) in order to
avoid hyperinflation and barotrauma.252
Tracheostomy Equipment
Currently, the indications of tracheostomy in children are
mainly subglottic stenosis, congenital airway malformations, prolonged respiratory support (e.g., extensive burns, Ondines syndrome, end-stage neuromuscular diseases), and acquired airway
obstruction (tumors).300 Short-term tracheostomy is sometimes used for complex craniofacial surgery. The mortality and
morbidity of tracheostomy in children are lower than in the
past, provided these patients are cared for in a PICU where immediate intervention by trained staff is available.301 Nevertheless,
complications still occur, mainly in infants younger than 1 year,
during the perioperative period (pneumothorax), during the
cannulation period (tube obstruction, accidental decannulation),
or after decannulation (emergency recannulation, hypoxic cardiac
arrest).300
CLASSIC TRACHEOSTOMY TUBES: Tracheostomy tubes are now

all made of implant tested radio-opaque PVC and are soft and
malleable in order to be as atraumatic as possible. A 15-mm male
connector is necessary to connect them to a breathing circuit or to
an HME. The most commonly used models are the Shiley, Great
Ormond Street, Bivona, and Portex. The Shiley models have the
advantage of providing different lengths for the same diameter
(Table 3838), which allows individual matching of the best
diameter and intratracheal length in order to provide the largest
airway possible with minimal risk of accidental decannulation or
bronchial intubation. Children with a tracheostomy tube usually
have a leak around it. This allows an expiratory leak around the
tube and enables them to speak. Some tubes are fenestrated or
allow the insertion of a speaking device (Bielsaki cannula).
Usually, the size of the tracheostomy tube is equivalent to the ID
in millimeters of the TT predicted from the age formula but their
OD is larger. To manage the airway of a child with a tracheostomy
tube, leave the tracheostomy tube in place and connect the
breathing circuit to it, replace the tracheostomy tube with a cuffed
TT 0.5-mm ID smaller, or take the tracheostomy tube out and
intubate orally with a TT.301
PERCUTANEOUS DILATIONAL TRACHEOSTOMY: Percutaneous

dilational tracheostomy is widely used in adults instead of the
TABLE 38-38. Dimensions of Shiley Pediatric

Tracheostomy Tubes
Age
Neonatal 3.0
3.5
4.0
4.5
Pediatric 3.0
3.5
4.0
4.5
5.0
5.5
Long pediatric 5.0
5.5
6.0
6.5
ID, mm
OD, mm
Length, mm
3.0
3.5
4.0
4.5
3.0
3.5
4.0
4.5
5.0
5.5
5.0
5.5
6.0
6.5
4.5
5.2
5.9
6.5
4.5
5.2
5.9
6.5
7.1
7.7
7.1
7.7
8.3
9.0
30
32
34
36
39
40
41 same if cuffed
42 same if cuffed
44 same if cuffed
46 same if cuffed
50 same if cuffed
52 same if cuffed
54 same if cuffed
56 same if cuffed
classic open surgical tracheostomy. Experience in pediatric patients

is limited to children older than 10 years302,303 because only adultsize kits are available at present: with multiple dilators (Ciagla
Percutaneous Tracheostomy Introducer, PercuQuick), with one
dilator (Ciagla Blue Rhino), or with a special Kelly forceps to dilate
the trachea and subcutaneous tissue (Percutaneous Tracheostomy
set by Sims). Using a Seldinger technique, a guidewire is inserted
percutaneously between the first and the third tracheal rings
into the trachea. Progressive dilation of the tract is performed
using blunt-tipped dilators or a Kelly forceps. The size of the percutaneous tract is appropriate when it is two dilators larger than
the dilator over which the anticipated tracheostomy tube fits
snugly. The lubricated tracheostomy tube is loaded on this dilator
and introduced with it into the trachea. Endoscopic control of the
introduction of the guidewire and dilators is recommended
to avoid creation of a false passage into the neck, esophagus, or
mediastinum. The childs trachea is more pliable and narrower
than an adults. It presents an increased tendency to collapse when
pressure is exerted with the dilators, which increases the risk of
tracheal wall damage. Fracture-disruption of tracheal cartilages
may favor the occurrence of tracheal stenosis.303 The open surgical
technique should be preferred until more information is available
about the risk of tracheal stenosis following percutaneous dilational
tracheostomy in children.
TRANSLARYNGEAL TRACHEOSTOMY304: Translaryngeal tracheostomy (TLT) has been described in adults as well as in small
children using a TLT kit. A special needle is introduced through
the second interannular space into the trachea under visual control with a special rigid tracheoscope or a fiberoptic bronchoscope.
A metallic guidewire is then inserted through the needle and directed cranially as if retrograde intubation was anticipated. The
patient can be ventilated during the procedure using a special
4-mm ID TT with the cuff positioned close to the carina or with
jet ventilation. A special cone-cannula with a metal tip is threaded
onto the guidewire and pulled through the larynx, trachea, and
neck tissues using a special pull-handle. Firm traction is applied
with the handle, which is counterbalanced by the operators fingers
positioned around the guidewire. Once half of the cone-cannula
is extracted through the skin, the cone is separated from the
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CHAPTER 38
TABLE 38-39. Dimensions of Pediatric Silicone Tracheal T-tubes
T-Tube
BMP pediatric
Hood pediatric
Hood radioopaque
BMP pediatric
Hood pediatric
radio-opaque
BMP pediatric
BMP tapered
Hood standard
Hood long
BMP pediatric
Hood standard
BMP Extra long
BMP tapered
Hood
BMP
Hood
Superior
Limb
OD, mm
Inferior
Limb
OD, mm
Anterior Uncuffed
Cuffed TT Uncuffed
Cuffed TT TT Connector TracheLimb
TT Superior Superior TT Anterior Anterior Anterior
ostomy
OD, mm Limb
Limb
Limb
Limb
Limb
Tube
6
6
6
6
6
6
6
6
5
2.5
2.53.0
2.53.0
2.5
2.5
2.02.5
3.5
3.5
3.0
4.0
4.0
3.0
7
7
7
7
6
6
3.0
3.0
2.5
2.5
3.5
3.5
4.0
4.0
3.54.0
3.54.0
3.54.0
3.54.0
4.5
4.5
4.55.0
4.55.0
4.55.0
5.05.5
5.05.5
4.0
4.0
4.0
4.0
4.0
4.5
4.5
3.54.0
3.5 4.0
2.5
2.53.0
3.54.0
3.54.0
3.54.0
5.05.5
3.54.0
5.05.5
4.04.5
4.0
5.0
5.0
3.5
4.0
5.0
5.0
5.0
6.5
5.0
6.5
5.5
5.5
5.5 (long)
4.0
4.5
5.5 (long)
5.5 (long)
5.5 (long)
Adult 6.0
5.5 (long)
Adult 6.0
6.0 (long)
8
8/10
8
8
9
9
10
10/13
10
11
11
8
8/10
8
8
9
9
10
10/13
10
11
11
8
8
6
6.5
8
8
8
11
8
11
9
BMP = Boston Medical Products.

cannula. A special obturator or a telescope is introduced into the

cannula to pursue the extraction until the cannula is completely
straight: it is then rotated 180 degrees (the black line on its shaft
should face cranially) and pushed downward, toward the carina.
This technique has been successfully used with no complications
in a small series of children aged 2 months to 7 years.304
TRACHEAL T-TUBES305: Uncuffed silicone tracheal T-tubes, also

called Montgomery tubes, are used as a stent after surgical procedures on the cervical trachea or in case of severe tracheomalacia
or tracheal tumor. The T shape is the result of the arrangement of
an upper intraluminal limb, a lower intraluminal limb, and a
smaller extraluminal limb that can be occluded to allow speech.
Different anesthetic techniques can be used to control the airway:
An anesthesia circuit can be connected directly to the extraluminal limb using the appropriate standard 15-mm connector or
TT (Table 3839), but positive-pressure ventilation is not possible unless the upper limb is occluded. A Fogarty catheter introduced upward through the extraluminal limb or with an
LMA can be used to occlude. However, it is preferable to maintain spontaneous ventilation at all times.
Bag and mask ventilation or insertion of a supraglottic airway
with the anterior limb of the T-tube plugged can be used.
Introduction of a small, uncuffed TT through the upper limb
of the T-tube with its anterior plugged.
These silicone T-tubes are small and very flexible and thus
easily kinked, displaced during suction, or plugged by secretions.
Equipment for Difficult Intubation

The supraglottic airways and the different laryngoscope blades
that may be used in case of difficult intubation have already been
considered. All the devices and techniques described hereafter
require training in children with normal airways and sustained

experience in order to be used efficiently in case of foreseen or
unforeseen difficult airway.
Videolaryngoscopes
Videolaryngoscopes can be divided in two categories: (1) standard
laryngoscopic blades equipped with a video channel or (2) new
models of blades designed to show a clear view of the glottis
without alignment of the oral, pharyngeal and tracheal axe (i.e.,
without moving the head and neck).
VIDEOLARYNGOSCOPY: Both Miller and Macintosh blades

equipped with an external fiberoptic bundle (2.8 mm such as
X-Lite Video or Fiberoptic Laryngoscope)306 or in which a fiberoptic lens is integrated and coupled with a camera through the
handle are available. They are useful for teaching direct laryngoscopy (the instructor can directly guide the novice) and when
external laryngeal manipulation is necessary for intubation. These
devices provide a better view of the glottis and tracheal intubation
time remains the same. Intubation is not always easier until proper
training to learn how to use a flat two-dimensional image instead
of the three-dimensional direct vision is done.307,308
GLIDESCOPE: The Glidescope Cobalt (Verathon, Inc.) is made of

a high-resolution video imaging tube enclosed in a reusable
handle (baton) and a single-use plastic blade (Stats) (Figure
3825). It provides a view of the laryngeal structure on a separate
screen and looks like a Macintosh blade bent at 60 degrees with the
handle. Four sizes of blades are available (Table 3840). Although
the glottic view is usually easy and excellent, it is often not easy to
introduce the TT into the glottic opening. For oral intubation, the
use of the accompanying stylet or of a standard stylet to bend the
TT makes the manipulations of the TT toward the glottis easier.
It seems that bending at 90 degrees is more successful than
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A sterile transparent blade covers the reusable camera-blade
assembly. It can be used in the same way as a classic laryngoscope,
but the blade is best introduced in the middle of the mouth, using
a curving motion until the glottis is seen. Although the glottic view
is excellent, the TT needs to be mounted on a stylet bent upward
at 60 degrees to facilitate intubation. The McGrath videolaryngoscope can be used in big children and adolescents if the smallest
length of blade is chosen.
Fiberoptic Laryngoscope
DESCRIPTION: The fiberoptic laryngoscope (FL) or bronchoscope
Figure 38-25. Glidescope videolaryngoscope.

60 degrees at first attempt.309 This videolaryngoscope should be
introduced under direct vision in the middle of the tongue with
the head in the neutral position. One should look at the monitor
to obtain the best view of the epiglottis and glottic opening. The
blade is generally used like a Macintosh blade, without lifting
the epiglottis. The TT and its stylet are carefully introduced from
the right corner of the mouth under direct vision up to near the tip
of the blade to avoid any damage to intraoral structures.310 When
the TT is close to the tip of the blade, one should look again to
the monitor to complete the intubation process under video
control. Some manipulations such as turning the TT 180 degrees
or removing the stylet are often necessary to avoid the TT hitting
the anterior wall of the glottis or subglottis. It can be used in case
of difficult intubation, provided the patients mouth opening is
greater than 15 mm.
AIRWAY SCOPE: The Airway Scope (Pentax) is made of a handle,

in which a 6-cm liquid crystal display (LCD) screen is included,
and a flexible image tube with a camera and LED light source at
the tip. The disposable polycarbonate blade placed on the handle
has one channel to protect the image tube, a right-sided groove to
guide the insertion of the TT, and a separate channel for suction.
The tip of the blade is placed posterior to the epiglottis in order to
lift it during laryngoscopy. A target symbol on the LCD screen
helps guide the tip of the TT within the larynx. The adult version
is 325 mm long, and a minimum mouth opening of 2.5 cm is
needed to introduce the blade in the oropharynx. No pediatric
model has been designed so far.311
MCGRATH: The McGrath laryngoscope incorporates a light
source and a miniature camera in a blade (the length of which can
be modified to match the patients characteristics) and a handle
onto which a small LCD screen is mounted to display the image.
TABLE 38-40. Description of the Glidescope Cobalt Blades
Patients weight, kg
Blade length, mm
Blade thickness
Video baton, #
<3.6
38
8.7
12
1.810
51
8.7
12
10adult
80
16
34
>40
95
16
34
includes an ocular with focus ring, a handle to control the flexion

of its distal tip, a light cord connected to a light source, and a long
shaft with a short distal section that can be actively bended. A large
FL also has a working channel with access ports. The smallest FL
available has an OD of only 1.8 mm but has neither a working
channel nor a flexible end. The 2.2-mm OD FL, which can be
inserted into a 2.5-mm ID TT, is equipped with a fully flexible
distal end but has no working channel. The smallest FLs with a
working channel are the Circon AUR-7 (OD 2.4 mm), which can
be inserted in a 3-mm ID TT, and the Wolf 2.5-mm OD ultrathin
bronchoscope. A working channel allows the administration of
O2, local anesthetics, or suction or the introduction of a guidewire.
Successful use of a FL requires training, continuous experience,
and careful preparation (Table 3841). The use of a special fiberoptic intubation cart, on which all the equipment and drugs
needed are available, is strongly recommended.
INDICATIONS: In pediatric anesthesia, the FL is used primarily for

difficult tracheal intubation. It allows tracheal intubation or
insertion of a guide into the glottis under direct visual control
and also verifies the position of TTs or bronchial blockers and
diagnostic or therapeutic bronchoscopy. In case of bronchoscopy,
ventilation is achieved via either the TT or the LMA through
which the FL is inserted. Cases have been described in which
oxygenation was achieved with jet ventilation performed through
the suction channel of the FL.312 This is not recommended because
one cannot control the pressure actually delivered into the distal
airways. The FL can be used in several ways to achieve endotracheal intubation:
Direct over-the-scope intubation is performed in the same way

as in adults, but this is feasible only if the FL can be inserted into
the selected TT. To prevent difficulty advancing the TT caused
by its hanging up on the arytenoids or on the epiglottis, the
FL should nearly fill the lumen of the TT.
TABLE 38-41. Preparation for Fiberoptic Laryngoscopy
1. Attach the fiberoptic light guide cable to the light source and
adjust light intensity.
2. Check the insertion cord for abnormalities such as kinking,
dents, wrinkles.
3. Check the function of the angulation lever.
4. Focus the fiberscope to your eyes.
5. Connect the suction line to the suction port and ensure its
proper functioning.
6. Apply some antifogging solution on the lens.
7. Lubricate the insertion cord and the TT, but not the lens!
TT = tracheal tube.
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A CLMA, PLMA, air-Q intubating LMA, or other supraglottic

airway can be used to guide the FL near to the glottic opening.171
The TT can be slid over the scope during intubation or a
guidewire can be introduced under visual control into the
trachea, allowing subsequent tracheal intubation by sliding
the TT over the wire. One of the potential problems using the
scope for intubation is removing it without pulling the TT out
of the trachea. Proper lubrication is needed and different tricks
have been used to prevent this complication: inserting a smaller
TT in the proximal end of the intratracheal one,313 using a
laryngeal forceps to grasp the end of the TT,314 or cutting the
proximal part of the supraglottic airway. It should be borne in
mind that a reusable LMA can admit a larger TT than a singleuse LMA of the same size.315 Cuffed TTs are more difficult to
insert because of the space needed to pass the pilot balloon into
the LMA.
A guidewire technique has to be used when the available FL is
too big for the childs anticipated TT. The guidewire is either
passed through the suction channel of the FL316 or inserted
through a nostril317 and directed into the glottis under visual
control. The TT is thereafter railroaded on the guidewire.
A TT exchange catheter can be introduced into a supraglottic
airway and the trachea either under visual control via the FL or
after being loaded onto a thin FL.318
A retrograde-assisted technique can be used when a guidewire
has been inserted through the cricothyroid membrane and
retrieved in the mouth or nose. The guidewire is introduced
through the suction channel of the FL and used to guide the FL
to the glottis.319
The retrograde introduction of the FL through a tracheocutaneous fistula.
To facilitate fiberoptic laryngoscopy, it is very important to lift

the tongue off the posterior pharyngeal wall by pulling it gently out
the mouth with a Magill forceps or a piece of gauze or by asking an
assistant to perform a jaw-thrust. When the oral approach is used,
it is critical to stay in the midline to help identify the supraglottic
structures. This can be achieved with the intubators fingers, a
modified oral airway, an LMA, or even a feeding teat in neonates.320
FLs are expensive and fragile. They should be handled and maintained carefully. Their use is more difficult in the presence of
secretions or blood. A vagolytic premedication is useful when a
difficult intubation is foreseen, and in case of unexpected difficult
intubation, one should switch to a fiberoptic technique before any
trauma has occurred.
CLEANING AND STERILIZATION: The manufacturers instructions

should be followed scrupulously. One important point to note is
whether the eyepiece and head of the FL are immersible or not.
The FL should be cleaned immediately after use by wiping its
outer surface with alcohol or an aqueous solution of chlorhexidine
and by flushing its working channels with a detergent solution.
It should be carefully rinsed with water before undergoing disinfection with a glutaraldehyde or peracetic acid solution. After
disinfection, the FL should be rinsed with sterile water to remove
all traces of disinfectants.
Lightwand321
The basic principle of the lightwand is to use a malleable stylet
with a light at the end to transilluminate the neck and guide the
blind placement of the TT into the trachea. It has recently be
TABLE 38-42. Lightwand Intubation: Indications

and Contraindications.
Indications
1. Orofacial types of airway problems: micrognathia, restricted
mouth opening.
2. Soft tissue type of airway difficulty provided the glottis
is known to be normal: glossoptosis, macroglossia.
3. Restricted access to the airway: halo traction.
4. Restricted movement of the neck: trauma, vertebral
abnormalities.
Contraindications
1. Inability to transilluminate: thick neck, goiter, obesity, local
inflammation.
2. Inability to align the airway axes: extrinsic lesions (tumor,
hematoma), torticollis, tracheal deviation.
3. Laryngeal pathology: stridor, papilloma, epiglottitis, glottic
or subglottic stenosis.
4. Risk of blind trauma: foreign body, pharyngeal abscess.
recommended to help position a PLMA322 or even to perform
digital intubation in neonates and infants323 (Table 3842). This
equipment is very popular in North America but used much less
elsewhere. Ideally, the pediatric lightwand should have a variableintensity light source because too much brightness can make
esophageal intubation difficult to diagnose in infants, a rigid stylet
component to make its manipulation easier, and an appropriate
handle above the loaded TT to prevent twisting during use.
The Pediatric Lighted Stylet is a reusable metal-wrapped fiber
bundle with no controllable brightness. It exists in a 21-cm-long
pediatric version that can be introduced in a 3.5-mm ID TT. The
Imagica device has a rheostat-controlled light source and can be
introduced in a 2.5-mm ID TT, but it is very flexible and has no
handle. A homemade lighted stylet for use in small infants can
be made with a single fiberoptic light bundle introduced in the
TT alongside a rigid plastic-covered stylet. The light bundle is
connected to a rheostat-controlled xenon light source.324 These
lightwands are inserted in the TT in the same way as a nonilluminated stylet.
The Trachlight consists of a reusable handle (with a lock to
secure the connector of the TT), a plastic flexible wand with a light
bulb, and a malleable and retractable internal stylet. It exists in an
infant and a child version for TTs 2.0 to 4.0 mm ID and 4.5 to
6.0 mm ID, respectively. The light beam is very bright, which
allows using the device in normal ambient light. It shines forward
and laterally to provide better transillumination of the soft tissues
of the neck. The light blinks automatically every 30 seconds. The
temperature of the bulb is 55 6C at the first blink and increases
to 103 10C after 10 blinks, but no histopathologic signs of
burn injury have been detected in an animal model.325 The TT is
lubricated, mounted on the wand and stylet, and fixed to the
handle. The styletted wand and TT are bent at an angle of 85 to
90 degrees a few centimeters from the tip. When using a lightwand
for nasal intubation, which in the authors opinion carries a
traumatic risk, the distal part should be slightly longer and bent
more sharply (<90 degrees).326 Whatever the particular device
used, attention to the following details are essential:
The use of a shoulder roll and slight head extension, especially

in small infants, to facilitate transillumination of the anterior
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part of the neck. However, if needed, the neck can also be maintained in the neutral position.
Grasping and lifting the jaw upward from the side with the
thumb and index finger of the intubators nondominant hand
in order to bring the tongue forward and to lift the epiglottis off
the pharyngeal posterior wall.
Midline insertion of the lightwand in the oral cavity and around
the tongue.
Holding the wand rather than its handle to obtain better tactile
sensations.
Gentle handling of the wand using a rocking motion while staying in the midline and using the glow of the light as a guide toward the thyroid prominence. Do not advance against resistance!
Correct positioning is indicated by bright transillumination in
the midline below the level of the thyroid prominence. This is
often accompanied by the tactile sensation of a click when
the lightwand is advanced past the epiglottis. If a Trachlight is
used, the stylet is withdrawn 3 to 4 cm and the TT and the flexible wand is advanced down the trachea until the sternal notch
is transilluminated. This indicates correct placement of the TT
in the middle of the trachea.
Esophageal intubation causes a more diffuse glow. Lateral deviation into a pyriform sinus gives lateral illumination, and
catching the stylet in the vallecula produces a more proximal illumination.
Although the use of a lightwand is a simple and easy-to-learn

technique, it requires some training and experience in normal
airways before it is used for difficult airway management. The
most common causes of failure are entrapment in the vallecula or
aryepiglottic folds and vocal cord closure caused by insufficient
anesthesia. These devices are not very expensive and are easy to
clean and reusable. Lightwands, and the wand and stylet of the
Trachlight, should be washed and scrubbed in between cases and
undergo proper gas sterilization or immersion in a disinfectant
solution everyday.
BONFILS AND BRAMBRINK RETROMOLAR INTUBATION FIBERSCOPES (STORZ): They are reusable rigid fiberscope with a
40-degree curved tip and an eyepiece on the handle. Light is
provided via a cold light source or with a handle with a battery. It
is equipped with a special connector that fits a 15-mm standard
TT connector designed to secure the TT position on the scope
and allow insufflation of O2 to prevent fogging of the distal lens.
The Brambrink is a 2.0-mm OD, 22-cm long optical rod suitable
for TT with an ID of 2.5 to 3.5 mm. The Bonfils fiberscope is
available in two pediatric sizes: the 3.5-mm OD model should
be used for TTs of 4.0 to 5.5 mm ID and the 5-mm OD model
(equipped with a suction channel) for larger ones. Both the outer
surface of the device and the inner surface of the TT should be
lubricated. The fiberscope is inserted in the TT up to 0.5 to 1 cm
proximal to its end. The TT is then fixed to the fiberscope using
the special connector.
The childs head should be in the neutral position and the
scope is inserted from the right side of the mouth. A jaw-thrust
maneuver is helpful to enlarge the space between the epiglottis
and the posterior pharyngeal wall. The scope is advanced under
visual control until its tip is at the level of the glottis. The TT is
disconnected and advanced over the fiberscope into the trachea.
A team recommends using the Bonfils fiberscope like a Trachlight.
A midline approach grasping the jaw with the nondominant hand
is suggested, allowing the tip to advance slowly down to the level
of the epiglottis along the pharyngeal wall. The Bonfils fiberscope
is rotated anteriorly toward the epiglottis and advanced under it
to uncover the glottis.328 Others use a standard laryngoscope
blade to position the device behind the epiglottis. An evaluation
of the Bonfils device in children with normal airways had a
significant failure rate and its use cannot be recommended.329 The
failures were mainly caused by poor visualization of the glottic
structures because of the presence of secretions and the small
pharyngeal space.
Optic Laryngoscopes
Optical Intubation Stylets
THE SHILKANI OPTICAL STYLET (CLARUS MEDICAL, MINNEAPOLIS, MINN): The Shilkani Optical Stylet is a malleable
stainless steel fiberoptic stylet equipped with an eyepiece that can
be connected to either a video camera or the light source of a
special or standard FL handle. It is easy to use and does not require
a long learning process. It combines the advantages of a lightwand
and a fiberoptic bronchoscope. The only drawbacks are the limited
depth of the visual field (1 cm) and loss of visibility once secretions cover the lens. The pediatric version is 27 cm long and can
be introduced in a 2.5-mm ID TT. The adult version can be used
with a 5.5-ID TT or larger. Both the outer surface of the stylet and
the inner surface of the TT should be lubricated. The stylet is
introduced in the TT so that the distal lens does not exit past the
end of the TT. This position is secured using the tube stop device
through which a flow of O2 can also be administered. The TT
equipped with the stylet is introduced in the pharynx and
advanced toward the glottis under both external transillumination
and direct endoscopic visual control. An assistant performing a
light jaw-thrust or pulling the childs tongue of its mouth is often
helpful to enlarge the space between the epiglottis and the posterior pharyngeal wall. The TT is advanced on the stylet and
introduced in the trachea when the trachea is just entered.327
AIRTRAQ: The Airtraq (Prodol Meditec, Spain) is a single-use

indirect laryngoscope in which the exaggerated curvature of the
blade and the configuration of the optical components provide a
view of the glottis without need to align the oral, pharyngeal, and
tracheal axes (Figure 3826). The main channel of the device
contains the optical components (with a built-in light source and
antifog system) and a right-sided parallel channel equipped with
a groove to place the adequate TT and guide its insertion. Five
sizes are available (Table 3843).
The Airtraq should be introduced under direct vision in the
middle of the tongue with the head in the neutral position. When
the monitor (built-in small optical system or wireless monitor)
gives the best view of the epiglottis, the tip should be placed in the
vallecula. The handle should then be lifted up vertically to lift the
epiglottis and expose the glottic opening. The latter should be
aligned with the center of the visual field because the right-sided
groove is designed to direct the tip of the TT toward the center of
the visual field. The tip of the TT is guided into the glottic opening
under direct visual control. After intubation, the TT is separated
from the Airtraq by pulling it laterally. The Airtraq is rotated
backward and taken out of the mouth. The Airtraq improves
visualization of the glottis and facilitates both normal and difficult
intubation in adults while reducing the hemodynamic response
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childs head is best placed in the neutral position. A stylet (a special

Optishape stylet is provided with the blade) is introduced into the
TT to give the correct angulation (a hockey-stick shape, usually).
The Truview EVO2 is introduced in the middle of the mouth over
the tongue. When the glottic opening is seen in the eyepiece, the
TT is introduced in the mouth along the side of the blade under
visual control until its distal part is seen in the eyepiece. It is
advanced slightly upward to enter the cords. This system provides
an excellent view of the glottis but requires some practice to get
good eye-hand coordination.331
BULLARD LARYNGOSCOPE321: The Bullard laryngoscope (BL) is
Figure 38-26. Pediatric size Airtraq optical laryngoscope (light

on) loaded with a 5.0-ID (inner diameter) tracheal tube.
to laryngoscopy. Only a few case reports of successful intubation
in pediatric difficult intubation cases have been published.330
TRUVIEW LARYNGOSCOPE BLADE: The Truview infant EVO2

laryngoscope blade includes a fiberoptic light, an integrated
optical lens system, and a 46-degree angulated tip. This provides
a good indirect view of the glottis through a magnifying optic side
port without needing to align oral, pharyngeal, and tracheal axes.
There is an integrated O2 jet (flow rate 25 L/min) to prevent
fogging and allow O2 administration during laryngoscopy. The
TABLE 38-43. Sizes of Airtraq Laryngoscopes
Minimum
Mouth Opening
Needed, mm
a ladle-shaped intubating device designed to perform indirect

laryngoscopy by passing behind the tongue and lifting it from the
pharyngeal wall with minimal movement the childs neck or temporomandibular joint. It comprises a slightly curved L-shaped
blade, a fiberoptic viewing channel, and a light source. There is
also a channel that is bifurcated at its proximal end. One port
allows the insufflation of O2, the injection of local anesthesia,
the application of suction, or even the introduction of a small
bougie,332 whereas the other is designed to connect a special hollow nonmalleable stylet that runs parallel to the blade and holds
the TT close to the underside of it.
Three sizes of BL are available: pediatric (02 y), pediatric long
(010 y), and adult. They all have the same blade thickness
(0.64 cm), but the width of the pediatric blades is smaller (1.3 and
1.6 cm vs 2.5 cm in the adult version) as is their internal radius of
curvature (3.3 cm vs 1.9 cm). Different intubating devices can be
used with the BL. The special nonmalleable stylet, an independently styletted TT, or a bougie may be used to introduce the
TT into the trachea under visual control. If an independent stylet
is used, it should be lubricated, preloaded with the connector-free
selected TT, and shaped to mimic the curve of the Bullard blade,
taking care to position the tip of the stylet inside of the TT.
Conversely, if the special nonmalleable stylet is used, the TT
should be slid proximally over the stylet because it is designed to
point directly at the glottic aperture and the presence of the TT
at its distal end would direct the stylet away from the blade and
thus from the glottis. In both cases, proper hand grip of the BL is
essential to keep the styletted TT in correct position. The thumb
of the hand holding the BL should wrap the handle, eyepiece, and
distal part of the stylet while the other fingers rest on the styletted
TT to hold it against the backside of the blade. The insertion
technique is
Color Code
Size
TT Size
Infant
Pediatric
Small
Regular
Pediatric
nasotracheal
For nasotracheal
intubation
For doublelumen tubes
2.53.5
45.5
67.5
78.5
12.5
12.5
16
18
12.5
Gray
Purple
Green
Blue
White
18
Orange
3541 Fr
19
Yellow
TT = tracheal tube.
The nasotracheal versions are designed without the right-sided groove in order
to favor anterior movement of the TT coming from the nasopharynx.
Before use, the distal end of the viewing channel is treated with
an antifogging solution.
The laryngoscopist stays at the patients head and holds the BL
with the handle horizontal.
The blade is inserted in the midline of the mouth and the handle is progressively rotated to the vertical position when the
blade slides around the tongue.
Once the handle is fully vertical, the blade is elevated against
the posterior surface of the tongue; the epiglottis or the glottis
then comes into view.
To improve the vision, the blade can either be used to lift the
epiglottis, which is mandatory when the special stylet is used or
be placed in the vallecula.
The TT is directed toward the glottis under visual control.
After intubation, the TT has to be held steady at its proximal end
while the stylet and the BL are removed from the childs mouth.
The BL is very useful in case of limited cervical mobility or small
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mouth opening (its blade is only 0.64 cm thick at the viewing

tip) and usually gives a superb vision of the childs glottis, but
practice is needed to insert the TT into it. This device is expensive but more robust than a fiberoptic bronchoscope. It can also
be used to guide nasotracheal intubation.333 An anesthesiologist
skilled in the use of the BL can use the adult model to intubate
the trachea of children older than 12 months with a normal airway, although multiple attempts may be necessary because of
contact with the right aryepiglottic fold or with the anterior aspect of the vocal cords.334
The BL requires careful cleaning after use. It should be washed
and scrubbed between cases before undergoing gas sterilization
or immersion in a disinfectant solution, taking care to avoid
dipping the eyepiece.
Devices Suitable for Retrograde Intubation335

The basic principle of the retrograde intubation technique is to
introduce a guidewire into the trachea through the cricothyroid
membrane, to thread it cephalad through the larynx into the
mouth, and to subsequently advance a TT over it. Although special
sets are commercially available (Retrograde intubation set by
Cook, with a 6-French version usable in TTs down to 2.5 mm ID),
a standard I.V. cannula can be used with a long (100-cm) atraumatic guidewire. Technical details of critical importance are319
Place a folded towel under the childs shoulders to help identify

the cricothyroid membrane.
Insert the I.V. cannula, attached to a saline- or local anesthetic
filled syringe, in the middle of the membrane and in a slightly
cephalad direction (45 degrees) until air is aspirated.
The catheter of the cannula is then advanced only a few millimeters into the trachea, bearing in mind that both the vocal
cords and the posterior tracheal wall are very close.
The guidewire is inserted through the catheter in a cephalad direction and retrieved in the oral cavity.
The guidewire is secured at its cutaneous entry point with a
clamp to avoid pulling it totally into the trachea during the subsequent maneuvers.
If a nasotracheal intubation is anticipated, a small suction
catheter is passed in the mouth down a nostril, attached to the
oral end of the guidewire, and used to advance it through the
nostril.
The guidewire may be used in several ways to intubate the

trachea. If the TT is advanced directly over the guidewire, it should
be threaded through its Murphy hole because this allows an
additional 10 mm of the TT to be within the trachea before
removal of the guidewire.335 Some tension should be maintained
on both ends of the guidewire during advancement of the TT to
avoid its impaction on the laryngeal structures (arytenoids, vocal
cords, and epiglottis). If this occurs, a 90-degree rotation of the
tube or slightly reducing the tension on the guide might help. To
avoid this hanging up phenomenon, the cephalad end of the
guidewire can be passed through the suction port of a fiberoptic
bronchoscope onto which a TT has been loaded; this allows both
the visual control of the passage of the TT into the glottis and a
quicker fiberoptic laryngoscopy because the laryngoscopist needs
only to follow the path of the guidewire. If an ultrathin FL with
no working channel is used, it can be passed through the TT and
alongside the guidewire and follow the guide path to the glottis.
Anterior Commissure Laryngoscope

The anterior commissure laryngoscope is used by ear, nose, and
throat surgeons to visualize the glottis and trachea. It also allows
oral intubation in patients with micrognathia or in whom edema,
blood, an intraoral mass, or scar tissue would make the use of a
classic blade or even fiberoptic laryngoscopy impossible. The
tubular blade displaces or compresses the tongue and pharyngeal
soft tissues and prevents them from obstructing the access to
the glottis.
If a usual Jackson anterior commissure laryngoscope is used, its
proximal end should be placed laterally into the oral commissure
(and not in the midline as for diagnostic suspension laryngoscopy)
to allow increased anterior angulation of the blade and easier
visualization of the glottis.
A modified version has been designed that allows the use
of direct suspension laryngoscopy.336 It is a two-piece tubular
pharyngolaryngoscope (model 52-2220 modified, by Pilling
Instruments) made of two handle blades and a knurled screw that
holds the two blades together during intubation and allows their
separation once intubation is completed. Moreover, a fiberoptic
light at the tip provides illumination of the glottis. With both
instruments, the tip of the blade elevates the epiglottis and is
placed into the laryngeal inlet. The TT (without connector) is then
introduced directly through the blade into the glottis. Drawbacks
of the technique are temporary loss of vision of the larynx when
the TT is advanced into the laryngoscope and difficulty in stabilizing the TT during removal of the tubular laryngoscope.
This equipment should be washed and scrubbed between cases
before undergoing autoclaving, gas sterilization, or immersion in
a disinfectant solution.
POSTANESTHESIA CARE UNIT

The medical aspects of recovery from anesthesia and surgery are
described in Chapter 58. Moreover, the PACU has an important
role in the management of postoperative pain because the major
pain relief techniques (e.g., PCA, continuous I.V. morphine,
epidural infusions) as well as more common techniques (e.g., I.V.
titration of fentanyl or morphine, I.V. or rectal non-steroidal antiinflammatory drugs [NSAIDs]) are initiated and evaluated there.
Organization
The PACU should be located close to the main operating suite to
shorten the childs transport time from the operating room but
also to allow anesthesiologists and surgeons to be quickly available
in case of any problem. It should also be able to quickly obtain
laboratory results (e.g., blood gases, hemoglobin, electrolytes) and
be equipped with a mobile x-ray machine to make emergency
chest x-rays (e.g., to exclude a low-pressure pulmonary edema
after upper airway obstruction, a pneumothorax). The PACU
should be well ventilated to avoid exposing the nurses to excessive
levels of anesthetic gases exhaled by the patients.337
The size of the unit should be adapted to the caseload of the
department: the most commonly used rule is 1.5 PACU beds per
operating room used, but this can result in overcrowding if many
short-lasting surgical procedures are performed or if children
recovering from deep sedation or anesthesia outside the operating
room are also cared for in the PACU. In general hospitals, where
both adult and pediatric patients come to the PACU, a part of the
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PACU should be dedicated to pediatric patients; this allows permitting one parent to be close to the child without disturbing the
privacy of some adult patients while also avoiding adult patients
being disturbed by the cries of agitated children. Although a large
open ward with movable curtains is optimal for patient care, it is
useful to have at least one isolation room for the management of
patients who are infected, immunocompromised, or allergic to
latex. The personnel required varies according to the childs age
and procedure performed: a high-risk expremature infant or a
major surgery case requires one or two nurses, whereas a nursing
ratio of one for two to three children may be sufficient for healthy
children undergoing superficial surgery.
Each bed space should be equipped with piped-in O2 (and
devices to administer it), air, and vacuum for suction. Pulse
oximetry is the essential monitoring device in the PACU, but ECG,
NIBP, and if possible, nasal capnography should also be available.
Direct intra-arterial monitoring of BP should be possible if major
cases are cared for in the PACU and in case of vital emergency.
Special equipment for the nebulization of racemic epinephrine or
bronchodilators should be available for the symptomatic treatment
of postintubation croup or bronchospasm, respectively. Moreover,
the following emergency equipment should be immediately
available in the PACU:
An emergency airway cart with manual resuscitators, laryngoscopes, oral and nasopharyngeal airways, endotracheal tubes of
all sizes, supraglottic airways, and cricothyrotomy devices.
A resuscitation cart with emergency (e.g., atropine, epinephrine) and anesthetic (protocol, thiopental, diazepam, succinylcholine) drugs, replacement fluids (crystalloids and colloids),
at least one infusion pump and a chest tube to drain a hemo- or
pneumothorax, and a central venous access tray.
A cardiac defibrillator.
Oxygen Delivery Devices

Supplemental O2 needs to be administered during postoperative
transport of the patient, during part of its stay in the PACU, and
sometimes also in the ward. Only simple devices allowing the
administration of O2 to children breathing spontaneously are
considered here. The other devices such as manual resuscitators and
pediatric anesthetic circuits are described in the preceding sections.
Simple Blow-by Administration of

2 to 6 L/min O2 Close to the Childs Face
This allows the delivery of an unknown FIO2 but without stimulating the child, which is sometimes useful in the recovery period.
The presence of nasal prongs or a facemask may indeed stimulate
the child and result in dislodgment of the device and, thus, intermittent therapy and further agitation. In one study, 80% of the
children rejected the facemask but all accepted blow-by O2 during
their stay in the recovery room.338 The adequacy of O2 administration can easily be monitored using clinical observation and pulse
oximetry. This technique is best avoided in small expremature
infants because the administration of a cold airstream close to their
face could induce reflex apnea by stimulation of the trigeminal area.
The Oxygen Hood

In small infants, supplemental O2 is usually administered in an
oxygen hood, which is a headbox enclosing the head and neck.
The FIO2 actually delivered to the infant depends on the O2 flow

rate, the volume of the box, the size of the leak around the neck,
and the frequency of opening. It should be measured using an O2
sensor placed close to the infants head. In fact, rebreathing can
occur when the flow rate is low (a gas flow of 23 L/kg/min is
necessary to avoid rebreathing) and a close seal around the neck
is achieved. It should also be borne in mind that in small infants
the administration of cold nonhumidified O2 into the hood can
induce an important thermal stress.
Nasal Prongs, Catheters, and

Airways and Simple Facemasks
They provide unpredictable FIO2 because it depends on not only
the O2 flow provided but also the inspiratory flow rate, minute
ventilation, and expiratory pause. The entrainment of ambient air
decreases FIO2 when the patients inspiratory flow rate exceeds the
O2 flow. Conversely, O2 can accumulate in the nasopharynx during
the expiratory pause, creating a small reservoir to supplement the
O2 content at the beginning of the following inspiration. Nasal
prongs or catheters are usually well tolerated. The sampling line
of a sidestream capnometer can be adapted to nasal prongs to
monitor PETCO2. If a nasogastric tube is in place, the nasal catheter
should be placed in the same nostril in order to avoid total nasal
obstruction and increased resistance to breathing. If CPAP is
needed, this is best achieved using a nasopharyngeal airway. In
infants younger than 2 years, an FIO2 of 50% can be achieved by
administering 150 mL/kg of O2 through the nasal catheter. Higher
flow rates are usually poorly tolerated and result in drying of the
nasal mucosa. When an 8-French catheter is used to administer O2
in the nasopharynx, moderate amounts of CPAP are produced. It
increases approximately by 1.5 cmH2O for every increase of flow
by 100 mL/kg/min.339
Simple lightweight plastic facemasks allow the administration
of an FIO2 varying from 35 to 50% with flow rates of O2 of 6 to 10
L/min. Ambient air is entrained through the sideports and a little
O2 can accumulate in the mask during the expiratory pause. The
use of a facemask equipped with a reservoir bag into which the O2
delivered during the patients expiration can accumulate (e.g.,
Paediatric high concentration mask with 1-L reservoir bag, by
Intersurgical) and with flap valves to prevent entrainment of
ambient air allows the delivery of higher FIO2. This is rarely used
in children.
Fixed Performance Facemask

(Venturi System)
The only fixed performance device available (i.e., where the FIO2
actually delivered to the patient) depends only on the O2 flow rate.
It is fitted to a special facemask or to a T-piece attachment.
According to the design of the jet, FIO2 of 24, 28, 25, 40, and 60%
is delivered with a total flow of 60 L/min. Unfortunately, high
flows of air blowing into the face is sometimes poorly tolerated
by children.
THE MRI SUITE

MRI uses high-strength changing magnetic fields to provide
digitalized tomographic imaging of any tissue in the body. The
strength of the magnetic fields used varies from 0.5 to 3.0 Tesla
(T; 1 T = 10,000 Gauss; the normal magnetic field at the surface
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of the earth is 0.51.0 G). Different problems have to be taken

into account:
Access to the patient is limited once she or he is placed within

the magnet bore. The different techniques that can be used to
overcome it are described in Chapter 56.
Ferromagnetic objects are strongly attracted by the static magnetic field used by the MRI system and can become projectiles,
increasing risk of injury to the patient, personnel, and equipment.
The time-varying magnetic field gradients and radiofrequency
currents can cause malfunction of anesthetic equipment (e.g.,
monitoring, infusion pumps) or induce heat in the monitoring
leads with a risk of skin burns.221
Radiofrequency currents produced by monitoring equipment
may affect the quality of the images obtained.
Interferences of the Monitoring Equipment340

Electronic noise caused by the monitoring equipment is of two
types:
1. Artifact lines across the entire image are generated by electronic
noise occurring at a specific frequency (or a submultiple of this
frequency) that is within the band of the radiofrequency
receiver of the MRI system. This type of artifact is easily
detectable.
2. The loss of radiologic details and poor diagnostic quality of the
image occur when broad-band electronic noise is produced.
This artifact is spread uniformly across the image and could be
overlooked.
By definition, MRI-compatible equipment must be used to

prevent injury and to ensure that the quality of the images will not
be affected. Up-to-date information regarding safety and testing of
equipment can be found on the following websites: MRIsafety.com,
IMRSER.org, MagneticResonanceSafetyTesting.com, or kanal.arad.
upmc.edu/mrsafety.html
In order to avoid these artifacts, every monitor must be tested

in the MRI setting where it will be used according to the guidelines
described by Jorgensen and colleagues.340 After having been
checked outside the MRI scanner with a hand magnet to make
sure it does not contain ferromagnetic components, the monitor
should be tested in its off and on modes to measure the magnitude of the radiofrequency currents and the electronic noise
it produces.
Exclusion of Ferromagnetic Equipment

From the Magnetic Field
Monitoring Devices
Vigilance and caution are necessary to prevent injury to the

patient, personnel, and equipment from propelled ferromagnetic
items. All people entering the MRI scanner room should remove
pens, scissors, watches, needles, and any other ferromagnetic
objects from their garments. In order to alert everyone of the
increased danger of propelled objects, a line should be drawn on
the floor to limit the areas where magnetic fields of 5 and 50 G are
present around the magnet. In recent MRI units, the 5-G limit
corresponds with the walls of the scanner room. A checklist
should be completed for every patient entering the MRI scanner
room to exclude the presence of ferromagnetic implants that
could become inactivated (e.g., a pacemaker) or displaced (e.g.,
nontitanium hemostatic clips, an ocular or dental prosthesis, coils,
stents, a cochlear implant, ear grommets, a metallic foreign body)
and nonferromagnetic material that could heat during MRI
scanning (e.g., orthopedic pins and plates). The setting of the valve
of ventricular shunting devices that are controlled with a magnet
should be checked after the MRI scanning. Lastly, credit cards and
electronic devices (e.g., watch, portable calculators) should also
be left outside the scanning room to avoid their inactivation.
Concerning the anesthetic equipment, two solutions are possible:
Integrated MRI-compatible multiparameter monitoring units

are currently available (e.g., Omni-Trak 3100 or 3150 MRI vital
signs monitoring, Multigas model 9500 MRI monitor, AS3 MRI
compatible) that also use telemetry or fiberoptic transmission to
transmit information onto a screen placed in the control room.
These expensive units allow the continuous monitoring of all the
vital signs parameters (ECG, invasive BP or NIBP, SpO2, PETCO2,
respiratory rate) and the anesthetic vapors administered to the
child. However, many anesthesiologists still do not monitor all
vital signs during MRI scanning and use either only a MRIcompatible pulse oximeter or standard monitoring items placed
outside the 50-G line and connected to the patient with long leads
or extension lines. Safety rules to be observed when using these
monitoring devices in the MRI room are summarized in Table
3844. The installation of a videocamera focused on the patients
head and chest allows continuous remote control from outside the
scanner room.
1. The equipment is used outside the magnetic field. Depending

on the magnetic field strength and on the shielding of the MRI
scanner, attraction of ferromagnetic items occurs between
the 30- and the 50-G lines. This equipment should be placed
outside the 50-G line drawn on the floor of the MRI scanner
room or even outside the scanner room if radiofrequency ports
are inserted through its shielding to provide a passage for
tubings and cables.
2. The equipment is used close to the magnet. It should be
checked outside the MRI scanner with a hand magnet (those
used to evaluate pacemakers are sufficiently strong) to ensure
it does not contain any ferromagnetic material and its possible
interferences with the MRI system should have been evaluated
(see the next section).
When a cuffed TT or a supraglottic airway is used for MRI, care

should be taken to place the pilot valve away from the coil because
it contains a small metallic spring that interferes with the quality
of the image. Moreover, all connectors should be plastic. Most
laryngoscope handles and blades are made of stainless steel or
chrome-plated brass but some are ferromagnetic. They should be
tested with a hand magnet before being introduced in the MRI
scanning room. A plastic laryngoscope can be used instead. The
other major problem with laryngoscopes is the nature of their
batteries. Alkaline batteries are highly magnetic and lithium
batteries, or an external source of light, should be used instead.
In case of life-threatening emergency, it is probably safer to quickly
take the patient out of the MRI scanning room and to resuscitate
him or her in the preparation room rather than introducing
Anesthetic Equipment
Control of the Airway
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TABLE 38-44. Patient Monitoring in the Magnetic
Resonance Scanning Room
Preuse check of monitoring leads: their electrical insulation
must be intact
Positioning of monitoring leads: to prevent burns:
Do not form loops (closed, U- or S-shaped) within the magnet
bore.
Avoid contact between leads.
Separate the leads from the patients skin (e.g., with a
towel).
Keep the leads away from the area examined.
ECG
Use nonferromagnetic electrodes.
Carefully position of the electrodes close together in a single
line.
Parallel to the magnetic field lines.
Cables should exit the magnet down the center of the patient
table.
ECG tracing will be modified during MR scanning: it cannot
be used to interpret ST segment changes for ischemia or to
interpret the cardiac rhythm!
Pulse Oximeter
Probe placed on a distal extremity, as far as possible from the
scan site.
NIBP
Ferrous connections should be changed to nylon ones.
Tubings should be lengthened as necessary.
Capnograph
Only sidestream capnometers can be used.
Tubing should be prolonged: it results in delay of the response.
ECG = electrocardiogram; MR = magnetic resonance; NIBP = noninvasive

blood pressure.
untested equipment close to the magnet bore (risk of attraction

into it or of injury).
The Anesthesia Machine

Any anesthesia machine can be used in the MRI scanner room if
all ferromagnetic material has been replaced with aluminum (e.g.,
cylinders) or nonmagnetic stainless steel. The Fortec II vaporizer
can be used within the MRI scanner room without altering the
quality of the images obtained. However, some aberrancy of its
output can occur if it is placed very close to the scanner. Monitoring
the expired gases is useful when using a vaporizer inside the MRI
scanner room.341 Care must be taken when using a vaporizer inside
the MRI suite. One case of flying vaporizer (Sevoflurane 19.3 by
Drager) has been published.342 All breathing systems can be used
provided they do not contain any ferromagnetic components.
It should be remembered that increasing the length of the expiratory limb of the Mapleson D system increases its resistance to
expiration in spontaneous ventilation.
The Ventilator
If the childs ventilation has to be controlled, an MRI-compatible
ventilator can be adapted to the anesthesia machine (e.g., the
Air Shields Ventimeter II, ventiPAC, paraPAC, or babyPAC, or the
North American Drager MRI-compatible ventilator). The SiemensElema 900 C can also be used provided it is placed outside the
50-G line because its PEEP valve is a solenoid type. If an MRIcompatible ventilator is not available, any anesthesia ventilator
can be used provided it is placed outside the 50-G line or outside the scanning room. This necessitates extended disposable
plastic tubing and increases either the compression volume of the
system or the end-expiratory pressure, depending on the breathing
system used.
The Infusion Pumps

The high magnetic field can result in malfunction of infusion
pumps. In order to lessen the risk of attraction and malfunction,
the infusion pump should be kept as near as possible to the center
of the long axis of the magnetic field (i.e., on the axis and at the
foot of the table where the patient is lying) and outside the 50-G
line. Long extension tubing is necessary.
Prevention of Hypothermia
Air conditioning of the magnet room (~20C) and air flow directed
through the MRI scanner increase heat loss. Hypothermia should
be prevented, especially in small infants. Single-use thermal packs
(e.g., Porta-Warm, Porta-Warmers) can be placed under the
patient. Covering the child with a (prewarmed) blanket or a plastic
sheet usually prevents the occurrence of hypothermia. However, a
small increase in body core temperature (+0.30.7C) following
MRI has been described in infants and children in whom no efforts
were made to avoid heat loss. This is because of radiofrequency
radiation absorbed by the patient during MRI scanning and is
more important during 3-T or long-lasting scans.343,344 Monitoring
of body temperature before and after MRI is important.
CONCLUSION
At the end of this detailed review of all equipment and monitoring
available currently for pediatric anesthesia, some points need
to be stressed. To avoid failure of the equipment, it should be
inspected daily, ideally with a checklist, before starting the first
anesthesia. An abbreviated form of the checklist should be used
between cases in order to verify the parts of equipment that have
been changed. It should also be regularly maintained according to
the manufacturers recommendations. To decrease the incidence
of patient injury caused by misuse (i.e., human fault or error
associated with the preparation), maintenance or use of the device
and initial and ongoing education should be provided to all
anesthesia providers to make them understand the functioning of
their equipment and its possible pitfalls. In the same way, more
and more complex monitoring devices are available. Education is
essential to avoid misinterpretation of the data provided by these
devices. A dialogue should be established with the manufacturers to improve their ergonomics and to make them more userfriendly. Lastly, establishing a medical device surveillance network,
at either a national or a regional level, is very helpful to identify
anesthesia-related incidents or accidents possibly caused by
anesthetic equipment, warn the users, and help the industry find
adequate solutions.
We should not forget that humans interface continuously with
these equipment and monitoring devices, interpret their data, and
take action accordingly. Adequate theoretical and clinical training,
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if possible with the help of simulator training to learn handling

rare emergencies, as well as vigilance remain the cornerstones of
safety in anesthesia whatever the equipment and monitoring
available.
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of patients with tracheal T-tubes. Paediatr Anaesth. 2009;19:349357.
306. Weiss M, Schwarz U, Dillier CM, Gerber AC. Teaching and supervising
tracheal intubation in paediatric patients using videolaryngoscopy.
307. Macnair D, Baraclough D, Wilson G, et al. Pediatric airway management:
comparing the Berci-Kaplan laryngoscope with direct laryngoscopy.
308. Fiadjoe JE, Stricker PA, Hackell RS, et al. The efficacy of the Storz Miller
1 video laryngoscope in a simulated infant difficult intubation. Anesth
Analg. 2009;108:17831786.
309. Redel A, Karademir F, Schliterlau A, et al. Validation of the Glidescope
videolaryngoscope in pediatric patients. Paediatr Anaesth. 2009;19:
667661.
310. Vincent RD, Wimberly MP, Brockwell RC, Magnuson JS. Soft palate
perforation during orotracheal intubation facilitated by the Glidescope
videolaryngoscope. J Clin Anesth. 2007;19:619621.
311. Asai T, Enomoto Y, Shimizu K, et al. The Pentax-AWS video-laryngoscope: the first experience with one hundred patients. Anesth Analg.
2008;106:257259.
312. Baraka A. Jet ventilation via the suction port during fiberoptic
bronchoscopy in a child [letter]. Paediatr Anaesth. 1997;7:8788.
313. Weiss M, Gerber AC, Schmitz A. Continuous ventilation technique for
laryngeal mask airway removal after fiberoptic intubation in children.
314. Stricker PA, Fiadjoe JE, McCloskey JJ. Additional measures to facilitate
fiberoptic guided tracheal intubation through the classic laryngeal mask
airway in children. Paediatr Anaesth. 2009;19:410411.
315. Cain JM, Mason LJ, Martin RD. Airway management in two newborns
with Pierre Robin sequence: the use of disposable vs multiple use LMA
for fiberoptic intubation. Paediatr Anaesth. 2006;16:12741276.
316. Stile CM. A flexible bronchoscope for endotracheal intubation of infants.
Anesth Analg. 1974;53:10171019.
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317. Alferry DD, Ward CF, Harwood IR, et al. Airway management for a neonate with congenital fusion of the jaws. Anesthesiology. 1979;51:340342.
catheter and tracheal intubation fiberscope. Paediatr Anaesth. 2001;
11:618621.
319. Audenaert SM, Montgomery CL, Stone B, et al. Retrograde-assisted
fiberoptic tracheal intubation in children with difficult airways. Anesth
Analg. 1991;73:660664.
320. Goskowicz R, Colt HG, Voulelis LD. Fiberoptic tracheal intubation using
a nipple guide [letter]. Anesthesiology. 1996;85:12101211.
321. Gutstein HB. Use of the Bullard laryngoscope and lightwand in pediatric
patients. In: Riazi J, editor. The Difficult Pediatric Airway. Anesthesiol
Clin North Am. Philadelphia: WB Saunders; 1998. pp. 795812.
322. Xue FS, Liu H-P, Liao X, Xiong J. Use of Trachlight to facilitate the
insertion of Proseal laryngeal mask airway in children. Paediatr Anaesth.
2009;19:704706.
323. Xue FS, Liu JH, Zhang YM, Liao X. The lightwand-guided digital intubation in newborns and infants with difficult airways. Paediatr Anaesth.
2009;19:702704.
324. Cook-Sather SD, Schreiner MS. A simple homemade lighted stylet for
neonates and infants: a description and case report of its use in an infant
with the Pierre Robin anomalad. Paediatr Anaesth. 1997;7:233235.
325. Nishiyama T, Matsukawa T, Hanaoka K. Safety of a new lightwand device
(Trachlight): temperature and histopathological study. Anesth Analg.
1998;87:717718.
326. Rehman MA, Schreiner MS. Oral and nasotracheal lightwand guided
intubation after failed fibreoptic bronchoscopy. Paediatr Anaesth.
1997;7:349351.
327. Jansen AH, Johnston G. The Shikani Optical Stylet: a useful adjunct to
airway management in a neonate with popliteal pterygium syndrome.
328. Xue FS, Liao X, Zhang YM, Luo MP. More maneuvers to facilitate
endotracheal intubation using the Bonfils fiberscope in children with
difficult airways [2 letters]. Paediatr Anaesth. 2009;19:418421.
329. Bein B, Wortmann F, Meybohm P, et al. Evaluation of the pediatric
Bonfils fiberscope for elective endotracheal intubation. Paediatr Anaesth.
2008;18:10401044.
330. Vlatten A, Soder C. Airtraq optical laryngoscope intubation in a
5-month-old infant with a difficult airway because of Robin sequence.
331. Singh R, Singh P, Vajifdar H. A comparison of Truview EVO2 laryngoscope

with the Miller blade in neonates and infants. Paediatr Anaesth.
2009;19:338342.
332. Baraka A, Muallem M. Bullard laryngoscopy for tracheal intubation in
a neonate with Pierre-Robin syndrome. Paediatr Anaesth. 1994;4:
111114.
333. Brown RE Jr, Vollers JM, Rader GR, et al. Nasotracheal intubation in a
child with Treacher Collins syndrome using a Bullard intubating
laryngoscope. J Clin Anesth. 1993;5:492493.
334. Shulman GB, Connelly NR, Gibson C. The adult Bullard laryngoscope
in paediatric patients. Can J Anaesth. 1997;4:969972.
335. Borland LM, Swan DM, Leff S. Difficult pediatric endotracheal
intubation: a new approach to the retrograde technique. Anesthesiology.
1981;55:577578.
336. Diaz JH, Guarisco JL, LeJeune FE. A modified tubular pharyngolaryngoscope for difficult pediatric laryngoscopy [letter]. Anesthesiology.
1990;73:357358.
337. Sessler DI, Badgwell JM. Exposure of postoperative nurses to exhaled
anesthetic gases. Anesth Analg. 1998;87:10831088.
338. Amar D, Brodman LE, Winikoff SA, et al. An alternative oxygen delivery
system for infants and children in the postanaesthesia care unit. Can J
Anaesth. 1991;38:4953.
339. Frey B, McQuillan PJ, Shann F, Freezer N. Nasopharyngeal oxygen
therapy produces positive end-expiratory pressure in infants. Eur J
Pediatr. 2001;160:556560.
340. Jorgensen NH, Messick JM, Gray J, et al. ASA monitoring standards and
magnetic resonance imaging. Anesth Analg. 1994;79:11411147.
341. Kross J, Drummond JC. Successful use of a Fortec II vaporizer in
the MRI suite: a case report with observations regarding magnetic
fieldinduced vaporizer aberrancy. Can J Anaesth. 1991;38:1065
1069.
342. Zimmer C, Janssen MN, Treschan TA, Peters J. Near-miss accident
during magnetic resonance imaging by a flying sevoflurane vaporizer
due to ferromagnetism undetectable by handheld magnet. Anesthesiology. 2004;100:12391230.
343. Bryan YF, Templeton TW, Nick TG, et al. Brain magnetic resonance
imaging increases core body temperature in sedated children. Anesth
Analg. 2006;102:16741679.
344. Machata AM, Willschke H, Kabon B, et al. Effect of brain magnetic
resonance imaging on body core temperature in sedated infants and
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Induction of Anesthesia
Cengiz Karsli and Lisa A. Isaac
INTRODUCTION
The unpredictable nature of small children and the unique
characteristics of pediatric anatomy and physiology create a
genuine challenge for those contemplating induction of anesthesia
in these young patients. Indeed, the process of induction may well
be the most critical moments of a childs anesthetic and, for this
reason, meticulous preparation and expertise are essential. The
approach to induction of anesthesia depends on the age and the
health status of the child, as well as the nature (type and urgency)
of the surgery.
The anesthesiologist must formulate a plan for the anesthetic
including the induction, but may also need to revert to back-up
plans in the event of a rapidly changing clinical situation (e.g.,
the child who suddenly becomes uncooperative). Whatever
the clinical situation, the goals for induction are similar: (1) an
atraumatic separation from parents if possible; (2) a cooperative
patient at the time of induction; (3) a smooth and uneventful
induction sequence; (4) establishment and maintenance of stable
respiratory and hemodynamic values during induction; and
(5) sleep, analgesia, and relaxation.
PREPARATION AND PLANNING

FOR INDUCTION
Before any encounter with a patient, the anesthesiologist will have
established a mental blueprint of the induction sequence. This
preliminary framework will be formulated after a review of the
operating room schedule. Critical pieces of information include
patient age and weight, emergency versus elective surgery, ambulatory surgery patient versus an inpatient, and finally, the nature
of the surgery. With this information, issues such as the need for
tracheal intubation, prolonged anesthesia, postoperative pain
management, ventilation, and the need for intensive care support
can be determined and planned before induction. Once these
initial plans have been formulated, a more refined version can
be developed after the preoperative encounter with the patient
and parents. Although the induction sequence may take as little
as 3 to 5 minutes, the preparation may be substantially longer.
Preoperative assessment and preparation of the child is covered
in Chapter 36.
This chapter details the tools required to provide a safe and
efficient anesthetic induction for the pediatric patient. Areas
covered include (1) operating room preparation; (2) strategies to
maintain patient cooperation; (3) the clinical use of induction
agents; (4) adjuvant drugs for anesthetic induction; (5) monitoring
39
C H A P T E R
in pediatric anesthesia; and (6) induction strategies for a variety of

clinical situations.
Operating Room Preparation

Appropriate preparation of the operating room is essential
and depends on the patients size and clinical status, surgical
procedure, and method of anesthetic induction and subsequent airway management. The anesthetic machine and monitors
should be checked and ventilator settings adjusted to suit the
patients size (See Chapter 42). Appropriately sized masks should
be available, as well as a selection of oral airways. A properly sized
functioning laryngoscope and blade should be placed on the
anesthetic machine, along with appropriately sized endotracheal
tubes and stylets.
Drugs that should be drawn up and labeled include those
planned for use during anesthetic induction as well as emergency
medications such as succinylcholine and atropine. In addition,
resuscitation drugs should be available in the operating room,
including epinephrine, calcium, and sodium bicarbonate. Because
the small child has a much larger body surface areatomass ratio,
the operating room must be kept at an appropriate temperature to
avoid hypothermia. Other methods to maintain the patients body
temperature may also be required, including overhead warmers,
forced-air warming blankets, warmed linen, and operating table
warming pads (See Chapter 38).
Equipment necessary to secure venous access, along with
suitable tubing and intravenous (I.V.) fluid delivery devices,
whether passive (gravity feed) or active (infusion pump), must be
prepared. Finally, a qualified assistant should be available to help
the anesthesiologist with both airway management and securing
venous access. In certain circumstances (e.g., airway surgery or
the critically ill child), the surgeon should also be ready in the
operating room before induction.
Parental Presence
One of the main goals of the pediatric anesthesiologist is to
provide as smooth a perioperative course as possible. This aim is
becoming increasingly important as awareness of and attempts
to prevent postoperative behavioral upset are increasing. There
are many ways to accomplish this goal, which is facilitated by a
multidimensional approach. After establishing a trust and rapport
with the child and the parents, there are several options to improve
patient acceptance and compliance, which may potentially improve postoperative well-being.
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The perioperative period is a very stressful event for most

children and their parents. Preoperative preparation, parental
presence at induction of anesthesia, and preoperative sedatives/
anxiolytics are methods of allaying patient anxiety. Many pediatric
centers have preoperative videos or guided tours to familiarize
the outpatient with the hospital environment. This may help to
alleviate the anxiety associated with an unfamiliar environment,
especially in preschool children, and to prepare them for the plans
for induction and separation.1
Parental presence at induction of anesthesia has been studied
as a method of reducing the childs anxiety associated with separation and fear of the unknown. Anxiety experienced during
separation from parents before induction of anesthesia is associated with negative postoperative behavioral changes.2,3 It is
unknown whether this association is causative. Studies have
looked at parental presence to reduce childrens anxiety at induction and found that reduction in childrens anxiety is variable.
Children who were older than 4 years or those with a parent with
a low level of anxiety benefited from parental presence during
induction.4 An anxious parent is unlikely to benefit the child at
induction more than separation before induction,5 and in fact,
only a calm parent appears to be of benefit to the anxious child.6
In the adequately sedated child, parental presence for induction
is not necessary, because it has no effect on the childs level of
anxiety.7 Despite this, many parents who are invited or request to
be present feel that their presence is helpful to their child.8 Parental
presence at induction of anesthesia demands careful, directed
instruction to the family. Parental presence in conjunction with
directed preoperative preparation has been shown to be helpful
for reduction of preoperative anxiety in the child and the parent
and to improve postoperative outcomes such as time to discharge
and pain medication requirements.9 Parental presence at induction is not always beneficial, and in cases in which the parents
cannot, or prefer not to, be present, preoperative pharmacologic
sedation may be indicated (See Chapters 30 and 37).
Preoperative Sedation
The ideal preoperative sedative should (1) be painless and easily
accepted; (2) have a rapid onset of anxiolysis; (3) have minimal
side effects; (4) have a short duration of action to reduce postoperative sedation and delay of discharge; and (5) prevent
postoperative anxiety and secondary behavioral disturbances
related to anesthesia and surgery.
Midazolam is a commonly used preoperative anxiolytic.
Advantages include its relatively rapid onset (1530 min orally,
510 min intranasal/sublingual) and short duration of action
(peak 30 min, duration 12 h). It is effective in improving
cooperation at induction and decreasing agitation and crying
at parental separation in doses of 0.5 to 0.75 mg/kg orally or
sublingually,1013 although it may delay discharge and have
limited efficacy in up to 14% of younger and extremely anxious
patients.14 Bioavailability is significantly decreased after oral
dosing, and hence, the difference in dosing compared with that of
the I.V. route.
I.V. midazolam can be given to the child with established I.V.
access in a dose of 0.05 to 0.1 mg/kg. Rectal midazolam (0.5 mg/
kg) and intranasal midazolam (0.20.3 mg/kg) are also effective.
In a study comparing intranasal midazolam to intranasal
sufentanil, Karl and coworkers found that both were effective
sedatives, but that midazolam was preferable owing to a shorter

duration of action and lack of ventilatory depression. A drawback
of intranasal midazolam is its bitter taste and discomfort on
insertion.15
Diazepam is an alternative to midazolam. The average oral dose
is 0.1 to 0.5 mg/kg and rectally 1 mg/kg. Peak concentrations after
oral administration occur after 15 to 30 minutes in children, and
after rectal administration, within 20 minutes. Its primary
disadvantage is its long half-life, particularly in patients with
immature or altered hepatic function. Lorazepam, like diazepam,
has a slow onset of action and a long half-life but is well tolerated
orally at a dose of 0.05 mg/kg to a maximum of 4 mg.
Oral ketamine is well tolerated by children and does not have
the bitter taste associated with midazolam. At a dose of 6 mg/
kg, it produces sedation within 10 to 20 minutes and has few
significant side effects in healthy children, although dose-related
sialorrhea, nystagmus, random limb movements, and tongue
fasciculations are possible.16,17 Preoperative sedation with oral
ketamine may delay discharge compared with midazolam.11
There have been rare reports of postoperative dysphoria secondary to ketamine, although these studies involved small patient
populations. The addition of a benzodiazepine seems to eliminate
this side effect. Intranasal ketamine, in a dose of 3 mg/kg, is easily
accepted by the pediatric patient, with no increase in discharge
time when compared with placebo.18 It produces a dissociative
state in most patients within 4 to 12 minutes of administration.
Rectal ketamine, in a dose of 3 mg/kg, was not as effective as midazolam 0.5 mg/kg or the combination of ketamine and midazolam.19 However, the dose of ketamine used in this study may not
have been large enough for adequate comparison.
Rectal thiopental, in a dose of 35 mg/kg, works as well as or
better than 0.5 mg/kg of oral midazolam20 but delays recovery.
This dose of thiopental causes sedation in 30 minutes and lasts
for at least 45 minutes.21 Pentobarbitone has a bitter taste, but it
has been used as a preoperative sedative with good results, in doses
of 3 mg/kg orally.22 It produces sedation in 90 to 120 minutes.
Methohexital has a shorter duration of action than thiopental,
and rectal dosing for sedation is 20 to 30 mg/kg. Sedative effects
are seen within 10 to 15 minutes and last approximately 1 hour.
Absorption is variable, and patients given larger doses must be
monitored carefully for loss of airway reflexes.
Clonidine has seen a recent resurgence in popularity. In studies
of healthy pediatric patients, clonidine 4 g/kg orally, in combination with atropine 0.03 mg/kg orally, provided better sedation
for separation from parents, acceptance of the mask, attenuation
of the hemodynamic response to intubation,23 and postoperative
analgesia,24 than clonidine 2 g/kg, diazepam 0.4 mg/kg, or
placebo. Compared with oral clonidine 4 g/kg, the intranasal
use of clonidine had equivalent acceptance and similar onset of
action (47 min vs 38 min for oral formulation).25 Compared with
midazolam, clonidine has a slower onset of action; however, it may
offer superior sedative effects.26 It has also been used to facilitate
controlled hypotension and may improve postoperative pain
control.27
More recently, dexmedetomidine has been used in an
intranasal formulation28 with sedating effects equivalent to those
of oral midazolam 0.5 mg/kg. It was fairly well tolerated, with none
of the patients complaining of pain on insertion. However, this
deserves further study, because I.V. dexmedetomidine has
been associated with significant bradycardia and hypotension or
hypertension.
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CHAPTER 39
Oral transmucosal fentanyl citrate has been studied for use
as a preoperative sedative in children. In doses of 20 mg/kg or
more, the incidence of nausea and vomiting both before induction
and postoperatively seems to be very high. In an attempt to
decrease these side effects, a lower dose has been used (15 mg/kg).
However, a recent study demonstrated that this did not provide
adequate preoperative sedation.29
I.V. Induction Agents

With the use of sedative premedication and topical local anesthetic
agents such as EMLA (eutectic mixture of local anesthetics) or
Maxilene, I.V. induction in the elective patient has become
increasingly easy. Although topical anesthetics may be applied to
virtually any pediatric patient, it is particularly useful in the sick
child. Currently, the most common I.V. induction agents for
infants and children are propofol and thiopental (See Chapter 23).
Other agents frequently used include ketamine, methohexital,
etomidate, and midazolam.
Propofol is a rapid-onset, ultrashort-acting induction agent,
administered in a dose of 3 to 5 mg/kg intravenously. Infants 1 to
6 months of age may require up to 7 mg/kg for loss of consciousness, whereas neonates and older children usually require 4 to
5 mg/kg. Unconsciousness and apnea are most often produced in
less than 30 seconds, and awakening is more rapid and complete
than with thiopental or midazolam.30,31 However, despite the
addition of lidocaine ( 1 mg/kg), there is still a high incidence
of pain on injection, particularly in veins on the dorsum of the
hand.31,32 Propofol has been used as a mixture with thiopental in
adults to decrease the pain on injection, with more rapid emergence
than with thiopental alone.33 New medium-chain triglyceride/longchain triglyceride formulations may decrease pain on injection,34
whereas diluting this formulation of propofol to 5 mg/mL may
further decrease pain.35 Propofol is equally effective for a rapidsequence induction,36 but it has a greater incidence of hypotension
secondary to decreased systemic vascular resistance.30,37 In comparison with thiopental, propofol is better at attenuating the
hemodynamic response to intubation.36
Thiopental is the I.V. induction agent with the longest history
in pediatric use. It is an ultrashort-acting barbiturate, with a rapid
distribution half-time. It is administered in a dose of 3 to 5 mg/kg
intravenously in neonates and older children and as high as
8 mg/kg intravenously in infants 1 to 6 months of age. It may cause
a decrease in cardiac output and systolic blood pressure, although
these effects are less than those seen with propofol.3740 Thiopental
may cause delayed awakening relative to methohexital41 and
propofol.31,36
Methohexital is also a short-acting barbiturate that has a faster
onset of action and more rapid distribution than thiopental. It is
given in I.V. doses of 2 to 3 mg/kg for induction, and at this dose,
awakening is faster than with thiopental.41 Its major drawbacks,
however, include a high incidence of excitatory phenomena
(involuntary movements, hiccoughing) on induction. In fact,
when methohexital is administered as a continuous infusion,
it is associated with postoperative seizures in a full one third
of patients.42
Ketamine is unique in its analgesic properties and tends to
maintain airway reflexes and ventilation more than propofol
or thiopental in equipotent doses.43 In doses of 1 to 2 mg/kg
Induction of Anesthesia 671
intravenously, it induces anesthesia rapidly and is as effective as

halothane in preventing experimentally induced bronchospasm
in dogs.44 It is particularly useful, therefore, in asthmatics and in
those patients who do not require tracheal intubation but in whom
preservation of spontaneous ventilation is desirable. Another
advantage is that it maintains hemodynamic stability in hypovolemic patients who cannot be adequately resuscitated before
induction, provided they have not already been maximally sympathetically stimulated. Ketamine can be used in most pediatric
patients with cyanotic heart disease, even those with elevated
pulmonary arterial pressure.45 Major side effects include dosedependent sialorrhea, nystagmus, random limb movements, and
tongue fasciculations.16,17 Emergence delirium can be attenuated
by the co-administration of benzodiazepines. Unfortunately,
ketamine can increase cerebral blood flow and intracranial
pressure (ICP) in the presence of intracranial pathology. Studies
in adults have demonstrated that this increase may be blunted
if ketamine is preceded by the administration of thiopental
or midazolam.46
Etomidate may be used as an alternative to thiopental in the
hemodynamically unstable patient. Its advantages include a very
stable hemodynamic profile, protection from cerebral ischemia,
decreases in intracranial and intraocular pressures (IOPs), and
minimal histamine release. After an I.V. induction dose of 0.3 mg/
kg, unconsciousness is achieved as quickly as with thiopental.
Apart from a minimal decrease in systemic vascular resistance,
cardiovascular variables remain essentially unchanged. The main
disadvantage of etomidate is adrenocortical suppression. Although
adrenal insufficiency has been reported in patients receiving
etomidate as a continuous infusion, many feel that clinically
significant adrenal suppression is unlikely when used as an
induction agent.47 Other disadvantages include pain on injection,
a high incidence of myoclonus, potentiation of seizures in
epileptics, and the lack of blunting of the sympathetic response
to intubation.
Intramuscular Induction Agents

Ketamine 4 to 5 mg/kg intramuscularly is useful as an induction
agent, particularly in the uncooperative combative child or
adolescent. The child will be deeply sedated within 3 to 4 minutes
after receiving this dose. The addition of intramuscular atropine,
0.02 mg/kg, will help decrease airway secretions. In one study, the
use of a lower dose of ketamine (2 mg/kg) was not associated with
unpleasant dreams, emergence phenomena, or excessive salivation and resulted in calm, cooperative children for halothane
induction.48 However, in the larger, extremely uncooperative
child, this dose may not be adequate. Intramuscular midazolam
0.05 mg/kg can also be added to reduce the chance of emergence
delirium. However, respiratory depression and loss of airway
reflexes are possible.
Rectal Induction Agents

Ketamine, methohexital, and thiopental can be used rectally for
induction of anesthesia. Ketamine is used in doses of 6 to 10 mg/kg.
Induction with ketamine results in delayed discharge. Methohexital
(2530 mg/kg) produces no significant hemodynamic effect except
an increase in heart rate.49 Thiopental (30 mg/kg) has a very long
half-life.
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Inhalation Induction Agents

Inhalation induction is the most common method of anesthetic
induction in children (See Chapter 21). It is generally rapid, painfree, and well-tolerated. Uptake and equilibration are particularly
rapid in neonates, infants, and small children compared with
adults because of the (1) increased minute ventilationto
functional residual capacity ratio; (2) lower blood-gas partition
coefficient; (3) greater cardiac output per kilogram of body
mass; and (4) relatively higher blood flow to vessel-rich groups
(including brain). These factors frequently allow for a smooth,
rapid, and nonstressful anesthetic induction or, at least, decrease
the duration of a sometimes unpleasant experience for the child.2,50
Desflurane, an inhalational agent with a very pungent smell, is
unsuitable for induction because of a high incidence of coughing,
breath-holding, and laryngospasm whether used with or without
preoperative sedation.51 Although desflurane causes a decrease in
blood pressure during anesthetic maintenance,52 it has been
associated with hypertension and tachycardia (>120% baseline
values) with rapid increases in inspired concentration.51 Its advantages include a faster washout, shorter emergence times,53 and
minimal metabolism.
Sevoflurane has low pungency that allows a rapid and smooth
induction of anesthesia. If using a high-dose induction technique
(beginning at 8% until loss of consciousness, then decreasing to
1 to 2 minimal alveolar concentration [MAC]), it decreases
patient struggling compared with induction with 5% halothane.54
Although loss of consciousness is achieved more rapidly with
sevoflurane, inhalation induction with halothane yields satisfactory intubating conditions in a shorter period of time than with
sevoflurane.55,56 Hemodynamic effects are similar to those of
isoflurane, although sevoflurane is associated with less tachycardia.
Arrhythmias are uncommon with sevoflurane, and it produces less
myocardial sensitization to epinephrine than halothane.57 It also
causes less myocardial depression than halothane when used for
induction of anesthesia.58 The respiratory effects of sevoflurane are
similar to those of isoflurane. Although it has been shown to more
rapidly decrease minute ventilation and respiratory frequency in
infants and children compared with halothane, end-tidal carbon
dioxide concentrations are maintained.59 Sevoflurane appears to
be effective in reversing bronchoconstriction.60 Concerns about
the effect of sevoflurane and the production of compound A have
limited its use in low-flow anesthesia. Although there have been
no reports of compound A toxicity in children, the U.S. Food and
Drug Administration (FDA) has recommended that sevoflurane
should not exceed 2 MAC/h at flow rates of 1 to 2L/min and that
fresh gas flow rates less than 1 L/min are not recommended.61
Emergence delirium has been more of a problem with sevoflurane
than with other inhalational agents. This might be related to a more
rapid recovery, but the cause is not yet clear. Several drugs have
been administered to reduce the incidence of emergence agitation
with sevoflurane, including ketamine, clonidine, midazolam, and
propofol with some effect. Recently, sevoflurane has been studied
in pediatric patients with cyanotic heart disease and was found to
increase the incidence of hypotension compared with ketamine.62
Halothane has been used for decades and has many advantages
for pediatric anesthesia. The primary advantage is its long history
of safety and tolerability. Halothane depresses airway reflexes,
causes some bronchial dilatation, and is relatively nonirritant.
This makes it a useful agent for asthmatic patients. Disadvantages
include sensitization of the myocardium to exogenous catechola-
mines; thus, epinephrine infiltration must be limited to less than

10 g/kg and given no more frequently than every 20 minutes.63
Halothane is also a direct myocardial depressant and may cause
dose-dependent bradycardia and hypotension, even in healthy
patients. Of all the potent inhalation agents currently in use,
halothane causes the greatest increase in cerebral blood flow and
ICP and the smallest reduction in cerebral metabolic oxygen
requirements (CMRO2) and, as such, may not be ideal for patients
with intracranial hypertension. Halothane hepatitis has been
described in adults; however, the true incidence in children is
unclear but has been implicated in isolated cases.
Isoflurane is less well tolerated for inhalation induction than
halothane. It has a more pungent odor, is more irritating to the
airway, and may cause more excitement during induction than
halothane. It also causes myocardial depression, but hypotension
from isoflurane is related to peripheral vasodilatation more than
to its effect on myocardial contractility. It has less tendency to
cause bradycardia than halothane and, in fact, may cause reflex
tachycardia.64 Emergence tends to be faster than with halothane
and depends on the duration of exposure.65 As such, isoflurane is
more useful for maintenance than induction of anesthesia. It is also
the inhalation agent of choice for patients with intracranial hypertension. Isoflurane causes a dose-dependent reduction of CMRO2
and does not cause increases in cerebral blood flow or ICP.
Nitrous oxide (N2O) is used as commonly in children as it is in
adults. Its pharmacology is discussed in Chapter 20. With a MAC
of 105%, it is limited as a sole anesthetic agent but is a relatively
potent analgesic. It causes a decrease in heart rate, blood pressure,
and cardiac output similar to equianesthetic concentrations of
isoflurane or halothane.66 Although increases in pulmonary artery
pressure have been demonstrated in adult patients, N2O has
minimal effect on infants with normal and elevated pulmonary
artery pressures.45 With its low blood-gas solubility, N2O can
leave the blood to enter an air-filled cavity approximately 34 times
faster than nitrogen can leave the cavity and, thus, is of concern
in all-closed, air-filled spaces such as a pneumothorax, bowel
obstruction, or tympanoplasty. The most common use of N2O is
as an adjunct to other anesthetic agents. It may be used in a
balanced anesthetic technique, in combination with an opioid and
(usually) a muscle relaxant. N2O is also very useful in decreasing
the requirements of the potent inhalation agents. It has an additive
effect on the MAC of the inhalational agents; however, it seems to
decrease their requirements to varying degrees. For example, it
appears that 60% N2O decreases the MAC of desflurane by only
25%, as opposed to the expected 55% (given a MAC of N2O of
105% in children).67 Concerning anesthetic induction in the
pediatric patient, N2O is commonly used as (1) an analgesic when
securing I.V. access in the awake child; (2) a precursor to one of the
potent volatile agents during inhalation induction; and (3) a
co-induction agent to increase the speed of induction with
halothane. The risk of using N2O during induction is the faster
and more profound desaturation occurring with breath-holding,
airway obstruction, and laryngospasm, if used without previous
preoxygenation.
Xenon is an inert gas, first used in humans in 1951.68 It is
smooth and rapid for inhalational induction, with rapid emergence, regardless of the duration of anesthesia. Side effects appear
to be minimal but may include increased airway resistance at high
inspired concentrations,69 and it may cause a greater incidence of
nausea and vomiting than propofol-based anesthesia70 despite its
5-hydroxytryptamine type 3 receptor antagonism. Importantly,
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TABLE 39-1. Recommended Intubating Doses of Muscle Relaxants

Agent
Atracurium
Cis-atracurium
Mivacurium
Pancuronium
Rocuronium
Succinylcholine
Vecuronium
Dose, mg/kg, I.V.

0.30.5
0.080.2
0.20.4
0.1
0.51.2
1.52.0
0.10.4
Onset
Duration
Effects on CVS
Intermediate
Slow to intermediate
Intermediate
Intermediate
Rapid
Rapid
Intermediate
Intermediate
Intermediate to long
Short
Intermediate to long
Intermediate
Short
Intermediate
Rare hypotension
None
Rare hypotension
Tachycardia, hypertension
Minimal
Occasional bradycardia
None
CVS = cardiovascular system.

Adapted from Fisher DM. Neuromuscular blocking agents in paediatric anaesthesia. Br J Anaesth. 1999;83:5864.
it does not appear to trigger malignant hyperthermia. Xenon

is thought to inhibit N-methyl-D-aspartic acid (NMDA) receptor
signaling to induce anesthesia and appears to be neuroprotective via an antiapoptic mechanism. To date, it has not found its
way into mainstream anesthesia owing to its high cost and
limited availability. Although approved for use in some European
countries, the cost is very high and delivery is difficult because
specialized closed circuit anesthetic machines are required to
deliver the gas.
Neuromuscular Blocking Agents

Neuromuscular blocking agents are used for muscle relaxation to
facilitate abdominal and thoracic surgery and tracheal intubation,
to ensure immobility during critical times in surgery, and to
facilitate mechanical pulmonary ventilation (See Chapter 27).
They also facilitate the use of minimal effective doses of inhalation
anesthetics. Neonates, infants, and children respond differently
to neuromuscular blocking agents. Age-related differences in
volumes of distribution and clearance account for variability
in drug onset and duration. The ideal neuromuscular blocking
agent (which does not as yet exist) would be of rapid onset, short
duration, and devoid of side effects. Table 391 lists muscle
relaxants commonly used for induction in pediatric patients.
Succinylcholine has been in use for many years. Well known for
its rapid onset and short duration, it is the only depolarizing muscle
relaxant in clinical use. However, there are many contraindications
to its use. These include patients with muscular dystrophy and
other disorders of the neuromuscular junction; patients with burns
during the hypermetabolic phase; and other states with muscle
breakdown; acute hyperkalemia, and malignant hyperthermia.
There have been reports of cardiac arrest after the administration
of succinylcholine in patients with undiagnosed muscular dystrophy. Masseter muscle rigidity, or masseter spasm, associated
with succinylcholine after inhalational induction,71 has raised
concern about the possibility of malignant hyperthermia in these
patients. There is no absolute way to prove the presence or absence
of malignant hyperthermia in these patients, because the gold
standard of testing, the muscle biopsy, is not 100% specific. Other
side effects include myalgia and increased intragastric, intracranial,
and IOP. Severe bradyarrhythmias or asystole may be seen when
two doses of succinylcholine are given within 5 minutes of one
another, particularly in the absence of atropine premedication.
Table 392 outlines the possible side effects of succinylcholine.
One cannot ignore the advantages of succinylcholine, however,
with its rapid onset and short duration of action. It is, thus, ideal for
treating laryngospasm. The I.V. dose is 1.5 to 2.0 mg/kg. It may
also be given intramuscularly, at a dose of 2.5 to 4.0 mg/kg, yielding

intubating conditions within 2 to 3 minutes.
The nondepolarizing agents differ primarily in their duration
of action and metabolism. Pancuronium causes an increase in
heart rate, and atracurium and mivacurium may cause hypotension owing to histamine release. Vecuronium, rocuronium, and
cis-atracurium do not have any significant hemodynamic effects.
Pancuronium has an intermediate onset and long duration of
action, which is prolonged in kidney failure because of its high
renal elimination. It tends to produce tachycardia and increases
systemic blood pressure in children. These effects may be advantageous when pancuronium is used in conjunction with high
doses of opioid agents. The intubating dose is less and onset times
are faster for infants than for older children.72
Atracurium and cis-atracurium, as bisquaternary benzylquinolinium diesters, are useful in renal failure because of multiple
elimination pathways, mostly independent of renal or hepatic
function and primarily by Hofmann elimination. Atracurium, an
agent of intermediate duration, is given as a bolus dose of 0.3 to
0.5 mg/kg, yielding good intubating conditions in 1.4 minutes in
children and 0.9 minute in infants.73 Infants appear to require less
atracurium than older children. Atracurium is associated with
histamine release, in a dose-dependent manner. Although higher
doses may be associated with hypotension, the amount of histamine release and the severity of reactions appear to be less in
children than in adults.74 Cis-atracurium does not cause histamine
release and is hemodynamically neutral. It is used as a long-acting
neuromuscular blocker; its duration of action is similar to that of
pancuronium.
TABLE 39-2. Possible Side Effects of Succinylcholine
Allergy/anaphylaxis
Increased intraocular pressure
Hyperkalemia
Increased intragastric pressure
Bradydysrhythmias
Increased intracranial pressure
Fasciculations
Masseter muscle rigidity
Myalgias
Malignant hyperthermia
Prolonged duration of action with pseudocholinesterase
deficiency
Modified from Bevan DR, Donati F: Muscle relaxants. In: Barash PG, Cullen BF,
Stoelting RK, editors. Clinical Anesthesia. 3rd ed. Philadelphia: LippincottRaven; 1997. pp. 388390.
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Mivacurium, structurally similar to atracurium, was developed

in the search for a short-acting nondepolarizing neuromuscular
blocker. Although it may cause histamine release, it does not seem
to be associated with clinically significant heart rate or blood pressure changes.75 Mivacurium is metabolized by plasma cholinesterases, and thus, its length of action is independent of organ
function. Its duration of action will be significantly prolonged,
however, in those patients with pseudocholinesterase deficiency.
Although its effects wear off quickly (18 min, similar to succinylcholine), it also has a slow onset of action in children, which has
limited its popularity.75 In addition, mivacuriums onset and
duration times seem to show a significant degree of interindividual
variability.76 Good intubating conditions are achieved in 1.8
and 1.1 minutes after doses of 0.2 and 0.25 mg/kg intravenously,
respectively.75,77
Vecuronium, a monoquaternary amino steroid, given in a
dose of 0.07 to 0.1 mg/kg intravenously, has a duration of 20 to
24 minutes in children and 55 minutes in infants.78 It is hemodynamically neutral and has a recovery time similar to that of
atracurium.79,80 It has been used for rapid-sequence induction, in
doses of 0.4 mg/kg; however, this results in a prolonged duration
of action.81
Rocuronium, an analogue of vecuronium, was developed in the
quest for the ideal muscle relaxant. Although it is rapid in onset
(within 60 s at a dose of 1.2 mg/kg intravenously), it does not
match succinylcholines short duration of action.82 Still suitable for
rapid-sequence induction in some situations, it is not ideal for
those in whom a careful airway assessment has revealed potential for difficulty with management. Rocuroniums duration of
action is similar to that of vecuronium, with the caveat that its
duration of action is potentiated by sevoflurane.83 Withdrawal after
injection of rocuronium is common and can be prevented by
lidocaine or remifentanil. Rocuronium can also be used via the
intramuscular route. Doses of 1 mg/kg in infants and 1.8 mg/kg in
children were found to have onset times within 2.5 and 3 minutes,
respectively, via the deltoid muscle.84 This is useful in emergency
situations, where rapid control of the airway is needed in patients
without I.V. access. It is a safe drug, with no hemodynamic effects,
and is thus useful for the hemodynamically unstable child.
Compared with succinylcholine, rocuronium has fewer side
effects, a slightly longer time to onset, and a longer duration of
action. It is minimally metabolized and is eliminated by biliary
excretion.
Rapacuronium, an amino steroidal nondepolarizing muscle
relaxant with rapid onset of action, was marketed to replace succinylcholine, but was withdrawn because of the high incidence of
bronchospasm in infants and children.85
Suggamadex may result in a change in the practice of muscle
relaxation during anesthesia. It is a modified gamma-cyclodextrin
compound that forms a water-soluble complex with steroidal
neuromuscular blocking agents, rapidly reversing the neuromuscular blocking action. This complex is renally excreted and, thus
far, appears to be devoid of significant side effects.86 As of the fall
of 2008, suggamadex was undergoing phase 3 trials.
Adjuvant Drugs for Induction

Opiates
Opioid analgesics are being used with increasing frequency in
the pediatric population (See Chapter 25). After years of avoidance because of exaggerated concerns over side effects such
as respiratory depression, these agents are becoming popular

co-induction and maintenance agents. As sole agents, the opioids
are not entirely useful because they have no intrinsic amnesic
properties. They have been used in combination with benzodiazepines and/or N2O in a balanced anesthetic technique, with
resultant excellent hemodynamic profiles in healthy children.
Opioid analgesics do not cause myocardial depression, except
when used in combination with benzodiazepines or N2O. This is
of little clinical consequence unless the child is hemodynamically
unstable or has pre-existing cardiac abnormalities. In the healthy
child, opioid agents are primarily used for postoperative pain
control and to provide intraoperative hemodynamic stability
by decreasing the requirements of the potent inhalation agents.
When used as co-induction agents, they effectively blunt the
hemodynamic response to tracheal intubation.87 All of the opioid
agonists cause dose-dependent respiratory depression. With
appropriate dosing, however, several studies have demonstrated
that narcotic agents can safely be used in young infants.8889
The fentanyl derivatives (sufentanil, alfentanil, remifentanil)
are all associated with chest wall rigidity when given rapidly in
large-bolus doses. This can be avoided with slow bolus dosing,
low initial doses, or when given as an infusion. Chest wall rigidity
can be reversed with muscle relaxation or naloxone 0.001 to 0.01
mg/kg intravenously. Opioid analgesics are bound by 1 acid
glycoproteins in the plasma, the levels of which are lower in the
newborn. As such, narcotic administration results in a higher free
fraction of drug in the first few months of life. Fentanyl has a long
history of safety and efficacy.
Fentanyl is similar to its derivatives, alfentanil, sufentanil, and
remifentanil, but with a longer half-life. It is metabolized by the
liver, and clearance increases progressively in the first year of life.
Compared with morphine, fentanyl has an intermediate duration
of action. Like other opioids, it decreases the ventilatory response
to carbon dioxide, and its I.V. formulation should be used only
with respiratory monitoring and resuscitation equipment available, particularly if used in combination with benzodiazepines
or other sedatives.88 Fentanyl 1 g/kg is equivalent to morphine
100 g/kg.
Sufentanil has a high hepatic extraction ratio and, thus, is not
cleared as rapidly in the neonate. In children aged 2 to 8 years,
clearance is approximately twice that of adults and dosing is about
1.5 times that of adults.89 Sufentanil blunts the hemodynamic
response to intubation as well as fentanyl.90 With prolonged
infusion, sufentanil has a shorter duration of action than alfentanil
or fentanyl.91 As with all opioid agents, sufentanil can cause chest
wall rigidity, particularly when injected rapidly. Because it is
approximately 1000 times more potent than morphine, sufentanil
0.1 g/kg is equivalent to morphine 0.1 mg/kg.
Alfentanil is also effective in blunting the hemodynamic
response to intubation, but it is associated with nausea and vomiting equivalent to that of remifentanil.92 Although infants younger
than 1 year have been safely anesthetized with alfentanil, there
appears to be significant pharmacokinetic variability within the
first few years of life. As such, alfentanil may be more unpredictable in the neonate and small child. Alfentanil 0.05 mg/kg is
equivalent to morphine 0.1 mg/kg, although alfentanil has a
significantly shorter duration of action.
Remifentanil is the newest synthetic opioid agent in use.
Its advantages are its rapid onset and rapid clearance, which is
independent of dose or hepatic function. Remifentanil is rapidly
metabolized by tissue and plasma esterases and, therefore, has a
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very short half-life (10 min). It provides outstanding intraoperative analgesia and hemodynamic stability, but it may not be
suitable for postoperative analgesia. In this regard, it can be used
in combination with longer-acting opioid agonists. Remifentanil
is associated with bradycardia, only partially preventable by
atropine,93 and hypotension. When combined with induction
drugs such as propofol or 5% sevoflurane, remifentanil has been
shown to provide good intubating conditions at a dose of 1 to
3 g/kg9496 Importantly, remifentanil may be associated with acute
opioid tolerance when infused for prolonged periods.97 This may
be modified by co-administration with other opioids, but this has
yet to be verified.
Morphine has the longest record of safety, despite the fact that
it may cause histamine release and has been more frequently
associated with hypotension than the other opioid agonists. These
effects are clinically irrelevant, however, in the normal, euvolemic
patient. Morphine has a much longer onset and half-life than the
fentanyl derivatives and, thus, is mainly useful for providing
analgesia into the postoperative period. Boluses of 0.05 to 0.1 mg/
kg intravenously are used in pediatric practice. Hydromorphone,
a derivative of morphine, is five times more potent than morphine,
has a similar duration of action, and may have fewer side effects
at equipotent doses. Meperidine (pethidine) is about one tenth
as potent as morphine, and at doses of 0.25 to 0.5 mg/kg intravenously, has a duration of action of 1 to 3 hours. Side effects are
similar to those of other opioid analgesics. Meperidine is contraindicated in patients receiving monoamine oxidase inhibitors, and
it has been associated with seizures when given to patients with
renal insufficiency, secondary to accumulation of the long-acting
metabolite normeperidine.
Histamine Type 2 Receptor Blockers

Since the original description of aspiration pneumonitis by
Mendelson,98 various measures have been implemented in an
attempt to prevent this complication in the patient with a suspected full stomach. Factors that increase the risk of significant
pneumonitis following aspiration include gastric pH less than 2.5
and particulate matter and large aspirate volumes (>0.4 ml/kg).
Histamine potentiates the effects of acetylcholine and gastrin,
causing an increase in the production of gastric acid. Ranitidine,
a histamine type 2 receptor blocker, acts to reduce the production
of acid in the stomach. Given intravenously at least 30 minutes
before the planned procedure, it has been shown to increase the
pH of the stomach contents in adults. Ranitidine has very few
side effects and does not cross the blood-brain barrier. Very rarely,
it may cause interstitial nephritis, a transient increase in transaminases, decrease hepatic blood flow, or a mild bradycardia. The
recommended preoperative dose is 0.5 mg/kg intravenously.
Metaclopramide
Metaclopramide has been shown to augment gastric emptying in
adults.99 Previous administration of atropine or an opioid antagonizes the effect of metaclopramide; however, this effect has not
been studied in children. Its side effects are mild and rare, particularly if given as a single dose. It may cause extrapyramidal
reactions and should, therefore, be avoided in patients receiving
phenothiazines or butyrophenones and in those with epilepsy.
It may also cause akathesia (motor restlessness), especially in
patients with renal dysfunction. Metaclopramide is contrain-
dicated in the presence of a bowel obstruction. With long-term

use, metaclopramide has been associated with glossal and periorbital edema, hirsutism, and an urticarial or maculopapular rash.
Sedation, dysphoria, agitation, and dry mouth are other effects
that can be annoying to long-term users. Metaclopramide
0.15 mg/kg intravenously can be used preoperatively to decrease
the volume of gastric contents, and this same dose has antiemetic
properties that extend into the postoperative period.
I.V. Lidocaine
I.V. lidocaine is frequently used as an adjuvant to anesthetic
induction. In this respect, it has been used (1) to blunt the intracranial and IOP increases associated with laryngoscopy; (2) to
decrease the incidence of bronchospasm in asthmatic patients; and
(3) to diminish the pain associated with propofol or rocuronium
injection.34,100102 In fact, studies looking at the effects of I.V.
lidocaine on hemodynamic variables at induction have yielded
variable results.102105 Although it has not been shown to attenuate
the hemodynamic response to intubation in nonpremedicated
healthy children, no studies have looked at its effect in children
with increased ICP. In addition, the I.V. bolus dose of lidocaine
should be lowered in infants in order to reduce the risk of severe
bradydysrhythmias.
Vagal Blockers
Atropine has been a common component of anesthetic induction
in infants and children for many years. It has been used to prevent
the bradycardia associated with succinylcholine administration,
halothane induction, and laryngoscopy. With the increasing use
of agents other than halothane and succinylcholine, the standard
use of atropine at induction has been questioned. It has been
shown to increase the heart rate during both halothane and isoflurane anesthesia, with secondary increases in cardiac output.106
Even with low doses of halothane, atropine 10 g/kg intravenously
will promote sinus rhythm and increase heart rate, systolic blood
pressure, and cardiac output.107,108 In one study, premedication
with oral atropine 40 g/kg reduced airway complications such
as breath-holding and laryngospasm in patients younger than
one year; however, the incidence of arterial desaturation was
not increased in unpremedicated infants.107 Atropine can cause
mydriasis, and it should be avoided, if possible, in patients
with acute-angle glaucoma. It crosses the blood-brain barrier
and has been implicated as a cause of postoperative restlessness,
somnolence, and anhydrosis (i.e., the central anticholinergic
syndrome).
Glycopyrrolate has been used to decrease airway secretions,
having antisialogogue properties superior to those of atropine.
At a dose of 5 g/kg intravenously, glycopyrrolate is similar to
atropine in its ability to prevent bradycardia associated with
halothane and succinylcholine use.109 It does not seem to be
as effective as atropine when given orally or by intramuscular
injection.110
Monitoring in Pediatric Anesthesia

By far the most important monitor is the presence of an
appropriately trained, vigilant physician; other monitors are
simply aids to the physician (see Part IV). It is the responsibility of
the anesthesiologist to ensure that monitoring equipment is
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available and functioning for all patients receiving any level

of anesthesia, including regional blocks and sedation. Required
equipment, according to the 2008 Canadian Anesthesiologists
Society Standards, include pulse oximetry, a blood pressure
measuring device (invasive or noninvasive), electrocardiography,
and capnography when tracheal tubes or laryngeal mask airways
(LMAs) are used.111 The standards for basic anesthetic monitoring
as accepted by the American Society of Anesthesiologists (ASA)
House of Delegates requires that qualified anesthesia personnel
shall be present in the room throughout the conduct of all general
anesthetics, regional anesthetics and monitored anesthesia
care, and the patients oxygenation, ventilation, circulation and
temperature shall be continually evaluated. Pulse oximetry has
been shown to be very effective in detecting early or minor
desaturation during anesthetic induction.112 Although it is unclear
whether a minor desaturation has clinical significance, it may
prompt the anesthesiologist to take early preventive measures,
possibly avoiding more significant desaturation. Given that
approximately 25 to 30% of healthy, elective patients younger
than 1 year desaturate to less than 90% during anesthetic
induction or venous cannulation, it is important to always monitor
oxygen saturations during induction.113115 End-tidal carbon
dioxide monitoring has been shown to be a reliable monitor
of arterial carbon dioxide and is, thus, useful in verifying adequate
ventilation in the child.116 Finally, because of the hemodynamic
effects of the various induction agents, it is clear that both
electrocardiography and blood pressure monitoring are useful
adjuncts during anesthetic induction.
Other important equipment includes a temperature monitor,
peripheral nerve stimulator, a stethoscope, and appropriate
lighting to visualize the exposed portion of the patient.
Temperature should be measured for both hypothermia
and hyperthermia. The pediatric patient is at greater risk
for hypothermia than the adult patient because of the greater
surface areatomass ratio. During surgery, heat loss is often
greater than heat production, and thermal radiation is the
most important mechanism of heat loss.117 Children, like adults,
are unable to increase their metabolic rate in response to
hypothermia when given I.V. or inhalation anesthetics.118
Perioperative effects of hypothermia include prolongation of
neuromuscular blockade and anesthetic recovery, shivering and
vasoconstriction, and a predisposition to postoperative wound
infections.119 Hyperthermia is a signal of increased metabolism,
such as from malignant hyperthermia, overzealous attempts at
heating, or a response to pyrogens.
The bispectral index (BIS) monitor measures an
electroencephalogram (EEG)derived variable in an attempt to
gauge anesthetic depth (see Chapter 75). The FDA approved BIS
monitoring in 1996 for assessing the hypnotic effects of general
anesthetics and sedatives. In 2003, the BIS was approved as a
parameter that could help to control intraoperative awareness.
However, in a prospective study involving 2000 high-risk adult
patients, BIS-guided anesthesia did not reduce the incidence of
aware-ness compared with a protocol based on end-tidal
anesthetic gas concentration. Furthermore, the use of BIS was not
associated with reduced administration of volatile anesthetic
gas.120 The authors concluded that the routine use of BIS
monitoring as part of standard practice cannot be supported.
Other monitors may be used at the discretion of the attending
anesthesiologist and will be determined by surgical and patient
factors. These include urinary catheters and invasive arterial,
central venous, and pulmonary artery pressure monitors. Placement of some of these monitors requires technical skill, especially
in small infants and neonates. Peripheral arterial lines (radial,
brachial, posterior tibial, and dorsalis pedis) are used with cannulas ranging in size from 24 gauge in the premature neonate to
20 gauge in older children. There are also a wide variety of types
and sizes of central venous catheters on the market. Except under
exceptional circumstances, these invasive monitors are usually
placed after anesthetic induction. The reader should refer to
Chapters 69 and 70 for more information.
INDUCTION TECHNIQUES
AND STRATEGIES
This section is devoted to considerations required for safe
and efficient anesthetic induction in the pediatric patient under
a variety of specific circumstances. From the healthy patient
undergoing routine surgery to the difficult airway or critically ill
child, the smooth induction of anesthesia requires knowledge
and application of pharmacology, adequate preparation, expertise,
and an understanding of the unique psychological and emotional
requirements of the pediatric patient.
The Healthy, Fasted Patient

for Routine Surgery
Once the preoperative assessment of the patient is complete,
a mental plan for anesthetic induction formulated, and the
operating room appropriately prepared, the induction sequence
begins with transportation of the child from the preoperative
holding area to the operating room. This critical phase of the
patients experience may dictate subsequent steps of the induction
process. A smooth transition from playroom to operating room
may be accomplished through playful distraction, parental accompaniment, pharmacologically, or a combination of these elements.
Parental presence and preoperative sedation have already been
discussed. The greatest amount of effort and ingenuity must be
concentrated on those children in whom separation anxiety is
most prevalent, namely, those 18 months to 6 years of age. Simple
measures to keep a child distracted during transport to the
operating room include telling a story or singing familiar songs to
the child, creative artwork along the walls, or a wagon ride to the
operating room (Figure 391).
The cooperative, calm patient will tolerate placement of
standard anesthetic monitors, particularly if done in a playful or
gentle manner. Fortunately, most children will accept the application of pulse oximetry, considered by many to be the most
valuable mechanical monitor during anesthetic induction. The
anesthesiologist must weigh the advantages of having a full complement of standard monitors applied with the potential risk of
frightening the child during this endeavor. Once the patient has
lost consciousness, all remaining standard monitors should be
applied immediately. Although adults may tend to prefer I.V. over
sevoflurane anesthetic induction,121 insertion of an I.V. catheter
tends to cause significant anxiety in the awake child. Sevoflurane
anesthesia is associated with more rapid emergence and increased
postoperative agitation in children, compared with propofol.
Despite this, there is no evidence to suggest that any one particular
method of induction is superior to another in the healthy child.122
As such, the anesthesiologists choice should be based on personal
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Figure 39-1. Wagon ride to the operating room to distract the

young child/toddler.
preference, experience and comfort, patient factors, and surgical
requirements. Regardless of the method of induction chosen, the
anesthesiologist must be prepared to adapt to a rapidly changing
situation; a planned I.V. induction may need to be converted to an
inhalation technique if the child suddenly becomes agitated or if
I.V. access cannot be secured quickly or easily.
Application of a facemask and mask induction of the pediatric
patient is not as straightforward as it is for the adult patient.
A frightened child will not voluntarily accept an anesthetic mask,
and different strategies will be required to gain the trust of the
infant, toddler, young child, and prepubescent patient. Infants and
toddlers will accept the anesthetic mask more readily when
distraction methods are used. Singing songs, pointing out pictures on the walls or ceiling, and asking the patient to blow up
the balloon are popular techniques. Distraction using video
Figure 39-2. Inhalation induction on the

lap of the anesthesiologist or parent.
has become popular in pediatric dental offices, for diagnostic

imaging procedures, and for minor surgical procedures under
local anesthetic.123 The use of this and other modalities to distract
the child during I.V. or inhalation induction is gaining popularity,
particularly as video devices become increasingly compact and
affordable.124,125 The older child will participate more readily if the
induction process is treated like a game. The child may even help
hold the space mask, blow up the anesthetic balloon, or take deep
breaths while pretending to blow out birthday candles. An appropriately sized mask should be chosen that will allow for a proper
seal without having to exert excessive pressure on the childs face.
If the child is cooperative, induction may begin with N2O and
oxygen followed by the gradual introduction of sevoflurane in an
incremental fashion.
Mask induction of the anxious child may be made easier if the
patient is induced in the sitting position, either on the table or on
the lap of a parent or the anesthesiologist (Figure 392). If a parent
is present for anesthetic induction, a system must be in place to
escort this parent back to the waiting room once the child begins
to lose consciousness. Compared with the conventional tidal
volume technique of inhalation induction, a vital capacity
induction with sevoflurane 7% in 50% O2/N2O was preferred by
children older than 5 years.126 This technique may be particularly
useful in the anxious but cooperative child and is not associated
with an increased incidence of side effects compared with tidal
volume induction. Either technique of anesthetic induction
may be combined with a bear hug technique of applying the
facemask, in which the childs arms are gently restrained and
the upper body is supported (Figure 393). As the patient loses
consciousness, the remaining monitors are applied and induction
of anesthesia proceeds with the patient in the supine position.
Increasing depth of anesthesia is indicated by regular, rhythmic,
and diaphragmatic breathing, loss of limb muscular tone, and
conjugate eye gaze with reactive midsized pupils. Careful monitoring of the patients vital signs, respiratory pattern, and heart
sounds is important if an anesthetic overdose is to be avoided. If
and when the patient becomes apneic, it is vitally important that
the anesthetic machine and monitors be quickly scanned for
appropriate anesthetic delivery and monitoring of vital signs.
A particularly hazardous situation is forgetting to decrease the
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Figure 39-3. The bear hug technique of mask induction of the

anxious child. The childs upper limbs are gently restrained and
the upper body supported during inhalation induction.
inspired concentration of the anesthetic agent once the patient
becomes apneic and intermittent positive-pressure mask ventilation is instituted during induction. At any point during the
induction sequence, the airway may become partially or completely obstructed. The most likely cause is backward displacement of the tongue, and simple measures such as jaw thrust, chin
lift, two-person technique. and oral airway insertion (provided
anesthetic depth is adequate) will almost always overcome the
obstruction. In children. a proper jaw-thrust maneuver requires
that the forward thrust be applied at the head of the mandible
(behind the ears, Figure 394A) and not at the angle of the mandible (see Figure 394B).
Securing venous access in the pediatric patient (whether awake
or anesthetized) presents the anesthesiologist with challenges
unique to this age group. Methods to increase the chances
of successful I.V. access include using sites that are reliable (Table
393), keeping the room warm, using warm packs, and EMLA
or Ametop. However, the most important factor is having an
experienced person obtain venous access. A tourniquet may be
Figure 39-4. Correct (A) and incorrect (B) techniques of jaw

thrust in the pediatric patient. The index or middle fingers are
placed behind the head of the mandible (A) and not the angle
of the mandible (B).
applied using an Esmarch drain, commercially available silicone
tourniquets (latex-free), or the trained assistants hand. The latter
may be preferable, because the experienced assistant can provide
an excellent tourniquet for venipuncture, keep the limb immobilized, and distract the awake child simultaneously. This may
be combined with a single-hand technique of venipuncture,
which allows the anesthesiologist to secure venous access while
maintaining the patients airway (Figure 395). For neonates and
small infants, an elastic band around the forehead makes for an
effective tourniquet for scalp vein cannulation. Proper lighting is
TABLE 39-3. Reliable Sites for Venous Access

Site
Cephalic vein tributariesa
Lateral aspect of wrist
Dorsum of hand
Dorsum of wrist
Palmar wrist veins
Antecubital veins
Great saphenous veina
Dorsum of foot
Scalp veins
Femoral vein
Internal jugular vein
Subclavian vein
a
Comment
Internists vein. Beware radial artery in anatomic snuffbox.
Over third ray, or between third and fourth rays.
Relatively fixed and easy to cannulate at bifurcation.
Small veins, painful cannulation, beware median nerve deep to veins. More frequently used in neonates.
Deeper and more difficult than in adults. Beware brachial artery puncture.
Superficial over or just anterior to medial malleolus, runs cephalad posteromedial to tibia.
Multiple tributaries, many are small and tortuous.
May be best option in premature neonates. Use elastic band tourniquet. Fragile veins, easily dislodged,
beware interstitial or extradural infiltration.
Beware nerve, artery, acetabular puncture.
Requires central venous catheter. Beware damage to major nerves, carotid artery, apex of lung, trachea.
Risk of pneumothorax, subclavian artery puncture.
Often successful with a blind technique.

Adapted in part from Stovroff M, Teague WG. Intravenous access in infants and children. Pediatr Clin North Am. 1998;45:13731393.
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Figure 39-5. Single-hand technique of venipuncture. The

anesthesiologist is able to secure venous access while managing
the patients airway. The assistant provides a tourniquet, immobilizes the limb, and holds the skin distal to the needle insertion
site in countertension to prevent it from buckling as the needle
pierces the skin.
also essential when securing I.V. access. Direct, intense lighting
may cause glare, making visualization of veins difficult. Ideally,
lighting should be shone at an angle to cast shadows adjacent to
underlying veins. The skin distal to the site of puncture should be
grasped firmly, with sufficient countertension to prevent the skin
from buckling as the needle pierces skin. Of equal importance
is the timing of obtaining I.V. access. Although it is intuitively
desirable to have access immediately upon loss of consciousness,
there is evidence to suggest that delaying the I.V. start may be safer
and more convenient in children. In a prospective study involving
300 children, waiting 2 minutes after loss of lid reflex to obtain
I.V. access decreased the degree of patient movement and decreased the incidence of laryngospasm.127
Airway management of the healthy pediatric patient for elective
surgery may consist of nasal prongs, facemask, mask anesthesia
with or without an oropharyngeal airway, LMA, or tracheal
intubation. Again, this will depend on surgical factors (e.g., shared
airway, prolonged surgery, muscle relaxation required), patient
factors, and the anesthesiologists personal preference. For
example, many anesthesiologists prefer to intubate the neonate or
small infant for all but the most rapid or minor procedures.
If tracheal intubation is planned, specific considerations for the
neonate and small infant deserve special mention. Differences
between the infant airway and that of the older child and adult
are numerous and include a relatively large head, prominent
occiput, short neck, narrow nares, relatively large tongue in the
absence of teeth, high glottis, slanting vocal cords, and a narrow
epiglottis that is angled away from the axis of the trachea.128 These
differences explain why straight laryngoscope blades are preferable
to curved ones when intubating an infant or neonate. The infants
head should be stabilized in a head ring, with the neck neither
flexed nor extended. The relatively large head will then automatically assume a sniffing position. The straight blade is
inserted in the extreme right hand corner of the mouth, lateral to
the tongue and essentially at right angles to the operating room
table. As it reaches the tongue base, the blade tip is then directed
slightly medial and caudad toward the larynx. This will minimize
the chance of the epiglottis flipping down, obscuring the view.
Traditionally, children younger than 8 years are intubated with
uncuffed tracheal tubes. Until that age, the larynx assumes a
conical shape, with the cricoid ring forming the narrowest part of
the upper airway. A properly sized uncuffed tube should allow for
an air leak at approximately 20 cmH2O ventilating pressure to
minimize the risk of mucosal ischemia at the level of the cricoid
ring. However, recent evidence would suggest that the advantages
of using uncuffed tracheal tubes in children may be just another
myth of pediatric anesthesia.
Although an uncuffed tracheal tube does allow a tube of
larger internal diameter (ID) to be used, minimizing the
work of breathing during spontaneous ventilation, a cuffed
tracheal tube can offer many advantages. These include greater
ease of intubation, better control of air leakage, lower flow rate
and better control of anesthetic gases, and decreased risk of
aspiration and infection.129 Cuffed tracheal tubes are being
used with increasing regularity in small children by pediatric
anesthesiologists and in critical care units. In studies comparing
cuffed and uncuffed tracheal tubes in pediatric patients, the
incidence of postextubation stridor was not increased with the
use of cuffed tracheal tubes in the postoperative setting130 as well
as in critically ill children.131 Provided that properly sized cuffed
tracheal tubes of modern design (low pressure, high volume)
are used and that cuff pressures do not exceed 25 cmH2O,
they may be preferable to uncuffed tubes for most airway
management situations in children.129 A tracheal tube less than
3.5 mm ID carries an increased risk of tube blockage from
dried secretions. This complication can be minimized with the
use of a heat and moisture exchanger.
Recommended formulas for choosing an appropriate sized
cuffed and uncuffed tracheal tube are
Uncuffed tube size (ID, mm) = (age/4) + 4.5
Cuffed tube size (ID, mm) = (age/4) + 3
Use of the LMA has gained widespread popularity in pediatric
anesthetic practice, both for elective airway management and as a
salvage airway device in the event of failed tracheal intubation.
Other reported uses of the LMA are as a conduit for diagnostic
fiberoptic bronchoscopy and fiberoptic intubation.132 Pediatric
versions of the reusable LMA133 and Proseal134 provide advantages
over the LMA-Classic and are gaining popularity. Disadvantages
or limitations of the use of the LMA in pediatric anesthetic
practice include (1) it does not provide a seal against regurgitated
gastric contents; (2) malpositioning is more common in children
(especially size #1); (3) it was not designed for use with positivepressure ventilation; and (4) it does not guarantee a patent airway.
The Child With a Full Stomach

The child with a full stomach represents a frequently encountered challenge for the pediatric anesthesiologist. The obvious
potential complication is aspiration of gastric contents with
subsequent development of aspiration pneumonitis. The incidence
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TABLE 39-4. Conditions Predisposing to Perioperative

Aspiration in Children
Recent meal
Obesity
Physical injury
Head injury
Neurologic damage
General anesthesia
Mechanical obstruction
Narcotics
Functional digestion dysfunction
Depressed level of consciousness
In-coordination of swallowing and respiration
Gastroesophageal junction incompetence
Previous esophageal surgery
Lack of experience of the anesthesiologist
Adapted from Ct CJ. NPO after midnight for childrena reappraisal.
of pulmonary aspiration in children is 1:2000135 to 1:4000136 and is

often associated with bucking, coughing, and straining during
induction or tracheal intubation. In a large prospective study
of perioperative aspiration in infants and children, aspiration
occurred 10 times more frequently in emergency than in elective
procedures, the majority of aspiration events happened just before
or during laryngoscopy, and most patients younger than 3 years
who aspirated had a bowel obstruction or ileus.135 However,
conditions predisposing the child to pulmonary aspiration
are numerous and are not restricted to intestinal obstruction
(Table 394).137
In planning the induction of a child with a full stomach, the
anesthesiologist must ascertain whether there are any conflicting
anesthetic considerations, such as hypovolemia, difficult airway,
reactive airway disease, or poor I.V. access. These coexisting conditions should be corrected or optimized if at all possible before
induction of anesthesia. They may also influence the choice of
induction technique (e.g., preinduction bronchodilators, I.V.
lidocaine, and ketamine induction for the severely asthmatic
patient). Indeed, in the event of severe or multiple coexisting
conditions, the anesthesiologist must weigh the risks and benefits
of proceeding versus postponing to optimize the patients condition. This must be done in consultation with the surgeon.
Assuming there are no overriding conflicting anesthetic
contraindications, prevention of hypoxemia should take priority,
followed by aspiration prevention and full stomach precautions.
Regardless of the method of induction chosen, measures to
decrease the volume and acidity of stomach contents should
be considered. These include delaying the start of surgery to allow
for gastric emptying, ranitidine or omeprazole to reduce gastric
acidity, motility agents such as metaclopromide, and nasogastric
suctioning. None of these techniques is 100% effective in preventing gastric regurgitation. Typically, the child with a full stomach
has been managed with a rapid-sequence induction, using a
predetermined dose of anesthetic agent and a rapid-onset muscle
relaxant after preoxygenation and the application of cricoid pressure. Increasingly, the use of cricoid pressure has come under
scrutiny, because there is no evidence that its use has improved
patient outcome.138,139 In addition, cricoid pressure is often applied
incorrectly,140 frequently makes laryngoscopy more difficult,
and may in fact reduce lower esophageal sphincter tone.141 An
increasing number of pediatric anesthesiologists are abandoning

cricoid pressure in favor of gentle manual ventilation after induction of anesthesia to maintain oxygenation.139 Mask ventilation
with pressures not exceeding 1 to 12 cmH2O allows oxygenation
and ventilation without causing gastric inflation. Arguments
favoring the use of gentle manual ventilation include the fact
that the small infant will not tolerate the 60 seconds of apnea
traditionally required to allow for adequate muscle relaxation.
In addition, the small child will not cooperate or voluntarily
hyperventilate during preoxygenation.
If cricoid pressure is to be used, it should be applied by a trained
assistant, using a single-hand technique with the thumb and
middle fingers on either side of the cricoid cartilage and index
finger above preventing lateral movement. Based on studies in
adults, a force of 20 N should be applied to the awake patient,
increasing the force to 30 N with loss of consciousness. Practically
speaking, this is the same pressure required to cause some discomfort if the maneuver were to be performed over the bridge
of the operators nose. If laryngoscopy is difficult, the pressure
should be reduced to 20 N temporarily for a repeat attempt at
intubation and should be released altogether if intubation is still
unsuccessful.138 Similar studies on the force of cricoid pressure
required in children have not as yet been done. In addition, the
infant or small child will probably not tolerate awake cricoid
pressure. If mask ventilation is difficult in the presence of cricoid pressure, it may be relaxed in order to improve ventilation,
provided inspiratory pressures are limited to reduce the risk of
gastric distention.
The choice of anesthetic induction agent depends on the
patients underlying condition and the anesthesiologists preference. Experience and expertise are far more important
factors than pharmacologic diversity leading to safe induction
of the full-stomach patient. The anesthesiologist can, however,
take advantage of differences between pharmacodynamic
actions of some of the common induction agents. For example,
ketamine and etomidate may be chosen for the patient in whom
volume status is a concern, and ketamine is a particularly good
bronchodilator. Induction agents commonly used for rapidsequence induction include propofol thiopental, ketamine, and
etomidate.
The current and possible future role of succinylcholine use
deserves mention. In surveys conducted in the United Kingdom,
succinylcholine remains the muscle relaxant of choice when both
rapid onset and offset of neuromuscular blockade are required.142
Despite this, succinylcholine use is on the decline in adult and
pediatric practice. Although 84% of U.K. anesthetists surveyed in
1996 routinely used succinylcholine for intubation in children,143
only 45% were using it in 1999.144 Compared with rocuronium,
succinylcholine allows for a more rapid tracheal intubation
sequence and creates superior intubation conditions in adults.145
However, in a prospective study in children, rocuronium 0.9 mg/
kg provided similar intubating conditions to succinylcholine 1.5
mg/kg after 30 seconds during modified rapid-sequence induction.146 Controversy over the use of succinylcholine originated
in the 1980s, when a number of children given succinylcholine
developed hyperkalemic cardiac arrest and were later found to
have an underlying muscular dystrophy. Indeed, the anesthesiologist must be familiar with the side effects and contraindications
to the use of succinylcholine (see Table 392).
To date, succinylcholine remains the gold standard of care in
the event of laryngospasm not relieved by conservative measures,
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although even this indication has recently come under question.147
Propofol given at a low dose (0.5 mg/kg intravenously) has been
shown to relieve laryngospasm in obstetric patients148 and avoids
the unwanted side effects of succinlycholine. In a prospective
cohort study, I.V. propofol 0.8 mg/kg relieved laryngospasm in
76.9% of children.149 In the remaining patients, succinlylcholine
administration and tracheal intubation were required to improve
oxygenation. The authors concluded that propofol may be a suitable alternative for laryngospasm in situations in which succinylcholine is contraindicated.149 When rapid offset of neuromuscular
blockade is not crucial, moderately high doses of a nondepolarizing muscle relaxant like rocuronium provides intubating
conditions in less than 60 seconds, comparable with succinylcholine. Sugammadex is a fast-acting, selective binding agent
specifically designed to rapidly reverse rocuronium-induced
neuromuscular blockade. It has been shown to provide rapid
and dose-dependent reversal of profound blockade induced by
high-dose rocuronium with few side effects reported to date.150
Although it is too early in its development to be recommended for
routine clinical use, this agent may hold promise in the future and
may obviate the need for succinylcholine for rapid-sequence
induction. Table 391 outlines some of the muscle relaxants used
in pediatric anesthetic practice.
There are certain circumstances that may be appropriate for
inhalation induction in a patient with a full stomach. An example
might be a patient with an airway foreign body. In certain centers,
anesthesia for pyloromyotomy may consist of inhalation induction
followed by tracheal intubation. Cricoid pressure may be applied
during the inhalation induction, but it should be released if it
affects ventilation.138 However, cricoid pressure is contraindicated
in the presence of a sharp airway or esophageal foreign body.
If manual ventilation must be used during induction, care must
be taken to avoid gastric distention caused by excessive inflationary pressures. Invariably, a patient who has a full stomach on
induction will also have a full stomach on emergence. The trachea
of these patients should be extubated only when awake and airway
reflexes have returned.
Difficult I.V. Access

Difficult venous access is not uncommon in pediatric anesthesia.
Conditions leading to difficult venous access may be physiologic
or pathologic (Table 395). The anesthesiologist must pay particular attention to the patient who has poor venous access secondary to profound dehydration and hypovolemia. Induction of
TABLE 39-5. Causes of Difficult Venous Access in Children
Physiologic
Pathologic
Increased subcutaneous fat

6 mo2 y
Obesity
Hypovolemia (any cause)
Uncooperative
awake child
Numerous previous venipunctures.

Skin anomalies (dermis, epidermis)
Congenital (e.g., epidermolysis bullosa)
Acquired (e.g., burns)
Interstitial edema
Chronic systemic illness
Muscle disorders (e.g., myopathy,
myotonias)
anesthesia in these patients may lead to cardiovascular collapse,

and rehydration (enteral or parenteral) should precede all but the
direst of emergencies.
Often in otherwise healthy patients with difficult venous access,
anesthesia can be induced with a potent inhalation agent and
a peripheral I.V. infusion started a short time later. Veins that
were initially nonexistent often appear secondary to either direct
vasodilation or a decrease in sympathetic tone caused by the inhalation agent. This approach is riskier if the situation is complicated
by a difficult airway, severe organ dysfunction, or a full stomach.
The anesthesiologist must have a plan in case peripheral I.V.
access cannot be obtained. Options include (1) central venous
access; (2) waking the patient up; (3) proceeding without I.V.
access; and (4) invasive access (cut-down, intraosseous). In this
situation, having an expert assistant is essential, because the
patients airway and respiratory and cardiovascular status must be
continuously monitored and maintained while venous access is
sought. The anesthesiologist may elect to proceed without having
venous access provided the proposed procedure will not interfere
with the patients airway, breathing, or cardiovascular status.
The surgeon may be very instrumental in providing an I.V. cutdown or central venous access. If necessary, atropine and muscle
relaxants may be given intramuscularly to facilitate ventilation,
laryngoscopy, and intubation. Alternatively, an appropriately
sized LMA may be inserted to free up the anesthesiologists
hands in order to secure I.V. access. Again, the patients airway
and cardiopulmonary status must be continuously monitored,
and the risk-to-benefit ratio of proceeding without I.V. access
must be frequently reevaluated. Chapters 69 and 70 deal with the
specific technical aspects of obtaining peripheral and central
venous access in the pediatric patient.
The Bleeding Tonsil

The postadenotonsillectomy bleed is a surgical emergency.
Although bleeding is usually of venous origin from the tonsillar
bed, it may nonetheless be very brisk and the child may be severely
hypovolemic. Significant amounts of blood may be swallowed, and
the patient should be considered to have a full stomach.
The anesthetic goals of managing the child with a posttonsillectomy bleed include (1) volume resuscitation; (2) preparation
for the operating room; and (3) safely and rapidly securing the
airway. Adequate fluid resuscitation is vital and may well include
blood and blood products if the bleed has been significant,
although fluid resuscitation should begin with isotonic crystalloid
solutions. Appropriate I.V. access should be secured as soon
as possible and fluid replacement started, while blood should
be sent for immediate hemoglobin, hematocrit, coagulation
profile, and type and cross-match. Occasionally, uncross-matched
type O Rh-negative blood may have to be used. During volume
resuscitation, the patients status should be continuously monitored, supplemental oxygen should be applied by facemask, and
large-bore suction should be available. A variety of laryngoscope
blades and styletted tracheal tubes should be available, as well as
suction, blood products, and a method to warm and infuse fluids.
The patient should be attended to constantly by a qualified health
care professional while these preparations are made.
Induction of anesthesia should take place only after the
patient has been fluid resuscitated. The most common method of
induction involves preoxygenation followed by a rapid-sequence
induction and tracheal intubation with cricoid pressure applied.
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In addition to the full stomach, an added consideration in this

situation includes bleeding into the airway that may make intubation difficult. Etomidate or ketamine may be considered when
the volume status is in question. Expert assistance is mandatory in
managing the challenging airway. Resuscitation should continue
after the airway is secured, and gastric contents should be aspirated by the surgeon under direct vision of the oropharynx before
emergence to avoid further damage to the tonsillar bed.
Open Eye Injury

Management of a child with an open eye injury presents specific
challenges to the anesthesiologist. These include control of IOP,
the possibility of the oculocardiac reflex, and management of
the patient with open eye and full stomach considerations. Not
all eye injuries are considered open eye, and consultation with
the ophthalmologist is vital to identify the extent of injury to the
eye. Occasionally, proper examination of the globe requires an
anesthetized child, in which case a significant open eye injury
should be assumed.
If the eye is salvageable and the patient does not have a full
stomach, the goals of anesthetic induction are to avoid increases
in IOP. Coughing, straining, and vomiting can increase IOP by
40 mmHg or more and should be prevented.151 This may be done
with either I.V. or inhalation induction, followed by administration
of a nondepolarizing muscle relaxant to avoid coughing on the
tracheal tube and antiemetics to prevent postoperative vomiting.152
More often, however, the patient with an open globe injury also
has a full stomach and the anesthesiologist is faced with conflicting
anesthetic goals of smooth induction to prevent increases in IOP
and the need for a rapid-sequence induction for the full stomach.
In addition, concern over succinylcholines tendency to increase
IOP has led to its avoidance by many anesthesiologists. Indeed,
approximately an 8-mmHg increase in IOP is seen within 1 to
4 minutes of an I.V. dose of succinylcholine,153 and pharmacologic
methods to blunt this increase in IOP are not entirely reliable.151
Despite this, there have not been any reports of extrusion of eye
contents attributed to succinylcholine to date. In a study comparing muscle relaxants and IOP, succinylcholine 1.5 mg/kg and
laryngoscopy increased IOP by an average of 7.3 mmHg, whereas
intubation after rocuronium 0.9 mg/kg resulted in no increase in
IOP and offered equally good intubating conditions.154 If the
penetrating eye injury is very small or pinpoint, modest increases
in IOP are very unlikely to cause extrusion of eye contents. As
such, succinylcholine may be a reasonable choice in the patient
with a full stomach with a documented very small eye laceration,
particularly if a short duration of action is desired. If the laceration
is more extensive, the anesthesiologist may consider the use of
nondepolarizing muscle relaxants, accepting the longer duration
of action of these agents.
The oculocardiac reflex, consisting of bradydysrhythmias with
manipulation of the globe or extraocular muscles, is seen more
commonly in children than adults; thus, anesthetic preinduction
with atropine 0.02 mg/kg or glycopyrrolate 0.01 mg/kg may be
warranted to avoid this reflex.
The Difficult Airway

The causes of a difficult pediatric airway are numerous and
include pathology unique to the newborn period, craniofacial
dysmorphologies, acute and chronic inflammatory diseases, traumatic injuries, mass lesions, musculoskeletal and metabolic disorders, as well as a myriad of other rare diseases and syndromes.155
Despite the ongoing development of novel airway tools, the
approach to the patient with a difficult airway requires a common
sense, organized thought process. The ideal induction plan is one
that
1.
2.
3.
4.
5.
Maintains oxygenation and ventilation.

Provides as smooth an induction as possible.
Has back-up options in case the original plan fails.
Can be safely aborted if back-up plans fail.
Involves airway experts and experienced personnel.
A careful history, physical examination, and review of previous

anesthetic records will usually (but not always) identify patients
with a challenging airway. Although certain predictors of a difficult
airway are similar to those in adults (limited head extension, small
mandible, large tongue), other indicators including Mallampati
classification are insensitive and unreliable in the pediatric population.156 Certain syndromes are characterized by progressive worsening of the airway anatomy (e.g., Goldenhar syndrome), such that
previous successful intubations should not lull the anesthesiologist into a false sense of security. Despite this, previous anesthetic
records may prove very useful if documentation of airway management is thorough and honest. A recommended difficult pediatric
airway algorithm is outlined in Figure 396 and is summarized in
the following sections.
Preparation
Regardless of the planned method of induction and airway
management, preparation of the patient and equipment is
essential. A difficult airway cart properly stocked with a variety of
laryngoscope blades, LMAs, tracheal tube guides, oral and nasal
airways, and fiberoptic instruments should be readily available.
Eliciting the help of an experienced assistant is just as important
Figure 39-6. Difficult pediatric airway algorithm. GA = General

anesthesia. *Maintain spontaneous ventilation, if possible;
**blind or fiberoptic guided; ***options for intubation include
direct laryngoscopy, digitally guided, blind oral or nasal,
retrograde, Glidescope videolaryngoscope, gum elastic bougie,
lighted stylet, fiberoptic bronchoscope, Bullard laryngoscope.
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as having a full complement of airway instruments. The patient
with a difficult airway should have I.V. access secured before
induction, if at all possible. This may be facilitated by the use of
EMLA or Ametop and judicious doses of anxiolytics, provided the
patient is adequately monitored. Anticholinergic agents such as
atropine or glycopyrrolate should be considered, both for their
antisialogogue properties and to avoid bradycardia associated with
anesthetic induction and laryngoscopy.
The Different Approaches

AWAKE INTUBATION: Direct laryngoscopy and intubation of the
awake pediatric patient is a practice that is decreasing in frequency
among pediatric anesthesiologists. The reasons for this trend
include (1) evidence of psychological trauma and behavioral upset
in pediatric patients intubated awake versus asleep157; (2) a higher
incidence of oxygen desaturation with awake intubation in
neonates and small children114; (3) small infants are more easily
and rapidly intubated when anesthetized158; and (4) availability of
an increasing number of airway tools designed for the difficult
pediatric airway. There are, however, certain instances in which
an awake intubation may be considered. The first is awake airway
topicalization followed by fiberoptic intubation in the mature and
cooperative older child, as described for the adult patient.159 The
second is direct laryngoscopy in a small infant in whom mask
ventilation would likely be difficult. An example of this would be
the baby with a large cystic hygroma significantly distorting facial
and laryngotracheal anatomy. An alternative to awake intubation,
which has been described in patients with Robin sequence and
Goldenhar syndrome, is awake insertion of an LMA following
airway topicalization.160 Provided the LMA is placed properly and
the airway is patent, anesthesia may be induced and the patient
managed with laryngeal mask anesthesia. Alternatively, a tracheal
tube may be inserted through the LMA.161164 This technique is
discussed in the section Alternative Approach.
THE CLASSIC APPROACH: Traditionally, the patient with a

difficult airway is anesthetized by inhalation induction,
spontaneous respirations are maintained, and laryngoscopy
is attempted with a one- or two-person technique (one person
performing laryngoscopy and pushing the larynx into view and
the second person intubating the trachea). This may be used in
conjunction with a retromolar approach, whereby the laryngoscope blade is inserted at the extreme right side of the mouth, just
behind the last molar tooth. The axes of the laryngoscope blade
and trachea are aligned by turning the head to the left and pushing
the larynx to the right.165 Care must be taken to avoid repeated
attempts at laryngoscopy, because oxygen desaturation occurs
more quickly in children than adults, and trauma to the airway
may progress to the cant intubate, cant ventilate situation.
ALTERNATIVE APPROACHES: If tracheal intubation is deemed

unnecessary, the anesthesiologist may choose to proceed with
the mask or LMA after induction of anesthesia. Although use of
the LMA in pediatric practice is widespread, the anesthesiologist
must be aware of its limitations, as previously discussed.132 In the
event that access to the patients airway is limited (e.g., surgery
above the clavicles), the patient has a history of gastric reflux,
or intermittent positive pressure is required, tracheal intubation may be advisable. Intubation choices in this setting are
numerous, involve a choice of several new airway tools, and
depend on the anesthesiologists experience and personal pre-
TABLE 39-6. Intubation Choices

Technique
Direct laryngoscopy
Special blades
Retromolar approach
Two-person technique
Through laryngeal mask airway
Blind
Flexible fiberoptic
Digitally guided
Blind oral or nasal
Retrograde
Tube guides
Gum elastic bougie
Lit stylet
Fiberoptic instruments
Glidescope video
laryngoscope
Flexible bronchoscope
Bullard laryngoscope
Adapted from Frei FJ, Ummenhofer W. Difficult intubation in paediatrics

[clinical review]. Paediatr Anaesth. 1996;6:251263.
ference (Table 396).155 Regardless of the method chosen, constant

vigilance and monitoring of the anesthetized childs status are
essential during airway manipulation. Care must be taken to
ensure that anesthetic depth is appropriate, and patient safety must
take priority over stubborn persistence. Mastering the use of these
intubating devices requires practice with the elective, normal
airway patient before they can be relied upon in the patient with
a difficult airway.
Although there are no gold standards, most pediatric anesthesiologists are familiar with the use of fiberoptic bronchoscopes.
Asleep fiberoptic intubation usually involves a two-person
technique, is made easier if the assistant pulls the patients tongue
outward, and can be achieved orally or nasally. Table 397 outlines
the different fiberoptic bronchoscope sizes available for use in
pediatric practice. Some centers also carry the ultrathin 2.2-mm
outer diameter (OD) scope that fits through a size 2.5-mm
tracheal tube; but this instrument does not have a suction channel.
If the nasal route is chosen, topical vasoconstrictor nose drops may
reduce the incidence of epistaxis and make insertion of the
tracheal tube easier. After insertion into the nasopharynx, the
tracheal tube is guided through the vocal cords with the flexible
fiberoptic bronchoscope. Oral secretions, light anesthesia, and
blood in the oral cavity make fiberoptic intubation difficult.
The flexible fiberoptic bronchoscope has also been used in
pediatric practice to guide a tracheal tube through a properly
placed LMA (Figure 397).161 A common problem encountered
during this technique is in maintaining tracheal tube position while
removing the fiberoptic bronchoscope and LMA.166 Methods to
overcome this problem include
1. Using long (uncut) tracheal tubes.
2. Keeping the LMA in place until extubation.
3. Removing the LMA over a gum elastic bougie or tracheal tube
exchanger in the event the tube is pulled out with the LMA.
4. Wedging a half-size smaller tracheal tube into the existing one
before LMA removal in order to temporarily increase the
tracheal tube length.
The sequence of steps involved in this technique should be
practiced to minimize delays that may lead to oxygen desaturation.
Although blind intubation through the LMA has been described in
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TABLE 39-7. Laryngeal Mask Airway, Tracheal Tube, and Corresponding Flexible Fiberoptic Bronchoscope Sizes
Patient Age/Size
Neonate (<5 kg)
Infant (<10 kg)
Child (1020 kg)
Child (2030 kg)
Small adult (30 kg)
Adult
LMA Size
1
1.5
2
2.5
3
4
Cuff Volume, mL
24
<7
<10
<14
<25
<35
Largest TT Size, ID, mma

3.5
3.5
4.5
5.5
6.0
6.5
Largest FOB Size, OD, mm

2.8
2.8
3.6
3.6
5.0 cuffed
5.0 cuffed
TT = tracheal tube; FOB- fiberoptic bronchoscope; ID = internal diameter; LMA = laryngral mask airway; OD = outer diameter.
a
TT sizes quoted are the largest ones that will comfortably fit through the corresponding LMA lumen with relative ease (provided the TT is lubricated). Appropriate
sizing of the TT should initially be based on the patients age and size.
b
Olympus Endoscopy System fiberoptic bronchoscopes.
children, this technique may be less successful than in adults.161

The size 3 Fastrach intubating LMA has been used successfully in
children weighing more than 30 kg.167 The Bullard laryngoscope is
an indirect rigid intubating instrument that uses fiberoptics
to look around a corner to visualize the larynx. Although the
adult version has been used in children, a pediatric scope is also
available.168170 The Bullard laryngoscope may be particularly useful
in the patient with limited mouth opening or with cervical spine
immobilization. Like all fiberoptic instruments, however, visualization is difficult in the presence of blood and other secretions,
and occasionally difficulty is encountered in retracting a long
and floppy epiglottis.171 The GlideScope Video Laryngoscope has
been shown to provide a comparable or superior laryngoscopic
view than direct laryngoscopy in both adults172 and children.173
This intubating device has gained widespread popularity and is
becoming a favorite among many anesthesiologists.
Lit stylets (lightwand) such as the Trachlight are available in a
wide variety of sizes and have been used with a high degree of
success in children with normal and difficult airways. Tracheal

intubation with a lit stylet is a technique that is easily learned
but requires regular practice to maintain proficiency. Proper
placement of the lightwand is indicated by a focused increase in
light intensity transmitted through the cricothyroid membrane
and anterior neck as the tip passes through the vocal cords. The
tracheal tube is then passed further into the trachea over the stylet,
and proper tube placement is verified clinically in the usual
manner. Lightwand intubation involves less expensive equipment
and less time and preparation than fiberoptic intubation. In
addition, its use is not as limited as fiberoptic instruments in the
presence of airway blood or secretions. There have been reports of
successful lightwand intubation in failed direct laryngoscopy
patients.174,175
Finally, the retrograde technique of intubation remains
an option in the event that anterograde intubation has failed or
is not feasible.176 A modification of the traditional technique
involves external retrograde placement of a guidewire through
the cricothyroid membrane into the suction port of a fiberoptic
bronchoscope mounted with a tracheal tube, followed by anterograde fiberoptic intubation.177 This technique is quite difficult in
infants and small children because the cricothyroid membrane is
very narrow and cephalad.
The Lost Airway
Figure 39-7. Tracheal intubation through the laryngeal mask

airway (LMA). The tracheal tube may be secured (with tape or
cloth ties) to the LMA, and both may be kept in place until
extubation. See text for details.
Airway obstruction may develop at any stage of the induction

process, and the anesthesiologist must be able to rapidly identify
and manage this life-threatening situation. Immediate measures
include jaw thrust, adjusting head position, confirming a tight
mask fit (may require two-handed technique) with continuous
positive airway pressure, eliciting the help of expert assistance,
inserting an oral airway, and providing 100% oxygen. If these
conservative measures are successful, the anesthesiologist must
determine whether to proceed with the induction or awaken the
patient and whether the patient can be managed safely with mask
or LMA anesthesia as opposed to tracheal intubation. In the event
that the obstruction does not improve, an appropriately sized
LMA may be life-saving. At this point, the anesthesiologist should
have a mental plan of how to proceed if the situation fails to
improve. Although maintaining spontaneous respiration is
desirable, the clinical situation may dictate the need to have muscle
relaxation in order to improve ventilation. If so, atropine 10 g/kg
and I.V. or lingual succinylcholine 0.1 mg/kg is very efficient in
relaxing laryngeal muscles without causing total body paralysis.
If it is felt that neuromuscular blockade would not improve the
situation and the airway is still obstructed, the anesthesiologist
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CHAPTER 39
may need to move quickly toward establishing a surgical airway.
Eliciting the help of an experienced surgeon may be advantageous.
Cricothyroidotomy kits are available commercially but may
also be prepared rapidly with existing equipment. Needle cricothyroidotomy may be performed by inserting an I.V. catheter
(any size) through the cricothyroid membrane and removing
the needle. Proper placement is verified by aspirating air bubbles
into a syringe partially filled with saline or water. A 15-mm
adapter from a size 3.0 tracheal tube will fit snugly into the hub of
the I.V. cannula and may be attached to any standard bag-mask
or ventilation system. Once ventilation is ensured, a guidewire
inserted through the catheter may be used to place a larger cricothyroid airway using the Seldinger technique. Alternatively, jet
ventilation is possible via the I.V. cannula, with the understanding
that barotrauma, pneumothorax, and pneumomediastinum are
possible complications. Depending on the patients status and
clinical situation, one may elect to wake the patient up or proceed
with surgical tracheostomy. It may be unwise to persist with
intubation attempts with only a needle cricothyroidotomy airway.
At the end of the case, the difficult intubation patient now
becomes a difficult extubation and should be extubated only
when fully awake and airway reflexes have returned. Sudden
airway obstruction on tracheal extubation secondary to laryngeal
and hypopharyngeal edema may be seen in the patient who has
undergone several intubation attempts. For this reason, the patient
may be extubated over a tracheal tube exchanger, which acts a
guide should re-intubation be required. Occasionally, it may be in
the patients best interests to perform a surgical tracheostomy at
the end of the case.
Other Situations
Cervical Spine Immobilizers
Patients presenting to the operating room in a cervical spine collar
or halo are often trauma victims and consideration must be given
to the management of the multiply injured patient (See Chapter
93). Anesthetic induction in these patients may be particularly
challenging. The traumatized patient should be considered to have
a full stomach, yet may be hypovolemic and may not tolerate a
classic rapid-sequence induction. Induction strategies may also
have to be tailored to suit a patient with increased ICP and an
unstable cervical spine. It must be remembered that, in children,
neck collars do not reliably immobilize the cervical spine. Instead,
their purpose is to remind the anesthesiologist of the possibility of
an underlying cervical spine injury. Despite all these risks and
considerations, preventing hypoxemia takes priority, followed by
maintaining hemodynamic stability. Once the patients blood
volume has been restored as rapidly and as best as possible,
anesthetic induction and airway management usually involve a
modified rapid-sequence induction with cricoid pressure (one- or
two-handed technique) and direct laryngoscopy with in-line
manual stabilization of the neck. The rapid-sequence induction
may be modified by premedicating with lidocaine 1.5 mg/kg
90 seconds before intubation in an attempt to attenuate the ICP
response to laryngoscopy. The induction dose of anesthetic agent
should be tailored according to the patients blood volume status.
In infants, the dose of lidocaine should be reduced to avoid cardiac
dysrhythmias such as bradycardia and asystole. Intubation with
in-line manual stabilization can be done safely in the patient with
an unclear cervical spine.178
Alternatively, the previously mentioned difficult airway

instruments have been used for rapid-sequence induction in
patients with immobilized cervical spines. Again, the use of these
special intubating tools in this situation should be restricted to
those very familiar with their use. A difficult intubation cart must
be readily available, and a back-up plan may be needed in case the
initial intubation attempts fail. One must remember that proper
application of an anesthetic facemask and adequate ventilation
may be life-saving and may buy enough time to obtain the help
and equipment necessary to secure the patients airway. The patient
with cervical spine immobilization who does not have a full
stomach or the recent trauma victim may be managed according
to the aforementioned difficult pediatric airway algorithm,
provided the neck is immobilized throughout induction. In the
mature, cooperative child, awake fiberoptic intubation after airway
topicalization and careful sedation may be an attractive option.
Anesthesia is induced after ensuring no new neurologic deficits
have developed during tracheal intubation.
The Ventilator-dependent Patient

The ventilated patient in the intensive care unit may have multiple organ dysfunction, be inotrope-dependent, and have special
ventilation requirements (positive end-expiratory pressure
dependent, high-frequency oscillator, or pressure control). In
these patients, the period of highest risk may be in fact during
transportation from the intensive care unit to the operating
room. The anesthesiologist must weigh the risks of transporting
a critically ill child against the need for the proposed surgery.
As such, proper communication between anesthesia, surgery, and
critical care staff is essential.
Often, anesthetic machines are not able to match the ventilation
requirements of critically ill intensive care unit patients. If such a
patient must go to the operating room, arrangements should be
made to have an appropriate intensive care unit ventilator set up in
the operating room. Again, transport and management of these
critically ill patients is not without risks, and the feasibility of
delaying surgery in order to improve the patients condition may
need to be considered. The transporting team should be experienced and ready to resuscitate the hemodynamically unstable child
or manage a lost airway. Because these patients do not need (and
may not tolerate) a rapid induction of anesthesia, careful titration
of I.V. narcotics followed by total intravenous anesthesia (TIVA)
or titration of inhalation agents is a popular option.
The Patient With a Tracheostomy

Although these patients may present to the operating room for any
type of procedure, often they are scheduled for airway examination
(suspension microlaryngoscopy, flexible and rigid bronchoscopy)
or airway surgery (vocal cord papilloma excision, tracheoplasty,
tracheotomy change). Specifics of these procedures and their
anesthetic considerations are covered in Chapter 99. In planning
the anesthetic induction in these patients, important points to
consider are (1) proposed procedure (diagnostic or surgical); (2)
comorbid conditions (cardiorespiratory systems); (3) will an
alternative airway be required (e.g., oral intubation, changing existing
tracheotomy to a tracheal tube)?; and (4) methods of ventilation
(spontaneous vs positive-pressure vs jet ventilation).
In virtually no other type of surgery is proper communication
with the surgeon more essential. The ear, nose, and throat
surgeons plan must be made clear to the entire operating room
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team, and alternative methods to secure and maintain the airway

must be immediately available (e.g., tracheal tubes, alternate
tracheostomy tubes, rigid bronchoscope). If the tracheostomy
tube is to be removed soon after induction, oxygenation and
ventilation must be maintained either via the tracheostomy or
from above (orally or nasally). Depending on the reason for the
tracheostomy, however, ventilation by mouth may be impossible
(e.g., severe subglottic stenosis, airway papillomata or granulation
tissue).
Maintaining spontaneous respiration may be advantageous,
and this may be achieved by inhalation or I.V. induction. Before
anesthetic induction, the ability to manually ventilate via the
tracheostomy tube should be ensured. Occasionally, the leak
around the tracheostomy tube is excessive, and the tube should be
up-sized using a tracheal tube placed in the tracheostomy site or
simply a larger tracheostomy tube. Care must be taken when
changing tracheal tubes in these children. The otolaryngologist
should be present in the operating room and be prepared to help
the anesthesiologist. Tracheal tubes placed in a tracheostomy site
need to be secured in place carefully to prevent inadvertent
extubation or bronchial intubation. Often, these patients undergo
suspension microlaryngoscopy and laser excision of vocal cord
papillomata or granulation tissue. If surgery is limited to the
glottis, airway management may consist of ventilation through the
tracheostomy tube. If the tracheostomy tube must be removed,
spontaneous ventilation should be maintained and anesthesia
may be by inhalation (via the tracheostomy) or TIVA. Monitors
such as capnography and airway gases may be lost temporarily,
and therefore, the anesthesiologist must be able to visualize the
patients respiration at all times. A precordial stethoscope may be
useful in this setting. Often, the otolaryngologist needs to pass a
rigid bronchoscope from above, in which case, the tracheostomy
tube will eventually have to be removed. Anesthetic ventilator
tubing may be attached to the bronchoscope side port and the
patient ventilated manually. The tracheostomy site will need
to be occluded to allow for effective ventilation. Because the
airway may constantly be changed during these procedures, the
anesthesiologist may elect to deliver anesthesia via TIVA from
the outset or must be ready to switch to a TIVA at any time after
induction.
For airway laser surgery, all laser precautions must be taken
(limit fractional concentration of oxygen in inspired gas [FIO2],
protective masks and eyewear, wet gauze packs, laser-resistant
tracheal tubes) as outlined in Chapters 98 and 99.
CONCLUSION
This chapter has presented the anesthesiologist with the tools
required to provide an efficient and safe anesthetic induction
for the pediatric patient. The pediatric anesthesiologist is faced
with a specific set of challenges owing to the unique anatomic,
physiologic, and emotional characteristics of the child. A thorough
knowledge of pharmacology is required, because it relates to
anesthetic induction in the child. In addition, the approach and
skills required to carry out a smooth induction sequence in the
child are significantly different to those for the adult. The patients
underlying condition, emotional status, and surgical requirements
are factors that will influence the method of induction chosen.
Furthermore, the anesthesiologist must be ready to modify this
induction plan without delay, in the event of a rapidly changing
clinical situation.
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82. Reynolds LM, Lau M, Brown R, et al. Intramuscular rocuronium in
infants and children. Dose-ranging and tracheal intubating conditions.
83. Woloszczuk-Gebicka B, Wyska E, Grabowski T. Sevoflurane increases
fade of neuromuscular response to TOF stimulation following rocuronium administration in children. A PK/PD analysis. Paediatr Anaesth.
2007;17:637646.
84. Kaplan RF, Fletcher JE, Hannallah RS, et al. The potency (ED50) and
cardiovascular effects of rapacuronium (Org 9487) during narcotic
nitrous oxidepropofol anesthesia in neonates, infants, and children.
Anesth Analg. 1999;89:11721176.
85. Meakin GH, Pronske EH, Lerman J, et al. Bronchospasm after
rapacuronium in infants and children. Anesthesiology. 2001;94:926927.
86. Staals LM, Snoeck MMJ, Driessen JJ, et al. Multicentre, parallel-group,
comparative trial evaluating the efficacy and safety of sugammadex
in patients with end-stage renal failure or normal renal function.
Br J Anaesth. 2008;101:492497.
87. Korpinen R, Saarnivaara L, Siren K. QT interval of the ECG, heart rate
and arterial pressure during anaesthetic induction: comparative effects
of alfentanil and esmolol. Acta Anaesthesiol Scand. 1995;39:809813.
88. Yaster M, Nichols DG, Deshpande JK, et al. Midazolam-fentanyl intravenous sedation in children: case report of respiratory arrest. Pediatrics.
1990;86:463467.
90. Hickey PR, Hansen DD. Fentanyl- and sufentanil-oxygen-pancuronium
anesthesia for cardiac surgery in infants. Anesth Analg. 1984;63:117124.
91. Hughes MA, Glass PS, Jacobs JR. Context-sensitive half-time in multicompartment pharmacokinetic models for intravenous anesthetic drugs.
92. Davis PJ, Lerman J, Suresh S, et al. A randomized multicenter study
of remifentanil compared with alfentanil, isoflurane, or propofol in
anesthetized pediatric patients undergoing elective strabismus surgery.
Anesth Analg. 1997;84:982989.
93. Davis PJ, Finkel JC, Orr RJ, et al. A randomized, double-blinded study
of remifentanil versus fentanyl for tonsillectomy and adenoidectomy
surgery in pediatric ambulatory surgical patients. Anesth Analg. 2000;
90:863871.
94. Min SK, Kwak YL, Park SY Kim JS. The optimal dose of remifentanil for
intubation during sevoflurane induction without neuromuscular
blockade in children. Anaesthesia. 2007;62:446450.
95. Morgan JM, Barker I, Peacock JE, Eissa A. A comparison of intubating
conditions in children following induction of anaesthesia with propofol
and suxamethonium or propofol and remifentanil. Anaesthesia. 2007;
62:135139.
96. Crawford MW, Hayes J, Tan JM. Dose-response of remifentanil for
tracheal intubation in infants. Anesth Analg. 2005;100:15991604.
97. Crawford MW, Hickey C, Zaarour C, et al. Development of acute opioid
tolerance during infusion of remifentanil for pediatric scoliosis surgery.
Anesth Analg. 2006;102:16621667.
98. Mendelson C. The aspiration of stomach contents in to the lungs during
obstetric anesthesia. Am J Obstet Gynecol. 1946;52:191205.
99. Olsson GL, Hallen B. Pharmacological evacuation of the stomach with
metoclopramide. Acta Anaesthesiol Scand. 1982;26:417420.
100. Shevchenko Y, Jocson JC, McRae VA, et al. The use of lidocaine for
preventing the withdrawal associated with the injection of rocuronium
in children and adolescents. Anesth Analg. 1999;88:746748.
101. Groeben H, Silvanus MT, Beste M, Peters J. Both intravenous and
inhaled lidocaine attenuate reflex bronchoconstriction but at different
plasma concentrations. Am J Respir Crit Care Med. 1999;159:530535.
102. Chraemmer JB, Hoilund CP, Marving J, et al. Lack of effect of intravenous lidocaine on hemodynamic responses to rapid sequence
induction of general anesthesia: a double-blind controlled clinical trial.
Anesth Analg. 1986;65:10371041.
103. Abou MM, Keszler H, Yacoub JM. Cardiovascular reactions to laryngoscopy and tracheal intubation following small and large intravenous
doses of lidocaine. Can Anaesth Soc J. 1977;24:1219.
104. Stoelting RK. Circulatory changes during direct laryngoscopy and
tracheal intubation: influence of duration of laryngoscopy with or
without prior lidocaine. Anesthesiology. 1977;47:381384.
105. Splinter WM. Intravenous lidocaine does not attenuate the haemodynamic response of children to laryngoscopy and tracheal intubation.
Can J Anaesth. 1990;37:440443.
106. Murray DJ, Forbes RB, Dillman JB, et al. Haemodynamic effects of
atropine during halothane or isoflurane anaesthesia in infants and small
107. Shaw CA, Kelleher AA, Gill CP, et al. Comparison of the incidence of
complications at induction and emergence in infants receiving oral
atropine vs no premedication. Br J Anaesth. 2000;84:174178.
108. Lavis DM, Lunn JN, Rosen M. Glycopyrrolate in children. A comparison
between the effects of glycopyrrolate and atropine administered before
induction of anaesthesia. Anaesthesia. 1980;35:10681071.
109. Mirakhur RK. Premedication with atropine or glycopyrrolate in children.
Effects on heart rate and rhythm during induction and maintenance of
anesthesia. Anaesthesia. 1982;37:10321036.
110. Cartabuke RS, Davidson PJ, Warner LO. Is premedication with oral
glycopyrrolate as effective as oral atropine in attenuating cardiovascular
depression in infants receiving halothane for induction of anesthesia?
Anesth Analg. 1991;73:271274.
111. Canadian Anesthesiologists Society Website. Guidelines to the
Practice of Anesthesia. Revised 2008. http://www.cas.ca/members/
sign_in/guidelines/practice_of_anesthesia/default.asp?load=appendix_iii
112. Cote CJ, Goldstein EA, Cote MA, et al. A single-blind study of pulse
oximetry in children. Anesthesiology. 1988;68:184188.
113. Laycock GJ, McNicol LR. Hypoxaemia during induction of anaesthesia
an audit of children who underwent general anaesthesia for routine
elective surgery. Anaesthesia. 1988;43:981984.
114. Kong AS, Brennan L, Bingham R, et al. An audit of induction of anaesthesia in neonates and small infants using pulse oximetry. Anaesthesia.
1992;47:896899.
115. Gombar KK, Nain SS, Singh B, et al. Arterial oxygen desaturation during
peripheral venous cannulation in children. Can J Anaesth. 1994;41:
288290.
116. Campbell FA, McLeod ME, Bissonnette B, Swartz JS. End-tidal carbon
dioxide measurement in infants and children during and after general
anaesthesia. Can J Anaesth. 1994;41:107110.
117. Davis AJM, Bissonnette B. Thermal regulation and mild intraoperative
hypothermia. Curr Opin Anaesthesiol. 1999;12:303309.
118. Plattner O, Semsroth M, Sessler DI, et al. Lack of nonshivering
thermogenesis in infants anesthetized with fentanyl and propofol.
119. Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to reduce
the incidence of surgical-wound infection and shorten hospitalization.
Study of Wound Infection and Temperature Group. N Engl J Med. 1996;
334:12091215.
120. Avidan MS, Zhang L, Burnside BA, et al. Anesthesia awareness and the
Bispectral Index. N Engl J Med. 2008;358:10971108.
121. Joo HS, Perks WJ. Sevoflurane versus propofol for anesthetic induction:
a meta-analysis. Anesth Analg. 2000;91:213219.
122. Lopez Gil M, Brimacombe J, Clar B. Sevoflurane versus propofol for
induction and maintenance of anesthesia with the laryngeal mask airway
123. Sinha M, Christopher NC, Fenn R, Reeves L. Evaluation of nonpharmocologic methods of pain and anxiety management for laceration
repair in the pediatric emergency department. Pediatrics. 2006;117:
11621168.
124. Patel A, Schieble T, Davidson M, et al. Distraction with a hand-held
video game reduces pediatric preoperative anxiety. Paediatr Anaesth.
2006;16:10191027.
125. Denman WT, Tuason PM, Ahmed MI, et al. The PediSedate device, a
novel approach to pediatric sedation that provides distraction and
inhaled nitrous oxide: clinical evaluation in a large case series. Paediatr
Anaesth. 2007;17:162166.
126. Lejus C, Bazin V, Fernandez M, et al. Inhalation induction using
sevoflurane in children: the single-breath vital capacity technique compared to the tidal volume technique. Anaesthesia. 2006;61:
535540.
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127. Schwartz D, Connelly NR, Gutta S, et al. Early intravenous cannulation
in children during sevoflurane anesthesia. Paediatr Anaesth. 2004;14:
820824.
128. Creighton RE. The infant airway [editorial; comment]. Can J Anaesth.
1994;41:174176.
129. Fine G, Borland LM. The future of the cuffed endotracheal tube. Paediatr
Anaesth. 2004;14:3842.
130. Rhine HH, Corddry DH, Kettrick RG, et al. Comparison of cuffed and
131. Newth CJL, Rachman B, Patel N, Hammer J. The use of cuffed versus
uncuffed endotracheal tubes in pediatric intensive care. J Pediatr.
2004;144:333337.
132. Haynes S, Morton N. The laryngeal mask airway: a review of its use in
133. Flynn P, Ahmed FB, Mitchell V, et al. A randomized comparison of the
single use LMA Flexible with the reusable LMA Flexible in paediatric
dental day-case patients. Anaesthesia. 2007;62:12811284.
134. Lardner DRR, Cox RG, Ewen A, Dickinson D. Comparison of the
laryngeal mask airway (LMA)-Proseal and the LMA-Classic in
ventilated children receiving neuromuscular blockade. Can J Anaesth.
2008;55:2935.
136. Neelakanta G, Chikyarappa A. A review of patients with pulmonary
aspiration of gastric contents during anesthesia reported to the Departmental Quality Assurance Committee. J Clin Anesth. 2006;18:102107.
137. Ct CJ. NPO after midnight for childrena reappraisal [comment].
138. Brimacombe J, Berry A. Cricoid pressure. Can J Anaesth. 1997;44:414.
139. Weiss M, Gerber AC. Rapid sequence induction in childrenits not a
matter of time! Paediatr Anaesth. 2008;18:9799.
140. Meek T, Gittins N, Duggan JE. Cricoid pressure: knowledge and performance amongst anaesthetic assistants. Anaesthesia. 1999;54:5962.
141. Tournadre JP, Chassard D, Berrada KR, et al. Cricoid cartilage pressure
decreases lower esophageal sphincter tone. Anesthesiology. 1997;86:79.
142. Stedeford J, Stoddart P. RSI in pediatric anesthesiais it used by
nonpediatric anesthetists? A survey from south-west England. Paediatr
Anaesth. 2007;17:235242.
143. Robinson AL, Jerwood DC, Stokes MA. Routine suxamethonium in
144. Hatcher IS, Stack CG. Postal survey of the anaesthetic techniques used
for paediatric tonsillectomy surgery. Paediatr Anaesth. 1999;9:311315.
145. Sluga M, Ummenhofer W, Studer W, et al. Rocuronium versus succinylcholine for rapid sequence induction of anesthesia and endotracheal
intubation: a prospective, randomized trial in emergent cases. Anesth
Analg. 2005;101:356361.
146. Cheng CAY, Aun CST, Gin T. Comparison of rocuronium and
suxamethonium for rapid tracheal intubation in children. Paediatr
Anaesth. 2002;12:140145.
147. Alalami A, Ayoub CM, Baraka AS. Laryngospasm: review of different
prevention and treatment modalities. Paediatr Anaesth. 2008;18:281288.
148. Fodale V, Pratico C, Leto G, et al. Propofol relieves post extubation laryngospasm in obstetric anesthesia. Int J Obstet Anesth. 2004;13:196197.
149. Afshan G, Chohan U, Qamar-Ul-Hoda M, Kamal RS. Is there a role of
a small dose of propofol in the treatment of laryngeal spasm? Paediatr
Anaesth. 2002;12:625628.
150. Phringer FK, Rex C, Sielenkmper AW, et al. Reversal of profound,
high-dose rocuronium-induced neuromuscular blockade by sugammadex at two different time points: an international, multicenter,
randomized, dose-finding, safety assessor-blinded, phase II trial.
151. McGoldrick KE. The open globe: is an alternative to succinylcholine
necessary? J Clin Anesth. 1993;5:14.
152. Watcha MF, Bras PJ, Cieslak GD, et al. The dose-response relationship of
ondansetron in preventing postoperative emesis in pediatric patients
undergoing ambulatory surgery. Anesthesiology. 1995;82:4752.
153. Lincoff HA, Ellis CH, Devoe AG, et al. The effect of succinylcholine on
intraocular pressure. Am J Ophthalmol. 1955;40:501510.
154. Chiu CL, Jaais F, Wang CY. Effect of rocuronium compared with
succinylcholine on intraocular pressure during rapid sequence induction
of anaesthesia. Br J Anaesth. 1999;82:757.
155. Frei FJ, Ummenhofer W. Difficult intubation in paediatrics. Paediatr
Anaesth. 1996;6:251.
156. Kopp VJ, Bailey A, Valley RD, et al. Utility of the Mallampati classification for predicting difficult intubation in pediatric patients.
157. Meyers EF, Muravchick S. Anesthesia induction techniques in pediatric
patients: a controlled study of behavioral consequences. Anesth Analg.
1977;56:538542.
158. Cook-Sather SD, Tulloch HV, Cubina ML, et al. A comparison of awake
versus paralyzed tracheal intubation for infants with pyloric stenosis.
159. Practice guidelines for management of the difficult airway. A report by
the American Society of Anesthesiologists Task Force on Management
of the Difficult Airway. Anesthesiology. 1993;78:597602.
160. Markakis DA, Sayson SC, Schreiner MS. Insertion of the laryngeal mask
airway in awake infants with the Robin sequence. Anesth Analg. 1992;
75:822824.
161. White A. Laryngeal mask guided tracheal intubation in paediatric
anaesthesiacorrespondence. Paediatr Anaesth. 1992;2:265267.
162. Rabb MF, Minkowitz HS, Hagberg CA. Blind intubation through the
laryngeal mask airway for management of the difficult airway in infants.
163. Johnson CM, Sims C. Awake fibreoptic intubation via a laryngeal
mask in an infant with Goldenhars syndrome. Anaesth Intensive Care.
1994;22:194197.
164. Selim M, Mowafi H, Al-Ghamdi A, Adu-Gyamfi Y. Intubation via LMA
in pediatric patients with difficult airways. Can J Anaesth. 1999;46:
891893.
165. Akdikmen SA. A modified technique for direct laryngoscopy and
tracheal intubation. Anesthesiology. 1966;27:321.
166. Brimacombe J. Laryngeal mask airway for difficult intubation and head
and neck surgery in children. Paediatr Anaesth. 1993;3:320321.
167. Maigrot F, Shehata R, Cros AM, et al. Intubation with size 3 Fastrach in
pediatric anesthesia. Anesthesiology. 1998;89:A571.
168. Borland LM, Casselbrant M. The Bullard laryngoscope. A new indirect
oral laryngoscope (pediatric version). Anesth Analg. 1990;70:105108.
169. Shulman B, Connelly NR. The adult Bullard laryngoscope as an
alternative to the Wis-Hipple 1(1/2) in paediatric patients. Paediatr
Anaesth. 2000;10:4145.
170. Shulman GB, Connelly NR, Gibson C. The adult Bullard laryngoscope
in paediatric patients. Can J Anaesth. 1997;44:969972.
171. Crosby ET, Cooper RM, Douglas MJ, et al. The unanticipated difficult
airway with recommendations for management. Can J Anaesth. 1998;
45:757776.
172. Sun DA, Warriner CB, Parsons DG, et al. The Glidescope Video
Laryngoscope: randomized clinical trial in 200 patients. Br J Anaesth.
2005;94:381384.
173. Kim JT, Na HS, Bae JY, et al. GlideScope video laryngoscope: a
randomized clinical trial in 203 paediatric patients. Br J Anaesth. 2008;
101:531534.
174. Fisher QA, Tunkel DE. Lightwand intubation of infants and children.
J Clin Anesth. 1997;9:275279.
175. Holzman RS, Nargozian CD, Florence FB. Lightwand intubation
in children with abnormal upper airways. Anesthesiology. 1988;69:
784787.
176. Borland LM, Swan DM, Leff S. Difficult pediatric endotracheal intubation: a new approach to the retrograde technique. Anesthesiology.
1981;55:577578.
177. Seavello J, Hammer GB. Tracheal intubation in a child with trismus
pseudocamptodactyly (Hecht) syndrome. J Clin Anesth. 1999;11:254256.
178. Bohn D, Armstrong D, Becker L, et al. Cervical spine injuries in children.
J Trauma. 1990;30:463469.
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Maintenance of Anesthesia:
Inhalational Agents
Olivier Paut, Frdric Lamy, and Magalie Gurin
INTRODUCTION
The goals of the maintenance phase of anesthesia are to ensure an
adequate depth of anesthesia, amnesia, and analgesia, while
providing physiologic stability and optimal operating conditions
for the surgeon.1,2 To achieve these goals, the anesthetist uses a
variety of drugs and techniques, most often in combination.
Physiologic modifications occur during growth and development
and the anesthetist caring for children must address important
variations in body compositions, renal and hepatic function, and
protein binding.3
The childs disease, and the surgical procedure for which
anesthesia is provided, can cause further physiologic changes
that may challenge the anesthetist. Since the early 1990s, a large
number of well-designed studies have contributed to the growing
knowledge of pediatric anesthesia. New monitoring techniques,
new drugs, and new combinations have been introduced that offer
a large choice of safe anesthesia techniques. This chapter reviews
the main drugs and techniques used in pediatric anesthesia.
SUITABLE AGENTS
Volatile Agents
Halothane
Despite the emergence of new anesthetic agents such as propofol
and sevoflurane, halothane is still widely used in pediatric anesthesia around the world.4 Since the beginning of 2000, halothane
has virtually disappeared from the anesthesia pharmacopeia in
developed countries,5 whereas it remains popular in developing
countries because of the low cost.6,7 Halothane has been popular
in children because of it has a nonpungent (sweet) smell with low
airway irritability with high patient acceptance. As with other
volatile agents, halothane produces unconsciousness, amnesia, and
mild analgesia.
Halothane is a potent cardiovascular depressant causing a
decrease in systolic arterial pressure in a dose-dependent manner,
a decrease in heart rate, depression of myocardial contractility, and
peripheral vasodilation.8,9 Cardiovascular depression is age-related
and has been shown to be more pronounced in neonates and
infants anesthetized with 2 or 1.7 minimal alveolar concentration
(MAC) halothane than in older children.10 The myocardial
depression in neonates induced by halothane may be mediated by
inhibition of plasma membrane Na+-Ca2+ exchange (NCX) and
Ca2+ influx channels rather than inhibition of the sarcoplasmic
Ca2+ release.11 Atropine has been shown to reverse the halothaneinduced decrease in cardiac output. Halothane sensitizes the
myocardium to catecholamines and is arrhythmogenic. Lifethreatening arrhythmias can occur when epinephrine is used in
children undergoing halothane anesthesia.12 A maximum 5 g/kg
epinephrine is usually recommended when used concomitantly
with halothane. Halothane causes a dose-dependent respiratory
depression: tidal volume (VT) is decreased, the response to carbon
dioxide is attenuated, and the respiratory rate is increased.13
Infants have a greater reduction in VT during halothane anesthesia
than children.14 Intercostal muscle activity is attenuated and
paradoxical breathing may occur at concentrations above 1%,
particularly in infants and neonates.12 Halothane is a potent
bronchodilator and is particularly useful in asthmatics.15 Halothane is a potent cerebral vasodilator; it increases cerebral blood
flow, cerebral blood flow velocities, cerebral blood volume, and
intracranial pressure (ICP).16,17 It should be used with caution, at
low concentration or avoided in patients with suspected elevation
of ICP. During halothane anesthesia, 20% may undergo metabolism by the liver through either oxidative or reductive pathways.
Halothane-induced hepatitis is believed to occur less frequently
in children than in adults.
Enflurane
Enflurane has never been as popular as halothane in pediatric
anesthesia, mainly because of its undesirable respiratory effects.
Enflurane is a profound respiratory depressant. In young children,
enflurane does not modify respiratory rate but is associated with
a larger decrease in alveolar ventilation than isoflurane and halothane.13 Enflurane produces a greater depression of minute volume
E) and increase in carbon dioxide tension than does halothane
(V
or isoflurane.18 Enflurane causes bronchodilation. The cardiovascular effects of enflurane are similar to those of halothane: a
negative inotropic effect on the myocardium, peripheral vasodilation with a decrease in blood pressure, and a decrease in
cardiac output.19 Enflurane produces a moderate increase in
cerebral blood flow velocities20 and is epileptogenic. Enflurane
should be avoided in patients predisposed to seizures. In epilepsy
surgery, it may be used judiciously as a potent synchronizer and
activator of the epileptogenic focus, making it easier to identify.21
Enflurane also profoundly inhibits the thermoregulatory response
in children to a greater extent than isoflurane or halothane.22 Two
percent of enflurane may undergo metabolism by the cytochrome
P450-IIE1 isoenzyme located in the liver.12 The inorganic fluoride
metabolite can have deleterious effects on the kidney, but nephrotoxicity has not been demonstrated in clinical practice, because the plasma concentrations of inorganic fluoride are relatively
low.23
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In view of its marked respiratory depressant effects, children

should be ventilated to prevent airway and respiratory problems
during enflurane anesthesia. Airway problems are more common
in spontaneously breathing children undergoing ear, nose, and
throat surgery with enflurane than with halothane or isoflurane.24
In expremature infants undergoing inguinal herniotomy,

recovery was significantly shorter in the desflurane group than in
the sevoflurane group, whereas there was no difference in postoperative respiratory events.33 Desflurane has been associated with
emergence agitation/delirium.34,35
Isoflurane
Sevoflurane
Isoflurane, an isomer of enflurane, is not popular as an induction

agent because of its pungent odor and irritant effect on the airway.
Isoflurane is very popular as a maintenance agent in children. The
MAC of isoflurane varies with age: maintenance concentration
range from 1 to 2.5%. The respiratory depression effect is similar
to that of halothane but less than that produced by enflurane.18
Isoflurane decreases systemic blood pressure and vascular
resistance and increases heart rate.25 Cardiac output is more
preserved during isoflurane than during halothane anesthesia.12,25
Isoflurane decreases cerebral metabolism and increases cerebral
blood flow. However, this increase is limited and, during normocapnia, 0.5 to 1.5 MAC of isoflurane does not change the
cerebral blood flow velocity in children. Isoflurane (1 MAC) has
minimal effects on the cerebral reactivity to CO2.26 Isoflurane is
poorly metabolized (0.2%) and does not produce liver toxicity.
Isoflurane is not absorbed nor metabolized in the presence of
soda lime.12
Sevoflurane is a fluorinated ether with a low blood-gas solubility

coefficient. It has gained a great popularity in pediatric anesthesia
because of its suitability for induction of anesthesia. The MAC of
sevoflurane decreases from 3.3% in infancy to 2.6% in children
1 to 12 years of age36 and the MAC sparing effect of 60% N2O is
about 25%.36
During sevoflurane anesthesia, heart rate remains stable in
children younger than 3 years and increases slightly (by 10%) in
older children.36 Sevoflurane lowers blood pressure and systolic
vascular resistance. It has negative inotropic properties, but to a
lesser extent than halothane.11,37 Arrhythmias are uncommon with
sevoflurane, and it produces less myocardial sensitization to
epinephrine than halothane in adults.4 Sevoflurane is a respiratory
depressant decreasing VT in a dose-related manner. At concentrations above 1 MAC, respiratory rate falls, leading to a drop in
minute ventilation and, as a consequence, to an increase in endtidal carbon dioxide (ETCO2). Respiratory depression with sevoflurane is more pronounced when compared with equipotent
concentrations of halothane.
Sevoflurane is metabolized by cytochrome P450 IIE1 in the
liver with the production of inorganic fluoride. Plasma concentrations of inorganic fluoride remain within safe limits after
1 MAC/h exposure to sevoflurane.36 Sevoflurane does not alter
cerebral blood flow velocities between 0.5 and 1.5 MAC.38 Sevoflurane can promote seizure-like movements during induction of
anesthesia. This epileptogenic effect has been recently reviewed.39,40 The incidence of seizure activity varies markedly between
studies and the mechanism is not clear. An activation of the
N-methyl-D-aspartic acid (NMDA) neuronal receptors is possible.
Avoiding hypocapnea and sevoflurane concentrations greater than
1.5 MAC during maintenance may be protective.40
Degradation of sevoflurane in soda lime produces compound A.
Compound A causes renal toxicity in rats. No renal toxicity has
been reported in humans, but the U.S. Food and Drug Administration (FDA) does not recommend its use with flow rates less
than 2 L/min. This restriction is not made in the European
countries.4
Sevoflurane is associated with a higher incidence of emergence
agitation/delirium than either halothane or propofol.34,41 Contributing factors include younger age, anxiety, and pain. Prevention or treatment of this side effect is not clearly defined.34
Desflurane
Desflurane has a low blood-gas partition coefficient similar to that
of nitrous oxide (N2O). The MAC of desflurane is age-dependent.
Desflurane has a high incidence of respiratory side effects during
induction of anesthesia, and its use is reserved for maintenance
of anesthesia.27 N2O decreases the MAC of desflurane by 25%.27
When used together with N2O, the MAC of desflurane varies from
7.5% in infants to 6.4% in children.27
Desflurane has cardiovascular effects similar to those of isoflurane. It decreases systemic vascular resistance and increases
heart rate. During 1 MAC desflurane anesthesia, the negative
inotropic effect of desflurane is counterbalanced by the increase in
heart rate and drop in vascular resistance, thereby preserving
cardiac output.28 A rapid increase in desflurane concentration
from 0.55 to 1.66 MAC causes sympathetic stimulation and
catecholamine release, which manifests as an increase in heart rate
and blood pressure. Desflurane causes dose-dependent respiratory
E, maximal inspiratory flow, and ventilation
depression: V T, V
drive in response to CO2 are all diminished, whereas the respiratory rate is increased. Desflurane can be used during spontaneous ventilation below 1 MAC. Higher concentrations produce
significant respiratory depression by decreasing V T and apnea in
some instances.29 Recently, it was shown that desflurane causes
adverse changes in airway mechanics30 that included an increase
in airway resistance. Airway narrowing was markedly enhanced in
children with airway irritability,30 suggesting that desflurane
should not be used in children with asthma or recent airway
infection. The low solubility of desflurane allows rapid emergence
and recovery. However, in children maintained with desflurane,
despite the shorter emergence times, the length of stay in the
postanesthesia care unit (PACU) is not shortened and episodes of
agitation are more frequent.31 Compared with isoflurane,
desflurane had significantly shorter recovery based on time to first
movement, eye opening, and tracheal extubation.32
N2O
N2O was first used more than 150 years ago and is still widely used
as an inhalational agent.42 N2O offers many advantages in pediatric
anesthesia including absence of odor, low blood-gas solubility
coefficient (0.47), second gas effects, and concentration effects,
allowing a rapid uptake and distribution. Although the validity
of the second gas effect of N2O has been questioned,43 its duration
and its clinical relevance is low.44 The MAC of N2O is 104%, and
therefore, it is not possible to use N2O as a sole anesthetic at
normal atmospheric pressure.45
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N2O has hypnotic and analgesic actions. Currently, N2O is used

as an analgesic at concentrations between 50 and 70%, reducing
the dose requirements of other anesthetics. N2O does not always
reduce the anesthetic requirements of the new volatile or
intravenous agents (propofol).46
N2O has few side effects. Its causes minimal respiratory
depression and mild sympathetic stimulation.2 The effect of N2O
on systemic and pulmonary hemodynamics has been studied in
infants after cardiac surgery by Hickey and coworkers.47 N2O
(50%) produced a mild decrease in heart rate (average 12%), mean
arterial pressure, and cardiac index and no effect on other
hemodynamic parameters, particularly pulmonary vascular resistance and pulmonary arterial pressure.47 These cardiovascular
changes are not clinically significant in healthy children, but
caution must be taken in a child with a low cardiovascular reserve.
Furthermore, N2O diminishes the oxygen half-saturation (P-50) of
hemoglobin (8 mmHg), leading to an increase in oxygen affinity
of hemoglobin that could interfere with oxygen delivery.
Therefore, N2O should be avoided (or used at low concentrations
(30%) during bronchoscopy, severe anemia, and shock states.1
The concept that the addition of N2O to volatile anesthetics
produces less cardiovascular depression than equianesthetic
concentrations of volatile anesthetics can no longer be supported.
Indeed, it has been shown that 60% N2O with 0.9 MAC halothane
or isoflurane produced a decrease in heart rate, blood pressure,
and contractility (ejection fraction) than equianesthetic concentrations (1.5 MAC) of those volatile agents.8 N2O is associated
with postoperative nausea and vomiting.48 Many of the other
adverse effects of N2O are brought about by the inhibition of
vitamin B12, which inhibits methionine synthase, folate metabolism, and DNA synthesis. These mechanisms explain neurologic toxicity with prolonged N2O administration and a possible
risk of teratogenicity.49 These effects are of particular importance
for operating room personnel.
The continued use of N2O has come under scrutiny, and in
some centers, its use has been dramatically reduced.50 In a recent
survey of members of the Association of Paediatric Anaesthetists
of Great Britain and Ireland, 57% of the responders stated that
their use of N2O had decreased over the previous 5 yearsmainly
for potential deleterious effects on patients (57%) rather than
deleterious effects on staff members (24%).51 However, only 18%
considered that some restriction on the availability would be
opportune.51 This is in accordance with the conclusions drawn by
Sanders and colleagues in a recent review on the biologic effects of
N2O.52 More evidence is necessary before discarding the only
anesthetic drug that has stood the test of time.
The MAC for each volatile agent is presented in Table 401.
TABLE 40-1. Minimal Alveolar Concentrations of the
Volatile Anesthetics Used in Children
MAC
Neonate,
%
Nitrous oxide
Halothane
Enflurane
Isoflurane
Desflurane
Sevoflurane
0.87
1.6
9.2
3.3
MAC
Infant 16
mo, %
1.1
1.7
9.4
3.2
MAC = minimal alveolar concentration.
MAC
Children
310 y, %
0.91
2
1.6
8.6
2.5
MAC
Adult, %
105
0.7
1.6
1.2
7.3
2
Xenon
Xenon is an inert gas known to have anesthetic properties for
50 years.53 Xenon is a nonexplosive, nontoxic agent that does not
undergo biotransformation and has no teratogenic potential.
Recent literature has shown that xenon has favorable anesthetic
properties54 with some characteristics that make it a potential
alternative to N2O. Its MAC is 63% and its blood-gas partition
coefficient is 0.115 that compares favorably with those of N2O
(105% and 0.47%, respectively). Xenon provides rapid induction
and rapid emergence from anesthesia. The analgesic potency of
xenon is approximately 1.5 times greater than that of N2O.55
Xenon seems to exert its anesthetic properties mainly through
glutamate receptors, with NMDA receptors being the most
important site of action.54 The incidence and nature of side effects
are very close to those of N2O: laughing, nausea, vomiting.56
Despite inhibiting the 5-hydroxytryptamine type 3 (5-HT3)
receptor, xenon is associated with a higher incidence of nausea
and vomiting than with propofol infusions.57
Xenon maintains hemodynamic stability, even in patients at
cardiovascular risk.58 The higher density and viscosity of xenon
with respect to air causes a 35% increase in peak airway pressure
during mechanical ventilation. This can be prevented by a 50%
reduction in inspiratory flow rate.59 This increase in peak airway
pressure may limit its use in small children. Numerous ongoing
studies in adults will determine whether the clinical benefits of
xenon outweigh the costs. Pediatric studies are still warranted.
Intravenous Agents
Opioids
MORPHINE: Morphine is largely used for postoperative pain
control but is still useful for intraoperative analgesia. High-dose
morphine has been associated with vasodilation, hypotension,
histamine release, and bradycardia. In pediatric outpatients, during
balanced anesthesia, morphine bolus doses of 50 to 100 g/kg
provide adequate analgesia for surgery lasting 1 to 2 hours.60 If
needed, additional doses can be given. For major surgery, higher
doses of morphine 200 g/kg are needed before surgery, with
additional bolus of 100 g/kg every 2 to 4 hours.61
Morphine, a water-soluble compound, is metabolized in liver to
3- and 6-glucuronide. These two metabolites are eliminated in
urine and prolonged elimination half-life has been reported in
patients with renal failure and in neonates because of a decreased
plasma clearance in this age group. The elimination half-life
decreases and plasma clearance increases with maturation from
the first days of life to infancy.62 The volume of distribution of
morphine in children is similar to that in adults
FENTANYL: Fentanyl is a lipophilic opioid agonist that is highly

protein-bound. Elimination half-life is age-dependent, prolonged
in premature infants compared with children (17.7 and 4.9 h,
respectively), and is a consequence of the combination of a high
volume of distribution and a low plasma clearance.63 In children,
fentanyl plasma clearance is greater (31 mL/kg/min vs 18 mL/
kg/min) and elimination half-life shorter (68 min vs 121 min)
when compared with adults.64 As a consequence, children older
than 3 months are less prone than adults to develop a fentanylinduced respiratory depression.65
Fentanyl has minimal hemodynamic effect. Bradycardia is
related to its vagolytic properties and can be reversed or prevented
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by administration of atropine. Fentanyl is associated with a minimal decrease in mean blood pressure and systemic vascular
resistance.47 In neonates, fentanyl alters the baroceptor reflex
control of the heart.66 A high dose of fentanyl can produce chest
wall rigidity, which can impede ventilation. It can be avoided by
slow administration of the opioid or used with a muscle relaxant.
A single dose of fentanyl has a short onset (~3 min) and duration
(~2030 min). Repeated doses of fentanyl can eventually saturate
inactive tissue sites (muscle, fat), leading to prolongation of action.
Fentanyl can be delivered by intermittent boluses or continuous
infusion. During balanced general anesthesia, an initial bolus of
2 to 5 g/kg followed with intermittent administration of 1 to
2 g/kg every 30 to 45 minutes, as needed, usually provides
effective analgesia. This equates to a fentanyl hourly administration
rate of 2 to 4 g/kg.67 Doses up to 5 to 10 g/kg are compatible with
a postoperative tracheal extubation. Continuous infusion of
fentanyl ensures a consistent blood level of drug and can be used for
extended periods of analgesia. Higher doses of fentanyl are used in
cardiac surgery: after a bolus dose of 25 to 50 g/kg, continuous
infusion of 10 g/kg/h is often necessary.68,69
ALFENTANIL: Alfentanil is a short-acting lipophilic opioid with a

high plasma protein-binding rate (8895%). Alfentanil is mainly
un-ionized in plasma. Cerebral penetration is rapid and explains
its short onset of action. The volume of distribution of alfentanil
is one third than that of fentanyl.
Alfentanil pharmacokinetics has a wide interpatient variability.70 In children between 4 and 8 years of age, alfentanil has a
shorter distribution and elimination half-life compared with that
in adults. This is related to a smaller volume of distribution
combined with a similar plasma clearance.71 Neonates and premature infants have a larger volume of distribution and a lower
plasma clearance, resulting in a larger elimination half-life.72 In
healthy adults, the mean context-sensitive half-time of alfentanil
is 47 minutes, and its mean pharmacodynamic offset time is
54 minutes.73
Alfentanil does not produce major hemodynamic changes,3,74
but chest wall rigidity is an unwanted side effect that can impede
ventilation.74 A bolus dose of alfentanil (1050 g/kg) is often used
during induction of anesthesia.67,75,76 Maintenance bolus doses
are within the same range, usually 10 to 50 g/kg.77 During cardiac catheterization in spontaneously breathing children, it was
shown that the mean hourly maintenance dose of alfentanil was
30 g/kg/h, with intervals between doses of 6 to 9 minutes.67
Alfentanil infusions are widely used. In cardiac patients, heavily
premedicated, an infusion of 10 g/kg/h was sufficient to provide
adequate sedation during cardiac catheterization.78 In other
surgical procedures, the infusion rate of alfentanil varies from 30
to 150 g/kg/h.3,79,80 depending on the associated anesthetics. High
infusion rates may be associated with a high incidence of postoperative hypoxemia and the use of naloxone.3
SUFENTANIL: Sufentanil is a thienyl derivative of fentanyl. Sufentanil, more lipid-soluble than fentanyl with a high plasma
proteinbinding rate (93.5%), distributes rapidly and extensively
to all tissues. The main pharmacokinetic parameters are agedependent. The volume of distribution at steady state (Vdss) is
maximal in the neonatal period, whereas plasma clearance
increases to its maximum in infants and children. Elimination
half-life decreases to a minimum in children 2 to 12 years old.81 In
children, the Vdss concentration is 1.5 times greater and the
clearance twice those described in adults.82
693
In infants and young children, a high bolus dose of 15 g/kg

of sufentanil produces a limited decrease in heart rate and systolic
blood pressure during surgery of congenital heart defect.83 As with
other opioids, sufentanil can produce respiratory depression and
chest wall rigidity.84 Chronic renal failure is not associated with a
decreased plasma clearance of sufentanil, but rather a wider
pharmacokinetic variability.85 After an induction dose between
0.2 and 0.5 g/kg, maintenance sufentanil administration is performed using either intermittent bolus doses (0.10.2 g/kg) or
continuous sufentanil infusion (0.31 g/kg/h). In orthopedic
children, a single bolus dose of 0.5 g/kg provided good quality of
analgesia in the perioperative period and stable hemodynamic
conditions during intubation and incision.86 In cardiac surgery,
sufentanil can be used as the sole anesthetic in doses ranging from
5 to 20 g/kg.81,87,88
REMIFENTANIL: Remifentanil, the latest mu receptor agonist to be

released, is an ultrashort-acting opioid. Its unique metabolism,
esterification by nonspecific plasma esterases, ensures an
ultrashort termination half-life to remifentanil independent of the
duration of infusion.73 Plasma protein binding (70%) is the lowest
of the opioids, and distribution to the tissues is rapid.
The context-sensitive half-life (i.e., the time for the blood
concentration to halve after termination of an infusion designed
to maintain a constant concentration) is a more satisfactory
parameter to describe the offset of drug duration than elimination
half-time in drugs whose pharmacokinetics can be described by a
multicompartment model.73 Remifentanil context-sensitive halftime (measured or modeled by a computer) is very short, about
3 minutes in adults (compared with 47 min for alfentanil).73
Ross and associates have studied the pharmacokinetics of
remifentanil in children.89 They found age-related changes in the
pharmacokinetic profile of this unique opioid. The clearance was
more rapid and the volume of distribution was greater in infants
younger than 2 months when compared with older children.89 The
elimination half-life did not change with age. This pharmacokinetic profile is unique because, for other opioids, the neonates
have the slowest clearance, the largest Vdss, and the longest halflife. This pharmacokinetic profile is also not modified during
cardiac surgery or extracorporeal circulation.90
Remifentanil has a very short onset time, and its maximal effect
is reached in 1 to 1.5 minutes. As a mu receptor agonist, remifentanil produces respiratory depression, but because of its pharmacokinetic profile, respiratory depression is of short duration.
Minute ventilation resolved after a mean time of 5 minutes.73
Cardiovascular effects include bradycardia and a 15 to 20% decrease in blood pressure. This hemodynamic response is no
different from other maintenance techniques using alfentanil or
propofol.3 Up to 31% of children receiving 0.25 g/kg/min of
remifentanil during balanced anesthesia required intervention to
treat hypotension and/or bradycardia. These were easily managed
with fluid or anticholinergic drugs.91 In a randomized trial during
sevoflurane anesthesia, the use of remifentanil (bolus dose 1 g/kg
and infusion rate 0.250.5 g/kg/h) was associated with a decrease
in heart rate, blood pressure, and cardiac index.92 Although the
decrease in cardiac index was mainly caused by the decrease in
heart rate, it was not completely prevented by the administration of
atropine.92
Remifentanil should be infused within an intravenous line
devoted to its use. A bolus dose (1 g/kg over 3060 s) is administered during induction.3,80,9193 Higher bolus doses have been
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used during induction, during cardiac surgery,94,95 or for facilitating tracheal intubation.96
A large range of infusion rates has been used for remifentanil.
The mean maintenance dose reported in the literature is
0.25 g/kg/min when remifentanil is a component of balanced anesthesia,91,93,97 varying from 0.05 to 0.2 g/kg/min during minor
surgery to 0.25 to 0.5 g/kg/min during major surgery under
balanced anesthesia technique with isoflurane/N2O.91 Remifentanil
(1 g/kg/min) associated with N2O has been used as the main
anesthesia technique for strabismus surgery.3
Remifentanil (mean maintenance dose 0.4 g/kg/min) has been
used in combination with low dose of midazolam for sedation
during brief painful procedures in spontaneously breathing children. However, although this drug regimen is associated with rapid
discharge times, the high incidence of respiratory depression has
reduced its popularity in this setting.98 Balanced anesthesia with
remifentanil (0.25 g/kg/min) is as effective as epidural block for
providing intraoperative analgesia, but it is associated with more
episodes of hypotension or bradycardia.91
Although remifentanil provides excellent intraoperative
analgesia and fast extubation times, early postoperative pain is a
frequent problem that must be anticipated.93 It has been shown
that high remifentanil infusion rates during maintenance of
anesthesia are associated with opioid tolerance, hyperalgesia, and
high pain scores postoperatively.99 In order to reduce postoperative
hyperalgesia, the current practice is to use a low infusion rate of
remifentanil (between 0.1 and 0.2 g/kg/min) perioperatively and
to administer long-acting analgesics, such as morphine, on
termination of the remifentanil infusion approximately 15 minutes
before completion of surgery.
WHICH OPIOID SHOULD BE USED? Important factors that may

influence drug selection are experience, convenience, and cost.
Selection of an opioid in clinical practice is based on our knowledge of pharmacokinetics and pharmacodynamics. However, the
simple comparison of half-lives for selecting an opioid is not fully
appropriate. Experimental studies have focused on more precise
pharmacokinetic models to rationalize opioid selection. Although
these studies have been performed with adults, the results with
pharmacokinetic models with three opioids (alfentanil, sufentanil,
and fentanyl) make interesting discussion.100 After a bolus administration, the effect-site (biophase) concentration of alfentanil of
37% of the initial plasma concentration is greater than those of
sufentanil and fentanyl (20% and 17%, respectively). There is a
more rapid decrease in effect-site concentration of alfentanil that
persists over many hours.
Despite the lower relative concentrations of sufentanil (5 h) and
fentanyl (135 min) after bolus administration compared with
alfentanil, the more rapid plasma effect-site equilibration seen
with alfentanil explains why, for short procedures or for intubation
when only a single peak effect is desired, alfentanil is the drug of
choice.100 There is very little difference in the offset of drug effect
between alfentanil, fentanyl, and sufentanil after a brief infusion
(designed to maintain a stable biophase concentration for 10 min)
because the decline in effect-site concentration is indistinguishable
for 60 minutes.100 After a long infusion, the recovery profile will
depend on the target opioid concentration during maintenance
anesthesia, which itself depends on the type of surgery and
associated anesthetics. Target opioid concentrations are given in
Table 402. If only a small decrease (10%) in effect-site concentration is required at the conclusion of infusion, recovery will
TABLE 40-2. Target Opioid Concentrations That

Suppressed Intraoperative Noxious Stimuli Response
or Permit Adequate Ventilation on Emergencea
Induction and
intubation
Thiopental
O2/N2O only
Maintenance
N2O/potent vapor
O2/N2O only
O2 only
Adequate
ventilation
on emergence
Fentanyl
Alfentanil
Sufentanil
35
810
250400
400750
0.40.6
0.81.2
1.54
1.510
1560
1.5
100300
100750
10004000
125
0.250.5
0.251
28, 1060
0.25
a
Opioid concentrations are in ng/mL. These concentrations are those reported in
adult studies and need to be adapted for children. The relative changes between
the opioid concentrations and the anesthesia technique or the anesthesia time
are of interest.
From reference 100.
be prompt once the infusion is terminated, whatever the opioid

used. If the opioid concentration during anesthesia is about twice
as large as the concentration desired at emergence, sufentanil
would be a rational selection for infusions of less than 8 hours
duration and alfentanil for infusions longer than 8 hours. If opioid
concentrations during maintenance need to be higher, as in opioidoxygen anesthesia technique, sufentanil is the drug of choice for
infusions shorter than 3 hours and alfentanil for longer infusions.100
Another important parameter that must be taken into account
when comparing the offset of action is the context-sensitive halftime. This represents the time taken to halve the concentration
after termination of an infusion designed to maintain stable
plasma concentrations. It is a more useful measure of the offset of
drug action than the terminal half-life.73 In adults, the measured
context-sensitive half-time for remifentanil is about 3 minutes,
considerably shorter than that of alfentanil (47 min) after a 3-hour
infusion with a target-controlled device.73 For infusions of 240
minutes duration, the context-sensitive half-time was 3.7 minutes
for remifentanil, and 33.9, 58.5, and 262.5 minutes for sufentanil,
alfentanil, and fentanyl, respectively.101 Figure 401 represents the
time course of context-sensitive half-time of the four opioids in
current use.102
Muscle Relaxants
GENERAL CONSIDERATIONS: Physiologic changes during growth
explain most of the clinical and pharmacologic differences of
muscle relaxants in infants, children, and adults. The extracellular
fluid space, in which neuromuscular blocking agents distribute,
decreases markedly during the first year of life. The largest Vdss
of muscle relaxants is thus seen in infancy. This leads to a smaller
plasma concentration for a given weight-normalized dose of
muscle relaxant.
Infants have an increased sensitivity to muscle relaxants based
on several physiologic differences in neuromuscular function,
which are partly counterbalanced by the decrease in Vdss. Weightnormalized clearance does not vary with age, and this, combined
with a larger Vdss, results in prolonged half-life of elimination in
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695
In children between 3 and 11 years, using a closed-loop system

and maintaining a stable neuromuscular block T1 twitch height
depression between 90 and 99%, the infusion rate of rocuronium
can be reduced from 20% (halothane and isoflurane) to 50%
(sevoflurane) when compared with a control group.111 The mean
infusion rate to reach this level of muscle relaxation under 1 MAC
sevoflurane was 0.5 mg/kg/h.111,112
Figure 40-1. Context-sensitive half-times as a function of infusion duration of four opioids. Context-sensitive half-time is the
time necessary to achieve a 50% decrease in drug concentration
in plasma after a variable length of opioid infusion. Modified
from reference 102.
infants.103 This, however, is not true for drugs such atracurium or
mivacurium that are metabolized in plasma by ester hydrolysis and Hoffman degradation or cholinesterases, respectively.
The elimination half-life of these agents varies minimally with
maturation.
One uniform finding is that the onset of all relaxants is more
rapid in infants than in children. Children require more of all
neuromuscular blockers on a weight-normalized basis to obtain
the same effect than infants or adults. Children recover from
neuromuscular blockade more rapidly than do patients in other
age groups.104
RAPACURONIUM: Rapacuronium was a rapid-onset, short-acting

neuromuscular blocking drug. Rapacuronium produced satisfactory intubating conditions within 60 seconds (in infants after
1.5 mg/kg doses and in children after 2 mg/kg doses). Recovery of
triiodothyronine (T3) was slower in infants than in older children,
and it was associated with a short duration of action.77 Rapacuronium was not associated with hemodynamic changes.
However, despite these qualities, the incidence of life-threatening
bronchospasm led to its withdrawal from clinical practice.105
ROCURONIUM: Rocuronium is a monoquaternary amino steroid,

derived from vecuronium, with a short onset and an intermediate
duration of action.103 After a dose of 0.6 mg/kg (95% effective dose
[ED95] 2) during halothane anesthesia, tracheal intubation can
be performed within 1.3 0.7 minutes and a duration of action of
27 7 minutes.106 Increasing the dose to 0.8 mg/kg shortened the
onset of action to 28 9 seconds while increasing the duration of
action to 32 12 minutes.
Rocuronium, like vecuronium, has a longer duration of action
in infants than in children, and the onset of action is similar in
both age groups.107 The duration of action varies widely in infants.
A dose of 0.6 mg/kg has a significantly longer duration of action
in neonates than in infants aged 5 to 12 months. Rocuronium 0.45
mg/kg provides rapid and good relaxation in infants without longlasting effects.108 In children with renal insufficiency, a single dose
of 0.3 mg/kg rocuronium has a slower onset of action but does not
prolong the duration of action compared with a control group.109
Continuous infusions of rocuronium have been used during
anesthesia and in critically ill children in the intensive care unit.110
PANCURONIUM: Pancuronium is a long-acting steroidal nondepolarizing agent, derived from D-tubocurarine. Onset of action
is 150 seconds after a dose of 0.07 to 0.1 mg/kg. Duration of action
after this dose is prolonged.103 Pancuronium causes tachycardia,
which may be beneficial for young children, counterbalancing the
vagolytic hemodynamic effects of some anesthetics. Pancuronium
is partly metabolized in the liver and partly eliminated by the
kidney. Renal or hepatic failure increases the duration of action.
VECURONIUM: Vecuronium is a steroid muscle relaxant with no
cardiovascular effects. Vecuronium is an intermediate-acting
muscle relaxant in children. However, at twice the ED95, vecuronium duration of action is prolonged in infants (73 min)
compared with children (35 min).113 The infusion rate for children
aged 2 to 10 years, aimed to provide 95% muscular blockade
during maintenance of anesthesia, has been studied.114 The
effective vecuronium infusion increased from 1.5 g/kg/min
during isoflurane anesthesia to 1.9 g/kg/min during halothane
anesthesia and 2.4 g/kg/min during narcotic-based anesthesia.114
For both potent inhalation anesthetics, but not for opioid-based
anesthesia, infusion requirements decreased significantly after
30 minutes but did not change with more prolonged infusion time.
The mean recovery index (T2575%) after termination of the infusion was 13.7 minutes.
In another study, it was shown that the mean infusion rate to
maintain 90 to 95% neuromuscular block in children (2.5 g/kg/
min) was greater than for infants (1 g/kg/min) and adolescents (1.5
g/kg/min). Sevoflurane potentiates vecuronium to a greater
extent than halothane or opioid-based anesthesia as measured by
the reduced effective doses and prolonged recovery.115 Vecuronium
remains popular. A recent survey in Great Britain showed that it was
the most frequently used muscle relaxant in pediatric intensive care.116
ATRACURIUM: Atracurium is an intermediate-acting nondepolarizing agent. Atracurium spontaneously decomposes by

Hoffmann elimination and is metabolized by nonspecific esterases. Degradation is independent of renal or liver function.
Atracurium is noncumulative and devoid of cardiovascular effects.
High doses of atracurium administered rapidly can cause histamine release and hypotension, but to a lesser extent than
D-tubocurarine. ED95 is lowest in infants (150 g/kg) than in children
aged 2 to 10 years (280350 g/kg).
After administration of an intubation dose of atracurium
(0.3 g/kg, i.e., twice ED95), the mean duration was 32 minutes.117
To maintain 95% neuromuscular blockade during a continuous
infusion, the rate varies from a mean 9.3 g/kg/min with narcoticbased anesthesia to 6.3 g/kg/min with volatile anesthetics.118
Using this dose-regimen, spontaneous recovery to 95% muscle
strength was 20.9 minutes (2.5 min with the use of neostigmine),
suggesting no accumulation with an atracurium infusion. 118 In
another study performed in critically ill children, a prolonged
infusion of atracurium was shown to be negatively correlated
with the offset time. The offset time was significantly reduced with
increasing tolerance.119
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CISATRACURIUM: Cisatracurium is an isomer of atracurium and is

also metabolized via the Hoffmann elimination and nonspecific
plasma esterases. Cisatracurium is not associated with histamine
release even in large doses. It has a slow-intermediate onset of
action.103 After a bolus dose of 80 g/kg (ED95 2), administered
during balanced anesthesia using halothane, the mean onset time
was 2.5 minutes. The mean times to 25 and 95% electromyographic
(EMG) recovery after this dose were 30 and 55 minutes, respectively. Maintenance doses of cisatracurium (20 g/kg, ED95
0.5) administered at 10% of EMG response produced a neuromuscular block of a mean 13 minutes duration, without signs of
cumulative effect when repeated.120
The pharmacodynamic properties of a single dose of cisatracurium (0.1 mg/kg) during a propofol-N2O anesthesia are comparable with those obtained after halothane or opioid anesthesia.121
Although 0.15 mg/kg cisatracurium provides excellent or good
intubation conditions in almost 95% of patients, the anesthetic
used can significantly influence its duration of action.122 The
recovery time from a single dose of cisatracurium is prolonged
during halothane anesthesia compared with a thiopental-fentanyl
anesthetic.122 Prolonged infusion of cisatracurium (infusion rate
0.23 mg/kg/h) is associated with a significantly shorter recovery
than vecuronium (infusion rate 0.16 mg/kg/h), 52 minutes versus
123 minutes, respectively.123
MIVACURIUM: Mivacurium is a short-acting competitive neuromuscular blocking agent widely used in some countries.124 In
children, it is devoid of hemodynamic side effects at almost twice
the ED95.125 It undergoes hydrolysis by plasma cholinesterase.
Prolonged neuromuscular block has been described in children
with unanticipated plasma cholinesterase deficiency.126 There is no
major pharmacokinetic and pharmacodynamic difference between young (36 y) and older (1014 y) children.124 With a dose of
0.2 mg/kg, mivacurium has an intermediate onset of action and a
short duration of action.103 After a bolus dose of 0.25 mg/kg, the
mean time to complete recovery (T4/T1 > 0.75) is about 20 minutes.127 Maintenance of neuromuscular block during anesthesia is
best performed using a continuous infusion rather than bolus doses
of mivacurium. After a mivacurium bolus of 0.1 mg/kg, a mean
continuous infusion of mivacurium 10 to 14 g/kg/min provides
satisfactory muscle relaxation (T1 at 9099% of control values).128

Prolonged infusion (294 min) is associated with no change in
infusion requirements or recovery, which usually occurred within
13 minutes.128
Volatile anesthetics potentiate neuromuscular block more than
opioid-based anesthesia. Volatile anesthetics decrease the need for
mivacurium from 35 to 70% but have no clinically significant
effect on the duration of action.129 A computerized infusion system
has been used with success in children to achieve and maintain
neuromuscular block with mivacurium.
WHEN TO USE MUSCLE RELAXANTS AND WHAT DRUG SHOULD

BE USED? The choice of the agent is determined by several factors:
its onset and duration of action, the childs age, the duration of the
surgical procedure, the presence of pre-existing renal or liver
disease, the cost, and the anesthesiologists preferences. Two
clinical scenerios can be separated according to the need or not
for muscle relaxation during surgery.
Muscle relaxant is usually not warranted for pediatric surgery.
Muscle relaxation is used to facilitate tracheal intubation. If
the anticipated duration of anesthesia is less than 30 minutes,
mivacurium can be used. If the anticipated duration is between
45 and 120 minutes, an intermediate-acting muscle relaxant could
be used (vecuronium, except for infants; atracurium; rocuronium;
and cisatracurium). Intubating doses of muscle relaxant are usually
equivalent to twice the ED95.
Muscle relaxant is warranted for abdominal and thoracic
surgery. Muscle paralysis facilitates the surgical procedure and
parietal closure. Muscle relaxants are used also during meticulous
phases of surgery such as strabismus surgery or for difficult
orthopedic reductions. The degree of the neuromuscular blockade
depends on the surgical requirements, the length of parietal
closure, and its difficulty. Usually, muscle relaxants of intermediate
duration of action are given by iterative bolus doses (usually 0.5
ED95) or by continuous infusion. The dose requirements of muscle
relaxants for maintenance of neuromuscular blockade are shown in
Table 403. Bolus doses to reach a 95% decrease in twitch response
can be repeated as frequently as every 10 to 15 minutes. This can
be offset by a continuous administration of muscle relaxants.
However, continuous infusions have some drawbacks. They require
TABLE 40-3. Maintenance Doses of the Main Muscle Relaxants Used in Pediatric Anesthesiaa
Maintenance Dose Given As a
Continuous Infusion, g/kg/min, mg/kg/h
Maintenance Dose Given

as a Bolus, mg/kg
Atracurium
610, 0.360.6
0.1
Cisatracurium
13, 0.060.18
0.02
Mivacurium
1016, 0.60.9
0.1
Pancuronium
0.02
Rocuronium
15, 0.9
0.30.5
Vecuronium
12.5, 0.060.15
0.0150.025
ED95, g/kg
Infants 150
Children 280350
Children 40
Infants 6594
Children 90
Infants 72
Children 6093
Infants 250
Children 400
Infants 2447
Children 3875
ED95 = 95% effective dose.

a
The dose ranges for different muscle relaxants reflect the interindividual variability and the effects of age (infants often need a lower dose than children) and
associated anesthetics (opioid-based anesthesia requires a larger dose of muscle relaxant than anesthesia with volatile agents).
Derived from 103, 106, 107, 113, 114, 117, 118, 120, 122, 125, 127.
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additional equipment (e.g., syringe pump) and a dedicated venous
line to avoid rate variability and chemical incompatibility.
Whatever the method of muscle relaxation chosen, it is recommended that neuromuscular blockade during maintenance and
recovery is monitored (see Table 403). Accelerography can be
used to monitor the neuromuscular response.130
New reversal agents are expected to change our practice of
muscle relaxation. Sugammadex is a novel, selective relaxantbinding agent designed to reverse rocuronium-induced neuromuscular blockade. In adults, sugammadex provided a rapid
reversal of motor blockade produced by high dose of rocuronium.131 The dose-response of sugammadex was recently studied
in infants, children, adolescents, and adults.132 There was a doseresponse relationship in all groups except infants, and sugammadex
was associated with a rapid and safe reversal of neuromuscular
blockade.132
Hypnotics Agents Used as Adjuvants

KETAMINE: Ketamine is chemically derived from phencyclidine
and has been used since the early 1970s as an intravenous
anesthetic. It produces dissociative anesthesia, that is, a functional
and elec-trophysiologic break between thalamocortical and limbic
systems. Ketamine is a racemic mixture of two enantiomers.
S+ ketamine is three times more active, but is only available in
some countries. It has no significant advantages.133,134
Ketamine metabolism consists mainly of hepatic transformation to norketamine that is a third as potent as ketamine.
Ketamine causes central stimulation and release of endogenous
catecholamines, resulting in stimulation of the cardiovascular
system, which manifests as an increase in heart rate and blood
pressure. Ketamine depresses myocardial contractility in the
isolated heart.135 Ketamine produces a significant increase in ICP
in patients at risk of elevated ICP. In animals, ketamine causes
significant cerebral vasodilation that is related to central cholinergic stimulation and is thought to be the mechanism for the
increase in ICP.136
Respiration is well maintained during ketamine administration.137 Although ketamine maintains chest wall muscle tone and
maintains functional residual capacity (FRC).138 When used for
total intravenous anesthesia (TIVA), ketamine does not affect
E but significantly alters
resting respiratory rate, VT, ETCO2, or V
the ventilatory response to CO2.139 Ketamine has bronchodilating
effects but increases airway secretions that can be minimized with
the concomitant use of an anticholinergic agent. Its effects on
airway protective reflexes remain uncertain.135
Emergence delirium is thought to be infrequent in children. It
was shown that ketamine was associated with a relative low incidence of emergence agitation and that the addition of midazolam
to ketamine had no measurably beneficial effect.140
Ketamine is widely used for cardiac catheterization in children,141,142 in precarious hospital environments, such in war surgery,143 and for sedation in pediatric intensive care.137 Ketamine
(oral or intramuscular) is also used outside the operating room by
nonanesthetist physicians.144
For intravenous administration, the induction dose is usually
2 to 2.5 mg/kg and the maintenance dose varies from 40 to 130 g/
kg/min (2.47.7 mg/kg/h) in anesthesia and 10 to 15 g/kg/min
(0.60.9 mg/kg/h) for sedation in intensive care in spontaneously
breathing children.137,139,142,143
697
Two properties pertinent to the improvement in patient comfort explain the new interest for this old drug, that is, ketamine
has antihyperalgesia antiproinflammatory properties. Acute
opioid tolerance and hyperalgesia have been described with the
new short-acting opioids, a mechanism that involves activation of
NMDA systems. Ketamine, an anti-NMDA agent, alleviates both
tissue destruction and opiate-induced hyperalgesia in adults.
However, three recent studies in children showed no effect of
low-dose ketamine on morphine consumption after major surgery
or tonsillectomy in children.145147 An antiproinflammatory effect
of ketamine has been suggested, but to date, its clinical implication
in children is trivial.133
PROPOFOL: Propofol, 2,6-di-isopropylphenol, was first introduced

as an induction agent. It was rapidly used to maintain anesthesia
and was shown to be suitable for sedation. Propofol has a rapid
onset of action and recovery. It has a rapid metabolic clearance
that exceeds hepatic blood flow, suggesting that propofol is also
metabolized in extrahepatic sites. Propofol has a context-sensitive
half-time of less than 25 minutes after infusions lasting as long as
3 hours, and the half-time is still only 50 minutes after prolonged
infusions.
Cardiovascular effects of propofol are mild in healthy children.
They have been shown to be related to peak arterial concentrations
and can be minimized by reducing the rate of administration.148
Propofol is associated with a decrease in mean blood pressure
(10%), mainly secondary to a decrease in systemic vascular resistance,149 whereas cardiac index is reduced by 10%. These cardiovascular effects can lead to an increase in right-to-left shunt in
children with cyanotic congenital heart disease, causing clinically
relevant arterial desaturation.149 Decrease in blood pressure is not
associated with an increase in heart rate. Furthermore, a 20%
reduction in heart rate is a common feature.148 However, when
propofol is used for maintenance in strabismus surgery (associated
with a high incidence of vagal stimulations), bradycardia is
common.150
Propofol is associated with respiratory depression. Transient
apnea frequently occurs after induction of anesthesia with
propofol, whereas VT and respiratory rate decrease, leading to
hypercarbia.151 Involuntary movements can occur during induction and maintenance anesthesia. Propofol has been shown to
have antiemetic effects.150
Rapid recovery after propofol anesthesia has been well documented.152154 In children, 1 mg/kg of propofol significantly reduces
the incidence of emergence agitation after sevoflurane anesthesia.155
Propofol can also be used to achieve a rapid increase in the depth
of anesthesia. The pharmacokinetic profile of propofol makes it an
ideal agent for maintenance of anesthesia. The maintenance
infusion doses of propofol for either TIVA or target-controlled
intravenous anesthesia are described in Chapter 41.
MONITORING AND SAFETY

PRECAUTIONS DURING
MAINTENANCE OF ANESTHESIA
Routine Monitoring
Hemodynamics
Monitoring heart rate is crucial during anesthesia because,
in young children, cardiac output is heart ratedependent.
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Electrocardiography detects conduction and rhythm abnormalities

and lead II is preferred for detection of dysrhythmias. Ischemic
changes are rare in children. Pulse oximetry can estimate peripheral perfusion, and loss of the oximeter signal is often associated
with poor peripheral perfusion states. Evaluation of heart tone with
a precordial or esophageal stethoscope can provide useful information on cardiac contractility and volume status. Capillary refill
time (normal < 3 s) and core-peripheral temperature gradient
(difference between central temperature and peripheral temperature, normal < 3.5C) are often used to evaluate the systemic
vascular resistance, but their reliability is low. In neonates, capillary
refilling time has been shown to be correlated with cardiac index.156
Noninvasive blood pressure is accurately measured with oscillotonometry. In case of technical difficulties, systolic blood pressure
can be measured using a Doppler ultrasonic flow detector placed
on an artery distal to the occluding cuff. Invasive arterial catheterization allows beat-to-beat information about blood pressure
and is indicated when major changes in peroperative hemodynamics are anticipated. This may be caused by the patients
cardiovascular status, the surgery, or both. Central venous catheters
can be used to monitor the filling pressures. Swan-Ganz catheters
can be used for monitoring capillary wedge pressure and/or
intermittent cardiac output assessment. Continuous monitoring of
mixed venous saturation has been used in some institutions for
intraoperative and postoperative cardiac monitoring during
cardiac surgery or when hemorrhage is anticipated during surgery,
such as liver transplantation. Continuous monitoring of jugular
venous saturation can also be useful when surgical hemorrhage
is anticipated. The place of hemodynamic monitors such as
thoracic bioimpedance, transesophageal echocardiography, Pulse
Impedance Contour Cardiac Output monitor (PiCCO), and NonInvasive Contour Cardiac Output monitor (NiCCO) are discussed
in Chapter 38. Urine output is monitored when variations in
hemodynamics are anticipated. A normal urine flow is ranges
between 0.8 and 1 mL/kg/h.
Respiratory
Ventilation is assessed clinically by observing the rate and depth of
respiration, the expansion of the chest, the manual estimation of
pulmonary compliance, the color of the skin, and the existence of
abnormal breath sounds on auscultation or simple listening. Pulse
oximetry has become widely accepted as a routine monitor during
anesthesia since the early 1990s. It accurately measures oxygen
saturation (SpO2), and its use significantly reduces the occurrence
and duration of hypoxic events during anesthesia in children.21
Pulse oximetry is more sensitive than clinical examination to
detect hypoxemia in children,157 but its impact on the outcome of
anesthesia has been questioned.158
Capnography provides information about the inspired CO2 and
ETCO2. Capnography can be used in several clinical situations.
Absence or disappearance of the ETCO2 trace may indicate an esophageal intubation, an accidental extubation, or a ventilatory circuit
disconnection. The sudden reduction of ETCO2 indicates a sudden
deterioration in hemodynamic status or a pulmonary embolus. A
rapid increase in ETCO2 associated with a fever suggests malignant
hyperthermia crisis. The failure of the capnograph to return to the
baseline ETCO2 suggests rebreathing owing to inadequate fresh gas
flow (FGF). During mechanical ventilation, there is a good correlation between ETCO2 and arterial carbon dioxide pressure (PaCO2)
in children with normal pulmonary function; the gradient between
PaCO2 and ETCO2 is less than 1 mmHg. In children with a pulmo-
nary disease or cyanotic heart disease, ETCO2 frequently underestimates PaCO2.159 Quantitative end-tidal capnography is limited in
neonates and infants who exhale small VTs at high respiratory rates.
In these patients, measuring ETCO2 at the distal end of the endotracheal tube (ETT) is more accurate.160 During spontaneous ventilation with a laryngeal mask airway (LMA), ETCO2 underestimates
PaCO2, and distal sampling is also more accurate than proximal
sampling of ETCO2. Capnography is less sensitive than SpO2 in
detecting intraoperative respiratory complications in pediatric
anesthesia,157 but it allows fine-tuning of ventilator settings during
anesthesia, to prevent hypercarbia or hypocarbia. New ventilators
on modern anesthesia machines can accurately monitor VT, peak
E during mechanical ventilation. Blood
inspiratory pressure, and V
gas analysis, after arterial or capillary blood sampling, is commonly
used to detect acid-base imbalance and/or to monitor the adequacy
of the ventilation.
Muscle Relaxation
Monitoring muscle relaxation in children is important because of
wide individual variability in muscle relaxant effects. Unanticipated
residual neuromuscular block may occur in the postoperative
period as a result. In clinical practice, three sites of neurostimulation can be used: surface electrodes are positioned either
on the ulnar, posterotibial, or facial nerves. Muscles show some
difference in sensitivity to muscle relaxants. The orbicularis oculi
is used for timing good intubation conditions, whereas the
adductor pollicis is used to predict recovery from neuromuscular
blockade.161 Different modes of stimulation are used: simple twitch
(ST), train of four (TOF), posttetanic count (PTC), and doubleburst stimulation (DBS). They represent valuable tools for assessing
neuromuscular blockade at different times during anesthesia.
Interpretation of neuromuscular block monitoring during maintenance and recovery are represented in Table 404. Motor
response after nerve stimulation is usually assessed visually or
using accelerometry.162 In infants, the amplitude of thumb movement is sometimes insufficient to be accurately recorded with
acceleromyography. It is possible to augment the movement amplitude by placing the piezoelectric sensor on a piece of wood, for
example, attached to the childs thumb.
Temperature Monitoring
Perioperative measurement of body temperature is necessary in
infants and children to detect hypothermia, which readily occurs
during surgical procedures, especially those involving body
cavities; and to detect malignant hyperthermia. Central temperature monitoring is preferable to determine the degree of heat
loss in pediatric anesthesia. Tympanic membrane, pulmonary
artery, rectal, nasopharyngeal, and esophageal temperatures give
similar indications of central temperature. An axillary temperature
probe best detects the rise in temperature associated with
malignant hyperthermia because it lies in close proximity to the
muscle mass of the shoulder and the axillary artery. At the other
extreme, it is equally important to regularly check the temperature
to prevent hypothermia during anesthesia.
Monitoring the Depth of Anesthesia

Clinical Monitoring
General anesthesia has two closely linked components: loss of
consciousness and loss of reaction to painful stimuli. In the past,
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TABLE 40-4. Interpretation of Neuromuscular Block
Monitoring During Maintenance and Recovery
Perioperative Monitoring
Profound neuromuscular block monitoring
TOF with facial nerve stimulation
0 response: deep neuromuscular block.
13 responses: adequate neuromuscular block,
compatible with good surgical conditions.
4 responses: insufficient neuromuscular block: additional
muscle relaxant dose administration.
Moderate neuromuscular block monitoring
TOF with ulnar or posterior tibial nerve stimulation
0 response: too deep neuromuscular block.
13 responses: adequate neuromuscular block,
compatible good surgical conditions
4 responses: insufficient neuromuscular block: additional
muscle relaxant dose administration
Recovery
Can reversal of paralysis be achieved?
TOF with ulnar nerve stimulation
Long duration of action muscle relaxant (pancuronium
or vecuronium in infants)
3 responses: insufficient spontaneous recovery. Wait
before reversal.
4 responses: reversal can proceed.
Intermediate duration of action muscle relaxant
1 response: insufficient spontaneous recovery. Wait
before reversal.
2 responses: reversal can be performed.
Is neuromuscular block completely reversed?
DBS with ulnar nerve stimulation
Second response is weaker than the first one:
incomplete recovery.
2 identical responses: complete recovery of
neuromuscular function.
DBS = double-burst stimulation; TOF = train of four.
Guedels stages and planes of ether anesthesia were the cornerstone

of clinical monitoring and focused on ventilation, pupil size, eyeball
activity, muscle tone, and brainstem reflexes.163 Routine monitoring
of depth in modern anesthesia still relies on clinical observation.
When the depth of anesthesia increases, several planes or levels of
consciousness will be progressively obtunded: loss of awareness
(recall or explicit memory) is the first step, followed by loss of
wakefulness (implicit memory). Awareness during anesthesia is a
major cause for patient complaints.164 Obtunding motor response
is occurs at more profound levels of anesthesia levels.
Currently, clinical signs associated with loss of memory are
lacking and anesthetists use motor response, as well the ventilatory
and hemodynamic responses to noxious stimulation, to determine
the depth of anesthesia.154,165,166 Evanss pressure, heart rate (HR),
sweating, tears (PRST) score for depth of anesthesia assessment
relies on blood pressure, heart rate, sweating, and tear production.167 Clinical monitoring has some major limitations: it is an a
posteriori evaluation (limb movement or tachycardia in response
to a noxious stimulus means that the depth of anesthesia is not
adequate), and medications can blunt these responses (muscle
relaxants, blockers blockers). Fur-thermore, clinical measures
that appear relevant for a single drug may not be relevant if drugs
are used in combination.164
699
Bispectral Index Analysis and

Cerebral State Monitor
Analysis of the electroencephalogram (EEG) has been used for
several years to monitor the depth of anesthesia. Bispectral index
(BIS) is based on bispectral processing that determines the
harmonic and phase relations among the various EEG frequencies calculated by Fouriers analysis. BIS is a proprietary
nonlinear, single variable that is based on pooled adult data
(clinical and EEG assessments); its algorithm is extremely complex.164 BIS, a processed EEG parameter, varies from 0 to 100. The
deeper the level of anesthesia, the lower the BIS value recorded.
The BIS was developed for use in adults, and although its EEG
algorithm was not designed for children, it has been used in the
children without software modification.5 BIS is inversely proportional to the end-tidal concentration of sevoflurane (BIS = 50
at 1.5% and 1.25% end-tidal sevoflurane in infants and children,
respectively).168
The increase in BIS with decreasing age is supported by four
recent studies.169172 Halothane has different effects on BIS values
than desflurane or sevoflurane at equivalent MAC concentrations.
The BIS reading during 1 MAC halothane was significantly greater
than during 1 MAC sevoflurane in Edwards and coworkers study
(61 7 vs 44 14).171 In Tirel and colleagues study, the BIS reading
during 1 MAC halothane anesthesia was significantly greater than
during 1 MAC desflurane (62 7 vs 34 14).170 The effect-site
equilibrium half-life of sevoflurane is shorter in young children
than in adults. This difference has a significant clinical implication, that is, the faster offset of sevoflurane effect in young
children.172 Most maturational changes occur early in life, during
infancy. Therefore, the BIS is unable to monitor the depth of
anesthesia when used with halothane.
Other devices such the cerebral state monitor (CSM) have been
developed to guide anesthetic administration with the EEG. It uses
its own algorithms and gives a value, the cerebral state index (CSI).
It has been shown that pharmacokinetic and pharmacodynamic
modeling of the sevoflurane effects are different with CSI and BIS.
The maximal response is higher when using CSI versus BIS, and
these differences should be considered.173 In another study, CSI
was shown to be correlated with a clinical sedation scale. Repeated
doses of propofol produced an increase in sedation that was
associated with a gradual decrease in CSI.174
Auditory Evoked Potentials

Auditory evoked potentials (AEPs) have been sparsely used to
monitor the depth of anesthesia in children. The auditory evoked
potential index (AEPI) is derived from AEPs and has been
proposed as a single numerical variable. AEPI reflects the overall
morphology of the AEP curves and is calculated from the amplitude difference between successive segments of the curves.175
AEP patterns in children older than 2 years are similar to those in
adults but are unreliable in children younger than 2 years because
of the presence of artifacts that highlight the technical difficulties
of conventional AEP monitoring in this age group.176
Midlatency segments of the auditory evoked potentials
(MLAEPs) in children showed inconsistent results when compared those in adults. MLAEP amplitudes show a high interindividual variability and are not dependent on childrens age. The
MLAEP occurs 10 to 100 ms after the auditory stimulus and is the
section of the AEP that is most useful for grading anesthesia effect.
It represents the earliest cortical response to an acoustic stimulus.
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The AEP latencies increase during anesthesia and are correlated

with age, according to an ongoing process of maturation of the
auditory pathway.177 Three recent studies have dealt with a
composite auditory evoked potential index (cAAI).174,178,179 The
composite A line ARX index is generated by a combination of
MLAEP and EEG. Specifically, the cAAI is preferably derived from
MLAEP, but if the MLAEP signal is weak, it is entirely derived from
EEG. cAAI was comparable with BIS for monitoring the depth of
anesthesia in children older than 2 years.178 cAAI is strongly
correlated with a clinical score of sedation during propofol anesthesia and varies with the level of sedation: cAAI decreases
during induction and maintenance and cAAI increases during
emergence.174 During an isoflurane-maintained anesthesia, cAAI
was similar to BIS for monitoring the depth of anesthesia.178
Because of faster signal processing, the cAAI seemed to be superior
to the BIS for the prediction of loss of consciousness.178 These
results, however, need to be confirmed.
COMMONLY USED
MAINTENANCE TECHNIQUES
Maintenance of Anesthesia
with Hypnotics and N2O
This is the most widely used maintenance technique for children
undergoing short procedures with limited or no anticipated postoperative pain such as gastroscopy, bronchoscopy, dental restoration, myringotomy, simple reduction of closed fracture, total body
irradiation, and diagnostic imaging. This maintenance technique is
also widely used in children undergoing more painful surgery in
which postoperative analgesia is provided with a regional block154
or infiltration of the surgical wound with local anesthetics.165
Muscle relaxants can be used depending on the airway management and surgical needs. Both volatile agents and propofol are
effective as hypnotics. Although pediatric anesthesiologists have
the most experience with volatile agents, since about 2000 the
emergence of intravenous maintenance, mainly propofol. This is
also described in Chapter 41. Maintenance of anesthesia with
volatile agents has been compared with propofol in numerous
studies. During pediatric myringotomy, propofol maintenance with
the use of iterative bolus doses (0.5 mg/kg) was associated with
more intraoperative movements and, although some recovery
variables were achieved more rapidly in the propofol group than in
the halothane group, the authors found no benefit in using propofol
for maintenance in this very short duration anesthesia.180 In
another study, there was no difference in operating conditions and
early recovery variables in children anesthetized with N2O, regional
anesthesia, and either propofol or halothane (0.52%) used for
maintenance.181 Maintenance with isoflurane was compared with
propofol in pediatric outpatients. No difference was shown in the
recovery score, whereas the incidence of vomiting and airway
obstruction in the postanesthesia care unit (PACU) was reduced
in the propofol group. Propofol was compared with sevoflurane in
children undergoing minor surgery. Although heart rate tended to
be higher in the sevoflurane group, both maintenance techniques
provided stable intraoperative cardiorespiratory conditions.
Emergence was more rapid but agitation more frequent in children
anesthetized with sevoflurane.182 Volatile anesthetics have been
compared. In children undergoing ambulatory surgery under
caudal block with anesthesia maintained with 1 MAC halothane
or desflurane, early recovery and recovery room time duration

were shorter with desflurane, but the difference (mean length of
stay in the PACU 21 min vs 29 min) was not clinically significant.
The authors reported a trend for a higher incidence of postoperative delirium with desflurane.183 In dental surgery of short
duration, induction and maintenance of anesthesia with halothane
were compared with sevoflurane. The incidence of peroperative
cardiac arrhythmias was significantly higher during halothane than
during sevoflurane anesthesia (44% vs 24%). The quality of
anesthesia and recovery characteristics were similar in both groups,
but agitation was more frequent in the sevoflurane group.184 In a
study comparing sevoflurane with halothane used at 3.0 MACequivalent concentrations for gastroscopy or bronchoscopy in
children, cardiac arrhythmias were more frequent with halothane
whereas the psychomotor performance recovered more rapidly
with sevoflurane, leading to a shorter length of stay in the PACU.185
In children undergoing adenoidectomy and myringotomy, desflurane anesthesia (1.3 MAC) was associated with a fastest emergence from anesthesia in the early period, when compared with
equipotent concentrations of sevoflurane or halothane, but was also
associated with a greater incidence of agitation during recovery.
Furthermore, there was no difference in home discharge times
among the different volatiles agents.31
In conclusion, both volatiles agents have been shown to provide
adequate maintenance of anesthesia. They are most often used
in combination with N2O, which allows a significant reduction in inspired concentration of volatile agents for equivalent
effect.186 The choice between intravenous anesthetics and volatile
agents is based on surgical requirements, anesthesiologists
choice, pharmacologic properties (quality of recovery, antiemetic action can favor propofol), resource utilization, and cost.
Among volatile agents, sevoflurane has become the agent of choice
because of its smooth induction and use in maintenance of
anesthesia. Halothane continues to play a role in pediatric anesthetic practice in many countries where it remains the only
affordable agent.4
Balanced Anesthesia Techniques

The cornerstones of balanced anesthesia are to provide loss of
consciousness with amnesia, analgesia, muscle relaxation, physiologic stability, and reduced stress response. Balanced anesthesia
can be provided using various combinations of drugs. Although
previously described using a combination of thiopental, N2O, and
opioids, balanced anesthesia later referred to any technique using
a combination of opioid, hypnotic (either intravenous or volatile
agent), and muscle relaxant if needed. Balanced anesthesia reduces
the need for volatile or intravenous anesthetics, thereby reducing
their side effects. A small bolus dose of fentanyl 1.5 g/kg decreased the MAC of desflurane and isoflurane blocks the cardiovascular response to surgical incision (MAC-BAR).187 In adults,
a 50% reduction of MAC isoflurane is produced by plasma
concentrations at 1.37 ng/mL for remifentanil, 1.67 ng/mL for
fentanyl, and 0.14 ng/mL for sufentanil.188 Furthermore, although
intraoperative analgesia (100 g/kg of morphine or regional
anesthesia) reduces the concentrations of intraoperative anesthetics, it does not affect the concentration of halothane at which
children spontaneously open their eyes.48 Thus, by decreasing the
MAC of volatile agents with no change in the awakening MAC,
the recovery time should be shorter with this technique, without
compromising effective analgesia.
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During balanced anesthesia in children, bolus doses or continuous infusion of various opioids are used, in combination with
other volatile or intravenous agents. The opioid and anesthetic
dose varies widely with the surgical procedure and the patients
response to surgical stimulus.93,97,182 Anesthesiologist often rely on
the cardiovascular response (20% within the baseline) for balance anesthesia. During short surgical procedures, a single bolus
of opioid administered before surgery is generally sufficient to
provide adequate analgesia during the procedure. If the case is
more prolonged, additional boluses or a continuous injection is
necessary. Table 405 shows guidelines for using opioids during
balanced anesthesia.
Maintenance and Regional Anesthesia

Regional anesthesia is now widely used in children. In two French
surveys, more than 25% of pediatric anesthesia cases were provided
using regional anesthesia.189,190 Regional anesthesia is thought to
improve the quality of analgesia during and after surgery, and
although performed under general anesthesia most often, it allows
a reduction in the need for anesthesia (and, as a consequence, can
shorten recovery time) and postoperative analgesics.191
The Pediatric Paradox

Although regional anesthesia is usually performed in awake adults,
only a minority of regional blocks are performed without sedation
or general anesthesia in children without affecting morbidity.189,190
Spinal block can be performed in premedicated children between
1 and 13 years of age, but sedation is often required.192 Furthermore, up to 30% of children operated on with a caudal block as
the sole anesthetic needed a general anesthesia for completion of
the surgical procedure.193 The fact that most blocks require supplementary general anesthesia suggests that regional anesthetics can
be used only for analgesia rather than as a sole anesthesia technique in children.
Regional Anesthesia As the

Sole Anesthesia Technique
Spinal anesthesia or caudal anesthesia is commonly used as the
sole anesthetic technique in expremature babies undergoing
inguinal herniotomy with the aim of reducing the incidence of
postoperative apnea associated with general anesthesia in this age
group.194 Spinal or epidural anesthesia has been described in older
children with poor medical status operated on for spine fusion in
the prone position and spontaneous ventilation with no sedation or
general anesthesia.195 Supraclavicular brachial plexus block have
been used as the sole anesthetic technique in a large series of

children aged 5 to 12 years undergoing closed reduction of arm
fractures. Although the success rate was 91%, the overall acceptance of the block by the children was 72%, which is far from ideal
in pediatric anesthesia.196 Finally, awake regional anesthesia can be
performed for various surgical procedures in adolescents.
Maintenance of General Anesthesia

in Children With a Regional Block
Anesthesia is frequently maintained using volatile agents. Low
concentrations of enflurane (between 0.5 and 1.5%) in N2O were
used during caudal and continuous epidural anesthesia.13 In
another large series of children with caudal block, anesthesia was
maintained with 0.25 to 0.5% of halothane or 0.5 to 1% of isoflurane in N2O.197 N2O (60%) in oxygen and pancuronium have been
used successfully as the sole maintenance drugs during epidural
anesthesia for urologic and abdominal surgery, but this technique
poses the problem of awareness and recall during anesthesia.
Which Regional Block to Use

and When to Perform It?
Several local anesthetics are available for use in children and a
wide variety of regional blocks can be performed. Detailed descriptions of these blocks are provided in Chapters 44 to 51. The
choice depends upon several factors including the duration and
sensory level of surgery, the intensity of postoperative pain
anticipated, and the personal skills of the anesthesiologist. Adjuvants, such as clonidine or opioids, can increase the duration
and/or the quality of analgesia provided by central blockade.84,192
New regional anesthesia techniques have been developed in recent
years. Although single-shot blocks are routinely used, caudal block
still being the most popular among them, peripheral nerve
blockades have increased in children.190 Two French surveys of
regional anesthesia in children showed that the complication rate
after peripheral blocks is low, much lower than that after central
blocks, and gives a solid argument for their use.189,190
Continuous peripheral nerve blockade using peripheral nerve
catheters has become increasingly popular in adults and has also
been studied in children.198,199 In a recent study, continuous
popliteal sciatic block was shown to be as effective as continuous
epidural anesthesia in providing postoperative pain control and
was associated with a lower incidence of side effects.199 Regional
anesthesia can be performed before surgery or after induction of
anesthesia for intraoperative and postoperative pain relief or after
completion of surgery (for postoperative pain relief). Preoperative
and postoperative placement has been shown to be equally
TABLE 40-5. Suggested Dosage of Opioid During Maintenance of Anesthesia
Opioid
Alfentanil
Fentanyl
Morphine
Remifentanil
Sufentanil
Minor Surgery
Bolus, g/kg
1030
13
50100
0.20.3
Moderate to
Major Surgery
Bolus, g/kg
50100
510
100200
0.51
701
Infusion Rate
During Balanced
Anesthesia, g/kg/h
30100
310
0.10.5
515
Cardiac Surgery
Bolus, g/kg
200500
50100
20003000
0.31
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effective in providing pain relief after circumcision under caudal

block200 or hand and forearm surgery under axillary block.201
Other authors have shown that preemptive caudal anesthesia with
a combination of bupivacaine and morphine was more effective
in providing prolonged postoperative pain relief than the same
technique performed after surgery.202
Ventilation During Maintenance

of Anesthesia
Low-flow Anesthesia in Children
Various anesthetic breathing systems are currently used in
children and have been reviewed in Chapter 38. The most widely
used pediatric breathing systems are the Jackson-Rees system,
the Mapleson D system, and its modified coaxial form, the Bain
circuit.203 The recommended FGF varies with the circuit: about
E with a Jackson-Rees circuit, 150 to
three times the patients V
200 mL/kg/min and 70 mL/kg/min, respectively, during spontaneous and controlled ventilation in a Mapleson D system.203
Low-flow anesthesia and closed anesthesia systems have gained
popularity in pediatric anesthesia for several reasons. Economic
factors are particularly important since the introduction of more
expensive volatile agents into clinical practice.204 Low-flow
anesthesia is defined by the use of a flow rate less than the patients
alveolar ventilation.204 A closed circuit is a system in which FGF is
just sufficient to replace the volume of gas and vapor taken up by
the patient.204 The main advantages of these anesthesia systems
include the reduction of heat loss and moisture, cost savings, and
reduced operating theater pollution. The low-flow anesthesia
techniques require equipment designed for children to minimize
apparatus deadspace.
THE USE OF PEDIATRIC CIRCLE SYSTEMS: The pediatric circle

system was designed to use low FGF in children. However, one
major concern is the increased resistance across valves and
canister. Despite validation of the pediatric circle in spontaneous
breathing children, which compared favorably with Jackson-Rees
circuit,205 this system has not gained wide acceptance.204
THE USE OF ADULT CIRCLE SYSTEMS IN PEDIATRIC ANESTHESIA:

Pediatric anesthesia centers frequently use adult circle systems.206
Modifications are required for children weighing less than 20 to
30 kg. These include the use of 15-mm internal diameter tubes and
connectors with a minimal deadspace. In an infant lung model,
mechanical ventilation with an adult circle system is effective and
compares favorably with the Bain system or ventilation using
intensive care unitdesigned neonatal ventilators,206 allowing its
use for a wide range of pediatric patients.204 Leaks in the breathing
system limit the use of low-flow circuits.
LMAs and ETTs have been shown to provide similar airway
sealing to allow low-flow or closed anesthesia to be used even in
young children.207 The risk of compound A production with
sevoflurane is also a concern with low flows in a circle system.
Neither 2 L/min flows nor a lower flow rate (600 mL/min)
produced toxic concentrations of compound A.208 Two studies in
children have shown that low-flow anesthesia significantly reduces
the volatile agent expenditure and, as a consequence, the cost of
anesthesia.208,209 In some countries, guidelines for use of sevoflurane in rebreathing systems is restricted to minimal flow rates
of 2 L/min to prevent compound A formation. However, in Europe
and Japan, sevoflurane is used with flow rates as low as 600 mL/
min without apparent side effects. At these low FGFs, accurate

monitoring of inhaled and exhaled gas, oxygen saturation, and
ETCO2 must be used, and FGF must be kept high enough to
prevent rebreathing (ETCO2 < 0.2 kPa).
High-flow Closed Circuit Anesthesia

The ability to monitor volatile agents during anesthesia has
contributed to the development of closed circuit anesthesia using
low gas flows. However, induction administered via a closed, lowflow circuit is not possible because of an excessive equilibrium
time between inhaled and end-expiratory gas concentrations ratio.
The Rotterdam anesthesia ventilator (Physioflex, Drager, Inc) was
the first generation of new anesthesia machines allowing inhalational anesthesia with a target-controlled end-expiratory
concentration of anesthetic gas.210 The Zeus (Drager, Inc) represents the latest in the evolution of the Rotterdam anesthesia
ventilator commercially available.
The Felix-AInOC (Taema, Inc) is another relatively new anesthesia platform allowing target-controlled inhalation anesthesia.
The clinician sets the target parameter (i.e., the end-expiratory
agent concentration) and the machines computer adapts gas flows
in order to reach the target end-tidal concentration quickly. In
theory, the main advantage lies in significant cost savings by limiting consumption of the volatile agents.210 In reality, this is
probably true only if the child accepts the mask during induction
of anesthesia. To date, few papers have dealt with target-controlled
anesthesia in children. In a recent study, it was shown that targetcontrolled inhalation induction was feasible in children and that
the targeted sevoflurane concentration could be reached quicker
with fewer adjustments in gas concentration.211
Spontaneous or Mechanical Ventilation

During Maintenance of Anesthesia?
General anesthesia is associated with respiratory depression,
which is related to both centrally and peripherally acting drugs
and/or to the surgical intervention. Thus, the anesthesiologist
must choose the type of airway management and the mode of
ventilation during maintenance of anesthesia.
Spontaneous ventilation can be maintained via a facemask,
LMA, or ETT. Spontaneous ventilation, irrespective of the airway
used, should be limited to procedures of short duration (lasting
< 30 min) and is generally not recommended for the youngest
E has been evaluated during mask
patients, particularly neonates. V
halothane/N2O anesthesia in children undergoing elective
herniorraphy with an ilioinguinal field block. Although there was
E between infants and older children, there
no difference in V
was a greater reduction in VT in infants predisposing them to
hypercarbia during spontaneous ventilation.14 Spontaneous
ventilation during halothane anesthesia with an LMA or ETT
E and V were greater and paradoxical
has also been compared. V
T
inspiratory movements less frequent in the LMA group when
compared with the ETT group.212 Facemask with an oral airway
was associated with a decreased incidence of airway complications
compared with an LMA in infants.213 This difference is probably
the related to the difficulties in maintaining the airway with small
LMAs (sizes 1 and 1.5).214
Intermittent positive-pressure ventilation (IPPV) is indicated
when muscle relaxants are used, when the surgery is lasting more
than 30 minutes, in small children, or when the surgical procedure
dictates. IPPV is sometimes used for short surgical procedures.
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IPPV has been compared with spontaneous ventilation in children
undergoing tonsillectomy under halothane/N2O anesthesia and
was shown to provide a statistically significant more rapid
recovery (1.8 min vs 3.9 min), but the clinical relevance of this
difference is unclear.215 The ventilator settings during mechanical
ventilation are reported in Table 406. A positive end-expiratory
pressure (PEEP) of 2 to 3 cmH2O can reduce the decrease in FRC
and the increase in pulmonary shunt associated with general
anesthesia or with the patients condition such as morbid obesity.
The ventilators available with new anesthesia machines allow
for synchronized intermittent mandatory ventilation (SIMV).
SIMV could have some benefits at the end of anesthesia, while the
child is transitioning to spontaneous ventilation. In recent years,
pressure-support and pressure-controlled ventilation modes have
become available with the new anesthesia ventilators. These modes
can be useful during induction and maintenance of anesthesia.
EMERGENCE TECHNIQUES
Emergence from anesthesia is a complex phenomenon that begins
when the anesthesiologist reduces or stops the administration of
the anesthetic drugs.1 The anesthesiologist must anticipate the
conclusion of surgery and taper the anesthetic drugs used for
maintenance. When patients are mechanically ventilated, the
anesthesiologists priority is to re-establish adequate spontaneous
ventilation. The pharmacologic properties of the agents used
determine when they should be discontinued. When satisfactory
E,
spontaneous ventilation has been re-established (i.e., normal V
VT and respiratory rate and lack of paradoxical chest movement),
the trachea can be extubated or the LMA removed. When muscle
relaxants have been antagonized, the anesthesiologist must verify
adequate recovery of neuromuscular function using clinical
criteria and neuromuscular function monitors. Adequate analgesia
to ensure a pain-free, comfortable child during recovery must be
established. Pain during emergence from anesthesia must be
cautiously treated without delay. Morphine (50100 g/kg) or lowdose fentanyl (0.250.5 g/kg) is commonly used.
Timing of Tracheal Extubation

or LMA Removal
Tracheal Extubation
TRACHEAL EXTUBATION IN THE AWAKE OR DEEPLY
ANESTHETIZED CHILD: Tracheal extubation can be performed
while patients are deeply anesthetized or when they are awake.
TABLE 40-6. Initial Ventilator Settings in Infants and
Children During Intermittent Positive-Pressure Ventilationa
Weight, kg
V
E, mL/kg/min
VT, mL
Respiratory rate,
breaths/min
Inspiratory time, s
I:E
10
20
40
200
35
2040
200
70
2040
150
140
2030
100
280
1525
0.40.5
1/1.5
0.75/1.5
1/2
1/1.5
1/2
I = inspiratory time E = expiratory time; VE = minute volume;

VT = tidal volume.
a
VT is set initially at 7 mL/kg and can be increased to 10 mL/kg.
1.2/1.4
1/3
703
Awake extubation means removing the ETT when the patient

is fully awake and airway reflexes have been re-established. The
child is able to breath adequately, grimace, open eyes, cough,
and make purposeful movements. This usually correlates with
end-tidal concentrations of less than 0.15% halothane and
sevoflurane.216
Deep extubation means removing the ETT when the patient is
deeply anesthetized and breathing spontaneously. Spontaneous
ventilation is maintained during surgery or re-established at the
end of the surgery. For deep extubation, some anesthesiologists
simply maintain surgical anesthesia with the use of both volatile
agents and N2O whereas others prefer to discontinue N2O and
increase the concentration of inhaled anesthetic (e.g., 35%
of isoflurane).216 The stomach and the posterior pharynx are
suctioned carefully before extubation. Stimulation should not be
accompanied by cardiovascular response or movement, provided
an adequate depth of anesthesia is maintained. Immediately after
tracheal extubation, 100% oxygen is administered by facemask,
the child is positioned on its side, and respiratory monitoring is
maintained, The minimal end-tidal halothane concentration at
which tracheal extubation can be performed is 0.8%.217 MAC
extubation (MACext) has been studied for several volatile agents;
these are reported in Table 407.
WHICH METHOD OF TRACHEAL EXTUBATION SHOULD BE

USED? Tracheal extubation augments catecholamine release and
induces a cardiovascular responses.221 These cardiovascular responses (increase in heart rate, blood pressure) can be attenuated
with a premedication with oral clonidine (4 g/kg).222 Intraocular
pressure can also increase during tracheal extubation.223 The main
respiratory complications during extubation include coughing,
bucking, breath-holding, bronchospasm, laryngospasm, and airway obstruction.
Each technique used for tracheal extubation has advantages and
disadvantages.224 Deep extubation remains controversial but oxygen saturations were shown to be higher during the first 5 minutes
after deep extubation than in awake children, but there was no
difference in the number of children requiring supplemental O2
nor in the incidence of airway-related complications.217 In another
study in young children, awake tracheal extubation led to significantly more episodes of desaturation than deep extubation.225
When awake extubation was performed, children anesthetized
with isoflurane had more episodes of coughing and airway obstruction than those anesthetized with halothane.225
The difference between the two techniques of extubation is not
clear-cut, and ultimately, the choice is based on the preference and
training of the anesthesiologist, or occasionally, surgical need may
dictate the choice. The patients condition may also influence the
choice. Awake extubation is recommended for infants younger
than 2 years, those with full stomachs, obesity, difficult airways, or
TABLE 40-7. Extubation in Deeply Anesthetized Childrena
Volatile Agent
Isoflurane
Sevoflurane
Desflurane
MACext, %
MACext 95%, %
1.27
1.64
7.7
1.46
1.87
8.5
Reference
Neelankata218
Inomata219
Cranfield220
MAC = minimal alveolar concentration.

a
MAC for a smooth tracheal extubation in 50% (MACext) or 95% (MACext 95%) of
children.
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obstructive sleep apnea. Deep extubation is recommended in

asthma or in cases with increased intraocular pressure so that
bucking and coughing can be avoided.216
LMA Removal
Several investigators have studied LMA removal in awake and
deeply anesthetized children. The complication rate after LMA
removal in awake patients was twice that seen in deeply anesthetized children.226 In another study, coughing was more frequent
in children when the LMA was removed while awake than when
the LMA was removed while under anesthesia. There was no
difference in the incidence of desaturation or laryngospasm.227
Criticism of these studies include that the end point for awake
LMA removal is either not well described226 or the authors removed
the LMA when the child was able to swallow, which could represent
an inadequate or light level of anesthesia.228,229 When Brains
recommendations for LMA removal are respected (onset of
swallowing, ability to open mouth on command or to expel the
LMA spontaneously),229 there was no difference in the incidence
of airway complications whether the LMA is removed in the
anesthetized or fully awake children.228
CONCLUSION
Maintenance of anesthesia with inhalation techniques is widely
used in children over the world. Anesthesia can be safely provided
with a great variety of drugs or combinations of drugs in children.
The anesthesiologist must choose the maintenance technique to
meet the need of the individual child. New agents can provide
effective anesthesia in children with increased safety. Some questions are not yet fully answered. The impact of technique or drug
on the outcome of anesthesia needs further research.
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Maintenance of Anesthesia:
Total Intravenous Anesthesia
Neil S. Morton
DEFINITIONS
Total intravenous anesthesia (TIVA) has developed since the early
1990s after the introduction of propofol and short-acting opioids
into clinical practice and the development of reliable, precise
infusion devices. TIVA involves induction and maintenance of
anesthesia exclusively by the intravenous (I.V.) route. I.V. administration establishes a blood concentration of drug, but distribution
from blood to tissues, metabolism, and excretion continually alter
this blood concentration in a complex way. This pharmacokinetic
phase also includes distribution to the effect-site in the central
nervous system and production of the clinical effect of sedation
and anesthesia, the pharmacodynamic phase. A three-compartment
pharmacokinetic model (Figure 411) is a useful aid to understanding.
The definitions of terms used to describe a three-compartment
pharmacokinetic model are listed in Table 411.
To understand the disposition of drugs after an I.V. dose, in the
three-compartment pharmacokinetic model (see Figure 411), the
drug is delivered and eliminated from a central compartment,
V1 (which includes the blood), but also distributes to and redistributes from two peripheral compartments, one representing wellperfused organs and tissues (fast compartment, V2) and the other
representing more poorly perfused tissues such as fat (slow
compartment, V3). The transfer of the drug between the central
compartment (V1) and the two peripheral compartments (V2 and
V3) and also the elimination of the drug from the central
Figure 41-1. Schematic of the threecompartment model.
41
C H A P T E R
compartment is described by a series of rate constants indicating

the speed of movement back and forth between compartments and
also elimination. The target organ for I.V. anesthetic agents is the
brain. Therefore, a fourth set of rate constants is used to describe
the equilibration between the central compartment (V1) and the
effect-site (Ce) in the brain (k1e, ke0). This compartment has no
volume, and so these constants represent the time lag before
changes in the blood concentration are reflected in the Ce and
vice versa.
Another helpful way of illustrating these concepts is the
hydraulic model (Figure 412). In this model, the central compartment is connected to the peripheral compartments and effectsite by pipes of different diameters, and a drainage pipe represents
elimination. The height of each column of fluid represents the
concentration of drug in each compartment. The diameters of
the interconnecting pipes and the drainage channel represent
clearances. This hydraulic analogy is used in the TIVA Trainer
simulation program1 and can be animated to illustrate dynamic
changes over time.
PRINCIPLES OF TIVA2
For healthy children, a relatively high dose of I.V. agent is needed
for both induction and maintenance of a satisfactory level of
anesthesia. In the immature neonate, the critically ill child, or
those with major organ failure, considerably smaller doses of I.V.
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TABLE 41-1. Pharmacokinetic Definitions and

Nomenclature for Target-controlled Infusions
Term
Meaning
TCI
Vc or V1
V2
Target-controlled infusion
Central compartment volume
Fast compartment volume
(vessel-rich group)
V2 = V1 k12/k21
Slow compartment volume (vesselpoor group)
V3 = V1 k13/k31
Elimination clearance
Cl1 = V1 k10
Clearance between V1 and V2
Cl2 = V2 k21
Clearance between V1 and V3
Cl3 = V3 k31
Blood or plasma concentration
Effect-site concentration
Target concentration
Concentration calculated by
TCI software
Concentration measured
Elimination rate constant
Rate constant for distribution from
blood to effect-site
Rate constant for redistribution away
from effect-site
Rate constants for movement
between V1 and V2
Rate constants for movement
between V1 and V3
V3
Cl1
Cl2
Cl3
Cp
Ce
T
CALC
MEAS
k10
k1e
ke0
k12, k21
k13, k31
Units
L
L
L
L/h
L/h
L/h
1/min
1/min
1/min
1/min
1/min
anesthetic agents are needed because of reduced clearance of the

drug and, for propofol, also of the lipid vehicle used in the formulation. Titration to clinical end points supplemented by electronic
monitoring is advisable to allow for the wide interindividual
variation in pharmacokinetics and pharmacodynamics. Because
regional blood flow, body composition, and body proportions
vary during development, the pharmacokinetics and pharmacodynamics are even more complex in children. The apparent
volume into which drugs distribute (Vd) varies between individual

children, between the same individual at different stages of
development, and among drugs. A drug that is very lipid-soluble
will have a very large volume of distribution (Vd), as will one that
is highly bound to plasma proteins. Elimination of drugs and
their metabolites usually occurs by metabolism in the liver and
subsequent excretion via the kidneys. Thus, immature or reduced
hepatic and renal function will reduce elimination. Clearance (Cl),
which is the volume of blood from which the drug is eliminated
per unit of time, is a measure of elimination. The time required
for the drug concentration in blood to decrease by 50% is known
as the elimination half-tme (T1/2). Prolongation of the elimination
of a drug reflects either an increase in the Vd, or a reduction in
clearance, or both.
A bolus dose or loading infusion of drug will start to fill
the central compartment, and in time, the drug will reach the
effect-site. As drug is delivered into the central compartment, it
continuously distributes into the peripheral compartments and
to the effect-site but is also continuously being eliminated. To
maintain a constant effect-site concentration, the infusion rate
must vary because it has to match the changes in the contribution
of distribution and elimination as the infusion continues. The rate
of infusion should decrease in a stepwise manner.
When the infusion is stopped, elimination will continue
to drain the central compartment and drug will continue to
distribute to V2 and V3 along concentration gradients from
V1 for some time. Equilibrium may be reached for a short period,
but as the central compartment concentration falls, the drug also
moves back from the peripheral compartments into the central
compartment along concentration gradients, maintaining the
central compartment drug concentration for a period of time. This
depot effect is particularly evident for lipid-soluble drugs in which
the slow peripheral compartment can hold a large amount of drug.
Eventually, the central compartment concentration will decrease
and the effect-site concentration will follow.
Context-Sensitive Half-Time
The longer the duration of an infusion, the more drug will have
distributed into the peripheral compartments and the larger
the reservoir of drug there will be to redistribute back into the
central compartment and to be eliminated once the infusion
ceases. The half-time of the decrease in drug concentration,
therefore, is related to the duration of the infusion for most drugs.
This is termed the context-sensitive half-time (CSHT), in which the
context is the duration of the infusion (Figures 413 and 414).
Fentanyl has a short CSHT when given by infusion for a short
time but this increases markedly as the duration of the infusion
increases. Alfentanils CSHT becomes constant after approximately
90 minutes of infusion. The half-time of remifentanil becomes
context-insensitive almost immediately after initiation of the
infusion because its elimination is rapid and complete because of
esterase metabolism.
Interactions
Figure 41-2. Hydraulic representation of the three-compartment
model (see text for description).
Both pharmacokinetic and pharmacodynamic drug interactions

are seen when multiple agents are used for TIVA. Administration
of propofol can affect its own distribution and elimination by
altering regional blood flow. Both fentanyl and alfentanil increase
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Figure 41-3. Context-sensitive half-times after short-duration infusions.

the volume of V1 and clearance of propofol, whereas propofol and
midazolam inhibit the metabolism of alfentanil by competing for
the same cytochrome P450 enzyme isoform CYP3A4.
Propofol-sparing Techniques
For TIVA techniques in children, concurrent administration of
opioids has a significant propofol-sparing effect while provid-
ing analgesia and stress control.3,4 Local and regional analgesia

techniques also allow significant propofol dose reduction once
the block becomes established. Nitrous oxide and low doses of
volatile agents also act synergistically with propofol and opioids.
All these techniques to reduce propofol and lipid dose are helpful
in reducing the risk of propofol infusion syndrome, but the
most useful way to do this is always to use 2% propofol, which
immediately halves the lipid load.
Figure 41-4. Context-sensitive half-times (CSHTs) after longer-duration infusions.
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TABLE 41-2. Adult and Pediatric Pharmacokinetic

Parameters for Propofol
Age, y
13
11
Adult
Vd, mL/kg
9500
9700
4700
Elimination
T1/2, min
188
398
312
Clearance,
mL/min/kg
53
34
28
T1/2 = half-life; Vd = distribution volume.
METHODS FOR DELIVERING TIVA

Manual Infusion Schemes
A simple manual scheme for propofol infusion was devised
by Roberts and coworkers5 to maintain a blood concentration
of propofol in healthy adults of 3 g/mL. A bolus dose of 1 mg/kg,
then a continuous infusion of 10 mg/kg/h for 10 minutes, then
8 mg/kg/h for 10 minutes, then 6 mg/kg/h thereafter was suggested. When this 10,8,6 regimen is tested clinically or modeled using the Marsh model6 for an adult patient, the estimated
blood concentration slightly exceeds 3 g/mL but remains
reasonably stable. However, when the same regimen is used in
children, a subtherapeutic blood concentration of propofol is
delivered because of a relatively larger central compartment and an
increased clearance of propofol in children compared with adults
(Table 412).
When pediatric pharmacokinetic parameters are used to
calculate the dose of propofol required to achieve a blood con-
centration of 3 g/mL, the bolus dose needed is 50% greater

than in adults (1.5 mg/kg), and the infusion rates needed are
approximately 19,15,12 each for 10 minutes. In addition, it takes
approximately 15 minutes for the effect-site concentration to reach
3 g/mL. A simulation illustrates this (Figure 415).
In addition, it takes approximately 15 minutes for the effect-site
concentration to reach 3 g/mL. A simulation illustrates this
(Figure 415). An example of the infusion sequence is given with
a 1 mg/kg bolus dose (Table 413). The infusion is stopped
at 60 minutes. The effect-site concentration dose not equilibrate
until 20 minutes. Blood and effect-site concentrations stabilize
around 2.4 g/mL but gradually rise over the subsequent hour to
2.6 g/mL.
McFarlan and colleagues7 found that a regimen consisting of a
loading dose of 2.5 mg/kg followed by infusion rates of 15 mg/kg/h
for 15 minutes, then 13 mg/kg/h for 15 minutes, then gradually
reducing to 9 mg/kg/h allowed maintenance of a steady target
plasma concentration of 3 g/mL in children aged 3 to 11 years.
Engelhardt and associates8 found an adaptation of this manual
regimen could be used clinically to achieve three distinct levels of
propofol anesthesia (Table 413).
Target-controlled Infusion10
A target-controlled infusion (TCI) is controlled by a computer that
performs rapid sequential calculations to determine the infusion
rate required to produce a user-defined target drug concentration
in the blood or at the effect-site. Thus, TCI may be blood-targeted
(Figure 416) or effect-sitetargeted (Figure 417).
Figure 41-5. Manual infusion of propofol in a 1-y-old child of weight 10 kg. Red line = blood concentration; green line = effect-site
concentration; white boxes = infusion rate (mL/h).
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TABLE 41-3. Manual Infusion Schemes

Drug
Loading dose
Maintenance infusion
Notes
Propofol
1 mg/kg
10 mg/kg/h1 for 10 min, then

8 mg/kg/h for 10 min, then
6 mg/kg/h thereafter
Propofol
1 mg/kg
Propofol
2.5 mg/kg
Pediatric regimen to achieve blood

concentration of 3 g/mL in children
age 311 y
Alfentanil
1050 g/kg

9 mg/kg/h thereafter
11 mg/kg/h tapering to
9 mg/kg/h
15 g/kg/min
Adult regimen to achieve blood concentration

of 3 g/mL
Underdelivers to children and achieves lower
blood concentration of 2 g/mL
Concurrent with alfentanil infusion
Remifentanil
0.25 g/kg/min
0.10.5 g/kg/min
Produces blood concentrations of 510 ng/mL
10
Sufentanil
0.5 g/kg/min
for 3 min
0.51.0 g/kg
over 1 min
0.10.5 g/kg
Results in blood concentration of 50200

ng/mL
Produces blood concentrations of 69 ng/mL
0.0050.01 g/kg/min
10, 11
Sufentanil
15 g/kg
0.010.05 g/kg/min
Fentanyl
Ketamine
Midazolam
110 g/kg
12 mg/kg
0.050.1 mg/kg
0.10.2 g/kg/min
540 g/kg/min
0.10.3 mg/kg/h
Results in blood concentrations of 0.2 ng/mL

for sedation and analgesia
Results in blood concentrations of 0.63.0
ng/mL for anesthesia
Remifentanil
References
10
10, 11
9
9
9
Figure 41-6. Blood-targeted infusion of propofol in a healthy 1-y-old child of 10 kg body weight. Paedfusor PK data set. Blood
target = 3 g/mL. Infusion stopped at 60 min, that is, Blood target = 0 g/mL. Delivers a bolus dose of 1.4 mg/kg, then a stepwise
reducing infusion of from 19.1 mg/kg/h to 9.5 mg/kg/h at 1 h. Effect-site concentration does not reach 3 g/mL until 15 min 44 s.
Total dose of propofol = 13.6 mg/kg. Context-sensitive half-time = 10 min. Red line = blood concentration; green line = effect-site
concentration; orange line = target concentration; white boxes = infusion rate (mL/h).
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Figure 41-7. Effect-site-targeted infusion of propofol in a healthy 1-y-old child of 10 kg body weight. Paedfusor PK dataset. Effectsite target = 3 g/mL. Infusion stopped at 60 min, that is, effect-site target = 0 g/mL. Delivers a bolus dose of 3.4 mg/kg at 45.5 mL/h
to accentuate the gradient from blood to effect-site. Then infusion switches off for 4 min. Peak blood concentration after bolus dose =
7.1 g/mL. Stepwise-reducing infusion of from 15.7 mg/kg/h to 9.5 mg/kg/h at 1 h. Effect-site concentration reaches 3 g/mL at 3 min
39 s. Total dose of propofol = 14 mg/kg. Context-sensitive half-time = 10 min 37 s. Red line = blood concentration; green line = effectsite concentration; orange line = target concentration; white boxes = infusion rate (mL/h).
Syringe drivers capable of infusion rates up to 1200 mL/h with
a precision of 0.1 mL/h are used that incorporate a user interface
and display and a range of safety alarms, monitoring functions,
and warning systems. The software suitable for use in children is
quite limited in its applicability to various age groups. Studies of
small numbers of healthy patients form the basis of the model data
sets and are only a guide to drug administration for an individual
patient. The accuracy of TCI propofol was assessed by Marsh and
coworkers6,12 in children. The model was found to perform well
in a small prospective series of healthy children. In children
undergoing cardiac surgery, the model performed significantly
better than the adult model in adults.13,14 A modified version of
the commercial Diprifusor device, the Paedfusor14 has been
evaluated and performs well in children from ages 1 to 15 years
(Table 414).6,12,15,16
A model developed by Kataria and colleagues18 has also been
validated for children ages 3 years and older (Table 415).
The Paedfusor model makes an allowance for the steady
increase in elimination clearance in younger children particularly
below 30 kg in weight. In the Paedfusor program, the adult value
for ke0 of 0.26 is used but there is no value for this parameter in the
Kataria model (see Table 415). Munoz and associates19 attempted
to define a more accurate ke0 for children using auditory evoked
responses. They found that the time to peak effect after a bolus
dose was greater in children than in adults and the median ke0
values for the Paedfusor and Kataria models for children ages
3 to 11 years were 0.91/min and 0.41/min. Using these pediatric
TABLE 41-4. Paedfusor Pharmacokinetic Data Set6,13,14,17

Age 112 Y
V1 = 0.4584 weight; V2 = V1 k12/k21; V3 = V1 k13/k31
k10 = 0.1527 weight0.3
k12 = 0.114; k21 = 0.055
k13 = 0.0419; k31 = 0.0033
ke0 = 0.26
Age 13 Y
V1 = 0.400 weight
k10 = 0.0678
(other constants as above)
Age 14 Y
V1 = 0.342 weight
k10 = 0.0792
Age 15 Y
V1 = 0.284 weight
k10 = 0.0954
Age 16 Y
V1 = 0.22857 weight
k10 = 0.119
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TABLE 41-5. Comparison Between Paedfusor6,13,14,17 and
Kataria18 Pharmacokinetic Data Sets for Propofol in Children
V1
V2
V3
k10
k12
k21
k13
k31
ke0
Paedfusor
Kataria
0.458 weight
0.95 weight
5.82 weight
0.1527 weight0.3
0.114
0.055
0.0419
0.0033
0.26a
0.41 weight
0.78 weight + 3.1 age
6.9 weight
0.085
0.188
0.102
0.063
0.0038
n/aa
Abbreviations See Table 41-1
values, they then used bispectral index (BIS) monitoring to

estimate the effect-site concentrations of propofol associated
with hypnosis in children.20 This showed that similar effect-site
concentrations of 3 to 4 g/mL are needed to produce a BIS value
less than 50 in healthy children ages 3 to 11 years as in adults.20
INDICATIONS FOR TIVA6,10,12,15,16,21,22

TIVA may be indicated in children in whom volatile agents are to
be avoided (malignant hyperthermiasusceptible patients); when
there is a high risk of postoperative nausea and vomiting; for brief
radiologic or painful procedures in which rapid recovery is needed
(e.g., magnetic resonance imaging [MRI], bone marrow aspiration,
gastrointestinal endoscopy); for frequent repeated anesthesia
(e.g., radiation therapy); for children undergoing major surgery
to control the stress response; during neurosurgical procedures
to assist with control of intracranial pressure and for cerebral
metabolic protection; for spinal instrumentation with evoked
motor and auditory brain potentials; for children in need of airway
endoscopy.
SPECIFIC CONTRAINDICATIONS
In pediatric intensive care, propofol is specifically contraindicated because of increased mortality from propofol infusion
syndrome.2332 Allergy to propofol or its formulation components
is also a contraindication. A variety of propofol formulations are
now available (see Chapter 23).
REFERENCES
1. Engbers F, Sutcliffe N, Kenny GNC. TIVA Trainer. 8th ed. Leiden,
Germany: Frank Engbers; 2006.
2. Hill SA. Pharmacokinetics of drug infusions. Continuing Education in
Anaesthesia. Crit Care Pain. 2004;4:7680.
3. Drover DR, Litalien C, Wellis V, et al. Determination of the pharmacodynamic interaction of propofol and remifentanil during esophagogastroduodenoscopy in children. Anesthesiology. 2004;100:1382
1386.
4. Browne BL, Prys-Roberts C, Wolf AR. Propofol and alfentanil in children:
infusion technique and dose requirement for total I.V. anaesthesia.
Br J Anaesth. 1992;69:570576.
715
5. Roberts FL, Dixon J, Lewis GT, et al. Induction and maintenance of

propofol anaesthesia. A manual infusion scheme. Anaesthesia. 1988;43
(Suppl):1417.
6. Marsh B, White M, Morton N, et al. Pharmacokinetic model driven
infusion of propofol in children.[see comment]. Br J Anaesth. 1991;67:
4148.
7. McFarlan CS, Anderson BJ, Short TG. The use of propofol infusions
in paediatric anaesthesia: a practical guide. Paediatr Anaesth. 1999;9:
209216.
8. Engelhardt T, McCheyne AJ, Morton N, et al. Clinical adaptation of a
pharmacokinetic model of propofol plasma concentrations in children.
9. Shann F. Drug Doses. 13th ed. Melbourne, Australia: Royal Childrens
Hospital; 2005.
10. Absalom A, Struys MMRF. An Overview of TCI and TIVA. Gent, Belgium:
Academia Press; 2005.
11. Glass PSA, Shafer SL, Reves JG. Intravenous drug delivery systems. In:
Miller RD, editor. Anesthesia. 5th ed. New York: Churchill-Livingstone;
2000. pp. 377411.
12. Marsh BJ, Morton NS, White M, et al. A computer controlled infusion of
propofol for induction and maintenance of anaesthesia in children. Can
J Anaesth. 1990;37:S97.
13. Amutike D, Lal A, Absalom A, et al. Accuracy of the Paedfusor: A new
propofol target-controlled infusion system for children. Br J Anaesth.
2001;87:175P176P.
14. Absalom A, Amutike D, Lal A, et al. Accuracy of the Paedfusor in
children undergoing cardiac surgery or catheterization. Br J Anaesth.
2003;91:507513.
15. Doyle E, McFadzean W, Morton NS. IV anaesthesia with propofol using
a target-controlled infusion system: comparison with inhalation
anaesthesia for general surgical procedures in children. Br J Anaesth.
1993;70:542545.
16. Varveris DA, Morton NS. Target controlled infusion of propofol for
induction and maintenance of anaesthesia using the Paedfusor: an open
pilot study. Paediatr Anaesth. 2002;12:589593.
17. Absalom A, Kenny GNC. Paedfusor pharmacokinetic data set. Br J
Anaesth. 2005;95:110.
18. Kataria BK, Ved SA, Nicodemus HF, et al. The pharmacokinetics of
propofol in children using three different data analysis approaches.
19. Munoz HR, Cortinez LI, Ibacache ME, et al. Estimation of the plasma
effect site equilibration rate constant (ke0) of propofol in children using
the time to peak effect: comparison with adults. Anesthesiology. 2004;101:
12691274.
20. Munoz HR, Cortinez LI, Ibacache ME, et al. Effect site concentrations of
propofol producing hypnosis in children and adults: comparison using
the bispectral index. Acta Anaesthesiol Scand. 2006;50:882887.
21. Morton NS. Total intravenous anaesthesia (TIVA) in paediatrics:
advantages and disadvantages. Paediatr Anaesth. 1998;8:189194.
22. Eyres R. Update on TIVA. Paediatr Anaesth. 2004;14:374379.
23. Bray RJ. Propofol infusion syndrome in children. Paediatr Anaesth.
1998;8:491499.
24. Bray RJ. Propofol-infusion syndrome in children. Lancet. 1999;12:
20742075.
25. Hatch DJ. Propofol-infusion syndrome in children. Lancet. 1999;3:
11171118.
26. Murdoch SD, Cohen AT. Propofol-infusion syndrome in children. Lancet.
1999;12:20742075.
27. Kelly DF. Propofol-infusion syndrome. J Neurosurg. 2001;95:925926.
28. Wolf A, Weir P, Segar P, et al. Impaired fatty acid oxidation in propofol
infusion syndrome. Lancet. 2001;24:606607.
29. Short TG, Young Y. Toxicity of intravenous anaesthetics. Best Pract Res
Clin Anaesthesiol. 2003;17:7789.
30. Vasile B, Rasulo F, Candiani A, et al. The pathophysiology of propofol
infusion syndrome: a simple name for a complex syndrome [see comment]. Intensive Care Med. 2003;29:14171425.
31. Riker RR, Fraser GL. Adverse events associated with sedatives, analgesics,
and other drugs that provide patient comfort in the intensive care unit.
Pharmacotherapy. 2005;25:8S18S.
32. Tobias JD. Sedation and analgesia in the pediatric intensive care unit.
Pediatr Ann. 2005;34:636645.
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Modern Modes of Ventilation

in the Operating Room
Niall Wilton and David Buckley
INTRODUCTION
Applying optimal ventilation strategies to children requires
utilization of knowledge from a variety of areas. It requires an
understanding of respiratory physiology as it applies to neonates,
infants, and older children and how this is altered by anesthesia
and the application of controlled mechanical ventilation as well as
patient-triggered ventilation. The imposition of anesthetic equipment in the form of airway devices, breathing filters, and anesthetic circuits also influences decisions regarding optimal ventilation
techniques. Certain procedures make special demands on ventilation strategies; the most relevant of these are discussed.
APPLIED PHYSIOLOGY OF
PULMONARY VENTILATION
The normal mechanism of respiration in infants and children is
altered by the effects of anesthesia, surgery, and the position that
has to be assumed for these to occur. This frequently results in the
need to assist or augment ventilation, usually involving mechanical
and/or electronic devices to allow the functions of respiration to
continue. The impact of anesthesia and the application of ventilatory support alter the normal mechanisms and patterns of
pulmonary ventilation, so a brief overview of those aspects of
pulmonary physiology follows. For a fuller discussion, reader is
referred to Chapter 9.
Static Lung Volumes

Lung volumes change as the lung performs its main function of
delivering oxygen to and removing carbon dioxide from the
tissues. A number of formally defined volumes have been used to
define and compare aspects of lung volume for over 150 years.1
Four major subdivisions of lung volume are residual lung volume
(RV), expiratory reserve volume (ERV), tidal volume (VT), and
inspiratory reserve volume (IRV). These are combined to form
four capacities: total lung capacity (TLC), vital capacity (VC),
inspiratory capacity (IC), and functional residual capacity (FRC)
as shown in Figure 421.
TLC is the maximum lung volume attainable by expansion of
the thorax and lungs. This and other lung measurements are
difficult to measure in infants and small children. It appears,
however, that lung capacity in small infants is significantly less
(60 mL/kg) than it is in older children and adolescents (90 mL/
kg).2 RV is the volume remaining after maximal expiration and is
approximately 25% of TLC in healthy children. FRC is the lung
volume at the end of a normal expiration and reflects the equilibrium achieved between the outward pull of the chest wall and
the inward elastic recoil of the lungs. This usually approximates
to 50% of TLC in upright healthy children and about 40% in the
supine position.3 FRC in adults is approximately 2.9 L (40 mL/kg)
when sitting, reducing to 2.1 L (30 mL/kg) when supine.4 In
neonates and young infants, the FRC appears to be less stable or
predictable and is more dependent on dynamic factors, which is
discussed in Respiratory Mechanics. Normal VTs of 6 to 8 mL/kg
are established early in the neonatal period and these values
remain essentially unchanged throughout life.
Respiratory Mechanics
During spontaneous respiration, the inspiratory muscles (predominantly the diaphragm) create a negative driving pressure that
draws air from the outside into the lungs. With most types of
mechanical ventilation employed in the operating room, during
Figure 42-1. Lung volumes and capacities.
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717
compliance during routine clinical practice measures respiratory

system compliance (CRS), which is the combined compliance of the
lungs and the chest wall. It is expressed as liters per kilopascal (L/kp)
or milliliters per centimeter of water (mL/cmH2O), and may be
measured as static or dynamic compliance. Static compliance
measurements occur during an expiratory pause following the
delivery of a predetermined volume, whereas dynamic compliance
is measured from the no flow points on a pressure-volume loop.
The inspiratory and expiratory limbs of the pressure-volume
curve are different, with the lung volume at a given pressure during
expiration being greater than during inspiration. This is known as
hysteresis (Figure 423). Without an expiratory pause, lung units
with longer time constants (see Time Constants) will be underrepresented and dynamic compliance measurements will be
decreased relative to static measurements. Dynamic compliance is,
therefore, decreased as respiratory frequency is increased. This data
can be measured clinically with some ventilators.
Lung compliance depends on lung size, with lung compliance
in infants significantly less than adults. If lung compliance is
Figure 42-2. Relationship between resistance (R), compliance

(C), flow (F), and volume (V). Pi = inspiratory pressure; T =
time constant.
inspiration, a positive driving pressure pushes air into the chest. In
both types of respiration, exhalation is usually passive with the
driving pressure produced by the elastic recoil of the chest while
it is above its FRC.
The inspiratory driving pressure predominantly has to overcome two main forces, elastic resistance and nonelastic (or respiratory system) resistance. Elastic resistance is caused primarily
by the elastic recoil of the lungs and chest wall with a small component from surface forces at the alveolar-gas interface. This is
normally expressed as its reciprocalcompliance. Nonelastic
resistance results mostly from frictional resistance to air flow with
a small component caused by tissue deformation. Additional
forces owing to inertance, which arise from the acceleration and
deceleration of gas flow and the lung tissue, are small and are
usually ignored.5
Mathematically, the pressure required to inflate the lung
(Pi) can be summarized using the equation of motion as:
Pi = (volume compliance) + (resistance flow).
Conceptually, this can be imagined as a box containing a tube
connected to a balloon (Figure 422). None of the components in
this system remains static. The size of the box may change with
changing abdominal contents and supine versus prone positioning.
Factors affecting compliance and resistance are discussed in
sections Compliance and Resistance and Airflow.
Compliance
Lung compliance is defined as the change in lung volume per unit
change in transmural pressure gradient. Any measurement of
Figure 42-3. Dynamic and static compliance measurements.

A: Dynamic compliance measured from no flow points on
pressure-volume loop (horizontal part of the loop). B: Static compliance measured from tidal volume and plateau pressure (P2).
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TABLE 42-1. Normal Values for Lung Function of Children and Young Adults
Age
1 Wk
1Y
3Y
5Y
8Y
12 Y
15 Y, Male
21 Y, Male
21 Y, Female
Weight, kg
VC, mL
FRC, mL
FRC/weight, mL/kg
Vd, mL
VT (mL)
Vd/VT
f.
V E, L/min
C1, mL/cmH2O
R, cmH2O/L/s
3.3
100
75
25
7.5
17
0.44
30
0.55
5
29
10
475
263
26
21
78
0.27
24
1.8
16
13
15
910
532
37
37
112
0.33
22
2.5
32
10
18
1100
660
36
49
130
0.38
20
2.6
44
8
26
1855
1174
46
75
180
0.42
18
3.2
71
6
39
2830
1855
48
105
260
0.40
16
4.2
91
5
57
4300
2800
49
141
360
0.39
14
5
130
3
73
4620
3030
42
150
500
0.30
12
6
163
2
57
3380
2350
41
126
420
0.30
12
5
130
2
.
C1 = lung compliance; f = frequency; FRC = functional residual capacity; R = resistance; VC, vital capacity; Vd = volume of distribution; VE = minute volume;
VT = tidal volume.
Adapted from Motoyama EK. Respiratory Physiology in Infants and Children. In: Motoyama EK, Davis PJ, editors. Smiths Anesthesia for Infants and Children. 7th ed.
Mosby Elsevier: St-Louis; 2006. pp. 1269: Table 2.2.
standardized to FRC, however, infants and adults have a similar

compliance-to-FRC ratio of 0.065.6 Some comparative data for this
and other lung function data are shown in Table 421. In normal
patients during spontaneous ventilation, normal VTs are produced by a transpulmonary pressure of 4 to 6 cmH2O, required to
overcome the compliance of the lung. When employing positivepressure ventilation, transthoracic inflation pressures in most
patients are approximately twice this (812 cmH2O) because the
chest wall has to be passively expanded as well. Neonates, however,
have a highly compliant chest wall and, thus, lower inflation
pressures are to be expected.7
Resistance and Airflow

The pressure required to overcome nonelastic resistance depends
on the rate and pattern of flow. At low flow rates, flow is laminar
and the driving pressure is proportional to the flow rate (P = KV)
The pressure-flow characteristics are defined by the HagenPoiseuille formula:
Resistance = 8 nl/r4
where n = viscosity, l = length, r = radius. This highlights the
importance of radius, because halving the radius induces a 16-fold
increase in resistance. This type of flow also has a velocity profile
across a tube that results in the gas at the center moving at twice
the velocity of the average flow.5 As the flow rate increases, this
orderly pattern of flow becomes increasingly disorganized,
eventually resulting in turbulent flow. This is likely to occur at
branching points, areas of narrowing, and any sharp angles.5,8 With
turbulent flow, pressure is proportional to the square of the flow
rate (P = KV2), thus a much higher driving pressure is required to
produce the same flow. When this occurs, the driving pressure is
also proportional to the density rather than the viscosity of the gas
and the fifth (rather than the fourth) power of the radius of the
airway. The likelihood of this occurring can be predicted based
on the value of a dimensionless number called Reynolds number,
which can be expressed as follows:
Linear velocity of gas tube diameter gas density/gas viscosity
Thus, for a given flow rate and a given tube diameter, this
number is affected by the ratio of density to viscosity. Empirically,
it has been determined that, when Reynolds number is less than

2000, flow is predominantly laminar; above 4000, it is likely to
be turbulent; and between these limits, flow will be mixed.8
The relative vapor density/viscosity for 100% oxygen, 30% O2/70%
N2O, and 20% O2/80% He (heliox) are 1:1.6:0.3, respectively.5 In
this situation, the substitution of a less dense gas (helium)
for nitrogen or N2O may improve gas flow and, hence, oxygen
delivery.9,10
Despite concerns about peripheral airways disease and
increased airflow resistance (Raw), in healthy patients, the small
airways contribute only a small amount to total airway resistance
(Rrs) owing to the dramatic increase in cross-sectional area that
occurs in the small bronchi after the sixth- to eighth-generation
airways.11 About two thirds of the Rrs is thought to occur between
the oral or nasal airways and the trachea, with the peripheral
airways contributing only about 10% of the total resistance.12
In infants, nasal resistance alone makes up approximately 30 to
50% of Rrs.13 An important point in infants is that occlusion of one
nares by the insertion of a nasogastric tube can increase the Rrs
by as much as 50%; thus, earlier consideration of ventilatory
support may be required.14 During positive-pressure ventilation,
a significant part of the normal R aw is bypassed but substituted
by the resistance of a laryngeal mask airway (LMA) or an
endotracheal tube (ETT). In neonates, Raw in absolute terms is
about 15 times that of a normal adult.6 What this means in context,
however, is difficult to determine because flow rates in the neonate
are less than adults, as are overall ventilatory pressures.
Tissue viscoelastic resistance (Rvisc) is not often considered
separately from Raw, as a component of Rrs. This form of resistance,
which counters the viscoelasticity of the lungs and thoracic tissues,
makes up a greater part of the Rrs than was previously assumed.15
Raw tends to increase with increasing flow because of increasing
turbulence but to decrease with increasing lung volume as airway
caliber increases. Rvisc, however, decreases with increasing flow
(at constant volume) and increases with increasing lung volume
(at constant flow).16 Rvisc is an important part of Rrs. Studies in
anesthetized and ventilated children have demonstrated that
tissue Rvisc changes in the opposite direction to changes in R aw.
Thus, although Rrs decreases with increasing flow as it does in
adults, it is not affected by lung volume.17,18 In Patients with
primary airway obstruction, the increase in Raw > Rvisc, whereas in
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those with interstitial lung disease or pulmonary edema, it is more
likely that an increase in Rvisc is the primary problem.19 Thus, with
airway obstruction, a relatively slow flow rate and a large VT would
be most beneficial in minimizing Rrs and work of breathing,
whereas with restrictive disease, a high flow rate and small VTs are
more likely to decrease Rrs and minimize work of breathing.18,19
Positive end-expiratory pressure (PEEP) will also be necessary to
increase FRC toward normal levels and minimize any decrease
in compliance.
Time Constants
It requires a finite amount of time to both inflate and deflate the
lungs with a given volume of gas. This is proportional to both
compliance and resistance (see Figure 422). Thus, during
inflation with a constant applied pressure (as with pressurecontrolled ventilation [PCV]), this time is a function of the
inflation pressure, compliance, and Raw. Mathematically this is can
be represented as an exponential function and as such can be
expressed in terms of a time constant (T). This represents the time
for the change to occur if the initial rate of change was maintained
such that after one T, 63% of the change will have occurred and
after three time constants 95%. An increase in resistance will
prolong the time constant and a decrease in compliance will
shorten the time constant. For a given compliance, an increase in
resistance will prolong the time constant but not affect the final
volume achieved providing inspiratory time is greater than three
Ts. For a given resistance, a decrease in compliance will shorten (or
decrease) the time constant and the maximum volume achievable
will be decreased proportionally. The impact of changes in
compliance and resistance and the resulting effect on time
constants and delivered volumes for a constant driving pressure
are shown in Figure 424. These concepts may be applied to the
lungs as a whole or to various different functional subunits within
the lung. If the various regional time constants are equal, the
buildup of pressure in the different units will be identical at all
times during inflation. If the regional time constants differ, as
occurs with most respiratory pathology, however, the distribution
of inspired gas to the various units will depend on the rate,

duration, and frequency of inspiration.
The same principles apply when the lung is allowed to empty
passively from end-inspiration to FRC: the speed of deflation
can be represented by a T. The volume time profile is again an
exponential decay, in which one time constant represents a 63%
reduction in VT with three time constants required to complete
exhalation to FRC. In healthy adults, this expiratory time constant
is 0.4 to 0.5 second, whereas in neonates, it is shorter at 0.2 to 0.3
second.20 Initiating the next inspiration before the previous
expiration is complete (<3 T) will tend to increase lung volumes,
producing hyperinflation.
Dynamic Nature of Lung Volumes in Infants:

Important Factors Affecting the FRC
Under static conditions (apnea, general anesthesia (GA), or
paralysis), FRC in neonates and infants is significantly lower than
the figures suggested earlier owing to the low elastic recoil of the
thorax, reaching a level incompatible with normal gas exchange
(<15% TLC).7 In these patients, the FRC is considered to be
dynamically rather than statically determined by a number of
mechanisms acting to prevent lung collapse. These result in the
FRC of the neonate being approximately 25 to 30 mL/kg, which is
not dissimilar on a milliliter per kilogram basis to that found in
supine adults. The mechanisms involved in maintaining the FRC
include sustained activity of the inspiratory muscles throughout
the respiratory cycle (including the diaphragm), narrowing of the
glottis during expiration, initiation of inspiration during midexpiration, and a high respiratory rate relative to expiratory time.
These mechanisms in effect create auto-PEEP. Importantly, these
are lost with anesthesia, intubation, or muscle relaxation.21
The important contribution of laryngeal function in maintaining lung volumes is often ignored in discussions regarding
pulmonary ventilation, but it is relevant with the increasing use
of supraglottic airways in neonates and infants. The glottis widens
during inspiration but narrows during expiration, increasing
laryngeal resistance (a phenomenon known as laryngeal braking).22,23 This mechanism is of particular importance in neonates
and infants because regulation of resistance at this level,24 often
combined with prolongation of inspiratory muscle tone during
expiration, assists in maintaining FRC.25 Infants also terminate the
expiratory phase of the breathing cycle before the lung volume
reaches true FRC, which tends to raise the FRC.26 This mechanism
is augmented by the relatively long time constants of the respiratory system relative to the high respiratory rate, further contributing to intrinsic PEEP.27 When awake, tonic contraction of the
diaphragm and intercostal muscles also assist in maintaining FRC
by stiffening the chest wall.28 These mechanisms are summarized
in Table 422. All these protective mechanisms for maintaining
TABLE 42-2. Mechanisms for Maintaining Functional
Residual Capacity in Infants Lost During Anesthesia
Figure 42-4. Effect of changes in compliance and resistance

on time constants and delivered lung volume over time with
pressure control ventilation.
719
Laryngeal braking (glottic narrowing during expiration)

Maintenance of inspiratory muscle tone during expiration
(diaphragm and intercostal)
Early activation of inspiratory muscles during expiration
Short expiratory time (high respiratory rate) relative to
expiratory time constants
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FRC are lost under anesthesia, and without methods to increase

the FRC (such as PEEP), airway closure and atelectasis are likely
to occur.29
Closing capacity is a very important concept related to
oxygenation during positive-pressure ventilation. It is the volume
of gas present when small conducting airways begin to collapse.30
Once this occurs, gas exchange distal to the point of collapse
cannot occur and deadspace increases. Furthermore, once the
collapse has occurred, a high transpulmonary pressure (3040
cm/H2O) is required to re-expand those areas of the lungs affected
(see Atelectasis, PEEP, and Lung Expansion, later). In healthy
adults, closing capacity increases with age, such that it equals FRC
at about 65 years of age when upright but as early as 40 years in the
supine position. Closing capacity also approximates FRC in young
children in the supine position.31 In neonates and infants, it is
likely that closing capacity is greater than FRC owing to the lower
resting volumes secondary to the more compliant rib cage. As FRC
decreases further under general anesthesia, airway closure with
atelectasis and hypoxemia will rapidly follow.32
result is that impedance increases, resulting in a decelerating flow

pattern. Artificial ventilation may also be achieved by use of
constant flow, rather than constant pressure, followed by a passive
expiration. Assuming that resistance and compliance remain
constant, the equivalent changes in pressure, volume, and flow for
the two types of ventilation are demonstrated in Figure 425.
Changes in inflation pressure do not alter the time constant for
inflation but do affect the volume of air introduced per time
constant. For a given pressure, however, changes in compliance
affect both equilibrium VT and the time constant, such that when
compliance is doubled, the time constant is also doubled, which
means that the equilibrium volume is approached more slowly.
The opposite applies with decreases in compliance. By contrast,
changes in resistance also affect the time constant but do not
have an effect on the equilibrium VT. In this situation, increased
resistance reduces the flow rate for a given pressure, potentially
resulting in a decreased VT. This can be overcome by prolonging
inspiration or increasing the inflation pressure, as shown earlier in
Figure 424.
Driving Forces of Ventilation
Work of Breathing
The work required to effect the changes in lung volume that occur
during respiration is performed by the respiratory muscles, of
which the diaphragm is the most important. Usually only the
inspiratory phase of ventilation is active, whereas expiration
normally occurs passively down to FRC.
The movement of the diaphragm during inspiration is complex
but is generally considered to function as a piston in an expanding
cylinder.33 In the supine position, however, movement is even
more complex with additional changes in shape, which involves
the tilting and flattening of the diaphragm in the anteriorposterior direction.34 This movement plus the involvement of the
rib cage muscles results in a pattern of ventilation within the lungs
that, in the awake state, is well matched to the perfusion of the
lungs. This ideal relationship, however, is frequently disturbed
during anesthesia and the application of mechanical ventilation. In
the supine position, this results in a more cephalad position of the
diaphragm with an increase in diaphragmatic activity and its
contribution to ventilation.4 This parallels the decrease in FRC
observed.
The infants thorax is more cylindrical than an adults thorax
(which is elliptical) with the ribs being more horizontally oriented and softer. This limits the effectiveness of the intercostal
muscles. The diaphragm insertion is also different, inserting more
horizontally into the rib cage, which in the presence of airway
obstruction, tends to result in an inward movement of the lower
rib cage rather than downward movement of the diaphragm. In
addition, the lower relative muscle mass and lower proportion of
type 1 slow twitch, high-oxidative (high-endurance) muscle fibers
make diaphragmatic fatigue more likely with any form of resistive
loading such as that occurring during anesthesia.35
During positive-pressure ventilation, the driving pressure is
required to overcome elastic resistance (the lung volume above
FRC the total dynamic compliance) and air flow resistance (air
flow resistance instantaneous flow rate), both of which vary
during inspiration. When a constant positive pressure is applied,
the component overcoming air flow resistance is maximal initially and then declines exponentially, whereas the component
overcoming elastic resistance increases with lung volume. The net
The work of breathing performed by the respiratory muscles

is small in otherwise healthy subjects, accounting for only about
2% of the metabolic rate, but may increase significantly with
respiratory or cardiac disease. In normal situations, the work of
breathing is performed only during inspiration by the inspiratory
muscles. The work of breathing overcomes the two main sources
of impedance, the elastic recoil of the elastic recoil of the lungs
and chest wall (compliance) and nonelastic resistance
to gas flow
.
.
(resistance). For a constant minute volume (VE), the work VE
performed against elastic resistance increases when breathing is
slow and deep, but the work performed against air flow resistance increases when breathing is rapid and shallow. The resting
respiratory rate, therefore, represents a balance between these two
opposing forces. The high respiratory rates seen in newborns
seems to coincide with the minimum calculated work.6 When
there is a decrease in compliance (as in pulmonary fibrosis), the
optimal (most efficient) frequency is increased, whereas in
the presence of increased air flow resistance (such as asthma), the
optimal frequency is decreased.
The increase in work required to produce a given lung volume
in the presence of poorly compliant lungs can be estimated from
analyzing pressure-volume loops, as shown in Figure 426A, C.
The horizontally shaded area represents the work of breathing
against elastic resistance (compliance) during passive inflation.
Although the pressure-volume line is flatter during inflation in
Figure 426C, the increased area of the triangle ACD represents an
increase in work performed against elastic resistance. Additional
pressure is also required to overcome air flow resistance. With the
increasing resistance shown in Figure 426B, the increase in the
area ABC (vertically shaded area) represents the increase in work
required to overcome this.
Distribution of Gas Flow Within the Lung

Because of the arrangements previously described in Resistance
and Airflow, the distribution of airflow within the lungs is different
when a child breathes spontaneously than with positive-pressure
ventilation. During spontaneous inspiration in the supine position,
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721
Figure 42-5. Comparison of pressure control ventilation (A) and volume control ventilation (B) on inflation pressure, volume,
and flow.
airflow is preferentially directed toward the inferior and dorsal zones
of the lung. With positive-pressure ventilation, however, greater
airflow (and volume change) occurs in the anterior lung zones,
because the mediastinal and abdominal contents compress the dorsal
regions.36 This produces a mismatch between ventilation and
perfusion.
Atelectasis, PEEP, and Lung Expansion

Anesthesia adversely affects lung volumes such that the FRC
decreases for the reasons discussed in Respiratory Mechanics. It is
important to remember that all the mechanisms usually applied in
maintaining FRC are lost with anesthesia with or without muscle
relaxation. In children as well as adults, this results in the lung
volumes at FRC being reduced and, therefore, on the lower and

flatter part of the pressure-volume curve.2 This reduction in lung
volume is instrumental in the formation of atelectasis that occurs
during anesthesia. Mechanisms that cause atelectasis are airway
closure, compression, and gas resorption.37 After induction of
anesthesia, the cephalad displacement of the diaphragm leads to
an increase in pressure in the dependent parts of the lung, which
compresses the surrounding lung tissue.38 This is exacerbated during controlled ventilation when ventilation preferentially occurs
in the upper nondependent part of the lung.36 Gas absorption
further contributes to the problem in both patent and nonpatent
airways. In areas with patent airways but underventilation, increasing FIO2 (fractional concentration of oxygen in inspired gas)
leads to alveolar denitrogenation and subsequent loss of alveolar
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Figure 42-6. Breakdown of work of breathing in normal

lungs (A) and lungs with increased airflow resistance (B) and
decreased lung compliance (C). FRC = functional residual
capacity. AC: Adapted from reference 5.
volume.39 In areas with complete obstruction, gas uptake continues, but with gas inflow prevented, the alveoli again collapse.40
Atelectasis occurs rapidly after the onset of anesthesia in children

even when preoxygenation is avoided.29 The rapid onset of atelectasis suggests that physical compression is the major cause. Even
though the percentage of atelectasis is usually small as demonstrated by computed tomography (CT) scans, because of the compressed nature of the area of atelectasis, even a small area of
around 3% equates to around 10% of lung tissue and can be the
cause of a significant shunt.41,42
Prevention and treatment of atelectasis should be part of the
goals of modern anesthetic practice. Traditionally, we have been
less concerned than our intensive care colleagues regarding the
consequences of atelectasis, but there is increasing evidence that
minimizing atelecatasis by using PEEP may limit proinflammatory
changes in the lung that occur after major surgery.43 The judicious
use of PEEP is an important component in the techniques to avoid
atelectasis under anesthesia. Five centimeters of PEEP applied
early after induction of anesthesia appears adequate to prevent the
onset of atelectasis in children29 (Figure 427). This occurs despite
the fact that 5 cmH2O PEEP is still associated with a significant
reduction in FRC.18 In neonates and infants, however, this amount
of PEEP results in a significant increase in CRS.21 If 100% oxygen
is used, a more aggressive approach may be required to reverse
atelectasis such as a lung recruitment maneuver followed by PEEP
of up to 15 cmH2O.
Once atelectasis has occurred, lung recruitment maneuvers
plus the continued use of PEEP are required to prevent recurrent
atelectasis. In adults, two techniques have been described. Three
VC breaths of 15 seconds duration every 3 to 5 minutes followed
by a further breath of 40 cmH2O has been shown to be effective.44
The first VC breath is responsible for a 50% reduction in the area
of atelectasis, but complete reduction occurs only with the final
VC breath. Alternatively, increasing the PEEP levels to 15 cmH2O
and then increasing the VT until peak airway pressures of
40 cmH2O were achieved for 10 breaths followed by continuous
PEEP was also effective.45 Whether such prolonged maneuvers or
high pressures are required in children has not been determined,
Figure 42-7. Computed tomography scans. A: Bilateral atelectasis after induction of anesthesia on mechanical ventilation
without positive end-expiratory pressure (PEEP). B: The disappearance of the lower atelectasis can be observed after the
addition of 5 cmH2O of PEEP.
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but because those areas of atelectasis, whatever the age of the
patient, contain lung units with prolonged time constants, it is
likely that long periods of high pressure will be required. Direct
observation in neonates and infants undergoing thoracotomy
suggests that long and repeated inspiratory pressures in excess of
20 cmH2O are frequently required to reverse areas of atelectasis
from lung compression.
The use of continuous positive airway pressure (CPAP) during
induction has also been shown to prevent atelectasis in adults; in
children, its continued use during spontaneous ventilation may
minimize the formation of atelectasis.46,47 Patients with tracheomalacia are particularly prone to airway collapse and will also
benefit from CPAP.48 The routine use of CPAP during spontaneous
ventilation with either an ETT or an LMA should also assist in
minimizing the work of breathing by increasing lung volumes
and restoring these to the more efficient part of the pressurevolume curve.
DESIGN PRINCIPLES OF
MECHANICAL VENTILATORS
Anesthesia ventilators have undergone significant advances since
the late 1990s, changing from being adjuncts or add-ons to the
anesthesia machine to their current position as a prominent and
integral part of the modern anesthesia work station. In parallel,
advances in electronics and microprocessing have led to a number
of advanced features that were limited to intensive care unit (ICU)
ventilators now being available and integrated into anesthesia
ventilators. Thus, more modes of ventilation are available to the
practicing anesthetist in the operating room setting. The speed
of these changes afforded by advances in technology mean that
software updates can be applied to existing anesthesia systems
to improve their function without necessarily requiring replacement of the whole anesthesia machine. Different manufacturers
incorporate different technology into their anesthesia machines
and these models frequently change, so general principles rather
than details of specific machines are discussed whenever possible.
At the same time, practice in ICUs has been moving toward providing respiratory support augmenting or assisting patients
breathing rather than completely replacing it, as is the case with
controlled ventilation. Philosophically, the same approach can
now be applied to anesthetized patients if paralysis is not required
for the surgical procedure.
There is no single classification system for ventilators, but
they can be classified according to their power source, drive
mechanism, cycling mechanism, and bellows type. In addition,
anesthesia ventilators may be described as single-circuit or doublecircuit depending on whether there is a separate gas supply to
power the bellows independent from the gas flowing in the patient
circuit. The power source provides the energy necessary to operate
a mechanical ventilator and is usually electrical or pneumatic.
Many older pneumatic ventilators required only a source of
compressed gas to function. Most contemporary ventilators,
however, require an electrical or electrical plus pneumatic power
source. The drive system provides the actual force required to
generate the gas flow, and in the operating room setting, this
requires a pressure gradient to be developed between the ventilator and the lungs. They also require a mechanism to provide
variable PEEP.
723
Double-circuit and Single-circuit Systems

Most anesthesia machine ventilators can be classified as doublecircuit, pneumatically driven ventilators, but this is changing.
In the double-circuit system, the driving force (i.e., compressed
gas) compresses a bag or bellows, which then delivers gas to the
patient. The driving gas can be either 100% oxygen or a mixture
of oxygen and air.
Some newer anesthesia systems are classified as singlecircuit, piston-driven, and electronically controlled with fresh gas
decoupling (FGD). The important difference with these systems from
traditional anesthesia circle systems is that, rather than having
separate circuits for the patient gas and drive gas, there is only a single
gas circuit for the patient. The piston functions in the same way as
the plunger of a syringe and can be set to deliver a predetermined
VT or airway pressure to the patient. This type of ventilator uses a
computer-controlled stepper motor rather than compressed gas to
generate gas flow within the circuit. These systems also incorporate
a feature known as fresh gas decoupling (FGD), which is required
for the safe functioning of the systems and is described in Monitoring the System: FGF Compensation, Compliance Compensation.
Although both types of system are widely used in pediatric
practice, the single-circuit, piston-driven anesthesia breathing
systems may perform more reliably when used at high frequencies
and in pressure-control mode likely to be used with neonates and
infants.49
Bellows
Bellows can be classified by the direction of movement during the
expiratory phase into ascending and descending bellows. As the
names suggest, ascending bellows ascend during the expiratory
phase, whereas descending (hanging) bellows, descend during the
expiratory phase. Most modern electronic ventilators using a
bellows system have an ascending design that is inherently safer
because these bellows do not fill if a total disconnection occurs.
Descending bellows, however, may continue to fill during disconnection because, although the driving gas pushes the bellows
upward during the inspiratory phase, during the expiratory phase,
the weight of the bellows as they descend may entrain air into the
breathing system. The situation has become more complicated
recently because some of the new anesthesia systems have incorporated descending bellows as part of their FGD system. The
operating principles of ascending bellows in a traditional system
are shown in Figure 428, with the ventilator relief valve shown to
the right of the bellows. During the inspiratory phase, the driving
gas entering the bellows chamber causes the pressure within it to
increase, which closes the ventilator relief valve and forces the
anesthetic gas within the bellows into the lungs. During the
expiratory phase, the driving gas exits the bellows chamber and
the pressure within declines to zero. This allows the ventilator
relief valve to open and the gas exhaled by the patient to fill the
bellows and be exhaled via the ventilator relief valve. Gas flows
preferentially to fill the bellows before being scavenged through
the ventilator relief valve, by utilizing a weighted ball in the
ventilator relief valve that produces 2 to 3 cm of back pressure.
This design means that all ascending bellows ventilators produce
2 to 3 cm of PEEP within the circuit, whether PEEP is set on the
machine or not. This is not enough, however, to prevent atelectasis
with controlled ventilation. Scavenging occurs only during the
expiratory phase when the ventilator relief valve is open. Oxygen
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Figure 42-8. Traditional anesthesia circle

system demonstrating auto-PEEP of 3
cmH2O during expiration with ascending
bellows.
flushing during the inspiratory phase can result in barotrauma
because the excess volume cannot be vented because the ventilator
relief valve is closed and the breathing systems adjustable pressurelimiting (APL) valve (pop-off valve) is out of circuit, resulting in
an increase in pressure.50
Adaptations From Traditional Circle

Circuit Arrangements: Fresh Gas Inlet
to the Patients Side of the Inspiratory
Valve and FGD
A number of changes to the traditional arrangement of the circle
system have been incorporated into some of the newer anesthesia
work stations that potentially affect the function of the system and
are of relevance to pediatric practice.
Moving the fresh gas inlet to the patients side of the inspiratory
valve is considered to be more efficient by delivering fresh gas to
the patient and preferentially eliminating exhaled gases. This has
the potential advantage during inhalational induction of more rapidly
increasing the inspired agent concentration, particularly when a lowvolume absorber is also incorporated into the system. Another
change that is potentially beneficial in pediatric use is the reorien-
tation of the unidirectional valves from a horizontal to a vertical

position, which decreases the resistance of the breathing circuit
during spontaneous ventilation. This is thought to occur because
the vertically orientated valves only have to be moved away from
the vertical position to be opened, whereas the horizontal valve disks
have to be physically lifted off the valve seat, overcoming both gravity
and surface tension effects.50 Accurate measurement of VTs with this
arrangement requires relocation of the spirometer sensor to the Yconnector, because fresh gas flow (FGF)compensation is not
possible if the flow sensors are positioned in their more common
position distal to the inspiratory and expiratory valves in the
anesthesia machine housing (see Monitoring the System: FGF
Compensation, Complicance Compensation for explanation).
In a traditional circle system, the total volume delivered to the
patients lungs is the sum of the volume from the ventilator plus the
volume of gas that enters the circle through the common gas inlet.
In this arrangement, the fresh gas flow is considered to be coupled
directly into the circle system. With FGD, the fresh gas coming
from the anesthesia machine during the inspiratory phase is
diverted into a reservoir bag by a decoupling valve positioned
between the fresh gas source and the circle breathing system rather
than enter the breathing circuit directly (Figure 429). During
expiration, the decoupling valve opens allowing cumulated fresh
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725
Figure 42-9. Anesthesia breathing system design changes. A: Classic circle: double-circuit, ascending bellows. B: Fresh gas flow
(FGF) compensation, improved tidal volume (VT) measurement. C: FGF relocation, FGF compensation, compliance compensation.
D: Single-circuit, piston ventilator, compliance compensated, FGF decoupling.
gas in the reservoir bag to enter the circle system and assist in
refilling the piston ventilators chamber. A significant advantage
of this type of system is a decreased risk of barotrauma during
flushing because the fresh gas is prevented from entering the
circle system during inspiration while the ventilators exhaust valve
is closed.50 A negative-pressure relief valve is also included in the
circuit to avoid development of negative airway pressure; this
opens if the circuit pressure falls below a preset value (2 cmH2O).
At this point, room air can be entrained into the patients circuit,
raising the possibility of diluting both the inhaled anesthetic
agents and the enriched oxygen mixture with potential consequences of awareness and hypoxia.
Monitoring the System: FGF Compensation,

Compliance Compensation
Changes in FGF may affect the VT delivered to the patient if this
is not adequately measured and compensated for by the anesthetic
machine or ventilator. This effect will be greatest with infants and
small children anesthetized using volume-controlled ventilation
(VCV) and high FGFs.51 Without appropriate compensation, the
delivered volume to an infant may be twice that set if .high FGFs
are used. For example, a 10-kg infant with a set VE of 2 L,
inspiratory-to-expiratory (I:E) ratio
. of 1:2, and an FGF of 6 L
may receive an additional 2 L of VE from the FGF without FGF
compensation. Most modern anesthesia systems include com-
pensation for FGF by measuring flow on both the inspiratory and

the expiratory limbs of the anesthesia circuit and electronically
adjusting the ventilator to deliver the correct V T by subtracting
the inspiratory flow. With PCV in the absence of FGF compensation, delivery of VT to the patient will not be affected by changes
in FGF but measurement problems may still occur, because flow
detected on the expiratory limb will include the flow from the FGF
as well as the patient.
Breathing circuit compliance compensation adjusts for that
volume of delivered VT lost to the internal volume of the anesthesia
system owing to gas compression and tubing compliance. Compliance compensation is a feature of some but not all anesthesia
ventilators. Even within the same manufacturer, different ventilators may or may not include compliance compensation. In the
absence of compliance compensation, that volume lost because of
the distensible nature of the breathing circuit will still be measured
by a spirometer located at the anesthesia machine even though it
has not contributed to the patients VT. With PCV, delivered VT
decreases as lung compliance decreases. With low lung compliance, measured VT may overestimate delivered VT by up to 40%.
Similarly, with VCV, delivered VT may be only 60 to 70% of the
measured VT with a normal breathing circuit and as low as
50% with an extended circuit52 (Figure 4210). This loss can be
compensated for by using an algorithm to adjust the measured
volume when flow is measured away from the patient, at the
anesthesia machine. When compliance compensation is used,
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Figure 42-10. Percent of set VT delivered to airway

with ventilator-controlled ventilation (VCV) in
breathing systems with and without compliance
compensation. A: Circuits without compliance
compensation. B: With compliance compensation.
A and B: Modified from reference 53.
accurate delivery of VT occurs even with low lung volumes and
lung compliance.52 Most systems using compliance compensation
perform a preuse check that determines the compliance of the
system before use and compensates appropriately. This is important
to remember when a variable-length circuit is used or when changing from an adult to a pediatric circuit. Lengthening the circuit will
increase the circuit compliance and decrease the VT. Conversely,
shortening a circuit or changing from an adult to a pediatric circuit
will decrease the compliance and may result in an increase in VT
delivered to the patient. In the absence of breathing circuit compliance compensation, improved accuracy of delivered patient
volumes can be achieved by measuring volumes at the patient end
of the system (i.e., the Y-connector).52,53
Cycling
Any ventilator functions through four distinct phases: inspiratory
phase, change-over from inspiration to expiration, expiratory
phase, and the change-over from expiration to inspiration. Cycling
refers to the mechanism by which these change-overs are initiated.
All ventilators require a triggering mechanism to cycle. This

may be time, pressure, volume, or flow. Most anesthesia machine
ventilators are time-cycled when providing ventilatory support
in the control mode with inspiration initiated and terminated
by an electronic timing device. Time-triggered breaths do not
require patient effort but may be synchronized to the patients
efforts as in synchronized intermittent mandatory ventilation
(SIMV). When the ventilator is used to assist rather than control ventilation, pressure- or flow-triggering rather than time
is usually used to initiate the inspiratory phase and flow is
used to terminate the assisted breath (see Pressure-supported
Ventilation, later).
The method of cycling from inspiration to expiration
may also affect the volume delivered. With constant-flow
generators (as in VCV), inspiratory time has a direct effect
on VT. With constant-pressure generators, however, the relationship is more complex. If cycling occurs at three or more
time constants, a reasonably steady volume will result, but if the
cycling occurs well before this, a variable volume may result (see
Figure 425).
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CHAPTER 42
IMPOSITION OF
ANESTHETIC EQUIPMENT
All anesthesia equipment used to connect the patient to a
ventilator has an impact on the resistance and deadspace of the
overall breathing system. In the spontaneously breathing patient,
this affects the work of breathing and the patients ability to cycle
ventilation.
Resistance
Much has been written about the resistance imposed by ETTs
placed for the purpose of anesthesia and the consequent increase
in work of breathing. Although resistance of these tubes obeys the
law of physics, which dictates that the resistance to flow is inversely
proportional to the fourth power of the radius (assuming laminar
flow), this increase is seldom considered in the context of the area
that such tubes bypass. This is important because, during quiet
breathing, upper Raw accounts for more than half of the Rrs. In
adults, there is significant difference between mouth breathing
and nose breathing, such that, with quiet nasal breathing, Raw is
approximately twice that found during mouth breathing.54 In
infants, nasal resistance contributes approximately 50% of Rrs in
European infants, but only about 30% in those of African origin.13
Thus, bypassing the upper airways with an ETT or LMA in
patients may not contribute much to an increase in the work of
breathing.
Deadspace
The physiologic deadspace is the sum of all parts of the VT that do
not participate in gas exchange. This includes the alveolar
deadspace, anatomic deadspace, and importantly in the context of
this chapter, apparatus deadspace. Irrespective of whether an
increase in physiologic deadspace exists in the apparatus, anatomic,
or alveolar component, alveolar ventilation is reduced unless there
is a compensatory increase in VE. In the awake, conscious adult,
physiologic deadspace makes up approximately one third of the VT
and includes the anatomic deadspace comprising the mouth,
pharynx, trachea, and subcarinal volume in addition to the alveolar
deadspace. During anesthesia, a similar deadspace-to-VT ratio of
one third is seen, but this is measured from the carina distally and
specifically excludes the trachea, pharynx, and mouth. Thus, the
use of any additional equipment will need to be considered in the
overall physiologic deadspace.
In adults, the anatomic deadspace is approximately 2 mL/kg
comprising an upper extrathoracic airway deadspace of about
1 mL/kg and an intrathoracic deadspace of a similar volume.55
Thus, tracheal intubation or LMA bypasses approximately half the
anatomic deadspace55,56 In infants and small children, compared
with adults, the anatomic deadspace is increased. The anatomic
deadspace is approximately 3.3 mL/kg in the infant, decreasing
exponentially to the adult value of 2 mL/kg by the age of 6 years.
The increase in anatomic deadspace is caused solely by the
extrathoracic component because the intrathoracic component
remains constant at just under 1 mL/kg.57 Thus, theoretically
following intubation in a neonate, the anatomic deadspace may
be reduced by approximately 8 mL, and in a 10-kg child by about
20 mL minus the volume of the LMA or ETT. Although the use of
an artificial airway bypasses most of the normal anatomic
727
deadspace of the mouth and pharynx, this volume needs to be

included in calculations of deadspace for the purposes of
calculating alveolar ventilation during anesthesia. When measured
during anesthesia with an ETT or LMA however, total deadspace
increases to approximately 50% of VT.56 When using a facemask,
the total deadspace is even greater and may be as much as two
thirds of VT.56 Interestingly, at low VTs, the anatomic deadspace is
less than the expected space calculated from geometric volumes.58
This has been attributed to axial streaming and the mixing
produced by heart beat pulsation. This, combined with the
reduced metabolic rates seen under anesthesia, limits some of the
consequences of alveolar hypoventilation that might be expected
if nothing else changed. Any potential advantage, however, is
usually lost by the addition of further apparatus deadspace to the
breathing system, particularly the use of a breathing system filter.59
Supraglottic Airways and ETTs

Under anesthesia, the upper airway is usually bypassed, frequently
using an oral airway during induction and then an LMA or ETT.
The change in deadspace and resistance caused by these devices
potentially affects the work of breathing, which may be important
during spontaneous ventilation. Resistance caused by an LMA is
less than that of an equivalent ETT, presumably because of the
increased internal diameter of the LMA.60 As a consequence, in
lung model studies, the imposed work of breathing owing to
an LMA is considerably less than that of an ETT61 (Figure 4211).
In comparative clinical studies, however, the results are less
obvious because smaller tidal volumes and VEs are a feature of
spontaneous ventilation via an ETT tube compared with an LMA.
Initial studies demonstrating less paradoxical chest movement
concluded that work of breathing was decreased with LMA.62 By
contrast, a subsequent study, measuring work of breathing,
showed that, compared with a facemask and an LMA, work of
breathing was less through an ETT, which was primarily attributed
to the decrease in tidal volume and VE.63 It is likely that some of
the increase in the work of breathing observed with the LMA is
caused by supraglottic obstruction at the level of the epiglottis.
Work of breathing correlates with the degree of supraglottic
obstruction, and both improve significantly with CPAP, such that
with CPAP, the work of breathing with an LMA is indistinguishable from that with an ETT63 (Figure 4212). Thus, during
spontaneous respiration, CPAP should be used with an LMA to
minimize work of breathing. In nonparalyzed patients, work of
breathing can be decreased further by 40% using pressuresupported ventilation (PSV) of 10 cmH2O rather than CPAP.64
When using an LMA with positive-pressure ventilation, concern
is sometimes raised regarding a suitable seal from the LMA cuff
to allow adequate ventilation and minimize the risk of gastric
distention. Classic LMAs and the ProSeal LMA may both be used
for positive-pressure ventilation. The ProSeal LMA, however, has
consistently been shown to form a more effective seal than the
classic LMA, with a leak pressure about 5 cmH2O higher.65,66 The
higher leak pressure with the ProSeal LMA makes it more reliable
for use with PEEP, which also improves gas exchange when used
with PCV.67 Both PCV and VCV may be successfully used with an
LMA, although PCV is preferred because it is associated with
lower peak inspiratory airway pressures for a given VT.68 The size
1 LMA is the most difficult to use because of a poor seal and
excessive gas leakage. With careful positioning, however, it is still
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Figure 42-11. Increased work of

breathing (WOB) with endotracheal
tubes (ETTs) compared with laryngeal
mask airways (LMAs). A: Individual
pressure-volume loop demonstrating
a 10 times increase in WOB with ETT
vs LMA. B: Simulated comparisons
between LMA and ETT of different
sizes at varying flow rates. A and B:
possible to obtain VTs of 10 mL/kg at an inspiratory pressure
of 15 cmH2O.69
ETT use is changing as more suitable cuffed ETTs come on
the market. Old dogma regarding the need for uncuffed ETTs in
infants and small children is giving way to a more balanced

approach.70 When using a cuffed ETT, one half size smaller than
an uncuffed ETT is usually recommended.71 In patients breathing
spontaneously, a smaller ETT with a narrower diameter has
the potential to increase Raw and, hence, the work of breathing.
This is less of an issue with augmented or supported ventilation.
Uncuffed as well as cuffed ETTs may be used for PSV provided
the leak with uncuffed ETTs is not excessive. Controlled ventilation is possible with both uncuffed and cuffed ETTs. With
uncuffed ETTs, PCV is preferable to VCV because this mode of
ventilation compensates better for the inevitable leak with an
uncuffed ETT. With a cuffed ETT, VCV may be an alternative
option to consider with a modern anesthesia ventilator, because
volume is guaranteed if lung compliance changes.52 To protect
against barotraumas, flow rate needs to be adjusted and a pressure
limit should be set.
Airway Filters
Figure 42-12. Comparison of WOB with and without continuous positive airway pressure (CPAP) between facemask, LMA,
and ETT. Adapted from reference 64).
Breathing filters are often placed between the anesthesia circuit

and the patient to protect the equipment from contamination and
to recycle heat and moisture from the expired gas, although their
use is far from universal.72 In some countries, the use of such filters
is recommended by their professional anesthesia societies (United
Kingdom and Australasia), and in others, it is not (United States
and Canada). Depending on the various combinations of filters
and angle pieces chosen, there may be considerable apparatus
deadspace imposed, proximal to the ETT or LMA, which in
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CHAPTER 42
729
Figure 42-13. Effect of breathing filter on minute ventilation and WOB in children. A: Percent increase in minute ventilation
required to maintain normocarbia after insertion of a filter with 22 mL deadspace. B: Increase in WOB after insertion of a filter
with 12 mL deadspace. Adapted from references 76 and 77.
infants and small children, may markedly affect the performance
of the breathing system particularly with spontaneous ventilation. In a lung model study designed to model a 1-year-old child
weighing 7 to 8 kg with a VT of 37 mL attached to an ETT, using
a Jackson Rees circuit, the use of a filter increased the deadspace
from 0.6 to 0.85 with an FGF of 6 L and from 0.65 to 0.9 with an
FGF of 3 L.73 The implication is that spontaneous ventilation can
occur only at the consequence of a significant increase in minute
ventilation in neonates or small infants when a filter is used in the
circuit. This is clearly not the whole story, because clinical experience has shown that, particularly with new anesthesia systems,
spontaneous ventilation may well be possible in these patients, but
it suggests that, for anything but the shortest operations, controlled
or assisted ventilation should be considered.
The use of an airway filter significantly increases the work of
breathing associated with its use, mainly owing to the increase in
deadspace, leading to an increase in minute ventilation to maintain
constant alveolar ventilation.59,74 Although this additional burden
may be readily overcome when using mechanical ventilation, it can
be a significant issue even in adult patients when weaning from
mechanical ventilation.59,75 In infants, the addition of a 22-mL
deadspace anesthesia bacterial/viral filter required a 100% mean
increase in minute ventilation to maintain the same end-tidal
carbon dioxide pressure (PETCO2)76 (Figure 4213A). Not surprisingly, the smaller the infant, the greater the proportional increase
required. Furthermore, PETCO2 measured from the filter sampling
port underestimated that measured at the ETT by.almost 6 mmHg.
Smaller filters will require a smaller increase in VE but produce a
greater increase in resistance, which may significantly increase the
work of breathing. Interposition of a 12-mL deadspace filter in
spontaneously breathing
. infants weighing 3 to 8 kg is associated
with 20% increase in VE and a 40% median increase in the work of
breathing77 (see Figure 4213B).
It should also be noted that the large increase in deadspace
resulting from the use of a filter probably makes the difference
between breathing circuits of minimal importance by comparison
with either spontaneous or mechanical ventilation. If problems are
encountered with controlling the arterial carbon dioxide pressure
(PaCO2) while using a filter in neonates or small infants, the filter
can be moved from its usual position by the ETT to the expiratory
limb of the anesthesia breathing circuit, thereby decreasing the
apparatus deadspace yet maintaining the sterility of the anesthesia

machine. Because most filters also perform as heat and moisture
exchangers, the humidifying function of the device will be lost.
Adding humidification has caused problems with flowmeters
used in some modern breathing systems, but this appears to have
been solved.78
Circle Systems (Including

Compression Volume Issues)
A variety of different anesthesia breathing circuits are used around
the world. Most modern anesthesia systems are designed to be
used with circle systems, and improvements in the performance
of these systems has made them easier to use with children of all
ages, including neonates. Earlier concerns regarding increased
deadspace and resistance with these systems are not as relevant in
modern practice owing to both improvements in design and
changes in the way we practice.79 Resistance in a typical circle
system is derived from the circuit, the unidirectional valves,
and the absorber. Although the valves account for two thirds
of the total resistance, the pressure decrease across the system
at normal adult peak flows is less than 0.75 cmH2O.80 With the
lower peak flows seen in infants, the pressure decrease in this
group of children is only about 0.25 cmH2O. This is approximately
10 times less than the resistance across an ETT in a similarly sized
patient.81
Compression volume of the anesthesia circuit was a problem
with older anesthesia systems. Compression volumes of 7 to
10 mL/cmH2O were not uncommon with older adult circle
systems. This required set VTs in excess of 25 to 125 mL/kg
to produce adequate ventilation in neonates and small infants
when using VCV.82 Modern breathing systems have improved
the compliance of the breathing circuit such that the volume loss
from this source is small. Modern pediatric circle systems use
lightweight 150-mm-diameter tubing rather than adult 22-mm
tubing attached to the anesthesia machine. These pediatric
circle systems also have a low compression volume of less than
1 mL/cmH2O which is similar to a T-piece system and less than
half that of an adult circle system.83
The differences in resistance between these circuits and
the T-piece systems are small. Different studies have produced
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TABLE 42-3. Ideal Characteristics of Pediatric Anesthesia

Breathing System
Multiple modes of controlled ventilation
PCV, VCV, and IMV
Multiple modes of assisted/hybrid ventilation
PSV, SIMV
Proportional assist and volume target-controlled ventilation
Accurate and adjustable PEEP
Accurate and adjustable CPAP
Accurate delivery of set VTs
FGF compensation
Compliance compensation
Small internal volume
FGF close to patient to allow rapid equilibration of inspired
agent during induction
Range of FIO2 0.211
Adjustable inspiratory time (I:E ratio)
Accurate spirometry
Sensitive alarms
Range of VT 10700 mL
Range RR 660 breaths/min
Range of FGF 0.59 L
Use with T-piece system
CPAP = continuous positive airway pressure; FGF = fresh gas flow; FIO2 = IMV
= intermittent mandatory ventilation; I:E = inspiratory-to-expiratory; PCV =
pressure-controlled ventilation; PEEP = positive end-expiratory pressure; RR =
respiratory rate; SIMV = synchronized intermittent mandatory ventilation; VCV
= ventilator-controlled ventilation; Vt = tidal volume.
different results. In one, the inspiratory resistance in the pediatric

circle was slightly higher than that of a T-piece84; in another, the
expiratory resistance and work of breathing were minimally
increased85; and in another, the respiratory load with the T-piece
was higher than that with a circle system.86 The modern circle
system has the advantage that most of the monitors and alarms
of ventilation are an integral part of the anesthesia machine and
low-flow anesthesia with the benefits of improved humidity of
airway gases, cost savings, and less environmental pollution is
easily attained. Almost all of the modes of ventilation described
later in this chapter use circle systems.
On the basis of the previous discussion, the ideal characteristics
of a pediatric breathing system (and ventilator) are summarized in
Table 423.
T-Piece Systems
Many practitioners still prefer to use T-piece systems, particularly
in neonates and infants, for induction of anesthesia and for patient
transport. The original benefits of this system, low resistance and
deadspace, still apply today. This is achieved by not having any
unidirectional valves and having the FGF enter the circuit close
to the patient.87 Interestingly, the original design had the fresh gas
entering into the lumen of the wide-bore tube in a coaxial way,
which would have provided CPAP.88 This situation is mimicked
by the Bain coaxial breathing circuit.89 The addition of an openended reservoir bag to the expiratory limb allowed the system to
be readily adapted for manual ventilation.90 Replacing the reservoir bag and attaching the expiratory limb allows the system to be
used with a ventilator. Because of the absence of any unidirectional
valves, there is no physical separation between the inspiratory and
Figure 42-14. The interrelationship between FGF and minute

ventilation showing isopleths of equal arterial carbon dioxide
pressure (PaCO2). The bottom horizontal part of the graph
demonstrates the influence of FGF and the relative insensitivity
to changes in ventilation desirable during controlled ventilation.
the expiratory gas. Performance of the system is dependent on the
FGF, respiratory rate, VT, and duration of the expiratory pause.91
During inspiration, the inspired gas comes from the FGF until the
inspiratory flow rate exceeds the FGF rate, at which time, gas is
entrained from the expiratory limb. If the FGF is high or there is
a long expiratory time, the gas in the expiratory limb will be
predominantly fresh gas. If, however, the FGF is low and/or the
expiratory time is short, patient expired gas (containing CO2 and
water vapor) will be at the proximal end of the expiratory limb
and will be inspired (rebreathed). During spontaneous ventilation,
inhaling CO2-containing gas will increase the respiratory rate and
increase the work of breathing, or if the minute ventilation does
not increase, the CO2 will rise. A number of formulas exist, but an
FGF equivalent to the mean inspiratory
flow rate or two to three
.
times the patients calculated VE minimizes rebreathing and is
clinically acceptable.92,93 Lower FGF rates may result in normocapnea but at a significantly increased minute ventilation.94,95
During controlled ventilation, however, rebreathing may be an
advantage because it provides humidification of the inspired air.
Providing that ventilation is increased to compensate for inspiring
CO2-containing gas, adequate PaCO2 can be obtained. This was
beautifully demonstrated by Rose and Froese who showed that
when a high FGF (>100 mL/kg/min) is used, the PaCO2 was determined by ventilation, but when a lower FGF rate was used,
provided a minute ventilation of at least 140 mL/kg/min is used,
the PaCO2 was influenced by the FGF, not ventilation96 (Figure
4214). Extrapolating from their data suggests that hyperventilating the patients with this system and using low FGFs (i.e., the
horizontal part of the curve), in addition to allowing some
humidification, also allows compensation for some decrease
in minute ventilation owing to either the use of uncuffed tubes or
changes in lung compliance. Again, a number of different formulas
have been proposed.9698 The two-part formula proposed by Rose
and Froese serves as a useful starting point for ventilator settings
and is summarized96:
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731
FGF requirements for controlled ventilation (minute ventilation must be two times FGF)
Weight
1030 kg
>30 kg
Predicted PaCO2: 4.9 kPa Predicted PaCO2: 4.0 kPa

1000 + 100 mL/kg
1600 + 100 mL/kg
2000 + 50 mL/kg
3200 + 50 mL/kg
Inevitably, there is some variation because the recommendations were predicted assuming normal metabolic rates and
will be influenced by hypothermia and hypermetabolic states
(e.g., hyperthermia and sepsis).99,100 In modern practice, adjustments can be made depending on the measured PETCO2.
Manual ventilation with the T-piece has been heralded as the
optimal method of ventilation for neonates and small infants.
Although this may have been so several years ago, this approach
has been questioned, particularly in the context of younger
practitioners with less experience in the use of T-piece systems.101
The educated hand may not be as educated as we like to believe.
Although the compression volume of a T-piece system is less than
that of a circle system, changes in resistance and compliance and
even occlusion may not be reliably detected during manual
ventilation.102,103 In inexperienced hands, bag and mask ventilation
with the T-piece may also be associated with increased gastric
insufflation in small children.104 In the absence of a pressure relief
valve on the expiratory limb, barotrauma and tension pneumothorax may result from overenthusiastic manual ventilation.105
VENTILATION MODES IN
CLINICAL PRACTICE
A variety of different modes of ventilation are available to the
clinician. Although the classification and terminology of the
different modes are not universally agreed, from a clinical
perspective, the patients ventilation and work of breathing may
be controlled or assisted (augmented) by the ventilator. The main
driving force may be pressure or flow, and the breathing sequence
one of continuous mandatory ventilation (CMV), intermittent
mandatory ventilation (IMV), or continuous spontaneous ventilation (CSV).106 The term continuous mandatory ventilation
(CMV) is more commonly used in the ICU setting; the equivalent
in the operating room is controlled ventilation. In the operating
room, CSV may be either unaided or more commonly achieved
using patient-triggered PSV. A comparison of machine- and
patient-controlled variables for the different modes of ventilation is shown in Tables 424 and Table 425. With the increasing
sophistication of electronic and microprocessor-driven ventilators,
combination modes offering a variety of different modes are also
available. The pressure-time curves for the different modes are
shown in Figure 4215. The two most common forms of CMV
are PCV and VCV. These have fundamentally different pressurevolume and flow-time curves, as was discussed in Driving Forces
of Ventilation and shown in Figure 425.
Controlled Mandatory Modes of Ventilation

Volume-controlled Ventilation
Volume-controlled time-cycled ventilation is probably the most
common mode of mechanical ventilation in adult anesthesia but
is used less commonly in pediatric anesthesia. In this mode, the
VT is set and inspiratory flow rate determines the inspiratory time
and the peak inspiratory pressure. The peak inspiratory pressure
Figure 42-15. Comparative pressure time displays of the most

common modes of ventilation used in the operating room.
is variable, being influenced by machine factors (inspiratory flow
and time) and patient factors (respiratory resistance and compliance). In this mode, most modern ventilators reliably deliver the
preset inspiratory VTs. In this mode, flow during inspiration is
constant and is less likely to be delivered uniformly to lung units
with different time constants. Increasing inspiratory time by using
an inspiratory pause (maintaining a volume at the end of inspiration), allows gas redistribution to lung units of different time
TABLE 42-4. Machine Versus Patient Variables With
Different Modes of Ventilation
Inspiratory trigger
Inspiratory time
Volume
Pressure
Expiratory trigger
VCV
PCV
Assist
Control
SIMV PSV
M
M
M
P/M
M
M
M
P
M
M
M/P
M
M
P/M
M
M/P
M
M/P
P/M
M
P
P/M
P
M
P
M = machine; P = patient; PSV = pressure-support ventilation; SIMV =

synchronized intermittent mandatory ventilation; VCV = ventilator-controlled
ventilation.
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TABLE 42-5. Modes of Ventilation

Mode
VCV
IMV
SIMV
PCV
PSV
VTV
PAV
PTV
(Machine/
Patient)
M
M
M and P
P
P
Time
Time
Time/rescue
Time
Flow/pressure
1-degree
Control Variable
Limit
Termination
(cycle)
Flow
Flow
Flow
P
P
Volume
Volume
Volume
Pressure
Pressure
Time
Time
Time
Time
Flow
IMV = intermittent mandatory ventilation; M = machine; P = patient; PAV = proportional assist ventilation; PCV = patient-controlled ventilation; PSV = pressuresupport ventilation; PTV = patient-triggered ventilation; SIMV = synchronized intermittent mandatory ventilation; VCV = ventilator-controlled ventilation;
VTV = volume-targeted ventilation.
constants, which reduces the deadspace, resulting in a lower

PaCO2 for the same VE.107 Inverse I:E ratio ventilation has the
effect of increasing the mean lung volume predominantly by the
generation of auto-PEEP, while at that same time allowing a lower
peak inflation pressure. This same problem is overcome in more
advanced ventilators by having a volume-guarantee mode, which
uses a decelerating flow pattern but delivers a set VT.
Compensation for changes in FGF, small leaks, and gas compression upstream from the sensors can be made by most modern
systems but less reliably for leaks occurring downstream. If the
sensors are placed remote from the patient, by the expiratory
valves, the delivered volume will include the compression
volume lost to the ventilator circuit, which, if not compensated
for, may dramatically underestimate the VT delivered to the
patient. Modern pediatric circuits with their smaller diameter,
stiffer construction, and lower internal volume have a compression
volume of less than 1 mL/cmH2O.83 The potential for error from
underdelivery of preset VTs to the patient, however, increases as
the patients size decreases and the compression volume of the
circuit relative to the patient volume increases. Thus, for a 3-kg
neonate with a measured delivered VT of 24 mL, even with a moderate peak inspiratory pressure of 16 cmH2O and a noncompliant
circuit with an assumed compliance of 0.5 mL/cmH2O, a minimum of 8 mL is likely to be lost to the circuit and only 16 mL (or
66%) delivered to the patient in the absence of compliance
compensation. If the circuit compliance is a not unreasonable
value of 1 mL/cmH2O, the delivered VT will be only 33% of the
set volume or measured volume if the sensor is on the expiratory
limb housed in the anesthesia machine (a not uncommon position). Thus, if this mode of ventilator management is chosen,
VTs of at least 10 to 12 mL/kg should be set to ensure adequate
VTs are delivered to the patient. In a patient with decreased lung
compliance, higher ventilator pressure will result in greater losses
to the breathing circuit.
When there is a leak in the system, as frequently occurs with
the use of uncuffed ETTs, the effective VT delivered to the patient
will be further reduced relative to the volume delivered by the
ventilator. This will be readily detected because most ventilators
measure both inspired and expired VT.
Pressure-controlled Ventilation
Pressure-controlled time-cycled ventilation has become the most
common mode of mechanical ventilation in neonates, infants,
and young children undergoing anesthesia because it overcomes
several of the problems highlighted with VCV. In this mode, the
peak inspiratory pressure reaches its preset limit early in inspiration, which is then maintained during the remainder of the
inspiratory phase. The pressure at the beginning of inspiration is
produced by a very high flow, which then decelerates exponentially.
This pattern of flow may improve distribution of gas flow, particularly in lungs composed of units with heterogeneous time
constants.108 The VT delivered to the patient depends on the compliance and resistance both of the ventilator circuit and of the
patients lung. Despite the potential for change in these variables,
this mode of ventilation seems to offer a more stable ventilatory
pattern in most children than volume-regulated ventilation. This
may well be because the system as a whole compensates better for
the compression volume and compliance of the breathing system
than does VCV. Anesthesia ventilators from different manufacturers demonstrate differences in their performance in PCV mode
when compared in a test lung. Variation in initial peak flow and
accuracy of the set pressure influence the VT delivered.109 The peak
inspiratory flow with anesthesia ventilators tends to be lower than
that with ICU ventilators. As a consequence, they take longer to
achieve their preset pressure, which may exceed 1 second with
some ventilators.49 Thus, at rapid rates with short inspiratory times,
the preset pressure may not be reliably achieved and VTs reduced
as a consequence. Similarly, settings applied to a patient with one
system may need to be modified if the patient is transferred to a
different ventilator for any reason. During surgery in which either
lung compliance or Raw is likely to change (e.g., thoracic, cardiac,
and laparoscopic surgery), changes in the peak inspiratory pressure
will need to be made to match the clinical conditions. Potential
changes in lung volumes with PCV are shown in Figure 424.
Unless exhaled volume is measured close to the airway (which is
not the usual situation in anesthesia systems), fluctuations in VTs
may not be readily detected.53
Assisted Modes of Ventilation

Assist Control
Assist control was an early method of patient-triggered ventilation
that allowed the patient to trigger a breath and initiate a machineset predetermined breath. It was popular in ICUs, particularly in
North America, but does not appear to have been incorporated into
anesthesia ventilators. Although this mode allows the patient to
trigger a breath in a manner similar to that described in the following section on Pressure-supported Ventilation, a preset volume is
delivered to the patient and all variables are controlled by the ventilator, not by the patient. This can cause problems synchronizing the
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Figure 42-16. Components of pressure-support ventilation

(PSV) breath. A: PSV. B: Machine-defined flow to achieve set
pressure. C: Magnitude of pressure support. D: Pressure-support
termination. AD: Modified from reference 110.
ventilator with patient effort on both initiating and terminating
inspiration. These problems have been minimized by the use of PSV,
which allows more variables to be controlled by the patient, which
improves the synchronization between machine and patient.
Pressure-supported Ventilation
PSV is the most common type of patient-triggered CSV available
with anesthesia ventilators. All support ventilation modes require
the patient to trigger the ventilator in order to provide a breath.
The main challenge with ventilator design has been to develop
systems that can respond rapidly, sensitively, and accurately
enough to synchronize the ventilator with the patients spontaneous
breaths. If the synchronization is inadequate, when the patient
develops reasonable spontaneous respiratory effort, she or he will
fight the ventilator, which leads to deteriorating gas exchange,
increased work of breathing, and disturbance of the surgical field.
Machine factors that affect the likely success of PSV include trigger
sensing, trigger response time (trigger delay), time from onset of
inspiration to beginning of positive-pressure inflation, degree of
pressure support, and timing of the expiratory trigger110 (Figure
4216). These may present clinically as problems arising from
failure to trigger a supported breath, autotriggering, and patientventilator asynchrony. When applied correctly, compared with
spontaneous ventilation, PSV improves gas exchange and reduces
the work of breathing in both adults and children.111113 This
applies to both ETTs and LMAs whether or not CPAP is used with
spontaneous ventilation.64,69
Patient triggering of a pressure-supported breath can be
initiated in response to either an increase in flow rate or a decrease
in circuit pressure produced by patient inspiration. It is generally
believed that flow is a better trigger than pressure in neonates,
older children, and adults because it is associated with shorter
trigger delays and greater sensitivity.114117 To initiate a ventilatorassisted breath, the ventilator has to activate the bellows or
piston to produce the assisted breath. Delays in this activation will
result in an increase in work of breathing and potentially less
augmentation of the assisted breath. With pressure sensors, a
733
preset threshold of 0.5 to (2 cmH2O is sufficient to trigger a

ventilator breath.118,119 The pressure wave travels rapidly through
the circuit at approximately the speed of sound to reach the sensor.
By the time the pressure sensor responds and flow is provided to
the circuit, these events take approximately 100 milliseconds. The
pressure drop required to trigger inspiration is usually measured
relative to the circuit rather than atmospheric pressure, which
allows the use of CPAP or PEEP during PSV. More sensitive
triggering is achieved by placing the pressure or flow sensor closer
to the patient. Most modern ventilators use flow triggering, which
in ICU ventilators, is achieved by the ventilator having a constant
flow going around the circuit and triggering inspiration when a
difference in flow out to flow in is detected. This difference is
referred to as the flow trigger. With anesthesia systems, there is less
continuous flow but effective flow triggering is still possible. In
adults, the trigger is often set at 1 to 2 L/min,118,120 but for children,
the optimal flow trigger sensitivity is lower, with a range of 0.2 to
0.6 L/min recently suggested for use in the anesthetized patient.69
If the flow trigger is set too low and the ETT has a moderate leak,
the ventilator will self-trigger, giving the illusion that the patient
is breathing in a certain pattern. Progressive work with ICU ventilators has suggested that a triggering delay of less than 100 milliseconds is required for successful triggering that minimally affects
the respiratory workload.118,121,122 The response time for neonatal
ventilators is frequently shorter than this, often around 50 milliseconds.123 There has been concern that, because anesthesia ventilators, unlike ICU ventilators, do not have a continuous base flow
through the ventilator circuit, the response time of anesthesia
ventilator systems may not be adequate to allow successful PSV.
Recent anesthesia machines have a triggering delay approaching 100 milliseconds, comparable with that of ICU machines,
although some of the older ventilators have a slower trigger
delay.124 The single-circuit systems with a piston ventilator appear
to have the shortest delays. All the current anesthesia ventilators
use flow as the inspiratory trigger, and some also have a pressure
trigger. Of importance in the operating room, the triggering performance of the new anesthesia ventilators is unaffected by PEEP
or the use of high versus low FGFs, despite concerns that triggering sensitivity might be reduced with high flows.124
Once the pressure support has been triggered, the more rapidly
the set pressure is reached, the higher the initial flow rate and the
less the patients work of breathing.125 The newer anesthesia
ventilators have rapid pressurization characteristics similar to those
of modern ICU ventilators in some settings but pressurization
decreases as inspiratory effort increases and pressurization of
older (bellows) ventilators with PEEP is about half that of ICU
ventilators. FGF does not appear to affect performance. Those with
the best response tend to be electrically driven piston rather than
pneumatic ventilators.124
The optimal degree of pressure support differs between patients
and the degree to which the clinician wishes to unload the muscle
work of ventilation. Increasing pressure support in children is
associated with decreased work of breathing.112 In adult patients,
complete unloading of respiratory muscle work is achieved by VTs
of 10 to 12 mL/kg.126,127 This may not be required under anesthesia.
Comparison of different sized children with PSV to achieve
similar VTs of 10 mL/kg demonstrates that a higher level of
pressure support is required in infants than in older children
(Figure 4217A). This is may be because of the higher imposed
work of breathing from anesthesia airway equipment with younger
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Figure 42-17. PSV with an LMA. A: Correlation of inflation pressure vs weight to achieve a VT of 10 mL/kg (r = 0.72).
B: Correlation between pressure support and resistance (r = 0.95). A and B: Modified from reference 69.
patients, but interestingly, the best correlation was with the
patients Raw (see Figure 4217B). For patients larger than 20 kg, a
pressure of 9 cmH2O above PEEP is required, and for those 11 to
20 kg, 10 cmH2O is required. For those less than 10 kg, 15 cmH2O
above PEEP was needed to deliver the required VTs.69 In clinical
practice, the amount of pressure support is more variable depending on the desired VT and the degree of patient respiratory drive.
With less patient effort or respiratory drive, greater pressure
may be required to produce a given VT. Thus, in patients recovering from a neuromuscular blocker or narcotics, a higher level of
pressure support will be required than when these drugs have
worn off.
During PSV, the ventilator also needs to cycle from inspiration
to expiration when the inspiratory flow decreases to a certain point.
Ideally, this should coincide with the end of the patients inspiratory
effort, but technically, this may be difficult to achieve.128 Most
ventilators stop inspiration when the flow decreases to a percentage
of the peak inspiratory flow. For many ICU ventilators, a decrease
to approximately 25% of peak inspiratory flow is commonly used
to cycle from inspiration to expiration,110,129 but the more modern
systems, including anesthesia ventilators, allow the clinician to vary
the flow at which expiratory cycling occurs. If the pressure support
is terminated too early, respiratory effort will continue and doubletriggering (two PSV breaths per single inspiratory effort) may
occur with inadequate VTs usually resulting.130,131 Late termination
of pressure support may result in ineffective triggering, auto-PEEP,
and increased respiratory work during expiration.131133 Data from
ICU patients suggest that patients with lung pathology defined by
short time constants such as restrictive lung disease benefit from
having the expiratory trigger set to a lower percentage of peak
inspiratory flow, whereas those with lung pathology associated
with long time constants benefit from the expiratory trigger being
set at a higher percentage of peak inspiratory flow.134136 The most
appropriate setting for the expiratory trigger in anesthetized
patients, adults or children, has not been defined, but in this
authors experience, double-triggering and inadequate ventilation
increase significantly as the expiratory trigger approaches 50%.
At the other extreme, ventilator asynchrony may be a problem as
the expiratory trigger approaches 10%.
Ensuring an appropriately short trigger time is particularly

important if these ventilators are to be used in neonates and small
infants with their faster respiratory rates. In order to take optimum
advantage of these new triggers, patient or circuit leaks must be
minimized and the lowest and most sensitive setting that prevents
auto-triggering should be used (0.20.6 L/min).69
Autotriggering in which pressure support is activated in the
absence of respiratory effort needs to be avoided and can be prevented by increasing the flow trigger, ensuring that only spontaneous breaths trigger the pressure support. A common cause of
autotriggering is cardiac oscillations, which may be overcome by
increasing the trigger threshold.137139 Autotriggering may also
occur because of water in the circuit or leaks and is more likely
with low inspiratory drive and slow respiratory rates as may occur
when narcotics are used during anesthesia.131,140,141 With a large
ETT leak, pressure support may be ineffective because triggering
inspiration and cycling to expiration will not reflect the patients
breathing pattern.
A summary of the variables potentially under the anesthesiologists control during PSV is presented in Table 426.
Combined Modes of Ventilation

The once clear boundary between controlled ventilation and
spontaneous supported ventilation has become blurred with the
increasing sophistication afforded by modern microprocesses and
electronics.
TABLE 42-6. Pressure-Support Ventilation for Pediatrics:
Potential Variables Under Physician Control
Variable
Pressure, cmH2O
Trigger sensitivity, L/min
Termination flow, % peak flow
Peak inspiratory flow, L/min
Inspiratory rise time, s
Average
Setting
Useful
Range
10
0.4
2.5
60
0
515
0.21
1040
10120
01
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Synchronized Intermittent Mandatory Ventilation

Intermittent mandatory ventilation (IMV) refers to a pattern of
controlled ventilation in which spontaneous breathing between
mandatory machine breaths is possible. In its original form,
spontaneous breaths were not assisted by ventilator breaths and
the VTs generated by spontaneous breathing depended on the
patients effort rather than on ventilator support. In most modern
ICU ventilators, the inspiratory flow requirements of spontaneous
breathing are met from a demand valve that needs to be opened or
triggered by the patient, which potentially increases the inspiratory work of breathing. The patient is able to breathe spontaneously at his or her own rate and timing, generating a VT dependent
on their effort. This mode of breathing was not very efficient
because the patients breath was not assisted.
Synchronized intermittent mandatory ventilation (SIMV) is
IMV synchronized with the patients inspiratory efforts. For this
to work effectively, a timing (trigger) window is created before
the next mandatory breath. This is now available with many
anesthesia ventilators. If the patient takes a spontaneous breath
during the timing window, a mandatory breath is delivered,
synchronized with the patients effort. This breath is the same VT
breath that would have been delivered by the ventilator if the
patient had not spontaneously initiated it. Every time a synchronized breath is delivered, the machine recalculates the time
required to deliver the next mandatory breath. With this mode of
ventilation, the total number of mandatory breaths will equal the
preset frequency of those breaths despite any patient-initiated
breaths. If the patient fails to trigger a breath within the allotted
time period, the ventilator will deliver a machine breath to the
patient. Spontaneous respiratory efforts occurring outside the
trigger window will not result in a mandatory breath but will allow
the spontaneous breath either to continue unsupported or to be
assisted by PSV, depending on the ventilator settings.
Most modern anesthesia systems now provide modes that
allow supported mechanical ventilation with the backup provision
of mandatory mechanical ventilation. The balance between the
two modes can be set by the user to suit the individual patient.
Arguably the most appropriate mode is PSV with a backup in
neonates and infants of mandatory pressure-regulated breaths
(pressure-controlled) and in older children volume-controlled,
SIMV. This provides the safety backup of mandatory ventilation should the patient cease spontaneous respiration, such
as might occur with intermittent narcotic boluses. It also allows
the resumption of spontaneous PSV as the effects of narcotics
wane. Most systems allow the inflation pressure in the control
(mandatory) mode to be set independently of that required in the
support mode. The time period between the last spontaneous
breath and the onset of mandatory ventilation may be set by the
user. It is important to remember that, although a 30-second delay
may be appropriate in an adult patient, a shorter window before
the triggering of mandatory breaths should be used with neonates
and infants.
Volume-targeted Ventilation
Volume-targeted ventilation (VTV) is a mode of ventilation that
has been developed in recognition that volume as well as pressure
is important in determining ventilator-induced lung injury, particularly in neonates.142 Different manufacturers have responded to
the challenge in different ways. Pressure-controlled, volumeguaranteed ventilation (PCV-VG) is one mode offered with some
735
modern anesthesia ventilators. The VT is set and the ventilator

delivers that volume using a decelerating flow and a constant
pressure. The ventilator then adjusts the inspiratory pressure
required to deliver the VT on a breath-by-breath basis. A maximum pressure can be set.143 Inspiratory pressure and inspiratory
time will vary in order to compensate for changes in resistance,
compliance, and any leak from the ETT. With increasing usage of
cuffed ETTs in neonates and infants, it is likely that this mode will
be increasingly used in the operating room as it becomes available
on the next generation of anesthesia machines. ICU ventilator
manufacturers use slightly different terminology to describe
similar modes of ventilation. Volume-guaranteed ventilation is
used to describe a mode in which the inflation pressure is determined from the difference between the set volume and the
previous expiratory VT, and the term targeted VT has been used
to describe a mode in which inflation is terminated once a preset
VT is delivered or a set inflation time is exceeded.144
Proportional Assist Ventilation

Proportional assist ventilation (PAV) represents the next development phase of PSV in that the ventilator generates pressure in
proportion to the patients inspiratory effort. The greater the
patients initial inspiratory flow, the greater the pressure generated by the machine. In the ICU, this may be used without any
preselected target volume or pressure depth and frequency of
the breaths being determined solely by the patients ventilatory
drive.145 Despite theoretical advantages, it has not been shown to
be superior to PSV in the ICU and is largely untried in anesthetized patients in the operating room.
SPECIFIC SITUATIONS
Neonates
Neonates presenting for surgery tend to fall into three groups: those
who are relatively healthy (but may have respiratory issues related
to prematurity) for minor surgerymost commonly, inguinal
hernia repair; those requiring major abdominal surgery or thoracic
surgery (e.g., malrotation, small bowel atresia, tracheoesophageal
fistula repair) who are not intubated preoperatively; and those who
are critically ill and are already intubated and ventilated.
Management of neonates for minor surgery need not entail
intubation and controlled ventilation with modern anesthesia
ventilators and breathing systems. Spontaneous ventilation with
the smallest size LMA may be used for short procedures, providing
the LMA is positioned satisfactorily and the work of breathing is
not excessive. Great care needs to be employed in positioning the
LMA and ensuring it does not move or rotate during the surgical
procedure. If ventilation using this device is not optimal, an ETT
should be substituted. PSV using low trigger flows and support
pressures of 12 to 15 cmH2O may be advantageous in reducing the
work of breathing, taking care to ensure ventilator asynchrony
does not occur.69 Minimizing deadspace may require moving the
filter from the Y-connector to the expiratory limb of the circle,
when this is used.77
For patients requiring major surgery, controlled ventilation using
PCV is currently the most popular technique and, for reasons
discussed in Atelectasis, PEEP, and Lung Expansion, PEEP should
also be applied. This is likely change if the use of cuffed ETTs
becomes more widespread in this age group and VTV, used in the
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neonatal intensive care unit (NICU), becomes available in the

operating room.
In the NICU, the increasing use of surfactant and CPAP has
allowed many premature babies to avoid the need for ventilation,
but whether or not this will decrease the incidence and severity
of bronchopulmonary dysplasia is as yet unproved.146 For those
neonates who do require positive-pressure ventilation, there has
been a shift in thinking toward minimizing ventilator-induced
lung injury (VILI) by adapting many of the lung-protective
strategies used in adults into neonatal practice. These ideas are not
new in neonatal intensive care but have become more widely
acceptable only recently.147 It is generally accepted that high pressures, high volumes, and recurrent airway/alveolar collapse are
harmful to the lung. In addition, hyperventilation with high concentrations of oxygen that was common in neonatal anesthesia
can be extremely harmful not only causing direct organ damage148
but also because of the effects of increased intrathoracic pressure
and decreased PaCO2 leading to cerebral hypoperfusion.149,150
Adoption of so-called gentle ventilation has resulted in improved outcomes in some neonatal disease states.151 Newer modes
of neonatal ventilation aim for some form of volume control,
maintaining lung volumes with adequate PEEP, and allowing
permissive hypercapnia. Despite theoretical reasons why these
modes may be superior, there is little evidence that they improve
long-term rates of chronic lung disease.152 The main modes of
relevance to anesthesia involve VTV.
VTV is being used more frequently in neonates as either
volume support or volume guarantee. The advantages are that it
achieves consistent minute ventilation, which allows a constant
PaCO2, and by maintaining lung volume, it may reduce VILI. The
disadvantages are that inspiratory pressure may be excessive,
circuit leaks may limit adequate ventilation, and there is not
continuous flow. Volume support provides a preset VT with each
breath, thus allowing the inspiratory time and pressure to vary so
it is important to have a peak inspiratory pressure limit set.
Volume-guaranteed ventilation is a form of time-cycled, pressurelimited ventilation in which an expiratory V T is set and the
ventilator will adjust the inspiratory pressure within limits to
achieve the desired VT.144
Other neonatal modes used in ICUs are noninvasive synchronized ventilation, proportional assist ventilation (airway
pressure alters with patient volume or flow, allowing unloading of
the respiratory muscles), and mandatory minute ventilation
(patient
breaths result in decreased ventilator breaths as long as a
.
set VE is reached).
Although neonatal units do not usually paralyze or sedate
ventilated babies, this is not the case when they come to the operating room. Sedation and paralysis may result in inadequate ventilation owing to excessive ETT leak and cardiovascular instability
owing to changes in vascular resistance, intrathoracic pressures,
and PaCO2. Being prepared for this allows for a smooth induction
of anesthesia. The increasing use of cuffed ETTs in neonates and
infants makes ETT leak less of an issue, but cuff inflation pressures
need to be monitored carefully to minimize the risk of subglottic
damage.153 Ventilation during surgery should avoid hypocapnea
(unless specifically required as in some neurosurgical procedures).
Deliberate hypercapnea may be beneficial154 to the neonate.
Adequate humidification and airway toilet are important for
neonates undergoing lengthy anesthetic procedures to maintain
ETT patency and to enhance mucociliary function.
The Lateral Position

In the lateral position, the lower dome of the diaphragm is pushed
higher into the chest by the weight of the abdominal contents. In
this position, at FRC, the lower lung is close to RV whereas the
upper lung is closer to IC. In awake adults, because the lower dome
retains its piston-like shape and position, it is able to contract more
efficiently than the upper lung such that the ventilation of the
lower lung is about twice that of the upper lung.155 In awake
spontaneously breathing neonates, infants, and young children
both with and without radiologic evidence of lung disease, ventilation appears preferentially increased in the upper lung and
decreased in the dependent lung compared with the supine
position.156158 This is probably because the infants chest wall is
more compliant than the adults, so that the dependent lung is at
RV with pleural pressure near that of atmospheric. Under these
circumstances, airway closure occurs, and therefore, in the lateral
position, ventilation preferentially shifts to the upper lung, which
would fall on the steeper part of the pressure-volume curve.156
Perfusion, however, remains preferentially directed to the lower
lung similar to that in adults, but because of the smaller physical
size of the patient, these effects are less pronounced.158 The
differences in postural distribution of ventilation between children
and adults appears to change in the second decade of life.157
Under anesthesia, however, patterns in the distribution of
ventilation in children similar to those seen in adults result,
and the differences observed in the awake state no longer hold
true.159,160 Thus, under anesthesia, the distribution of ventilation
more closely resembles the awake state of children. With the
induction of anesthesia in the lateral position, ventilation to the
upper lung increases owing to the decrease in FRC, which places
the upper lung on the steep part of the pressure-volume curve and
the lower lung on the flatter part of this curve. In the anesthetized
patient undergoing positive-pressure ventilation, the upper lung
tends to be better ventilated in both children and adults and this
is exacerbated with an open chest161,162 (Figure 4218). The change
in the distribution between ventilation and perfusion with
anesthesia is, therefore, greater in adults than in children, which
gives rise to the fall in arterial oxygen pressure (PaO2) and SpO2
(oxygen saturation of hemoglobin monitored with pulse oximetry)
Figure 42-18. Conceptual changes in distribution of ventilation

in children in lateral position: comparison of awake, anesthetized
closed chest, and open chest states.
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CHAPTER 42
compared with the supine position.163,164 In the lateral position
with a closed chest, FRC in children is maintained or improved
compared with the supine position, as are lung compliance and
PaO2.159,165 With neuromuscular blockade, however, a decrease in
FRC and ventilation homogeneity occurs that is reversed by the
addition of PEEP.166
Thus, assuming the lateral position and ventilating children with
a closed chest are less likely to result in oxygen desaturation than in
adults. PEEP is likely to be beneficial by increasing the FRC and
improving ventilation homogeneity, particularly during neuromuscular blockade.166 No studies have addressed the impact of different
modes of ventilation in this position. It seems reasonable, however,
that if neuromuscular blockade is not required for the surgical
procedure (e.g., orthopedic procedure), to use PSV plus PEEP. With
controlled ventilation, the use of a cuffed tube will allow PEEP to
be more reliably applied. Whether VCV or PCV makes any
difference with the closed chest in this position is unknown.
Thoracotomy, Thoracoscopy,
and One-lung Ventilation
For open procedures, the principles of ventilation outlined in the
Section on Ventilation Modes in Clinical Practice remain the same,
whether the lung is retracted or whether lung separation is
preferred. When the chest is opened and the lung retracted,
overall decreases in FRC, lung compliance, and PaO2 occur.165
Figure 42-19. Changes in oxygenation, lung compliance, and

functional residual capacity (FRC) with open thoracotomy in
children. Modified from reference 162.
737
Overventilation of the upper lung is exacerbated by opening the

chest wall, whereas the lower lung will continue to be relatively
noncompliant, underventilated, and overperfused. These improve
when the lung is re-expanded and the chest closed (Figure 4219).
Surgical compression or retraction of the upper lung in this
situation may improve the distribution of ventilation to the lower
lung by limiting the expansion (and, hence, decreasing the
compliance) of the upper lung.167 PEEP will improve respiratory
mechanics and oxygenation by increasing FRC of the dependent
lung. PEEP may also reduce the likelihood of lung injury from
collapse and reopening of alveoli and inflammatory changes that
occur without PEEP and one-lung anesthesia in adults.168
Different modes of ventilation will result in different responses
to thoracotomy. With VCV, volume will be maintained when
the chest is opened. When the chest is first opened, the peak
inspiratory pressures may fall as chest wall compliance decreases,
but with lung retraction, increased pressures are likely owing to the
decrease in lung compliance.165 With PCV, however, while a
constant pressure will be maintained, lung volume will initially
increase but then decrease with lung retraction owing again to the
decrease in compliance caused by lung retraction. In this situation,
increased inflation pressures will need to be increased to maintain
should be avoided with
VT. Excessive pressures and volumes
.
either mode of ventilation, and VE should be maintained with an
increase in respiratory rate to avoid problems with barotrauma and
inflammation within the lung.168,169 PCV, therefore, seems a more
rational approach than VCV for these patients.170 PCV plus PEEP
may be the optimal mode of ventilation for these patients.171 In some
situations in which high pressures are needed, permissive
hypercapnea is an option to decrease the risk of barotrauma. When
re-inflating the nondependent lung at the end of the procedure, it
is important to remember to use a re-expansion maneuver and
maintain additional PEEP to prevent a recurrence of airway
collapse as described in Atelectasis, PEEP, and Lung Expansion.
Changes in surgical techniques have led to an increasing
number of thoracic procedures now being performed thoracoscopically in neonates and infants (e.g., diaghragmatic hernia,
tracheoesophageal fistula, and congenital cyst adenomatous
malformation of the lung [CCAM]).172,173 The impact of thoracoscopic surgery needs to be considered when selecting a mode of
ventilation. The insufflation of gas under a positive pressure will
tend to decrease lung volumes, especially FRC, and therefore to
increase the risk of hypoxemia and atelectasis, dictating the routine
use of PEEP. For certain procedures, such as tracheoesophageal
fistula, this also means spontaneous ventilation techniques are not
acceptable and positive-pressure ventilation will be required.173,174
A similar ventilation strategy as for thoracotomy should be
employed, but adjusting ventilator volumes to accommodate the
changes in lung compliance resulting from the procedure requires
continuous close monitoring.
Pure one-lung ventilation is undertaken less commonly in
children than in adults because thoracic surgery is frequently
performed with an ETT and retraction of the lung using either
surgical retractors or packs. However, lung separation techniques
are being increasingly used as equipment improves.175
Prone Position and Issues

Relating to Scoliosis Surgery
Ventilation in the prone position during anesthesia is most
commonly used in patients undergoing scoliosis surgery. Blood
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flow distribution when prone is not simply the reversal of the

supine position. Although there is a gravitational dependence,
the blood flow appears to become more uniform in the prone
position.176,177 The distribution of ventilation is also more uniform
than is seen in the supine position.178 Chest wall compliance in the
prone position is decreased owing to the restriction imposed
on rib cage movement.179 For a given volume, this tends to increase
the transpulmonary gradient and might help prevent atelectasis
from developing or allow previously collapsed segments to reexpand.180 In addition, less volume reduction in the dependent
areas of the lung occurs because they do not incur the weight
of the mediastinum and heart that is a feature of the supine
position.181 FRC in the prone position without the pelvis and
thorax supported is similar to lying supine.180,182 When patients
are positioned so that the upper chest and pelvis are supported
allowing the abdomen to move freely, further improvements in
respiratory mechanics occur. The FRC is increased and ventilation
homogeneity is improved compared with the supine or unsupported prone position.181,182 Taking all these factors into consideration, compared with the supine position, higher inflation
pressures are likely to be required, less PEEP may be needed to
prevent atelectasis, and oxygenation may be improved owing to
both improved ventilation-perfusion matching and less atelectasis.
Laparoscopic Surgery
The main physiologic changes affecting ventilation during
laparoscopic surgery are caused by an increase in abdominal
pressure, changes in position (either Trendelenberg or reverse
Trendelenberg), and the effects of CO2 insufflation. The increase
in abdominal pressure, which is usually 10 to 12 cmH2O, causes
cephalad displacement of the diaphragm resulting in decreased
FRC (plus VC and TLC) and pulmonary compliance. In children,
CRS decreases by almost 40%183 and Rrs increases by 20%.184 CO2 is
usually used as the insufflating gas to produce the pneumoperitoneum, and its absorption may increase the PaCO2. The increase
in minute ventilation required to maintain normocarbia is highly
variable. Some patients require no increase in minute ventilation,
most require a modest increase of 20 to 60%, but some may
require a 100% increase.185 With PCV, a significant increase in
driving pressure will be required to maintain a preinsufflation

VT, and with VCV, increases in driving pressure will occur. The
reliability of PETCO2 to accurately guide ventilation is somewhat
questionable because both increases in PETCO2 gradient as well as
reversal of the PETCO2 gradient have been reported.185,186 Despite
the physiologic changes described, intubation with an ETT is not
always required. ProSeal LMAs may be used with positivepressure ventilation as an alternative to an ETT. Sizes of 1.5 and
greater have been shown to provide a reliable seal with leak
pressures greater than 25 cmH2O reliably obtained when used for
laparoscopic surgery.187 PEEP has been shown to be of benefit in
adult patients undergoing prolonged laparoscopic surgery by
minimizing atelectasis and preventing hypoxemia and presumably
has the same benefit in children.188 Spontaneous ventilation using
an LMA for brief laparoscopic inspection of the peritoneum has
been described,189 but this would appear advisable only for short
procedures in older children with minimal insufflation pressures.
Magnetic Resonance Imaging

Anesthetizing patients in the magnetic resonance imaging
(MRI) suite poses a number of problems relating to the harsh
environment for electrical and mechanical equipment. Although
an increasing amount of equipment is MRI-compatible, allowing
the anesthetist and her or his equipment to be in close proximity
to the patient, the anesthesia machine is frequently located outside
the MRI room, requiring an extended breathing circuit, often
10 to 12 m in length. Not surprisingly, this affects the performance
of the breathing system. The main problems resulting from this
configuration are an increase in resistance to breathing and in
compression volume from compliance and gas compression
whether a circle, T-piece, or Bain system is used.190192 Despite theoretical concerns regarding increased resistance caused by the
circuit length, spontaneous ventilation with near normal PETCO2
may be used.193 With smaller patients, some form of ventilatory
support is usually advisable. PSV with an LMA may be used
in many infants because, clinically, the trigger response time
appears short enough to allow this mode to function adequately.
A significant increase in bellows excursion is apparent with most
circle systems when PCV or PSV is used, to compensate for the
Figure 42-20. Decrease in delivered VT in the

absence of compliance compensation with VCV
using contracted and extended breathing circuits.
A SmartVent 7900 with infant text lung compliance = 0.0025 L/cmH2O and set volume at 100 mL.
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volume and pressure loss into the circuit. With a 10-m circuit of
low compliance such as 0.5 mL/m/cmH2O and assuming an
inflation pressure of 16 cmH2O, the volume loss to compression
will be 80 mL, a significant amount in an infant. With VCV, if the
system is not
. compliance-compensated, underventilation with
normal set VE is likely52 (Figure 4220). With PCV, an increase in
driving pressure is usually required to compensate for the loss
caused by circuit compliance and gas compression. From
simulation studies of a 10-kg infant, 10 to 20% of set volume may
be not be delivered to the patient with a 10-m Jackson Rees or Bain
circuit,191,192 and this is likely to be greater if a circle system is used.
Adequate monitoring of VTs and PETCO2 is, therefore, important
in this environment.
Respiratory Pathophysiology
739
For patients with asthma, similar principles apply. Hyperinflation can lead to both cardiovascular instability and pulmonary
barotrauma.204 The use of PEEP in the acute phase is more controversial but may be beneficial in some patients.205 Controlled
ventilation should be set to minimize airway plateau pressure by
limiting VT, shortening inspiratory time, and prolonging expiratory time. High inspiratory pressures with the risk of barotraumas should be avoided. Hypercapnea may occur in this
situation but is usually well tolerated.
In both airway obstruction and gas trapping diseases, there
may be a role for heliox (a mixture of helium and oxygen), which
is less dense than air. Where turbulent flow exists, its use should
result in higher flow rates for the same pressure gradient as an
air/oxygen gas mixture.206 However, heliox is expensive, has a low
FIO2, and has shown mixed results in trials, making it unsuitable
for routine use in these conditions.
Airway Obstruction
The most common cause of airway obstruction is a foreign
body, and anesthesia for bronchoscopy is discussed in Chapter 99.
Far more difficult diagnostically and therapeutically are conditions that result in airway obstruction from collapse, congenital
narrowing, or external airway compression. These conditions may
be diagnosed preoperatively but may become more severe during
anesthesia or they may first present as difficulty with ventilation
and/or intubation. Upper airway obstruction can be bypassed by
an ETT; lower airway obstruction, however, may be more difficult
to manage. The more common causes of this include tracheobronchomalacia, vascular rings and slings,194 complete tracheal
rings,195 and mediastinal masses. These usually present during
anesthesia with prolonged and incomplete expiration but may
present as complete inability to ventilate. Those who present with
incomplete expiration need to be ventilated as for air-trapping
diseases (see the next section) with emphasis on splinting the
airway open and allowing time for expiration. In those who cannot
be ventilated, manipulating the ETT (in or out) and may provide
a means for ventilation, but if unsuccessful, rigid bronchoscopy
may be required196 to secure the airway or, exceptionally, they may
require extracorporeal methods of gas exchange.197 Spontaneous
ventilation with CPAP or PSV plus PEEP is probably the best
initial approach in these patients until definitive airway management can be established.
Air-trapping Diseases
Asthma, tracheobronchiomalacia, bronchiolitis, and external
airway compression may result in air trapping. These patients
often have a history of expiratory wheeze that fluctuates but
seldom disappears. Frequently, they have been treated for asthma
with little improvement.198 The principles of ventilation are
to maintain oxygenation, provide PEEP to splint the airway(s)
open, and allow adequate time for expiration in order to prevent
dynamic hyperinflation.199201
Patients with airway collapse will benefit from PEEP or CPAP
to splint the airway open.202 These patients may be better breathing spontaneously with pressure support rather than being
paralyzed and ventilated. Excessive gas trapping or PEEP may
result in intrathoracic pressures that are high enough to impede
venous return to the heart, which can result in cardiovascular
collapse.203 The use of airway graphics and capnography may help
to identify this problem early, thereby reducing the likelihood
of problems.
Intraparenchymal Lung Disease

Intraparenchymal lung disease includes acute respiratory distress
syndrome (ARDS), pneumonia, and cystic fibrosis. Within the
lung, there will be a continuum of lung units ranging from normal
to those that are completely destroyed (i.e., the lung becomes a
heterogeneous structure). Mechanical ventilation must try to
ventilate those areas in which gas exchange can occur without
overdistending them while at the same time trying to recruit and
ventilate those areas of the lung that are closed or collapsed. At all
times, the aim must be to minimize VILI. In the operating room,
the patient may require frequent ventilatory adjustments to
optimize PEEP, recruit the lung, avoid hyperinflation, and remove
secretions. Sudden deterioration in ventilation requires ETT
suctioning and consideration of a pneumothorax with or without
tension. Patients with cystic fibrosis can have very thick secretions
that may require repeated suctioning.
Neuromuscular Disorders
Patients with neuromuscular disorders include those with muscular dystrophies, other neuromuscular disorders, and myopathies. These patients should in theory have normal lungs but weak
and/or uncoordinated muscles of respiration. Often, they have
additional problems owing to weak cough, incoordinate swallow,
and limited movement resulting in retained secretions and areas
of atelectasis. Depending upon the severity of their disease, they
may have chronic hypoventilation resulting in a compensated
respiratory acidosis.
Spontaneous ventilation should be avoided for all but the
shortest procedure unless pressure support is used. Support
pressures should be adjusted to provide reasonable VTs of 7 to
10 mL/kg and will depend on the severity of the neuromuscular
disease. When using controlled ventilation, be aware of any preexisting hypercapnea and avoid overventilation. Muscle relaxants
should be avoided as should any anesthetic agents that have a
residual sedative effect.
Pulmonary Hypertension
In pediatrics, pulmonary hypertension is primarily a problem of
neonates and may be primary as in persistent pulmonary hypertension of the newborn or secondary as in meconium aspiration,
congenital diaphragmatic hernia, and some congenital heart lesions.
Treatment of these patients involves avoiding all the factors that
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can exacerbate pulmonary hypertension (e.g., acidosis, hypoxia,

atelectasis, altered lung volumes) and, if necessary, promoting pulmonary vasodilatation with inhaled nitric oxide.207 Hyperventilation, once a therapeutic modality for pulmonary hypertension in
neonates, should be avoided because excessive pressure may damage
the lung and hypocapnia may seriously impair cerebral blood flow
in a patient who may already be hypoxic.208
Cardiorespiratory Interactions
Mechanical ventilation with positive pressure has predictable
effects on the circulation that may be harmful or beneficial
depending upon the underlying circulatory state, the circulation
involved, and the degree of positive pressure applied.209
Patients with a normal circulation who undergo positivepressure ventilation will often develop some hypotension owing
to a decrease in venous return to the right ventricle caused by an
increase in intrathoracic pressure. PSV compared with PCV
results in a modest increase in cardiac output owing to both a
decrease in mean airway pressure and a shorter inspiratory time
for the same minute ventilation.210 The higher the intrathoracic
pressure, the greater effect this will have on venous return. This is
most obvious during a sustained inflation or if the patient begins
straining against the ventilator. In some patients with respiratory
disease, ventilating with high levels of inspiratory pressure and/or
PEEP may decrease their tissue oxygen delivery by negatively
affecting the cardiac output despite having reasonable arterial
saturations.
Right ventricular afterload is determined primarily by pulmonary vascular resistance (PVR), which is in turn, determined by
lung volume (excluding those patients who have a primary
pulmonary vascular problem). The effects of positive pressure on
right ventricular afterload depend upon lung volume.211 PVR is
minimized by ventilation around FRC.209 Low lung volumes

increase PVR owing to atelectasis plus regional hypoxic vasoconstriction, whereas high lung volumes increase PVR owing to
airway compression of small blood vessels (Figure 4221).
Positive-pressure ventilation may have beneficial effects on
the left ventricle because increased intrathoracic pressure will
decrease left ventricular wall tension and, therefore, decrease left
ventricular afterload. This may, however, be more than offset by a
decrease in preload leading to a decrease in cardiac output. In
patients with left ventricular failure and pulmonary edema, both
decreased left ventricular afterload and decreased venous return
are beneficial.
By knowing the effects that different patterns of ventilation
have on the circulation in patients with normal hearts and in
those with congenital heart disease, ventilation can be used to
manipulate the preload and afterload of each side of the heart and
can, therefore, be used to control the circulation. Positive-pressure
ventilation also has indirect effects on the circulation that
are mediated by atrial naturetic peptide (ANP).212 Increasing
intrathoracic pressure may decrease atrial stretch, resulting in
decreased production of ANP and subsequent retention of sodium
and water.
Single-ventricle Pathophysiology
Single-ventricle physiology differs from the normal circulation in
that, in the native state, instead of there being systemic and
pulmonary circulations connected in series, they are connected in
parallel.213
This results in
Figure 42-21. Effect of extremes of lung volume on pulmonary

vascular resistance (PVR). At low volume, tortuosity and narrowing and of extra-alveolar vessels increases PVR whereas at
high volumes, stretching of capillaries reduces their caliber and
increases PVR.
Volume overload of the single ventricle as it receives blood from

both the systemic and the pulmonary veins.
Blood leaving the heart is a mixture of arterial and venous blood
and the arterial saturation will reflect this.
Blood leaving the heart will take the path of least resistance
and, if there is no obstruction to outflow, most of the cardiac
output will go to the lungs with less to the systemic circulation
(PVR < SVR [systemic vascular resistance]).
Initial ventilatory management of these patients (most of

whom will be neonates or young infants) requires a strategy that
results in systemic and pulmonary blood flows being equal. This
often means aiming to increase the PVR through a combination of
raising PaCO2, lowering PaO2, raising intrathoracic pressure, and
lowering pH. This should be done in such a way that the overall
cardiac output is not decreased.
This situation is seldom seen today beyond the infant or young
toddler age group because most of these patients will have
undergone a separation of the two circulations by virtue of a
Fontan procedure. This procedure has the benefit of restoring
near-normal saturations and limiting the volume overload on
the single ventricle.213 It does, however, have some important
disadvantages that are caused by the fact that pulmonary blood
flow occurs without a pumping ventricle and is, therefore, driven
solely by a venous pressure.214 There are three important consequences of this:
Relatively small increases in PVR can substantially impede pulmonary blood flow unless the venous pressure increases. This
will cause not only desaturation but also decreased cardiac output because less blood is returning to the heart.
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741
Changes in intrathoracic pressure can have a major effect on

pulmonary venous return to the heart.
Low driving pressure can produce sluggish flow with the risk of
thrombosis.
These patients may tolerate any form of positive pressure
poorly owing to increases in intrathoracic pressure and usually
have better hemodynamics when breathing spontaneously. For any
surgical procedure in which this is possible, this is the preferred
approach.215 PSV is also likely to be better tolerated than PCV or
VCV because the initial negative pressure and limitation of
positive pressure during the inspiratory cycle should minimize any
deleterious effect on venous return. If the surgical procedure
requires the patient to be ventilated, limiting intrathoracic pressure
and changes in PVR should be the goal. If the positive pressure
required for ventilation exceeds the perfusion pressure in the
Fontan circuit (usually 1216 cmH2O), consideration should be
given to shortening the inspiratory time, even if this results in an
increase in driving pressure, to minimize the time that pulmonary
blood flow is impeded. High-frequency ventilation is associated
with a lower mean airway pressure and higher cardiac output than
conventional controlled ventilation in these patients.216 The patient
who has a failing Fontan circulation requires highly specialized
anesthetic care if undergoing any major surgical procedure.
Pediatric Intensive Care Unit

Patients in the Operating Room
The majority of pediatric intensive care unit (PICU) patients
coming to the operating room do not have an underlying
respiratory condition and are managed as for other operating
room patients. These patients will often be already intubated and
ventilated before coming to the operating room, and ventilatory
parameters should be noted at the time of hand-over and used in
the operating room. Most modern PICU ventilators are able to
generate a decelerating flow pattern in volume-control mode, and
volume control is being used increasingly in PICU patients.217
Operating room ventilators may lack this facility, and patients may,
therefore, be better on pressure control rather than on volume
control in the operating room.
Some patients will not be paralyzed in the PICU, allowing
assisted rather than controlled ventilation. If an uncuffed tube is
in place, a large tube leak with inadequate ventilation may occur
if they are paralyzed on arrival in the operating room. In this case,
the ETT will need to be upsized or a cuffed ETT used. PICU
patients who do have significant respiratory disease and need to
come to the operating room present a number of challenges to the
anesthetist. Modern PICU ventilation entails limiting V Ts and
inspiratory pressures, applying adequate PEEP (sometimes as high
as 20 cmH2O) and accepting high PaCO2 levels.218 This approach
has been shown to improve survival in adult patients with
ARDS,219 and there is no reason to believe that it will not do so in
children.220 It can be difficult for the anesthetist to accept a lower
than normal saturation and a high PaCO2 when these may be
rectified by increasing VTs.
Patients with severe ARDS may be best ventilated using a PICU
ventilator rather than an anesthesia ventilator. If this option is
used, most patients will require a total intravenous anesthesia
(TIVA)based anesthetic unless the ventilator has a volatile agent
vaporizer able to be used in a high-pressure circuit. Some of these
patients may be on inhaled nitric oxide and it is important that
Figure 42-22. High-frequency oscillator shown with the nitric

oxide cylinder on the right.
this is not suddenly stopped because this can result in severe
arterial desaturation.221
Specialized PICU Ventilation

High-frequency Ventilation
High-frequency ventilation involves ventilating patients at rapid
rates with small VTs in an attempt to maintain lung volume while
minimizing shear stress on the lung. There are several ways of
providing high-frequency ventilation, the most common being
with high-frequency oscillation (HFO). Patients who are on highfrequency ventilation in the PICU should have this mode
continued in the operating room if possible. If it is not compatible
with the surgery they are to undergo, switching back to conventional ventilation using a similar mean airway pressure should be
performed with the patient placed on a conventional ventilator
before leaving the PICU to ascertain whether they can tolerate
conventional ventilation.
HFO requires a specialized ventilator that may be unfamiliar to
some anesthetists. Essentially, it is a giant piston that oscillates at
rates of between 3 and 15 Hz (180900 cycles/min) around a set
mean airway pressure and actively moves very small VTs in and
out of the patient (Figure 4222). The mean airway pressure
and the FIO2 determine oxygenation, whereas the amount
of oscillation (the delta P) and the oscillatory rate control the
PaCO2.222 Somewhat counterintuitively decreasing the oscillatory
rate improves CO2 clearance by virtue of increasing VTs. This
mode of ventilation was originally introduced for neonates with
respiratory distress,223 and it is now becoming increasingly used
in older children and in adults with severe ARDS. There are a
number of excellent review articles on the use of HFO.222,224,225
Extracorporeal Membrane Oxygenation

Extracorporeal membrane oxygenation (ECMO) is becoming
increasingly used to support patients who develop severe reversible hypoxemia and cannot be supported with mechanical
ventilation.226 The technique involves using a pump to circulate
the patients blood through a membrane oxygenator (artificial
lung) that is outside of the body and then return the oxygenated
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as atraumatically as possible. Surgery on these patients requires
meticulous attention to surgical hemostasis and maintenance of
platelets and clotting factor levels.
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Figure 42-23. Diagrammatic representation of the venoarterial

(VA) extracorporeal membrane oxygenation (ECMO) circuit.
blood to the patient.227 Two types of ECMO are in common use
venovenous (VV) and venoarterial (VA) (Figure 4223).
Blood removed from a vein and returned to a vein is VV ECMO,
which supports the lung only. Patients likely to be encountered in
the operating room on VV ECMO are those who come to the
operating room on it (e.g., severe congenital diaphragmatic hernia)
and those who may be unventilatible during a procedure and are
placed on VV ECMO for surgery (e.g., some airway resections/
reconstructions). It may be that this mode of ECMO is superior for
respiratory failure compared with VA ECMO.228 With VA ECMO,
blood is removed from a vein and returned to an artery so that it
supports the heart as well as the lung. These are often patients with
a primary cardiac problem who may or may not have had recent
cardiac surgery.
To achieve flows that are sufficient to provide adequate
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the patient needs to be anticoagulated. This may be of a minor
nature (e.g., cannula site) or catastrophic (e.g., intracerebral
bleeding). Placement of intravenous lines, nasogastric tubes, and
other equipment needs to be carefully considered and carried out
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Crit Care. 2005;9:R274279.
226. Pettignano R, Fortenberry JD, Heard ML, et al. Primary use of the
venovenous approach for extracorporeal membrane oxygenation in
pediatric acute respiratory failure [see comment]. Pediatr Crit Care Med.
2003;4:291298.
227. Walker G, Liddell M, Davis C. Extracorporeal life supportstate of the
art. Paediatr Respir Rev. 2003;4:147152.
228. Zahraa JN, Moler FW, Annich GM, et al. Venovenous versus venoarterial
extracorporeal life support for pediatric respiratory failure: are there
differences in survival and acute complications? Crit Care Med.
2000;28:521525.
229. Cook LN. Update on extracorporeal membrane oxygenation. Paediatr
Respir Rev. 2004;5(Suppl A):S329S337.
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Which Endotracheal
Tube in Neonates, Infants,
and Small Children?
43
C H A P T E R
Gregory Moloney
INTRODUCTION
Uncuffed endotracheal tubes (ETTs) have been the cornerstone of
pediatric practice for many decades and have been recommended
in all children younger than 8 years. This belief and practice is
now being challenged and a detailed discussion of the apparent
advantages and disadvantages of cuffed versus uncuffed ETTs is
included. Unless otherwise stated, all discussion pertains to
uncuffed tubes and the tube size refers to inner diameter (ID).
Selecting an appropriate ETT is something anesthesiologists
do everyday with little more than a few seconds thought. The ease
of this decision is the result of evidence and experience accumulated since the 1950s of pediatric anesthetic practice. This
chapter examines the many aspects that make up our decision of
which ETT to use.
Until quite recently, uncuffed ETTs were considered the most
appropriate tubes in the younger age groups, but this practice is
changing with the development of better cuffed tubes.
ETT SELECTION
The correct size of an uncuffed ETT for any child is the largest that
passes easily through the larynx and trachea (more importantly.
the cricoid ring) with minimal leak under positive-pressure
ventilation (1820 cmH2O). Many different formulas have been
suggested to provide the most reliable estimation of the tube size.
Studies have shown that age is the best variable rather than weight,
height, or body surface area1 to use in calculating tube size.
The most well-established formula for choosing ETT size for an
uncuffed tube is the modified Cole formula25 (see footnote):
Age + 4
4
There are numerous other formulas. None is perfect; these
are guides only. It is sensible practice to have a size 0.5 mm above
and below the size selected available irrespective of the formula
used.
Footnote: The original formula put forward by Frank Cole in 195752 was
age + 17= French Catheter Gauge(FCG) of ETT. Although not stated, it
must refer to the external diameter of the tube being considered. To
convert to millimetres the formula becomes (Age 3) + 5.6 = external
diameter in mm. The graph of this formula (black line) and that of the
external diameter of todays Mallinckrodt uncuffed paediatric ETT can
be seen in the adjacent graph. The match is extraordinary.
TABLE 43-1. Endotracheal Tube Selection in Children

Younger Than 18 Months
Age/Weight
<1500 g
1500Term neonate
19 mo
918 mo
ETT Size, mm
2.5
3.0
3.5
4.0
ETT = endotracheal tube.
(Age 4) + 4 clearly does not apply to the first year of life with
accuracy when an infant will literally triple in size. Table 431
suggests a guide to ETT size selection in the first year of life. A
size 3.0 is a reasonable choice for any term neonate, but a size 3.5
may sometimes be required to avoid a large leak. By 1 month of
age, the default choice for a term infant should be a 3.5 mm, and
by age 9 months, a size 4.0 mm. In a premature infant, a 3.0-mm
ETT is a reasonable first choice down to 1500 g body weight.
Under this weight, a size 2.5 should be used.
A number of studies have examined the efficacy of the firstchoice formulas.69 In these studies, the first choice was too big
between 15 and 30% and too small between 11 and 27% of the
time. This is hardly surprising given the heterogeneous nature of
the population, the different outer diameter (OD) on different
brands, the formulas themselves, and the criteria used for changing the tube. Despite the emphasis on leak being present, the
pressure at which an ETT change is recommended varies among
authors between 20 and 40 cmH2O.10
Aspects of the patients history may alter your initial choice of
ETT. A recent anesthesia record may reveal difficulties with the
intubation or a previous episode of postextubation stridor. It would
be wise to start with a 0.5-mm smaller tube in these children and
TABLE 43-2. Reasons to Select Smaller Than Calculated
Endotracheal Tube Size
Previous postextubation stridor
Past history of croup (viral laryngotracheobronchitis)
Past history of subglottic stenosis
Previous airway surgery
Recent prolonged ventilation in NICU/PICU
Some syndrome (e.g., Down)
NICU = neonatal intensive care unit; PICU = pediatric intensive care unit.
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all those with a history of croup, subglottic stenosis, previous airway surgery, and recent ventilation in the neonatal intensive care
unit/pediatric intensive care unit (NICU/PICU). In those circumstances, in which the subglottis is suspected of being narrowed
or at least vulnerable to inflammation, it is no crime that your first
choice may be too small and needs upsizing (Table 432). The extra
time, care, and cost employed will be repaid by preventing unnecessary trauma and ischemia from the passage of an overly tight
ETT. A 0.5 to 1.0-mm size smaller cuffed ETT may have a role in
these circumstances (see Sizing).
Conversely, the patients previous anesthetic history may describe a large leak with the predicted formula selection, and your
first choice may then need to be upsized. When an ETT is upsized
and the leak is still present, the anesthesiologist should check that
the ETT has not become dislodged or withdrawn so that it is
sitting too high in the trachea. A very proximal ETT tip will have
a large leak. In rare circumstances, a laryngeal cleft may be the
reason for persistent leak despite a large ETT. Protagonists of
cuffed tubes in children feel that much of this discussion about
tube sizing and changing can be avoided with the transition to
cuffed tubes (see Cuffed Tubes).
Why is the presence of a leak traditionally emphasized when
uncuffed ETTs are used? The answer lies in anatomic considerations peculiar to neonates and small children and historical
solutions devised to avoid complications. The narrowest part of
the airway up to 10 to 12 years is at the cricoid cartilage (see
Chapter 8). The cricoid cartilage is the only circumferential
cartilage in the airway. Any swelling of the mucosa and submucosa
of the trachea at the cricoid cartilage can only expand into the
lumen. Any swelling into the lumen causes further narrowing. The
resistance to lamina airflow increases inversely by the fourth
power of the radius (Hagen-Poiseuille equation) so that small
reductions in radius cause sharp elevations in resistance. For
instance, a 15% reduction in the radius will double the resistance
and a 30% reduction in radius will quadruple the resistance. Any
degree of swelling is unwanted in the extubated state and could
lead to respiratory distress.
The two chief stimuli to tracheal mucosal swelling in the setting
of anesthesia are mucosal ischemia and trauma.12 The ETT must
pass easily and not cause pressure against the tracheal mucosa
resulting in ischemia. An air leak under positive-pressure ventilation is a surrogate sign that the contact pressure between ETT
and mucosa is not too high (i.e., less than the leak pressure). A leak
at a ventilatory pressure of 20 cmH2O or less is based on adult
human evidence that mucosal perfusion occurs below 30 cmH2O.13
To believe that the points of contact around the ETT are evenly
distributed and are at equal pressure is simplistic. The cricoid area
is in fact ovoid,14 whereas the ETT is circular in cross-section.
Evidence would suggest that the contact pressure begins initially
in the posterolateral areas of the trachea.15 Thus, firm contact and
poor mucosal perfusion may be occurring despite a reasonable
leak occurring in the anterior portion of the trachea. Nevertheless, this principle of sizing to a small leak put forward in the
1960s1618 has stood the test of time until the recent challenges
from protagonists for the use of cuffed ETTs. Whether scientifically sound or not, the principle of ensuring a leak at 20 cmH2O
seems to have kept the morbidity of intubation in the pediatric
anesthesia setting relatively low with postintubation croup rates
quoted at between 0.1 and 1%.19,20 It has also shown utility in PICU
setting with large audits supporting its use.21,22
The presence of a leak, however, has a downside. It has implications for protection of the airway against aspiration, effective
ventilation strategies, operating room pollution, and the economic

use of anesthetic gases.
Another problem in establishing a leak is that, in practice, it is
difficult to achieve one that is just right. For instance, upsizing a
tube with a large leak by just 0.5 mm can result in an ETT that has
no leak at the recommended 20 cmH2O pressure. The dilemma is
then whether to proceed with a troublesome leak with the attendant problems of variable ventilation, poor CO2 analysis, operating
room pollution, and wasteful gas flows or proceed with a tight tube
and risk mucosal swelling. Cuffed tubes offer a very reasonable
solution to this conundrum. Alternatively, a throat pack can be
used to limit the leak or changing head position may potentially
decrease or increase a leak.23
There are a number of reasons why maximizing ETT diameter
(while still ensuring the presence of a leak) is important. First, in
pediatric practice, the site of greatest resistance within an anesthesia circuit is the ETT itself.24 Maximizing the diameter will
reduce circuit resistance and reduce the work of breathing (Table
433). Although this is unlikely to be important during positivepressure ventilation or assisted ventilation modes, it becomes very
important during spontaneous ventilation anesthesia: during emergence from anesthesia or weaning from ventilation in the PICU.
Second, the larger lumen makes suctioning the airway easier
and decreases the risk of obstruction from airway secretions.
A size 8-French suction catheter will not pass into a 3.0-mm ETT
but it will pass into a 3.5-mm ETT. Likewise, a 10-French suction
catheter will not go down a 3.5-mm ETT but will go down a
4.0-mm tube.
Third, the larger the lumen, the greater the reserve against extraluminal compression from either oral or nasal tissue, surgical
instruments, or more commonly, a kink somewhere in the tube
path.25
Lastly, larger lumens facilitate fiberoptic bronchoscopy or
placement of an endobronchial blocker.
TUBE MATERIALS AND SHAPE

Polyvinylchloride (PVC) is the substance most widely used in
disposable ETTs.25,26 PVC is inert, and manufacturing has been
improved such that tissue reaction is very uncommon. PVC resists
kinking but softens slightly with body heat. It is transparent and
easy to cut.25
Reusable red rubber tubes are no longer used. They tend to
harden with recurrent sterilizing as well as become sticky on its
internal surface, making suctioning more difficult. It is nontransparent and can cause tissue reactions including latex allergy.
Silicon tubes are available, but they are prone to kinking and
easily compressed. Furthermore, silicone has memory and
attempts to modify the preshaped form are not possible. They
have a role as nasopharyngeal airways because they are inert
and soft.
TABLE 43-3. Reasons to Maximize Endotracheal Tube Size
Whenever Possible
Diminish work of breathing
Optimal suctioning of airway secretions
Resistance against compression and kinking
Passage of fiberoptic bronchoscopes or endobronchial blockers
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749
Reinforced or spiral embedded tubes are sometimes used in

pediatric practice. Their most useful feature is their resistance to
kinking. They also resist compression from teeth, bone, and surgical retractors. Spiral reinforced tubes have several disadvantages
in the pediatric setting. The thicker than usual wall necessitates a
smaller ID for any given OD. Therefore, a 0.5-mm downsizing is
required in smaller children. The smaller the ETT, the more
important this consideration becomes, particularly for long cases.
For example, the choice between a 3.0-mm reinforced and a 3.5mm PVC that have the same OD for a long craniofacial procedure
has implications for ETT patency and the clearance of secretions.
Once a reinforced tube becomes deformed (e.g., from a bite),
the lumen remains narrow and the airway will be compromised.2729 The use of motor evoked potentials during spinal cord
monitoring poses this biting risk even under deep anesthesia.
Suctioning can be difficult down the sticky internal lumen of
reinforced tubes. A bite block should prevent the patient biting
the tube.
Some customized, purpose-built ETTs are available. Oral RAE
tubes are perhaps the most frequently used preformed ETTs in
pediatric practice. The acronym RAE stands for Ring, Adair, Elwyn,
after three anesthesiologist from Salt Lake City who pioneered,
researched, and developed this tube design in the 1960s.30,31 These
preformed tubes are very useful for oral and dental surgery as well
as head and neck surgery. The seven-shaped oral RAE tube is used
in ear, nose, and throat (ENT) and cleft lip and palate surgery. The
intraoral portion of the tube can fit into a groove of the surgical
mouth gag and not interfere with surgical access. The extraoral
portion is then directed over the bottom lip and chin in a caudad
(south) direction. The risk of kinking is greatly reduced compared
with standard Magill tubes when a surgical mouth gag is used.
Preformed uncuffed tubes combine the correct diameter (best
related to age) with the correct distance from the bend to midtrachea (best related to patient size/height). This is so for both oral
and nasal varieties. The RAE tubes diameter is based on the childs
age, which the inventors found was the most reliable correlator.30
The bend at a fixed length means that the distal tracheal portion
may extend too far down the airway and endobronchial intubation
may occur, particularly in the neutral or flexed head positions.
Two holes (Murphy eyes) at the tubes tip protect against this
problem. The eye on the left above the bevel prevents one-lung
ventilation if the bevel tip is in the right main bronchus. The eye
on the right of the tube allows ventilation of the right upper lobe
in instances of right main bronchus intubation. The reliance on
the Murphy eyes has had criticism,3234 and the anesthesiologist
must remain vigilant of an endobronchial intubation when using
preformed tubes, whether nasal and oral.
When the subglottic space or nasal passages are narrowed or
smaller than expected for age (e.g., in Down syndrome), the
preformed ETT chosen must be a smaller diameter. The smaller
than expected ETT has a shorter distance between tube bend and
tracheal tip that may cause the tube to sit too proximally in the
trachea. Accidental extubation is a risk in this circumstance, particularly when the head is extended.
is timely, therefore, to review the advantages of cuffed tubes as

they relate to pediatric practice.
CUFFED ETTS
A cuffed ETT allows the airway to be sealed, reducing the risk of

aspiration. Cases in which uncuffed tubes have been ineffective at
preventing aspiration have been reported.42 Although aspiration
in children is rare (0.04% overall),39,43 some clinical situations carry
a much higher risk (laparotomy for obstructed bowel).43 In a study
by Warner and associates, the risk of aspiration in emergency cases
There is a growing literature to support the use of cuffed ETTs in

children.3539 Reviewers and critics of cuffed tubes have questioned, not unreasonably, the real benefit to be gained when
uncuffed tubes have a good track record of safety and utility.38,39 It
Sizing
The cuff allows for the variation in tracheal diameter that occurs
with age. The age-related formulas for appropriate ETT size are not
always right (see ETT Selection). The cuffed tube can reduce
unnecessary ETT changes prompted by excessive leaks.6 This
assumes, however, that the anesthesiologist is always selecting a
smaller tube than that predicted by the formulas for uncuffed tubes.
The two formulas used for sizing cuffed tube sizing in children
are
Age/4 + 3.5, as advocated by Deakers and coworkers3
or
Age/4 + 3 as used by Khine and colleagues6
A convenient feature of cuffed tubes is that they decrease the
economic and time burden associated with ETT changes as well as
the risk of trauma associated with ETT changes. In perhaps the
best-conducted comparative study between uncuffed and cuffed
ETTs (by Khine and colleagues6), the number of changes required
decreased from 24 to 1%, respectively. The rigid methodology of
this study has been criticized38 because an experienced anesthesiologist was not allowed to make an on the spot judgment,
using other patient factors (e.g., size for age, ENT pathology, previous clinical history) and appearance at laryngoscopy. However,
other studies confirm high exchange rates with uncuffed tubes,
suggesting that a cuffed tube is a reasonable alternative.
Economy of Gas Flow

Cuffed tubes allow low-flow anesthesia to be undertaken routinely
and reliably. This has obvious economic advantages. A difference
of just 1 L/min of fresh gas flow for 1 minimal alveolar concentration (MAC) of sevoflurane will save 6.6 mL/h of liquid
sevoflurane and for 1 MAC of desflurane it will save 17 mL/h of
liquid desflurane. The savings become obvious when you multiply
these figures by the cost per milliliter of solution and the number
of liters of fresh gas flow saved per year in your institution. This
saving is significant and could be the equivalent of one or two
anesthesiologists wages.
Diminished Pollution
Cuffed ETTs eliminate leaks, significantly reducing anesthetic
pollution in the operating room. This was proven in the Khine
and colleagues study using nitrous oxide as the tracer gas.6 This
more ably brings the operating room environment into international standards for pollution.40,41
Reduced Risk of Aspiration
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TABLE 43-4. Reasons for Considering Using a Cuffed

Endotracheal Tube in Children
Protection of the airway in at-risk cases (e.g., bowel obstruction)
Low-flow anesthesia economy
Reduced operating room pollution
Optimized ventilation when PaCO2 control important
(e.g., cardiac/neurosurgery)
Anticipate high inflation pressures
PaCO2 = arterial carbon dioxide pressure.
was almost 10-fold higher (0.3%)one third of these cases had

intestinal obstruction.43 A cuffed tube protects the airway not only
from vomitus but also from blood, secretions, and irrigation
during craniofacial or orthognathic surgery. Previously, with an
uncuffed tube, a throat pack would have been the only additional
protection. However, one must remember that, upon removal of a
cuffed ETT after regurgitation, proper suctioning within the
larynx, above the cuff, is essential to eliminate potentially accumulated debris.
Ventilation and Measurement

The ability of the cuff to seal the airway allows for more precise
ventilation (Table 434). In conditions in which arterial carbon
dioxide pressure (PaCO2) control is paramount (e.g., neurosurgery
or cardiac surgery), the minute ventilation is able to be controlled
with greater confidence and will be less affected by changes in
head position known to substantially alter leak.44 The sealed
airway allows for the maintenance of positive end-expiratory
pressure (PEEP) and the generation of high inspiratory pressures
sometimes required in burns,45 laparoscopy, the prone position,38
or significant lung disease.
Accurate determination of respiratory volumes for clinical
measurement or metabolic calculations can also be achieved with
a sealed airway.35,39
In unusual clinical situations, the cuff can be used to isolate
portions of the lung for ventilation purposes, for example, in
instances in which one lung ventilation is mandatory46 (ruptured
bronchus), preferred47 (thoracotomy/thoracoscopy), or helpful48
(obstructing a tracheoesophageal fistula).
Disadvantages With Cuffed Tubes

The greatest concern with the use of cuffed tubes is the potential
for damage to the subglottis or lower trachea from overinflation or
traumatic insertion. There is little evidence that this will happen
when the cuffed tubes are used correctly. Most studies and audits
confirm that, with correct use, the cuffed tubes have the same
frequency of complication as uncuffed tubes with respect to
postextubation stridor or subglottic stenosis.
Initial studies were nonrandomized and nonblinded audits.3,36,37
However, other more scientifically robust studies have confirmed
no difference.6 An important feature in the studies is a strict
adherence to monitoring cuff pressure. Weiss and coworkers state
that those not prepared to monitor cuffed pressures should not
use cuffed tubes.35 It is not unreasonable to postulate that, with
more widespread and liberal use of cuffed tubes, the potential for
complications may increase if cuffed pressures are not carefully
monitored. For example, cuff pressure increases steadily for the
Figure 43-1. Comparison of 15 brands of cuffed and uncuffed

pediatric endotracheal tubes (ETTs), clearly demonstrating a
wide variation in cuff placement and vocal cord markings. Some
locations show poor application of known pediatric anatomy.
From reference 51, reproduced with permission.
first 2 hours if nitrous oxide is used.49,50 Having said this, a large
audit in France revealed no increase in problems over 3 years of
routine use.37
Initial reviews of pediatric cuffed ETTs have revealed poor
design characteristics in many currently available brands.51 First,
tube markings indicating correct placement with respect to the
vocal cords can be misleading or incorrect. Second, the length and
the position of the cuff relative to the tracheal tip suggest a lack
of understanding of the pediatric airway anatomy. The cuff in
some brands can sit as high as the vocal cords when the tip is
correctly placed or, conversely, the tip is endobronchial when the
cuff is appropriately positioned within the trachea (Figure 431).
This is hardly encouraging for any prospective user.
Recently, a softer polyurethane cuffed ETT with improved cuff
positioning has been developed.52 Concerns over kinking have
led to a temporary withdrawal from clinical practice and more
studies are awaited. Cuffed pediatric ETTs currently available have
a PVC cuff that tends to be bulky and stiff. The cuff material is
welded onto the ETT exterior, adding substantially to its OD
(Figure 432). The stiffness of the baggy cuff, particularly in the
deflated state, makes insertion feel rough and sometimes difficult.
This is less so in the smaller sizes on which the small-volume cuff
is fusiform in shape. The bulkiness is perhaps greatest at size 5.0
when the cuff first changes from a fusiform to a cylindrical shape
(Figure 433).
Cuffed tubes clearly have many advantages to recommend
them. Why then has the pediatric anesthetic community not
embraced a change to cuffed tubes more universally? Clearly, the
design issues need to be addressed, but perhaps the more likely
reason is that the uncuffed tubes are cheaper and have a proven
safety record. To compete with such a record in a conservative and
litigious medical climate, the user needs to be convinced not just
of equivalence but also of superiority. Certainly, there are clear
advantages to using cuffed tubes in some clinical circumstances,
but to replace uncuffed tubes in routine practice (particularly in
neonates and infants) is a much bigger task. In small infants, the
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751
respiratory drive are often all that is needed. Nebulized epinephrine and intravenous dexamethasone may be indicated. Studies
looking at the prophylactic use of intravenous dexamethasone in
postextubation croup are contradictory.5456
Re-intubation may be required for severe distress and hypoxia.
This can be a challenging clinical situation.
Almost all cases of acquired subglottic stenosis are caused by
endotracheal intubation. Intubated neonates appear to be less
susceptible than older infants in this regard. The pathogenesis is
that of ischemia followed by edema and finally ulceration and
necrosis.53 Superadded infection may spread the extent of the
lesion in both thickness (cartilage affected) and length (to areas
not initially involved). Granulation tissue commences early and
scarring frequently follows.57
Figure 43-2. Comparison of 5.0 cuffed ETT and 5.0 uncuffed
ETT. Note the bulky and stiff appearance of the cuff. Note the
vocal cord marking on the uncuffed tube compared with the
welded segment of the cuffed tube and the proximal edge of
the cuff.
Figure 43-3. The evolution and shape from fusiform to cylindrical from size 3.0 to 5.0. The contact area with trachea is likely
to be much smaller and, therefore, tighter with the fusiform cuff.
ID = inner diameter.
loss of some ID, the increased resistance, the risk of kinking, the
policing of cuff pressure, and the reduced ability for suction
dissuade this author from switching until the indications become
more clear.
Complications
The two complications of tracheal intubation of greatest concern
are postextubation croup and laryngotracheal stenosis. As
mentioned in the Section on ETT Selection, the incidence of
postextubation croup varies from 0.1 to 1%.19,20 It is more likely to
occur in the 1- to 4-year-old age group and those with a previous
history of croup. Other risk factors include an ETT that is too tight
(no leak > 20 cmH2O), multiple tube changes, prolonged intubation
time greater than 1 hour, and where multiple head position changes
have been made.53
Treatment is based upon severity. Supportive care with oxygen
therapy and appropriate sedatives and analgesia to diminish
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31. Maltby JR (ed). Notable Names in Anaesthesia. London: The Royal Society
of Medicine Press Ltd; 2002. p. 167.
32. Harrison JF. A problem with Murphys eye. Anaesthesia. 1986;41:445.
33. Macgillivray RG, Odell JA. Eye to eye with Murphys law. Anaesthesia.
1986;41:334.
34. Nichols KP, Zornow MH. A potential complication of fiberoptic
intubation. Anesthesiology. 1989;70:562563.
35. Weiss M, Gerber AC. Cuffed tracheal tubes in childrenthings have
changed. Paediatr Anaesth. 2006;16:10051007.
36. Newth CJ, Rachman B, Patel N, et al. The use of cuffed versus uncuffed
endotracheal tubes in pediatric intensive care. J Pediatr. 2004;144:333337.
37. Murat I. Cuffed tubes in children: a 3-year experience in a single
institution. Paediatr Anaesth. 2001;11:748749.
38. Cox RG. Should endotracheal tubes be used routinely in children? Can J
Anaesth. 2005;52:669674.
39. James I. Cuffed tubes in children [editorial]. Paediatr Anaesth. 2001;
11:259263.
40. Patel C. Atmospheric pollution. In: Davey A, Diba A, editors. Wards Anaesthetic Equipment. Elsevier Saunders; Philadelphia; 2005. pp. 395398.
41. National Institute for Occupational Safety and Health. Criteria for a
Recommended Standard: Occupational Exposure to Waste Gases and
Vapors. DHEW Publication No. (NIOSH) 77140. Cincinnati, Ohio:
NIOSH; 1977.
42. Roy WL. Intraoperative aspiration in a paediatric patient. Can Anaesth
Soc J. 1985;32:639641.
tracheal tubes in children. Can Anaesth Soc J. 1985;32:326329.
45. Sheridan RL. Uncuffed endotracheal tubes should not be used in seriously
burned children. Pediatr Crit Care Med. 2006;7:258259.
46. Oh AY, Kwon WK, Kim KO, et al. Single-lung ventilation with a cuffed
endotracheal tube in a child with a left mainstem bronchus disruption.
Anesth Analg. 2003;96:696697.
47. Patankar SS. Single-lung ventilation in young children: practical tips on
using conventional cuffed endotracheal tubes for VATS. Anesth Analg.
2000;91:248.
48. Lucking-Famira KM, Schulzke S, Hammer J. Cuffed endotracheal tube
for occlusion of a tracheo-oesophageal fistula in an extremely low birthweight infant [letter]. Intensive Care Med. 2004;30:1249
49. Felten ML, Schmautz E, Delaporte-Cerceau S, et al. Endotracheal tube
cuff pressure is unpredictable in children. Anesth Analg. 2003;97:1612
1616.
50. Dullenkopf A, Gerber AC, Weiss M. Nitrous oxide diffusion into tracheal
tube cuffsefficacy of a new prototype cuff pressure release valve. Acta
51. Weiss M, Dullenkopf A, Gysin C, et al. Shortcomings of cuffed paediatric
tracheal tubes. Br J Anaesth. 2004;92:7888.
52. Weiss M, Gerber AC, Dullenkopf A. Appropriate placement of intubation
depth marks in a new cuffed paediatric tracheal tube. Br J Anaesth.
2005;112:167187.1.
53. Dullenkopf A, Gerber AC, Weiss M. Fit and seal characteristics of a new
paediatric tracheal tube with high volume-low pressure polyurethane cuff.
54. Anene O, Meert KL, Uy H, et al. Dexamethasone for the prevention of
postextubation airway obstruction: a prospective, randomized, doubleblind, placebo-controlled trial. Crit Care Med. 1996;24:16661669.
55. Couser RJ, Ferrara TB, Falde B, et al: Effectiveness of dexamethasone in
preventing extubation failure in preterm infants at increased risk for
airway edema. J Pediatr. 1992;121:591596.
56. Tellez DW, Galvis AG, Storgion SA, et al. Dexamethasone in the prevention of postextubation stridor in children. J Pediatr. 1991;118:
289294.
57. Benjamin B. Prolonged Intubation injures of the larynx: endoscopic
diagnosis, classification and treatment. Ann Otol Rhinol Laryngol. 1993;
160:115.
58. Cole F. Pediatric formulas for the anaesthesiologist. Am J Dis Child.
1957;94:472.
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Regional Anesthesia:
Principles of Localization
Using Manual Approaches
44
C H A P T E R
Hans Jutzi and Alain Borgeat
INTRODUCTION
Reasons for Regional Anesthesia
Using Manual Approaches
Postoperative analgesia in children is very important, because
nerve blocks may allow a pain-free awakening from surgery and,
thus, provide a quiet and unstressed child in the postoperative unit.
Especially former preterm infants, 44 to 60 weeks postconceptional
age,13 at risk of life-threatening respiratory complications occurring after general anesthesia may benefit from regional anesthesia (RA). Nerve blocks using a manual approach are performed
without the aid of nerve stimulators or ultrasound machines. They
can be performed in a sedated or an anesthetized child.
Conditions for RA Using

Manual Approaches
In the authors opinion, the following points are mandated before
RA can be performed without using special devices:
Define the landmarks for the puncture site.

Define the anatomic space at which the local anesthetic (LA)
will spread to block the desired nerves.
No other structure should be jeopardized.
AXILLARY BLOCK
Anatomic Considerations
The roots C5 to T1 enter the trunks, form the divisions, and over
the first rib transform to the cords and enter the axilla as ulnar,
radial, and median nerves. These three nerves are embedded
within the axillary sheath, appearing under the lateral edge of the
pectoral muscle and supplying the forearm. In the context of the
axillary block, it is important to be aware that the musculocutaneous nerve leaves the brachial plexus proximally and enters
the coracobrachialis muscle. It is only marginally involved by the
axillary block.
Landmarks and Performance of the Block

The patients arm is abducted to 90 degrees and flexed in the
elbow. The axillary artery is palpated as close to the pectoral
muscle as possible. After a small skin incision with a sharp needle,

a blunt, short-beveled needle is introduced in a slight cephalad
direction right to the artery. To detect the needle tip indirectly, it
is helpful to observe the needle hub. If it moves sideward, the
needle tip has passed the artery tangentially and must be corrected. If it pulsates in the longitudinal axis, the needle tip is riding
close on the artery. At this point, the needle can be advanced
carefully until penetration of the sheath containing the three
nerves. It is indicated by a slight click or give. The LA can be
injected after applying negative pressure to detect the presence of
blood. Compressing the sheath distal to the needle can direct the
LA proximally in an attempt to reach the musculocutaneous
nerve. An intra-arterial needle placement should be withdrawn to
the point at which bleeding stops. The LA can be injected.
Indications
Surgery and fractures of the forearm and hand.
PARAUMBILICAL BLOCK
(RECTUS SHEATH BLOCK)
The 10th intercostal nerves run from the intercostal space to the
rectus sheath between the internal and the transversus abdominis
muscles. After penetrating the posterior layer of the rectus sheath,
the nerve divides into several branches. These branches penetrate the rectus muscle within the rectus sheath aponeurosis and
supply the skin of the anterior abdominal wall.4 Injection of small
amounts of LA within the sheath at the desired level produces
blockade of the ipsilateral side.

With the child supine, the lateral border of the right and left rectus
muscle is identified. At the level of the umbilicus, a short-beveled
needle is introduced within the outer border of the muscle and
directed toward the upper portion of the umbilicus. Penetration of
the rectus sheath is indicated by a click or loss of resistance. The
LA is injected into this space and disperses along the aponeurosis.
After withdrawal, a subcutaneous injection is also recommended
to complement the block. The technique should be repeated on
the contralateral side to complete the block.
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Indications
Umbilical hernia, epigastric hernia, laparoscopy, and midline
incisions.
FIELD BLOCK FOR INGUINAL

SURGERY
The roots of L1 to L4 form the lumbar plexus. Off this latter spring
the ilioinguinal nerve (L1) and the genitofemoralis nerve (L1, L2),
respectively. The ilioinguinal, iliohypogastric, and genitofemoral
nerves arise from the lumbar plexus formed by the ventral roots of
L14. The iliohypogastric nerve separates in the psoas muscle
and parallels the ilioinguinal nerve along the trunk wall under
the outer fascia through the inguinal channel descending into the
scrotal pouch. The ilioinguinal nerve innervates the skin of the
mons pubis and the upper part of the scrotum and the labia major,
respectively, whereas the femoral branch of the genitofemoral
nerve innervates the lower part of the scrotum and the lower part
of the labia major, respectively.

With the child supine, a needle is introduced at the junction of
the first and second lateral quarters on a line drawn between the
umbilicus and the anterior superior iliac spine. A short beveled
needle is inserted at a 45- to 60-degree angle to the skin and directed toward the midpoint of the inguinal ligament. The external
oblique aponeurosis is penetrated with a give or a pop. A small
dose of LA is injected at this point. When performing a bilateral
block, the dose of LA should be carefully calculated and proper
monitoring used during injection.
Indications
For inguinal surgery including inguinal herniorrhaphy and orchidopexy. This block offers an alternative to a caudal block,
sparing the lower extremities and bladder function.
PENILE BLOCK
The sacral roots S35 form the pudendal nerves that are derived
from the lumbar sacral plexus. The nerves follow the wall of the
inferior pelvis. Posterior to the symphysis pubis, they divide into
the perineal nerves (that innervate the perineum, the posterior
part of the scrotum, and the labia majora, respectively) and the
dorsal nerve of penis. These leave the inferior pelvis under the
symphysis with the dorsal vein and the right and left dorsal
arteries as most lateral structures, respectively. They lie in the
penile fascia (Bucks fascia), overlying the corpora cavernosa. They
innervate the skin and the glans. The base of the penis and the
scrotum are innervated by branches of the genitofemoral nerves.

With the patient lightly sedated or anesthetized in the supine
position, the skin is punctured below the symphysis pubis
approximately 0.5 to 1 cm from the midline. The penis is pulled

downward to open the subpubic space. A short beveled needle is
introduced almost perpendicular to the skin until a slight give
(penetration of the outer layer of the Scarpa fascia) on each side is
felt.5 The LA is then injected after negative-pressure aspiration is
done to confirm the absence of blood.
Indications
Classically for circumcision surgery but also hypospadias repair
when appropriate.
FASCIA ILIACA BLOCK

The lumbar roots L14 form the lumbar plexus that gives rise to
the lateral cutaneous nerve of thigh (L2 and L3) and the femoral
nerve (L24). The femoral nerve is accompanied by the femoral
artery on its medial side. The relationship between these two
structures is inconsistent. At the level of the inguinal canal, the
femoral nerve separates into the anterior cutaneous branch and
the saphenous nerve. The saphenous nerve may reach as far
medial as the head of the first metatarsal. It provides sensory
innervation for most of the femur and of the hip, parts of the knee,
and ankle joints. The lateral cutaneous nerve and the femoral
nerve are embedded between the fascia iliaca and the psoas
muscle. LA injected under the fascia lata floods this space and
blocks these two nerves.

By contrast to femoral block, which is performed by identifying
the femoral nerve with a nerve stimulator, with the fascia iliaca
block, the LA is injected far away from the nerve and reaches
the nerve by spreading within this tissue plane or anatomic space.
The child is placed in the supine position sedated or anesthetized,
with the leg to be blocked slightly abducted. The important
structure is the inguinal ligament extending from the anterior
superior iliac spine to the pubic tubercle. The line between these
two points is divided by three. The point of insertion lies 0.5 to
1 cm caudal of a vertical line drawn from the junction of the lateral
with the medial two thirds. The injection point lies cranial to the
sartorius muscle. A short beveled needle is inserted vertically until
it pierces the fascia lata and the fascia iliaca, indicated by a slight
give. This tissue plane can be detected by a loss of resistance.
Indications
Hip and femur shaft fractures.
ANKLE BLOCK
The lumbar roots L4 and L5 merge together with the sacral roots
S13 to form the sacral plexus from which the sciatic nerve (L4
S4) arises. The forefoot is innervated by the following five nerves
originating from lumbar and sacral plexus: The superficial
peroneal nerve (L4S2), deep peroneal nerve (L4S2), tibial nerve
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Regional Anesthesia: Principles of Localization Using Manual Approaches 755
(L4S4), sural nerve (S13), and last but not least, saphenous
nerve originating from the femoral nerve (L14).
The saphenous nerve enters the foot on the medial side of the
tibia and lies very subcutaneously. It provides sensory innervation
to parts of the ankle joint and in a variable manner to the medial
side of the foot. In up to 2% of the patient, it reaches the head of
the first metatarsal. The superficial peroneal nerve leaves the
popliteal fossa and courses over the fibula to the lateral aspect of
the lower limb and runs subcutaneously, providing sensory
innervation to the dorsum of the feet except a small area between
the first and the second toe, which is supplied by the deep peroneal
nerve. The sural nerve runs subcutaneously lateral to the Achilles
tendon and innervates the lateral border of the foot. The tibial
nerve enters the foot by passing behind the medial malleolus,
accompanied by the tibial artery. It innervates the plantar aspect
of the foot except the very proximal and lateral parts. The deep
peroneal nerve leaves the popliteal fossa between the tibia and
the fibula, between the extensor muscles, to the frontal aspect of
the lower limb and finally enters the dorsum of the foot beneath
the extensor retinaculum between the dorsal foot artery and the
extensor pollicis longus tendon. It innervates the small extensor
muscles and the skin between the first and the second toe.
The patient lies either in a lateral decubitus or in the so-called frog

position. The operators finger of the nondominant hand can now
identify the entrance to the hiatus in the apex of this triangle. The
needle or cannula is introduced aiming to pass under the median
crest of the hiatus. The angle of insertion is 30 to 60 degrees to the
skin. Preferably, one starts with a high angle, lowering by sliding
the needle tip over the bone until the sacrococcygeal membrane is
pierced. This is felt by a click and is similar to loss of resistance
felt on entering the epidural space in the epidural anesthesia.
Busoni and Andreuccetti developed a nomogram indicating
the spread of the caudal block related to the injected volume and
the childs age and the body weight.6 Takasaki and coworkers7
found an arithmetical approach indicating the injected volume as
Body weight (kg) Number of segments to be blocked/20
This latter formula is valid for children up to 7 years. The rate
of injection does not influence the height of the block.8 The LA
must be injected slowly and incrementally to avoid cardiovascular
toxicity.
Indications
Inguinal and lower limb surgery are the main indications.

First, the three subcutaneous nervessaphenous nerve, superficial peroneal nerve, and sural nerveare anesthetized. This can
be done using a circumferential subcutaneous injection just
proximal to the ankle joint. This blocks all the sensory supply to
the foot except the small area between the first and the second toe.
Blockade of the tibial nerve and the deep peroneal nerve can then
be performed through an already anesthetized area. The dorsalis
pedis artery is palpated. The needle pierces the skin perpendicular
and medial to the artery and directed under the artery where a
small volume of LA can be placed. For blockade of the tibial nerve
behind the medial malleolus, the tibial artery is palpated. The
needle is inserted until contact with the distal end of the fibula is
made, the needle is withdrawn, and the LA is injected between the
artery and the Achilles tendon.
SPINAL ANESTHESIA
Indications
The child or infant is placed in a lateral or sitting position. The

spine should be flexed and the neck extended to maintain an open
airway when performing a spinal block in infants.10 At any age,
the intercristal line is used to determine the level of the puncture.
In small children and neonates, an introducer is not used, because
the skin is readily pierced and because of the small distance to the
subarachnoid space. A Quincke needle is preferred, because the
short bevel ensures complete placement within the subarachnoid
space, whereas the longer bevel of a Sprotte needle may be partly
within the intradural space and cause uncontrolled spread of the
LA within the cerebrospinal fluid.
If a hyperbaric LA is used, the child is placed in a sitting position to achieve a more pronounced caudal block. If the child is
placed in the supine position, a midthoracic level can be expected
because of the flatter spine.
Sedation should be used cautiously. It is recommended because
spinal anesthesia itself may provoke sedation.11 Together, they
might severely impair the oxygenation. Further, it can enhance
apnea in the premature infants, which is why this is a very good
indication for spinal anesthesia.
Any small surgery in the forefoot area.
CAUDAL BLOCK
The epidural space is accessible not only through the ligamentum
flavum but also through the sacral hiatus. This latter access is
enabled by incomplete fusion of the posterior arches of the lower
sacral vertebra. The sacrococcygeal membrane is continuous with
the ligamentum flavum beneath which lies the dural sac, the cauda
equine, and the filum terminale. This access is possible in children
aged up to 12 to 14 years.

The left and right posterior superior iliac spines and the sacral
hiatus form an isosceles triangle with the sacral hiatus at the apex.
The spinal cord has 12 thoracic, 5 lumbar, and 5 sacral pairs of
spinal nerves that supply the trunk and the lower extremities with
motor, sensory, and sympathetic nerves.9 Each of these spinal roots
leaves the vertebral column through the corresponding intervertebral foramen. In the adult, the spinal cord ends on the level of
the first lumbar vertebra. In the newborn, the spinal cord ends
between the first and the third lumbar vertebrae. The thoracic and
lumbar curves are much less prominent in children; in newborns,
the distance from the skin to the subarachnoid space is shorter.
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Indications
Surgical procedures for the lower part of the body for premature
infants, day case surgery.
EPIDURAL OR EXTRADURAL
ANESTHESIA
identification of the space when the loss of resistance is felt. An

epidural catheter is inserted. It should not be advanced more than
a few centimeters (i.e., 3 cm). If inserted further into the epidural
space, the position of the catheter tip becomes unpredictable. The
catheter is fixed and the puncture site is dressed. A test dose is
given to exclude a subarachnoid or intravascular injection before
the initial dose is given.
Indications
The spinal cord with its 25 pairs of nerve roots and the cerebrospinal fluid are enveloped in the dural sac. The dural sac with
its contents lies within the osseous channel of the spine. In the
adult, the dural sac reaches from the occiput to the second sacral
vertebra; it ends at the fourth sacral vertebra in the neonate.12 The
epidural space is defined as the space surrounding the dural sac. It
contains fat and epidural veins. These veins do not have valves and
may increase bleeding when injured. Dorsally, the epidural space is
bounded by the ligamentum flavum. In the adult and in the child,
the only access to the epidural space is via the intervertebral foramen by piercing the ligamentum flavum. The distance from the
skin to the epidural space is estimated as 1 mm/kg in children
between 1 and 10 years old.13 At the lumbar level, the epidural space
is widest (67 mm in the adult). In the child, the spinous processes
are more horizontal along the whole spine, including the thoracic
spine, allowing a median approach at any level. Furthermore, the
sacral vertebrae are not fully fused in young children, allowing a
sacrointervertebral approach to the epidural space.
By contrast to the spinal anesthesia and the caudal block, the

epidural anesthesia is a pure segmental anesthesia involving the
corresponding motor, sensory, and sympathetic nerves. The spread
depends on the puncture site and the position of catheter tip,
respectively, as well as the volume of LA injected. This has some
advantages. If the catheter tip is placed at the dermatomal level of
the surgical incision, only small volumes of LA good analgesia can
be provided with few side effects, such as urinary retention or
immobility of the lower limbs.

The child or infant is placed in a lateral or sitting position. The
level of puncture is chosen according the desired area to be anesthetized. The intervertebral space between the two spinous processes is identified. The wings of a Tuohy needle are held between
the thumb and the index finger while the operators hands are
propped against the childs back. The thumbs direct and push the
needle slightly paramedian of the interspinous ligament in a
slightly cranial and median direction. The needle is advanced until
a slight increase in resistance is felt, indicating that the needle has
reached the ligamentum flavum. At this point, the operators nondominant hand fixes the needle, and the loss of resistance device
filled with saline or air is attached with the dominant hand. The
needle is then further advanced with the thumb on the piston of
the syringe while generating slight positive pressure to allow easy
REFERENCES
1. Kurth CD, Spitzer AR, Broennle AM, et al. Postoperative apnea in
2. Liu LM, Ct CJ, Goudsouzian NG, et al. Life-threatening apnea in infants
recovering from anesthesia. Anesthesiology. 1983;59:506510.
3. Sims C, Johnson CM. Postoperative apnoea in infants. Anaesth Intensive
Care. 1994;22:4045.
4. Courreges P, Poddevin F. Rectus sheath block in infants: what suitability?
5. Dalens B, Vanneuville G, Dechelotte P. Penile block via the subpubic space
in 100 children. Anesth Analg. 1989;69:4145.
6. Busoni P, Andreuccetti T. The spread of caudal analgesia in children: a
mathematical model. Anaesth Intensive Care. 1986;14:140144.
7. Takasaki M, Dohi S, Kawabata Y, et al. Dosage of lidocaine for caudal
anesthesia in infants and children. Anesthesiology. 1977;47:527529.
8. Blanco D, Mazo V, Ortiz M, et al. Spread of local anesthetic into the
epidural caudal space for two rates of injection in children. Reg Anesth.
1996;21:442445.
9. Yaster M, Maxwell LG. Pediatric regional anesthesia. Anesthesiology.
1989;70:324338.
10. Gleason CA, Martin RJ, Anderson JV, et al. Optimal position for a spinal
tap in preterm infants. Pediatrics. 1983;71:3135.
11. Gentili M, Huu PC, Enel D, et al. Sedation depends on the level of sensory
block induced by spinal anaesthesia. Br J Anaesth. 1998;81:970971.
1989;70:324338.
13. Bosenberg AT, Gouws E. Skin-epidural distance in children. Anaesthesia.
1995;50:895897.
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Using Electrical Stimulation
45
C H A P T E R
Jean-Louis Feugeas, Frdric Lacroix, Olivier Choquet, and Xavier Capdevila
INTRODUCTION
Since the beginning of 2000, peripheral nerve blocks (PNBs) have
become routine practice for many pediatric anesthesiologists.
Techniques for locating nerve trunks such as paresthesia, loss of
resistance, or transarterial approach to the brachial plexus in the
axilla should no longer be used. Nowadays, despite the growing
use of ultrasound guidance, electrical stimulation remains the gold
standard of nerve location in adults1 and in children. Recent experimental and clinical studies improve our understanding in
some aspects of nerve stimulation. Primarily, this review focuses
on an updated synthesis of that knowledge. Second, because some
neuropathies are regularly reported during or after PNBs with or
without nerve stimulation,2,3 we suggest an optimized modern,
safe, and effective procedure for electrical location of peripheral
nerves and plexus. Finally, the use of low-current electrical stimulation of the spinal nerves, which has been described to
confirm caudal and epidural localization of needles and catheters,
is also beyond the scope of this chapter.46
PHYSIOLOGY OF
NERVE CONDUCTION
The generation and propagation of impulses in axons represent
the basic concept in regional anesthesia. The potential difference
between the inner part of the axon membrane and its surface
results from differences in the ionic composition of the intracellular and extracellular fluids. This difference in an unexcited
state is called the resting membrane potential. The inner aspect of
the cell membrane is negatively charged with respect to the
outside. The inside contains a lower concentration of sodium
(Na+) and a higher concentration of potassium (K+) than the
surrounding extracellular fluid. The mean resting membrane
potential measured in a neuron is approximately 70 mV. Cells
with excitable membranes (neurons and muscle) can generate
action potentials. The generation and propagation of impulses in
axons depend on ionic current fluxes through channels within the
membrane. These channels open and close in response to changes
in the membrane potential.
Hyperpolarization occurs when the membrane voltage increases, becoming more negative than the resting potential. Hyperpolarization decreases the probability of producing an action
potential. The reduction in membrane potential is called depolarization. The inside of the axon becomes less negative than the
resting potential. A change in the resting potential from 70mV

to a potential of 60mV is a depolarization. Depolarization increases the probability of producing an action potential. When the
axon is stimulated, permeability of the membrane to Na+ ions
increases rapidly (depolarization) and the potential become less
negative. A threshold stimulus must be applied to trigger an action
potential. This electrical impulse is then conducted along the
length of the axon. An action potential is an instant reversal of
membrane potential with total amplitude (change in voltage) of
about 100 mV. When a critical threshold of (50 mV is reached,
sodium conductance dramatically increases and the resting
potential becomes positive, reaching +30 mV. Depolarization is
completed within 0.1 to 0.2 second, whereas repolarization is
completed within 0.4 to 0.6 second.
NERVE ACTION POTENTIALS

Different stimuli can generate action potentials. A mechanical
stimulus gives a mechanical paresthesia above a threshold force
applied to the axons. Nerve stimulation techniques rely on the
stimulation of appropriate motor and/or sensory responses to the
electrical stimulus to confirm the proximity of the needle (or
catheter) to the targeted nerve. In other words, the generator
supplies an electrical pressure to depolarize a nerve. During each
impulse, a flow of negative charges (electrons) arrives at the tip of
the stimulating electrode. This current generates an electrical field.
This (negative) electrical field attracts the positive charges. The
outside of the axon becomes more negative. Inside the axon, the
attracted positive charges accumulate underneath the electrode.
The inside of the axon membrane becomes less negative in front of
the electric field. The concentration of negative ions and electrons
in the vicinity of the cathode causes the resting potential across the
cell membrane to be reduced to the point at which spontaneous
depolarization occurs. At a threshold potential around 50mV, the
action potential is created. The propagation of this electrical
phenomenon gives rise to sensory perception or muscle contraction, depending on the type of axon involved (Figure 451).
NERVE FIBERS,
CHRONAXIE, RHEOBASE
Nerve stimulation is based on the sensory or motor response to an
electrical stimulus. In descriptive terms, the intensity of the electrical
stimulus required to trigger an action potential is specific for each
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In clinical practice, electrode to nerve distance is the essential
factor. Pure sensory nerves are located with short current intensities and duration. When the current intensity is increased with
long impulse duration during nerve mapping, electrical paresthesias are felt before motor response occurs.7 In fact, increasing
the current duration does not affect the level of discomfort during
nerve localization if no powerful motor response resulting in
violent muscle contractions is triggered.7 The intensity (i.e., voltage) is the most important variable because the total energy
delivered to the tissue increases when current is higher.
UNDERSTANDING
NERVE STIMULATION
Electrophysiologic Bases and Equipment
Figure 45-1. Effect of current charges on the diameter of the
electric field.
nerve fiber (Table 451). Rheobase of an axon is the threshold current for an infinitely long-duration stimulus. Chronaxie is the
minimum time for which a direct current equivalent to twice the
intensity of the rheobase must be applied to trigger an action
potential.
There are two different types of nerve fibers: myelinated and
unmyelinated. The latter are usually classified as C fibers and
conduct nerve impulses slowly. Nociceptive impulses travel along
C fibers to reach the posterior horn of the spinal cord. The
myelinated fibers are classified into groups B (slow-conducting
sympathetic preganglionic motor fibers) and A (fast-conducting
myelinated fibers), efferent subgroups A (skeletal muscle motor
fibers), A (extrafusal motor), A (intrafusal motor), and afferent
subgroups represented by the axons that emerge from encapsulated receptors at skin (A) and joint level (A, A, and A)
and A fibers (nociceptive fibers). The chronaxie is inversely
proportional to the degree of fiber myelinization. Sensory fibers
are less myelinated than motor fibers. Consequently, a shortduration electrical stimulus should trigger action potentials in
motor fibers (A) without triggering the sensory fibers (A, C)
and, therefore, without inducing pain or paresthesias. The ability
to electrically stimulate peripheral nerves depends on the
conductive part of the electrode, impedance, electrode to nerve
distance, current intensity, and pulse duration.
To be effective, the spread of local anesthetics must be injected as

close as possible to the target nerve. The electrical impulses from
the needle tip are used to estimate the distance between needle tip
and nerves as we analyze the muscular and sensory responses
induced with the stimulation. Appropriate and well-maintained
equipment especially designed for children should be used
(Figures 452 and 453). Several manufacturers provide appropriate-size insulated Tuohy needle through which a catheter can be
inserted. However, the value of nerve stimulating catheters must
be further studied in children.
Nerve stimulators are current generators that can provide nearly rectangular DC impulsions every second (1 Hz) or twice in a
second (2 Hz). Precision of current delivery, particularly in the lowintensity range, is critical to ensure safety and accuracy of nerve
location. If the stimulator delivers current lower than that set by
the anesthesiologist, the needle could be closer than expected, with
a risk of causing inadvertent neural damage. If the stimulator
delivers too much current, the needle may be erroneously too far
away from the neural structures, thus increasing the risk of block
failure. Two electrodes allow the current to pass through the patients body (Figure 454). An adhesive electrocardiogram (ECG)
electrode serves as the anode (where the electrons flow in) and the
cathode is used for nerve detection and location. This cathode
(where the electrons flow out) can be the needle, a stimulating
catheter, or a percutaneous pencil. As a safety feature, the cathode
has a specific male connector designed to fit into the female
connector of the insulated needle. Nerve stimulators must have
indicators of disconnection and malfunction. Nerve stimulators deliver constant current for a large impedance range. Control
of parameters such as current intensity (between 0 and 6 mA),
TABLE 45-1. Physiologic and Anatomic Properties and Function of Different Nerve Fibers
Fiber Classification
Chronaxie, s
Diameter,
Functions
400
150
0.52
(unmyelinated)
<5 (myelinated)
40100
Pain, cold, warmth, crude

touch, and pressure
Deep pressure and touch,
pricking pain, cold
Predominantly motor
neurons; sensory neurons
for proprioception, hair
receptors, vibratory
sensors, high
discrimination touch
1020
(myelinated)
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Regional Anesthesia: Principles of Localization Using Electrical Stimulation
759
Figure 45-4. Wet (A) and dry (B) electrodes.
Figure 45-2. Nerve stimulators. A: Stimuplex HNS 11 BBraun.

B: Stimuplex HNS 12 BBraun. C: Stimuplex Dig BBraun.
D: Multistim Vario Pajunk. E: Multistim Sensor Pajunk.
F: Plexygon Vygon.
set for the impulses is occasionally different from the real intensity
applied because of higher resistances between electrodes. This can
be displayed in addition to the calculated or appraised values of
tissues resistance (R), charge of the impulses (Q), and the potential
difference (U) between electrodes.
The current intensity is the electrons flow out, measured in
milliamperes (mA). The calculated charge (Q = I t) in nanocoulombs (nC) is the electrical charge of all the electrons applied
during the impulse period of time (t). The resistance measured in
ohms () characterizes the strength that hinders the electrons
movement through biologic tissues. Low resistances are observed
in tissues containing a lot of water and ions (muscles, blood) by
contrast to tissues containing fat or bones and fascias that have high
resistance. The potential difference (U) between electrodes corresponds to the pressure of the electrons moving from the cathode
to the anode and is measured in volts (V). Ohms (U = R I) law
describes this interaction between resistance and intensity.
Intensity and Distance From Axons
Figure 45-3. Damaged wires. A: The damaged wire and the potential for short circuit when in contact. B: Damaged wires are
not always obvious and must be carefully checked before use.
duration (t) of impulses (usually 0.05, 0.1, 0.3, 0.5, or 1 ms), and
frequency of the impulses (1 or 2 Hz) is an important feature of
nerve stimulators that influences their efficacy. There is a wide
disparity in duration of the stimulus among models of nerve stimulators, and there are no standards for duration of the stimulating
current. A digital screen indicating the actual current delivery is
crucial. The new-generation nerve stimulators have a screen on
which these three parameters are displayed. Small current increments and linearity are important for accuracy in low-current settings in the final approach to the nerve. Large nonlinear increments
in the high range of current charge may be useful for nerve mapping and initial approach of deep nerves. For instance, the intensity
The principle of using the required threshold current to estimate the distance from the needle tip to the stimulated nerve
represents the basis of nerve electrolocation. The distance from
which the nerve is depolarized is reflected by Coulombs law8:
E = K (Q/r2), where E is the current required, K a constant dependent on the electrical properties of the medium through which the
current is transmitted, Q the minimal current, and r the distance
from the electrical source. The cathode, or negative electrode, is
three to four times more effective at nerve depolarization than
the anode, or positive electrode. The cathode is the stimulating
electrode and the anode is the surface electrode. The presence of
the inverse square means that a very high stimulus is needed when
the tip is some distance from the nerve. The threshold current
required to facilitate excitation of an axon is proportional to
the square of the distance from the electrode to the nerve fiber.
This relationship holds true as long as the needle is subjected to a
homogenous environment regardless of the distance from the
nerve. In reality, such a relationship is quite more complex, owing
to the fact that every tissue (muscle, fat, fascia) through which the
needle pass presents a different impedance spectrum.
Voltage, Intensity, and Resistance

The body contains different tissues that contain charged particles,
sodium, potassium, and chloride, which are free to move in the
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presence of an electric field. Conductors are substances in which

charged particles readily move when placed in an electric field.
Insulators do not tend to allow free movement of ions or electrons
when placed in an electric field. Capacitance is the ability of tissue
to store electricity. Impedance represents both the capacitance and
the resistive opposition to current flow. Impedance of tissues varies
according to tissue water and electrolyte content. Not all of the
bodys tissues conduct the electrical current identically. Current
flows more readily along excitable tissues with low impedance
than through tissue with high impedance. A higher voltage from
the stimulator is needed to pass an equivalent amount of current
through high-impedance low-conductivity tissue than would be
necessary to pass the same current through tissue with low impedance (high conductivity).
The electrical resistance between surface electrodes varies from
1 to 10 k for wet skin to more than 100 k for dry skin. The value
decreases upon penetrating the dermis to only 0.5 k. High skin
resistance could reduce the current intensity delivered to the target,
thus rendering nerve stimulation ineffective. The location of the
positive (cutaneous) electrode may influence the ability to stimulate a nerve. Some experts advise that the cutaneous electrode
should be placed in an area far from the block needle,6 whereas
others suggest placing it near the site of puncture.7 In fact, the site
of the cutaneous electrode is not essential under usual conditions.
With nerve mapping, it is recommended that the surface electrode
is placed at a distance to avoid confusing local muscle responses
and nerve stimulation. A nerve stimulator automatically adjusts
the voltage output to maintain the selected current intensity regardless of the impedance and clinical conditions between the needle
and the cutaneous electrode. Variations in the resistance do not
affect the current charge. Because every tissue through which the
needle tip passes represents different impedance, a motor response
can suddenly increase, decrease, or entirely disappear because of
these changes. When the impedance increases, the inner circuit of
the device automatically compensates by increasing voltage output
to maintain the stimulating current at the set level. The intensity
drops in cases of high resistance (dry skin or desiccated electrode)
because the generator capacity to adjust the voltage is exceeded.
This may be painful for the patient because excessive voltage would
be applied to the nerve through a very small area (i.e., the tip of the
stimulating needle), resulting in a very high current density.
Current Density and Duration

The current density is the amount of current flow per area. It is a
measure of the quantity of charged ions moving through a specific
cross-sectional area of body tissue. The greater the current density,
the greater the effect on the tissues. Density is usually relative to
the size of the electrode. Larger cross-sectional-area electrodes
disperse charge better than smaller ones and offer less resistance
to current flow. Conversely, current density is greater with a small
electrode, and consequently, a greater effect is obtained when the
active electrode is small. The current density doubles when the
contact area is halved. With the point of an insulated needle, the
surface area of contact is very small. The nerve stimulator pushes
the amount of current through a minimal surface area and the
current density increases with a deeper penetration. More nerve
fiber recruitment is possible, but at the same time, the small
electrode offers more resistance. The result can be a sharp stinging
response if the conductance of tissues is low, and the current
charge (i.e., voltage) is high.
The duration of the current determines the amount of energy

delivered to the tissue. In the case of an applied square wave, this
charge, in microcoulomb (C), is equal to the product of the
applied current intensity, measured in mA, and the duration of
the pulse or pulse width, measured in milliseconds (ms):
Q (C) = I (mA) t (ms)
The total energy delivered to the nerve(s) is greater with stimuli
of longer duration. Stimulus duration of 1.0 ms delivers 10 times
more energy than a stimulus of 0.1 ms. The charge (Q) determines
the strength of electrical field (F) around the stimulating needle
electrode. The current charge applied to the axons must be sufficient to generate a stimulus and, hence, the distance from which
the nerve is depolarized. The amount of current received by the
nerve membrane primarily depends on the distance between the
electrode (needle) tip and the nerve, thus, a higher charge allows
stimulating a nerve at a greater distance. An earlier study confirmed that longer impulses (0.3 ms) shorten block performance
time, probably by easier location of the nerves.9 Short impulses
carry a lower electrical charge than longer ones. Consequently, the
lower charge requires positioning the needle closer to the nerve.
This may make nerve stimulation more difficult, prolong block
performance time, and increase the number of needle passes.
Because the nerve stimulator is initially set to deliver a 2-mA
current with a long impulse, the first motor response is quickly
obtained.
THE PARADIGM OF ELECTRONIC

HYDRAULIC ANALOGY
Can we imagine the invisible electric current to be a kind of fluid?
The hydraulic equivalents to electrons could be water molecules;
the intensity (I) is the quantity of flowing water over time, the
charge applied during each impulse being equivalent to the
volume of water used during the impulse. The voltage or potential
difference is a difference in water pressure generated by a pump
between two points and the electron pressure applied against
tissues resistances, all obstacles encountered by the water flow
through the body. For instance, to illustrate Ohms law (U = R I),
in case of a simple pipe with a constant water flow (I), making a
constriction (R) causes an increase of pressure (U) to keep the
same flow of water. Put another way, if the pressure instead of the
water flow is kept constant, the flow decreases proportionally to
the decrease in the pipes diameter. Maintaining the initial flow
necessitates an increase of the generated pressure.
We can easily understand now why the intensity applied in a
100-volt delivery nerve stimulator circuit decreases when the
skin electrode is dried or withdrawn from the skin. According
to Ohms law, the nerve stimulator increases the voltage (electrons
pressure) as resistances increase to maintain the intensity (flow)
set by the user to the 100-volt limit, and then intensity fails. Nerves
are not good electrical conductors because of their very high resistance. The anesthesiologist should not be confused about the ability
to propagate ionic exchanges of an action potential across the axonal membrane at 100 m/s and the electric current of 300,000 m/s.
The resistance of the nerve fiber is greater when the fiber diameter increases and is covered with a myelin sheath (electrically
insulating dielectric phospholipid layer). According to Ohms law,
when an electron flow runs across fibers, the transmembrane
voltage increases more quickly for thick fibers than for thin fibers.
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When the pressure of electrons increases enough, it promotes

alteration of cell membranes and modifies voltage-gated channels
that result in an ionic exchange and an action potential. It is not
the intensity that is liable for action potential but the transmembrane voltage.10 Progressively increasing the intensity will
first stimulate big fibers such as motor neurons and then smaller
fibers of the somatic sensory system.
To extend the paradigm further, it is possible to imagine the
body as a lake of electrons in which we put an intermittent pump
that gives impulses of water (electrons). These impulses create
small waves at the surface or small spheres of pressure inside the
water in three dimensions. The waves propagate from the pump
through the body tissues and interfere with resistances encountered. For each open-close action of the flood gate, the magnitude
of the wave produced depends on the flow of water (intensity), on
the diameter of the pump opening (resistance), and on the duration of the open-close action.
In our paradigm, the waves are electrical charges that interact
with cell membranes. The greater the flow of water (intensity), the
bigger the wave. For a constant flow, the smaller the diameter of
the pump opening, the greater the pressure and the wave generated.
In addition, the longer the duration, the larger the wave generated.
In other words,
The greater the intensity of the stimulus, the higher the stimulating voltage and vice versa.
The smaller the contact surface between needle tip and tissues,
the higher the stimulating voltage and vice versa.
Finally, the longer the impulse duration, the greater the wave of
electrons and vice versa.
The clinical consequences are
To improve the accuracy when using a nerve stimulator to guide

the location of the needle, the intensity could be increased, the
contact surface between needle tip and tissues decreased, or the
duration of impulses increased.
To avoid pain during nerve stimulation, the intensity and/or the
impulse duration should be decreased rapidly as soon as a nerve
response is obtained.
To locate nerves from a long distance, insulated needles should
be used. Otherwise, the contact surface between the needle and
the tissues is too large and the impulse ineffective.
The disappearance or decrease in the motor response to nerve

stimulation when saline solution or local anesthetics is injected is
not a mechanical effect because the motor response is maintained
after injection of dextrose solution.11 The ionic solution at the
needle tip acts like a larger contact surface between the needle and
the tissues involved, decreasing the resistance around the needle
tip. Dextrose solution, a nonelectric conductor, can reverse this
situation by restoring the original contact between needle and
tissues. For this reason, dextrose solution is used during the stimulating catheter procedure to facilitate insertion without losing the
electrical responses.12
DISTINGUISHING INTRA- AND

EXTRANEURAL, EXTRA- AND
INTRAFASCICULAR NEEDLE LOCATION
OR LOCAL ANESTHETIC INJECTION
New information regarding the needle location in relation to the
nerve during a mechanical paresthesia has emerged, facilitating a
761
nerve response to a very low current stimulation. It is assumed

that paresthesia indicates a needle-to-nerve contact and that a
response at low intensity (0.5 mA0.1 ms) reflects a needle tip in
close proximity to the nerve. These concepts have recently been
challenged. The peripheral nerve is composed of fibers and
connective tissue. The connective tissue is thicker in canals and
foramen and increases in quantity from nerve root to the periphery. The endoneurium is the loose connective tissue surrounding each fiber; the perineurium is the dense connective tissue
covering a fascicule; and the epineurium is the outside layer of all
nerve bundles. The ultrasound image of a root is different from a
that of a peripheral nerve. A root is hypoechogenic, whereas a
peripheral nerve has a heterogeneous honeycomb appearance.
Classically, ultrasound guidance allows visualization of the nerve
and the needle, as it approaches to touch, push, and possibly
penetrate the nerve. The current practice is to monitor the local
anesthetic spread around the targeted nerve without intraneural
injection. The needle can be repositioned during the injection to
optimize the perineural local anesthetic spread.
In a recent study with ultrasound-guided axillary blocks, the
authors reported that contact between nerve and needle is often noted
without triggering paresthesias or an electrical response to nerve
stimulation up to 1 mA.13 In another trial using ultrasound without
normal saline (NS). The author deliberately tried to cause
paresthesias14: intraneural injections with swelling were observed
without sub-sequent pain or damage. These two studies demonstrated
that needle-to-nerve contact does not inevitably cause paresthesias
and that the needle may be positioned in contact with the nerve
without any electrical stimulation. In rats, intraneural injections of
ropi-vacaine have been performed without nerve damage.15 In dogs,
intrafascicular injection with high pressures (>20 psi) led to
persistent fascicular injuries by contrast to intraneural injection with
low pressure.16,17 These data are consistent with those of the intraneural microstimulation in which nerve fascicles are deliberately
punctured with needles smaller than those used for peripheral blocks.
The majority of patients described mechanical paresthesias, but only
10% had persistent paresthesias for few days. It is important to note
that the current needed to stimulate intrafascicularly is of
microampere magnitude whereas extrafascicular requires a
macroampere magnitude.18 In conclusion, there are three possible
needle tip locations and the local anesthetic injection must be defined
accordingly (i.e., extraneural, intraneural extrafascicular, and
intraneural intrafascicular).19
OPTIMIZE ELECTRICAL NERVE

STIMULATION PROCEDURE
Detecting Electrical Problems
A malfunction or an electrical disconnection may occur during
the nerve block procedure without the anesthesiologist realizing it.
The consequences for the patient can be multiple painful attempts
or a serious complication if nerve injury occurs. The most recent
devices indicate whether there is a disconnect alarms condition
and display the real current use during the procedure. Using these
nerve stimulators helps in the diagnosis of improper electrode
installation and/or the presence of current failure (Figure 455).
These devices have contributed to directly improve the safety of
the procedure.20 Failure in nerve location may be further linked
to a short circuit, misconnection, or disconnection. The short
circuit occurs when the cables or the electrodes are in contact and
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Figure 45-5. Algorithm for the diagnosis of electrical failure.

leads to the direct channel of current from one to the other,
bypassing the patient (Figure 456). It is easy to detect a short
circuit before closing the circuit. The effective current does not
remain at 0 mA when the set current is increased. This problem
cannot be diagnosed if the nerve stimulator is turned on after the
patients puncture. Conversely, consistency of values between real
current and set current may mislead the anesthesiologist.
The warning screen of the HNS12 BBraun displays that the
resistance is low (Figure 457). To ensure the absence of a short
circuit, the user must turn on the stimulator before closing the
circuit (i.e., before the needle passes the skin). Then, check that the
effective intensity remains zero while the set intensity is increased.
The anesthesiologist can then set the intensity to zero and penetrate
the skin. The electrical circuit is an open circuit if it lacks a
complete path between the positive and the negative ends of the
power source. If the circuit is not closed, no current passes. The
cause may be a dry electrode path, a broken wire, or a disconnection. The diagnosis of an open circuit is easy with a device
displaying the actual delivered current: the effective current
displayed remains at zero when the set current is increased. The
warning screen of the HNS12 BBraun displays that the resistance

is zero (see Figure 457). The physician must be aware of alarms.
When the external resistance is too high (especially between the
skin and the electrode), the effective current is not zero but remains
below the set value (see Figure 457). The nerve location is more
difficult and the most common cause is a dry electrode. The
diagnosis is difficult with a nerve stimulator displaying only the set
current record. Stimuplex Dig displays a flash indicating that the
impedance exceeds its compliance voltage. However, it is easy to
determine this problem with a nerve stimulator that displays the
real current. This characteristic is one of the five quality criteria
used in a recent review article in which 17 nerve stimulators were
assessed.21 The warning screens of the HNS12 BBraun and the
Stimpod Xavant display high resistances and that the patient
current is lower than the setting (Figure 458). When an electrical
failure is supposed, one must try to find the reason and correct the
problem (nerve stimulator, electrode path, needle) if needed.
LOCATING NERVES
THROUGH THE SKIN
PNBs may be challenging, particularly in young children (Table
452). Difficulty in identifying anatomic landmarks and the variable depth of nerves in the child are possible reasons. With the aid
of a peripheral nerve stimulator, the path of many superficial
peripheral nerves can be traced through the skin before skin
penetration2225 (Figure 459). This nerve mapping technique is a
useful teaching tool and may improve the success rate of PNBs in
children of all ages.26 Because the depth of many peripheral nerves
is significantly less in infants, more nerves can be defined percutaneously than in adults. By precisely locating the needle entry
point, the number of attempts for nerve location could be reduced,
thereby lowering the potential risk of injury to surrounding structures (Figure 4510). Trainees and novices seem more confident
to perform the different nerve blocks using the nerve mapping
technique. Those with experience in regional anesthesia may use
it only when they need to confirm the accuracy of their landmarks
in complex situations or patients.
A
Figure 45-6. Short circuit. Note that the resistance is low.
Stimuplex HNS 12 BBraun.
Figure 45-8. A: Warning screen of the HNS12 BBraun in the

presence of a high-resistance circuit. B: Warning screen of the
Stimpod Xavant when high resistance is recorded.
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763
B
The combined technique of ultrasound and nerve mapping is
also proposed as a reliable method of training, by which anesthesia
residents with little experience can improve their skills in identifying superficial nerve structures.27 Once the targeted nerve is
identified using the ultrasound technique, the probe of the stimulator can be applied over the skin in front of the ultrasound transducer. The current of the neurostimulator is gradually increased
until a motor response is elicited in the targeted nerve.
Under general anesthesia or appropriate sedation, the child is
positioned for the planned nerve block. If neuromuscular
blockade is planned, the muscle relaxants should be administered
after completion of the nerve block procedure. The nerve stimulator is set on a long pulse width, 1 ms if available, with a frequency
of 1 to 2 Hz. The positive ECG electrode (anode) of the nerve
Figure 45-7. A and B: Warning screens in case of an open

circuit for the Stimuplex HNS 12 Bbraun with the resistance
displayed. C: Warning screen of the Stimpod Xavant when an
open circuit is present.
stimulator is placed distant from the nerve to be localized. The
negative electrode (cathode), used as the mapping electrode, is
placed on the skin. The output current is increased up to 2 mA
and the electrode moved transversally across the suspected path of
the nerve until a distal motor response is evoked. If no motor
response occurs, the current is increased slightly and the procedure repeated. Direct local stimulation of muscle under the
mapping electrode, which may occur with a high initial current
charge, must be differentiated from the distal response of the
appropriated muscle supplied by the located nerve. The required
current charge depends on the surface area of the electrode, the
nerve-to-electrode distance (i.e., the depth of the nerve), and the
moistness and thickness of the overlying skin. Previous moistening
of the skin facilitates the response by reducing the skin impedance.
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TABLE 45-2. Guidelines: A Standard Nerve Identification and Regional Block Procedure
1. Check patients neurologic status (nerve function test). Set up the nerve stimulator according to the user manual.
2. Apply adhesive electrode on a clean and bald skin area remote from the puncture site.
3. Explain procedure to the patient, install, locate, and draw the usual surface landmarks to identify the puncture point, if possible
remote from tourniquet and surgical area.
4. Connect the cable to the needle (negative black connector) and the electrode (positive red connector), turn on the nerve
stimulator. After the self-test, make sure that the equipment is ready for use. Select a long stimulus duration (0.31 ms).
5. Check whether there is no short circuit by increasing the intensity before closing the circuit (i.e., before puncture): effective
current must remain at zero. Set the intensity to 0.00 mA.
6. Puncture the skin, gradually increase the intensity up to 23 mA or until the current is felt by the patient. The intensity can
often be increased to 4 or 5 mA without painful sensation. Check warning visual and sound indicators that the current passes
through tissue (electrical failure test) or check the cables and connections.
7. Check that patient current corresponds to the settings. If the patient current is too low compared with the setting, the electrical
resistance of the circuit is too high. The cause is almost always a dry electrode path or a dry or thick skin (too high skin resistance).
8. From the puncture point, introduce the needle progressively through the skin to detect a motor and/or sensory response.
Gradually reduce the electrical intensity as the needle tip progresses toward the nerve and maintain the muscle and/or sensory
response for an intensity of about 1 mA.
9. Select a short duration (0.1 ms) because small variations of distance are accompanied by greater variation of intensity. Increase
intensity to recover the response. Check if there is no response to an intensity of stimulation less than 0.2 mA (extrafascicular test).
10. Observe the immediate disappearance of the response to the injection of the first milliliters of local anesthetic (equivalent to
test dose). Follow usual safety measures: test dose, intermittent aspiration, and slow, incremental injection, without resistance.
Indentation of the skin directly over the nerve enhances the
response by reducing the distance to the nerve. A nerve can be
stimulated when the depth is less than 1 cm.
Because most children are anesthetized or sedated before a
PNB is performed, this technique can be used only to map the
motor component of nerves. Nerve mapping of sensory nerves
can also be performed in cooperative awake patients.28,29 This
requires cooperation and understanding from children. The
current is slowly increased until a tingling pain-free sensation
synchronous to the stimulator is felt in the distribution of the
nerve being stimulated. For mixed nerve, the current charge increases, first invoking an electrical paresthesia followed by a motor
response. Unpleasant sensation may be caused by violent muscle
contraction with high current or noxious arcing sensations across
dry skin with a finite stimulating electrode. Nerve mapping should

not be applied to patients with implanted electrical devices, such
as cardiac pacemakers, or in epileptics, pregnant patients, or on
damaged skin.
A variety of peripheral nerve stimulators with constant current
output are at present available for nerve mapping. The selected
nerve stimulator should deliver high current charge (i.e., long pulse
width and/or high intensity). Three among those studied (HNS12
BBraun, Sensor Pajunk, Stimpod Xavant) are specifically designed
for nerve mapping. Others can be modified for this purpose. The
tip of the crocodile clamp, a blunt electrode tip, or a stub needle
connected to a negative electrode has been proposed as alternative
stimulating electrodes. A sharp and finite electrode, which localizes
the current to a finite point, may evoke noxious stimulus because
B
Figure 45-9. A and B: Two nerve stimulators with a probe designed for nerve mapping.
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765
study in anesthetized pediatric patients reported a similar success

rate for PNB when using a lower stimulation threshold (<0.5 mA)
or a higher stimulation threshold (0.51 mA).33 It may not be necessary to achieve a very low stimulation threshold, because it
may increase the risk of neural damage without increase the success rate.
MAKING SURE THE NEEDLE

IS NOT INTRAFASCICULAR
Figure 45-10. Algorithm for the nerve stimulation procedure.

of high resistance. The point at which maximal motor response
occurs is the ideal position for the nerve block at a specific level.
Reposition the negative electrode along the points of maximum
motor response to trace the subcutaneous path of the nerve being
stimulated. Different branches of the plexus or nerve can be
mapped by seeking a distinct motor response. The point at which
the desired motor response remains just visible at the lowest
current is the ideal site for subsequent needle entry. The needle
connected to the nerve stimulator is then passed through the skin.
The current is slowly increased until a motor response is obtained.
The final approach to the nerve is then performed as usual.
STEP-BY-STEP NERVE APPROACH

A deep nerve cannot be located through the skin, but a search with
a high current can provide an initial response to a greater depth.
For the same intensity, use a long pulse width to obtain the initial
response to electrical nerve stimulation, reduce the number of
attempts, and shorten the procedure. In adults, for a motor response of equivalent amplitude, a long pulse width is no more painful than a short. The initial search for a nerve is easier.
In an awake child, the procedure can be made more comfortable
if the anesthesiologist avoids a painful charge of current invoking
a painful motor response.30 The stimulus should be gradually
increased until the child feels light electrical paresthesia synchronous to the impulses. In clinical practice, long pulse duration
must be selected for the initial approach. The intensity is reduced
in increments as the needle is advanced toward the nerve to obtain
a response at a low current. Around 0.5 mA at 0.1 ms, a short pulse
width is then selected and the current is re-augmented to obtain
the response. The final nerve approach is performed as usual.
NEVER ACHIEVE A TOO LOW

STIMULATION THRESHOLD
The precise current threshold at which of safe local anesthetic
injection can be performed is unknown. In adult patients, a current
less than 0.5 mA with a pulse width of 0.1 ms is considered by most
regional anesthesia practitioners as an acceptable indicator that the
needle is close enough for a nerve block success.31 In a study focused on the optimal stimulation threshold for blocking the brachial plexus, a success rate of 95% was reported when using a
current threshold between 0.6 and 0.8mA in adults.32 A recent
The modern stimulators are reliable and calibrated to generate a

constant current for lower intensities, with accuracy to within
0.1 mA. Unlike older devices, they can further refine the nerve
location without requiring the participation of the patient. These
accurate stimulators displaying the intensity actually delivered can
allow a differentiation between intra- and extrafascicular positions
of the needle tip. A persistent sensory or motor response to low
intensity indicates a possible intrafascicular position of the needle.
Around 0.5 mA for 0.1 ms, the disappearance of the response by
further reducing the intensity confirms that the needle tip is not
in contact with axons. A response obtained for a current intensity
of less than 0.2 mA for 0.1 ms may be associated with an intrafascicular position of the needle and should be avoided. Hadzic
and colleagues showed that 0.2 mA at 0.1 ms is possibly the lowest
required current setting for confirming nerve localization at the
brachial plexus and femoral nerve block sites in volunteers.34
The minimum intensity of stimulation (MIS) when approaching a
nerve for peripherals blocks is the lowest intensity for which a
response to electrical nerve stimulation is observed and below
which the response disappears.
The main rules of nerve location procedure are as follows: (1) to

use a calibrated nerve stimulator, including warning alarms
indicating a failing electrical system; (2) to monitor the integrity
of the circuit before and throughout the procedure; (3) to attest to
a lack of response to very low current charge (below 0.2 mA at
0.1 ms) stimulation; (4) to observe a clear response to low intensity
(~0.5 mA) with an insulated needle; (5) to observe the disappearance of the response after injection of the first milliliters of
local anesthetic; and (6) to ensure that the injection should be easy,
painless, and without any resistance during administration.
PERFORMANCE OF BLOCKS ON
ANESTHETIZED CHILDREN
In pediatric practice, regional anesthesia techniques are often
performed after induction of general anesthesia because of the
particular problems of communication and compliance in children.
Heavily sedated or anesthetized children lack the ability to provide
subjective warning signs that indicate a possible intraneural injection such as paresthesias from needle contact within the nerve
fasciculi and worsening of the paresthesias or pain during injection
of the local anesthetic. Regional blocks must be performed with
great care by practitioners with extensive knowledge of the relevant
anatomy, the technique being used, and the potential pitfalls
including the know-how to avoiding them. In a large prospective
study conducted in France, no complications related to PNBs
were observed in more than 1200 pediatric patients under general anesthesia in 89% of the cases.35 There is no evidence that
placement of PNBs in anesthetized children is dangerous. The
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debate is unlikely to be resolved because the performance of a study

to challenge this practice is unlikely. Those that extrapolate from
adults and refuse to perform blocks in anesthetized children do
children a disservice.36
13.
14.
CONCLUSION
PNBs are increasingly used but not yet as often as they should.
Nerve stimulation equipment has largely improved and is more
clinically safe. Surface mapping is a new technique of electrical
location that may significantly help locating the optimal puncture
site for the relevant superficial nerve or plexus trunk. Hydraulics
and ultrasound can improve our understanding of nerve stimulation. Ultrasound guidance techniques might represent the
gold standard in the near future, provided they improve accuracy,
safety, and practicality in large series of pediatric patients. Nerve
stimulation provides confirmation that the needle tip is extrafascicular and as a supplement for ultrasound guidance during the
initial learning stages. It may be prudent for the novice to combine
electrical stimulation when learning ultrasound guidance. The
combination of both techniques can help in most situations to
avoid the viscera; to go directly toward the target; to differentiate
extraneural, intraneural, and intrafascicular; to check the local
anesthetic spread; and ultimately, to increase comfort, safety, and
reliability.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
REFERENCES
1. Socit Franaise dAnesthsie et de Ranimation. Groupe de Consensus.
Les blocs priphriques des membres chez ladulte. Recommandations
pour la pratique clinique SFAR, Paris, France, 2003 Available at:
http://www.sfar.org/s/article.php3?id_article=184 Accessed July 19, 2010.
2. Auroy Y, Benhamou D, Bargues L, et al. Major complications of regional
anesthesia in France: the SOS Regional Anesthesia Hotline Service.
3. Borgeat A, Ekatodramis G, Kalberer F, et al. Acute and nonacute complications associated with interscalene block and shoulder surgery: a
prospective study. Anesthesiology. 2001;95:875880.
4. Tsui BC, Gupta S, Finucane B: Confirmation of epidural catheter placement using nerve stimulation. Can J Anaesth. 1998;45:640644.
5. Tsui BC, Seal R, Koller J: Thoracic epidural catheter placement via the
caudal approach in infants by using electrocardiographic guidance.
Anesth Analg. 2002;95:326330.
6. Tsui BC, Wagner AM, Cunningham K, et al: Can continuous low current
electrical stimulation distinguish insulated needle position in the epidural
and intrathecal spaces in pediatric patients? Paediatr Anaesth. 2005;
15:959963.
7. Choyce A, Chan VW, Middleton WJ, et al. What is the relationship
between paresthesia and nerve stimulation for axillary brachial plexus
block? Reg Anesth Pain Med. 2001;26:1004.
8. Pither CE, Raj PP, Ford DJ. The use of peripheral nerve stimulators for
regional anesthesia: a review of experimental characteristics, technique
and clinical applications. Reg Anesth. 1985;10:4958.
9. Koscielniak-Nielsen ZJ, Rassmussen H, Jepsen K. Effect of impulse
duration on patients perception of electrical stimulation and block
effectiveness during axillary block in unsedated ambulatory patients. Reg
Anesth Pain Med. 2001;26:428433.
10. Warman EN, Grill WM, Durand D. Modeling the effects of electric fields
on nerve fibers: determination of excitation thresholds. IEEE Trans
Biomed Eng. 1992;39:12441254.
11. Tsui BC, Kropelin B. The electrophysiological effect of dextrose 5% in
water on single-shot peripheral nerve stimulation. Anesth Analg. 2005;
100:18371839.
12. Tsui BC, Kropelin B, Ganapathy S, et al. Dextrose 5% in water: fluid
medium for maintaining electrical stimulation of peripheral nerves
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during stimulating catheter placement. Acta Anaesthesiol Scand. 2005;

49:15621565.
Perlas A, Niazi A, McCartney C, et al. The sensitivity of motor response
to nerve stimulation and paresthesia for nerve localization as evaluated by
ultrasound. Reg Anesth Pain Med. 2006;31:445450.
Bigeleisen PE. Nerve puncture and apparent intraneural injection during
ultrasound-guided axillary block does not invariably result in neurologic
injury. Anesthesiology. 2006;105:779783.
Iohom G, Lan GB, Diarra DP, et al. Long-term evaluation of motor
function following intraneural injection of ropivacaine using walking
track analysis in rats. Br J Anaesth. 2005;94:524529.
Hadzic A, Dilberovic F, Shah S, et al. Combination of intraneural injection
and high injection pressure leads to fascicular injury and neurologic
deficits in dogs. Reg Anesth Pain Med. 2004;29:417423.
Kapur E, Vuckovic I, Dilberovic F, et al. Neurologic and histologic
outcome after intraneural injections of lidocaine in canine sciatic nerves.
Rice AS. Peripheral nerve damage and regional anaesthesia. Br J Anaesth.
1995;75:116117.
Borgeat A. Regional anesthesia, intraneural injection, and nerve injury:
beyond the epineurium. Anesthesiology. 2006;105:647648.
Choquet O, Feugeas JL, Capdevila X, et al. Dfaut de circuit lectrique et
neurostimulation: cas cliniques et procdure de prvention. Ann Fr Anesth
Reanim. 2007;26:245248.
Jochum D, Iohom G, Diarra DP, et al. An objective assessment of nerve
stimulators used for peripheral nerve blockade. Anaesthesia. 2006;61:
557564.
Wassef MR. Use of nerve stimulators in search for optimal site of block
needle point of entry. Reg Anesth. 1996;21:491496.
Ganta R, Cajee RA, Henthorn RW. Use of transcutaneous nerve
stimulation to assist interscalene block. Anesth Analg. 1993;76:914915.
Urmey WF, Grossi P. Percutaneous electrode guidance: a noninvasive
technique for prelocation of peripheral nerves to facilitate peripheral
plexus or nerve block. Reg Anesth Pain Med. 2002;27:261267.
Capdevila X, Lopez S, Bernard N, et al. Percutaneous electrode guidance
using the insulated needle for prelocation of peripheral nerves during
axillary plexus blocks. Reg Anesth Pain Med. 2004;29:206211.
Bosenberg AT, Raw R, Boezaart AP: Surface mapping of peripheral nerves
in children with a nerve stimulator. Paediatr Anaesth. 2002;12:398403.
Chantzi C, Saranteas T, Paraskeuopoulos T, et al. Ultrasound and transcutaneous neurostimulator combined technique as a training method for
nerve identification in anesthesia residents. Reg Anesth Pain Med. 2007;
32:365366.
Shannon J, Lang SA, Yip RW, et al. Lateral femoral cutaneous nerve block
revisited. A nerve stimulator technique. Reg Anesth. 1995;20:100104.
Stone BA. Transcutaneous stimulation of the saphenous nerve to locate
injection site. Reg Anesth Pain Med. 2003;28:153154.
Hadzic A, Vloka JD, Claudio RE, et al. Electrical nerve localization: effects
of cutaneous electrode placement and duration of the stimulus on motor
response. Anesthesiology. 2004;100:15261530.
Hadzic A. Peripheral nerve stimulators: cracking the codeone at a time.
Carles M, Pulcini A, Macchi P, et al. An evaluation of the brachial plexus
block at the humeral canal using a neurostimulator (1417 patients): the
efficacy, safety, and predictive criteria of failure. Anesth Analg. 2001;
92:194198.
Gurnaney H, Ganesh A, Cucchiaro G. The relationship between current
intensity for nerve stimulation and success of peripheral nerve blocks
performed in pediatric patients under general anesthesia. Anesth Analg.
2007;105:16051609.
Hadzic A, Vloka JD, Hadzic N, et al. Nerve stimulators used for peripheral
nerve blocks vary in their electrical characteristics. Anesthesiology.
2003;98:969974.
Giaufre E, Dalens B, Gombert A. Epidemiology and morbidity of regional
anesthesia in children: a one-year prospective survey of the FrenchLanguage Society of Pediatric Anesthesiologists. Anesth Analg. 1996;
83:904912.
Bsenberg AT. New developments in paediatric regional anesthesia.
Southern African Journal of Anaesthesia and Analgesia (SAJAA). 2008;14:
8183.
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Using Ultrasound Techniques
46
C H A P T E R
Peter Marhofer
INTRODUCTION
Ultrasound imaging offers the anesthesiologist a visual aid to
improve the accuracy of local anesthetic placement in both adults
and children. There is no doubt that ultrasonographic guidance
improves the quality of regional anesthetic blockade. This chapter
serves as a short review of this promising technique. It cannot
replace knowledge of the recent literature but should provide
an overview of ultrasound technology and basic scanning techniques. The author strongly recommends further reading of
detailed literature.
A SHORT REVIEW OF THE HISTORY

AND SOME INITIAL CONSIDERATIONS
In 1978, La Grange and coworkers reported on the use of a
Doppler flow ultrasound detector to facilitate supraclavicular
blockade of the brachial plexus.1 To our knowledge, this was the
first study in which an indirect sonographic approach was used
for regional anesthesia. Because two-dimensional images could
not be obtained at high resolution, more advanced applications
of ultrasound were not available at the time. In 1994, Kapral and
colleagues published the first report on direct sonographic visualization in regional anesthesia.2 They also investigated supraclavicular blockade of the brachial plexus in adults and succeeded
in viewing the spread of local anesthetic.
Improvements in ultrasound technology since about 2000
made it possible to visualize even tiny anatomic structures. As a
result, the majority of regional anesthetic procedures can today be
performed under ultrasound guidance even in the smallest
children. The old adage that children are not a miniature version
of adults holds true for pediatric regional anesthesia (and vascular
cannulation).
Since the beginning of 2000, serious efforts were made to
introduce ultrasound into daily pediatric anesthesia practice. All
patients, particular our smallest patients, should benefit from direct
visualization of anatomic structures during invasive procedures. The
close proximity of important anatomic structuresone excellent
example is the position of the brachial plexus in relation to the
subclavian artery at the supraclavicular levelis one argument for
direct visualization of neuronal and adjacent anatomic structures.
Today, nearly all popular regional anesthetic techniques using
ultrasound guidance are described in children. It is not an
overstatement to suggest that these ultrasound techniques have
brought the specialty of pediatric regional anesthesia to new

levels. Recent studies have shown faster onset times and longer
duration of blocks. Ultrasound guidance allows relatively painless
blocks to be performed while avoiding muscle contractions during
nerve stimulation in fractured limbs, for instance.3
There is still no evidence that techniques performed under
ultrasound guidance and direct visualization are associated
with fewer complications and increased safety. Practically, it would
be extremely difficult to perform these studies because the
complication rates are low4 and a large number of cases would
need to be included to achieve adequate statistical power to answer
that question. Recent studies have shown the superiority of
ultrasound detection of neuronal structures over conventional
methods.
Knowledge of ultrasound is invaluable in pediatric regional
anesthesia, and it is important to master the basic techniques in
order to introduce them into daily clinical practice. Cost and
education unfortunately remain limiting factors for the widespread use of ultrasound.
BASIC PRINCIPLES OF
ULTRASONOGRAPHY
Ultrasound is mechanical energy transmitted through a medium.
The frequency of sound waves is measured in Hertz (Hz), that is,
the number of cycles per second. The frequency differentiates
between infrasound (<16 Hz), audible sound (16 Hz20 kHz),
ultrasound (20 kHz1 GHz), and hypersound (>1 GHz). The
speed of sound through different mediums varies (Table 461).
The basis of ultrasound is the piezoelectric effect, which describes
TABLE 46-1. Speed of Sound in Various Media
Medium
Air
Lung
Fat
Water
Liver
Muscle
Bone
Aluminium
Speed of Sound, m/s

330
600
1460
1480
1555
1600
4080
6400
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the ability of specific ceramic materials to generate an electric

potential in response to applied mechanical stress. This effect is
reversible (i.e., when electric stress generates force) and described
as the reversed piezoelectric effect. Pulse-echo instrumentation
is required to determine a time difference between a transmitted
and a received signal. This instrumentation utilizes pulse-echo
ultrasound to localize and image structures in the body. In
practice, different ultrasound modes can be distinguished:
A-mode: The A-mode is an amplitude-modulated imaging technique (A = amplitude) and the simplest form of image processing. Reflected echoes are represented as amplitudes or waves
whose height is proportional to the intensity of the reflected
sound wave. This technique used to be the standard mode,
but today, it is used only in specific neurologic diagnostic
examinations.
B-mode: B-mode is the method of choice today. The echo intensity is not represented as a wave but is coded into different
gray-scale values (B = brightness). The two-dimensional (2D)
B-mode technique produces a 2D image in the direction of the
sound cone with 20 to 50 or more pictures (frames) per second,
which allows pulses or respirations to be depicted almost instantaneously (real-time sonography).
M-mode: The M-mode (motion mode) is generated when the
one-dimensional (1D) B-mode is recorded over a time bar and
offers the highest time resolution. This mode is used mainly in
cardiology.
For a proper understanding of ultrasonography and to correctly

adjust the ultrasound image to achieve optimal visualization of
anatomic structures, different terms should be understood:
Resolution: Resolution describes the smallest possible distance

between two points that still allows them to be discriminated.
We can differentiate axial, lateral, and temporal resolution. Axial
and lateral resolution is also known as spatial resolution.
Lateral resolutionelectronic focusing: Lateral resolution is
vertical to the direction of the sound wave and is determined
by the aperture of the ultrasound probe and the image line density. Lateral resolution can be controlled by adjusting the electronic focus. It is greatest in the focus zone, but altogether two
to three times less than the axial resolution and its discrimination power lies around 4 to 5 wavelengths. The transmitted focus
describes the concentration of the transmitted energy to the target. In order to receive the highest amplitude from the target, a
receive focus is required. Both focus techniques are necessary to
get the highest signal-to-noise ratio over the full penetration
and the highest lateral resolution.
Axial resolution: The axial resolution (s) is determined by the
direction of the sound spread. It depends on the impulse length
and the ultrasound frequency. In order to prevent interference,
the echo impulse should be at least twice as long as the wavelength (2 s > 2 from which follows that s > = v/f). The
higher the frequency and the shorter the transmitting pulse
length, the better the axial resolution. Table 462 illustrates the
relationship between frequency and resolution.
Temporal resolution: Temporal resolution describes the time
resolution and correlates with frames/second (f/s).
Artifacts: Artifacts refer to technical structures visible in the
ultrasound image that have no anatomic correlate. These structures are the result of discrepancies between the ideal tissue
used for the image calculation and the real object of examina-
TABLE 46-2. The Relationship Between Frequency and

Axial Resolution
Frequency,
MHZ
1.0
3.5
5.0
7.5
10.0
13.0
15.0
Theoretical
Resolution, MM
1.54
0.44
0.30
0.20
0.15
0.12
0.10
Practical
Resolution, MM
3.00
0.90
0.60
0.40
0.30
0.25
0.20
tion. In general, these artifacts can make the interpretation of

images and tissues very difficult. Sometimes, however, they can
help diagnose certain conditions. In order to avoid wrong interpretation, it is important to examine structures that appear
pathologic in at least two ultrasound planes. Real structures will
be visible in both, whereas artifacts cannot be reproduced. The
following artifacts should be mentioned:
White noise: This phenomenon is caused by small and
medium-sized low-intensity echoes that are caused by too
much gain especially in superficial echo-poor areas (bladder,
gallbladder). It can be reduced by lowering the gain or deepening the focus.
Repetitive echoes: Also known as reverberation artifacts,
repetitive echoes are caused by repeated reflection of ultrasound waves on boundary layers with different acoustic resistance. They appear as bright bands or comet-tails and their
intensity decreases with increasing distance from the probe.
They are usually the result of insufficient coupling. Typical
examples for repetitive echoes are the artifacts caused by the
body of the needle during the in-plane (IP) technique.
Mirror artifacts: A strong reflecting surface such as the diaphragm can mirror the echo of a real anatomic structure.
Because of the delay in the return of the sound wave, the reflected echo appears in greater depth and in a different location. When the probe is moved, the mirror artifact will move
in the direction opposite to the probe.
Echo shadowing: There is often a dark, echo-free area behind
strongly reflecting or absorbing surfaces such as bone, stones,
or metallic implants. Although this prevents the tissue in this
area from being examined, dorsal echo shadowing is useful
when diagnosing kidney or gallbladder stones.
Lateral shadowing marking: Owing to refraction and scattering, a sound wave hitting a cyst will be deflected and cause
a braidlike hypoechoic structure to appear along the edges
behind the cyst.
Sound amplification: The (relative) dorsal sound amplification is another important criterion in diagnosing cysts.
The wave traveling through a liquid-filled cavity, with a low
absorption rate and impedance close to that of tissue, will be
absorbed less than waves traveling through tissue. The structures behind the cyst in the path of the same sound wave will
appear with higher echo intensity.
Delay artifacts: If the discrepancy between the calculated and
the true sound velocity is too great, anatomic structures can
appear convex and bloated. This effect is particularly impressive in neighboring structures with different propagation
velocities, such as cartilage and muscle.
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CHAPTER 46
Regional Anesthesia: Principles of Localization Using Ultrasound Techniques 769
Figure 46-1. Linear ultrasound probe (25-mm footprint,

613 MHz).
Boundary layer artifacts: These occur particularly along
boundary layers with high acoustic impedance (e.g., cyst

edges) and show a fringe of fine, soft echoes that can sometimes be mistaken for sediments.
Secondary cone artifacts: Secondary cones can originate
along strong reflecting surfaces. A convex line in the image
results when the echoes from these secondary cones are ascribed to the primary sound cone. This artifact occurs only in
one plane and disappears when the direction of the sound
cone is changed.
Ultrasound probes: It is important to be aware of different specifications of various probes. In principle two types of probes are
available:
Linear probes: The piezoelectric elements are arranged in parallel. They can be activated singly or in groups. The resulting
image is square, with good resolution in the near field but
narrow depth. Most of regional techniques (particularly in
children) can be performed with linear probes. Figure 461
illustrates a 25-mm linear probe (713 MHz).
Sector probes: The sound waves are emitted from a single
point and diverge fan-wise. This gives good resolution and
depth, but structures in the near field are very poorly imaged (Figure 462 illustrates a 2- to 5MHz sector probe).
The following adjustments are important in order to achieve

adequate quality of ultrasound images:
Image depth: The quality of the ultrasound image is significantly

reduced once the individual pixels become visible at larger magnifications. Therefore, an appropriate balance must be found
between overview and detail.
Gain: The gain must be carefully optimized for the existing
image depth. Some ultrasound systems offer independent gain
settings for different sections of an image. This feature is known
as time gain compensation (TGC). Other systems come with a
less-refined function of depth gain adjustment (surface/depth
gain).
Focus: Vertical anatomic structures are significantly more
condensed in children than in adults. Therefore, the focus of the
ultrasound image must be adjusted to capture the level of the
target structures as distinctly as possible. Although some ultrasound systems offer an opportunity to select different focal
zones, other systems use automatic adjustment of focus zones.
POSSIBLE ADVANTAGES AND

PITFALLS OF ULTRASOUND IN
PEDIATRIC REGIONAL ANESTHESIA
The use of ultrasonographic guidance for pediatric regional
block is still in its infancy and data are still lacking and confined
to small series. Nevertheless, data from adults can be extrapolated
and some evidence is based on expert opinions. The major
advantage of this technique is the direct visualization of neuronal
and adjacent anatomic structures as well as the spread of local
anesthetic during injection in real time. Another advantage is that
peripheral nerve blocks can be achieved using much lower
volumes of local anesthetics because precise needle placement
and the spread of local anesthetic can be observed. In the past,
high volumes of local anesthetics, which exposed children to the
risk of toxicity, were used to compensate for imprecise regional
anesthesia techniques based purely on anatomic landmarks.
Children, particularly neonates and infants, are at greater risk
of local anesthetic toxicity in view of their immature liver and
reduced levels of binding proteins.
Ultrasound-guided nerve blocks can be performed relatively
painlessly in awake or sedated children. Muscle contractions
caused by nerve stimulation are painful in the presence of a bone
fracture and can be avoided when ultrasound is used.3 These
advantages can be realized only with proper education and
training. The number of educators is still limited, and before
the technique is generally accepted, there needs to be a change of
mindset in practice. The approach to nerves needs to be redefined.
Classic approaches may not be optimal when using ultrasound
techniques. New, improved descriptions of specific techniques will
need to be described. Clear guidelines for education programs
should be developed in the future to establish an improved level of
awareness and knowledge in the field.
APPEARANCE OF NEURONAL
STRUCTURES IN ULTRASONOGRAPHY
Figure 46-2. Sector probe (25 MHz).
The ultrasonographic appearance of neuronal structures is heterogeneous, but follows certain rules. Most novices in ultrasonography have problems identifying peripheral nerve structures and
neuraxial anatomy. The more proximal parts of the brachial plexus
(nerve roots and trunks) appear as hypoechoic (gray to black)
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TABLE 46-3. Results of Neuraxial Imaging According
to Age Groups
Age, mo
Weight, kg
03
414
1535
3694
4.1 1.3
10.9 2.5
14.0 2.0
19.7 2.8
Visibility of the
Visibility of the
Lumbar Dura, % Thoracic Dura, %
80 14
58 15
41 13
30 17
70 32
28 13
29 13
21 13
Data from reference 29.
Figure 46-3. Hypoechoic nerve structures. C57 nerve roots at

the level of the posterior interscalene groove. Yellow arrow indicates the C5 root.
round to oval structures (Figure 463). By contrast, more peripheral nerve structures appear hyperechoic (white). With highresolution ultrasonography, it is possible to identify even the
internal structure of nerves (Figure 464). In the lower extremity
(lumbosacral plexus), most of the neuronal structures appear
hyperechoic. It is important to realize that every nerve has a
particular appearance in ultrasonography with regard to the shape
and the echogenicity. Both characteristics may change with the
angle of the ultrasound beam relative to the nerve structure.
The ultrasound probe needs to be carefully adjusted to achieve
optimal visualization of the nerve structures. In this context,
the term anisotropy describes the change in echogenicity of a
particular nerve depending on the angle of inclination of the
ultrasound beam. Visualization of neuraxial structures is agedependent. Because osseous structures reflect the ultrasound
beam, it is evident that neuraxial structures are less visible with
increased ossification of the spine (Table 463). By contrast to the
conventional loss of resistance method, where the flavum ligament

serves as the main structure, the dura mater is the main structure
with the ultrasonographic method owing to optimal visibility
(Figure 465). But it is also important to note that this technique
is a combination between the traditional loss of resistance and
direct visualization.
IDENTIFICATION OF ADJACENT
STRUCTURES IN ULTRASONOGRAPHY
Figure 46-4. Hyperechoic nerve structure. Musculocutaneus

nerve between the short head of the biceps and the coracobrachialis muscles.
Tendons: In a transverse view, the ultrasonographic appearance

of tendons is similar to that of nerves. An excellent method to
clearly discriminate between these two structures is to track
them over a short distance. Tendons disappear and the nerves
remain visible over the entire distance. Using a longitudinal
view, the internal structure of tendons is visualized as longitudinal continuous hypoechoic bands with hyperechoic intertendinous septae (fibrillar pattern).
Nerves do not have septa.
Vessels: Identification of vessels previous to and during regional
anesthetic techniques is of particular importance. Vessels guide
the practitioner to the neurovascular bundle. The infraclavicular portion of the brachial plexus and the femoral nerve lateral
to the femoral artery are examples. Discrimination between arteries and veins is possible with color Doppler. An additional
simple method to discriminate arteries from veins is to apply
pressure with the probe; veins are compressible and arteries remain as pulsatile round structures. A practical implication of
venous compression is that intravenous needle tip placement
may be missed. Direct observation of the spread of local anesthetic during injection is mandatory. In this way, intravascular
drug administration can be avoided.
Muscles: Muscles may appear as either heterogeneous structures
with bandlike hyperechoic intramuscular septae or homogenous
Figure 46-5. Ultrasonographic visualization of neuraxial structures at the thoracic level in a 1000-g neonate. White arrow =
posterior dura mater; gray arrow = flavum ligament; oblique
green arrow = epidural catheter.
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CHAPTER 46
Figure 46-6. Ultrasonographic appearance of a bone (femur).
structures. In general, muscles have a fibrolamellar ultrasonographic appearance. Muscle tissue is often an important reference structure with regard to the echogenicity of nerves. It is
also helpful to define the different muscle structures in relation
to the nerves.
Bones: The cortex of bone is hyperechoic and the contour of the
cortex may serve as a guide for specific block techniques (e.g.,
deep cervical plexus blockade). Because the ultrasound beam is
totally reflected by the cortex, the areas behind or deep to
the cortex are completely anechoic (distal ultrasound shadow).
Figure 466 illustrates the appearance of a bony structure in
ultrasonography.
Lymph nodes: Lymph nodes appear as oval- or bean-shaped with
a hyperechoic vascular hilus entering the lymph node. Usually
lymph nodes are 2 to 3 mm in length but may be larger. Reactive
lymph nodes are usually slightly enlarged oval structures and the
hilar structures are still present. Malignant lymph nodes are usually round, show no hilar structures, and have a low echogenicity.
Local anesthetic: Local anesthetic solution appears anechoic in
ultrasonography (Figure 467). Nerves are often more visible;
they light up as they are surrounded by local anesthetic.
Air: Air bubbles appear as hyperechoic artifacts with distal
shadows. Accidental co-administration of air bubbles should
Figure 46-7. Ultrasonographic appearance of local anesthetic at

the posterior rectus sheath. Arrows indicate the area where the
local anesthetic is located.
Figure 46-8. Position of the needle relative to the ultrasound probe

for the out-of-plane (OOP) technique (simulated technique).
be avoided while performing blocks because visualization of
adjacent anatomic structures is impaired
NEEDLE GUIDANCE TECHNIQUES

Ultrasound techniques fall into two major categories depending
on the needle position relative to the transducer. The first option
relies on a transverse needle orientation and is known as the outof-plane (OOP) technique (Figures 468 and 469). Only the
needle tip can be visualized with this approach, and therefore, it
must be precisely advanced toward the target structure by selecting
an appropriate insertion angle. The ultrasound image will reveal
both the target structure and the needle position. The needle can
Figure 46-9. Visualization of the tip of the needle (white arrow)

during performance of the OOP technique.
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Figure 46-10. Position of the needle relative to the ultrasound

probe for the in-plane (IP) technique (simulated technique).
also be identified by tissue movement and displacement or by an
acoustic shadow emerging distal to the tip. OOP imaging allows us
to use what was previously regarded as traditional methods of
needle insertion while performing ultrasound-guided blocks.
The second option is to advance the needle beneath the ultrasound beam and is known as the in-plane (IP) technique (Figures
4610 and 4611). The shaft of the needle should be visualized at
all times so that the location of the tip is known. The orientation of
the probe is crucial. Deviations as small as 1 to 2 mm will remove
the needle from the image.
STERILITY
Sterile preparation of the probe and the block area is an important prerequisite for any ultrasound-guided block technique. An
expert consensus in 2007 recommended that a sterile probe
Figure 46-11. Visualization of the needle during performance

of the IP technique (supraclavicular approach). White arrow =
tip of the needle; gray arrows = reverberation artifacts.
Figure 46-12. Ultrasound probe cover, where an adhesive sheet

(left red arrow) is connected to a plastic foil.
cover should be used for single and continuous block techniques (http://www.sono-nerve.com/Expert_Group_meeting_
Guidelines_final_draft_2nd_ed.pdf), recommends that a sterile
probe cover should be used for single and continuous block
techniques. Figures 4612 to 4614 show the latest development
Figure 46-13. Placement of the ultrasound probe on the

adhesive sheet (red arrow) of the probe cover. No ultrasound
jelly is required between the probe and the inner layer of the
probe cover.
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Figure 46-14. Final preparation of the sterile ultrasound probe.

in that field, in which a transparent adhesive sheet is connected to
a plastic foil and how it should be used. This unique arrangement
of two different materials allows the cover to be placed directly on
the probe, avoiding the need for extra gel. Gel on either side of the
cover is essential when other probe covers are used. A single gel
layer significantly improves the picture quality. A variety of
electrode or lubricating gels can be used in place of the more
expensive ultrasound-specific gel.
PRACTICAL PERFORMANCE IN
THE DAILY CLINICAL PRACTICE
The implementation of ultrasound-guided blocks into daily
practice offers new options for the management of various procedures. Since 2005, it is clear that almost all regional anesthetic
techniques in children had to be performed under general
anesthesia. With improved techniques, experience, and better hand
skills, it is now possible to perform various techniques even in awake
or slightly sedated children. In principle, a distinction between acute
trauma surgery and general surgery is necessary. Limb blocks are
mainly performed in acute trauma surgery, whereas the preferred
techniques in general surgery are neuraxial blocks. Of course, limb
blocks are also indicated in orthopedic or plastic and reconstructive
surgerythose children may be treated with techniques similar to
those of acute trauma surgery.
Whether a child is sedated or remains alert during the block
procedure in acute trauma surgery depends entirely on the
situation. Following adequate preparation and if a trust has been
established, it is perfectly feasible to conduct the block procedure
while the child is awake. Which medications are used is left up to
the anesthesiologists discretion and experience. It must always be
borne in mind, however, that acutely injured children are rarely
admitted with an empty stomach. Thus, it is necessary to maintain
Figure 46-15. Facette tip needle.
spontaneous breathing. Appropriate equipment and medication

for intubation must be present and ready for use.
If the child is in severe pain or immediate surgical intervention
is indicated (e.g., in cases in which perfusion is compromised),
regional anesthesia is performed without delay. If pain can be
controlled adequately by immobilizing the leg, however, another
option is to use 0.5 to 1 mg/kg oral or rectal midazolam as premedication before the peripheral venous access is established.
Application of EMLA (eutectic mixture of local anesthetics) for
local anesthesia at the puncture site is useful only if placed at
least 30 minutes before the puncture. If the child is in severe
pain or cannot be adequately calmed down, a venous access is
immediately established to provide sedation. It is reasonable to
assume that the establishment of a peripheral venous access is less
traumatizing in certain situations than waiting for the EMLA tape
to become effective. If EMLA is not applied at the puncture site, a
local infiltration (with xylocaine 1%) may be used.
In elective surgical procedures, the approach adopted depends
on the child. The anesthesiologist may elect to perform the entire
procedure with the child awake. Mild sedation will usually be
sufficient both to establish the block and to perform the surgical
procedure. General anesthesia with protection of the airway is
indicated if the surgical procedure is expected to take a very long
time. In the presence of specific injury patterns and types of
surgery (e.g., re-implantation procedures), general anesthesia is
mandatory. Most anesthesiologists choose to combine regional
anesthesia with general anesthesia
The authors sedation regime includes midazolam 0.1 mg/kg
and S(+) ketamine 0.5 to 1.0 mg/kg. The analgesic component of
S(+) ketamine can be used to good effect in this situation for limb
positioning or local infiltration in the puncture area. In some
situations, low-dose propofol (0.51.0 mg/kg) may be required.
It is important to note that these medications are administered
according to actual need. Assisted mask ventilation may be
indicated if deeper sedation is necessary. Continuous administration of propofol 5.0 mg/kg/h can be very helpful during
prolonged surgical procedures. For monitoring, pulse oximetry is
usually sufficient, because this provides information on oxygen
saturation and heart rate. A noninvasive blood pressure is not
routinely used for uncomplicated cases but is advisable in more
complicated cases.
NEEDLE AND CATHETER EQUIPMENT

Various ultrasound needles are available. The value of many of
these products over conventional needles has not been established.
In the authors practice, Facette tip needles with an injection line
and a relatively sharp tip are used for all peripheral nerve blocks
(Figure 4615). The main advantage of these needles is that precise
placement can be achieved. This is more difficult with blunt
needles because children have more elastic fascia and piercing
these structures with a blunt needle may require some force.
Facette tip needles allow smooth transition through fascial planes
and more precise placement.
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The ideal peripheral catheters are still not developed. Various

products are available, but most do not allow an immobile needle
technique, as described by Winnie and associates, to be used.4a
Nevertheless, with adequate training and hand skills, placement
of a peripheral catheter is possible in most cases. It is important
to realize that, for anatomic reasons, not all approaches to the
brachial and lumbosacral plexus are appropriate for catheter
techniques. For example, it is inappropriate to use a catheter for
the axillary approach whereas the supraclavicular approach is
perfectly suitable for catheter placement.
Neuraxial (epidural) catheter sets are available in many sizes
ranging from 18- to 21-gauge needle sizes with 21- to 25-gauge
catheter sizes. Twenty-five-gauge catheter sets are available with a
reinforcing wire in order to facilitate both placement and ultrasonographic visualization of the catheter. The major drawback of
these catheters is the tendency to kink. Nevertheless, with careful
fixation, kinking can be avoided in most of the cases.
PRACTICAL PERFORMANCE
OF REGIONAL TECHNIQUES
A short overview of current ultrasound-guided regional anesthetic
techniques in children follows. No recommendations for drugs or
dosage are included because not all local anesthetics are available
in all countries. Injecting local anesthetic until the peripheral
nerve is seen to be surrounded by local anesthetic is considered
optimal. Exceptions to these recommendations are neuraxial

blocks and those techniques in which the neuronal structures are
not directly visualized (e.g., rectus sheath block). Table 464 shows
a summary of the different regional anesthetic techniques under
ultrasonographic guidance.
Upper Limb Blocks

Upper limb blocks are underused in the daily pediatric anesthesia
practice. Since the year 2000, brachial plexus anesthesia has
become more popular for the management of upper limb surgery
in children. Particularly in pediatric trauma surgery in which
general anesthesia, which is associated with a high risk of aspiration, can be avoided. The goal should be to provide optimal
sensory and motor blockade as needed. Using conventional
methods, the axillary route provides a poor quality of sensory
analgesia in a significant number of patients. The infraclavicular
approach, as described by Kilka and coworkers in adults, should
not be applied to children because of the potential danger of
pneumothorax.5 All approaches to the brachial plexus (i.e., axillary
for forearm and hand surgery and periclavicular for elbow and
upper arm surgery) have been described in the past for children
using anatomic landmarks or a nerve stimulator. Methods using
ultrasonographic guidance have been developed for these regional
anesthetic techniques to increase the success rates and minimize
the risks of complications.
TABLE 46-4. Summary of Ultrasound-guided Regional Anesthetic Techniques

Guidance Technique,
Ultrasound Probe
Remarks
Multiple hypoechoic round to oval

structures lateral to the subclavian
artery.
Hyperechoic appearance of the cords
lateral and/or below the
subclavian artery.
IP, high-frequency linear

probe.
Close proximity to the cervical

pleura.
OOP, high- to middlefrequency linear probe.
Hyperechoic round to oval

structures, musculocutaneus
nerve hyperechoic and triangular
between the short head of the
biceps and the coracobrachialis
muscles.
In smaller children, hyperechoic. In
older children, lumbar plexus not
always directly visible.
OOP, high-frequency linear

probe.
In older children, sometimes

impaired visualization of
neuronal structuresin those
cases, lower ultrasound
frequencies are recommended.
Single-injection technique of all
single nerves, additional
injection for subfascial blockade
of the brachiocutaneous nerve.
Approach
Appearance of Neuronal Structures
Supraclavicular
Infraclavicular
Axillary
Psoas compartment
Sciatic
Proximal: hyperechoic.
Popliteal: isoechoic.
The shape of the nerve changes from
oval (proximal) to round (distal).
In smaller children, OOP.

In older children, IP.
Middle- to low-frequency
sector probe. In infants, a
high-frequency linear
probe can be used.
Proximal approach: OOP,
middle-frequency sector
probe.
Anterior approach: IP,
middle- to low-frequency
sector probe.
Popliteal approach: IP, highfrequency linear probe.
In older children, where the lumbar

plexus is not always directly
visible, the use of a sector probe
or nerve stimulator could be
considered.
In older children, longer onset
times.
(Continued)
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Guidance Technique,
Ultrasound Probe
Approach
Appearance of Neuronal Structures
Femoral
Slightly hyperechoic, lateral to the

femoral artery.
The nerve spreads soon after its
passage below the inguinal
ligament.

probe
Rectus sheath
Intercostal nerves VIIIX are usually

not visible at the posterior sheath
of the rectus abdominal muscle.

probe
Ilioinguinaliliohypogastric
Medial to the anterior superior iliac

spine and between the internal
oblique and the transverse
abdominal muscles: hyperechoic
appearance of both nerves, oval
shape.
Dura mater: longitudinal
hyperechoic band. Epidural space:
hyperechoic.

probe.
Epidural
Best view to the neuraxial

structures: paramedian
position of the probe,
downward movement of
the dura after injection of
local anesthetic; highfrequency linear probe.
Remarks
Block as proximal as possible. In
smaller children, co-blockade of
the lateral cutaneous femoral
nerve possible with 310 mL
local anesthetic (no exact data
available).
0.1 mL/kg/side as a predetermined
volume; injection into a space
without direct visualization of
nerves.
Both nerves are in close proximity
to each other; usually one needle
tip position is sufficient for
blockade of both nerves.
Combination of ultrasonographic
(medial approach) and loss of
resistance.
IP = in-plane; OOP = out-of-plane.
Supraclavicular Approach
Using ultrasound guidance, the supraclavicular approach to the
brachial plexus has become a very attractive option. The neuronal
structures in the transition zone between the trunks and the cords
of the brachial plexus lie in close proximity to one another and
close to an easily identifiable landmark, the subclavian artery. The
major problem associated with this approach is the close proximity
of the plexus to the pleura (Figure 4616). Advanced hand-eye
Figure 46-16. Ultrasonographic appearance of the supraclavicular portion of the brachial plexus and the close proximity to the
cervical pleura. Red arrow = subclavian artery; yellow arrows =
neuronal structures of the brachial plexus in the supraclavicular
region; white arrow = first rib; gray arrow = pleura.
coordination is required to avoid puncture the pleura or the artery.

In children, the distance between the interscalene approach and
the supraclavicular approach is marginal and, therefore, the
distribution of the each block is similar.
The supraclavicular block is performed with a high-frequency
ultrasound probe using the IP technique (Figure 4617). The
nerve structures of the supraclavicular portion of the brachial
Figure 46-17. Practical performance of the supraclavicular

brachial plexus blockade using the IP technique. White arrow =
mandible; gray arrow = clavicle (simulated technique).
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plexus appear as hypoechoic round to slightly oval structures

lateral and cranial to the subclavian artery. The dorsal scapula
artery may be visible as its courses through the brachial plexus.
Depending on the initial spread of local anesthetic, careful
repositioning of the needle might be necessary in order that all
neuronal structures are surrounded by local anesthetic. This
approach lends itself to a continuous catheter technique because
nerve structures are in close proximity to one another and a
continuous brachial plexus blockade can thus be provided. The
exact position of the catheter can be determined using ultrasound
to visualize the catheter or observe the spread of local anesthetic
from the catheter tip in real time.
Infraclavicular Approach
In 2002, Greher and colleagues showed, in an adult study,6 that the
landmarks for the vertical infraclavicular approach, as described
by Kilka and coworkers in 1995,5 are inappropriate when the
distance between the jugular fossa and the ventral part of the
acromium is less than 22 cm. On the basis of these findings,
Marhofer and associates developed a lateral infraclavicular approach to the brachial plexus in children using a nerve stimulator
and the coracoid process as a landmark.7 The landmarks are not
easily defined, but by using ultrasonographic guidance, a faster
onset of sensory and motor block of longer duration could be
achieved. A 6- to 13-MHz linear ultrasonographic probe should be
used for this block because the brachial plexus at this level is
relatively deep (particular in older children) and, therefore, lower
frequencies (10 MHz) are necessary. The overlying pectoralis
major and minor muscles reduce the overall quality of the
ultrasound picture. At this level, the brachial plexus has divided
into cords that lie lateral to the subclavian artery (Figures 4618
and 4619).
Figure 46-18. Position of the cords of the infraclavicular

portion of the brachial plexus lateral to the subclavian artery
(red arrow). White arrow = pleura; yellow arrows = cords of
the brachial plexus.
Figure 46-19. Practical performance of the infraclavicular

brachial plexus blockade using the OOP technique. Gray
arrow = clavicle (simulated technique).
Anatomic variants mainly of the posterior cord may be difficult
to visualize because they lie deep to and may lie in the ultrasound
shadow of the artery. Usually, a single injection of local anesthetic
will block the entire plexus and allow surgical procedures of the
upper arm. The optimal spread of local anesthetic should be lateral
and below the artery, to include the posterior cord.
Axillary Approach
The axillary approach to the brachial plexus is the most popular
technique for both adults and children. It is considered a safe
technique with a low incidence of complications. Using anatomic
landmarks or a nerve stimulator, the success rate is in the order of
60 to 70%.
An axillary brachial plexus block provides analgesia for forearm
and hand surgery. Using a high-frequency linear probe and an
OOP multiple-injection technique, each nerve radialmedian,
musculocutaneous, and ulnarcan be blocked individually to
achieve the best results (Figure 4620). For easy identification, it
is recommended that each nerve should be tracked with the
Figure 46-20. Practical performance of the axillary brachial

plexus blockade using the OOP technique (simulated technique).
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Figure 46-21. Ultrasonographic identification of the (hyperechoic) nerves of the axillary portion of the brachial plexus.
The musculocutaneus nerve is not visible in this view. Left side =
cranial; red arrow = axillary artery; left upper yellow arrow =
median nerve; right upper yellow arrow = ulnar nerve; lower
yellow arrow = radial nerve.
ultrasound (Figure 4621). Analogous to other blocks, the onset
time is significantly shortened using ultrasound guidance.
Peripheral Nerve Blocks of the Upper Extremity

It is possible to block the median, radial, and ulnar nerves at any
level in the upper and forearm. Indications are small and are
dictated by the extent of surgery. Figures 4622 to 4624 show the
ultrasonographic appearance of the three peripheral nerves at the
level of the forearm.
Lower Limb Blocks
Figure 46-23. Ultrasonographic identification of the ulnar

nerve (yellow arrow) at the level of the middle third of the
forearm. Red arrow = ulnar artery.
observation has shown that the lateral cutaneous femoral nerve
can be blocked by lateral spread when larger volumes of local
anesthetics are used for a femoral nerve block. The precise volume
to achieve a block of both nerves has yet to be determined in
children of different ages. An attempt should be made to identify
the lateral femoral cutaneous nerve so that it can be blocked
separately. In smaller children, this may be difficult. Simply
doubling the dose of the femoral block in these children should
block both nerves.
Femoral Nerve Approach

Femoral nerve block is an easy block to perform and provides
analgesia for fractures of the femoral shaft or surgical procedures
in the femoral nerve distribution. It is a relatively superficial
structure and is best visualized with a high-frequency linear probe
lateral to the femoral artery. The nerve divides proximally close to
the inguinal ligament (Figure 4625). This should be taken into
account when blocking the nerve. Low volumes placed proximally
will achieve the best results.8
The three-in-on block, in which the femoral, lateral cutaneous femoral, and obturator nerves are blocked by one single
injection, seldom achieves an obturator nerve block. Clinical
Lumbar Plexus or Psoas Compartment Block
Figure 46-22. Ultrasonographic identification of the median

nerve (yellow arrow) at the level of the middle third of the
forearm.
Figure 46-24. Ultrasonographic identification of the radial

nerve at the level of the upper third of the forearm. Left yellow
arrow = profound branch; right yellow arrow = superficial branch.
The lumbar plexus is formed by the femoral, genitofemoral,

lateral femoral cutaneous, and obturator nerves and some portions
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Figure 46-25. Ultrasonographic view of the femoral nerve

(yellow arrow) slightly distal the inguinal ligament. Red arrow =
femoral artery.
of the sacral plexus. A lumbar plexus or psoas compartment block
is indicated for surgical procedures on the hip, femur, and knee
joint as well as pain management of femoral fractures. A supplementary sciatic nerve block will allow surgery on any aspect of the
lower limb.
The posterior approach carries the risk of undetected epidural,
intrathecal, or intravascular injection. Care must be also be taken
to avoid damage to the kidneys, which may extend down to the
L45 level in small children.9 Bilateral distribution of local
anesthetic via the epidural space has also been reported.10 The
posterior approach to the lumbar plexus was first described in
adults by Chayen and coworkers11 and Winnie and associates
(1969). Chayen and coworkerscoined the term psoas compartment
block.11 Dalens and colleagues compared two posterior approaches
in children for surgical procedures of the hip and femur.12 The
depth of the plexus varied greatly with age and correlates with
body weight.13 According to Kirchmair and associates,14 the
lumbar plexus is located two thirds into the anteroposterior
extension of the psoas muscle. The lumbar plexus and its
surrounding structures are best seen with convex transducers
(spatial array) in children.15 Accurate measurements of its depth
can be made.15 The neural and paravertebral are better visualized
in children because the depth in small children allows the use of
probes of higher resolution. High-frequency linear transducers
produce better images in newborns and infants.
The first step is to define the access level. Usually, L45 is
selected because it is a useful landmark to start imaging. A paravertebral longitudinal section is used to visualize the transverse
processes of the lumbar vertebrae. Starting at the dorsal ultrasound reflection of the sacrum, the processes are counted from
caudal to cranial. On reaching the L45 intervertebral space, the
transducer probe is turned through 90 degrees to a transverse
plane. The lumbar plexus can be located inside the posterior
segment of the psoas major muscle (Figure 4626). In infants and
Figure 46-26. Ultrasonographic view of a lumbar nerve root inside the psoas major muscle in a 10-year-old child. The nerve
roots are not directly visible, but can be assumed between the
middle and the posterior third of the psoas major muscle (gray
arrow). Lower white arrow = vertebral body; upper white arrow =
spinous process.
small children, the needle should be oriented perpendicular and
transverse to the probe (OOP) because the plexus is only 2 to
3 cm away. A different approach should be selected for larger
children and adults, in whom the IP technique is preferable
(Figure 4627).14 A fixed dose (0.3 mL/kg) for psoas compartment
blocks in children is recommended because the neuronal structures are not always visible and observation of the spread of local
anesthetic is difficult.15
Sciatic Nerve Block: Approaches

There are a number of indications for the sciatic nerve block.
When used in combination with the femoral nerve or psoas
Figure 46-27. IP technique for a psoas compartment block.

Arrow = spinous process; left side = cranial (simulated technique).
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Figure 46-30. OOP technique for a proximal sciatic nerve block

(simulated technique).
Figure 46-28. Ultrasonographic view of the sciatic nerve (left

yellow arrow) slightly distal to the gluteal fold. Right yellow
arrow = cutaneous femoral posterior nerve.
compartment block, most surgical procedures in the lower
extremity could be performed. An advantage of ultrasoundguided nerve blocks is that nerves can be blocked wherever they
are visualized, independent of landmarks. The sciatic nerve in
children can be visualized at an infragluteal level (Figure 4628)
down to the popliteal level (Figure 4629), where the division can
be detected. High-frequency linear probes provide the best images
of the sciatic nerve blocks at all levels. The sciatic is the most
anisotropic nerve, which means that the ultrasound beam should
be perpendicular to the nerve to achieve an optimal visualization.
An OOP technique is suggested for proximal block, whereas
an IP technique is used for the popliteal approach (Figures 4630
Figure 46-29. Ultrasonographic view of the sciatic nerve at the

popliteal area, where the nerve is already divided in its tibial
(right yellow arrow) and peroneal (left yellow arrow) branches.
and 4631). In view of the large diameter of the nerve (particularly

in older children), a longer onset time can be expected.
Truncal Blocks
ILIOINGUINAL-ILIOHYPOGASTRIC NERVE BLOCK: This is one of
the most popular regional anesthetic techniques in pediatric
anesthesia, and it provides analgesia for all surgical procedures in
the inguinal area. Ilioinguinal blocks can be equally effective as
caudal blocks.16 Techniques based on anatomic landmarks and
fascial clicks have a high failure rate and complications such as
intestinal puncture or pelvic hematoma1719 have been reported.
The ilioinguinal and iliohypogastric nerves can be visualized
medial to the anterior superior iliac spine with ultrasonography.20
In that anatomic region, both nerves lie between the internal
oblique and the transverse abdominal muscles (Figure 4632).
The iliohypogastric nerve is located superior and medial to the
ilioinguinal nerve. In the region of the anterior superior iliac spine,
the iliohypogastric nerve bifurcates into two terminal branches.
Figure 46-31. IP technique for a popliteal sciatic nerve block

(simulated technique).
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Figure 46-34. Ultrasonographic visualization of the posterior

rectus sheath (yellow arrow). Left side = umbilicus.
Repositioning the needle to block the iliohypogastric nerve is
usually not necessary.
RECTUS SHEATH BLOCK: Indications for the rectus sheath block
Figure 46-32. Ultrasonographic visualization of the ilioinguinaliliohypogastric nerves (yellow arrow) between the internal
oblique and the transverse abdominal muscles. White arrow =
anterior superior iliac spine.
The lateral cutaneous branch passes through the internal oblique
and external oblique muscle to supply sensory innervation to the
anterior buttock region. The medial cutaneous branch crosses
through the internal oblique and the external oblique aponeurosis to innervate the abdominal wall above the symphysis.
The ilioinguinal nerve supplies the skin below the area supplied
by the iliohypogastric nerve and the upper anterior part of the
scrotum.
Ultrasonography should be performed using a high-frequency
linear probe. The needle should be inserted using the OOP technique (Figure 4633). Using ultrasound, much smaller doses
of local anesthetic (0.1 mL/kg) can be used. This is considerably
smaller than those recommended in the literature21 for using
anatomic landmarkbased techniques. This makes the procedure much safer, especially in infants in whom very high local
anesthetic agent levels have been reported for this technique.22
include umbilical or epigastric hernia surgery and laparoscopic

port insertion. Until the late 1990s, rectus sheath blocks were
poorly documented in the literature.23,24 The rectus abdominis
muscles extend from the xiphisternum and costal cartilages
down to the pubic crest. They lie within a fibrous sheath (linea
semilunaris) formed by the aponeurotic layers of the abdominal
muscles (external and internal oblique, transverse abdominis).
The lateral border of the sheath complex descends from the tip of
the ninth costal cartilage. There are three tendinous intersections
within the sheath at three levels: the xiphisternum, the umbilicus,
and midway between both on either side.
The ventral rami of the VIIth to XIIth intercostal nerves pass
anterior and downward from their respective intercostal space.
They pierce the posterolateral aspect of the rectus sheath and
cross anteriorly through the muscle to supply the overlying skin.
Sensory input from the umbilicus is supplied by the nerves at
levels T911. A high-frequency `ultrasound probe should be used
for this technique. After identification of the posterior rectus
sheath (Figure 4634), 0.1 mL/kg/side local anesthetic should
be injected by using the OOP technique (Figure 4635).25
A predetermined volume of local anesthetic is useful because the
nerves are not directly visible.
Neuraxial Techniques
EPIDURAL BLOCKADE: Epidural blockade is increasing in popularity, although still performed only by the minority of pediatric
Figure 46-33. OOP plane technique for the ilioinguinaliliohypogastric nerve blockade (simulated technique).
Figure 46-35. OOP plane technique for the rectus sheath blockade. White arrow = umbilicus (simulated technique).
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anesthesiologists in children of all ages, especially neonates. The

advantages of continuous epidural infusions include profound
analgesia without the risk of respiration depression, reduction in
the need for postoperative ventilatory support, improved gastrointestinal function, and immunomodulation.
Epidural catheter placement in children requires dexterity and
knowledge of anatomy to perform these techniques in a safe and
effective manner. The most recent addition to pediatric epidural
catheter placement is the use of ultrasonography to identify the
relevant anatomic structures, to guide the placement of the epidural
needle in the epidural space, to avoid accidental dural puncture, and
to detect the spread of local anesthetic within the epidural space.
In adults, the image of the neuraxial structures is impaired by
bone that reflects the ultrasound waves.2628 Because the vertebral
column of infants is still in the process of ossifying and the depth
of the neuraxial structures is reduced, visualizing neuraxial
structures is a function of both weight and age.29 At the lumbar and
thoracic levels, the best view of the dura is achieved with a linear
probe from the paramedian longitudinal position. Ultrasound can
be used to determine the skin-to-epidural distance and can be
combined with the traditional loss-of-resistance technique to
facilitate epidural placement in children up to 4 years of age30,31
(Figure 4636). In children older than 4 years, visualization of the
neuraxial structures is difficult. The downward movement of the
dura mater on the ultrasonograph confirms correct placement of
the needle within the epidural space (Figure 4637). Spread of local
anesthetic within the epidural space confirms correct catheter
placement and the position of the catheter tip.
Figure 46-37. Ultrasonographic appearance of the neuraxial

structures in an 1800-g neonate in which the dura (yellow arrows)
moves downward during injection of the local anesthetic. Right
side = caudal, from where the local anesthetic is administered.
as central line placement, needle aspiration of lymph nodes, or
drainage of cysts. These indications should be considered to
conjure up financial/clinical support from other disciplines when
considering the purchase of ultrasound equipment in difficult
economic climates. Fast onset times, improved success rates with
smaller volumes of local anesthetic, and fewer complications
are all strong motivating factors for the purchase of ultrasound
equipment.
FUTURE DEVELOPMENTS
Education
Ultrasonographic guidance in regional anesthesia is advancing

rapidly. As with all new techniques, there is a learning curve that
is associated with some problems and pitfalls. In order to advance
ultrasonographic guidance in regional anesthesia, it is important
to highlight some important points.
Specific education to achieve an adequate level of knowledge and

hand skills is an absolute prerequisite before the introduction of
ultrasound into daily clinical practice. As with any developing
field, new advances are being made. It is important that the art
and science of ultrasonography is developed and widely disseminated so that all children of the world can benefit of its advantages. The increasing number of publications bears testimony
to that, but care should be taken to ensure that the level of science
is high. As the knowledge of anatomy in growing children increases among practitioners, the quality of all pediatric regional
anesthetic techniques should improve. Ultrasound is a useful tool
in this regard.
Equipment
Portable equipments at relatively affordable prices have become
available. These machines can be used for other purposes such
REFERENCES
Figure 46-36. Ultrasound-guided continuous epidural blockade

with a paramedian position of the ultrasound probe and a median
needle direction.
1. La Grange P, Foster PA, Pretorius LK. Application of the Doppler

ultrasound blood flow detector in supraclavicular brachial plexus block.
Br J Anaesth. 1978;50:965967.
2. Kapral S, Krafft P, Eibenberger K, et al. Ultrasound-guided supraclavicular
approach for regional anesthesia of the brachial plexus. Anesth Analg.
1994;78:507513.
3. Marhofer P, Sitzwohl C, Greher M, et al. Ultrasound guidance for
infraclavicular brachial plexus anaesthesia in children. Anaesthesia.
2004;59:642646.
4. Giaufre E, Dalens B, Gombert A: Epidemiology and morbidity of regional
anesthesia in children: a one-year prospective survey of the FrenchLanguage Society of Pediatric Anesthesiologists. Anesth Analg. 1996;83:
904912.
4a. Winnie AP. An "Immobile needle" for nerve blocks. Anesthesiology 1969;
31:577578.
5. Kilka HG, Geiger P, Mehrkens HH: Infraclavicular vertical brachial plexus
blockade. A new method for anesthesia of the upper extremity; an
anatomical and clinical study. Anaesthesist. 1995;44:339344.
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6. Greher M, Retzl G, Niel P, et al. Ultrasonographic assessment of

topographic anatomy in volunteers suggests a modification of the
infraclavicular vertical brachial plexus block. Br J Anaesth. 2002;88:
632636.
7. Fleischmann E, Marhofer P, Greher M, et al. Brachial plexus anaesthesia
in children: lateral infraclavicular vs axillary approach. Paediatr Anaesth.
2003;13:103108.
8. Oberndorfer U, Marhofer P, Bosenberg A, et al. Ultrasonographic
guidance for sciatic and femoral nerve blocks in children. Br J Anaesth.
2007;98:797801.
9. Rauber A, Kopsch F, Leonhardt H. (eds). Anatomie des Menschen. Innere
Organe. Thieme, Stuttgart, 1987;576.
10. Mannion S, OCallaghan S, Walsh M, et al. In with the new, out with the
old? Comparison of two approaches for psoas compartment block. Anesth
Analg. 2005;101:259264.
11. Chayen D, Nathan H, Chayen M: The psoas compartment block.
12. Dalens B, Tanguy A, Vanneuville G: Lumbar plexus block in children:
a comparison of two procedures in 50 patients. Anesth Analg. 1988;67:
750758.
13. Dalens B: Regional anesthesia in children. Miller RD, editor. Anesthesia.
Philadelphia: Churchill Livingstone; 2000;20882118
14. Kirchmair L, Entner T, Kapral S, et al. Ultrasound guidance for the psoas
compartment block: an imaging study. Anesth Analg. 2002;94:706710;
table of contents.
15. Kirchmair L, Enna B, Mitterschiffthaler G, et al. Lumbar plexus in
children. A sonographic study and its relevance to pediatric regional
16. Markham SJ, Tomlinson J, Hain WR: Ilioinguinal nerve block in children.
A comparison with caudal block for intra- and postoperative analgesia.
Anaesthesia. 1986;41:10981103.
17. Amory C, Mariscal A, Guyot E, et al. Is ilioinguinal/iliohypogastric nerve
block always totally safe in children? Paediatr Anaesth. 2003;13:164166.
18. Johr M, Sossai R: Colonic puncture during ilioinguinal nerve block in a
child. Anesth Analg. 1999;88:10511052.
19. Vaisman J: Pelvic hematoma after an ilioinguinal nerve block for

orchialgia. Anesth Analg. 2001;92:10481049.
20. Willschke H, Marhofer P, Bosenberg A, et al. Ultrasonography for
ilioinguinal/iliohypogastric nerve blocks in children. Br J Anaesth. 2005;
95:226230.
21. Willschke H, Bosenberg A, Marhofer P, et al. Ultrasonographic-guided
ilioinguinal/iliohypogastric nerve block in pediatric anesthesia: what is
the optimal volume? Anesth Analg. 2006;102:16801684.
22. Smith T, Moratin P, Wulf H: Smaller children have greater bupivacaine
plasma concentrations after ilioinguinal block. Br J Anaesth. 1996;76:
452455.
23. Ferguson S, Thomas V, Lewis I: The rectus sheath block in paediatric
anaesthesia: new indications for an old technique. Paediatr Anaesth.
1996;6:463466.
24. Courreges P, Poddevin F, Lecoutre D: Para-umbilical block: a new concept
for regional anaesthesia in children. Paediatr Anaesth. 1997;7:211214.
25. Willschke H, Bosenberg A, Marhofer P, et al. Ultrasonography-guided
rectus sheath block in paediatric anaesthesiaa new approach to an old
technique. Br J Anaesth. 2006;97:244249.
26. Grau T, Leipold R, Conradi R, et al. Ultrasonography and peridural
anesthesia. Technical possibilities and limitations of ultrasonic examination of the epidural space. Anaesthesist. 2001;50:94101.
27. Grau T, Leipold RW, Delorme S, et al. Ultrasound imaging of the thoracic
epidural space. Reg Anesth Pain Med. 2002;27:200206.
28. Grau T, Leipold RW, Conradi R, et al. Efficacy of ultrasound imaging in
obstetric epidural anesthesia. J Clin Anesth. 2002;14:169175.
29. Marhofer P, Bosenberg A, Sitzwohl C, et al. Pilot study of neuraxial
imaging by ultrasound in infants and children. Paediatr Anaesth.
2005;15:671676.
30. Willschke H, Marhofer P, Bosenberg A, et al. Epidural catheter placement in children: comparing a novel approach using ultrasound guidance and a standard loss-of-resistance technique. Br J Anaesth. 2006;97:
200207.
31. Willschke H, Bosenberg A, Marhofer P, et al. Epidural catheter placement
in neonates: sonoanatomy and feasibility of ultrasonographic guidance
in term and preterm neonates. Reg Anesth Pain Med. 2007;32:3440.
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Upper Limb Blocks
47
Katherine Keech and Adrian Bsenberg
INTRODUCTION
Regional anesthesia is commonly used as an adjunct to general
anesthesia and plays a key role in the multimodal approach to
perioperative pain management in children. Its use in pediatric
orthopedic surgery is gaining popularity13 despite concerns from
some orthopedic surgeons that the profound analgesia offered
may make evaluation of nerve function difficult and may mask
ischemic pain of compartment syndromes.
The worldwide trend toward more day case surgery and the
advantages offered has provided the impetus for increased use of
regional techniques. Furthermore, the advent of more complex
and innovative surgical procedures in children has improved
outcome but has led to more invasive surgery and, consequently,
more pain in the postoperative period. These have led to the
development of continuous peripheral nerve block techniques that
target the site of surgery in both children1,4,5 and adolescents.
The practice of peripheral nerve blockade continues to improve
with the development of age-appropriate equipment and the
introduction of safer, long-acting local anesthetic agents such as
ropivacaine and levobupivacaine. The safety of peripheral nerve
blocks has been established in large-scale prospective studies in
children.6 As a consequence, peripheral nerve blocks are recommended rather than central neuraxial techniques where appropriate.6 The majority of peripheral nerve blocks are performed in
the perioperative arena by experienced anesthesiologists, but
several blocks, such as axillary nerve or digital block, may be
considered in emergency room or even intensive care settings.
The purpose of this chapter is to outline some methods used to
identify and block individual nerves and regional anesthetic
techniques that can be used for surgical procedures of the upper
limb in children. The choice of technique will be dictated by the
pathology, the extent of surgery, the childs body habitus, the
presence of contractures, the experience of the practitioner, and
the availability of ancillary equipment. The differences between
adults and children are highlighted together with techniques to
improve the success of blocks.
METHODS TO IMPROVE ACCURACY

OF PERIPHERAL NERVE BLOCKS
Upper limb nerve blocks, particularly in young children, can be
challenging. Anatomic landmarks are poorly defined and vary
according to the stage of the development of the child, particularly
in those children with congenital limb defects. The success of
placing these blocks requires an awareness of these differences,
knowledge of developmental anatomy, and an understanding of
C H A P T E R
the equipment used. For most blocks presented in this chapter, use
of an insulated needle together with ultrasound guidance or peripheral nerve stimulators7 is recommended, although successful
blocks may be achieved with noninsulated needles.8
Given the difficulty in obtaining a childs cooperation, particularly in young infants, nerve blocks are performed under general
anesthesia or sedation in children of all ages. Care should be taken
when placing blocks because paresthesias and/or pain cannot be
used as a potential warning sign. In situations in which the block
is performed in awake children, seeking paresthesia is of little
benefit9
Relatively new techniques for improving the success of
peripheral nerve blocks include surface nerve mapping10 and ultrasonography.11,12 Both techniques are particularly useful in small
childrena group considered to be at greater risk of complications or failurebecause most peripheral nerves are relatively
superficial.
Ultrasound Imaging
Ultrasound imaging may facilitate brachial plexus blockade in
several ways.13 In a sedated or anesthetized child, direct visualization of the target nerves and their surrounding structures
(vessels, tendons, and bones), anatomic variants, or pathology can
be identified. Because most peripheral nerves lie within the range
of portable ultrasound probes, good definition is obtained. Using
real-time imaging, the correct needle position and local anesthetic
placement around the nerve can be verified. In this way, the risk
of intraneural or intravascular injection is potentially reduced. The
position of continuous catheters can also be identified.
Proponents of ultrasound guidance claim earlier onset times,
improved quality and duration of block using smaller volumes of
local anaesthetic, and fewer complications in children.12,13 Some
anesthesiologists prefer to use nerve stimulation in conjunction
with ultrasound, but whether this adds value to ultrasound is
uncertain. Using a nerve stimulator to confirm that the structure
visualized is a nerve is fraught with imprecision.
Nerve Stimulator
A number of basic principles need to be emphasized when using
a nerve stimulator.7 In order to accurately locate a peripheral nerve
or plexus, neuromuscular blocking agents must be withheld until
after completion of the nerve block. The proper functioning of the
nerve stimulator, according to the manufacturers specifications,
should be understood before use.7,8 With the flood of peripheral
nerve stimulators currently on the market, it is best to familiarize
oneself with the nuances of a particular device and to stick with it.8
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The negative electrode should be connected to the needle and

the positive electrode is connected to the patient using a standard
electrocardiographic (ECG) electrode. Once the appropriate landmarks have been determined or surface-mapped, and with the
peripheral nerve stimulator initially set at 1 to1.5 mA and 1 to 2 Hz,
the needle should be advanced through the skin and underlying
tissue planes until appropriate distal muscle contractions are elicited.
When performing a brachial plexus block, superior trunk stimulation causes deltoid stimulation; musculocutaneous stimulation
cause flexion of the arm at the elbow; median nerve stimulation
causes forearm pronation, wrist flexion, and opposition of the
thumb; ulnar nerve stimulation causes ulnar deviation of the wrist,
flexion of the little finger, thumb adduction, and flaring of the fingers; and radial nerve stimulation causes wrist and finger extension.
Once the appropriate distal muscle contractions have been
elicited, the output should be decreased and the location of the
needle adjusted until maximum motor response is elicited with
the least amount of current (i.e., ~0.30.5 mA). The appropriate
dose of local anesthetic should be injected at this point. The
muscle stimulation will immediately cease, indicating that a
successful block is likely. Failure to elicit this response requires
that the needle be repositioned before repeating the process. The
local anesthetic should not be injected if intense muscle contraction is elicited at less than 0.2 mA or if there resistance to
injection. Both suggest that the tip of the needle may be intraneural and the nerve may be damaged by further injection.
Surface Nerve Mapping

Surface nerve mapping is a modification of the standard nerve
stimulator technique.10 The path of a superficial peripheral nerve
or plexus can be traced before skin penetration by stimulating the
motor component of the nerve transcutaneously. The nerve stimulator output should be set at 2 to 5 mA at 1 to 2 Hz, whereas the
negative electrode is used as the mapping electrode. The current
required varies and depends on the depth of the nerve and the
moistness of the overlying skin. The point at which the maximal
motor response in the muscles supplied by that nerve is elicited is
marked and used as the landmark for that specific nerve block.
Direct muscle stimulation is finer and more localized and
should be recognized as a false-positive response. Excessive pressure applied over the nerve may inhibit the response. The nerve
mapping technique may be used for various approaches to the brachial plexus as well as the axillary, musculocutaneous, ulnar,
median, and radial nerve blocks of the upper limb. Surface nerve
mapping is particular useful where classic anatomic landmarks are
absent or difficult to define as in children with arthrogryposis or
major congenital limb defects.
REGIONAL ANESTHESIA
FOR THE UPPER LIMB
The motor and sensory innervation of the upper limb, with the
exception of part of the shoulder (innervated by the cervical
plexus) and the medial aspect of the upper arm (innervated by the
intercostobrachial nerve, a sensory branch of the second intercostal nerve), is provided by the brachial plexus.
Anatomy of the Brachial Plexus1416

The brachial plexus is a complex network of nerves that originate
as roots, unite to form trunks, divide into divisions, form cords,
and end distally in terminal branches. The anterior primary
(ventral) rami of C58 and the bulk of T1 form the brachial plexus.
These five roots emerge from the intervertebral foramina,
immediately posterior to the vertebral artery, to lie between the
scalenus anterior and the scalenus medius muscles (which attach
to the anterior and posterior tubercles of the transverse processes
of the cervical vertebrae, respectively) (Figure 471).
Figure 47-1. Schematic diagram of the brachial plexus. Different approaches block different levels of the brachial plexus resulting
in different distributions of cutaneous anesthesia.
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CHAPTER 47
The fascia from these muscles encloses the plexus in a sheath
that extends laterally into the axilla. The extent of this fascia is
controversial, but longitudinal and circumferential spread within
the loose connective tissue of the sheath is more predictable in
children. A single injection within this sheath produces more
complete plexus blockade by blocking the trunks (supraclavicular
approaches), divisions (posterior to the clavicle), or cords (infraclavicular approaches).
As the spinal roots pass between the scalenus muscles, they
unite to form three trunksupper (C56); middle (C7); and lower
(C8T1). Emerging from the interscalene groove, the three trunks
pass downward and laterally to lie posterolateral to the subclavian
artery as it crosses the upper surface of the first rib. By contrast to
adults, the subclavian artery is not easily palpable above the
clavicle in infants and preadolescent children.
At the lateral border of the first rib, each trunk divides into
anterior (flexor) and posterior (extensor) divisions, which then
join to form the three cords, named according to their relationship
to the second part of the axillary arterylateral, medial, and
posterior. These cords then divide into the terminal nerves of the
brachial plexusmusculocutaneous, ulnar, median, and radial.
Although this is the classic description, seven major configurations of the brachial plexus have been described with none
having more than 57% representation. Many variations have been
described1419 even within individuals in which 60% exhibit rightleft asymmetry.14 The relationship to the axillary artery is also
variable.16
Many anatomic landmarks used in adults may be difficult to
elicit in children of different ages, particularly if they are sedated
or under anesthesia.10 Muscular landmarks are less well defined
in infants. The interscalene groove is difficult to delineate because
the scalenus muscles are poorly developed. The plexus itself is
often palpable with the neck extended and rotated to the opposite
side. The external jugular overlies the interscalene groove at the
level of C6 but is not a reliable marker. The subclavian artery lies
medial to the plexus as it crosses to the first rib.
Other pertinent anatomy includes the phrenic nerve that
overlies the anterior scalene muscle. In view of its proximity to the
plexus, particularly in small children, the phrenic nerve can be
easily blocked by incorrect placement or use of excessive volumes
of the local anesthetic. The shoulder receives sensory innervation from the descending branches of the cervical plexus, and
the posterolateral aspect of the upper arm has input from the
intercostobrachial nerve, a branch of the second intercostal nerve.
Assessing the adequacy of the block or evaluating pre- or
postoperative neurologic fallout is clinically important. A quick
assessment of sensory and motor function can be performed
using the 4 Ps mnemonicpush against resistance by extending
the arm at the elbow (radial nerve), pull the forearm at the elbow
(musculocutaneous nerve); pinch response at the palmar base of
index finger (median nerve), and pinch at the palmar base of little
finger (ulnar nervve). When the arm is in a cast and only finger
movements are possible, the motor function can be evaluated by
assessing flexion of the thumb at the proximal interphalageal (PIP)
joint (median nerve), extension of the thumb at the PIP joint
(radial nerve), and crossing the fingers using the interosseous
muscles (ulnar nerve).
Approaches to the Brachial Plexus

Brachial plexus block may be used as a sole technique for
upper limb surgery, as an adjunct for upper limb surgery, for
Regional Anesthesia: Upper Limb Blocks 785
TABLE 47-1. Approaches to Brachial Plexus

Neck
Interscalene
Parascalene
Supraclavicular
Infraclavicular
Axillary
Perivascular approach
Transarterial approach
postoperative analgesia, or as a method of providing sympathetic block.3
The brachial plexus can be approached at various levels3,20
(Table 471). The choice of a particular technique is based on the
planned surgical procedure, the experience of the anesthesiologist,
the presence of contractures, and the potential benefits for the
patient, which include placing a catheter for continuous infusions.
The infraclavicular and the axillary approaches are considered
safer and easier for the placement and fixation of an indwelling
catheter for continuous peripheral nerve blocks. Although the
interscalene approach has been reported for shoulder surgery as
well as for elbow surgery in children,20 this approach should be
used with caution in children because of the increased risk of
pneumothorax, intravascular injection, intrathecal injection, or
temporary phrenic nerve palsy. The popularity of this block has
increased since the advent of ultrasound, allowing a more direct
approach with a lower risk of pneumothorax.
Axillary Approach to the Brachial Plexus

The axillary block is probably the most popular approach in
children.3,2025 It is relatively safe and provides good analgesia for
surgery of the forearm and hand that requires prolonged pain
relief. The primary advantages of axillary blockade include its ease
of placement and the low risk of complications. At this level, the
artery lies anterior to the radial nerve; posteromedial to the
median nerve, and posterolateral to the ulnar nerve, but significant
individual variation can occur16 (Figure 472).
The limitations of axillary block include incomplete blockade
of the shoulder and lateral aspect of the forearm onto the thenar
eminence (sensory distribution of the musculocutaneous nerve).
The axillary block has been used for a variety of procedures on
the forearm and hand. These include closed reduction of forearm
fractures22; lacerations particularly on the medial aspect of the
forearm; open reduction with internal fixation of the forearm
fractures; and repair of congenital hand anomalies (syndactyly).23
Axillary blocks can also be used to increase blood flow by decreasing the sympathetic tone in the presence of vascular insufficiency,25 finger re-implantation, and placement of peripherally
inserted central catheter (PICC) lines.26
AXILLARY PERIVASCULAR APPROACH24,27
Position: Supine, arm abducted 90 degrees, elbow flexed, hand

supinated or behind head.
Landmarks: Pectoralis major, coracobrachialis muscle, axillary
artery.
Aids: Surface nerve mapping, ultrasound, and nerve stimulator.
Dose: 0.2 to 0.3 mL/kg 0.25 to 0.5% bupivacaine, ropivacaine, or
levobupivacaine. Lower concentrations will reduce the degree
of motor block if required.
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Figure 47-2. Diagrammatic representation of the axillary approach to the brachial plexus with an ultrasound image. A: The axillary
artery (red) surrounded by the posterior medial and lateral cords (yellow) with the medial axillary vein (blue). B: The hyperechoic
humerus and distal shadow lie lateral to the artery and nerves. The musculocutaneous nerve lies in the groove between the coracobrachialis and the biceps muscles (see also Figure 475).
TECHNIQUE: Palpate the axillary artery and brachial plexus in the
tissues overlying the upper aspect of the humerus at the junction
of the lower border of pectoralis major and coracobrachialis
muscles or as high as possible in the axilla. An insulated needle
should be introduced immediately superior to the axillary arterial
pulsation at a 45 to 60-degree angle to the skin and directed
parallel to the artery24 or toward the midpoint of the clavicle with
the nerve stimulator set at 1 mA. Distal muscle twitches are usually
elicited in the median or radial nerve distribution (rarely in the
ulnar nerve) as the sheath is penetrated. The output of the nerve
stimulator should then be gradually reduced to approximately 0.3
to 0.4 mA whereas the muscle twitch is maintained, adjusting the
position of the needle as needed. Local anesthetic solution can
then be injected.
A nerve stimulator set at 3 to 5 mA can be used to map the
median nerve, radial, and/or musculocutaneous nerve transcutaneously in the axilla on either side of the arterial pulsation before
injection. An insulated needle should be inserted at the point of
maximum muscle twitch.
The musculocutaneous nerve branches proximally, placing it
outside of the sheath at the axillary level. It may need to be blocked
separately to provide reliable analgesia of the lateral forearm (lateral
cutaneous nerve of forearm). This can be done by advancing a
needle, introduced perpendicularly to the skin, just above the
axillary pulsation, into the coracobrachialis muscle until forearm
flexion is elicited, using a nerve stimulator. Inject 0.5 to 1 mL of
local anesthetic solution just deep to the fascia.
Alternatively, a larger volume of local anesthetic can be used
and, by applying distal pressure, the local anesthetic may be
directed proximally up the sheath in the hope of blocking the
musculocutaneous nerve before it branches.
ULTRASOUND GUIDANCE:
High-resolution images of all four

nerves and the axillary artery can be obtained using a highfrequency probe. Ultrasound-guided axillary blocks can be performed using either an in-plane (IP) or an out-of-plane (OOP)
technique. A small hockey-stick probe can reach into the apex of
the axilla even in small babies. A multiple-injection technique can
be used to block each echogenic nerve around the artery. The
echogenic musculocutaneous nerve is identified separately in the
groove between the coracobrachialis and the biceps muscles or
within the belly of the nonechogenic coracobrachialis muscle.
Multiple-injection techniques have been described in both adults

and children,21 but there is little advantage in children because the
loose fascial attachments allow even spread of a single injection3
and adequate blockade of the brachial plexus can be achieved. As
the local anesthetic solution fills the sheath, a longitudinal swelling
may become evident beneath the skin, which should disappear
quickly as the solution spreads proximally. Distal pressure may be
applied during and immediately after injection while the arm
should be adducted to release the pressure from the head of the
humerus from the fossa to facilitate proximal spread of solution and
blockade of the musculocutaneous nerve, especially in infants.
When long-term pain relief is mandated or relief of chronic
pain required, an appropriate catheter can be introduced into
the axilla for the continuous infusion of a local anesthetic (see
Methods for Prolonging Analgesia). Immobilization, fixation, and
dressing of these catheters are rather difficult in the axilla, but this
may be overcome by tunneling the catheter medially onto the
chest or laterally over the deltoid area. After the initial block dose,
an infusion rate of 0.2 to 0.4 mg/kg/h should be adequate.
Complications of axillary block are rare, but include hematoma
from accidental vascular puncture. If the artery is inadvertently
punctured, pressure should be applied for at least 5 minutes to
avoid possible vascular insufficiency caused by a compressive
hematoma.
Transarterial Approach
The transarterial approach, traditionally used in adults,2729 is not
recommended in children3 but is included for completeness.
Proponents of this approach claim greater success with posterior
cord (musculocutaneous) blockade. The reasons for avoiding the
transarterial approach in children include the fact that most soft
tissue surgery of the upper extremity (e.g., syndactyly, reimplants)
is vascular in nature and, hence, important to avoid vascular
compromise caused by vessel spasm or hematoma formation.
The risk of toxicity is also high in children, and small doses
may produce toxic effects. Detection of intravascular injection and
toxicity under general anesthesia is difficult but may be noted by
transient changes in the heart rate or electrocardiogram.30 These
include changes in the amplitude of T-waves or ST segments when
using a local anesthetic solution containing epinephrine (usually
1:200,000).
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CHAPTER 47
Figure 47-3. A: Diagrammatic representation of the infraclavicular approach with an ultrasound image. B: The cords (yellow) lie
lateral, posterior, and medial to the subclavian artery (red) below the pectoral muscles (pink) at this level. The pleura and lung (not
well depicted on this ultrasound) lie medially.
Infraclavicular Approach13,3133
Position: Supine, pillow under shoulders, head turned to opposite side, upper arm adducted alongside body, elbow flexed to
90 degrees with forearm resting on abdomen.
Landmarks: Clavicle lower border, coracoid process of scapula,
axillary artery as it emerges beneath clavicle.
Aids: Nerve stimulator, surface nerve mapping, ultrasound.
Dose: 0.2 to 0.3 mL/kg 0.5% bupivacaine, 0.5% ropivacaine, or
0.5%. levobupivacaine. Lower concentrations may reduce the
degree of motor block.
TECHNIQUE: Safety considerations have steered practitioners away

from the supraclavicular approach in order to reduce the risk of
pneumothorax. A number of infraclavicular approaches have been
described3133; most have the insertion point close to the coracoid
process. With the child correctly positioned, the clavicle is divided
into three parts (Figure 473). A mark should be made at the point
at which the arterial pulsation is felt as it emerges below the
clavicle or where any distal flexion or pronation is mapped with a
nerve stimulator.
An insulated needle should be inserted infraclavicularly at
the junction of the middle and lateral third of the clavicle and
directed toward this mark. The needle passes lateral to the cupola
of the lung and has little chance of encountering the lung along its
course. Pronation or flexion at the elbow should be sought. Once
the nerve is located, the voltage on the nerve stimulator should be
reduced to 0.2 to 0.3 mA.
Alternatively, the needle can be inserted at the midpoint of the
lower border of the clavicle at a 45- to 60-degree angle and directed
toward the axilla in a similar manner until distal muscle twitches
are elicited.
A vertical infraclavicular approach using the coracoid process
as a landmark has been described in children.31,33 The site of
puncture is 1 to 2 cm caudad and 0.5 to 1 cm lateral to the coracoid
process in the lower part of the deltopectoral groove. An insulated
needle should be inserted perpendicular to the skin until distal
muscle twitches are elicited. Location of the brachial plexus may
be difficult in some patients; an ultrasound-guided approach
has been recommended.13 Proponents of the infraclavicular approach claim more effective sensory and motor block than with
the axillary approach.13,33
ULTRASOUND GUIDANCE: High-resolution images of the infraclavicular brachial plexus can be obtained in young and thin
children using a high-frequency probe. The probe is placed inferomedially to the coracoid process to obtain a sagittal view of the
axillary artery and vein (see Figure 473). A needle is directed
through the pectoralis major and minor initially toward the
posterior cord situated posterior to the subclavian artery using an
IP technique. Care should be taken to avoid the easily compressible cephalic (superficial) and subclavian (deep) veins that may lie
in the path of advancing needle. If necessary, separate injections
can be made around the medial and lateral cords. The dome pleura
should be avoided.
pain required, an appropriate catheter can be introduced for the
continuous infusion of a local anesthetic solution. Immobilization
and fixation of these catheters to the anterior chest wall is easier
than in the axilla and tunneling is seldom required.
Supraclavicular, Parascalene,
or Interscalene Approach4,34
These approaches are well described in adults, but in small
children, they virtually merge into one because the needle insertion
points are close together. For this reason, they are grouped together
in one section.
Position: Supine, pillow under shoulders, arm extended along

side the body, and head turned to opposite side.
Landmarks: Clavicle midpoint, transverse process of C6 (Chassaignacs tubercle); posterior border of the sternocleidomastoid
muscle; cricoid cartilage; brachial plexus.
Aids: Surface nerve mapping, nerve stimulator, and ultrasound.
Dose: 0.2 to 0.3 mL/kg 0.5% bupivacaine, 0.5% ropivacaine, or
0.5% levobupivacaine. Lower concentrations may reduce the
degree of motor block.
Indications: This approach is required for surgery on the shoulder or on the arm proximal to the elbow.
TECHNIQUE: The supraclavicular approach is indicated for all

upper extremity surgery but particularly if the shoulder is
involved. With the patient correctly positioned, the components of
the brachial plexus become more superficial and are easily
palpable in most young children. The site of puncture should be
at the junction of the middle third and the lower third of a line
joining Chassaignacs tubercle to the midpoint of the clavicle34
(if Chassaignacs tubercle cannot be palpated extending a line
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from the cricoid cartilage to the posterior border of sternocleidomastoid should suffice). The external jugular vein is often
very close to this point. The needle should be inserted almost
perpendicular to the skin aimed slightly caudad to avoid puncturing the vertebral vessels.
Alternatively, an insulated needle can be inserted perpendicular
to the skin at the point at which maximal distal muscle twitches
(usually flexion or extension at the elbow) can be mapped or
simply over the point at which the brachial plexus can be palpated
subcutaneously with the patient in this position. Although the
reported incidence in children is low,34 the fear of pneumothorax
remains high among pediatric anesthesiologists.
ULTRASOUND GUIDANCE: High-resolution images of the brachial

plexus can be obtained using a high-frequency probe (>10 MHz)
given that the plexus is superficial. The probe is placed about 2 cm
above and parallel to the clavicle over the interscalene groove.
Alternatively, follow the flat nonechogenic sternocleidomastoid
muscle laterally. At the lateral border, three nonechogenic roots
(snowman) can be seen between the scalene muscles (Figure
474). Once these roots are visualized, the needle can be advanced
(from lateral to medial direction) using an IP technique to enable
visualization of the entire length of the needle. Ideally, the local
anesthetic should be injected around the deepest nerve root
first. The remainder can be injected as the needle is withdrawn,
blocking the other roots. In this way, the anatomy of the deeper
structures are less distorted after injection. The OOP technique

has its advocates but the needle tip is more difficult to visualize.
Success rate is high,34 but complications caused by faulty technique include pneumothorax, vascular puncture, Horners syndrome, and hemidiaphragmatic paralysis from phrenic nerve
blockade.20 Nerve damage is possible with injudicious injection
against resistance, but the possibility of surgical damage should
always be excluded after shoulder surgery.
pain required, an appropriate catheter can be introduced for
the continuous infusion of a local anesthetic solution.35 Immobilization and fixation of the catheter can be achieved by tunneling
subcutaneously onto the chest or shoulder where appropriate.
Blocks at the Elbow

A single nerve or combination of nerves can be blocked at the
elbow to provide distal analgesia. These are particularly useful
for postoperative pain relief after surgical procedures of the
forearm or the hand without the risks associated with brachial plexus blocks. Four nervesthe median, radial, ulnar, and
musculocutaneouscan be located at the elbow. These can be
done by surface nerve mapping, using a nerve stimulator capable
of generating about 5 mA, as described previously. Once the
surface landmark has been mapped, the nerve can be blocked
Figure 47-4. A: Diagrammatic representation of an interscalene approach

to the brachial plexus with an ultrasound image. B: The roots or trunks
(yellow) lie between the scalenus anterior and the scalenus medius at this
level. The prominent internal jugular (blue) lies medially.
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using ultrasound or a nerve stimulator and a sheathed needle.
In this way, multiple punctures can be avoided, reducing the
potential risk of nerve injury.
ULTRASOUND GUIDANCE: High-resolution images of the

echogenic median and radial nerves can be obtained using a highfrequency probe (>10 MHz). The median nerve lies just medial to
the brachial artery and can be traced down the middle of the
forearm. The radial nerve lies adjacent to the anterolateral aspect
of the humerus just above the elbow and can traced down the
lateral aspect of the forearm. Blocks can be performed using either
an IP or an OOP technique.
Position: Supine, arm extended, elbow slightly flexed to accentuate the tendons of the biceps and the brachioradialis.
Landmarks: Cubital fossa, brachial artery, biceps tendon.
Dose: 0.1 to 0.2 mL/kg 0.25 to 0.5% bupivacaine, ropivacaine, or
levobupivacaine.
Anatomy: The median nerve in the cubital fossa is located medial to the brachial artery and the biceps tendon, beneath the
deep fascia.
Indication: Surgery on the volar aspect of the forearm and the
palmar portion of the hand.
TECHNIQUE: Using ultrasound guidance or after surface mapping

the median nerve, an insulated needle should be inserted medial to
the pulsation of the brachial artery. Pronation of the arm with opposition of the fingers is noted when the median nerve is stimulated.
Potential complications include hematoma, paresthesias, and
intravascular injection.
TECHNIQUE: The lateral condyle of the humerus and the tendon

of the biceps muscle should be identified. The radial nerve lies
adjacent to the condyle, lateral to the biceps tendon. With the arm
slightly flexed at the elbow, the radial nerve can be stimulated
with a mapping probe in this position. Movement of the thumb
confirms the location of the radial nerve and a small volume of
local anesthetic can be injected at that point.
Musculocutaneous Nerve
Median Nerve
Position: Arm extended or arm on abdomen.

Landmarks: Lateral condyle of humerus.
Dose: 1 to 2 mL 0.25 to 0.5% bupivacaine, ropivacaine, or
levobupivacaine.
TECHNIQUE: The musculocutaneous nerve courses superficially

along the lateral aspect of the forearm and can be easily blocked
in this location. A superficial ring of local anesthetic solution
(0.1 mL/kg) injected at the distal end of the lateral condyle of the
humerus along the pronator teres muscle should block the musculocutaneous nerve. The nerve can be mapped along most of its
course or traced with ultrasound.
Wrist Blocks
Analgesia for children undergoing minor surgical procedures
of the hand or fingers can be provided by an appropriate nerve
block at the wrist. The nerves that can be blocked at this level are
the median, ulnar, and radial. Small volumes of local anesthetic
(0.52 mL) can provide analgesia for a number of hours.
Median Nerve
Ulnar Nerve
Position: Supine, elbow flexed 90 degrees, arm on chest with

hand on opposite shoulder.
Landmarks: Olecranon groove.
Dose: 1 to 2 mL 0.25 to 0.5% bupivacaine, ropivacaine, or levobupivacaine.
Anatomy: The ulnar nerve lies in the groove posterior to the
medial condyle of the humerus midway between the olecranon
and the medial epicondyle.
Indications: For surgery in the ulnar distribution of the hand
including the medial aspect of the hand and fingers.
TECHNIQUE: The ulnar nerve can be easily blocked at the olecranon groove or more distally using ultrasound guidance or nerve
mapping. A small volume of 0.25% bupivacaine with 1:200,000
epinephrine should be used to avoid nerve compression, particularly if the local anesthetic is injected into the olecranon groove.
COMPLICATIONS: Nerve injury, compression of the nerve if

excessive volumes of local anesthesia are used.
Radial Nerve
Position: Supine, elbow slightly flexed.

Landmarks: Biceps tendon, lateral condyle of humerus.
Dose: 1 to 2 mL 0.25 to 0.5% bupivacaine, ropivacaine, or
levobupivacaine.
Position: Hand pronated.

Landmarks: Palmaris longus tendon, volar aspect of the wrist.
Aids: Surface nerve mapping, ultrasound, 25-g needle.
Dose: 0.5 to 1 mL 0.25 to 0.5% bupivacaine, ropivacaine, or
levobupivacaine.
The median nerve is the major sensory nerve of the hand, and
therefore, most surgical procedures of the hand will require at least
a median nerve block.
ANATOMY: The median nerve is located in a fascial sheath

between the palmaris longus tendon and the flexor carpii radialis.
Surface nerve mapping at this point will elicit opposition of the
thumb. The median nerve can be traced down from the middle
of the forearm using a high-frequency ultrasound probe. In this
way, the echogenic nerve can be differentiated from the tendons
at the wrist. A bursa that communicates with the neurovascular bundle is located at the ulnar aspect of the palmaris longus
tendon. A block of the median nerve can be achieved by injecting
into this bursa.
COMPLICATIONS: Rare; carpal tunnel syndrome or injury to the
median nerve can be avoided by using this technique or restricting
the volume of local anesthetic used.
Radial Nerve
Position: Hand supinated.

Landmarks: Anatomic snuffbox, styloid process radius, radial
artery.
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Dose: 1 to 2 mL 0.25 to 0.5% bupivacaine, ropivacaine, or levobupivacaine.
The radial nerve at the wrist is purely sensory and, thus, nerve
mapping is not possible in anesthetized children. The radial nerve
can be visualized using a high-frequency ultrasound probe.
Just above the styloid process, the radial nerve divides into two
branches, one supplying the dorsum of the hand and another
supplying the thenar eminence and 1.5 fingers.
TECHNIQUE: The nerve is superficial and proximal to the

anatomic snuffbox. A wheal of local anesthetic solution should be
injected subcutaneously starting lateral to the radial artery on the
lateral aspect of the wrist using a fine (25- to 27-g) needle.
Ulnar Nerve
Position: Hand supinated.

Landmarks: Flexor carpi ulnaris tendon, ulnar artery.
Aids: Surface nerve mapping, nerve stimulator.
Dose: 1 to 2 mlL 0.25 to 0.5% bupivacaine, ropivacaine, or
levobupivacaine.
The ulnar nerve is located in the palmar sheath immediately

lateral to the flexor carpii ulnaris tendon but medial to the ulnar
artery. Surface nerve mapping at this point will elicit flexion of the
little finger. The ulnar nerve can be visualized using a highfrequency ultrasound probe medial to the artery. Using a fine
needle, 1 to 2 mL of local anesthetic can be injected into the area
to provide analgesia for surgery on the ulnar aspect of the hand
and the medial 1.5 fingers.
METHODS FOR
PROLONGING ANALGESIA
Continuous Peripheral Nerve Blocks
Continuous peripheral nerve catheters have not been readily
available for use in children until relatively recently. Previously,
continuous peripheral neural blockade required improvisation.3
A variety of methods, some of which subsequently formed the
basis for the development of the modern designer catheters, were
used. As the appropriate equipment has become available, an
increasing number of reports of their use for continuous postoperative pain management or therapeutic care have been described.32,3543 Continuous peripheral nerve blocks have been
shown to decrease resting and dynamic pain and reduce opiate
requirements, side effects, and sleep disturbance after surgery
(Figures 475 and 476).
The main indications are for procedures are associated with
significant or prolonged postoperative pain, to improve peripheral
perfusion after microvascular surgery or in vasospastic disorders
involving the limbs, or for children who have significant painful
conditions.36 Patient-controlled analgesia is also feasible in selected
cases when children understand the concept.
Ideally, a commercially available kit should be used, because
these allow the use of a nerve stimulator to identify the nerve before
placement of the catheter. Several manufacturers now provide
insulated Tuohy needles of childfriendly length through which
a catheter can be passed. The role of stimulating versus nonstimulating catheters for continuous peripheral nerve blocks is the
subject of ongoing research.
Figure 47-5. Continuous nerve blocks. Specially designed

catheters can be introduced into the axillary sheath to provide
prolonged analgesia for complex surgery (division of syndactyly,
radial club hand) or chronic pain syndromes.
Alternatively, one could improvise with a modification of the
Seldinger technique whereby the nerve to be blocked is stimulated
via a guidewire passed through either a needle or an intravenous
cannula. Once maximal twitch has been obtained, the needle
can be removed and a catheter threaded over the wire or through
the cannula. These improvised methods are not conducive to
accurate catheter placement, and radiographic confirmation may
be required.
Continuous infusions have also been used to provide analgesia
and to allow physical therapy in chronic regional pain syndromes.
Blood levels reached during continuous brachial plexus infusions
are less than those reached during continuous epidural analgesia.
The dosage recommended for continuous infusions, after
an initial bolus dose, is 0.1 to 0.2 mL/kg/h of either ropivacaine
(0.150.2%) or bupivacaine (0.1250.25%). The lower rates are
Figure 47-6. Continuous axillary nerve blocks. Securing an axillary catheter can be challenging in a mobile arm. Subcutaneous
tunneling (not shown) is an option. The catheter should be
labeled to avoid drug errors.
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generally needed for upper extremity catheters. The infusion rate
may be adjusted as needed up to a maximum recommended
infusion rate of 0.2 mg/kg/h for infants younger than 6 months
and 0.4 mg/kg/h in children older than 6 months.40 Disposable
elastomeric infusion pumps, which may be programmed to deliver
local anesthetic based on a childs weight, are currently available
and may offer an option for outpatient pain control in the future.41
Various types of infusion pumps are available. Electronic pumps
generally provide accurate consistent flow during infusions. Conversely, elastomeric infusions and spring-loaded pumps tend to
provide higher than expected rates initially and vary as the reservoir is exhausted. To date, few complications have been reported
but include catheter-induced infection, particularly in immunocompromised patients, hematoma formation, catheter breakage, or
knot formation on removal. Securing the catheter is important43
because the arm and shoulder are difficult to immobilize and many
of these patients are ambulatory. The skin exit site should be sealed
with Dermabond (Ethicon, Somerville, NJ) and the catheter looped
and secured with an occlusive transparent adhesive dressing.
Additives and Adjuvants

Additives are used to prolong the duration of analgesia and to
improve the safety of the peripheral nerve block by reducing the
dose of local anesthetic required. By reducing the concentration,
some of the unwanted side effects such as motor blockade can
be eliminated.
A variety of agents have been studied in adults and include
opiates (morphine, fentanyl, sufentanil), ketamine, neostigmine,
ketorolac, hyaluronidase, and clonidine. One of the attractions
of regional anesthesia is the low incidence of nausea and vomiting,
but this advantage is lost with some additives without any convincing evidence that they enhance analgesia in the acute pain
setting.
Clonidine (0.51 g/kg) may have a peripherally mediated
effect. It seems to be effective in prolonging the analgesia of the
shorter-acting agents (e.g., mepivacaine) after single shot peripheral nerve blocks but is less effective when used with bupivacaine
or ropivacaine. Research in this area is ongoing because the clinical
efficacy of peripheral clonidine remains unresolved. Studies in
children are limited.44
CONCLUSION
There are a variety of reasons why regional anesthesia, particularly peripheral nerve blockade, is advantageous for children
who present for either elective or emergency orthopedic surgery.
Regional anesthesia provides good pain relief without the need for
additional analgesia both in healthy children and in those with
compromised respiratory function or even increased sensitivity to
opiates (muscle disorders, mucopolysaccharidoses, cerebral palsy,
kyphoscoliosis). The reduction of other unwanted side effects such
as nausea and vomiting can aid fast tracking of day stay patients
while improving the quality of care of hospitalized patients.
As better techniques are developed, the utilization of peripheral
nerve blocks in children should gradually increase. Surface nerve
mapping and, more recently, portable ultrasonography are promising developments. These should encourage both the skilled
practitioner to improve his or her success rate and the inexperienced practitioner to develop new skills.
Further development of continuous peripheral nerve blocks

will enhance patient comfort for longer in the postoperative
period. Their use in children has to date has been confined to
special circumstances. It is too early to judge the risk-benefit ratio
but it seems likely that they will find a place, particularly in
children with associated diseases.
REFERENCES
1. Suresh S, Wheeler M: Practical pediatric regional anesthesia. Anesthesiol
Clin North Am. 2002;20:83113.
2. Ross AK, Eck JB, Tobias JD. Pediatric regional anesthesia: beyond the
caudal. Anesth Analg. 2000;91:16.
3. Brown TCK, Eyres RL, McDougall RJ. Local and regional anesthesia.
Br J Anaesth. 1999 83:6577.
4. Ganesh A, Wells L, Ganley T, et al. Interscalene brachial plexus block for
postoperative analgesia following shoulder arthroscopy in children and
adolescents. Acta Anaesthesiol Scand. 2008;52:162163.
5. Ponde VC. Continuous infraclavicular brachial plexus block: a modified
technique to better secure catheter position in infants and children.
Anesth Analg. 2008;106:9496.
6. Giaufre E, Dalens B, Gombert A. Epidemiology and morbidity of regional
anesthesia in children: a one-year prospective survey of the Frenchlanguage Society of Pediatric Anesthesiologists. Anesth Analg. 1996;83:
904912.
7. Bsenberg AT. Lower limb blocks in children using unsheathed needles
and a nerve stimulator. Anaesthesia. 1995;50:206210.
8. Hadzic A. Peripheral nerve stimulators: cracking the codeone at a time.
Reg Anesth Pain Med. 2004; 29:185188.
9. Pande R, Pande M, Bhadani U, et al. Supraclavicular brachial plexus block
as a sole anaesthetic technique in children: an analysis of 200 cases.
Anaesthesia. 2000; 55: 798810.
10. Bosenberg AT, Raw R, Boezaart AP. Surface mapping of peripheral nerves
in children with a nerve stimulator. Paediatr Anaesth. 2002;12: 398403.
11. Chan V. Advances in regional anaesthesia and pain management. Can J
Anaesth. 1998;45:R49R63.
12. Marhofer P, Greher M, Kapral S. Ultrasound guidance in regional
13. Marhofer P, Sitzwohl C, Greher M, et al. Ultrasound guidance for infraclavicular brachial plexus anaesthesia in children. Anaesthesia. 2004;59:
642646.
14. Neal JM, Gerancher JC, Hebl JR, et al. Upper extremity regional anesthesia. Essentials of our current understanding 2008. Reg Anesth Pain
Med. 2009;34:134170.
15. McCann PD, Bindelglass DF. The brachial plexus: clinical anatomy.
Orthop Rev. 1991;20:413419.
16. Retzl G, Kapral S, Greher M, et al. Ultrasonographic findings in the
axillary part of the brachial plexus. Anesth Analg. 2001;92:12711275.
17. Kerr AT. The brachial plexus of nerves in man, the variations in its
formation and branches. Am J Anat. 1918;23:285395.
18. Harry WG, Bennet JDC, Guha SC. Scalene muscles and the brachial
plexus: anatomical variations and their clinical significance. Clin Anat.
1997;10:250252.
19. Natsis K, Totlis T, Tsikaras P, et al. Variations of the course of the upper
trunk of the brachial plexus and their clinical significance for the thoracic
outlet syndrome: a study on 93 cadavers. Am Surg. 2006;72:188192.
20. Tobias JD. Brachial plexus anaesthesia in children. Paediatr Anaesth.
2001;11:265.
21. Carre P, Joly A, Field BC, et al. Axillary block in children: single or
multiple injection? Paediatr Anaesth. 2000;10:3539.
22. Cramer KE, Glasson S, Mencio G, et al. Reduction of forearm fractures
in children using axillary block anesthesia. J Orthop Trauma. 1995;9:
407410.
23. Altintas F, Bozkurt P, Ipek N, et al. The efficacy of pre- versus postsurgical
axillary block on postoperative pain in paediatric patients. Paediatr
Anaesth. 2000;10:2328.
24. Fisher WJ, Bingham RM, Hall R. Axillary brachial plexus blocks for
perioperative analgesia in 250 children. Paediatr Anaesth. 1999;9:435438.
25. Breschan C, Kraschl R, Jost R, et al. Axillary brachial plexus block for
treatment of severe forearm ischemia after arterial cannulation in an
extremely low birth-weight infant. Paediatr Anaesth. 2004;14:681684.
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26. Messeri A, Calamandrei M. Percutaneous central venous catheterization

in small infants: axillary block can facilitate the insertion rate. Paediatr
Anaesth. 2000;10:527530.
27. Pere P, Pitkanen M, Tuominen M, et al: Clinical and radiological
comparison of perivascular and transarterial techniques of axillary
brachial plexus block. Br J Anaesth. 1993;70:276279.
28. Aantaa R, Kirvela O, Lahdenpera A, et al. Transarterial brachial plexus
anesthesia for hand surgery: a retrospective analysis of 346 cases. J Clin
Anesth. 1994;6:189192.
29. Hepp M, King R: Transarterial technique is significantly slower than the
peripheral nerve stimulator technique in achieving successful block. Reg
Anesth Pain Med. 2000;25:660661.
30. Freid EB, Bailey AG, Valley RD. Electrocardiographic and hemodynamic changes associated with unintentional intravascular injection of
bupivacaine with epinephrine in infants. Anesthesiology. 1993;79:394398.
31. Kilka HG, Geiger P, Mehrkens HH: Infraclavicular vertical brachial plexus
blockade. A new method for anesthesia of the upper extremity. An
anatomical and clinical study. Anaesthesist. 1995;44:339344.
32. Dadure C, Raux O, Troncin R, et al. Continuous infraclavicular brachial
plexus block for acute pain management in children. Anesth Analg. 2003;
97:691693.
33. Fleischman E, Marhofer P, Greher M, et al. Brachial plexus anaesthesia
in children: lateral infraclavicular vs axillary approach. Paediatr Anaesth.
2003;13:103108.
34. Dalens B, Vanneuville G, Tanguy A. A new parascalene approach to the
brachial plexus in children: comparison with the supraclavicular
approach. Anesth Analg. 1987;66:12641271.
35. Lehtipalo S, Koskinen LO, Johansson G, et al: Continuous interscalene
brachial plexus block for postoperative analgesia following shoulder
36. Diwan R, Lakshmi V, Shah T, et al. Continuous axillary block for upper
limb surgery in a patient with epidermolysis bullosa simplex. Paediatr
Anaesth. 2001;11:603606.
37. Klein SM, Grant SA, Greengrass RA, et al.: Interscalene brachial plexus
block with a continuous catheter insertion system and a disposable
infusion pump. Anesth Analg. 2000;91:14731478.
38. Theroux MC, Dixit D, Brislin R, et al. Axillary catheter for brachial plexus
analgesia in children for postoperative pain control and rigorous
physiotherapya simple and effective procedure. Paediatr Anaesth. 2007;
17:302303.
39. Ganesh A, Rose JB, Wells L, et al. Continuous peripheral nerve blockade
for inpatient and outpatient postoperative analgesia in children. Anesth
Analg. 2007;105:12341242.
40. Berde CB. Toxicity of local anesthetics in infants and children. J Pediatr.
1993;122:S14S20.
41. Dadure C, Pirat P, Raux O, et al. Perioperative continuous peripheral
nerve blocks with disposable infusion pumps in children: a prospective
descriptive study. Anesth Analg. 2003;97:687690.
42. Dadure C, Bringuier S, Raux O, et al. Continuous peripheral nerve
blocks for postoperative analgesia in children: feasibility and side
effects in a cohort study of 339 catheters. Can J Anaesth. 2009;56:
843850.
43. Ponde VC. Continuous infraclavicular brachial plexus block: a modified
technique to better secure catheter position in infants and children.
Anesth Analg. 2008;106:9496.
44. Ivani G, Conio A, De Negri P, et al. Spinal versus peripheral effects of
adjunct clonidine: comparison of the analgesic effect of a ropivacaineclonidine mixture when administered as a caudal or ilioinguinaliliohypogastric nerve blockade for inguinal surgery in children. Paediatr
Anaesth. 2002;12:680684.
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Lower Limb Blocks
48
Giorgio Ivani and Valeria Mossetti
INTRODUCTION
Regional anesthesia has gained worldwide acceptance in the new
millennium. Many factors have contributed to the widespread use
of regional anesthesia in children: the awareness of pain and the
need of adequate pain relief at any age, from premature babies
to adolescents13; the efficacy of regional anesthesia in the stress
control4,5; and the volume of publications on this topic.
Safety and efficacy have been demonstrated in large retrospective and prospective surveys showing that pediatric regional
anesthesia has a low rate of complications and no major sequelae
or deaths.68 In combination with sedation/light general anesthesia, a regional block offers optimal pain control throughout
surgery and excellent postoperative analgesia.
Basically, whenever appropriate, a peripheral nerve block
is preferable to a neuraxial block because of the lower risk involved.68 Peripheral nerve blocks are in fact safer, simpler, easier
to perform, and effective.9,10 Peripheral nerve blocks in children
remain underutilized. The key to success is a proper knowledge
of developmental anatomy, pharmacology, the equipment used
for regional anesthesia, and effective use of preprocedure sedation
and analgesia.11,12 This should go a long way to prevent an inadequate or failed block. Serious side effects are very rare. Nerve
damage depends in part on the size and type of the needle used
and the pressure generated during the injection of the local anesthetic. Pressures exceeding 20 psi have been associated with nerve
damage in an animal model, and intraneural injection associated
with a low pressure causes transitory damage.13
Nerve fibers in young children are small and myelination is
incomplete; therefore, the local anesthetic concentration necessary
to perform a nerve block can be reduced. In so doing, the risk of
systemic toxicity is lowered14,15 but may still occur after inadvertent
intravascular or intraosseous injection or an overdose. In children,
in fact, a large amount of local anesthetic remains unmetabolized
and active in young children in comparison with adults. Neonates
and infants up to 6 months have half the plasma cholinesterase
activity, reduced hepatic blood flow, and immature degradation
pathways. Moreover, neonates and infants are at greater risk of
toxic effects owing to lower levels of albumin and 1 acid glycoprotein resulting in a higher free fraction of local anesthetic.
To reduce the risk of toxicity, the use of S() enantiomers, ropivacaine and levobupivacaine, is preferred. The main pharmacologic aspects, in comparison with the racemic mixture, are the
minor cardiovascular and nervous affinity and toxicity and a
differential neural blockade with less motor than sensory block.1618
Adjuvants such as clonidine are used to prolong the duration of
the block. Clonidine, an 2 agonist, acts by stimulating descending
C H A P T E R
noradrenergic medullospinal pathways that inhibit the release of

nociceptive neurotransmitters in the dorsal horn of the spinal
cord. The addition of clonidine (12 g/kg) can improve the analgesic effect of local anesthetics for single-shot blockade as well as
prolong its duration of action without the unwanted side effects of
opioids. Higher doses of clonidine have been associated with
sedation and hemodynamic instability in the form of hypotension
and bradycardia.19,20
Nerve stimulators are useful adjuncts to regional anesthesia.
Localization of a plexus or a nerve trunk should not be performed
by seeking paresthesia with standard needles because of a danger
of direct nerve damage. Only short-beveled insulated needles
connected to a nerve stimulator are suitable. For most peripheral nerve blocks in children, 21- to 23-gauge, 35- to 50-mm-long
needles are used, depending on the type of block and the age of
the child.
New techniques have been developed, adding safety to our
work. In 2002, Bsenberg and coworkers described the surface
mapping of nerves, a simple but very effective method to improve
experience in reducing mistakes during the performance of a
peripheral block.21 In that same year, Urmey and Grossi described
the same technique in adults using a needle-through device that
further improved the accuracy.22,23 New devices such as the penlike
stimulator instead of the negative electrode have been developed to
allow easier mapping. All these techniques are blind and, even in
experienced hands, the risk of damaging a nerve is real. Ultrasound
guidance has been a major step forward in this regard. Ultrasound
is used extensively in many fields (e.g., cardiac, obstetrics, detecting
vessels) but can also be employed to find the nerves.24,25 This technology requires training and skill for its successful implementation.
Currently, relatively few practitioners are adequately skilled and
comfortable with the use of ultrasound in children for peripheral
nerve blockade. Few studies have been published on ultrasound
in children, but the results are very impressive.2640 The use of
ultrasound, in fact, has added much information with regard to the
landmarks for performing a block showing, for instance, the short
distance from skin to nerve and from nerve to peritoneum in case
of the ilioinguinal-iliohypogastric block or the paraumbilical block.
LOWER LIMB BLOCKS

The lower limb is innervated by the lumbar plexus that gives
origin to the femoral, ilioinguinal, iliohypogastric, obturator, and
lateral femoral cutaneous nerves and by the sciatic nerve that
originates from the sacral plexus and terminates in the lower third
of the thigh where it divides into the posterior tibial and peroneal
nerves. In this section, the main blocks of the lower limb for
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pediatric patients are considered. These include the femoral nerve

block, the fascia iliac compartment block, the saphenous nerve
block, and multiple approaches to the sciatic nerve block.
Femoral Nerve Block

The femoral nerve block is considered an elementary block, very
easy to learn, with a low risk of complications but with important
implications in surgery and pain treatment. This block is useful
for surgery of the anterior aspect of the thigh (including muscle
biopsy), the knee, and for pain management after surgery on the
femur (femoral fractures). When combined with the sciatic nerve
block, it provides complete anesthesia of the lower limb from the
midthigh to the foot. The success rate of this block is extremely
high, about 95%, without any particular complication.4143
Indications
Surgery of the anterior and medial aspect of the thigh and knee.
This block can be used as a single-shot technique or continuous
infusion.
Anatomy
The femoral nerve is the major branch of the lumbar plexus and
takes origin from roots LII, LIII, and LIV. It runs between the
fibers of the psoas muscle, emerges from the inferior edge and,
crossing the inguinal ligament, enters the thigh, where it becomes
more flat. In the groin, the femoral nerve is covered by the iliac
fascia that divides the nerve from the vascular structures. At this
level, the nerve is located immediately lateral and slightly deeper
to the femoral artery in most cases. The femoral nerve gives
branches for the iliac and pectineus muscles and for the muscles
of the anterior aspect of the thigh, cutaneous branches for the
anterior and inner aspect of the thigh, leg and foot (saphenous
nerve), and articular branches for hip and knee. The femoral nerve
block provides anesthesia for the anterior aspect of the thigh and
the majority of the hip and knee joints. It also provides anesthesia
for the skin on the medial aspect of the leg beneath the knee
(saphenous nerve).
the best twitch for this block is the contraction of the quadriceps
femoris muscle with the phenomenon described as the dancing
patella. Mark with the pen the point at which the best contraction
is elicited with the least amount of current.
The nerve stimulator is now set at a current of 1 mA. Insert the
needle at the marked point and advance it vertically until the
motor response is again elicited. Adjust the position of the needle
until the appropriate muscle response can be maintained with a
current of 0.4 mA or less (Figure 481).
A frequent response occurs when the contraction of the
sartorius muscle (a bandlike contraction through the thigh) is
frequently elicited. This contraction is not appropriate because the
branches to the sartorius muscle lie outside the femoral nerve
sheath and the block will be unsuccessful. In this case, the needle
has to be redirected laterally.
If no contractions are obtained, withdraw the needle to the
skin, and without moving the palpating hand, reintroduce the
needle with a lateral inclination. After a negative aspiration,
the local anesthetic solution should be injected very slowly and
incrementally.
DOSAGES: Ropivacaine 0.2% 0.5 mL/kg for children up to 7 years;

or levobupivacaine 0.5% for older children. Clonidine 2 g/kg can
be used as an adjuvant.
Continuous Technique
The continuous femoral nerve block is similar to the technique
described for the single-shot block. Only the direction of the
needle, which is inserted at an acute angle, is changed to allow the
passage of the catheter. The most common indications for this
technique in pediatric patients are surgery of the knee and femoral
fractures.44,45
MATERIALS: A 20-gauge, 33-mm-long, short-beveled (15-degree)

introducer needle with a plastic canola and a 24-gauge, 400-mmlong catheter.
Patient Position
The patient lies supine with the thigh slightly abducted.
Single-shot Technique
MATERIALS: A 23-gauge, 25- or 50-mm (depending on the age of
patient), insulated short-beveled needle.
ANATOMIC LANDMARKS: The anatomic landmarks for the
femoral nerve block are easy to find in any patient and include the
inguinal ligament and the femoral artery.
TECHNIQUE: The anesthesiologist is positioned lateral to the

patient with a hand palpating the pulsation of the femoral artery.
It is recommended that the path of the artery is marked with a
dermographic pen.
Initially, the nerve can be mapped by placing the pen vertically
on the skin at about 0.5 to 1 cm lateral to and inferior to the artery.
The nerve stimulator is set at a frequency of 2 Hz and a current of
2.5 mA. The femoral nerve innervates different muscular groups;
Figure 48-1. Anatomic landmarks: inguinal ligament and

femoral artery. The needle is almost vertical at about 0.5 cm
lateral to the pulse of the artery.
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Regional Anesthesia: Lower Limb Blocks 795
Figure 48-2. The needle is inserted with an acute angle at about

1 to 2 cm lateral to the femoral artery and the inguinal ligament.
TECHNIQUE: For the continuous femoral nerve block, the

anatomic landmarks are again the femoral artery and the inguinal
ligament. With the patient in a supine position, palpate the pulsing
of the femoral artery with one hand placing the middle finger on
the pulse, while the other fingers pull down on the skin to prevent
creasing the skin at the needle insertion site. The block needle
is inserted at an angle of 30 degrees to the skin in a cephalad
direction, 1 to 2 cm both distal to the inguinal ligament and lateral
to the femoral artery (Figure 482). The needle is advanced until
twitches of the quadriceps muscle are obtained at a current of
0.5 mA and the local anesthetic solution is slowly injected after a
negative aspiration test. The needle is then withdrawn and the
catheter is inserted through the plastic cannula, 2 to 3 cm beyond
the cannula tip. The catheter is fixed to the skin with a transparent
adhesive dressing.
DOSAGES: Ropivacaine 0.1% for children until 7 years old,
levobupivacaine 0.125 to 0.25% for older children. A bolus volume
0.5 mL/kg, for continuous infusion: 0.3 mL/kg/h. Clonidine
3 g/kg/h can also be used as an adjuvant.
Complications
The complications of the femoral nerve block are quite rare:
Figure 48-3. The linear ultrasound probe is positioned along

the inguinal crease on a transverse plane.
it along the inguinal crease on a transverse plane to obtain a
perpendicular scan of the nerve (Figure 483).
The femoral artery is easily visualized (anechoic and pulsing)
and the femoral vein (anechoic, compressible, and nonpulsing)
is medial. Immediately lateral to the artery, the femoral nerve
has a triangular hyperechoic appearance (Figure 484). The
authors prefer to use the in-plane technique to approach the
nerve because, in this way, it is possible to see the entire needle
as a linear hyperechoic structure. Insert a 50-mm insulated
needle parallel to the probe in a lateral to medial way in the
same plane of the probe until the tip of the needle reaches
the nerve (Figure 485). Confirmation of the position of the
needle in close proximity to the nerve can be made using the nerve
stimulator.
Once satisfied with the needle placement, inject local anesthetic. By adjusting the needle position, attempt to surround the
nerve with local anesthetic so that a hypoechoic ring of local anesthetic solution is visible around the hyperechoic nerve structure
(see Video 481).
Infection in the injection area. Always use a sterile technique. In

this area, it is difficult to keep a catheter sterile, therefore, it is
better to remove it after 48 hours.
Hematoma. When the femoral vessels are accidentally punctured, suspend the procedure and compress the femoral artery
for approximately 2 to 3 minutes before proceeding with the
block in a lateral site.
Intravascular injection. Carefully aspirating prior to injection
and injecting graduated doses can prevent this.
Nerve injury. Always use nerve stimulation and a slow
introduction of the needle while searching for the nerve. More
recently, the use of injection pressure monitoring has been suggested to provide additional information in preventing intraneural injections.
Ultrasound Technique
The femoral nerve block under ultrasound scanning is one of the
easiest to perform. The anatomic landmarks and the patient
position are exactly the same as for the classic technique. Use a
linear high-frequency (1012 MHz) ultrasound probe and place
Figure 48-4. Sonoanatomy of the inguinal area. FA = femoral

artery; FN = femoral nerve; FV = femoral vein.
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Figure 48-5. The needle is inserted with the in-plane approach in a lateral to medial direction.
Fascia Iliaca Compartment Block

The fascia iliaca compartment block, or 3-in-1 block, is popular
in pediatric anesthesia. It consists of a single injection of local
anesthetic made just beneath the fascial layer covering the psoas
muscle (i.e. the fascia iliaca). In this way, it is possible to block all
the terminal nerves of the lumbar plexus as they emerge from the
psoas muscle. The femoral nerve can be blocked in the 100% of
cases, and the lateral femoral cutaneous and the obturator nerves
in about the 70 to 90% of cases.46
Indications
This block provides anesthesia and postoperative analgesia
for surgery involving the thigh, the medial aspect of the leg, the
periosteum of the femur, and the knee. It can be used as a singleshot technique or a continuous infusion.
Patient Position
The patient lies supine with the thigh slightly abducted.
Figure 48-6. Anatomic landmarks. A line representing the inguinal ligament (anterior superior iliac spine to pubic tubercle)
is divided into three parts and the femoral artery (FA). Point of
insertion is 0.5 to 1 cm below the junction of the lateral third
and the medial two thirds of this line.
for older children. Clonidine 2 g/kg can be administered as
an adjuvant.
Continuous Technique
stimulating needle with a plastic cannula and a 24-gauge,
400-mm-long catheter.
TECHNIQUE: The continuous fascia iliaca compartment block
technique is almost similar to that for the single-shot block. The
site of puncture is exactly the same, but the needle is inserted at an
angle of 40 degrees to the skin to facilitate passage of the catheter.
The loss-of-resistance technique can be used with the stimulating
needle or the needle can be advanced until two pops (passage
through the fascia lata and iliaca) are felt. The catheter is then
inserted 3 to 7 cm into the fascial sheath.47
MATERIALS: A short-beveled needle (i.e., a caudal needle).
ANATOMIC LANDMARKS: The inguinal ligament is defined by a line
drawn from the pubic tubercle to the anterior superior iliac spine
TECHNIQUE: The inguinal ligament is marked and divided

into three equal parts. A needle is inserted 0.5 to 1 cm below the
junction of the lateral one third and the medial two thirds of this
linethis point is at least 2 to 3 cm lateral to the femoral artery.
A loss-of-resistance technique using a short-beveled needle
can be used to identify the correct tissue plane. Two losses of
resistance, respectively corresponding to the fascia lata and the
fascia iliaca, are felt (Figure 486). After careful aspiration to
exclude intravascular injection, inject local anesthetic solution
can be (Figure 487).
DOSAGES: Ropivacaine 0.2% 0.5 mL/kg can be injected for
children up to 7 years; levobupivacaine 0.5% can be considered
Figure 48-7. Use a pediatric caudal needle for this block.
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of 0.5 mL/kg must be administered. For continuous infusion,
0.3 mL/kg/h is recommended. Clonidine 3 g/kg/24 h is used as
an adjuvant.
Complications
The complications of the fascia iliaca compartment block are quite
rare and include
Infection in the injection area. Always use a sterile technique.

In this area, it is difficult to maintain a sterile catheter; therefore, it is preferable to tunnel the catheter or to remove it after
48 hours.
Hematoma. When the femoral vessels are accidentally punctured, suspend the maneuver and compress the femoral artery
for approximately 2 to 3 minutes before performing the block.
Intravascular injection. Aspirate carefully prior to injection and
inject in graduated doses.
Nerve injury.
Saphenous Nerve Block

The saphenous nerve is the sensory branch of the femoral nerve. It
innervates the skin of the medial, anteromedial, and posteromedial
aspecta of the leg from the knee to the first metatarsophalangeal
joint. The saphenous nerve runs close to the femoral artery in the
medial aspect of the thigh. At about midthigh, the femoral artery
moves to the popliteal fossa and the saphenous nerve continues
between the sartorius and the vastus medialis muscles.
Indications
This block is mostly used in combination with the sciatic or
popliteal nerve block to complete the anesthesia of lower limb for
surgery on the lower leg and foot.
Patient Position
The patient lies supine with the thigh in neutral position.
mapping technique and with the pen vertical to the skin in an

anteroposterior direction, seek a motor response of the vastus
medialis. The nerve stimulator should be set at a frequency of 2 Hz
and a current of 2.5 mA. Mark with the pen the point at which the
best response is obtained. The nerve stimulator should then be
set at a current output of 1 mA. The insulated needle is inserted
vertical to the skin at the predetermined mark and advanced until
the motor response is again elicited. Adjust the needle and reduce
the current output while maintaining the appropriate muscle
response with a current of less than 0.4 mA. After a negative
aspiration test, slowly inject the local anesthetic solution.
Dosages
Ropivacaine 0.2% 0.5 mL/kg for children up to 7 years.
Levobupivacaine 0.5% for older children. Clonidine 2 g/kg can
be used as an adjuvant.
This block is considered quite difficult to perform under
ultrasound scanning; therefore, it is only for experts. The anatomic
landmarks and the patient position are exactly the same as for the
classic technique. Use a linear high-frequency (1012 MHz)
ultrasound probe and place it on the medial aspect of the thigh
lateral to the sartorius muscle on a transverse plane to obtain a
perpendicular scan of the nerve (Figure 488). Remember that
the marker of the probe is on the right of the patient. It is possible
to recognize the femoral artery as an anechoic and pulsing
structure. Identify also the muscular bodies of the sartorius and
vastus medialis muscles. The saphenous nerve is a hyperechoic
tapered structure with hypoechoic echoes inside it (typical
honeycomb structure) wrapped in the posterior fascia of the
sartorius muscle. Sometimes, because the nerve is small, it is
difficult to visualize. In this situation, the local anesthetic can be
injected immediately beneath the fascia of the sartorius muscle.
The authors prefer to use the in-plane technique to approach
the nerve because, in this way, it is possible to see the entire needle
as a linear hyperechoic structure. Insert a 50-mm insulated needle
Materials
A 23- to 25-gauge 25- or 50-mm (depending on the age of patient)
insulated short-beveled needle.
Anatomic Landmarks
The femoral artery and the inguinal ligament.
Technique
Many techniques to block this nerve are described in literature.
The technique described in these pages48 is preferred because it
can be performed with the nerve stimulator. At midthigh level, the
saphenous nerve runs alongside the motor nerve to the vastus
medialis muscle. Using a nerve stimulator, contractions induced in
the vastus medialis muscle suggest close proximity to the saphenous nerve. This technique has been called the saphenous/vastus
medialis approach. The needle is introduced vertically, 0.5 cm
lateral to the femoral artery and 3 to 6 cm below the inguinal
ligament, depending to the patients age and size. Using a nerve
Figure 48-8. The linear ultrasound probe is placed on the medial aspect of the thigh lateral to the sartorius muscle on a transverse plane. The femoral arterial pulsation is a useful landmark
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parallel to the probe in a lateral to medial direction until the tip of

the needle reaches the nerve. Once satisfied with the needle
placement, inject local anesthetic. By adjusting the needle position,
attempt to surround the nerve with local anesthetic so that a
hypoechoic ring of local anesthetic solution is visible around the
hyperechoic nerve structure.
Sciatic Nerve Block

The sciatic nerve block has various applications for surgery and
pain therapy of the lower limb. It is particularly suitable for surgery
of the knee, calf, Achilles tendon, ankle, and foot. It provides
complete anesthesia of the leg under the knee, except for a medial
band of skin innervated by the saphenous nerve. When this block
is combined with a lumbar plexus or femoral block, anesthesia
of the lower limb is complete. In children, the sciatic nerve is
much more superficial than in adults and can be visualized with
ultrasound at all levels. The block can be performed at any point
from the gluteus to the popliteal fossa (posterior, subgluteal,
lateral, posterior popliteal, lateral popliteal approach). Depending
on the size of the child and the level of the approach, most are
performed with the patient in the supine position.
Anatomy
The sciatic nerve is part of the lumbosacral plexus (L4S3). It is the
largest nerve of the body and measures 2 cm at the root. It enters
the gluteal region through the greater sciatic foramen, passing
underneath the piriformis, on top of the obturator and gemelli
muscles, and deep to the gluteus maximus. The sciatic nerve
courses midway between the greater trochanter of the femur and
the ischial tuberosity, down the midline of the posterior thigh,
and divides into the tibial and common peroneal nerves, usually
within the popliteal fossa. The course of the nerve can be followed
superficially tracing a line from the apex of the popliteal fossa to
the midpoint of the line drawn between the greater trochanter and
the ischial tuberosity. The sciatic nerve and its branches provide
sensory input from the joints (hip and knee) and motor supply to
the muscles. The sciatic nerve block produces anesthesia of the
skin of the posterior aspect of the thigh when blocked proximally
(subgluteal and above).
Subgluteal Approach
The subgluteal is a common approach to the sciatic nerve in
children because the child may remain in a supine position.
A prone or lateral position is also possible.49,50 The nerve is easily
accessible, is relatively superficial, and lies in a palpable groove.
INDICATIONS: Surgery of the foot, ankle, and knee, as a singleshot technique or a continuous infusion.
ANATOMY: At this level, the sciatic nerve lies in a groove
Figure 48-9. Anatomic landmarks: the line joining the ischial

tuberosity and the greater trochanter.
MATERIALS: A 21-gauge 50 -mm, short-beveled insulated needle

or, in larger children, a 20-gauge 150-mm short-beveled insulated
needle.
ANATOMIC LANDMARKS: The bony landmarks are easy to identify: the greater trochanter and the ischial tuberosity.
SINGLE-SHOT TECHNIQUE
TECHNIQUE:
The sciatic nerve is located in the immediate

subgluteal area, between the gluteus maximus and quadratus
femoralis muscles laterally and the biceps femoris muscles medially.
In the majority of patients, it is possible to identify the anatomic
landmarks, despite the presence of fat in the gluteal region. The
greater trochanter and the ischial tuberosity are marked and a line
is drawn between them. At this level, the sciatic nerve is exactly in
the middle of this line (Figure 489).
In small children, the path of the nerve can be mapped with a
nerve stimulator. The mapping pen is moved vertically on the skin
until a motor response of the foot or toes is elicited. The nerve
stimulator should be set at a frequency of 2 Hz and a current of
2.5 mA. Mark the point at which the best contraction is found.
The nerve stimulator is set at a current output of 1 mA and the
insulated needle is inserted at the marked point and advanced
vertically until the motor response in the calf muscles, foot, or big
toe is again elicited (Figure 4810). Contraction of the gluteal
muscles indicates that the needle is too superficial. Dorsiflexion or
eversion of the toes and foot indicates that the common peroneal
nerve is being stimulated whereas plantar flexion or inversion of
foot and toes indicates that the tibial nerve is being stimulated.
Adjust the position of the needle while the appropriate muscle
response is maintained with a current of less than 0.4 mA. Following a negative aspiration, inject the local anesthetic solution slowly
and incrementally.
immediately below the gluteus maximus muscle at the midpoint

between the ischial tuberosity medially and the greater trochanter
laterally.
DOSAGES: Ropivacaine 0.2% 0.5 mL/kg for children up to 7 years,

levobupivacaine 0.5% for older children. Clonidine 2 g/kg as an
adjuvant.
PATIENT POSITION: This block is very easy to perform in small
CONTINUOUS TECHNIQUE: The continuous sciatic nerve block is
children. With the child supine, the leg can be flexed to 90 degrees
at the hip; with the knees flexed at 90 degrees, the sciatic nerve can
be blocked at any level. For older children, the lateral decubitus
position is preferred with the leg to be blocked flexed.
an advanced technique and should be performed by anesthesiologists with experience in the single-shot technique. The
procedure is similar to that described for the single-shot block
except the angle of the needle insertion changes to facilitate
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Figure 48-11. Sonoanatomy of the subgluteal region.
Figure 48-10. The needle is inserted perpendicular to the skin.

passage of the catheter. The most common indications in children
include surgery of the foot and ankle, especially for amputation of
the lower limb.
insulated needle with a plastic cannula and a 24-gauge, 400-mmlong catheter must be used. For larger children, 18-gauge 110-mm
short-beveled insulated needle with a plastic cannula and a
20-gauge, 1000-mm-long catheter is recommended.
TECHNIQUE:
For the continuous sciatic nerve block, the lateral

position is preferred because the patient is more stable. It allows
more precise placement of the catheter. The anatomic landmarks
are the same as for the single-shot technique. The needle is inserted
at 30 degrees to the skin in the midpoint of the line joining the
ischial tuberosity and the greater trochanter. The needle is inserted
in a caudal cephalad direction until twitches corresponding to the
sciatic nerve stimulation are obtained. Adjust the needle position
to obtain the best twitch with a current of less than 0.4 mA, and
following a negative aspiration, slowly inject the local anesthetic
solution. The insulated needle is then withdrawn and the catheter
introduced 2 to 4 cm through the plastic cannula into the sciatic
nerve sheath. The catheter is fixed to the skin with a transparent
adhesive dressing.
ULTRASOUND TECHNIQUE: The sciatic nerve block under ultrasound scanning is considered an advanced block. The anatomic
landmarks and the patient position are exactly the same as for the
classic technique. Use a linear high-frequency (7MHz) ultrasound probe and place it along the line between the ischial tuberosity and the great trochanter on a transverse plane to obtain a
perpendicular scan of the nerve. The hyperechoic bone structures
medially and laterally are useful landmarks. The body of the
gluteus maximus muscle can be identified; immediately under it,
in a central position, the sciatic nerve is a hyperechoic ribbon-like
flat structure (Figure 4811).
the nerve so that the entire needle is visible as a linear hyperechoic
structure. Insert a 50-/150-mm insulated needle parallel to the
probe in a lateral to medial manner in the same plane of the
probe until the tip of the needle reaches the nerve (Figure 4812).
Confirm the location of the needle using a nerve stimulator.
Once satisfied with the needle placement, inject local anesthetic. By adjusting the needle position, attempt to surround the
nerve with local anesthetic so that a hypoechoic ring of local
anesthetic solution surrounds the hyperechoic nerve structure.
DOSAGES:
Ropivacaine 0.1% for children up to 7 years old,

levobupivacaine 0.125 to 0.25% for older children. A bolus volume of 0.5 mL/kg is recommended. For continuous infusion,
0.3 mL/kg/h is used. Clonidine 3 g/kg/24 h can be used as an
adjuvant.
COMPLICATIONS
Infection in the injection area. Always use a sterile technique.

Hematoma. Avoid multiple insertions, especially in patients
with anticoagulant therapy.
Intravascular injection. Blood vessels are infrequently punctured with this technique; avoid introducing the needle too deep
(pelvis vessels).
Nerve injury. The risk of nerve injury, both mechanical and
compressive, is particularly high with this block.
Figure 48-12. In-plane approach at the subgluteal level.
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Lateral Approach
The sciatic nerve block using the lateral approach is considered
an easy block. It is especially useful in the pediatric population
because most children are sedated in the supine position.51,52
A combined sciatic and femoral or saphenous nerve block can be
used for lower extremity surgeries. In this situation, the total dose
of local anesthetic for each block should be reduced.
INDICATIONS: Anesthesia and postoperative analgesia for surgery

of the foot, ankle, and knee, as a single-shot technique or a continuous infusion
ANATOMY: The sciatic nerve runs in the midline of the posterior
aspect of the thigh to the apex of the popliteal fossa. It is covered
by the biceps femoris muscle and lies on the adductor magnus
muscle.
PATIENT POSITION: The patient is supine, with the leg in a neutral
position or rotated slightly inward.
MATERIALS: A 21-gauge 50-mm short-beveled insulated needle

or, in larger children, a 20-gauge 150-mm short-beveled insulated
needle.
ANATOMIC LANDMARKS: The greater trochanter of the femur.

SINGLE-SHOT TECHNIQUE
TECHNIQUE:
The anesthesiologist is positioned lateral to the

patient on the side to be blocked. The greater trochanter of the
femur should be palpated and marked at its lower border. At this
level even in small children, the sciatic nerve is too deep to allow
surface nerve mapping. With a nerve stimulator set at a current
of 1 mA and one hand on the greater trochanter, the needle is
introduced horizontally immediately below the greater trochanter.
The needle is advanced until it touches the bone and then redirected to pass immediately posterior to the femur. A motor
response in the foot and toes is sought. Inversion of the foot is an
indication of tibial nerve stimulation. Adjust the position of the
needle until the appropriate muscle response is maintained with a
current of 0.4 mA. After a negative aspiration test, inject the local
anesthetic solution slowly and incrementally (Figure 4813).
Eversion of the foot is an indication of common peroneal nerve
Figure 48-13. The needle is introduced horizontally immediately

below the greater trochanter.
stimulation; plantar flexion of the foot and toes may indicate a

potential failed blockade. If the biceps femoris tendon is contracting, the needle is withdrawn and inserted medially away from
the muscle belly of the biceps femoris.
DOSAGES:
Ropivacaine 0.2% 0.5 to 1 mL/kg for children up to

7 years and levobupivacaine 0.5% for older children. Clonidine
2 g/kg can be used as an adjuvant.
CONTINUOUS TECHNIQUE: The continuous sciatic nerve block

via this lateral approach is a quite easy and the authors preferred
approach. The patient position and the landmarks are the same as
the single-shot approach and a catheter can be introduced without
changing the angle of needle.53 The catheter is introduced through
the plastic cannula approximately 2 to 4 cm into the sciatic nerve
sheath and fixed with transparent dressing. The catheter can be
tunneled to allow more stable fixation and for prolonged infusions.
insulated needle with a plastic cannula and a 24-gauge, 400-mmlong catheter is recommended. For larger children, 18-gauge
110-mm short-beveled insulated needle with a plastic cannula and
a 20-gauge, 1000-mm-long catheter can be used.
of 0.5 mL/kg is recommended. For continuous infusion, 0.3 mL/
kg/h is suggested. Clonidine 3 g/kg/24 h can be used as an adjuvant.
COMPLICATIONS
Absence of complete block especially if plantar flexion or dorsiflexion twitches are obtained and eversion is not elicited.
Infection at the injection site. Always use a sterile technique.
Hematoma. Avoid multiple insertions, especially in patients
with anticoagulant therapy.
Intravascular injection. The puncture of vessels is infrequent
with this technique
Nerve injury. The risk of nerve injury, both mechanical and
compressive, is particularly elevated with this block. Always use
nerve stimulation and a slow introduction of the needle while
searching the nerve. Avoid pressure when injecting the local
anesthetic.
ULTRASOUND TECHNIQUE: The sciatic nerve block under

ultrasound scanning is considered an advanced block. The patient
is positioned in a lateral decubitus or a supine position with the leg
flexed at the hip and knee. Using a linear high-frequency (7MHz)
ultrasound probe, place the probe transversely over the midline
of the posterior aspect of the thigh to obtain a cross-sectional view
of the nerve (Figure 4814). The muscles that surround the nerve
at this level should be identified (i.e., biceps femoris and adductor
magnus). The sciatic nerve appears in the midline as a hyperechoic
flat triangular or oval structure (Figure 4815). Because the nerve
is large, it is possible to obtain a longitudinal view of the sciatic
nerve by simply turning the probe through 90 degrees.
the nerve because the full length of the needle can be visualized as
a linear hyperechoic structure. For catheter placement intended
for continuous infusions, it is preferable to visualize the nerve
in its longitudinal axis (Figure 4816). A 50-/150-mm insulated
needle is inserted in plane (i.e., parallel to the probe) in a lateral to
medial fashion until the tip of the needle reaches the nerve. The
position of the needle can be confirmed using a nerve stimulator.
Once satisfied with the needle placement, inject local anesthetic.
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By adjusting the needle position, attempt to surround the nerve

with local anesthetic so that a hypoechoic ring of local anesthetic
solution is visible around the hyperechoic nerve structure
(see Videos 482 and 483).
Popliteal Lateral Approach
Figure 48-14. The ultrasound probe is placed along the midline of the
posterior aspect of the thigh on a transverse plane.
There are two approaches to the sciatic nerve in the popliteal fossa,
a lateral approach and a posterior approach. For pediatric patient,
the authors prefer the lateral approach. The lateral approach to the
popliteal nerve is essentially a sciatic nerve block in the popliteal
fossa.5456 This technique has an intermediate level of difficulty.
A good knowledge of the anatomy of the sciatic nerve is required
to perform the block. A nerve stimulator can be used to assist the
anesthesiologist in identifying the nerve. This block is particularly
useful for surgery of the calf, Achilles tendon, ankle, and foot.
A combined sciatic and femoral or saphenous nerve block can be
used for lower limb surgeries. In this case, the total dose of local
anesthetic must be reduced for each block.
INDICATIONS: Anesthesia and postoperative analgesia for lower

limb surgery, especially for ankle and foot as a single-shot technique or a continuous infusion.
Figure 48-15. Sonoanatomy of the region: biceps femoris and adductor

magnus muscles surrounding the sciatic nerve.
ANATOMY: The sciatic nerve is formed by two nerve trunks, the

tibial and the common peroneal nerve. These two nerves are
surrounded by the same sheath as they emerge from the pelvis.
The sciatic nerve descends toward the knee and at approximately
5 to 7 cm from the popliteal crease, depending on the size of the
child; the two branches diverge into the tibial and the common
peroneal nerves. In infants and newborns, they divide within the
popliteal fossa.
The common peroneal nerve continues its descent around the
head and neck of the fibula, where it gives off important branches
to the knee joint and to the skin as the sural nerve, which supplies
the lateral aspect of the calf. The terminal branches form the
superficial and deep peroneal nerves.
The tibial nerve has a larger caliber, and its terminal branches
are represented by the lateral and medial plantar nerves. Other
branches supply the ankle joint and the calf muscles.
In the popliteal fossa, the sciatic nerve is lateral and superficial
to the popliteal artery and vein when viewed from the posterior
aspect. The nerve and popliteal artery lie in separate connective
tissue sheaths. Vascular puncture is thus very infrequent.
The popliteal fossa is diamond shaped, with the superior
triangle formed by the tendons of the semitendinosis and semimembranosis muscles medially and the biceps femoris tendon
laterally. In the popliteal fossa, the common peroneal nerve is
lateral and the tibial nerve is medial.
PATIENT POSITION: With the patient supine, the leg is kept in a
neutral position or rotated slightly inward. The foot to be blocked
should be positioned in such a way that allows all muscle twitches
to be seen.
MATERIALS: A 21-gauge 50-mm insulated short-beveled needle.

ANATOMIC LANDMARKS: The anatomic landmarks are the
patellar crest, the vastus lateralis muscle, and the tendon of the
long head of the biceps femoris muscle.
SINGLE-SHOT TECHNIQUES
Figure 48-16. Longitudinal scan of the sciatic nerve at this level:
a better approach to introduce a catheter.
TECHNIQUE: The anesthesiologist stands on the side to be blocked
with the leg. The needle insertion site is in the groove between the
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For the continuous technique, the authors prefer to elicit responses
in the tibial nerve.
DOSAGES:
Ropivacaine 0.1% for children until 7 years old,

of 0.5 mL/kg and for continuous infusion 0.3 mL/kg/h are recommended. Clonidine 3 g/kg/24 h can be used as an adjuvant.
COMPLICATIONS
Figure 48-17. The groove between the vastus lateralis muscle and the
tendon of the long head of the biceps femoris muscle, at a level corresponding at the superior edge of the patellar crest.
vastus lateralis muscle and the long head of biceps femoris tendon,
at a level corresponding to the superior edge of the patellar crest.
This point is marked approximately 5 to 6 cm above the popliteal
crease depending on the size of the patient (Figure 4817). Sometimes these landmarks can be difficult to identify and become
more visible when the leg is elevated on a pillow placed under the
knee. It is possible to nerve map these nerves in small infants only
with the knee flexed. With one hand stabilizing the leg, the needle,
connected to a nerve stimulator and set at a current output of
1 mA, can be introduced horizontally and perpendicularly to
the long axis of the leg. The needle is advanced until it touches
the femur and then redirected 30 degrees posteriorly to pass
immediately behind the femur until a motor response of the foot
and toes is elicited. Inversion of the foot is indication of tibial nerve
stimulation, and eversion is an indication of common peroneal
nerve stimulation. A response in either tibial or common peroneal
nerve distribution will produce a successful block. Adjust the
position of the needle so that the appropriate muscle response is
maintained with a current of 0.4 mA. After a negative aspiration
for blood, inject the local anesthetic solution slowly and incrementally. Isolated contractions of calf muscles should not be
considered because these can arise from stimulation of branches
of the sciatic nerve originating outside the nerve sheath.
Failure to block one of the branches of the sciatic nerve especially if division occurs proximally above the popliteal fossa.
Infection in the area of the injection. Always use a severe sterile technique.
Hematoma. Avoid multiple insertions, especially with the larger
needle used for the continuous technique.
Intravascular injection. Do not insert the needle too deeply
because the vessels are deeper and medial with respect to the
sciatic nerve.
Nerve injury. The risk of nerve injury is extremely rare with this
technique. Always use nerve stimulation and slow introduction
of the needle while searching for the nerve. Never inject against
resistance.
ULTRASOUND TECHNIQUE: The sciatic nerve block under

ultrasound scanning is considered an advanced block. The patient
is positioned in a lateral decubitus or a supine position with the leg
to be blocked flexed. The authors prefer the supine position for
children. Using a linear high-frequency (710 MHz) ultrasound
probe, place the probe transversely in the posterior aspect of the
popliteal fossa to obtain a cross-sectional view of the nerves.
Identify the popliteal artery, a hypoechoic pulsating structure, that
is easily visible with the color Doppler. Identify the biceps femoris,
semitendinosis, and semimembranosis muscles and, deeper to
them, the adductor magnus muscle that surrounds the nerve. The
sciatic nerve is slightly lateral to the popliteal artery and appears
like an oval hyperechoic structure with a hypoechoic honeycomb
center (Figure 4818). Scan the region proximally and distally
to assess the point at which the sciatic nerve divides; ideally, the
sciatic nerve should be blocked before it divides (Figure 4819).
DOSAGES: 0 Ropivacaine 0.2%.5 mL/kg for children up to 7 years,

levobupivacaine 0.5% for older children. Clonidine 2 g/kg
administered as an adjuvant.
CONTINUOUS TECHNIQUE: The continuous popliteal block is

considered an advanced technique and is similar to the single
shot, except that the inclination of the needle is more cephalad to
facilitate the introduction of the catheter. The patient position and
the anatomic landmarks are the same as the single-shot technique.
insulated needle with a plastic cannula and a 24-gauge, 400-mmlong catheter.

TECHNIQUE: The needle is introduced using the same landmarks
as the single-shot technique. After directing the needle slightly
cephalad and, while maintaining the appropriate muscle response,
slowly inject the local anesthetic solution after a negative aspiration
for blood. The needle can then be removed and the catheter introduced through the plastic cannula approximately 2 cm into the
sciatic nerve sheath and fixed in place with a transparent adhesive.
Figure 48-18. Sonoanatomy. The muscles that surround the sciatic

nerve include the biceps femoris, semitendinosis, and semimembranosis
muscles. The sciatic nerve is hyperechoic and about to divide in this
sonograph.
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Figure 48-19. The sciatic nerve, shown as a ribbon-like hyper echoic

structure, divides in the popliteal fossa.
Figure 48-21. The needle is inserted using the in-plane technique from
a lateral to a medial direction.
Because the nerve is large, it is possible to obtain a longitudinal

view of the nerve by simply turning the probe through 90 degree.
The authors prefer to use the in-plane technique to approach the
nerve because the full length of the needle can be visualized as a
linear hyperechoic structure. For catheter placement intended for
continuous infusions, it is preferable to visualize the nerve in its
longitudinal axis (Figure 4820). Insert a 50-mm insulated needle
from lateral to medial until the tip of the needle reaches the nerve
(Figure 4821). The position of the needle can be confirmed using
a nerve stimulator. Once satisfied with the needle placement, inject
local anesthetic. By adjusting the needle position, attempt to
surround the nerve with local anesthetic so that a hypoechoic
ring of local anesthetic solution is visible around the hyperechoic
nerve structure.
well as the cutaneous branch of the femoral nerve (saphenous

nerve) to be blocked. It is considered an elementary block with
few complications and effective for surgery of the foot and big
toe.57,58 It should be remembered that the ankle block provides
anesthesia for the foot but not the ankle joint.
Ankle Block
The ankle block requires four branches of the sciatic nerve
(superficial and deep peroneal, anterior tibial and sural nerves) as
INDICATIONS: Anesthesia and postoperative analgesia of the foot

and the big toe.
ANATOMY: It is useful to consider the ankle block as a block of
two deep nerves (tibial and deep peroneal) and three superficial
nerves (saphenous, sural, and superficial peroneal). This is important because the deep nerves are blocked by injecting local
anesthetic beneath the superficial fascia, and the superficial nerves
are blocked by subcutaneous infiltration of local anesthetic.
The deep peroneal nerve, at the ankle, lies anterior to the tibia
close to the dorsal pedis artery. It gives branches to the tarsometatarsal and metatarsophalangeal joints of all four toes except
the big toe. The superficial peroneal nerve through its cutaneous
branches provides sensory innervation to the dorsum of the foot.
The tibial nerve emerges laterally and behind the tibial artery at
the level of the medial malleolus. It innervates the ankle joint, the
Achilles tendon, and the medial malleolus.
The sural nerve is a sensory nerve that emerges above the
lateral malleolus lateral to the Achilles tendon. It gives branches
to the lateral malleolus, the Achilles tendon, and the skin of the
fifth toe.
The saphenous nerve is the terminal branch of the femoral
nerve and runs in the subcutaneous tissue on the medial aspect of
the ankle.
PATIENT POSITION: The patient lies supine with the foot in a

neutral position, slightly internally or externally rotated depending
on the nerve to be blocked.
MATERIALS: A 23- to 25-gauge 25-mm insulated short-beveled
needle and a short needle for the subcutaneous infiltration.
ANATOMIC LANDMARKS: The deep peroneal nerve is located
Figure 48-20. The longitudinal scan of the hyperechoic sciatic nerve as
it branches. This approach is preferable for catheter positioning when
continuous infusions are to be used.
immediately lateral to the tendon of the extensor hallucis longus

muscle of the big toe. The dorsalis pedis artery is palpable at this
point and the nerve lies immediately lateral to it. The tibial nerve
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lies posterior and distal to the medial malleolus. The tibial artery
is palpable at this point and the nerve lies immediately posterior.
The superficial peroneal, sural, and saphenous nerves are
distributed in the subcutaneous tissue around the ankle.
TECHNIQUE: It is useful to block the deeper nerves first because
infiltration of the subcutaneous tissue could distort the anatomy.
Identify the dorsalis pedis artery at the intermalleolar level. The
needle is inserted lateral to the artery, perpendicular to the skin,
toward the tarsal bones. After a negative aspiration for blood,
slowly inject the local anesthetic solution.
For the tibial nerve, use a nerve stimulator. The foot is rotated
laterally and the needle should be inserted medial to the tibial
artery between the medial malleolus and the Achilles tendon.
A nerve stimulator set at a frequency of 2 Hz, and a current of
1.5 mA can be used to elicit a motor response (plantar flexion
of the foot). The position of the needle is adjusted to maintain
the appropriate response with a current of 0.4 mA. After a negative
aspiration for blood, slowly inject the local anesthetic solution.
The superficial peroneal, sural, and saphenous nerves can
be blocked with a circumferential subcutaneous injection along
a line between the malleoli. The superficial peroneal nerve is
blocked by directing the needle toward the medial malleolus
from the anterior starting point. The sural nerve is blocked by a
subcutaneous infiltration between the lateral malleolus and the
Achilles tendon. The saphenous nerve is blocked by a circumferential subcutaneous injection approximately 2 cm above the
medial malleolus.
DOSAGES: Ropivacaine 0.2% 2 to 4 mL for each nerve.

COMPLICATIONS
Infection in the injection area. Always use a severe sterile technique.

Hematoma. Avoid multiple insertions. Use fine-gauge needles.
Intravascular injection. Avoid puncturing the arteries or the
saphenous vein at the medial malleolus. Always aspirate before
injecting.
Nerve injury. Never inject against pressure.
Only three of the nerves that innervate the foot are visible with
ultrasound: the saphenous, tibial, and deep peroneal nerve. The
saphenous nerve is a simple subcutaneous injection close to the
saphenous vein.
Tibial Nerve Block

With the patient in a supine position, a linear high-frequency
(1012 MHz) ultrasound probe is used. The probe it is placed on
the medial malleolus in a transverse plane to obtain a crosssectional scan of the nerve (Figure 4822). First, identify the tibial
artery as a hypoechoic pulsating structure medial to the malleolus
using the color Doppler. The tibial nerve lies posterior to the artery
and appears as a round hyperechoic structure. The authors prefer
to use the in-plane technique to approach the nerve. Insert a
25-mm insulated needle in an anterior to posterior direction until
the tip of the needle reaches the nerve (see Figure 4822). The
Figure 48-22. The ultrasound probe is placed on the medial malleolus

of the ankle in a transverse plane to obtain a cross-sectional view of
the nerve.
position of the needle can be confirmed using a nerve stimulator.

solution is visible around the hyperechoic nerve structure.
Deep Peroneal Nerve Block

With the patient in a supine position, place a linear high-frequency
(1012 MHz) ultrasound probe transversely on the anterior aspect
of the medial malleolus to obtain a cross-sectional view of the
nerve. First, identify the dorsal pedis artery, which appears a
hypoechoic pulsing structure, easily visible with the color Doppler,
lateral to the malleolus. The deep peroneal nerve is a round hyperechoic structure lateral to the artery. The authors prefer to use the
in-plane technique to approach the nerve. A 25-mm insulated
needle is inserted until the tip of the needle reaches the nerve.
solution is visible around the hyperechoic nerve structure.
REFERENCES
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anaesthesia in preterm babies undergoing surgery: effects on the stress
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3. Kokki H. Current management of pediatric postoperative pain. Expert
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4. Ivani G. Modification of the stress response by regional analgesia
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7. Ivani G, Taglietto M, LErario M, et al. 7605 Consecutive blocks in a
childrens hospital. Regional anesthesia is safe and effective. Anesthesiology. 2006;105:A1353.
8. Llewellyn N, Moriarty A. The national pediatric epidural audit. Paediatr
Anaesth. 2007;17:520533.
9. Ivani G, Mossetti V. Continuous peripheral nerve block (CPNB). Paediatr
Anaesth. 2005;15:8790.
10. Dadure C, Pirat P, Raux O, et al. Perioperative continuous peripheral
nerve block with disposable infusion pumps in children: a prospective
descriptive study. Anesth Analg. 2003;97:687690.
11. Dalens B. Regional Anaesthesia in Infants, Children and Adolescents.
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12. Ivani G. Paediatric Regional Anaesthesia, A Practical Approach. Firenze,
Italy. 2001, pp.
13. Hadzic A, Dilberovic F, Shah S, et al. Combination of intraneural injection
and high injection pressure leads to fascicular injury and neurologic
deficits in dogs. Reg Anesth Pain Med. 2004;29:417423.
14. Lnnqvist PA, Westrin P, Larsson BA, et al. Ropivacaine pharmacokinetics
after caudal block in 1-8 year old children. Br J Anaesth. 2000;85:506511.
15. Hansen TG, Ilett KF, Reid C, et al. Caudal ropivacaine in infants:
population pharmacokinetics and plasma concentrations. Anesthesiology.
2001;94:579584.
16. Ecoffey C. Local anesthetics in pediatric anesthesia: an update (review).
Minerva Anestesiol. 2005;71:357360.
17. Ivani G, De Negri P, Lonnquist PA. Caudal anesthesia for minor pediatric
surgery: a prospective randomized comparison of ropivacaine 0.2% vs
levobupivacaine 0.2%. Paediatr Anaesth. 2005;15:491494.
18. De Negri P, Ivani G, Tirri T. New local anesthetics for pediatric anesthesia.
for caudal blockade in children. Acta Anaesthesiol Scand. 2000;44:446449.
20. De Negri P, Ivani G, Visconti C, et al. The dose-response relationship for
clonidine added to a postoperative continuous epidural infusion of
21. Bsenberg A, Raw R, Boezaart AP. Surface mapping of peripheral nerves
in children with a nerve stimulator. Paediatr Anaesth. 2002;12:398403.
22. Urmey WF, Grossi P. Percutaneous electrode guidance: a noninvasive
technique for prelocation of peripheral nerves to facilitate peripheral
plexus or nerve block. Reg Anesth Pain Med. 2002;27:261267.
23. Urmey WF, Grossi P. Percutaneous electrode guidance and subcutaneous
stimulating electrode guidance: modifications of the original technique.
24. Marhofer P, Sitzwohl C, Greher M, Kapral S. Ultrasound guidance for
infraclavicular brachial plexus anaesthesia in children. Anaesthesia.
2004;59:642646.
25. Chan VW. Applying ultrasound imaging to interscalene brachial plexus
block. Reg Anesth Pain Med. 2003;28:340343.
26. Dingemans E, Williams SR, Arcand G, et al. Neurostimulation in
ultrasound-guided infraclavicular block: a prospective randomized trial.
Anesth Analg. 2007;104:12751280.
27. Bloc S, Garnier T, Komly B, et al. Spread of injectate associated with radial
or median nerve-type motor response during infraclavicular brachialplexus block: an ultrasound evaluation. Reg Anesth Pain Med. 2007;32:
130135.
28. Casati A, Baciarello M, Di Cianni S, et al. Effects of ultrasound guidance
on the minimum effective anaesthetic volume required to block the
femoral nerve. Br J Anaesth. 2007;98:823827.
29. Chan VWS. Applying ultrasound imaging to interscalene brachial plexus
block. Reg Anesth Pain Med. 28 (4): 34043, 2003
30. Perlas A, Chan VWS Ultrasound guided interscalene brachial plexus
block. Techn Reg Anesth Pain Manage. 2004;8:143148.
31. Marhofer P, Schrgendorfer K, Koinig H, et al. Ultrasonographic guidance
improves sensory block and onset time of three-in-one blocks. Anesth
Analg. 1997;85:854857.
32. Willschke H, Marhofer P, Bsenberg A. et al.Ultrasonography for
95:226230.
33. Grau T. Ultrasonography in the current practice of regional anaesthesia.

Best Pract Res Clin Anaesthesiol. 2005;19:175200.
34. Willschke H, Marhofer P, Bsenberg A. et al. Ultrasonography-guided
35. Chan VWS, Perlas A, Rawson R, Odukoya O. Ultrasound-guided
supraclavicular brachial plexus block. Anesth Analg. 2003;97:15141517.
36. Horlocker T, Wedel DJ. Ultrasound-guided regional anesthesia: in search
of the holy grail (editorial). Anesth Analg. 2007;104:1009.
37. Domingo-Triad V, Selfa S, Martnez F, et al. Ultrasound guidance for
lateral midfemoral sciatic nerve block: a prospective, comparative,
randomized study. Anesth Analg. 2007;104:12701274.
38. Sinha SK, Abrams JH, Weller RS. Ultrasound-guided interscalene needle
placement produces successful anesthesia regardless of motor stimulation
above or below 0.5 mA. Anesth Analg. 2007;105:848852.
39. Sites BD, Brull R, Chan VW, et al. Artifacts and pitfall errors associated
with ultrasound-guided regional anesthesia. Part I: understanding the
basic principles of ultrasound physics and machine operations. Reg Anesth
Pain Med. 2007;32:412418.
40. Sites BD, Brull R, Chan VW, et al. Artifacts and pitfall errors associated
with ultrasound-guided regional anesthesia. Part II: a pictorial approach
to understanding and avoidance. Reg Anesth Pain Med. 2007;32:419433.
41. Koo ST, Brown TCK. Femoral nerve block. The anatomical basis for a
single injection technique. Anaesth Intensive Care. 1983;11:40.
42. Ronchi L, Rosenbaum D, Athouel A, et al. Femoral nerve blockade in
children using bupivacaine. Anaesthesiology. 1989;70:622.
43. Maccani RM, Wedel DJ, Melton A. Femoral and lateral femoral cutaneous
nerve block for muscle biopsies in children. Paediatr Anaesth. 1995;5:
223227.
44. Tobias JD. Continuous femoral nerve block to provide analgesia following
femur fracture in a paediatric ICU population. Anaesth Intensive Care.
1994;22:616618.
45. Johnson CM. Continuous femoral nerve blockade for analgesia in
children with femoral fractures. Anaesth Intensive Care. 1994;22:281283.
46. Dalens B, Vanneuville G, Tanguy A. Comparison of the fascia iliaca
compartment block with the 3-in-1 block in children. Anesth Analg. 1989;
69:705.
47. Paut O, Sallabery M, Schreiber-Delurmeny E, et al. Continuous fascia
iliaca compartment block in children: a prospective evaluation of plasma
bupivacaine concentrations, pain scores, and side effects. Anesth Analg.
2001;92:11591163.
48. Bouaziz H, Benhamou D, Narchi P. A new approach for saphenous nerve
block. Reg Anesth. 1996;21:490.
49. Dalens B, Tanguy A, Vanneuvile G. Sciatic nerve block in children: a
comparison of the posterior, anterior and lateral approaches in 180
paediatric patients. Anesth Analg. 1990;70:131.
50. Ivani G, Tonetti F. Postoperative analgesia in infants and children: new
developments (review). Minerva Anestesiol. 2004;70:399403.
51. Ichikiyanagi K. Sciatic nerve block: lateral approach with the patient
supine. Anaesthesiology. 1959;20:601
52. Gardini R, Waldron BA, Wallace WA. Sciatic nerve block: a new lateral
approach. Acta Anaesthesiol Scand. 1985;29:515.
53. Ivani G, Codipietro L, Gagliardi F, et al. A long term infusion via a sciatic
catheter in a 3-year-old-boy. Paediatr Anaesth. 2003;13:718721.
54. McLeod DH, Wong DH, Vaghadia H, et al. Lateral popliteal sciatic nerve
block compared with ankle block for analgesia following foot surgery.
Can J Anaesth. 1995;42:765769.
55. Vloka JD, Hadzic A, Kitain E. Anatomic considerations for sciatic nerve
block in the popliteal fossa through the lateral approach. Reg Anesth.
1997;84:387390.
56. Ter Rahe C, Suresh S. Popliteal fossa block: lateral approach to the sciatic
nerve. Techn Reg Anesth Pain Manage. 2002;6:141143.
57. Schurman DJ. Ankle-block anesthesia for foot surgery. Anesthesiology.
1976;44:348352.
58. Dalens B. Lower limb blocks. Distal conduction blocks. In: Dalens B,
editor. Pediatric Regional Anesthesia. Boca Raton, Fla: CRC Press; 1990.
pp. 333348.
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Central Neuraxial Blocks
Adrian Bsenberg
HISTORY
Epidural anesthesia in children was first described in 1936.1,2 The
first large series of 6500 children was published in 1951.3 A quarter
of these were lumbar epidurals for urologic procedures in infants.
Continuous infusions were first used by Ruston in 1959.4 Ruston
had been using epidural blocks on infants and children for
12 years under light general anesthesia. He found that sick
children requiring surgery did well under epidural blockade,46
but his methods were not generally accepted and even condemned
by some. Even today, attitudes toward epidural anesthesia vary.
The first thoracic epidural in children was described by Isakob
and coworkers in 1971.7 They placed the epidural catheter between
T3 and T7 at the end of surgery and maintained analgesia for
2 to 3 days.
The safety of epidural even in difficult conditions was borne
out by a report from Zhan Zhen Gang of Beijing,1,8 describing
10,000 single neuraxial blocks performed under sedation in small
children without serious complication.
Since the mid-1980s, interest in regional anesthesia has
grown, driven by the concern for improved postoperative pain
management in children.9 This, coupled with a better understanding of the pharmacodynamics and pharmacokinetics of
local anesthetic agents in children of all ages, has led to a greater
worldwide usage.
In the past, the availability of appropriate-sized equipment has
been a limiting factor for continuous epidural analgesia. Manufacturers finally succumbed to market demand and led to the
advent of shorter, smaller-gauge Tuohy needles (1922 gauge)
more appropriate for neonates, infants, and children. This, together
with the introduction of alternate techniques,10,11 has made continuous epidural an option in even the smallest neonate.
Epidural anesthesia, established under sedation or general
anesthesia prior to surgery, provides effective intraoperative analgesia that can be extended postoperatively using a continuous
infusion of local anesthetic agents or by intermittent injection of
local anesthetic agents, with or without epidural opiates or other
adjuvants. The safety of epidural anesthesia has been highlighted
in a recent audit from the United Kingdom.11a Ninety-six incidents
were reported in 10,633 epidurals placed in 21 centers over a
5-year period. Only 1 had residual effects after 3 months but
resolved by 12 months.
The purpose of this chapter is to highlight some of the important anatomic, physiologic, and pharmacologic differences in
children compared with adults, to discuss the different approaches
to the epidural space in children, and to describe their use in postoperative pain management. Every anesthesiologist undertaking
neuraxial blockade in children should be conversant with these

differences as well as the psychological disposition of children of
different ages.1214
ANATOMIC DIFFERENCES1315
In utero, the cephalic end of the developing embryo or fetus
differentiates first and grows more rapidly. The newborn has a
large head attached to a medium-sized body and relatively small
legs. During subsequent growth, the pattern reverses, producing
the adult configuration. Thus, the anatomic relationship between
the different structures changes with age and landmarks used in
adults may not necessarily apply in children.
1. The position of conus medullaris (terminal end of the spinal
cord) varies with age. It is generally accepted that the conus
in neonates and infants (<1 y) is at L3 and the dural sac is at
S24 (i.e., located more caudad than in adults).16 However,
recent ultrasound studies have shown that, in the majority of
neonates and even in premature babies, the conus is at L1 and
some at L2.17 A conus extending below L3 suggests a tethered
cord.18,19 The conus moves with changes in position.20
2. The intercristal line is found at L5 in children and at the
L5S1 interspace in premature infants and neonates (adult
level L4).1719 But this is based on radiologic information and
does not take the unossified cartilage into account. Clinically,
the cartilaginous iliac crest line is at L4 as in adults.
3. The vertebral column forms a single, shallow, anteriorly concave curve extending from C1 to L5 at birth. The cervical curve
appears when the head is held upright (~6 mo) and the lumbar
curve (1 y) develops with weight-bearing.
4. The spinous processes are thus more parallel and horizontal,
facilitating a midline approach at all levels. Between T2 and T9,
the spinous processes are narrower, closer together, and angled
downward. Between T10 and T12, the orientation is similar to
the lumbar vertebra. The largest intervertebral space at this
level is T12L1.
5. The laminae of the vertebral bodies are poorly calcified in
neonates and infants. Using the laminae as bony landmarks
for the paramedian approach is more difficult.
6. In neonates, the L5S1 interspace is the largest and most easily
palpable.
7. The sacrum is narrower and flatter. The ossification of the sacral
vertebrae is incomplete in children and the sacral vertebrae are
separated by intervertebral disks. The ligamentum flavum
joining the superior and inferior aspect of the sacral arches still
persists, making sacral intervertebral block possible. Ossifi-
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8.
9.
10.
11.
12.
13.
14.
15.
cation of the posterior ligament starts at 15 years and the

sacrum is fully ossified by 25 years.
A sacral dimple may indicate the presence of an underlying
spina bifida.
The ligamentum flavum is thinner and less dense in infants
and young children. The resistance imparted to the advancing
epidural needle varies with age.
The cerebrospinal fluid (CSF) volume is relatively high in
infants weighing less than 1.5 kg (i.e., 4 mL/kg body weight)
in contrast to adults and older children (2 mL/kg). CSF
production is also increased (0.35 mL/min). This may explain
why infants require proportionately more local anesthetic
for spinal block than older children and the incidence of
postspinal headache is low in small children.
The ultrasound image of the epidural space in neonates and
infants is small (14 mm). The epidural space is less compliant than in adults.
The epidural fat is made up of spongy gelatinous lobules with
distinct spaces in the infant and small child. This offers less
resistance to the passage of local anesthetic and an epidural
catheter. In contrast, the epidural fat in the adult has more
densely packed lobules divided by fibrous strands.
The spinal canal is triangular and the spinal cord is ellipsoid in
cross-section. The widest part of the epidural space is located
in the midline; therefore, the posterior midline approach is
the safest. Epidural veins and arteries are also less dense in
the midline.
Epidural veins have no valves and connect directly with intracranial veinsthus, any air, drug, or materials inadvertently
injected into the epidural veins can reach the brain directly
and over a much shorter distance in infants.
Nerves are thinner with less myelination in the neonate
and young infants, allowing a lower concentration of local
anesthetic to be effective. The nerve trunks to the lower limbs
are fully myelinated by approximately the second year of life.
The degree of myelination of nerve fibers considerably influences the pharmacodynamic effects of local anesthetics.
PHYSIOLOGIC DIFFERENCES
There are important differences in the physiologic effects of
central blockade between children and adults.
Hemodynamic
Clinically significant hypotension is not a feature of central
blockade in children,15,2129 even without vasoconstrictors or
volume preloading. Children younger than 5 years show little or
no change in arterial pressure and heart rate after spinal blockade
to levels of T35.15,21,23,26 Arthur reported cardiovascular stability
in a series of young children after thoracic epidural.22 In the authors
experience, prepubertal children do not develop significant
hypotension except when they are on Ca2+ channel blockers. Murat
and colleagues found that, after lumbar epidural, children older
than 8 years behaved like adults, whereas those younger than
8 years showed no significant hypotension irrespective of the level
of blockade.23
This may be caused by
1. The relative immaturity of the sympathetic nervous system in
small children.
807
2. Lower vascular tone (peripheral resistance) so that sympathetic

blockade is unlikely to decrease the blood pressure.24,26
3. The relative smaller volume of the lower extremities in
proportion to the rest of the body.24 The volume under T10 in
a 5-year-old represents 30 to 40% of total body volume whereas
it represents up to 70% in an adult, thus
4. Compensatory vasoconstriction in the vessels that remain
unblocked in the upper body is large enough to maintain the
blood pressure.24
Respiratory3040
The effects of central blockade on ventilation depend on the level,
intensity of the blockade, (sympathetic, sensory, or motor), and
the clinical situation. Central blockade can affect the respiratory
mechanics of the chest wall and diaphragm by virtue of the
diminished intercostal activity, particularly in the compliant
chest walls of neonates and infants.30 Infants rely on the diaphragm
to a greater extent to maintain tidal volume. Excursion of the
diaphragm may be improved by neuraxial blockade.3032,34
In a separate study, resting minute ventilation was impaired
and the respiratory rate decreased after caudal anesthesia under
light halothane anesthesia in young children.34 Caudal block
resulted in a significant increase in functional residual capacity
and improvement in ventilation. The ventilatory response to CO2
is improved, resulting in a more efficient ventilation and maintenance of normocapnia.3336 A lower and less variable CO2, suggesting a more stable gas exchange, is seen in children who
received a caudal than those under general anesthesia.33,36 The pain
relief provided by epidural analgesia clearly improves ventilatory
mechanics22,34,39 and reduces the need for ventilation.40

Peripheral deafferentation induced by epidural or spinal anesthesia
reduces the degree of cortical arousal.41 Caudal blockade decreased
the degree of arousal, as measured by bispectral index (BIS), in
unstimulated children aged 2 to 5 years. No change in arousal was
detected in infants.41
Endocrine4246
The neurohumoral stress response to surgery occurs in children
even after minor surgical procedures. The degree depends on the
severity of the surgical insult. Epidural bupivacaine (upper level
T610) will significantly decrease the cortisol levels at the end of
surgery, and cortisol levels remain within normal levels up to
24 hours postoperative in children undergoing lower limb surgery
or hypospadias repair.42 Other investigators have shown that epidural analgesia suppresses the operative increase in epinephrine,
norepinephrine, and adrenocorticotropic hormone (ACTH) and
beta-endorphin42,4446 but not cortisol and prolactin when undergoing major abdominal surgery or urologic surgery.43,45 Central
blockade also preserves the insulin response to glucose in the
postoperative period.46
Thermoregulation
Epidural anesthesia (caudal) has little effect on the thermoregulatory threshold for vasoconstriction during halothane
anesthesia.47
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Gastrointestinal Motility
After abdominal surgery, gastrointestinal motility returns sooner
in patients who have had epidural bupivacaine before surgery
than those receiving opiates.48 Although this study has not been
repeated in children, clinical intuition suggests that this is also true
for children.
PHARMACOLOGIC DIFFERENCES
The pharmacologic differences observed in children vary with
age-related changes in plasma protein levels, body fluid compartments, distribution of cardiac output, and functional maturity of
liver and kidneys.
The relatively lower concentration of albumen and (1 acid
glycoprotein in neonates4953 results in reduced protein binding of
local anesthetics, particularly bupivacaine, potentially increasing
the free fraction of the drug. Plasma levels of 1 acid glycoprotein,
an acute-phase protein, increase with stress (surgery, infection)
negating this effect to a variable degree.50,51 Reduced plasma cholinesterase activity in neonates and infants younger than 6 months
(50% adult levels) delay clearance of ester local anesthetics.
Hepatic blood flow is reduced and metabolic degradation is
immature; consequently, a greater amount is excreted unchanged
in the urine.51,53 Neonate and infants are, thus, at a greater risk of
toxicity.50,53
Other important contributing factors to be considered in
children include the smaller fat content (15% body weight) and
skeletal mass (25% body weight),14 the proportionally larger brain
and liver, and the higher cardiac output and regional blood flow,
resulting in more rapid uptake.14 Despite this, the peak blood
concentrations in neonates and infants are lower than in adults
because their volume of distribution is significantly greater.
The lung function is also important. Sixty to 80% of an
intravenous lidocaine bolus is absorbed on the first pass through
the lungs. This may place children with right-to-left intracardiac
shunts at risk because, in an animal study,54 the plasma levels in the
young lambs with intracardiac shunts were double those of the
controls.
The site of injection, the vascularity of that site, and the regional
blood flow determine the rate of vascular uptake.5558 The pharmacokinetics of local anesthetics after caudal/epidural blocks
is well documented.51,55,5861 There is a rapid redistribution phase
and a slower elimination phase. Bupivacaine peak blood levels
are reached by 20 to 30 minutes after caudal55,58,61 and epidural
blockade.51,60 The elimination half-life is about 240 minutes.
Lidocaine plasma levels reach a peak after 30 to 45 minutes, and
it has an elimination half-life of approximately 100 minutes after
caudal administration.61,62 In the presence of a bloody tap, the
peak levels are greater and occur sooner.62 Special care should be
taken when injecting local anesthetic after a bloody tap.
The rate of vascular absorption, and therefore the peak blood
level, is considerably reduced by the addition of a vasoconstrictor.
During continuous epidural infusions, epinephrine has an initial
effect on the absorption of lidocaine and the accumulation of the
metabolite, monoethylglycinexylidide (MEGX), but the effect is
minimal after 3 hours.63 Epinephrine prolongs the action of local
anesthetics64 by up to 50% in small infants and 25% in 5-yearolds.63,65 In the authors experience, the duration of action of caudal
bupivacaine may be almost doubled by epinephrine in neonates
and prematures (unpublished data).
RISK-BENEFIT AND
POTENTIAL COMPLICATIONS
Prior to performing any procedure, the risk should be balanced
against the benefit. From the childs perspective, a block should be
performed without risk or complications. Most neuraxial blocks
are performed under sedation or general anesthesia. Neonates and
infants, as a group, are at greater risk under general anesthesia and
are also at greater risk of local anesthetic toxicity. Taking this into
account, there is some evidence that the combination of general
anesthesia and regional anesthesia may reduce the risks of both.
Inhalational agents raise the toxic threshold of local anesthetics,
whereas lower concentrations of inhalational agents can be used in
the presence of a successful block.
Large surveys have defined the risks in children.6675 The retrospective and prospective Association des Anesthsistes-Ranimateurs
Pdiatriques dExpression Franaise (ADARPEF) studies were
performed in the early 1990s.67,73 Since then, equipment more suitable
for use in children, particularly for infants and neonates, has been
developed. The National Epidural Audit in the United Kingdom
represents the risks in more recent times.74 In both of these prospective studies, representing two different decades, the risk of permanent injury is remarkably low compared with that in adults.
Fortunately, most complications are short-lived or easily treated.
The incidence of approximately 1 per 1000 blocks performed
is remarkably constant in these surveys conducted over four
decades.6873 In the recent U.K. audit, 96 incidents were reported
in 10,633 epidurals placed in 21 centers over a 5-year period.74
A 6-monthly audit performed during the 5-year period virtually
eliminated some of the problems. For example, the incidence of
pressure sores was virtually eliminated by reducing the concentration of the local anesthetic infusion. Only 1 child had residual
effects that resolved within 12 months. Nine serious incidents were
reported over 5 years. There were 5 nerve injuries recordedall
resolved. Two epidural abscesses, both from the same institution,
grew Staphylococcus aureus and were successfully treated with
antibiotics. Perhaps the most disturbing aspect was that 1 epidural
abscess presented at home a week after discharge.
Anecdotal reports of serious life-threatening complications (convulsions, dysrhythmia, cardiovascular collapse) after
neuraxial blocks are stark reminders that, without attention to
detail, potential disasters can and do occur. Epidural blockade has
been associated with severe neurologic sequelae in children.
Reports of spinal cord injury after a thoracic epidural76 and lumbar
epidural77,78; sacral osteomyelitis79 and subperiosteal haematoma
after caudal block bear testimony to this.
Venous air embolism has been suggested as the cause for
cardiorespiratory collapse in two case reports in which loss of
resistance (LOR) to air in large amounts was used for lumbar
epidural80 and caudal.81 This has led Sethna and Berde to advocate
the use of LOR to saline in children.82 LOR to saline, however,
carries a higher incidence of dural puncture.83 The authors
preference is for LOR to air but to limit the volume of air to 0.5 to
1 mLa volume that is not detectable by Doppler monitoring.84
The purpose of the LOR-to-air technique should be to determine
the change in resistance rather than to inject air into the epidural
space. Apart from the risk of venous embolism, excess volume of
air injected into the epidural space may result in a patchy block.84
The use of CO2 has been advocated to reduce this problem.84
Convulsions associated with pediatric regional anesthesia
are uncommon (0.05%) and usually without sequelae if treated
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promptly and effectively.7375 The low incidence could be explained
by the fact that most regional anesthetic procedures are performed
under general anesthesia, possibly masking the true incidence.
Myocardial depression, arrhythmia, or cardiovascular collapse may
indicate systemic toxicity.14,8587 Continuous infusions of bupivacaine epidurally have resulted in convulsions,8890 but by using
appropriate dosages, Berde et al have reported no convulsions
using continuous infusions in 1400 children.85
The incidence of dural puncture and postdural puncture
headache (PDPH) varies.90,91 Few cases of PDPH have been reported in children after epidural anesthesia. It is more common
after diagnostic lumbar puncture. Some studies suggest that PDPH
occurs only in children older than 10 years. The incidence varies
from 10% (1012 y) to 50% (1318 y). Risk factors include the
gauge of the needle used, the design of the needle tip, and the
number of punctures performed. The diagnostic criteria established by the International Headache Society92 are (1) bilateral
headache that develops less than 7 days after dural puncture,
(2) occurs or worsens less than 15 minutes after assuming the
upright position and disappears or improves less than 30 minutes
after resuming the recumbent position, and (3) disappears 14 days
after spinal puncture. PDPH is usually relieved by conservative
management (i.e., bed rest, intravenous fluids, mild analgesics
or opioids, and caffeine).91 If symptoms are severe or persist,
then epidural blood patch using is 0.25 to 0.3mL/kg of autologous
blood can be considered.
The risk of infection from short-term use of epidural infusions
is low,74,93 provided sterility is maintained during placement, but is
more likely to occur in immunocompromised patients.93 However,
reports describing meningitis,74,92,93 catheter site infection,93 and
epidural abscess74,94,95 indicate the need for aseptic catheter placement and vigilance in the postoperative period when continuous
infusions are used. S. aureus is the usual causative organism.74
CONTRAINDICATIONS
Contraindications to epidural anesthesia may be either relative or
absolute (Table 491).
EQUIPMENT
A large variety of needles, syringes, catheters, and ancillary items
have been developed commercially to facilitate epidural, caudal,
and spinal blockade.12 Since their introduction in the late 1980s,
the quality of equipment has improved, resolving many of the
TABLE 49-1. Contraindications to Epidural Anesthesia
May Be either Relative or Absolute
Absolute Contraindications Relative Contraindications
Infection at the site of
injection
Bleeding disorders
Allergy to local anesthetic
agents
Patient or parental refusal
From references 14, 62, 113, and 114.
Neurologic disease
Degenerative neurologic disorders
Congenital heart disease
Spinal anomalies
Vertebral implants (Harrington
rods)
Untreated hypotension
Septicemia
809
Figure 49-1. Pediatric epidural needles. Three widely used

Tuohy epidural needles (Portex, Braun, Arrow) showing
different markings and lengths. Inset, The eyes of the needles
that measure 1.7, 1.3, and 3.0 mm, respectively
hazards reported in decades past.12 A number of disposable kits
of variable quality are now available commercially. The choice is
very often determined by individual preferences, but the overall
selection must take into account the equipments suitability and
safety for a particular block in a particular patient.12 Practitioners
are advised to familiarize themselves with the idiosyncrasies of
individual kits before use (Figure 491).
Styleted needles are recommended to avoid implantation of
epidermal tissue in the epidural and subarachnoid spaces.9698
Previous reports have shown that these may take several years to
become symptomatic.96,98 However, risk of this complication is
probably overemphasized.
Commonly used spinal needles for infants are 25-gauge, shortbeveled (2.5-cm) and 22-gauge Quincke tip (3.8-cm) types. The
former is favored in former premature infants and newborns
because tissue resistance is better appreciated as the needle pierces
the dura or sacrococcygeal membrane. The short bevel permits
injection of local anesthetic agent into the narrow subarachnoid
space.12
An atraumatic Sprotte (Pajunk, Geisingen, Germany) and
Whitacre (Bectin Dickenson) are also available. The major
difference is that the lateral eye in the tip of the Sprotte is wider
than the Whitacre needle (1.2 mm vs 0.6 mm).99 This wide opening
makes accurate placement within the subarachnoid space difficult.
In addition, the Sprotte requires undue force to advance the
noncutting tip and puncture the dura of newborns.
Epidural needles commonly used in children are similar to
those used in adults. Desirable modifications for pediatric use
include a blunt point to allow appreciation of passage through
different tissues and LOR, small terminal needle opening, and a
well-fitting stylet.12 The epidural catheter should be biologically
inert, be resistant to kinking and stretching, have sufficient clarity
to visualize blood and CSF return, have an atraumatic tip design,
have suitable length markings, and be radio-opaque.12
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Figure 49-2. Neonatal epidural using loss of resistance to air.

The approach is almost perpendicular to the skin. The index
finger can be used as a brake to control needle advancement.
The drapes are purposefully incomplete so that correct
alignment can be maintained visually at all times.
The author favors the 19-gaugeG Portex epidural needle
(Hythe, Kent, UK) that is styleted and has winged handles and a
short round bevel. The shaft is 5 cm long and is graduated every
0.5 cm, and the orifice at the tip is 2 mm long. The epidural
catheter is a 21-gauge, open-ended, firm nylon catheter with an
atraumatic tip. The catheter is radio-opaque and marked at 1-cm
intervals with a broader mark at the point at which the catheter
emerges from the needle
The LOR syringe device should be made of high-quality glass
or plastic with a well-fitted glass piston or a silicon or latex plunger.
All syringes should be tested for smooth gliding prior to use. Wellfitted plungers allow steady or intermittent pressure to be applied
to the plunger of a syringe filled with air, saline, or both for sensing
the change in tissue resistance and LOR as the Tuohy needle is
advanced (Figure 492).
TEST DOSE
The standard test dose used as a marker for intravascular
injection is defined as an increase in heart rate (1020 beats/min)
or systolic blood pressure (10%) after the intravenous injection of
0.5 to 1 g/kg epinephrine in awake patients. The reliability of the
test dose is reduced under general anesthesia and varies under
different anesthetic conditions.100
Because most regional blocks are placed under general
anesthesia in children, the search for the ideal test dose to reduce
the risk of inadvertent intravascular injection continues. The use
of epinephrine containing solutions as a test dose under anesthesia may, but not always, produce an increase in heart rate when
injected intravascularly. These hemodynamic changes vary
with the anesthetic agent used (halothane,101 sevoflurane,102104 or
isoflurane105) and whether atropine has been administered.105
Atropine administered before the test dose improves the reliability
and may improve the sensitivity under halothane or isoflurane
anesthesia but not completely.
Isoproteronol (0.1 g/kg) has been advocated as an alternative.106109 Halothane, sevoflurane, and isoflurane attenuate
the tachycardic response to both epinephrine and isoproteronol.

Ephedrine has also been used in one study.110 However, the safety
of neither isoproteronol nor ephedrine in the epidural space has
been established.
Monitoring the electrocardiogram (ECG) changes for a greater
than 25% change in T-wave or ST segment changes, irrespective of
the lead chosen, is considered by some to be more specific and
more reliable.104,111,112 These changes have been questioned because
it seems that similar changes in heart rate, blood pressure, and
T-wave may be seen after a painful stimulus (surgical incision).103
The temporal relationship is important and a secondary drop in
pulse rate detected after intravenous epinephrine distinguishes
this from the response seen after a painful stimulus. Plethysmographic pulse wave amplitude (PPWA) has also been shown to be
effective in detecting an intravascular injection of a simulated
epidural test dose in children under sevoflurane anesthesia.113
The jury is still out as to which test is most specific and reliable.
Until an acceptably accurate test is found, the safe performance of
any regional block requires a negative aspiration test before the
injection of local anesthetic, an appropriate dose of local anesthetic
that should always be injected slowly and incrementally while
monitoring the ECG. There should be no resistance to the injection
of local anesthetic.
CAUDAL BLOCK
Caudal anesthesia is one of the most frequently used regional
anesthetic techniques in children for operations below the
umbilicus.14,6871,114116 Its popularity stems from its simplicity,
safety, and efficacy in all pediatric age groups67,75 and is widely
used for initial postoperative pain relief. It may be used as the sole
anesthetic, particularly in expremature infants, but is usually
used in conjunction with general anesthesia.
Anatomy
The sacral hiatus is formed as a consequence of failed fusion
of the fifth sacral vertebral arch. The remnants of the arch are
represented by two prominences, the sacral cornu, on either side
of the hiatus. The sacral hiatus extends from the sacral cornu to
the fused arch of the fourth sacral vertebra. The sacrococcygeal
membrane covers the sacral hiatus, separating the caudal space
from the subcutaneous tissue.
There is considerable variation in the sacral hiatal anatomy
mainly caused by incomplete posterior fusion of other sacral
vertebrae. However, a few important surface landmarks need to
be identified to enhance the success of the block in both normal
and abnormal sacra. The sacral hiatus virtually always lies at the
apex of an equilateral triangle that has the line drawn between the
posterior superior iliac spines as its base (Figures 493 and 494).
Another useful landmark for the sacral hiatus is where a line
drawn from the patella through the greater trochanter with the
hips flexed at 90 degrees transects a line drawn down the vertebral
column. The latter is particularly valuable in chubby infants whose
sacral hiatus is difficult to palpate (see Figure 494).
Technique
Caudal block is performed in the lateral decubitus position with
both knees drawn up. The prone knee-chest position has also been
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Figure 49-3. Caudal landmarks are obvious in this malnourished infant in the knee-chest position. The posterior superior
iliac spines form the base of an equilateral triangle with the sacral
hiatus at the apex (i.e., between the prominent sacral cornua).
described and is particularly useful when performing a caudal on
the awake high-risk expremature infant (see Figure 493). The
sacral hiatus and cornua are identified by palpation and can
be likened to the interspace between two metacarpophalangeal
joints (knuckles).
Under sterile conditions, a short-beveled needle held gently
between the thumb and the index finger is introduced approximately 45 degrees to the skin (i.e., with the bevel parallel to the
skin) at the sacral hiatus and advanced until it pierces the sacrococcygeal ligament.117 A give is felt as it enters the caudal epidural
space and can be confirmed by LOR. A 22-gauge intravenous
cannula is popular,118 but in the authors experience, it has a higher
incidence of failure (subcutaneous injection). Further needle
811
advancement, as described in adults, is unnecessary because it may

increase the risk of dural puncture or bloody tap.
Penetration of the sacrococcygeal membrane just above
the sacral cornua carries a lower incidence of bloody tap in the
authors experience. The caudal space at this point is deeper than
below the cornua, where it may be very narrow.
Failure to obtain LOR after the sacrococcygeal ligament has
been penetrated may indicate that the bevel is lying against the
anterior wall of the caudal space. This can be overcome by simply
rotating the needle through 180 degrees.
Once the needle position is confirmed and aspiration for blood
and CSF is negative, the appropriate volume of local anesthetic
can be injected. Aspiration should be gentle because strong
negative pressure may cause the low-pressure epidural vessels to
collapse before a positive aspiration test can be elicited.
In the event of a bloody tap, the needle should be redirected or
removed and carefully reinserted more cephalad. Injection of local
anesthetic in these circumstances should proceed with caution in
view of the greater risk of toxicity.62
Dosage
The most commonly used drugs for caudal block are bupivacaine,
ropivacaine, and lidocaine. Many formulas have been proposed
based on weight, age, and length.114116,118120
The most practical is that suggested by Armitagethat is,
0.5 mL/kg of local anesthetic for sacrolumbar dermatomes,
1.0 mL/kg for lumbar thoracic dermatomes (subumbilical), and
1.25 mL/ kg for midthoracic dermatomes (upper abdominal).62
The duration of analgesia depends upon the drug and dose administered, the age of the patient, the site of surgery, and whether
epinephrine is used.14,68,70 Bupivacaine 0.25% is effective for postoperative pain relief. Increasing the concentration does not offer
any additional advantage but may increase the incidence of side
effects and/or complications.
Concern over motor blockade, particularly in the outpatient
setting, has led investigators to seek the optimal concentration
with the least motor dysfunction.121123 Bupivacaine 0.125% seems
appropriate in this setting,123 although the duration of action may
be shorter.
Ropivacaine has also been evaluated at different concentrations.123128 The duration of analgesia is shorter with 0.1%
ropivacaine than with 0.2% ropivacaine, which in turn, has
duration of analgesia similar to that of 0.3% ropivacaine but with
less motor block.123 Recently, Hong and colleagues showed that a
larger volume (1.5 mL/kg) of diluted ropivacaine (0.15%) provides
analgesia of better quality and longer duration than a smaller
volume (1 mL/kg) of more concentrated ropivacaine (0.225%) in
children undergoing day- case orchiopexy.124 Caudal levobupivacaine and ropivacaine have a similar potency.125,129
Side Effects and Complications

Figure 49-4. Although the landmarks are obvious in this
malnourished 5-year-old child lying in the right lateral position,
a virtual line drawn from the patella through the greater
trochanter will indicate the level of the sacral hiatus in those
children in whom the sacral hiatus is difficult to palpate.
Dural puncture and subsequent injection of local anesthetic

solution may lead to a total spinal associated with cardiovascular
collapse or respiratory arrest (apnea).
Systemic toxicity may manifest as arrhythmia, cardiovascular
collapse, or convulsions after accidental intravascular or sacral
interosseous injections. The incidence of bloody tap varies with
experience, the age of the patient, and equipment used.
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Urinary retention and delayed micturition are related not

only to the duration of preoperative starvation but also to the
concentration of local anesthetic solution. The incidence is negligible when 0.25% bupivacaine is used.
Motor blockade and inability to walk are also concentrationdependent.121,122
Nerve injury and neurologic defect have been reported but are
extremely uncommon after caudal blockade and usually transient.
Inclusion dermoid is a reported complication but is difficult to
document. Styletted needles reduce the risk of tissue coring. The
risk of transporting nucleated epidermal cells from the stratum
spinosum during puncture for caudal block is low, and no
differences exist between 22-gauge hollow needle and 22-gauge
caudal block needle.96,97
Intrapelvic injections have been reported but, with appropriate
technique, should not occur.67,79,95
LUMBAR EPIDURAL
Lumbar epidural is indicated for abdominal, pelvic, and lower
limb surgery.130135 The dermatomes involved in a transverse
abdominal incision favored by pediatric surgeons are few and
can easily be covered by an accurately placed block. It is usually
performed under general anesthesia to ensure a stationary child,
but can also be performed under sedation or awake in a cooperative child.
The technique is essentially the same as in adults, but there
are some important differences. The resistance of the ligamentum flavum is weaker, particularly in infants and neonates.
The epidural space is less compliant15 and narrower in children.
A midline approach is technically easier and safer because the
epidural space is widest and the epidural vessels less dense at
this point.
The anatomic landmarks are easily palpated in the midlumbar region. The epidural needle can be advanced perpendicularly to the skin because the spinous processes are almost
horizontal when the back is flexed at this level131,132 (see Figure
492). The distance from the skin to the epidural space varies
considerably in the growing child, but a useful practical guideline
is 1 mm/kg body weight (for children between 1 and 10 y).135 Numerous authors have shown a good correlation with weight135137
and age.135137
Both air and saline have been advocated for the LOR test to
identify the epidural space.130135 Saline is more popular according to
one survey,138 but air is perhaps more sensitive.131,135 A microinfusion
technique has also been described for use in children.139
To confirm the occurrence of a dural puncture when saline is
used, a dextrostix test will give a positive reaction to sugar in the
presence of CSF and the CSF fluid will be at body temperature.140
An epidural catheter can be introduced 1 to 3 cm into the
epidural space for continuous infusion or intermittent top-up
dosages. This is best done after the test dose has been administered,
because this will facilitate the passage of the catheter.135,141 The
length of catheter introduced is important. Too much length runs
the risk of unilateral blockade.
Dosage
Various dosing schedules14,130133 have been advocated but depend
on whether both sensory and motor blockade are required.
Bupivacaine 0.5% 0.75 mL/kg of will achieve both sensory and

motor blockade for upper abdominal operations.131 However,
bupivacaine 0.25% in the same volume will provide satisfactory
analgesia.15,89 For children taller than 100 cm, 1 mL/10 cm height
is also clinically useful.23 The author has used this formula for
children taller than 50 cm. A recent study has suggested that 0.6
mL/kg is the optimal bolus dose for abdominal surgery.142
Ropivacaine and levobupivacaine have been studied and, for
practical purposes, the dose and infusion rates are the same.142144
Less motor blockade for the same concentration can be expected.
SACRAL EPIDURAL BLOCK

Two approaches to the sacral epidural space have been described
by Busoni and associates.145,146 The sacral intervertebral block145,147
is possible because the sacral vertebrae have not fused in childhood. It is particularly useful for children in whom the sacral
hiatus cannot be identified (e.g., obese infants or high anorectal
malformations).148
The modified Taylor approach146 to the epidural space between
L5S1 interspace is possible because of the large space between the
spinous process of the fifth lumbar vertebra and the rudimentary
spinous process of the first sacral vertebra.
Both these approaches reduce the risk of damage to the spinal
cord and spinal arteries because these structures are located
much higher in the spinal canal compared with lumbar epidural.
Similarly, because the dural sac usually ends at S2, the risk of dural
puncture is decreased. A cautious approach should always be used
because individual variation exists and the dural sac may extend
lower than expected.1620 The incidence of dural puncture is higher
than with the caudal approach.
Because both these sites are farther from the anus than the
sacral hiatus, there is less likelihood of infection. For this reason,
Busoni and Sarti suggest that continuous infusions are more
feasible at these sites.145
Technique
With the child in the left lateral position and the legs flexed, the
posterior superior iliac spines are identified. A line drawn between
the posterior superior iliac spines bisects the second sacral vertebral arch (S2). The largest sacral intervertebral space (S23) is
easily identified 0.5 to 1.0 cm caudad of this line.
The L5S1 interspace is located 0.5 to 1.0 cm cephalad of this
line. It is the largest interspace in the vertebral column and is also
easily palpable provided the fat overlying sacrum is not too great.
In this situation, the needle can be introduced down to bone and
then walked up or down the vertebral spine till the interspace is
identified.
After skin preparation, the skin is punctured with a large-bore
needle to facilitate insertion of the Tuohy needle. The epidural
space is identified by an LOR technique. No flexion is required
because the spinous processes of the sacrum are rudimentary.
The Tuohy needle can thus be inclined up to 50 degrees cephalad
to facilitate entry into the L5S1 interspace. This is not necessary
for the sacral intervertebral approach.
Dosage
Dosages are similar to those described for the caudal block.
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THORACIC EPIDURAL
Technique
Thoracic epidural should be performed only by experienced

anesthesiologists familiar with epidural techniques in children
because of the potential risk of trauma to the spinal cord. It is
preferable that the child is anesthetized to ensure complete absence
of movement.
The main indication for thoracic epidural in children is for
upper abdominal or thoracic surgery,131 particularly in poor-risk
patients with respiratory disabilities.32 Experience in children is
more limited than lumbar epidural with only few reports in the
literature.22,67,74,131,149155
With the child lightly anesthetized, an 18- or 20-gauge intravenous cannula is introduced into the caudal space.11 The gauge is
determined by the catheter, which should pass freely through
the intravenous cannula. Once the intravenous cannula is in
place, the needle stylet is removed. A 20- to 24-gauge epidural
catheter is measured against the infants back to the level of the
planned surgical incision. This predetermined length of catheter
can then be introduced gently up the epidural space (Figure 49
5). The exact location of the catheter can be confirmed radiographically,11,155 by nerve stimulation, or by ultrasound (see Ultrasound
Imaging of Spinal Cord). In the authors experience, the catheter
has passed up the midline to within one vertebral body of the
preselected level in more than 300 cases.11,114 Difficulties may also
occur with thin catheters (24 gauge) that are too flexible and may
curl in the epidural space.157
It is important not to force the catheter against any resistance
because the catheter tip may be impinging on a nerve root or
blood vessel. Flexion or extension of the infants spine,11,153 flushing
with saline,11,154 or twisting the catheter11,153 can be used to facilitate
the passage of the catheter when resistance is felt. Difficulties may
also occur with thin catheters (24 gauge) that are too flexible and
may curl in the epidural space. Styleted catheters can overcome
this problem but add to the cost.153
Technique
The midline approach is preferred because it is safer and easier to
perform than the lateral paraspinous approach. The angulation of
the Tuohy needle to skin depends on the age of the child and the
level of the epidural puncture required. The angulation is greatest
in the midthoracic region, whereas above or below this level, the
angle tends toward 90 degrees (i.e., perpendicular to the skin).
Skin-to-epidural distance (SED) correlates significantly with the
age and weight. The equation for the relation between SED (cm)
and age was 2.15 + (0.01 age [mo]) and for weight is 1.95 +
(0.045 weight [kg]).154
The thoracic interspace chosen should be as close to the
dermatome of the surgical incision as possible. The T57 interspaces are preferred because the Tuohy needle is inserted between the thoracic spines at a 45-degree angle.131 This increases the
effective depth of the extradural space.22 Furthermore, at this
angle, the rounded part of the Tuohy needle impinges on the dura
rather than the sharp end as occurs with approaches that are closer
to perpendicular.151 This strategy will further reduce the risk of
dural puncture.
No serious complications, except dural puncture, have been
reported in the published series.22,67,74,131,150,151 However, it has to
be recognized that the complications reported in adults can occur
in children. Anecdotal case reports are testimony to this.76
Dosage
The simplest formula is that described by Busoni.152 The aim is to
achieve a spread of analgesia extending from T2 to T12 when an
epidural is placed at the midthoracic level.
Children < 10 kg 0.33 mL/kg body weight of 0.5% bupivacaine
Children > 10 kg 0.25 mL/kg body weight of 0.5% bupivacaine
Top-up doses should be half the original dose.
In the authors experience, larger volumes of up to 0.5 mL/kg may
be required in small infants and a concentration of 0.25%
bupivacaine is adequate.
CAUDOTHORACIC EPIDURAL
Lumbar and thoracic epidural techniques are technically
more challenging than caudal epidural. The advantage of the
caudothoracic technique11 is that it makes use of the sacral hiatus
to gain access to the lumbar and thoracic epidural spaces in infants
and neonates.153,154 There is a reduced risk of dural puncture or
spinal cord injury,11,154 and it can be performed using universally
available equipment.11
Figure 49-5. Radiograph of a caudal catheter. The catheter can

be seen extending from the sacral hiatus to the level of L2. Radioopaque contrast can be seen overlying L2.
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To confirm accurate placement of epidural catheters, a variety

of techniques have been described and their use depends on
the facilities available. Epidurography,155 fluoroscopy, ultrasonography,158161 electrocardiographic confirmation,162 and nerve
stimulation162165 have been described. Ultrasonography is limited
by the degree of ossification of the vertebrae and the size of the
acoustic window. Electrical stimulation allows real-time adjustment but requires specifically designed equipment.
The Tsui test per se relies on epidural nerve root stimulation
manifesting as myotomal activity (muscle twitching) using low
monopolar electrical stimulation and a specific epidural kit
(Arrow Flexitip Plus Catheter) or a catheter meticulously filled
with normal saline.162,165 Stimulation of the upper thoracic (T16)
segments was manifested by visible or palpable intercostal muscle
twitches; lower thoracic (T712) by abdominal twitches of the
external oblique and rectus muscle, lumbar segments (L14) by
hip flexion, and caudal space by contraction of the anal sphincter.
Should the desired level not be achieved, further attempts to
feed the catheter against resistance are potentially harmful.
A larger volume of local anesthetic can be used to achieve the
necessary level of blockade.
Dosage
Bupivacaine 0.25% 0.5 to 0.75 mL/kg can be used, depending on
the number of dermatomes required to be blocked.11 This dosage
is somewhat higher than that indicated for thoracic epidural but
is possibly owing to the differences in age group or the catheter
used (terminal versus side holes).
ULTRASOUND IMAGING
OF SPINAL CORD
In infants younger than 6 months, the posterior elements of
the spinal canal are incompletely ossified, allowing an acoustic
window for sonographic imaging. With increasing age, the value
of ultrasound imaging decreases with more ossification and as the
depth to the epidural space and spinal cord increases. Of the
various scanning perspectives, the paramedian longitudinal
and the intervertebral axial planes offer the best views.158,159 The
size of these ultrasound windows decreases with age.158,159
The high-frequency 7- to 10-Hz linear array transducer probes
generate better images than the sector probes. The resolution
beyond approximately 3.5 cm is reduced. Accurate evaluation of
spinal cord structures of children weighing more than 25 to 30 kg
is thus limited if high-frequency probes are used.158
In axial ultrasound scans of the spinal canal (Figure 496), the
spinal cord is a hypoechoic (black) oval structure with a central
hyperechoic area that represents the depths of the invaginated
paramedian sulcus. The cord appears wider in the cervical and
lumbar region. The nerve roots appear as paired echogenic structures entering the cord ventrally and dorsally. The hypoechoic
spinal cord tapers to the conus medullaris whereas the rest of
the spinal canal is filled with multiple, small, rounded structures
representing the nerve roots of the cauda equina seen in cross
section.
The dura mater is seen as a hyperechoic (white) ring bordering
the spinal canal; the pia mater is seen as a hyperechoic ring closely
applied to the hypoechoic spinal cord. Outside the pia, the CSF
appears hypoechoic (black).
Figure 49-7. Longitudinal ultrasound image of spinal cord in

a neonate. The skin epidural distance is shown as 4.5 mm and
the depth of the epidural space is 1.2 mm. See text for detailed
description of the ultrasound image.
Normally, the spinal cord is free-floating in the spinal canal and
comes to lie in a ventral position, against the posterior aspect of
the vertebral bodies, when the ultrasound is performed in the
prone position. The dorsal CSF space is larger than the ventral
space. The paraspinous muscles appear as an ovoid hypoechoic
structures either side of the midline.
Longitudinal scans (Figure 497) of the lower spinal cord show
the spinal contents as a number of parallel hyperechoic lines.
The cord is homogenously hypoechoic with a central hyperechoic line and bounded by the hyperechoic pia. The dura mater
is a hyperechoic line closely applied to the bony elements. The
vertebral bodies can be identified ventrally with dorsal body
elements casting acoustic shadows (sawtooth) at regular intervals
across the spinal canal and its contents.
The best views are obtained in the more premature infants in
whom the relative lack of ossification allows a broader view of
the underlying structureseven those beneath the spinous or
transverse processes.
Additional information with regard to the anatomic relationships of the spinal cord, dura mater, and epidural space (size,
depth) can be put to good use.158161 The depth of ligamentum
flavum as determined by ultrasound can serve as a guide to the
depth at which LOR can be expected. The depth of the epidural
space varies from 4 to 12 mm in neonates depending on the level
and angle of entry. Good correlation between the depth of the
epidural space as determined by the ultrasound and the depth at
which LOR is detected has been shown.158,159
The epidural space in neonates and infants ranges from 1 to
3 mm in depth. The orifices of the 19-gauge (Portex) or 20-gaugeG
(Arrow) Tuohy needles are 2 and 3 mm, respectively (see Figure
491). This suggests that dural tenting must occur at the time of
either needle placement or epidural catheter insertion when
epidurals are placed in neonates and infants.
Using real-time imaging, the ultrasound can verify the correct
placement of the Tuohy epidural needle and both the injection
of local anesthetic and the position of the epidural catheter
within the epidural space.158,159 Ultrasound could also be used to
determine the position of the catheter tip introduced via the sacral
hiatus.159,161
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Figure 49-6. Axial ultrasound images of spinal cord at different levels. See text for detailed description.
The exact location of the conus can also be determined. The
conus ascends from its early fetal position in the sacral canal to
the eventual adult position. The precise timing of this ascent is a
matter of debate. Traditionally, the termination of the spinal cord
is said to lie at the L3 vertebral body at birth rising to the adult
level at L12 by 1 year of age.
A recent publication159 shows that the conus is located in the
adult position at the L1 interspace at birth in the majority of term
neonates (85%); and at L13 in premature and low-birthweight
babies. A conus detected below L3 at birth suggests a tethered cord
and requires further investigation. Epidural anesthesia may need

to proceed with caution in these infants.
Similarly, ultrasound may also provide information regarding
abnormal underlying anatomy in neonates,18,19 particularly those
with vertebral anomalies (e.g., VATER [vertebral abnormalities,
anal atresia, cardiac abnormalities, tracheoesophageal fistula and/
or esophageal atresia, and renal agenesis and dysplasia] syndrome),
unusual pits (Figure 498), or tufts of hair suggesting an underlying
spina bifida. Abnormal spinal cord anatomy (syrinx, diastomatomyelia) may also be detected.18,19
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Figure 49-8. Sacral pit in an infant. Usually considered a contraindication to caudal block, ultrasound imaging can determine
whether there is an underlying spinal deformity or not. A caudal
block was performed on this infant without problems.
CONTINUOUS EPIDURAL INFUSIONS

Postoperative analgesia can be maintained by using intermittent
top-up doses of local anesthetic11,23 or continuous infusion of local
anesthetic with or without adjuvants.60,89,128,134,149,156,157,166
Because individual requirements for analgesia vary, intermittent top-ups can give a better idea of the duration of analgesia
required. It may also avoid the potential for tachyphylaxis and the
toxicity associated with continuous infusions. Because significant
hypotension is unlikely, swings in blood pressurea problem
in adultsare not seen in children.15,23 Intermittent top-ups are
particularly useful in neonates and small infants.
A recent survey shows no clear consensus on the selection
of local anesthetic agent or concentration used in clinical
practice.134 Continuous epidural infusion of bupivacaine and
ropivacaine in low concentrations has been shown to be safe and
effective.51,52,74,88,114,115,134,166 No accumulation of plasma bupivacaine occurs after 48 hours of infusion in healthy children from
11 months to 15 years.52,123,135,137 Dosage guidelines suggested by
Berde for racemic bupivacaine (i.e., 0.2 mg/kg/h for infants and
neonates and 0.4 mg/kg/h for older children) have improved the
safety of continuous epidural infusions.85 Berde reported no complications in more than 1400 children who received continuous
epidural infusions according to these guidelines.85
Desparmet and coworkers used a smaller loading dose
0.5 mL/kg 0.25% bupivacaine followed 30 minutes later by an
infusion of 0.08 mL/kg/h using a volumetric infusion pump.166 In
the authors experience, this regime works well, but for simplification and ease of calculation, an infusion of 0.1 mL/kg/h (0.25
mg/kg/h) can be used. Meignier and colleagues used a lower
infusion rate (0.06 mL/kg/h) for thoracic epidurals in children
with respiratory difficulties.38
There is a trend toward using the single S(+) isomers, ropivacaine

and levobupivacaine, in modern pediatric practice.125,127,134,140,141,167
The reduced cardiac and central nervous system toxicity as well as
less motor blockade with little difference in onset time or analgesic
potency suggest that the single isomers may be more beneficial.
Pharmacokinetic studies on S(+) isomers give further support
to Berdes guidelines.43,85 However, infants younger than 6 months
are at risk of accumulation of bupivacaine when the infusions
extend beyond 48 hours. Little or no accumulation occurs when
ropivacaine 0.2% is infused for up to 72 hours in children older
than 3 months.51 Levels in neonates vary but are within safe
limits.51 The vasoconstrictive properties of ropivacaine may
delay its systemic absorption from the epidural space when compared with bupivacaine. Pharmacokinetic studies using levobupivacaine are currently limited to less than 24 hours or single-shot
caudals.127129
In children old enough to understand, patient-controlled
epidural analgesia (PCEA) provides satisfactory analgesia with a
small incidence of adverse side effects.169,170
For practical purposes, once a particular infusion rate has been
selected, regular assessment of the level of blockade should be
made and the appropriate adjustment made to the rate of infusion
as necessary. If the maximal infusion rate is reached and the child
still remains agitated, addition of a systemic or epidural opioid
should be considered.
EPIDURAL ADJUVANTS
A variety of agents are being used as adjuncts to local anesthesia
(Table 492).171178 Their purpose is to allow the concentration
of the local anesthetic agent to be reduced while maintaining analgesia, to prolong the duration of analgesia, or to improve
the quality of the blocks by reducing unwanted opiate side
effects.171,172,177,178
Most studies have used inguinal surgery as the model to
determine the efficacy of these additives. Is this ideal? Can these
findings be extrapolated to major abdominal or thoracic surgery?
The balance of risk versus benefit must be considered. The
potential risk of additives seems unjustified for relatively minor
day case surgery. Analgesics, administered orally or rectally, with
lesser risks are equally effective. However, experience with epidural opioids for more severe postoperative pain,175,176 as well as that
resulting from malignant diseases175,176 and other pain syndromes,178,179 is increasing.
Epidural opioids do not block the sympathetic or motor fibers
and, thus, do not affect muscle strength or blood pressure in a
manner that local anesthetics may. However, they are often used
in combination with local anesthetics, thereby reducing the risks
of both agents.
The epidural space can be entered anywhere along the neuraxis.
Factors affecting the site of the catheter placement include the
dermatomal distribution of the patients pain, the risk to the spinal
cord, and the lipid solubility of the adjuvant used. The lipidsoluble opioids, such as fentanyl and sufentanil, penetrate the
spinal cord rapidly and are less likely to migrate rostrally. Watersoluble opioids, such as morphine, do not penetrate as rapidly and,
therefore, migrate to a greater extent in the CSF. The affinity of
the drug for the spinal opioid receptor will also influence the
spread within the epidural space and CSF. Morphine, for example,
can be placed in the caudal or lumbar areathe sites most often
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TABLE 49-2. Regimens for Continuous Epidural Infusions Used in Children

Drug
Dose
Bupiv
Bupiv 0.25%
Bupiv 0.2%
Bupiv 0.2%
Bupiv 0.1%
Bupiv 0.125%
Bupiv 0.1250.25%
Bupiv 0.1%
Bupiv 0.25%
Bupiv 0.10.125%
Bupiv 0.125%
Bupiv 0.2%
0.2 mg/kg/h
0.4 mg/kg/h
4 mg/kg/d
0.1 mL/kg/h
0.1 mL/kg/h
0.2 mL/kg/h
0.20.3 mL/kg/h
0.25 mL/kg/h
0.10.5 mL/kg/h
0.08 mL/kg/h
0.5 mL/kg/h, max
0.375 mg/kg/h
0.2 mg/kg/h
Bupiv 0.2%
Bupiv 0.185%
Bupiv 0.1%
Ropiv 0.2%
Ropiv 0.2%
Ropiv 0.1%
Ropiv 0.20.25%
Ropiv 0.2%
0.2 mg/kg/h
0.16 mL/h
0.25 mL/kg/h
0.2 mL/kg/h
0.2 mL/kg/h
0.2 mL/kg/h
0.10.3 mL/kg/h
0.10.2 mL/kg/h
Additive
Ages
F 1 g/mL
D 50160 g/mL
F 1 g/mL
S 0.08 g/kg/h
F 0.06 g/kg/h
S 0.03 g/kg/h
F 0.02 g/kg/h
F 2 g/mL
C 0.040.12 g/kg/h
Neonate
Infant, child
6 mo15 y
Neonate
Neonate
Neonate, infant
Neonate4 m
Neonate6 y
Neonate16 y
11 mo15 y
1 mo18 y
17 mo
212 y
512 y
115 y
12 d18 y
3 mo6 y
4 m7 y
19 y
14 y
Children
Neonate1 y
Site
T
L, T
L
L
L, T
L, T
L
L, T
L
L
L
L
L
L
L, T
L
L
L
L, T
Reference
Berde85
Berde52,85
Meunier208
Bsenberg11,40
Larsson209
Murrell210
Wolf211
Luz207
Wilson212
Desparmet166
Wood213
Meunier208
Lejus217
Lejus214,217
Kokki215,216
Lejus217
Kart218
Hansen219
Yaster114
De Negri144,220
Moriarty221
Bsenberg51
Bupiv = Bupivacaine; C = clonidine; D = diamorphine; F = fentanyl; L = lumbar; Ropiv = ropivacaine; S = sufentanil; T = thoracic.
selected in childrenand analgesia can be provided in the

thoracic dermatomes.176
The duration of analgesia is variable depending on the age of
the patient, the type of surgery, the drug used, and the dosage
given.177 Morphine has been shown to provide 8 to 20 hours
of analgesia in children using a dose of 50 to 100 g/kg.173,180
Fentanyl, conversely, does not prolong the duration of analgesia
when added to single-shot caudal but significantly increases the
incidence of nausea and vomiting.181
Complications and Side Effects

1. Itching (+20%) usually more an annoyance than a major
problem. Facial or nasal pruritus is most common in children.
2. Nausea and vomiting (40%).
3. Urinary retention (30%).
4. Delayed respiratory depression may occur several hours after
opioid administration and is dose-related. One reported case in
a 22-month-old child who received 100 g/kg of morphine
became unconscious and cyanosed 32 hours after administration.180 Children younger than 1 year seem to be particularly
sensitive to epidural morphine, and it is probably best avoided
in this age group.182 Supplementation of intravenous opioids to
epidural opioids in older pediatric oncology has a much lower
complication rate (0.85%).181
All these side effects may be treated symptomatically or
specifically with naloxone in small doses so as to reverse the side
effect without reversing the analgesia.
Fentanyl is preferred by many.181183 However, its short duration
of action limits its use primarily to continuous infusions and
PCEA.170 It offers no advantage over bupivacaine 0.125%181 when
used for single-shot caudal or continuous infusion of 0.125%
ropivacaine.183
Sufentanil, a more potent and more highly lipid-soluble opioid,

has not been widely used28,184187 but is the authors preferred
adjuvant for continuous epidural bupivacaine or ropivacaine
infusions. Satisfactory analgesia, without complication, has been
provided in over 500 children using a concentration of 1 g/mL in
0.2% bupivacaine or ropivacaine and infused at 0.1 mL/kg/h after
an initial bolus dose 0.25 to 0.5 g/kg.
It is essential that the nursing staff caring for children who have
had epidural opiates should be well versed with the technique.
Most centers would advise that these children be admitted to a
high-care or intensive care area. They should have cardiorespiratory monitoring and, where possible, pulse oximetry and
capnography. Clearly, this is not always practical. A progressively
declining respiratory rate and excessive somnolence are very
suggestive of respiratory depression and a relative overdose.
EPIDURAL CLONIDINE
Epidurally administered clonidine enhances the quality and
duration of postoperative analgesia when it is used as an adjunct
to local anesthetics.188196 The direct 2 adrenergic action at the
spinal cord (antinociceptive) makes it attractive because it lacks
the side effects seen with epidural opiates.194
Clonidine 1 to 2 g/kg increases the duration of analgesia from
approximately 5 to 10 hours when combined with bupivacaine
0.1 to 0.25% or ropivacaine 0.08 to 0.2%. The quality of analgesia
provided is comparable with that of morphine or hydromorphone
after single-shot caudal191 and epidural fentanyl when used in
patients undergoing a Nuss procedure.195
The addition of 1 to 2 g/kg of clonidine to a caudal block with
0.25% bupivacaine significantly increases the duration of postoperative analgesia in children when compared with bupivacaine
with epinephrine.188,193
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Dexmedetomidine 2 g/kg, a shorter-acting 2 adrenergic, also

prolongs caudal analgesia without significant hemodynamic side
effects but has no advantage over clonidine.193
The combination of S(+) ketamine and clonidine has been
reported to provide satisfactory analgesia for up to 20 hours.196
Both agents at the higher dosage levels are associated with a
greater risk of sedation, apnea (particularly neonates and infants),
or nausea.
OTHER ADJUVANTS
Other agents, such as ketamine,197 tramadol,198,199 neostigmine,200202
midazolam,203205 buprenorphine, and magnesium,206 have their
advocates but all are associated with an unacceptably high
incidence of nausea and vomiting with minimal added benefit.
Concerns over the safety of these agents related to spinal cord
toxicity remain unanswered.172
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172. Lnnqvist PA. Adjuncts to caudal block in childrenquo vadis? Br J
Anaesth. 2005;95:431433.
173. Krane EJ, Jacobsen LE, Lynn AM, et al. Caudal morphine for
postoperative analgesia in children. Anesth Analg. 1987;66:647653.
174. Attia J, Ecoffey C, Sandouk P, et al. Epidural morphine in children.
Pharmacokinetics and CO2 sensitivity. Anesthesiology. 1986;65:590594.
175. Berde CB, Fischel N, Filardi JP, et al. Caudal epidural morphine analgesic
for an infant with advanced neuroblastoma. Pain. 1989;36:219223.
176. Rosen KR, Rosen DA. Caudal epidural morphine for control of pain
following open-heart surgery. Anesthesiology. 1989;70:418421.
177. Jensen BH. Caudal block for postoperative pain relief in children after
genital operations. A comparison between bupivacaine and morphine.
178. DAngelo R, Cohen IT, Brandon BW. Continuous epidural infusion of
bupivacaine and fentanyl for erythromelalgia in an adolescent. Anesth
Analg. 1992;74:142144.
179. Anghelescu DL, Ross CE, Oakes LL, et al. The safety of concurrent
administration of opioids via epidural and intravenous routes for
postoperative pain in pediatric oncology patients. J Pain Symptom Manage.
2008;35:412419.
180. Krane EJ. Delayed respiratory depression in a child after caudal epidural
morphine. Anesth Analg. 1988;67:7982.
181. Cho JE, Kim JY, Hong JY, et al. The addition of fentanyl to 1.5 mg/ml
ropivacaine has no advantage for paediatric epidural analgesia. Acta
182. Valley RD, Bailey AG. Caudal morphine for postoperative analgesia in
infants and children: a case report of 138 cases. Anesth Analg. 1991;72:
120124.
183. Campbell FA, Fear DW. Analgesic efficacy and safety of a caudal
bupivacaine-fentanyl mixture in children. Can J Anaesth. 1992;39:661664.
184. Benlabed M, Ecoffey C, Levron JC, et al. Analgesia and ventilatory
response to CO2 following epidural sufentanil in children. Anesthesiology.
1987;67:948951.
821
185. Cho JE, Kim JY, Kim JE, et al. Epidural sufentanil provides better
analgesia from 24 h after surgery compared with epidural fentanyl in
186. Sendasgupta C, Makhija N, Kiran U, et al. Caudal epidural sufentanil
and bupivacaine decreases stress response in paediatric cardiac surgery.
Ann Card Anaesth. 2009;12:2733.
187. Erol A, Tuncer S, Tavlan A, et al. Addition of sufentanil to bupivacaine
in caudal block effect on stress responses in children. Pediatr Int. 2007;
49:928932
188. Jamali S, Monin S, Begon C, et al. Clonidine in pediatric caudal
189. De Negri P, Ivani G, Visconti C, et al. The dose-response relationship
for clonidine added to a postoperative continuous epidural infusion of
190. Luz G, Innerhofer P, Oswald E, et al. Comparison of clonidine
1 microgram kg-1 with morphine 30 micrograms kg-1 for post-operative
caudal analgesia in children. Eur J Anaesthesiol. 1999;16:4246.
caudal clonidine, morphine, or hydromorphone combined with
ropivacaine in pediatric patients undergoing ureteral re-implantation.
Anesth Analg. 2007;104:1356363.
192. Joshi W, Connelly NR, Freeman K, et al. Analgesic effect of clonidine
added to bupivacaine 0.125% in paediatric caudal blockade. Paediatr
Anaesth. 2004;14:483486.
193. El-Hennawy AM, Abd-Elwahab AM, Abd-Elmaksoud AM, et al.
Addition of clonidine or dexmedetomidine to bupivacaine prolongs
194. Cucchiaro G, Dagher C, Baujard C, et al. Side-effects of postoperative
epidural analgesia in children: a randomized study comparing morphine
and clonidine. Paediatr Anaesth. 2003;13:318323.
195. Cucchiaro G, Adzick SN, Rose JB, et al. A comparison of epidural
bupivacaine-fentanyl and bupivacaine-clonidine in children undergoing
the Nuss procedure. Anesth Analg. 2006;103:322327.
196. Hager H, Marhofer P, Sitzwohl C, et al. Caudal clonidine prolongs
analgesia from caudal S(+)-ketamine in children. Anesth Analg. 2002;94:
11691172.
197. Margetts L, Carr A, McFadyen G, et al. A comparison of caudal
bupivacaine and ketamine with penile block for paediatric circumcision.
198. Khan S, Memon MI. Comparison of caudal bupivacaine and bupivacainetramadol for postoperative analgesia in children with hypospadias repair.
J Coll Physicians Surg Pak. 2008;18:601604.
Br J Anaesth. 2006;97:385388.
200. Karaaslan K, Gulcu N, Ozturk H, et al. Two different doses of caudal
neostigmine co-administered with levobupivacaine produces analgesia
201. Batra YK, Arya VK, Mahajan R, et al. Dose response study of caudal
neostigmine for postoperative analgesia in paediatric patients undergoing genitourinary surgery. Paediatr Anaesth. 2003;13:515521.
2004;51:702706.
203. Bhardwaj N, Yaddanapudi S, Ghai B, et al. Neostigmine does not prolong
the duration of analgesia produced by caudal bupivacaine in children
undergoing urethroplasty. J Postgrad Med. 2007;53:161165.
204. Baris S, Karakaya D, Kelsaka E, et al. Comparison of fentanylbupivacaine or midazolam-bupivacaine mixtures with plain bupivacaine
for caudal anaesthesia in children. Paediatr Anaesth. 2003;13:126131.
205. Ghai B, Makkar JK, Chari P, et al. Addition of midazolam to continuous
postoperative epidural bupivacaine infusion reduces requirement for
rescue analgesia in children undergoing upper abdominal and flank
surgery. J Clin Anesth. 2009;21:113119.
206. Birbicer H, Doruk N, Cinel I, et al. Could adding magnesium as adjuvant
to ropivacaine in caudal anaesthesia improve postoperative pain control?
Pediatr Surg Int. 2007;23:195198.
207. Luz G, Wieser C, Innerhofer P. Free and total bupivacaine plasma
concentrations after continuous epidural anaesthesia in infants and
children Paediatr Anaesth. 1998;8:473478.
208. Meunier JF, Goujard E, Dubousset AM. Pharmacokinetics of bupivacaine after continuous epidural in infants with or without biliary atresia.
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209. Larsson BA, Lnnqvist PA, Olsson GL. Plasma concentrations of

bupivacaine in neonates after continuous epidural infusions. Anesth
Analg. 1997;84:501505.
210. Murrell D, Gibson PR, Cohen RC. Continuous epidural analgesia in
newborn infants undergoing major surgery. J Pediatr Surg. 1993;28:
548553.
211. Wolf AR, Hughes DG. Pain relief for infants undergoing abdominal
surgery: comparison of morphine infusion and extradural bupivacaine.
Br J Anaesth. 1993;70:1016.
212. Wilson PT, Lloyd-Thomas AR. An audit of extradural infusion analgesia
in children using bupivacaine and diamorphine. Anaesthesia. 1995;48:
718723.
213. Wood CE, Goresky GV, Klassen KA. Complications of continuous
epidural infusions for postoperative analgesia in children. Can J Anaesth.
1994;41:613620.
214. Lejus C, Surbled M, Schwoerer D. Postoperative epidural analgesia with
bupivacaine and fentanyl: hourly pain assessment in 348 pediatric cases.
215. Kokki H, Tuovinen K, Hendolin H. The effect of intravenous ketoprofen
on postoperative epidural sufentanil analgesia in children. Anesth Analg.
1999;88:10361044.
216. Kokki H, Tuovinen K, Hendolin H. Intravenous ketoprofen and epidural

sufentanil in children after combined spinal-epidural anaesthesia. Acta
217. Lejus C, Schwoerer D, Furic I. Fentanyl versus sufentanil: plasma
concentrations during continuous epidural postoperative infusion in
218. Kart T, Walther-Larsen S, Svejborg TF. Comparison of continuous
epidural infusion of fentanyl and bupivacaine with intermittent epidural
morphine for postoperative pain management in children. Acta
219. Hansen TG, Ilett KF, Lim SI. Pharmocokinetics and clinical efficacy
of long term epidural ropivacaine infusion in children. Br J Anaesth.
2000;85:347353.
220. De Negri P, Ivani G, Visconti C. Dose response relationship for clonidine
added to a postoperative continuous epidural infusion of ropivacaine in
221. Moriarty A. Postoperative extradural infusions in children: preliminary
data from a comparison of bupivacaine/diamorphine with plain
ropivacaine. Paediatr Anaesth. 1999;9:423427.
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Head and Neck Blocks
Polina Voronov and Santhanam Suresh
INTRODUCTION
The demand and popularity in regional anesthesia are growing
rapidly in the practice of pediatric anesthesia. Children are exposed
to head and neck surgeries at all ages, including the newborn period.
Anesthesiologists are always looking for safer techniques to provide
perioperative analgesia. The authors routinely use regional anesthesia for intra- and postoperative pain control for most procedures
of the head and neck including, but not restricted to, otorhinolaryngologic, neurosurgical, and plastic surgical procedures.
Knowledge of the anatomic landmarks and the sensory supply
to the head and neck facilitates the performance of these blocks.
Although small doses of local anesthetics are required, there is still
a risk of achieving toxic levels of local anesthetic because the
nerves run close to vascular structures. The risk is low provided a
slow incremental injection is used. Unrecognized rapid injection
into a blood vessel can cause retrograde spread directly into the
brain. The risks of damaging these nerves are reduced because all
are terminal branches of sensory nerves (Table 501).
Another advantage of regional blocks is to reduce the need
for opioids in the postoperative care unit, thereby circumventing
the potentially harmful side effects such as somnolence, respiTABLE 50-1. Sensory Nerves for Regional Anesthesia of
the Head and Neck
Trigeminal Nerve
V1
Supraorbital nerve
Supratrochlear nerve
V2
Infraorbital nerve
Greater palatine nerve
V3
Mental nerve
Superficial Cervical Plexus CIIIV
Great auricular nerve
Lesser occipital nerve
Supraclavicular nerve
Anterior cervical nerve
CII
Greater occipital nerve
Auricular Branch of the Vagus Nerve
Nerve of Arnold
50
C H A P T E R
ratory depression, pruritus, and nausea and vomiting.1 Blocks of

the head and neck are easy to perform, can be used intraoperatively and postoperatively for the pain management of frequent
surgical procedures, and do not add significant time to the
anesthetic course.
ANATOMIC CONSIDERATIONS
Sensory innervation of the head and neck is supplied by three
branches of the trigeminal nerve: ophthalmic, maxillary, and
mandibular nerves. These nerves are associated with the C24
cervical nerve roots. The trigeminal nerve is often referred to as
the great sensory nerve of the head and neck. Three branches arise
from the trigeminal ganglion (semilunar ganglion or gasserian
ganglion), which contain the cell bodies of incoming sensory nerve
fibers and lie in a cavity of the dura mater near the apex of the
petrous part of the temporal bone.2 The trigeminal ganglion is
analogous to the dorsal root ganglia of the spinal cord. From
the trigeminal ganglion, a single large sensory root enters the
brainstem at the level of the pons. Immediately adjacent to the sensory root, a smaller motor root emerges from the pons at the
same level. The terminal sensory nerves of the major trigeminal
nerve branches become accessible for the block when they exit the
facial bones through the supraorbital, infraorbital, and mental
foramens or fissures in the skull that lie usually in a location
approximately in line with the pupil.
V1: OPHTHALMIC DIVISION

OF THE TRIGEMINAL NERVE
Anatomy
The ophthalmic division of the trigeminal nerve gives rise to
three branches, the lachrymal, frontal, and nasociliary nerves,
just before entering the orbit through the superior orbital fissure.
The frontal division is usually the superficial nerve that can
be easily blocked for various surgical procedures. The frontal
nerve splits into two peripheral branches, the supraorbital and
supratrochlear nerves, which emerge through the supraorbital and
supratrochlear notches and continue superiorly in between the
levator palpebrae superioris and the periosteum up to the coronal
suture. They carry the sensory innervation to the frontal scalp,
forehead, median portion of the upper eyelid, and bridge of the
nose. The supratrochlear nerve provides sensory supply to the
midportion of the forehead.
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TABLE 50-2. Ophthalmic, Supraorbital, and Supratrochleal Nerve Blocks

Nerves
Indications
Preparation
Technique
Complications
V1: ophthamic:
supraorbital,
supratrochleal
Frontal craniotomy
Ventriculo-peritoneal
shunt (frontal)
Dermoid cysts
Omaya reservoir
Pigmented nevi
1 mL 0.25% bupivacaine
with 1:200,000
epinephrine
1-mL syringe
30-gauge needle
1. Identify the foramen by

1. Hematoma
palpation of the orbital rim
2. Intraforaminal
from the midline.
injection
2. Advance the needle to the bone.
3. Withdraw the needle 1 mm and
inject.
4. Remove the needle and apply
firm pressure.
Indications
Technique
Blockade of this nerve can be used for frontal craniotomies,3

frontal ventriculoperitoneal shunt revision or placement,4 Omayya
reservoir placement,5 and excision of the pigmented nevus or
dermoid cyst6 (Table 502).
The supraorbital foramen can be easily palpated by following the

orbital rim from the midline. A 30-gauge needle is inserted to hit
the bone, then withdrawn back 1 mm to prevent intraforamen or
intraneural injection and 0.5 to 1.0 mL of 0.25% bupivacaine with
1:200,000 of epinephrine is injected. Pressure is applied to the area
to prevent a hematoma. If the supratrochlear nerve has to be
blocked without removal, the needle is directed about 0.5 cm
toward the midline and an additional 0.5 mL of local anesthetic is
injected (Figure 501).
Position
With the patient supine, the head is rested on a pillow or a donut
to prevent movement.
B
A
Figure 50-1. A: The supraorbital/supratrochlear nerves are

branches of the first division of the trigeminal nerve. The nerve
is blocked at the level of the eyebrow subcutaneous to the supraorbital foramen. B: Inject 1 mL of 0.25% bupivacaine to provide
analgesia in the distribution of the nerve. C: The nerves are superficial and the injection must be subcutaneous. A wheal must
be observed during injection.
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CHAPTER 50
Regional Anesthesia: Head and Neck Blocks 825
TABLE 50-3. Maxillary Nerve Block Technique

Nerves
Indications
Preparation
Technique
Complications
V2: maxillary:
Infraorbital
Endoscopic sinus
surgery
Cleft lip repair
Rhinoplasty
Pulse dye laser for
port-wine stain
Face lacerations
3-mL syringe
2 ml 0.25%
bupivacaine with
1:200,000 of
epinephrine
27-gauge needle
Intraoral approach:
1. Locate the foramen by palpation.
2. Bend the 27-gauge needle at
30 degrees.
3. Evert the upper lip and insert the
needle at the level of first
premolar in the subsulcal groove
4. Advance the needle toward the
landmark and inject the local
anesthetic.
5. Apply pressure.
Hematoma
Intravascular
injection
Intraforamen
injection
Penetration of
the globe
Complications
Hematoma, intraforaminal, or intravascular injections are very
rare complications of this block.
plasty, laser treatment of port-wine stains, dermabrasion, and

transsphenoidal hypophysectomy.12 Comparison of extra- and
intraoral approaches was studied on adult volunteers, and it
showed minimal increase in pain during the intraoral block but
significant increase in duration of the block13 (Table 503).
V2: MAXILLARY DIVISION

Position
Anatomy
Supine with the head rested on a stable pillow.
The maxillary nerve is pure sensory and begins in the semilunar

ganglion. While traveling in the cranium, pterygopalatine fossa,
and inferior orbital fissure, it sends multiple branches including
posterior, middle, and anterior superior alveolar nerves that
provide innervation to the nasal cavity, upper teeth, and maxillary
sinus. The nerve appears upon the face through the infraorbital
foramen in close proximity with the artery and vein and becomes
the infraorbital nerve. It divides into several branches: the inferior
palpebral, external nasal, and superior labial nerves. The nerve
lies beneath the quadratus labii superioris. The infraorbital nerve
provides the sensory innervation to the lower eyelid, upper
lip, and lateral portion of the nose, median cheek, and roof of
the mouth, upper teeth, and maxillary sinus. The infraorbital
foramen can be easily palpated in children, and it is usually
located approximately 2.5 cm lateral to the midline. By analyzing the anatomic location of the foramen using computed
tomography (CT)guided images, we were able to utilize the mathematical formula:
Distance from the midline = 21 mm + 0.5 age (y)7
Ahuja and coworkers applied the infraorbital nerve block in
children undergoing cleft lip repair.8 They found significant
improvement in pain scores in the block group. Bsenberg and
Kimble examined the infraorbital nerve anatomy in15 neonatal
cadavers and successfully applied the knowledge to perform the
block.9 In a recent study, an infraorbital block provided superior
analgesia compared with intravenous fentanyl in children undergoing cleft lip repair.10
Indications
The authors routinely utilize the infraorbital nerve block using
an intraoral approach (routinely for pain control in children
undergoing the endoscopic sinus surgeries,11 cleft lip repair, upper
lip scar revisions). This block can be used effectively for rhino-
Technique
Intraoral and extraoral approaches can be used to perform the
block. In our experience, the intraoral approach in children has a
lower risk of the hematoma formation and also eliminates visible
puncture marks on the childs face, which is important for parental
satisfaction (Figure 502).
Extraoral Approach
The foramen can be identified by the palpation of the floor of the
orbital rim. Eipe and colleagues described another landmark
the intersection of the vertical line through the pupil and horizontal line through the ala of the nose.13 They also confirmed
the successful analgesia for up to 24 hours after the block.
Advance a 27-gauge needle toward the bone. After the maxillary
process is contacted, withdraw the needle about 1 mm to prevent
intraforaminal or intraneural injection. Inject 0.5 to 2 mL of
0.25% bupivacaine with 1:200,000 of epinephrine after negative
aspiration. Pressure should be applied to prevent hematoma
formation.
Intraoral Approach
Localize the foramen as for the extraoral approach. The authors
recommend keeping a middle finger on the infraorbital foramen
throughout the procedure to avoid advancing the needle cephalad
and possibly damaging the globe. Using a 27-gauge needle bent at
30 degrees for easier introduction along the plane of the maxilla,
evert the upper lip and insert the needle at the level of first premolar into the buccal mucosa in the subsulcal groove. Advance
the needle cephalad toward the landmark point, withdraw
slightly, and inject 0.5 to 2mL of 0.25% bupivacaine with 1:200,000
of epinephrine. The spread of the local anesthetic should be
appreciated under the middle finger.
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Figure 50-2. A: The infraorbital nerve. B: A needle is inserted through the buccal mucosa in the infraorbital area to provide an intraoral approach to the maxillary division of the trigeminal nerve (V2) at the level of the canine. Inject 0.5 mL of 0.25% bupivacaine
for infants on each side and 12 mL for older children.
The block is performed frequently in infants; hence, we
recommend measuring the distance from the subsulcal groove to
the foramen by placing the needle externally (see Figure 502).
nerves provide the sensory innervation to the uvula, tonsils, and

soft palate.
Indications
Complications
Although rare, intravascular, intraforaminal, intraneural injection, or damage to the eye is possible. In view of the sensory
block, parents and or patient should be informed about prolonged upper lip numbness. They should be educated with
regard to drinking hot beverages, biting on the lip, and avoiding
chewing.
GREATER PALATINE NERVE

The greater palatine nerve (anterior palatine nerve) is a branch of
the pterygopalatine ganglion and descends through the greater
palatine canal and emerges upon the hard palate through the
greater palatine foramen. It continues in a groove of the hard
palate toward the incisor teeth. Descending palatine vessels
emerge through the palatine foramen as well. The greater palatine
nerve supplies the gums and the mucous membrane of the hard
palate and communicates in front with the terminal filaments
of the nasopalatine nerve, a sensory nerve that arises from the
pterygopalatine ganglion. The middle and posterior palatine
This block is indicated for cleft palate repair. Because this surgery
poses a high risk for postoperative airway obstruction, the authors
utilize this block as primary analgesia for cleft palate without
additional opioids (Table 504).
Position
Supine, mouth open; Dingmans mouth gag can be placed by
surgeon to expose the palate.
Technique
The foramen is located medial and anterior to the third and
second molars. Insert a 27-gauge needle into the mucosa and
inject 1 mL of 0.25% bupivacaine with 1:200,000 epinephrine at
each site after negative aspiration for blood (Figure 503).
Complications
Intravascular and intraneural injections.
TABLE 50-4. Greater Palatine Nerve Block Technique

Nerves
Indications
Preparation
Technique
Complications
V2: maxillary
Greater palatine nerve
Cleft palate
repair
3-mL syringe
2 mL 0.25% bupivacaine
with 1: 200,000
epinephrine
27-gauge needle
1. Locate the foramen medial and

anterior to the second molar.
2. Insert the 27-gauge needle into
the mucosa and inject 1 mL of
local anesthetic to each site.
Intravascular
injection
Intraneural
injection
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CHAPTER 50
Figure 50-3. A: The greater palatine foramen is located juxta to

the second molar lateral of the midline. B: The greater palatine
nerve is blocked (black marks) as the nerve exits the foramen
and runs its course along the mucosa. C: Inject 1 mL of 0.25%
bupivacaine on either side to provide analgesia.
V3: MANDIBULAR DIVISION

This is the largest branch of the trigeminal nerve thath also
contains a motor root to the muscles of mastication. After exiting
the cranium through the foramen ovale, the nerve splits into two
trunks, anterior and posterior. The trunk divides into several
nerves. The most important branches are the buccal nerve, the
lingual nerve, the inferior alveolar nerve, and the auriculotemporal
nerve. They convey sensory information from the anterior two
thirds of the tongue, buccal mucosa, lower teeth, lower lip, chin,
skin of the temporal area, and auricular.
C
The nerve of interest for regional blockade is the mental
nerve, the branch of the inferior alveolar nerve that provides sensory innervation to the chin and lower lip as well as
the anterior teeth and buccal mucosa. It emerges through the
mental foramen in the mandible and lies beneath the triangularis muscle.
Indications
Hemangiomas, lacerations of the lower lip, lesions of a chin
(Table 505).
TABLE 50-5. Mandibular Mental Nerve Block Technique

Nerves
Indications
Preparation
Technique
Complications
V3: mandibular
Mental nerve
Lower lip hemangiomas,

lacerations
Skin lesions on the chin
area
3-mL syringe
2 mLl 0.25%
bupivacaine with
1:200,000
epinephrine
27-gauge needle
1. Evert the lower lip and insert the

needle at the level of first
premolar in the subsulcal groove.
2. Advance the needle about 1 cm
caudad.
3. Inject local anesthetic solution.
Hematoma
Intravascular
injection
Intraneural
injection
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sation of the artery can be a helpful landmark for block placement.
The great occipital nerve provides the sensory innervation to the
posterior scalp. The greater occipital nerve has been investigated
for the diagnosis and treatment of occipital neuralgia. The block
has been used by neurosurgeons and in pain clinics to treat
migraine and other cervicogenic headaches.14 To identify more
reliable landmarks, Tubbs and associates completed 12 adult
cadaveric dissections and found that the mean distance of the nerve
from the external occipital protuberance was 4 cm.15 Anatomic
dissection of the nerve in 100 adult cadavers demonstrated that the
greater occipital nerve can be found approximately 3.8 cm lateral
to the external occipital protuberance. Other landmarks such as
palpation of the artery or one third of the distance from the midline
between the external occipital protuberance and the mastoid
process have also been described.
Indications
Figure 50-4. The mental nerve exits the mental foramen along
the midline of the mandible (purple mark). Inject 1 mL of 0.25%
bupivacaine intraorally to provide analgesia.
Posterior fossa craniotomy, posterior craniosynostosis, posterior

shunt placement or revision, diagnosis and treatment of occipital
neuralgia (Table 506).
Technique
Technique
The mental foramen is difficult to palpate not only in children but

in adults as well. It is located about 1 cm below the first premolar
tooth or in line with the supraorbital and infraorbital foramens.
Intraoral or extraoral approaches can be used, although the
authors prefer to use the intraoral approach. Evert the lower lip
and place the needle in the subsulcal area at the level of first
premolar tooth. Advance the needle approximately 1 cm and inject
local anesthetic after negative aspiration (Figure 504).
Position the patient in the lateral or prone position. One of these

landmarks can be use to locate the point of entry of the needle.
Palpation of the artery can be the most accurate, but sometimes, it
is not easy to appreciate. A 40-degree bend to the needle facilitates
the advancement of the full length of the needle. After negative
aspiration, inject 3 mL of local anesthetic while withdrawing the
needle is withdrawn. If landmarks other than pulsation of the
artery are used, the authors advise two or three passes of the needle
in a fanlike distribution to improve the success of the block
(Figure 505).
Complications
Hematoma, intravascular injection, intraneural injection.
Complications
GREATER OCCIPITAL NERVE
Intraneural injection, intravascular injection. Special precaution

should be taken in a patient with a posterior ventriculoperitoneal
shunt to avoid puncturing the shunt when inserting the needle.
Anatomy
The nerve greater occipital nerve arises from the posterior ramus
of the C2 and C3 nerve roots. It emerges through the aponeuroses
of the trapezius and semispinalis capitis muscles. The nerve follows
the occipital artery and becomes superficial at the level of the
superior nuchal line, medial and inferior to the artery. The pul-
SUPERFICIAL CERVICAL PLEXUS

The ventral rami of C24 form the superficial cervical plexus.
It lies behind the clavicular head of the sternocleidomastoid
muscle, wraps around it, and appears as four distinct nerves at the
TABLE 50-6. Greater Occipital Nerve Block Technique

Nerves
Indications
Preparation
Technique
Complications
C2: greater
occipital nerve
Posterior fossa craniotomy

Revision or insertion of
the ventriculoperitoneal
shunt
Diagnosis or treatment of
the occipital neuralgia
27-gauge needle
3 mL 0.25%
bupivacaine with
1:200,000 of
epinephrine
3-mL syringe
1. Bend the needle 40 degrees.

2. Palpate the arterial pulse.
3. Insert the needle medial and
lower to the pulse.
4. Insert the full length of the
needle in a cephalad direction.
5. Inject the local anesthetic after
negative aspiration of blood.
Intravascular
infection
Intraneural
injection
Ventriculoperitonea
l shunt puncture
Available at: http://en.wikipedia.org/wiki/Image:Mandibular_nerve_branches.png
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CHAPTER 50
Figure 50-5. A: The greater occipital nerve is located below the

superior nuchal line lateral to the occipital artery (red) under the
facial plane. B and C: Subcutaneously inject 2 mL 0.25% bupivacaine to fan the area lateral to the artery to provide adequate
blockade of the occipital nerve.
midpoint of the posterior border of the sternocleidomastoid
muscle. The plexus provides the sensory innervation to the
anterolateral skin of the neck, posterolateral part of the scalp, and
posterior and anterior lower third of the ear. The major cutaneous
branches are the lesser occipital nerve, the great auricular nerve,
the transverse cervical nerve, and the supraclavicular nerve.
The lesser occipital nerve is a branch of the C2, and innervates
the posterior lateral portion of the cranium and posterior auricular
area. In combination with a blockade of the greater occipital nerve,
it can be used for treatment of cervicogenic headaches and occipital
neuralgia. It is difficult to block as an individual nerve. The authors
recommend using the superficial plexus block in order to block
this nerve.
The great auricular nerve is the union of C23. The nerve
ascends beneath the platysma and divides into the posterior and
anterior branches. The anterior (facial branch) innervates skin
over the parotid gland. The posterior branch (mastoid) supplies
the skin behind the ear, lobule, and part of the concha. It also
communicates with the lesser occipital nerve.
The transverse cervical nerve (cutaneous cervical) arises
from C23, emerges with other nerves at the midpoint of the
posterior border of the sternomastoid muscle, crosses it, and
penetrates the deep cervical fascia. It gives several ascending and
C
descending branches to innervate the anterior and lateral part of
the neck.
The supraclavicular nerve arises from C34, travels downward
in the posterior cervical triangle, perforates the fascia near the
clavicle, and divides into three trunksanterior, middle, and
posterior.
Indications
Successful analgesia can be achieved by performing the superficial
cervical plexus block for tympanomastoid surgery, otoplasty, and
cochlear implant surgeries.16,17 This block is routinely performed
in our institution for all mastoid surgery, decreasing hospital
admissions and the incidence of postoperative nausea and vomiting. Other indications for the block include thyroidectomy18,19
(Table 507).
A review of the literature for the utilization of this block showed
that most of the studies were done on adults undergoing carotid
surgery or thyroidectomy. The use of the block remains controversial for both intra- and postoperative pain control. A study
looking at the efficacy of this block placed prior to tympanomastoid surgery did not demonstrate a significant improvement in
pain control.19
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TABLE 50-7. Superficial Cervical Plexus Nerve Block Technique

Nerves
Indications
Preparation
Technique
Complications
Superficial cervical
plexus block.
C24
Tympanoplasty
Otoplasty
Cochlea implant
Thyroidectomy
Parathyroidectomy
Clavicular fracture
Brachial cleft cyst
excision
3-mL syringe
27-gauge needle
3 ml 0.25%
bupivacaine with
epinephrine
1:200,000
1. Identify the point of entry by drawing a

line at the C6 level to the midpoint of
the posterior border of the
sternocleidomastoid muscle.
2. Bend the needle 40 degree to ensure
subcutaneous passage of the needle.
3. Introduce the needle upward along the
posterior border of the muscle.
4. After negative aspiration, inject local
anesthetic with small increments while
withdrawing the needle.
Hematoma
Intravascular
injection
Deep cervical
nerve block
Technique
Complications
Turn the head away from the side to be blocked, the point of
needle entry is at the intersection of the line drawn along the
posterior border of sternocleidomastoid muscle and a line drawn
posteriorly from C6 (Chassaignacs tubercle). This point is close to
where the external jugular vein crosses the sternomastoid muscle.
Use a 27-gauge needle, bent to about 40 degrees, to prevent needle
going deep into the neck structures. Direct the needle upward
toward the mastoid process and inject 3 mL of 0.25% bupivacaine
with 1:200,000 of epinephrine as the needle is withdrawn in
incremental doses. This technique should be used if the great
auricular and lesser occipital nerves need to be blocked (e.g.,
tympanomastoid surgery). If the transverse cervical nerve needs
to be blocked, the authors recommend that, after entering the
skin as directed, the needle should be directed anteriorly toward
the midline of the neck. In order to block the supraclavicular
branch, the needle should be directed inferiorly toward the clavicle
(Figure 506).
Hematoma, intravascular injection, and deep cervical nerve

block. Anatomic dissection of the neck was done in four cadavers by Pandit and coworkers.20 They performed a superficial
cervical block with the dye and then traced its spread in the
neck and found that the superficial space communicates with
the deep.20
GREAT NERVE OF ARNOLD

(AURICULAR BRANCH OF
THE VAGUS NERVE)
Anatomy
The nerve of Arnold is the terminal sensory branch of the
auricular portion of the vagus nerve (Figure 507). It innervates
the external auditory canal and the inferior portion of the
Figure 50-6. A: The superficial cervical plexus wraps around the belly of the sternocleidomastoid muscle at the level of the cricoid
cartilage to branch out into four branches, the lesser occipital, the great auricular nerve, the transverse cervical, and the supraclavicular nerve. B: The nerve can be blocked easily in this position by subcutaneously injecting 2 mL of 0.25% bupivacaine along the
posterior border of the sternocleidomastoid muscle to provide analgesia.
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CHAPTER 50
Figure 50-7. A: The auricular branch of the vagus nerve, often

termed Aldermans nerve or Arnolds nerve, can be blocked using
a 30-gauge needle behind the tragus. B and C: The injection of
0.2 mL of 0.25% bupivacaine provides adequate analgesia.
tympanic membrane where a myringotomy is performed. This
block can provide analgesia for myringotomy and tube placement.
It is easy to perform and has little effect on the duration of the
surgery.
Technique
Turn the patients head to the side, retract the tragus, and using
a 30-gauge needle, pierce the skin of the posterior wall of the
tragus and inject 0.2 mL of 0.25% bupivacaine. Blanching of
the skin confirms correct needle placement. If resistance is felt
on injection, withdraw the needle to avoid injecting into the
cartilage.
Complications
Low-risk block provided intracartilaginous injection is avoided.
CONCLUSION
The use of head and neck nerve blocks has become an integral
part of the authors practice in providing analgesia for children
undergoing head and neck procedures. The aim is to promote a
more rapid recovery and avoid using additional analgesics.
REFERENCES
1. Suresh S, Barcelona S, Young NM, et al. Postoperative pain management
in children undergoing tympanomastoid surgery: Is a local block better
than intravenous opioids? Anesthesiology. 1999;91:A1281.
2. Suresh S, Voronov P. Head and neck blocks in children: an anatomical
and procedural review. Paediatr Anaesth. 2006;16:910918.
3. Nguyen A, Girard F, Boudreault D, et al. Scalp nerve blocks decrease the
severity of pain after craniotomy. Anesth Analg. 2001;93:12721276.
4. Suresh S, Bellig G. Regional anesthesia in a very low-birth-weight neonate
for a neurosurgical procedure. Reg Anesth Pain Med. 2004;29:5859.
5. Uejima T, Suresh S. Ommaya and McComb reservoir placement in
infants: can this be done with regional anesthesia? Paediatr Anaesth.
2008;18:909911.
6. Suresh S, Wagner AM. Scalp excisions: getting ahead of pain. Pediatr
Dermatol. 2001;18:7476.
7. Suresh S, Voronov P, Curran J. Infraorbital nerve block in children: a
computerized tomographic measurement of the location of the
infraorbital foramen. Reg Anesth Pain Med. 2006; 31: 2114
8. Ahuja S, Datta A, Krishna A, et al. Infra-orbital nerve block for relief of
postoperative pain following cleft lip surgery in infants. Anaesthesia.
1994;49:441444.
9. Bsenberg AT, Kimble FW. Infraorbital nerve block in neonates for
cleft lip repair: anatomical study and clinical application. Br J Anaesth.
1995;74:50508
10. Rajamani A, Kamat V, Rajavel VP, et al. A comparison of bilateral
infraorbital nerve block with intravenous fentanyl for analgesia following
cleft lip repair in children. Paediatr Anaesth. 2007;17:133139
11. Suresh S, Patel A, Dunham ME, et al. A randomized double-blind
controlled trial of infraorbital nerve block versus intravenous morphine
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12.
13.
14.
15.
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sulfate for children undergoing endoscopic sinus surgery: are postoperative outcomes different? Anesthesiology. 2002;97:A1292.
McAdam D, Muro K, Suresh S. The use of infraorbital nerve block for
postoperative pain control after transsphenoidal hypophysectomy.
Eipe N, Choudhrie A, Pillai AD, et al. Regional anesthesia for cleft
lip repair: a preliminary study. Cleft Palate Craniofac J. 2006;43:138
141.
Busch V, Jakob W, Juergens T, et al. Occipital nerve blockade in chronic
cluster headache patients and functional connectivity between trigeminal
and occipital nerves. Cephalalgia. 2007;27:12061214.
Tubbs RS, Salter EG, Wellons JC, et al. Landmarks for the identification
of the cutaneous nerves of the occiput and nuchal regions. Clin Anat.
2007;20:235238.
16. Suresh S, Barcelona SL, Young NM, et al. Postoperative pain relief in
children undergoing tympanomastoid surgery: is a regional block better
than opioids? Anesth Analg. 2002;94:859862.
17. Cregg N, Conway F, Casey W: Analgesia after otoplasty: regional nerve
blockade vs local anaesthetic infiltration of the ear. Can J Anaesth.
1996;43:141147.
18. Aunac S, Carlier M, Singelyn F, et al. The analgesic efficacy of bilateral
combined superficial and deep cervical plexus block administered before
thyroid surgery under general anesthesia. Anesth Analg. 2002;95:746750.
19. Suresh S, Barcelona SL, Young NM, et al. Does a preemptive block of the
great auricular nerve improve postoperative analgesia in children
undergoing tympanomastoid surgery? Anesth Analg. 2004;98:330333.
20. Pandit JJ, Dutta D, Morris JF: Spread of injectate with superficial cervical
plexus block in humans: an anatomical study. Br J Anaesth. 2003;91:73375.
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Thorax and Abdomen Blocks
Michael J. Fredrickson
INTRODUCTION
Surgery involving the thorax and abdomen represents some of
the most frequently performed procedures in pediatric practice.
The requirement for regional blockade in this anatomic area
is, therefore, relatively high. Traditionally, the most commonly
employed regional technique for this type of surgery has been a
central neuraxial blockeither a caudal block or a continuous
thoracic/high lumbar epidural. Whereas central neuraxial blocks
still have a very important place in pediatric practice, the contemporary approach paralleling adult practice is to provide neural
blockade closer to the noxious stimuli. The potential advantages of
peripheral nerve blocks over central neuraxial blocks are listed in
Table 511.
The disadvantage of peripheral blocks over central blocks is the
need to learn different block techniques. Conversely, a single-shot
caudal or, when indicated, a continuous epidural can provide
excellent postoperative analgesia for almost all thoracoabdominal
procedures. Therefore, the central neuraxial approach may be
preferable for the nonspecialist pediatric anesthesiologist whereas
peripheral nerve blockade (particularly continuous blocks) may
in reality be feasible only for the specialist. The current popularity
of ultrasound guidance as a nerve localization technique may
exacerbate the issue because the technique has an arguably slower
learning curve.
Peripheral nerve blocks of the thorax and abdomen have been
traditionally performed using the end points of pops, a give, or a
loss of resistance. Although this approach may still be preferred
for some peripheral nerve blocks (e.g., paravertebral block), highresolution portable ultrasound technology has enabled many
peripheral nerve blocks to be performed without these variable
tactile sensations. Furthermore, the shorter distances from the
skin to the target neural structures make children particularly
suitable for ultrasound needle guidance.
TABLE 51-1. Advantages of Peripheral Nerve Blocks Over
Central Neuraxial Blocks
1. Less unwanted motor block (e.g., ilioinguinal vs high lumbar
epidural or caudal block).
2. Reduces need for urinary catheterization.
3. Avoids central neuraxial opioid side effects: nausea/vomiting,
pruritus.
4. Eliminates risk of central neuraxial needle/catheter placement:
a. Spinal cord trauma.
b. Epidural hematoma.
c. Epidural abscess.
51
C H A P T E R
The necessity to perform most peripheral nerve blocks under

deep sedation or general anesthesia is often cited as a reason to
avoid blocks in infants and children. However, the 1-year prospective study of 24,000 blocks in pediatric patients coordinated by
the French Language Society of Pediatric Anesthesia (ADARPEF)
revealed no permanent neurologic sequelae1 and, thus, confirmed
the safety of pediatric peripheral nerve blocks when performed by
experienced practitioners.
The very low neurologic complication rate observed in children
may be even lower than that reported in adults. Theoretical
explanations include the probable higher regeneration potential
of juvenile peripheral nerves and that nerve fascicles in children
are smaller than adults. Smaller nerve fascicles probably carry a
lower risk for intrafascicular needle placement for a given caliber
block needle.
Logistical factors may also contribute to the underutilization
of peripheral nerve blocks in infants and children. The requirement to perform blocks in children after the induction of anesthesia often results in competition between the block procedure and
the surgical procedure for available operating time.
Local anesthetics have important pharmacokinetic differences
in infants compared with adults applicable to peripheral nerve
blockade. Myelinization of peripheral nerves is not complete until
12 years of age.2 Consequently, local anesthetic agents penetrate
peripheral nerves more readily. As a consequence, onset times are
shorter and more dilute local anesthetic can be used effectively.2
This observation, and animal data supportive of neurotoxicity
from all local anesthetics,3 is the reason for the general recommendation that more dilute local anesthetic be used in infants
(e.g., ropivacaine < 0.375%).
The smaller diameter of infant peripheral nerves and higher
net vascularity result in a shorter local anesthetic duration of effect
than in adults. As a general rule, the duration of action of most
peripheral nerve blocks of the thorax and abdomen is in the order
of 4 to 8 hours. The notable exception is the penile nerve block
at the level of the fatty and avascular subpubic space, where up to
24 hours has been reported.
GENERAL PRINCIPLES
OF BLOCK TECHNIQUE
Needle Choice
Short-bevel needles are generally preferred to sharper longer bevels
such as standard hypodermic needles. The shorter bevel, while
minimizing the possibility of intraneural needle placement and
subsequent intraneural injection, allows the operator to more
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readily appreciate the tactile sensation of tissue plane penetration

(i.e., pops and loss of resistance). The choice of a particular type of
short bevel is often a compromise between the ability of the needle
to penetrate the skin and fascial planes and the ability to recognize
penetration of those planes. Very short bevel needles used for
brachial plexus anesthesia (e.g., Plexufix, BBraun, Bethlehem,
Penn) can be difficult to advance through the skin and fascial
layers of the abdominal wall.4 The slightly longer-beveled 22-gauge
short neonatal spinal needle penetrates these planes more readily
and is a good alternative. By observation of tissue displacement,
short-bevel needles can also assist the operator in determining
needle tip position during ultrasound-guided procedures.
Short Extension Tubing

A short extension tube placed between syringe and needle can
help identify that the block needle has been stabilized by, and
therefore penetrated, a fascial layer (e.g., Scarpas fascia during
penile nerve block). Removal of the tubing is advantageous5
during ultrasound-guided local anesthetic placement because
the need for a third hand during injection and simultaneous
sonographic observation is eliminated.
Needle Angle to the Skin

The more perpendicular a needle approaches a fascial layer, the
more readily it will penetrate that layer. Conversely, approaching
a fascial plane at an angle will potentially make penetration of that
layer more difficult. This can be useful in neonates in whom tactile
penetration of delicate fascial layers can be difficult.
Choice of Local Anesthetic

Peripheral nerve blocks of the thorax and abdomen are performed
for both intraoperative and, more important, postoperative analgesia. For this reason, a long-acting local anesthetic such as
ropivacaine or bupivacaine is used. Motor block is rarely a clinical
concern, therefore, depending on the volume required, a concentration of 0.25 to 0.5% is usually used. Concentrations higher than
0.375% are rarely indicated in infants.
Anatomy
The umbilicus is supplied bilaterally by the terminal cutaneous
branch of the T10 spinal (intercostal) nerves, which provide sensory innervation to the skin after passing through the rectus
abdominis muscles. The rectus sheath (fascia of the external/
internal oblique aponeurosis) envelops the two muscles. In so
doing, they provide a compartment for the injection of local
anesthetic. Injection of local anesthetic between the rectus muscle
and the posterior rectus sheath facilitates anesthetic spread in a
caudad and cephalad direction. It also minimizes the theoretical
concern of local anesthetic myotoxicity if local anesthetic is
injected directly into the rectus muscle.
Block Technique: Fascial Click Method

Palpate the outer border of the rectus muscle several centimeters
from the midline at the level of the umbilicus. In infants, this outer
border may not be readily palpated and a point 2 cm from the
midline is used. One hand stabilizes the skin while the other hand
introduces a short-bevel needle at the lateral border of the muscle
at an angle of approximately 45 degrees, advancing with short/
sharp motions until a distinct pop is appreciated (Figure 511).
Block Technique: Ultrasound Method

Place a linear ultrasound probe either side of the midline with the
purpose of identifying the rectus muscle, which is generally 1 to
2 cm deep (Figures 512 and 513 and Video 511). Then place
a short-bevel needle in the out-of-plane alignment a couple of
centimeters lateral to the midline and advanced with multiple
short/sharp movements while simultaneously observing for tissue
displacement within the rectus muscle. Perform one or more test
injections of local anesthetic until separation of the muscle and
posterior rectus sheath is observed7 (Figure 514). Then inject the
full dose and repeat the block on the opposite side.
Local anesthetic dose/volume: Fascial click method: 0.2 mL/kg
each side.
Ultrasound method: 0.1 mL/kg each side.
RECTUS SHEATH BLOCK

The rectus sheath block or (para) umbilical block has enjoyed a
resurgence in popularity since approximately 2000.46 It can be
effectively used for postoperative analgesia for all midline
abdominal procedures, but it is most commonly used for umbilical
hernia repair and laparoscopy. It is commonly performed with
ultrasound guidance because the rectus muscles are easily
recognized. This is the preferred approach because only 25% of
needles are correctly placed between the layers of the rectus sheath
when using the conventional fascial click method.7 In a similar
study using ultrasound guidance, 100% of block needles were
correctly placed between the two fascial layers.8
Rectus sheath block using blind fascial clicks was no more
effective than local infiltration for pediatric umbilical hernia.
In this study, however, both techniques required supplemental
opioid.9 Two recent prospective case series using ultrasound
needle guidance for rectus sheath block for similar surgery had a
high success rate without opioid supplementation.10,11
Figure 51-1. Fascial click rectus sheath block. Needle alignment

approximately 2 cm from the midline.
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CHAPTER 51
Regional Anesthesia: Thorax and Abdomen Blocks
835
ILIOINGUINALILIOHYPOGASTRIC BLOCK
Figure 51-2. Ultrasound-guided rectus sheath block. Needle/

probe alignment.
Figure 51-3. Ultrasound-guided rectus sheath block. Ultrasound

image before local anesthetic injection. RM = rectus muscle.
Ilioinguinal-iliohypogastric (IIIH) nerve block is commonly

used for inguinal procedures such as inguinal herniorrhaphy,
orchidopexy, and hydrocoele repair. Controversy exists around the
choice of ilioinguinal block versus caudal block for this surgery.
Initial studies failed to demonstrate superiority from either technique.1215 A more recent study showed a reduction in stress
hormone levels with caudal analgesia.16 The popularity of caudally
administered clonidine and ketamine has added further controversy with one study using caudally administered bupivacaine and
ketamine showing more prolonged postoperative analgesia than
fascial click IIIH block.17 Many practitioners place a caudal block
for these procedures because the caudal block is relatively simple
and has a high success rate. Potential advantages of the ilioinguinal
block include a low incidence of postoperative leg weakness,
provided low volumes are used, and the ability to place the block
in the supine position. Moreover, the ilioinguinal block represents
an alternative to the caudal block in children in whom anatomic
variants render a caudal block contraindicated or impossible.
An unresolved problem with the fascial click ilioinguinal block
technique is its relatively high failure rate. Success rates as low
as 80% have been reported,18,19 and this low accuracy has been
confirmed by sonographic observation of local anesthetic spread.20
Ultrasound has been shown to increase the success rate of this
block as measured by the number of patients requiring both
supplemental intraoperative and postoperative analgesia,21 but
plasma levels of local anesthetic are also higher.22
With ultrasound guidance, as little as 0.075 mL/kg of local
anesthetic can reliably block both the ilioinguinal and the
iliohypogastric nerves.23 Reducing the total volume of local anesthetic is likely to reduce the spread of local anesthetic below the
inguinal ligament and, therefore, the incidence of unwanted
femoral nerve blockade and leg weakness.24 A lower local anesthetic dose is also advantageous if additional blocks are to be
performed. In addition to unwanted femoral block, IIIH block has
been associated with bowel perforation,25 colonic puncture,26 and
pelvic hematoma.27 In one report, this was complicated by intestinal obstruction.28 It has been suggested that, with ultrasoundguided needle placement, the risk of intestinal perforation may
be reduced.21
Anatomy
Figure 51-4. Ultrasound-guided rectus sheath block. Ultrasound

image after initial local anesthetic injection. PS = posterior
sheath of rectus muscle; RM = rectus muscle.
Both the ilioinguinal and the iliohypogastric nerves arise from the
L1 root of the lumbar plexus. Both nerves supply the inguinal
region including the spermatic cord and round ligament, upper
part of the scrotum, penis, and labia. The position of these nerves
relative to the muscles is highly variable. Medial to the anterior
superior iliac spine, the two nerves run between the internal
oblique and the transversus abdominis muscles, but they later
pierce the internal oblique to lie deep to the external oblique
aponeurosis. In infants, the two nerves lie less than 0.5 cm medial
to the anterior superior iliac spine.29 The genital branch of the
genitofemoral nerve, which at this level lies deep to the internal
oblique muscle, also supplies the inguinal region. Additional
blockade of the genitofemoral nerve results in more complete
intraoperative anesthesia, but it is not essential for effective postoperative analgesia.30
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Figure 51-5. Fascial click ilioinguinal-iliohypogastric nerve

block. Needle position relative to anterior superior iliac spine.
Figure 51-6. Ultrasound-guided ilioinguinal-iliohypogastric

nerve block. Needle/probe alignment.
until spread is observed between the internal oblique and the

transversus abdominis muscles. Then inject the entire dose of local
anesthetic.
Insert a short-bevel needle approximately 0.25 to 2 cm (depending

on the size of the patient) medial to the anterior superior iliac
spine (Figure 515 and Video 512).29 The exact cephalad-caudad
position is not important,31 but an insertion point slightly cephalad
is usually used. Once through the skin, advance the needle until
a give is felt as the external oblique aponeurosis is penetrated.
Then inject local anesthetic, although slight withdrawal of the
needle may be required if resistance is encountered. If desired,
additional anesthesia of the inguinal region can be achieved with
a second injection after a second pop. Alternatively, the surgeon
can infiltrate directly.

Place a linear probe in the axial plane at the level of the anterior
superior iliac spine (Video 513A and B). Visualization of the
abdominal muscle layers at this level is particularly subject to
anisotropy. This is the phenomenon whereby the ultrasound
transducer only receives waves that have been projected directly
perpendicular to the target structures. For this reason, the optimal
placement of the probe is often above/cephalad of the anterior
superior iliac spine oriented in a slightly caudad direction and
often facing the contralateral foot. This orientation places the
probe directly perpendicular to the muscles of the inguinal region.
If a wide linear probe is used, it is often necessary to have the
lateral part of the probe overhang the anterior superior iliac spine
(Figure 516). Identification of the relevant muscles is from deep
to superficial because, in 50% of patients, the external oblique
muscle will not be visible cephalad of the anterior superior iliac
spine (Figure 517).21 If only two muscles are visible, it is probable
they represent the internal oblique and transversus abdominis
muscles and the probe is positioned caudad of the anterior
superior iliac spine.
Place a short-bevel needle in the out-of-plane orientation
and advance it with a series of short/sharp pushes while observing for tissue displacement within the external and internal
oblique muscles. Ideally, the needle tip should be visualized before
injection. Administer one or more test injections of local anesthetic
Local anesthetic volume: Fascial click method: 0.2 to 0.3 mL/

kg.13,3234
Ultrasound method: 0.1 to 0.2 mL/kg.21,23
PENILE BLOCK
The penile block includes both the dorsal penile nerve block
(DPNB) and the subcutaneous penile ring block. Both can be used
for all operative procedures of the distal penis; however, the DPNB
either alone35 or in combination with a ring block36 provides more
effective analgesia than a ring block alone. DPNB for postoperative
analgesia has a similar effectiveness to caudal analgesia but can be
performed more efficiently.37 A duration of action of up to 24 hours
has been reported, possibly because the subpubic space has
Figure 51-7. Ultrasound-guided ilioinguinal-iliohypogastric

nerve block. Ultrasound image before local anesthetic injection.
ASIS = anterior superior iliac spine; IO = internal oblique muscle; TA = transversus abdominis muscle.
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CHAPTER 51
TABLE 51-2. Neural Innervation of the Penis
Nerve
Area of Innervation
Dorsal nerve of penis

Perineal nerve
Genitofemoral nerve
Ilioinguinal nerve
Most of shaft/glans
Ventral shaft/frenulum
Base of shaft
Base of shaft
abundant fat and is poorly perfused. Large retrospective reviews

have confirmed an extremely low complication rate with this
block.38 However, traumatic injury to both the urethra and the
penile vessels can occur with one case reported of serious glans
ischemia.39 Adrenaline should never be used in this area because of
potential ischemia mediated by arterial vasoconstriction.40 Based
on a single case report, it has been suggested that the potentially
vasoconstrictive ropivacaine should be avoided.41 It is more likely
that injecting within Bucks fascia can lead to compartment
syndrome causing ischemia of the glans. This technique should
be avoided. Infectious complications are exceedingly rare.42 An
ultrasound-assisted technique has been described,43 although
satisfactory imaging can be technically challenging.
Anatomy
The innervation of the penis is summarized in Table 512. Both
the dorsal nerve of the penis and the perineal nerve arise from the
pudendal nerve, originating from the sacral plexus. The dorsal
nerves of the penis enter the subpubic space under the pubic
symphysis to lie deep to Scarpas fascia (Figure 518). Scarpas
fascia is a membranous layer of superficial fascia continuous with
the anterior abdominal wall and fuses with the fascia surrounding
the corpus cavernosum (Bucks fascia). The compartment of the
penis bounded by Bucks fascia is nonexpandable; therefore,
injection of local anesthetic within this compartment could result
in vascular compression and glans ischemia. Conversely, the
subpubic space is readily expandable and is a safe point for the
injection for local anesthetic. The dorsal nerves of the penis run
close to the midline directly adjacent to their corresponding penile
Figure 51-8. Penile nerve block. Sagittal

section of the relevant anatomic structures.
The dotted line shows the transversal section of the penis that is demonstrated in
Figure 51-9.
837
artery and vein either side of the midline suspensory ligament

(Figure 519). This midline ligament can divide the subpubic
space into two noncommunicating compartments.
Block Technique: Fascial Click DPNB 40

Retract the penis caudally with one hand in order to open the
subpubic space and stretch Scarpas fascia (Video 514). This helps
to identify when the block needle has penetrated the fascia.
With the other hand, insert a short-bevel needle 1 cm caudad of
the pubic bone 1 cm each side of midline. Advance the needle in
a slight caudad direction a distance of 2 to 3 cm, aiming to feel a
give as Scarpas fascia is penetrated (Figure 5110). This give is not
always appreciated. Stability of the needle is a useful, but not a
constant, sign that Scarpas fascia has been penetrated. Avoid
the midline to minimize the risk of urethral or vascular injury/
hematoma and subsequent glans ischemia. To block innervation
of the (posterior) frenulum, either a separate pudendal nerve block
can be performed at the level of the ischial tuberosity or, more
easily, a subcutaneous wheal can be raised on the ventral aspect
of the base of the shaft (Figure 5111). This is usually not necessary if the block is performed proximal to the division of the
dorsal nerve of penis.
Local anesthetic volume (avoid epinephrine): 0.1 mL/kg to a
5-mL maximum each side.44
Block Technique: Subcutaneous

Penile Ring Block
Inject a wheal of local anesthetic circumferentially around the base
of the penis. Injection superficial to Bucks fascia is important to
avoid possible pressure compression of the penile vessels.
PARAVERTEBRAL BLOCK
Paravertebral block, by either single injection or continuous
infusion, provides excellent postoperative analgesia in children
after thoracotomy or unilateral upper abdominal surgery (open
splenectomy or nephrectomy).45,46 A recent meta-analysis in adults
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Figure 51-9. Penile nerve block.

Transverse section corresponding to
the dotted line in Figure 518.
has confirmed that paravertebral blockade provides analgesia
as effective as a continuous epidural analgesia.47 Similar results in
children have also been reported.48 The paravertebral approach
avoids the potential complications associated with thoracic
epidural needle placement such as spinal cord trauma, epidural
hematoma, or epidural abscess. Single-shot lumbar paravertebral
block has also been used effectively for inguinal surgery, in hwich
it has been shown to provide improved analgesia compared with
systemic opioid49 and more prolonged analgesia compared with
fascial click ilioinguinal block.4,6
The frequency of complications after thoracic paravertebral
block has been well described in adults with 1% sustaining a pleura
puncturehalf of these developing a pneumothorax.50 No complications were noted in the 42 children included in this study.
An acceptable alternative to percutaneous placement is for
surgical placement of catheter under direct vision at the end of
surgery.45,51,52 This may be preferred in small infants owing to
the technical challenges of percutaneous catheter placement in

these patients.
Figure 51-10. Penile nerve block. Manual retraction of penis

and needle insertion.
Figure 51-11. Penile nerve block. Ventral subcutaneous

infiltration.
Anatomy
The thoracic paravertebral space is a wedge-shaped space bounded
medially by the vertebral bodies and intervertebral disks; posteriorly by the transverse processes, ribs, and costotransverse
ligaments; and anterolaterally by the parietal pleura (Figure 5112).
The space ends caudally at the T12 level where it is then filled by the
psoas muscle. Caudal spread of local anesthetic administered in the
thoracic region is thus limited to T12.53 In addition to the thoracic
spinal nerves, the paravertebral space contains the intercostal
vessels, azygous/hemiazygous veins, lymphatic ducts, and sympathetic chain. The distance from the skin to the paravertebral space
can be approximated with the following formula54:
Distance to paravertebral space (mm) = 20 + (0.5 weight [kg])
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CHAPTER 51
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Figure 51-12. Paravertebral nerve block.

Transverse section of the relevant anatomic
structures.
Block Technique
Place the patient in the lateral decubitus position with the
operative side uppermost (Video 515). The site of skin puncture
is 1 to 2 cm lateral to the relevant spinous process. Advance a
pediatric Tuohy needle (e.g., 5cm epidural needle) using a loss-ofresistance syringe. Advance both needle and plunger until either
bony contact is made or loss of resistance occurs as the needle
penetrates the costotransverse ligament. If bony contact is made,
the needle has contacted either the vertebral laminae or the
transverse process. The needle should, therefore, be redirected in
either a lateral or a caudad direction. It is imperative to avoid
directing the needle medially because the needle could enter an
intervertebral foramen. The initial puncture site should be as close
to the midline as possible because this increases the distance
between the entry point into the paravertebral space and the more
deeply located parietal pleura. Catheter threading may require
rotation of the bevel into a caudad or a cephalad direction or a
fluid bolus via needle. Introduce the catheter no more than 2 cm
to avoid positioning within an intercostal space. Ultrasound can be
used to estimate the distances to both the transverse processes and
the parietal pleura.
Local anesthetic volume: Bolus: 0.5 mL/kg.55
Infusion: 0.3 mL/kg/h (infants will require more dilute local
anesthetic concentration at this volume [e.g., ropivacaine
0.075%]).
INTERCOSTAL NERVE BLOCK

Intercostal nerves can provide effective analgesia after thoracotomy and upper abdominal procedures.56 They are also useful
for the treatment of rib fractures and intercostal drain insertion.
The main limitation of intercostal nerve block is the need to
perform multiple separate injections to cover multiple dermatomes. Repeat injections are also needed to provide analgesia for
more than a few hours. The risk of systemic local anesthetic
toxicity is high because of the vascularity and, therefore, rapid
absorption of local anesthetic.57 Dilute local anesthetic concentrations are often used for this reason.
For continuous thoracic spinal nerve blockade, the paravertebral approach is generally preferred over an intercostal
approach because blockade of more than one segment can be
achieved. Furthermore, the parietal pleura is closer to the skin at
the costal cartilage level than in the paravertebral area, potentially
increasing the risk of a needle puncture and pneumothorax.
Intercostal blocks are relatively easy to learn and, therefore, remain
popular in the emergency department and intensive care settings.
Anatomy
The thoracic spinal nerves travel with their corresponding
intercostal artery and vein in the groove underneath each rib and
costal cartilage. They give off posterior, lateral (at the midaxillary
line), and anterior cutaneous branches.
Block Technique
Insert a sharp needle typically in the posterior axillary line at a
point just caudad to the corresponding rib. Advance the needle
in a slightly cephalad direction until the rib is contacted. Then
redirect the needle slightly caudally and advance ot a further
0.5 to 1 cm. Inject the local anesthetic after careful aspiration.
A loss-of-resistance technique, or preferably an ultrasoundguided technique, can be used with a short-bevel or 20-gauge
Tuohy needle. Further injections at adjacent levels are required to
provide additional cover as indicated.
Local anesthetic volume: 1 to 3 mL at each intercostal space
according to weight.
TRANSVERSUS ABDOMINIS
PLANE BLOCK
The transverses abdominis plane (TAP) block can provide
blockade of the lower six thoracic and first lumbar spinal nerves
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via a single injection immediately above the iliac crest and slightly
posterior to the level of the midaxillary line.58,59 It can, therefore,
be used for most surgical procedures involving incisions of the
mid and lower abdominal wall.58 The TAP block can also easily be
performed with the assistance of ultrasound because the three
muscle layers of the abdominal wall are easily visualized at this
level.60 The TAP block has been described predominantly in
adults, but early reports in children are forthcoming. The authors
early experience with this block in children is that satisfactory
ultrasound images of the three muscle layers are easier to obtain
than in the inguinal area. It will undoubtedly develop a place in
the pediatric population for inguinal and lower abdominal
procedures such as ureteric re-implantation, colostomy, and open
appendectomy. At the time of writing, published reports were
limited to a case report in a 9-year-old for analgesia after open
appendicectomy61; and a small series by this author involving
children undergoing inguinal procedures62 and neonates having
a range of abdominal procedures.63 Regarding inguinal procedures, the authors clinical impression is that, when satisfactory
ultrasound imaging permits, a classic IIIH block (at the level of
the anterior superior iliac spine) provides better intra- and
postoperative analgesia than a classic TAP block (at the level of
the midaxillary line).
Figure 51-14. Fascial click transverses abdominis plane block.

Needle alignment.
muscles. In the TAP at the level of the triangle of Petit, the spinal
afferent nerves have not yet pierced the muscular abdominal wall.
This tissue plane provides a readily accessible compartment for
the placement and subsequent cephalad spread of local anesthetic.
Anatomy
The spinal afferent nerves supplying the abdominal wall travel
between the transversus abdominis and the internal oblique
muscles before reaching the rectus sheath. Access to this tissue
plane just posterior to the midaxillary line is via the triangle of
Petit (Figure 5113). This triangle is bounded posteriorly by the
latissimus dorsi muscle and anteriorly by the external oblique
muscle with the iliac crest forming the easily palpable base. The
transversus abdominis plane (TAP) refers to the potential space
between the transversus abdominis and the internal oblique

Palpate the iliac crest posteriorly until the latissimus dorsi is felt
(Video 516). Then place a short-bevel needle just anterior to the
latissimus dorsi immediately cephalad to the iliac crest. Once
through the skin, advance the needle in the coronal plane with
short/sharp movements until two distinct pops are felt as the
needle passes through first the external and then the internal
oblique muscles. Once in the TAP, inject the full dose of local
anesthetic (Figure 5114).
Figure 51-13. Transversus

abdominis plane block. Boundaries
of the triangle of Petit.
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841
INFILTRATION
ANESTHESIA/ANALGESIA
Infiltration analgesia for inguinal surgery provides better analgesia
than placebo64 and has been shown to be comparable with fascial
click IIIH block.29,59 The technique is usually performed intraoperatively by the surgeon. Local infiltration can be used for
virtually all surgical incisions of the thorax and abdomen. The
main limitations compared with an appropriate peripheral nerve
block are the relatively short duration of effect and the need to
administer relatively high doses of local anesthetic.
REFERENCES
Figure 51-15. Ultrasound-guided transverses abdominis plane

block. Needle/probe alignment.

Place a linear probe in the axial plane at the level of the triangle
of Petit or where the three muscle layers are most distinct on
ultrasound (Video 517). Using an in-plane approach, advance
the needle from anterior to posterior obliquely to the TAP and
nearly perpendicular to the ultrasound beam (Figure 5115).
Once the needle tip is visualized in or near the TAP, inject the full
dose of local anesthetic while simultaneously observing appropriate spread within the plane (Figure 5116).
Local anesthetic volume (extrapolated from adult data): 0.3 to
0.4 mL/kg.
B
Figure 51-16. A and B: Ultrasound-guided transversus abdominis plane block. Ultrasound image before local anesthetic
injection. EO = external oblique muscle; IO = internal oblique
muscle; N = needle; TA = transversus abdominis muscle.
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2. Benzon HT, Strichartz GR, Gissen AJ, et al. Developmental neurophysiology of mammalian peripheral nerves and age-related differential
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4. Ferguson S, Thomas V, Lewis I. The rectus sheath block in paediatric
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5. Courreges P, Poddevin F. Rectus sheath block in infants: what suitability?
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7. Chowdary K. Ultrasound study to determine the accuracy of needle
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9. Isaac LA, McEwen J, Hayes JA, et al. A pilot study of the rectus sheath
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10. de Jose Maria B, Gotzens V, Mabrok M. Ultrasound-guided umbilical
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11. Willschke H, Bosenberg A, Marhofer P, et al. Ultrasonography-guided
12. Fisher QA, McComiskey CM, Hill JL, et al. Postoperative voiding interval
and duration of analgesia following peripheral or caudal nerve blocks in
13. Hannallah RS, Broadman LM, Belman AB, et al. Comparison of caudal
and ilioinguinal/iliohypogastric nerve blocks for control of postorchiopexy pain in pediatric ambulatory surgery. Anesthesiology. 1987;66:
832834.
14. Splinter WM, Bass J, Komocar L. Regional anaesthesia for hernia repair
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15. Markham SJ, Tomlinson J, Hain WR. Ilioinguinal nerve block in children.
A comparison with caudal block for intra and postoperative analgesia.
Anaesthesia. 1986;41:10981103.
16. Somri M, Gaitini LA, Vaida SJ, et al. Effect of ilioinguinal nerve block on
the catecholamine plasma levels in orchidopexy: comparison with caudal
epidural block. Paediatr Anaesth. 2002;12:791797.
17. Findlow D, Aldridge LM, Doyle E. Comparison of caudal block using
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in children. Anaesthesia. 1997;52:11101113.
18. Trotter C, Martin P, Youngson G, et al. A comparison between
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surgeon for postoperative analgesia following groin surgery in children.
19. Lim SL, Ng Sb A, Tan GM. Ilioinguinal and iliohypogastric nerve block
revisited: single shot versus double shot technique for hernia repair in
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20. Weintraud M, Marhofer P, Bosenberg A, et al. Ilioinguinal/iliohypogastric

blocks in children: where do we administer the local anesthetic without
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21. Willschke H, Marhofer P, Bosenberg A, et al. Ultrasonography for
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22. Weintraud M, Lundblad M, Kettner SC, et al. Ultrasound versus
landmark-based technique for ilioinguinal-iliohypogastric nerve blockade
in children: the implications on plasma levels of ropivacaine. Anesth
Analg. 2009;108:14881492.
23. Willschke H, Bosenberg A, Marhofer P, et al. Ultrasonographic-guided
ilioinguinal/iliohypogastric nerve block in pediatric anesthesia: what is
the optimal volume? Anesth Analg. 2006;102:16801684.
24. Shivashanmugam T, Kundra P, Sudhakar S. Iliac compartment block
following ilioinguinal iliohypogastric nerve block. Paediatr Anaesth.
2006;16:10841086.
25. Frigon C, Mai R, Valois-Gomez T, et al. Bowel hematoma following
an iliohypogastric-ilioinguinal nerve block. Paediatr Anaesth. 2006;16:
993996.
26. Johr M, Sossai R. Colonic puncture during ilioinguinal nerve block in a
child. Anesth Analg. 1999;88:10511052.
27. Vaisman J. Pelvic hematoma after an ilioinguinal nerve block for
orchialgia. Anesth Analg. 2001;92:10481049.
28. Amory C, Mariscal A, Guyot E, et al. Is ilioinguinal/iliohypogastric nerve
block always totally safe in children? Paediatr Anaesth. 2003;13:164166.
29. van Schoor AN, Boon JM, Bosenberg AT, et al. Anatomical considerations
of the pediatric ilioinguinal/iliohypogastric nerve block. Paediatr Anaesth.
2005;15:371377.
30. Sasaoka N, Kawaguchi M, Yoshitani K, et al. Evaluation of genitofemoral
nerve block, in addition to ilioinguinal and iliohypogastric nerve block,
during inguinal hernia repair in children. Br J Anaesth. 2005;94:243246.
31. Kundra P, Sivashanmugam T, Ravishankar M. Effect of needle insertion
site on ilioinguinal-iliohypogastric nerve block in children. Acta Anaesthesiol Scand. 2006;50:622626.
32. Casey WF, Rice LJ, Hannallah RS, et al. A comparison between
bupivacaine instillation versus ilioinguinal/iliohypogastric nerve block
for postoperative analgesia following inguinal herniorrhaphy in children.
33. Dalens B, Ecoffey C, Joly A, et al. Pharmacokinetics and analgesic effect
of ropivacaine following ilioinguinal/iliohypogastric nerve block in
34. Gunter JB, Gregg T, Varughese AM, et al. Levobupivacaine for ilioinguinal/
iliohypogastric nerve block in children. Anesth Analg. 1999;89:647649.
35. Holder KJ, Peutrell JM, Weir PM. Regional anaesthesia for circumcision.
Subcutaneous ring block of the penis and subpubic penile block
compared. Eur J Anaesthesiol. 1997;14:495498.
36. Naja ZA, Ziade FM, Al-Tannir MA, et al. Addition of clonidine and
fentanyl: comparison between three different regional anesthetic
techniques in circumcision. Paediatr Anaesth. 2005;15:964970.
37. Weksler N, Atias I, Klein M, et al. Is penile block better than caudal
epidural block for postcircumcision analgesia? J Anesth. 2005;19:3639.
38. Soh CR, Ng SB, Lim SL. Dorsal penile nerve block. Paediatr Anaesth.
2003;13:329333.
39. Sara CA, Lowry CJ. A complication of circumcision and dorsal nerve
block of the penis. Anaesth Intensive Care. 1985;13:7982.
40. Berens R, Pontus SP Jr. A complication associated with dorsal penile nerve
block. Reg Anesth. 1990;15:309310.
41. Burke D, Joypaul V, Thomson MF. Circumcision supplemented by dorsal
penile nerve block with 0.75% ropivacaine: a complication. Reg Anesth
Pain Med. 2000;25:424427.
42. Abaci A, Makay B, Unsal E, et al. An unusual complication of dorsal penile
nerve block for circumcision. Paediatr Anaesth. 2006;16:10941095.
43. Sandeman DJ, Dilley AV. Ultrasound guided dorsal penile nerve block in
44. Dalens B, Vanneuville G, Dechelotte P. Penile block via the subpubic space
in 100 children. Anesth Analg. 1989;69:4145.
45. Karmakar MK, Booker PD, Franks R, et al. Continuous extrapleural
paravertebral infusion of bupivacaine for post-thoracotomy analgesia in
young infants. Br J Anaesth. 1996;76:811815.
46. Lonnqvist PA. Continuous paravertebral block in children. Initial
experience. Anaesthesia. 1992;47:607609.
47. Davies RG, Myles PS, Graham JM. A comparison of the analgesic efficacy
and side-effects of paravertebral vs epidural blockade for thoracotomy
a systematic review and meta-analysis of randomized trials. Br J Anaesth.
2006;96:418426.
48. Lonnqvist PA, Olsson GL. Paravertebral vs epidural block in children.
Effects on postoperative morphine requirement after renal surgery. Acta
49. Naja ZM, Raf M, El Rajab M, et al. Nerve stimulator-guided paravertebral
blockade combined with sevoflurane sedation versus general anesthesia
with systemic analgesia for postherniorrhaphy pain relief in children: a
prospective randomized trial. Anesthesiology. 2005;103:600605.
50. Lonnqvist PA, MacKenzie J, Soni AK, et al. Paravertebral blockade. Failure
rate and complications. Anaesthesia. 1995;50:813815.
51. Cheung SL, Booker PD, Franks R, et al. Serum concentrations of
bupivacaine during prolonged continuous paravertebral infusion in
young infants. Br J Anaesth. 1997;79:913.
52. Downs CS, Cooper MG. Continuous extrapleural intercostal nerve block
for post thoracotomy analgesia in children. Anaesth Intensive Care. 1997;
25:390397.
53. Lonnqvist PA, Hildingsson U. The caudal boundary of the thoracic
paravertebral space. A study in human cadavers. Anaesthesia. 1992;47:
10511052.
54. Lonnqvist PA. Depth from skin to the thoracic paravertebral space in
infants and children. Paediatr Anaesth. 1994;4:99.
55. Lonnqvist PA. Plasma concentrations of lignocaine after thoracic
paravertebral blockade in infants and children. Anaesthesia. 1993;48:
958960.
56. Shelly MP, Park GR. Intercostal nerve blockade for children. Anaesthesia.
1987;42:541544.
nerve blocks in children: blood concentrations and pharmacokinetics.
Anesth Analg. 1986;65:625632.
58. McDonnell JG, ODonnell B, Curley G , et al. The analgesic efficacy of
transversus abdominis plane block after abdominal surgery: a prospective
randomized controlled trial. Anesth Analg. 2007;104:193197.
59. McDonnell JG, ODonnell BD, Farrell T, et al. Transversus abdominis
plane block: a cadaveric and radiological evaluation. Reg Anesth Pain Med.
2007;32:399404.
60. Hebbard P, Fujiwara Y, Shibata Y, et al. Ultrasound-guided transversus abdominis plane (TAP) block. Anaesth Intensive Care. 2007;35:
616617.
61. Laghari ZA, Harmon D. Ultrasound-guided transabdominus plane block.
J Clin Anesth. 008;20:156158.
62. Fredrickson M, Seal P, Houghton J. Early experience with the transversus abdominis plane block in children. Paediatr Anaesth. 008;18:
891892.
63. Fredrickson MJ, Seal P. Ultrasound-guided transversus abdominis plane
block for neonatal abdominal surgery. Anaesth Intensive Care. 009;37:
469472.
64. Suraseranivongse S, Chowvanayotin S, Pirayavaraporn S, et al. Effect of
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Fluid Therapy for the

Pediatric Surgical Patient
Anne Laffargue Vetter
52
C H A P T E R
INTRODUCTION
The aims of fluid therapy in children during the perioperative
period are to correct fluid deficit, to provide maintenance fluid
requirements, and to replace deficits needed to maintain adequate
tissue perfusion. It should be thought of as fluid therapy considering the risk of inadequate perfusion in children. Understanding
physiologic changes in fluid status during childhood is essential.
The volume and composition of perioperative fluids should be
adapted to the patients preoperative status, the type of surgery,
and expected postoperative events.
Maintenance fluid requirements were calculated by Holliday
and Segar in 1957.1 The authors based their estimation on weight,
body surface area, and caloric intake. Recently, these formulas
have been questioned, and both volume and composition of intravenous infusion in the perioperative period have been reconsidered. In the operating room, the choice of fluid administration
must be kept simple so that it can be understood and remain
practical for everyone; thus, potentially dangerous mistakes can
be avoided.
Figure 52-1. Fluid compartments (% of body weight) changes

with age. ECF = extracellular fluid; ICF = intracellular fluid;
TBW = total body water.
choosing the composition of the solution to be administered intraoperatively. Intravenous administration of hypotonic solutions
such as 5% dextrose, considered free water, causes fluid to diffuse
rapidly into the interstitium, thus reducing osmolarity and shifting
water into cells, ultimately causing edema.4
Body Fluid Compartments
Maintenance Fluid Requirements
During the first year of life, important modifications occur in the

body fluid compartments.
Total body water (TBW) represents up to 90% of body weight
in the newborn. This decreases dramatically during the first
6 months, including 4 to 5% during the first week of life (reflected
in the weight loss during that period). After 1 year, TBW decreases
slowly to the adult levels of about 60%.2
Extracellular fluid (ECF) includes the intravascular blood or
plasma volume and the interstitial fluid. These components are
separated from each other by the vascular endothelium. The main
difference between them is that plasma contains protein. The ECF
compartment, in terms of body weight, is larger in premature and
term infants than in adults. ECF represents the most important
part of TBW in young children and decreases in parallel with
TBW content (i.e., from 45% at term to 2025% of adult levels by
age 1 year) (Figure 521).
Intracellular fluid (ICF) compartment, conversely, does not vary
much during infancy, from 30% at birth to 40% in adults.
Daily fluid shifts in young children essentially originate in the
ECF, usually in response to dehydration. Dehydration occurs more
rapidly in this age group because of the larger contribution of the
ECF in the fluid homeostasis.3 During the perioperative period,
most fluid administration aims to replace fluid losses from the
plasma and the interstitial compartment. This is important when
During the perioperative period, fluid requirements include

maintenance fluid and replacement of fluid losses induced by the
pathology (e.g., diarrhea, vomiting, gastric suction) or the surgery
(e.g., third space, exudation, blood losses). Maintenance fluids
are designed to ensure that water and electrolyte homeostasis is
maintained within normal limits. To determine what is needed,
two questions have to be considered: (1) What volume is needed
for maintenance? (2) What fluid should be used to maintain
electrolyte homeostasis?
Preoperative Assessment
Fasting
Usually, children do not have a significant preoperative fluid
deficit and the anesthesiologist has only preoperative fasting to
consider. Preoperative fasting is a prerequisite for elective surgery
since Mendelsons study showing a link between feeding and
pulmonary aspiration in parturient women.5 Prolonged fasting
does not eliminate the risk of aspiration during anesthesia.6 New
recommendations for preoperative fasting in children attempt to
reduce the stress associated with this period.7 The original rule of
NPO [nothing by mouth] after midnight no longer pertains.
Intake of clear liquid (i.e., that one can see through) can be taken
up to 2 hours before surgery and has no affect on the volume or
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TABLE 52-1. Preoperative Fasting Guidelines in Children

Ingested Substance
Fasting Period, h
Clear fluid
Breast milk
Formula feeds
Milk
Light meal
2
4
6
6
6
Intraoperative Fluids
Fluid Volume
8
the pH of the gastric content at induction in children or adults. In

children, it decreases thirst and hunger and increases patient
comfort and hydration. It reduces the risk of hypovolemia at
induction of anesthesia, especially in the young child. Guidelines
for preoperative fasting in children are shown in Table 521.
Preoperative Evaluation of Fluid Status

An estimate of fluid status should be done preoperatively, especially in infants and young children undergoing emergent abdominal surgery or when fluid losses such as vomiting, diarrhea,
fever, or third space sequestration have occurred (e.g., intestinal
obstruction). The degree of dehydration can be estimated from
the clinical history and physical examination of the child, including weight and urine output measurement. If needed, blood
samples for evaluation of the acid-base status, urea and electrolytes, serum creatinine, serum tonicity, and urinary creatinine and
osmolality should be done. Table 522 shows the clinical signs of
dehydration in children.
Correction of hypovolemia before surgery is absolutely
necessary. Crystalloids can be given as a bolus of 10 to 20 mL/kg,
repeated as needed before induction of anesthesia. If surgery is
not considered urgent, correction of metabolic and fluid status
should be done before transfer to the operating room. The best
example of this is the infant with hypertrophic pyloric stenosis
(HPS). This should never be considered an urgent surgical procedure, but rather an urgent medical condition. It is the most frequent gastrointestinal disease in infants younger than 3 months
of age. Typically, the metabolic derangement associated with this
condition consists of a hyponatremic hypochloremic hypokalemic
metabolic alkalosis, with variable degrees of dehydration. Correction of the dehydration is mandatory before induction of anesthesia, and surgery should proceed only when the metabolic
TABLE 52-2. Severity of Dehydration in Children
Clinical Signs
Mild
Moderate
Severe
Weight loss
Pulse
Blood pressure
5%
Normal
Normal
15%
Rapid/weak
Reduced
Anterior
fontanelle
Respiration
Skin turgor
Normal
10%
Rapid
Normal
or low
Sunken
Normal
Normal
Deep
Decreased
Moist
Dry
Deep and rapid

Markedly
decreased
Very dry
Reduced
Normal
Oliguria
>2 sec
Oliguria, anuria
>3 sec
Mucous
membrane
Urine
Capillary refill
derangements have been corrected. It is particularly important

to confirm that electrolytes, particularly potassium, have been
corrected. This can be confirmed by measuring urinary chlorine
excretion.
Very sunken
Methods for estimating the daily fluid requirements of children

have been in use for a long time. Various formulas are used to
calculate the fluid volume required, based on either weight, body
surface area, or caloric consumption. In 1957, Holliday and Segar
estimated the fluid requirements by calculating the metabolic
requirements for children at bed rest, midway between basal
metabolic rate and normal activity.1 Under physiologic conditions,
1 mL of water is needed to metabolize 1 kcal, taking into account
insensible water losses (skin, respiratory tract) and urinary water
loss. In their study, the daily caloric expenditure was 100 kcal/kg
for infants from 3 to 10 kg, 1000 kcal/kg + 50 kcal/kg for children
between 10 and 20 kg, and 1500 kcal/kg + 20 kcal/kg over 20 kg.
The corresponding rule derived for hourly water requirement is
known as the 4/2/1 rule (Table 523).
Anesthesia decreases energy expenditure and Lindhal reevaluated the caloric consumption in children undergoing halothane anesthesia in 1988.9 Comparing the method of calculating
energy expenditure in this study with that of Holliday and Segar,1
the energy needs were reported to be lower than those previously
calculated for hospitalized children and were found to be close to
the basal metabolic rate. Lindhal suggested that, during anesthesia,
166 mL of water were needed to metabolize 100 kcal, so that water
requirements were at least similar.9
Fever increases caloric and water requirements by 10 to 12%
for every degree Celsius rise above normal. Daily maintenance
fluids should also be increased by hyperventilation, high environmental temperature, neonatal jaundice, and phototherapy.10
In the perioperative period, maintenance fluid therapy has to
be individualized according to the clinical situation and the type
of surgery. Furthermore, the capacity of individual children to
regulate water metabolism must be taken into account, especially
after major surgery. After major surgery, the renal capacity to
excrete free water is reduced to inappropriate secretion of vasopressin and antidiuretic hormone (ADH).11
Glucose Need
Glucose administration during surgery in children is controversial1217 and remains one of the important questions related to
fluid therapy. Avoiding both hypo- and hyperglycemia is an
important clinical concern. Apart from newborns, the risk of
TABLE 52-3. Hourly (4/2/1) and Daily Water Requirements
Weight, kg
310
1020
>20
Hourly Water
Requirement
Daily Fluid
Requirement
4 mL/kg/h
40 mL/h + 2 mL/kg/h
per kg > 10 kg
60 mL/h + 1 mL/kg/h
per kg > 20 kg
100 mL/kg/d
1000 mL/d + 50 mL/kg/d
per kg > 10 kg
1500 mL/d + 20 mL/kg/d
per kg > 20 kg
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hypoglycemia during surgery is rare even after long periods of
fasting.12 Less than 2% developed hypoglycemia in a study including both inpatients and outpatients.13 When fasting guidelines
are respected, in particular if clear fluids are given 2 hours before
surgery, the presence of hypo- or hyperglycemia has not been
reported.14
Hyperglycemia is frequently induced by 5% glucose solutions
administered in the perioperative period.15,16 Significant hyperglycemia can cause osmotic diuresis, electrolyte disturbances, or
dehydration, which has been shown to increase the risk of hypoxic
brain or spinal cord damage in animal studies.17,18 Neurologic
impairment could be attributed to osmotic dehydration of cerebral
nerve cells induced by hyperglycemia or compromised cerebral
circulation even in the absence of generalized hypoxemia.19
Anaerobic lactate production from cerebral glucose metabolism
has been associated with increased cerebral injuries.20 Intraoperative hyperglycemia should be prevented, especially when
cerebral ischemia could occur, particularly in neurosurgery.21
Many studies have reported that low-dextrose infusions should
prevent both hypo- and hyperglycemia in healthy American
Society of Anesthesiologists (ASA) 1 or 2 children undergoing
elective surgery.2225 Glucose infusion at a rate of 120 mg/kg/h is
sufficient to maintain normal blood glucose concentrations
and prevent lipid mobilization during surgery of up to 1.5 hours
duration in healthy children.26 However, some clinical situations
may be associated with a higher risk of hypoglycemia. These
include small infants, young children with diabetes, cardiomyopathy treated by adrenergic blockers, preoperative parenteral
nutrition,27 prolonged surgical procedures, or regional anesthesia
combined with general anesthesia (by reducing the stress response
to surgery). In these cases, monitoring of blood glucose concentration must be done intraoperatively, ideally after induction to
establish a baseline value, and subsequently every hour.
Electrolytes
For years, children have received hypotonic solutions according
to Holliday and Segars recommendations.1 In their study, they
calculated the daily electrolyte needs, based on the amount in
human milk. Daily sodium requirements are 3 to 4 mEq/kg and
potassium 2 to 4 mEq/kg. When these needs and daily fluid
volume requirements are combined, the result is a hypotonic
electrolyte solution (i.e., 0.20.3% saline in dextrose). The fear of
causing hypernatremia by using isotonic solutions was a real,
but unfounded, concern for practitioners. Free water distributes
proportionately between intracellular and extracellular spaces,
Fluid Therapy for the Pediatric Surgical Patient 845
increasing the intracellular volume whereas isotonic solutions

expand the extracellular volume. The increases in intracellular
volume can affect the brain, leading to encephalopathy. The surgical stress response, which leads to vasopressin release preventing
the normal free water excretion by the kidney, compounds the
problem. During surgery, insensible fluid losses and ongoing
losses associated with surgery are from the extracellular compartment. This should logically be replaced by a solution approximating the composition of ECF. Hypotonic solutions would
decrease plasma sodium concentration.
Balanced salt solutions have thus been recommended for fluid
replacement during surgery in standard pediatric texts for many
years. It is obvious that free glucose solutions should be removed
from the operating room environment because of the increased
risk of hyponatremia in the postoperative period.28,29
If used, intravenous solutions administered intraoperatively to
children should contain only low concentrations of dextrose and
be isotonic to plasma to avoid hyponatremia. Many solutions have
been proposed. They contain 2 or 2.5% dextrose but are associated
with induced hyperglycemia, even with initial acceptable blood
glucose levels.23,26 All studies involving very low dextrose solutions
(0.9 or 1%) have demonstrated that, in healthy young children,
hypo- and hyperglycemia are avoided during surgery.22,24,30,31 These
solutions have to be isotonic. After the age of 5 years, glucose-free
isotonic solutions can be administered, as in adults. Table 524
shows the osmolality and electrolyte composition of different
intravenous solutions available for children.
Postoperative Fluids
Most children are permitted to have oral fluid intake within
few hours of surgery, allowing the intravenous infusion to be
discontinued. If intravenous fluids are needed, for example
after abdominal surgery or other major procedures, the need for
maintenance fluids and replacement losses must be determined.Previous guidelines for postoperative intravenous perfusion led to the administration of hypotonic solutions. This
practice has been reconsidered after the risk of hyponatremia was
demonstrated in hospitalized children when hypotonic solutions
are used.3235 This risk is increased by factors contributing to water
retention, such as in the syndrome of inappropriate antidiuretic
hormone secretion (SIADH).36,37 This physiologic response has
been clearly demonstrated in many studies and clinical trials.
A recent review involving six surgical and medical trials
on intravenous fluid administration showed that the risk of
developing hyponatremia was more than 17 times higher when
TABLE 52-4. Composition of Different Intravenous Solutions

Intravenous Fluid
Saline 0.9%
Ringers lactate
(formula USP XXIII)
Saline 0.45%/dextrose 2.5%
Saline 0.18%/dextrose 4%
Dextrose 5%
Ringers/dextrose 1%
Isofundine
Polyionique B66
Sodium,
mmol/L
Chloride,
mmol/L
Potassium,
mmol/L
Osmolality,
mOsm/kg H2O
154
131
154
108
0
4
308
271
0
0
75
30
0
131
140
120
75
30
0
154
127
109
0
0
0
4
4
4
293
252
252
138
222
277
55
0
0
304
Dextrose,
mmol/L
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hypotonic fluid solutions were used than with hypotonic maintenance fluids.38 The dangers of hyponatremia are well documented
and reports of neurologic morbidity, including death, have been
reported since the mid-1990s. Severe acute hyponatremia can
induce encephalopathy by cerebral oedema and permanent brain
damage.39 Death has even been reported after minor surgery.29
Children have not only a higher risk of developing hyponatremic
encephalopathy than adults but also higher sodium levels than
adults (120 mmol/L vs 111 mmol/L).40 This is because of the
higher ratio of brain volumetointracranial volume and the
reduction of Na+-K+-ATPase pump activity.41
ADH secretion is unpredictable during the postoperative
period.42 Non-osmotic secretion of ADH can occur in many situations, including prolonged fasting associated with hypovolemia43
and stress response even in minor surgery.44 Anxiety, pain, nausea
and vomiting, and morphine are also factors contributing to raise
ADH plasma levels in the postoperative period.32,39
SIADH consists of hyponatremia, low plasma osmolality,
production of inappropriately concentrated urine with elevated
urine osmolality (>200 mOsm/kg), and excessive urine sodium
excretion (U Na > 30 mEq/L).45 The current recommendations are
to reduce the infusion to half maintenance rate in the first 24 hours
after major surgery.46 Isotonic solution should be used to first
replace fluid deficit; sodium plasma levels concentrations should
be monitored daily as long as intravenous therapy is needed.47,48
Pediatric anesthesiologists should keep in mind that intravenous infusion of inappropriate solutions in young children can
lead to severe complications and death. Recent editorials have
called for the rational use of isotonic solutions in the perioperative
period.49,50 Changes in practice are not easy, despite the evidence
of risk.51
REPLACEMENT FLUIDS
Replacement fluid therapy is designed to replace fluid and
electrolyte losses during surgery. The constituents of these losses
differ from the composition of the solutions used for maintenance.
Increasing the rate of infusion (i.e., volume) used for maintenance
to compensate for these losses can be hazardous during major
surgical procedures. During minor surgery, this is not as crucial
and the same solution can be used for both maintenance and
replacement.
Fluid losses during major surgery in children are from the ECF
compartment and should be replaced by solutions containing
the similar electrolyte composition (i.e., high sodium and chloride
and low potassium, bicarbonate, and calcium concentrations.
Fluid losses during the postoperative period have ideally to be
replaced by liquid with the same electrolyte composition. Isotonic
normal saline can be used, but hyperchloremic metabolic acidosis
can occur if large amounts are administered.52 A balanced salt
solution such as lactated Ringers, containing approximately 130 or
140 mEq/L of sodium and lactate, which is rapidly degraded into
bicarbonate in the liver and behaves like a buffer. Lactated Ringers
is probably the best solution for fluid replacement in major
surgery, such as spinal fusion or renal transplantation.53,54 Table
525 shows the composition of the usual fluid losses and their
electrolyte composition.
Balanced salt solutions, such as lactated Ringers, can be used
for these losses, at least for the first 10 to 20 mL/kg replacement.
In case of a larger volume of replacements, analysis of the fluid
composition (e.g., gastric suction, ileostomy) must be done in
TABLE 52-5. Usual Body Fluid Electrolyte Composition

Electrolytes, mEq/L
Body Fluid
Na+
K+
Cl
HCO3
Gastric
Pancreas
Bile
Ileostomy
Diarrhea
70
140
130
130
50
515
5
5
1520
35
120
50100
100
120
40
0
100
40
2530
50
order to replace losses as accurately as possible. This can be used

in combination with serial serum electrolyte assessments.
Intraoperative Clinical Guidelines

Fluid therapy during the perioperative period must be able
to provide both maintenance and replacement of fluid losses.
In healthy children undergoing elective surgery, the fluid deficit at
induction of anesthesia is represented by fasting deficit only, and
fluid losses during surgery, in the absence of important blood
losses, depend on the severity of surgical trauma and environmental factors. Berrys guidelines for fasting compensation according to age are still commonly used.55 This requires multiplying the
hourly maintenance fluid by the numbers of hours fasted, even
though the new NPO guidelines should minimize the fasting fluid
deficit.55 The volume for compensating preoperative fasting
is relatively higher in young children in view of their increased
metabolic rate. After the first hour of surgery, fluid volumes are
calculated by adding the maintenance rate and estimating fluid
needs according to the severity of surgical trauma (Table 526).
During minor surgery, the need for administration of intraoperative fluids can be decided on the basis of several factors: the
duration of the preoperative fast, the duration and the extent of
the procedure, and whether the child is expected to have oral fluid
intake soon after surgery. Provided the fluid deficit is minor, it will
be easily compensated for in the postoperative period. However,
intraoperative intravenous therapy reduces nausea and vomiting
in children undergoing minor ambulatory surgery, especially
those who have received opioid analgesia.56 Studies in adults have
shown that perioperative intravenous fluid therapy, even for minor
surgery, decreases postoperative nausea and pain after gynecologic
surgery.57
In conclusion, to simplify fluid administration using only one
type of fluid, a low-dextrosecontaining balanced salt solution
such as lactated Ringers can be used intraoperatively and for both
TABLE 52-6. Guidelines for Intraoperative Fluids in
Pediatric Patients
1. First hour (plus item 3 below)
25 mL/kg in children < 3 y
15 mL/kg in children > 4 y
2. All other hours (plus item 3 below)
Maintenance + trauma = basic hourly fluid
4 mL/kg + mild trauma (2 mL/kg) = 6 mL/kg
4 mL/kg + moderate trauma (4 mL/kg) = 8 mL/kg
4 mL/kg + severe trauma (6 mL/kg) = 10 mL/kg
3. Blood replacement with 3/1 volume replacement with
crystalloid or 1/1 with blood or colloids
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CHAPTER 52
maintenance and replacement fluid administration.23,24 Exceptions

to this guideline include newborns or major surgery in which fluid
losses can be considerable. In situations in which the risk of hypoglycemia is increased or during major surgery, maintenance fluid
and compensation for losses must be determined. Table 527
proposes guidelines for qualitative fluid therapy during the intraoperative period.
warmers or from mechanical ventilation, and transepithelial losses

from premature infants increase basal fluid requirements in the
perioperative period. Intraoperatively, maintenance fluid requirement is between 1 and 4 mL/kg/h, but this can increase significantly in certain surgical procedures, such as gastroschisis or
necrotizing enterocolitis, in which fluid requirements can be as
high as 50 to 100 mL/kg/h to maintain normovolemia.
In the neonate, it is important to consider all fluid intake, even
those used to flush catheters or administer medications. The fluid
given when using active humidification of the airway should also
be taken into consideration. Specially designed devices should be
used and include infusion pumps with the ability to deliver limited
volumes. Drug dilutions should be minimal so as to limit the fluid
intake, especially in very low birthweight babies.
Neonates have low energy reserves because they have reduced
glycogen and glucose stores and absence of body fat. They have
significantly higher metabolic rates and, therefore, higher oxygen
consumption than older children. Glucose deprivation may cause
hypoglycemia in neonates. However, measurements of plasma free
acids during surgery shows that without intraoperative glucose
supply, neonates mobilize fat from adipose tissue stores and
maintain blood glucose concentration.59 Glucose administration
should be administered intraoperatively, at a rate of 5 to 7 mg/
kg/min (0.30.4 g/kg/h).60 Marked hyperglycemia should be
avoided to prevent glycosuria and osmotic polyuria that may
lead to dehydration. Monitoring plasma glucose levels before and
during surgery is essential and adjustments of the glucose infusion
must be done as necessary.
FLUIDS IN NEONATES
MONITORING
Fluid therapy is different for preterm and newborns in view of

their distinctive physiology. Changes in body fluid compartments
and water composition occur in the first days of life, requiring
modification of fluid requirements. The immaturity of the renal
function (see Chapter 10) complicates the handling of fluid and
the appropriate response to fluid depletion or overload.
In neonates, renal blood flow is relatively low and at birth the
glomerular filtration rate (GFR) is only 25 to 30% of adult values.
The GFR increases rapidly during the first few weeks of life, and
then increases more gradually, reaching adult levels by 2 years of
age. This low GFR limits the ability to excrete a water load or
excess solute or drugs.
However, infants can handle a high water load despite this low
GFR because of the low concentrating capacity. In response to
water deprivation, the neonatal kidney can increase urine osmolality to a maximum of 600 to 700 mOsm/kg versus 1200 mOsm/
kg in adults.58 Proteinuria, in the form of albumin excretion, may
occur in up to 20% of premature infants. Newborn infants also
have a lower renal threshold for bicarbonate than do adults,
manifesting as a lower serum bicarbonate level (2021 mmol/L)
and a plasma pH of 7.35. The ability of the immature tubule to
excrete acid is reduced in the preterm infant, thus impairing renal
compensation of the acidotic state. The diluting and concentrating
capacities of the newborns kidney mature rapidly during the early
months of the first year. Renal tubular function reaches peak
capacity by 2 to 3 years of age.
Fluid requirements are influenced by the environment and the
clinical status of the newborn. Insensible water losses caused by
hyperthermia, increased evaporative losses caused by radiant
Fluid balance during anesthesia is monitored using the usual basic

variables such as heart sounds, breath sounds, electrocardiography, heart rate, blood pressure, oxygen saturation of hemoglobin
measured with pulse oximetry, end-tidal carbon dioxide, body
temperature, and skin color. Recently, new tools have been
implemented in monitoring systems to assist in the detection of
volume changes. These include the peripheral perfusion index
(PI), which indicates the quality of peripheral tissue perfusion.61
During major or long surgical procedures, urine output should
be measured continuously by placement of a urinary catheter.
In the face of large fluid or blood losses, urine output more than
0.5 mL/kg/h must be maintained. In the postoperative period,
urine output greater than 1 mL/kg/h indicates an adequate fluid
perfusion. Glucose measurements are essential in all situations in
which hypoglycemia can occur, or when glucose is administered
in order to adjust the glucose infusion. As described earlier (see
Intraoperative Fluids/electrolytes), in major surgery and in all
situations in which inappropriate secretion of vasopressin is
suspected, urine output can be low and measurements of urine
sodium levels and osmolality should be done to adjust fluid
administration.
TABLE 52-7. Guidelines for Iintraoperative

Fluid Administration
Maintenance Fluid
Fasting compensation
Infant > 3 mo
No hypoglycemia
risk
Minor surgery
Infant > 3 mo
No hypoglycemia
risk
Major surgery
Low-dextrose
balanced salt
or lactated Ringers
solution
Low-dextrose
balanced salt
or lactated Ringers
solution
Monitoring of dextrose
concentration ++
Infant < 3 mo
Dextrose 5% balanced
Hypoglycemia risk
salt solution
Monitoring of dextrose
concentration +++
Losses
Replacement
Same solution
Lactated Ringers
Lactated Ringers
CONCLUSION
Fluid therapy for pediatric surgical patients requires an understanding of fluid physiology in children and an appreciation of the
changes that occur during surgery. Maintenance and replacement
fluids represent the core of fluid management in anesthesia.
In most cases, balanced salt solutions with no or low-glucose
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concentration (<1%) must be used to meet the fluid requirements

and to avoid hyper- or hypoglycemia and hyponatremia. Glucose
infusion must be used intraoperatively in certain circumstances
but requires close monitoring. Anesthesiologists should keep in
mind that hypotonic solutions can lead to severe hyponatremia
and the risk of permanent brain damage, especially in the postoperative period when stress hormonerelated changes in water
excretion occur.
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editor. Anesthetic Management of Difficult and Routine Pediatric Patients.
2nd ed. New York: Churchill Livingstone; 1990.
56. Kearney R, Mack C, Entwistle L. Withholding oral fluids from children

undergoing day surgery reduces vomiting. Paediatr Anaesth. 1998;8:331336.
57. Maharaj CH, Kallam SR, Malik A, et al. Preoperative intravenous fluid
therapy decreases postoperative nausea and pain in high risk patients.
Anesth Analg. 2005;100:675682.
58. Travis LB: Disorders of water, electrolyte, and acid-base physiology.
In: Rudolph AM, Hoffman JIE, Rudolph CD, editors. Rudolphs Pediatrics.
20th ed. Stamford, Conn: Appleton & Lange; 1996. p. 1319.
59. Sandstrom K, Nilsson K, Andreasson S, et al. Metabolic consequences
of different perioperative fluid therapies in the neonatal period.
60. Mikawa K, Maekawa N, Goto R, et al. Effects of exogenous intravenous
glucose on plasma glucose and lipid homeostasis in anesthetized children.
61. Lima A, Bakker J. Noninvasive monitoring of peripheral perfusion.
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Transfusion for the

Pediatric Patient
Nathalie Bourdaud and Gilles Orliaguet
INTRODUCTION
Blood transfusion is a very old medical practice. The first reported
transfusion is said to have taken place in 1492 and was proposed
to save the life of Pope Innocent VIII, but it seems that it was given
orally. During the 17th century, some authors reported attempts of
blood transfusion using animal or human blood without success.
Since then, significant progress has been made allowing blood
transfusion to become part of daily practice.1
Perioperative blood transfusion includes not only red blood
cell (RBC) transfusion but also platelet and fresh frozen plasma
(FFP) transfusion. Several guidelines regarding preoperative blood
transfusion have been published for adult patients, but only a few
recommendations are available for children. Some aspects of the
adult recommendations are valid for children; others are more
specific for children.
RBC TRANSFUSION
The first aim of allogenic RBC transfusion is to adequately restore
tissue oxygenation, especially when oxygen demand exceeds oxygen supply, attributable to a decrease in hemoglobin concentration. RBC transfusion, however, may be associated with significant
risks and side effects. The decision to transfuse or not should
follow the proper analysis of the risk-benefit ratio.
Physiologic Aspects
Clinical indications and efficacy of RBC transfusion are essentially
based on physiologic and pathophysiologic concepts given that
no study compares RBC transfusion with placebo to correct acute
anemia or hemorrhagic shock. The physiologic concepts may provide information relevant to RBC decisions. Transfusion modalities and the threshold for RBC transfusion are different in children
than in adults in view of their specific physiologic differences.
These physiologic differences are inversely proportional to the
age of the patients and are most important in the neonates. The
expected effect of an RBC transfusion is an improvement in oxygen transport and, ultimately, tissue oxygenation.
Oxygen Transport
Oxygen supply must meet oxygen demand to provide sufficient
tissue oxygenation and aerobic cell respiration. A continuous and
adequate oxygen delivery (DO2) to the cells allows aerobic metabolism. An inadequate oxygen supply may lead to tissue hypoxia,
resulting in anaerobic metabolism and the production of lactate.

DO2 depends on the cardiac output (CO) and the arterial oxygen
content (CaO2):
DO2 = CO CaO2 (DO2 in mL/min,
CO in L/min and CaO2 in mL/L)
CaO2 is the sum of the hemoglobin-bound oxygen and
dissolved oxygen in the plasma:
CaO2 = (SaO2 1.34 Hb) + (0.03 PaO2)
where SaO2 is the arterial saturation in oxygen (in %), Hb is
the hemoglobin concentration (in g/dL), and PaO2 is the partial
pressure of oxygen in arterial blood (in mmHg).
Under physiologic circumstances, dissolved oxygen represents
a very small part of the global amount of body oxygen. More than
98% of the oxygen is transported by hemoglobin. When breathing
ambient air under normal conditions, the amount of oxygen
dissolved in the plasma is negligible, but when breathing 100%
oxygen, the amount of oxygen dissolved into the plasma is significantly increased. Global oxygen consumption (VO2) is the
amount of oxygen consumed by the whole body per minute. Under
physiologic conditions, VO2 ranges from 200 to 300 mL/min in a
normal adult and DO2 ranges from 800 to 1200 mL/min. DO2 is
three to four times higher than VO2 under normal conditions. The
relationship between VO2 and DO2 is presented in Figure 531.
An isolated and marked decrease in DO2 will not necessarily
result in a decrease of VO2. Indeed, above a critical value of DO2,
there is an independent relationship between VO2 and DO2 and
the curve is a plateau because of an increase in oxygen extraction.
This situation may occur, for example, in the case of acute normovolemic anemia, in which DO2 decreases with the fall in Hb. When
the DO2 critical value (DO2CRIT) is reached, VO2 decreases proportionally to the decrease in DO2, becoming DO2-dependent, and
tissue hypoxia develops. The DO2CRIT value is not a fixed value but
varies with basal metabolism, some diseases states, and perhaps
patients age or genetic factors. Some studies have shown that the
DO2CRIT value ranges from 4 to 8 mL/min.2,3 Oxygen diffusion
across the alveolar-capillary barrier or from the capillary network
into the tissues is another important concept. Ficks first law of
diffusion describes that the oxygen rate of diffusion depends on a
diffusion coefficient of oxygen within the medium (K), the surface
area of diffusion (A), the pressure gradient across the diffusion
barrier (P), and the distance over which diffusion occurs (D):
O2 rate of diffusion = K A P/D
Accordingly, an increase in PaO2 will enhance oxygen diffusion
because P will be increased.4 Under normal conditions, dissolved
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851
Figure 53-1. Relationship between oxygen

consumption (VO2) and oxygen transport
(DO2) diagram. Adapted from reference 5.
oxygen contributes little to CaO2 and an increase in PaO2 has only
little benefit because more than 90% of hemoglobin is already
saturated with oxygen. In acute normovolemic anemia, the plasma
compartment is increased and even little variations in PaO2 will
have an important impact on DO2.57
Normal hemoglobin values in term neonates vary from 14 to
20 g/dL. These elevated values decrease during the first month of
life and reach a nadir at 2 to 3 months. The decrease in Hb is
caused by a decreased erythropoietin level and a reduced RBC
half-life.8 In addition, in neonates and children younger than
6 months, several types of hemoglobin coexist. At birth, 75 to 80%
of the hemoglobin is composed of hemoglobin F (fetal; HbF),
which has a lower affinity for oxygen than adult hemoglobin
(A and A2). The level of HbF decreases during the first 6 months
of life. The oxyhemoglobin dissociation curve of HbF is shifted to
the left and the release of oxygen from hemoglobin to the tissues
is reduced (Figure 532). In addition, the high concentration
of HbF is responsible for changes in blood viscosity owing to a
decreased RBC deformity.9 Conversely, infants have an increased
Figure 53-2. Oxyhemoglobin dissociation

curve. Compared with adults, the oxyhemoglobin dissociation curve is shifted to the
left in newborns (high concentration of
hemoglobin F) and to the right in infants
(high concentration of 2,3-diphosphoglycerate
[2,3-DPG]). At a same oxygen partial venous
pressure (40 mmHg), the delivery of oxygen
to the tissue is lower in newborns and higher
in infants. Adapted from reference 72.
2,3-diphosphoglycerate (2,3-DPG) concentration resulting in a

low oxygen affinity.10 Thus, at the nadir of Hb (23 mo of life), the
oxyhemoglobin dissociation curve is shifted to the right and the
release of oxygen from hemoglobin increases.11
Compensatory Mechanisms
in Normovolemic Anemia
Adaptation to Anemia
After blood loss, hypovolemia may be compensated by the infusion
of crystalloids or colloids resulting in a state of normovolemic
anemia. When normovolemic anemia occurs, several compensatory mechanisms are activated to maintain adequate oxygen
delivery. These mechanisms include
1. An increase in the blood flow (heart rate, stroke volume, and
CO increase) and in the extraction of oxygen.
2. A redistribution of blood flow from nonvital organs toward the
brain and heart.
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3. Modification of the oxyhemoglobin dissociation curve with a

decrease in the affinity of hemoglobin for oxygen and an
increased in erythropoietin production.9
Blood flow increase is obtained by an increase in the CO via
a decrease in blood viscosity and an increase in sympathetic
stimulation.
Impairment in Adaptive Mechanisms

In children, the possibility of adaptation to acute anemia is reduced
compared with adults, mainly because of important differences
in cardiovascular physiology. The heart rate is higher, and quasimaximal at baseline, in children compared with adults (140
beats/min 20 in neonates, 130 beats/min 20 in infants). The
ability to increase heart rate and CO is also reduced because of a high
baseline adrenergic tone. Furthermore, neonatal myocardium
operates at a near-maximum level of performance at baseline. Thus,
the adaptive capacities to acute anemia are rather limited in children.8
TRANSFUSION TRIGGER IN CHILDREN

Only a few studies are available regarding transfusion trigger in
children. The indication for blood transfusion should not be based
on a hemoglobin concentration level alone; it must take clinical
and paraclinical aspects into account. Hemoglobin concentration
does not reflect tissue DO2 but represents only a component of
the oxygen transport capacity.12 The transfusion decision must,
therefore, take into account the age of the patient, the rapidity
of development of the anemia, the volume of blood loss, and
the presence of any comorbidity that may impair oxygenation
(i.e., pulmonary or cardiac failure).
In American Society of Anesthesiologists (ASA) class 1 adults,
Hb less than 7 g/dL during surgery or 8 g/dL in the postoperative
period represent commonly accepted triggers for RBC transfusion.
Healthy children normally tolerate a low Hb very well provided
that normovolemia is maintained. The triggers for RBC transfusion
correspond to signs and symptoms indicating insufficient oxygenation (anaerobic metabolism). These usually appear at very
low hemoglobin levels (<56 g/dL). In hemodynamically stable
children, a hemoglobin value of 7 g/dL, after an acute blood loss,
seems to be an acceptable trigger. In fact, this value has proved to
be acceptable in otherwise stable critically ill children and is, thus,
associated with a decrease in transfusion requirements without
increasing adverse outcomes.13
Newborns in intensive care units are particularly at risk of blood
transfusions in view of the repeated diagnostic blood sampling.
Because the normal hemoglobin value in newborns is higher
than in children and adults, the hemoglobin threshold for blood
transfusion is also higher. In newborns, the signs of inadequate
oxygenation are different and include episodes of apnea, tachypnea,
bradycardia, tachycardia, or insufficient weight gain.14
Intraoperatively, it is worth calculating the maximum allowable
blood loss (MABL). Further blood loss would indicate that blood
transfusion is required:
MABL (ml) = EBV (Hctpt Hctmin)/Hctpt
where EBV = the estimated blood volume, Hctpt = the initial
hematocrit, and Hctmin is the minimum acceptable hematocrit
(Table 531). In infants and children, MABL may be reached quite
quickly because of a rather small blood volume (estimated at
90 mL/kg in infants and 80 mL/kg in children).
TABLE 53-1. Estimated Blood Volume According to Age

Age
Volume, mL/kg
Premature
Newborn
Infant
Child
Adolescent
90100
8090
7580
7075
6570
From reference 15.
This blood loss may be replaced using crystalloid and colloid

solutions. However, once the estimated blood loss reaches MABL,
RBC transfusion should be initiated.15,16 However, in clinical
practice, it may be difficult to precisely assess blood volume loss in
pediatric patients. Therefore, it seems wiser to obtain a hematocrit
or hemoglobin measurement before deciding to transfuse a child
when approaching MABL, unless there is ongoing blood loss.
In this situation, it is important that hemoglobin measurements
are readily available and can be done in the operating room using
simple devices.
Children who need RBC transfusion receive a calculated
volume of blood based on their weight, by contrast to a number of
units that adults may require. A useful equation to determine the
volume of blood to transfuse is
Weight (kg) desired Hb (g/dL)
actual Hb (g/dL) the transfusion factor
The transfusion factor is usually 3, according to different
authors.17 This formula calculates the blood volume required in
children whose bleeding has stopped. By contrast, in case of persistent bleeding, this formula is inaccurate because of the ongoing
hemorrhage.
Recent studies have shown that the former formula (using a
transfusion factor of 3) led to an underestimation of the volume
of RBCs required. The authors suggest that a transfusion factor of
either 4.8 (4.8 weight [kg] desired rise in Hb [g/dL]) or 3/
hematocrit level of RBCs (3/Hct level of RBCs weight [kg]
desired rise in Hb [g/dL])1820 be used. It should be borne in
mind that the hematocrit level of RBCs stored in citratephosphate-dextrose-adenine-1 ranges from 0.70 to 0.75, whereas
RBCs stored in additive solution such as Adsol (AS-1), Nutricel
(AS-3) or Optisol (AS-5) range from 0.50 to 0.60. 100 mL of one
of these additive solutions added to RBCs with CP2D or CPDA-1
prolongs shelf life to 42 days and decrease viscosity. Most RBCS
transfused in the USA are Adsol units.
EFFICACY OF RBC TRANSFUSION

Effects of RBC Transfusion on DO2 and VO2
Only few studies analyze the effects of RBC transfusions on
oxygenation, and the results are controversial. Some studies found
no increase in DO2 despite a significant increase in Hb after RBC
transfusion. By contrast, other studies showed an increase in DO2.
Few have shown a concomitant increase in VO2.21,22 Using these
parameters, the majority of the studies failed to show any efficacy
of the blood transfusion. There are various explanations for
such surprising results; one may be related to the fact that DO2
before RBC transfusion was probably sufficient, with a VO2 still
independent from DO2. All these studies were performed in the
adult population, mainly in cardiac patients.
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The only pediatric studies were performed in children in
septic shock.23,24 In one, the authors reported that transfusion
significantly increased Hb (10.2 0.8 to 13.2 1.4 g/dL) and DO2
(599 65 to 818 189 mL/min/m2) but without a concomitant
increase in VO2 (166 68 to 176 74 mL/min/m2). The authors
concluded that increasing CaO2 by blood transfusion was not able
to increase VO2 in pediatric septic shock patients.23 However,
septic shock and hemorrhage are different situations, particularly
because there is a defect in oxygen extraction in septic shock,25
whereas oxygen extraction increases during bleeding, maintaining DO2 and VO2 in the normal range, provided normovolemia
is maintained.26
Effects of Blood Storage

The increasing concern about the efficacy of blood transfusion
compels the question about the impact of the storage on RBCs
functions. RBCs are commonly stored with preservative solutions
for up to 42 days.27 These improvements have greatly increased
our ability to meet transfusion requirements despite a shortage
of donors.
RBCs undergo a number of changes during storage that
affect their ability to deliver oxygen to the tissues adequately. The
biomechanical alterations affect the RBCs membrane properties.
The biconcave structure is modified during the storage, and RBCs
become echinocytes with protrusions and, finally, spheroechinocytes with decreased deformability. These membrane changes may
be related to adenosine triphosphate (ATP) depletion or to a loss
of membrane phospholipids during storage. However, membrane
853
changes appear to be reversible, at least in part, by the use of improved storage conditions and rejuvenation solutions.28 About one
fifth to one fourth of transfused RBCs is destroyed within the first
24 hours.
The biochemical changes inside the RBCs during storage may
also be crucial. The intracellular ATP levels decrease after 4 to
5 weeks of storage and can drop to 60% of normal level. The
2,3-DPG that plays a crucial role in hemoglobin oxygen affinity
decreases quickly during the first 2 weeks of storage to almost
undetectable levels.29 This decrease in 2,3-DPG is enhanced by the
low pH of the storage fluid.30,31 The 2,3-DPG levels increase during
the first hours after transfusion, even though it can take up to
72 hours to normalize. In the presence of hemorrhage, this may
seem quite long. However, many authors who compared the DO2
capacity of RBCs stored for 2 to 3 weeks with fresh (26 d) RBCs
failed to demonstrate any differences between the two groups.32,33
As a result of these alterations in RBC function during prolonged storage, fresh (<7 d) RBCs are often reserved for neonates
because of the need for iterative transfusions and the risk of
hyperkalemia.3436
RISKS AND OUTCOMES

Since the HIV crisis of the late 1980s, clinicians are more aware of
transfusion-associated risks. Additional concerns include the risk
of infections (viruses, bacteria, parasites, and prions), immunologic
reactions including blood group incompatibility, and transfusion
errors. The incidences of the different risks and outcomes are
shown in Table 532 and Figure 533.
Figure 53-3. Serious Hazard of Transfusion (SHOT) in the United Kingdom: cumulative data 19962006. ATR = allergic transfusion reaction; DTR = delayed transfusion reaction; HTR = hemolytic transfusion reaction; IBCT = incorrect blood component
transfused; PTP = posttransfusion purpura; TA-GVHD = transfusion-associated graft-versus-host disease; TRALI = transfusionrelated acute lung injury; TTI = transfusion transmitted infection. From reference 77.
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TABLE 53-2. Risks Associated With Blood Transfusion

Risks
Type of Risk
Estimated Incidence
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Hepatitis B
Hepatitis C
HIV
HTLV
TTV
West Nile virus
CMV conversion
EBV
TRALI
ABO mismatch occurrence
mortality
Delayed hemolytic reaction
Alloimmunization (PLTs
and WBCs)
Alloimmunization (RBCs)
Allergic reactions
Febrile reaction
GVHD
Volume overload
Depressed erythropoiesis
1/58001/150,000 units
1/872,000 units
1/1.41/2.4 million
1/1.5 million
52%
1/1.4 million
7%
0.5%
1/50001/500,000
1/60001/20,000
11.
12.
13.
14.
15.
16.
17.
18.
1/2500
1/10
1%
14%
0.11%
1/4001/10,000
1040%
Universal
CMV = cytomegalovirus; EBV = Epstein-Barr virus; GVHD = graft-versus-host

disease; HTLV = human T cell lymphotrophic virus; PLTs = platelets; RBCs = red
blood cells; TRALI = transfusion-related acute lung injury; TTV = transfusiontransmitted virus; WBCs = white blood cells.
From reference 38.
Infectious Risks
Blood transfusionrelated infections depend on the pathogen
concerned. The risks vary worldwide. The risk in developing countries is far greater than in those with a high human development
index (HDI). The risk of viral transmission has been greatly
reduced in developed countries since about 2000 as result of
improved viral genomic screening. Viral screening of each unit of
blood includes HIV-1 and HIV-2, hepatitis C virus (HCV), cytomegalovirus (CMV), human T-cell lymphotrophic virus (HTLV)I
and HTLV-II, presence of hepatitis B (HBV) surface antigen, and
HIV-1 p24 antigen. Blood is also screened for malaria and syphilis.
Other viruses that may be transmitted by blood transfusion include
West Nile virus, hepatitis D virus, hepatitis A virus (HAV), EpsteinBarr virus, parvovirus B19, transfusion-transmitted virus, and
hepatitis G virus.
The risk of viral transmission dropped from 1/65,000 to
1/350,000 transfused products in France between the years 1992
and 2002.37 The residual risk of viral transmission (HIV, HCV,
HBV, and HTLV) was evaluated to be about 2.84 per million
units withdrawn in France in 2003.38 With the decline in the viral
risk, bacterial contamination has become the leading cause of
infection with an observed frequency of 1/167,500 packed RBCs
transfused.37 A few cases of variant Creutzfeldt-Jakob disease
(vCJD) have been attributed to blood transfusion. However, the
transmissibility of the disease by prions in blood is difficult to
establish because of the diseases long incubation period.39,40
Transfusion-related Acute Lung Injury

Transfusion-related acute lung injury (TRALI) is a syndrome of
acute lung insufficiency associated with transfusion and was
TABLE 53-3. Diagnostic Criteria for Transfusion-related

Acute Lung Injury and Possible Transfusion-related Acute
Lung Injury
1. TRALI criteria
a. ALI
i. Acute onset
ii. Hypoxemia
Research setting:
PaO2/FIO2 300,
or SpO2 < 90% on room air
Nonresearch setting:
PaO2/FIO2 300
or SpO2 < 90% on room air
or other clinical evidence of hypoxemia
iii. Bilateral infiltrates on chest radiograph
iv. No evidence of left atrial hypertrophy or circulatory
overload
b. No pre-existing ALI before transfusion
c. During or within 6 h of transfusion
d. No temporal relationship to an alternative risk factor
for ALI
2. Possible TRALI
a. ALI
b. No pre-existing ALI before transfusion
c. During or within 6 h of transfusion
d. A clear temporal relationship to an alternative risk factor
for ALI
ALI = acute lung injury; FIO2 = fractional concentration of oxygen in inspired
gas; PaO2 = arterial oxygen pressure; SpO2 = oxygen saturation of hemoglobin
monitored with pulse oximetry; TRALI = transfusion-related acute lung injury.
From reference 42.
described in 1985 by Popovsky and Moore.41 TRALI is defined as

a new episode of acute lung injury (ALI) that occurs during or
within 6 hours of a transfusion and that is not temporally related
to a competing etiology for ALI (Table 533).42 TRALI is a clinical
diagnosis that includes tachypnea, cough, cyanosis, frothy endotracheal aspirate (in tracheally intubated patients), fever, hypotension, tachycardia, and an increase in oxygen requirement.
An acute and transient leukopenia may occur, but it may be easily
missed because the marginating pool of neutrophils move rapidly
into the circulation.43 Symptoms associated with TRALI can be
sudden and fulminant and most commonly occur between 1 and
2 hours after the onset of transfusion, but may develop within
30 minutes of transfusion. Almost all reactions occur within
6 hours. Chest x-ray shows bilateral pulmonary infiltrates.
The actual incidence of TRALI is not yet known in view of the
difficulties with the diagnosis. The reported incidence of TRALI
varies and ranges from 1/1000 to 1/5000 transfusions; there is a
great variability among different geographic localities.41,44,45 Data
on the severity and outcomes of TRALI are also limited. A mortality rate of 5 to 10% is widely accepted.46 The pathophysiology
remains unclear. There are two main hypotheses, which are not
exclusive.47 According to the first hypothesis, leukocyte antibodies
in donors, often multiparous women, activate recipient neutrophils in pulmonary capillaries and cause pulmonary damage and
capillary leak. In the second hypothesis, TRALI is caused by two
events.48 The first event is linked to the patients condition at the
time of the transfusion (e.g., sepsis, surgery), which induces
a sequestration of neutrophils in the lungs. The second event is
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the transfusion of biologically active substances (e.g., lipids or
cytokines) that activate neutrophils, leading to lung damage and
capillary leak.49
Treatment is symptomatic and may necessitate mechanical
ventilation and/or vasopressors. Most patients recover within
72 hours. With regard to prevention of TRALI, leukocyte depletion is probably inefficient because TRALI is caused by donor
antibodies and not by the leucocytes themselves.50 Some authors
recommend excluding donors who were suspected of having
TRALI previously.
855
are classically considered as a type 1 hypersensitivity reaction, the

etiology of ATR has not yet been fully established. Most ATRs are
moderate and often associated with hives, with or without pruritus.
The ATR may be severe with an anaphylactic reaction and symptoms include dyspnea, wheezing, hypotension, tachycardia, shock,
and in rare cases, death. Fever is usually not observed. Some
authors suggest using antihistamines in patients with a history of
ATR to decrease the risk of further reactions, but there is no
evidence that antihistamines decrease the incidence of ATRs.55
Transfusion-Associated Graft-versus-Host Disease
Immunologic Risks
The immunologic risk is inevitable because of the polymorphism
of RBCs. Currently 25 erythrocytic systems have been discovered,
including about 200 antigens. This is the reason why the immunocompatibility between blood donor and recipient cannot be
perfect. The two main systems are the ABO and Rhesus systems.
When a blood transfusion is necessary, donor and recipient blood
must be compatible with regard to the major ABO groups and Rh
type. The other phenotypes of the rhesus (C, E) and the Kell system
are verified afterward. For some immunized patients, it may be
necessary to test the compatibility in other phenotypes or systems.51
The Febrile Nonhemolytic Transfusion Reaction

The most common reaction after transfusion is the febrile nonhemolytic transfusion reaction (FNHTR), which may involve
several mechanisms. The first hypothesis is that leukocyte antibodies in the patients plasma react with leucocytes present in the
blood product, resulting in the production and release of endogenous pyrogens causing fever and other symptoms.52 Another
explanation may be the accumulation of biologic response
modifiers (BRMs), including complement fragments, lipids, and
cytokines, during RBC storage. This reaction is rather benign and
is associated with a moderate increase in body temperature (1C
from baseline). Symptoms of chills, cold, rigors, and/or discomfort
are common. Clinical signs and symptoms often appear toward
the end of or after the transfusion. FNHTR occurs in about 1%
of RBC transfusion, but it is more frequently associated with
platelet transfusions (~10%). It seems that immunologic mechanisms are different in the case of platelets transfusions.52 Transfusion of leucocyte-depleted RBCs decreases the incidence of
FNHTR, whereas prestorage leucocyte depletion of apheresis
platelets is the most effective method to reduce FNHTR owing to
platelet transfusions. Thus, all components other than granulocytes should be leucocyte depleted (5 106 leucocytes/unit) at
the time of manufacture.53
The Acute Hemolytic Reaction

Acute hemolytic reactions are a much less frequent but more
severe reaction caused by incompatibility between donor antibodies and recipient RBCs. More than 80% of acute hemolytic
reactions are caused by incompatible transfusion (see Transfusion
Error).54 The other causes of acute hemolytic reaction are the
presence of allo- or autoantibodies that interact with erythrocytes.
Allergic Transfusion Reaction

The allergic transfusion reaction (ATR) is an interaction between donor allergen and recipient antibodies. Although ATRs
Transfusion-associated graft-versus-host disease (TA-GVHD) is

an infrequent but nearly always fatal complication of blood
transfusion. The pathophysiology is now well described. The graft
contains immunologic competent cells (T lymphocytes) and
the host appears foreign to the graft (transfusion). Under certain
circumstances, for example, immunosuppression, the host is
unable to mount an effective immunologic reaction against the
graft. The classic symptoms include fever, rash, liver dysfunction,
and diarrhea that begin within 4 to 10 days after transfusion.
Leucopenia and marrow aplasia can occur within 2 to 3 weeks.
The mortality rate is very high (>90%).56 Patients at risk for
TA-GVHD must be identified and transfused using irradiated
cellular blood products. Irradiation inhibits the proliferation
of donor lymphocytes, thereby blocking the initiation of graftversus-host disease (GVHD).57 Leucocyte depletion cannot be
used as the sole method to prevent TA-GVHD in a patient at
risk, but it seems that universal leucocyte depletion in the United
Kingdom reduces the already low risk of TA-GVHD in immunocompetent recipients.58
Transfusion Errors
Transfusion errors typically occur at the bedside just before
transfusion. Data from the U.S. Food and Drug Administration
(FDA) and from other sources in Europe have documented that
transfusion errors are the leading cause of serious morbidity and
mortality from blood transfusions. Inadequate patient identification at the bedside is the root cause.59 Seventy percent of incidents reported to the U.K. Serious Hazard of Transfusion scheme
(SHOT) are related to transfusion errors.60 Acute intravascular
hemolysis may results from major ABO incompatibility and is
associated with a high risk of death or morbidity.
The clinical presentation of transfusion errors includes hemoglobinuria and acute anemia, fever, discomfort, and pain. Hypotension, shock, renal failure, and disseminated intravascular
coagulation are frequent complications. Transfusion errors may
have less severe consequences, but they invariably compromise
future transfusions or increase the risk of hemolytic disease of
the fetus and newborn in subsequent pregnancies. The risk of
transfusion errors is at least 100 times greater than the risk of HIV
or HCV transmission. The estimated risk ranges from 1/1000 to
1/10,000 transfusions.61 This is probably an underestimation
because it is based upon voluntary reported errors, not on a systematic review of each transfusion.
In view of the potential severity of a transfusion error, a
thorough bedside check must be performed before every transfusion. Blood transfusion is a complex process that involves
several persons including laboratory personnel. It begins with the
donor (blood collection) and ends with the patient. At each step
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Figure 53-4. Transfusion safety: process and products. Safe transfusion depends upon a series of linked processes and includes
more than just blood safety. Numbers 13 refer to the three zones of potential error in the process of transfusion. Adapted from
reference 59.
of the process, different kinds of error can be made. The most
frequent errors occur at three zones of the process: patient
sample collection, indication of transfusion, and bedside administration59,61 (Figure 534). Because the main cause of incompatible
transfusion is human error and because human error is inevitable,
it is necessary to audit processes so that errors can be detected
before harming the patient. New technology has been developed
for this reason and includes the use of a radiofrequency bracelet or
handheld bar code scanner to limit errors of identification.6265
This technology is quite expensive and not widely used.
Other Risks and Outcomes

Transfusion-Associated Circulatory Overload
Transfusion-associated circulatory overload (TACO) has a clinical
presentation similar to that of other causes of hydrostatic pulmonary edema. In addition to dyspnea, tachypnea, and jugular
venous distention, elevated systolic blood pressure is usually
present. The clinical profile of the patient at risk for TACO is a
child 3 years of age or younger.66 By contrast to the TRALI, echocardiographic imaging shows cardiac dysfunction, and plasma
levels of brain natriuretic peptide are increased. Treatment
includes oxygen administration (mechanical ventilation may be
required) as well as diuretics. It is recommended that, in patients
with underlying cardiac dysfunction, a slower transfusion rate
(1 mL/kg/h) and diuretics are required to prevent the development of TACO.67
Posttransfusion Purpura
Posttransfusion purpura is a rare syndrome characterized by
severe thrombocytopenia and bleeding. It is caused by alloimmunization to human plateletspecific antigens after a blood com-
ponent transfusion. In this case, thrombocytopenia is refractory to

platelets transfusion.
Complications After Massive Transfusion

There are several definitions for massive transfusion, but the
one most commonly used is the replacement of one blood volume
over a period of 24 hours. The main consequences are dilution
coagulopathy, thrombocytopenia, hypothermia, and multiorgan
failure.68,69 Electrolyte and metabolic disturbances may also occur.
These include hypocalcaemia, hypo- or hyperkalemia, hypomagnesemia, and metabolic alkalosis. Premature infants are more
susceptible to hypocalcaemia and hypothermia after transfusion
of large volumes of blood. Ionized hypocalcemia is related to
citrate toxicity and is more likely in the presence of abnormal liver
function because of reduced citrate metabolism.70 Intravenous
infusion of approximately 0.3 mL/kg 10% calcium chloride
(30 mg/kg) will correct the hypocalcemia The use of calcium gluconate is less effective because it requires intact liver metabolism
to release ionized calcium.69
TYPES OF TRANSFUSED COMPONENTS

Neonates and children are at higher risks for TA-GVHD and CMV
infection than adults. The type of packed RBC transfusion should,
therefore, be carefully chosen (Table 534). For the past several
years, all packed RBCs are leucocyte depleted. Leucocyte depletion
has decreased the incidence of FNHTR.71 For immunodeficient
patients (including stem cell transplant recipients), it is recommended that irradiated and CMV-seronegative RBCs be transfused to limit the risks of TA-GVHD and CMV infection.
Newborns may be considered as having an immature immune
system. For this reason, some authors recommend transfusing
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TABLE 53-4. Indications for Specific Preparations of
Blood Products
Phenotyped
Feminine Sex (Better: All Children)
CMV-negative
Birthweight < 1000 g

Birthweight < 1000 g and CMV-negative
mother
Bone marrow or pulmonary transplantation
and CMV-negative child
Immunodeficiency
Aplasia owing to chemotherapy
DiGeorges syndrome
Prematurity
Full-term newborn
Hodgkins disease
Bone marrow transplantation
IgA deficit with autoantibodies anti-IgA
Necrotizing enterocolitis
Severe allergy to previous transfusion
Alloimmunization anti-RBC
Irradiate
Washed
Compatible
CMV = cytomegalovirus; IgA = immunoglobulin A; RBC, red blood cell.

72
neonates with irradiated products. For similar reasons, blood

transfused in the first year of life should be CMV-negative.17 In
view of the risk of hyperkalemia during massive blood transfusion,
the use of RBCs stored less than 2 weeks is recommended, especially in young children. Neonates, particularly premature newborns, may require iterative transfusions with small volumes
on each occasion. To reduce the risks, it is possible to transfuse
RBCs from a single donor. Maternal ABO and RhD group must
be considered when transfusing neonates and infants in the first
4 postnatal months. Blood component transfusions must be of the
neonates own ABO and RhD group (or an alternative compatible
ABO and RhD group) and compatible with any ABO or atypical
red cell antibody present in the maternal or neonatal plasma.17
Platelet Transfusions
Platelet transfusions are indicated for the prevention and
treatment of hemorrhage in patients with thrombocytopenia or
platelet dysfunction. Indications for platelets transfusion in
children do not significantly differ from adults. Perioperatively,
the hemorrhagic risk threshold for surgery is considered to be
50 109/L in the absence of platelet dysfunction.73 In the actively
bleeding patient, it is recommended that the platelet count be
maintained above this critical level (50 109/L).69 A platelet count
of 50 109/L may be anticipated when approximately two blood
volumes have been replaced by fluid or RBC components. The
transfusion of platelets should be started even though there may
be marked individual variation.74
In children, a platelet transfusion of 5 to 10 mL/kg will raise
the platelets count from 50 to 100 109/L (i.e., for each 10 mL/kg,
the platelet is raised by 10,000). For children over 10 kg, a dose of
1 unit/10 kg should produce the same results.75 The following
formula can also be used to calculate the platelet dose:
Dose (109) = Pl EBV 0.67
where Pl = the desired platelet increment (109) and EBV =
the estimated blood volume (L).
857
TABLE 53-5. Indications for Fresh Frozen

Plasma Transfusion
Single coagulation
factor deficiencies
Multiple coagulation
factors deficit
Liver disease
Surgical bleeding and
massive transfusion
Thrombotic
thrombocytopenic
purpura
When no virus-safe fractionated

product is available. Currently
applies mainly to Factor V.
When there are demonstrable
multifactor deficiencies associated
with severe bleeding and/or
disseminated intravascular
coagulation.
For prevention of bleeding in patient
with liver disease and prolonged
prothrombin time.
In case of massive blood loss, guided
by timely tests of coagulation,
including bedside tests.
Single-volume daily plasma exchange
commenced at presentation and
ideally within 24 h.
From reference 76.
Platelets should be ABO- and RhD-compatible with the

recipient. Although platelet membranes do not carry RhD antigen,
platelet concentrates contain enough red cell stroma to stimulate
Rh immunization. Therefore, RhD-negative girls should be
transfused with RhD-negative products or should receive anti-D
immunoglobulin if only RhD-positive products are available.20
Platelets can be transfused using a blood-giving set, although a
specific platelet-giving set reduces wastage because of a reduced
deadspace. Transfusion of platelets using a giving set previously
used for transfusion of RBCs is not recommended.
Fresh Frozen Plasma

Indications and contraindications for FFP transfusion are the same
for both children and adults. Indications of FFP transfusion are
summarized in Table 535. The volume of FFP for children is
usually 10 to 20 mL/kg. This raises the level of coagulation factors
by about 20% just after the transfusion. Posttransfusion efficacy
must be verified for optimal treatment. Reference values for
coagulation tests in children older than 6 months are the same as
for adults. In newborns and small infants, the concentrations of
coagulation Factors IX, X, and XI are lower and may prolong the
activated partial thromboplastin time without increasing the
bleeding risk. The correction of the prolonged coagulation tests
by FFP transfusion is unpredictable and should, therefore, be
verified after administration.76
FFP should never be used as volume replacement therapy.
Albumin maintains oncotic pressure and allows plasma volume
expansion. Albumin may be used for large-volume losses, although
it is preferable to use a nonblood product whenever possible
because of the lower risk of infectious transmission. FFP should
be ABO-compatible with the recipients RBCs (i.e., it should not
contain antibodies that could react with recipient A and/or B
antigens). Usually, the RhD group need not be considered (Table
536).20 The main risks related to FFP transfusion are allergy,
TRALI, and transmission of infectious diseases. Bacterial contamination is highly unlikely because the freezing process inactivates bacteria. The risk of viruses (such as HAV, HBV, HCV, HIV-1
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TABLE 53-6. Choice of ABO Group for Administration

of Blood Products in Children
ABO Group of Blood Products
to Be Transfused
Patients ABO group
Red Cells
Platelets
FFPa
O
First choice
Second choice
O
A or B
O
A or B or AB
A
First choice
Second choice
Third choice
A
O
A
Bb,c
Ob
A
AB
Bb
B
First choice
Second choice
Third choice
B
O
Bb,c
Ab
Ob
B
AB
Ab
AB
First choice
Second choice
Third choice
AB
A or B
Ob
ABc
Ab or Bb,c
Ob
AB
Ab
Bb
FFP = fresh frozen plasma.

a
Group O FFP should only be given to patients of group O. Although group AB
FFP can be given to people of any ABO blood group, supplies are usually limited
b
Components that test negatively for highlevel anti-A and/or anti-B should
be selected. The use of group O platelets for non-O patients should be avoided as
much as possible.
c
Platelet concentrates of group B or AB may not be available.
From reference 53.
and -2, and parvovirus B19) remains because they are not inactivated by freezing. However, the residual risk is very low (1.0 in
10 million for HIV-1 and -2; 0.2 in 10 million for HCV, and 0.83 in
10 million for HBV).76 No TA-GVHD has been reported with FFP
transfusion, so it is not necessary to irradiate the FFP.
Plasma is a major source (68%) of prions, whereas only
26% are present in platelets and the remainder are found on
RBCs and leucocytes. Because of the risk of vCJD in Great
Britain, U.K. departments of health have recommended that
the FFP given to neonates and children born after January 1, 1996,
should be pathogen-reduced and obtained from donors who
have not been in endemic areas of bovine spongiform encephalopathy.76
PRACTICAL ASPECTS OF BLOOD

TRANSFUSION IN CHILDREN
When the medical decision for transfusion is made and the blood
component is delivered, it is mandatory to perform a bedside
check that includes patient identification, matching wristband
identification to the blood compatibility label, matching patient
identifiers with the blood request, and reviewing information
regarding compatibility and expiry. A cross-match between the
patients blood, RBCs, and anti-A and anti-B serum (Beth-Vincent
test) must be performed before each transfusion (see Video 531).
All components should be transfused through a standard bloodgiving set with a screen filter (170200 ) or an alternative system
incorporating the same filtration. For small-volume transfusion, it
is possible to use a syringe with an appropriate filter,17 but the

diameter of the perfusion line must not be too small in order to
avoid mechanical hemolysis.
Children are less capable of maintaining normothermia than
adults. Because RBCs are stored at low temperature, it is necessary
to warm RBCs during the transfusion process. Different methods
can be used to prevent hypothermia.
Usually, a slow transfusion rate is recommended to avoid
TACO, but in case of active massive bleeding, it may be necessary
to transfuse at a high rate. Special systems (pneumatic accelerator
of blood transfusion, hot line) may be required. Special attention
must be paid to avoid overtransfusion of RBCs under these
circumstances because the calculated volume may be quickly
reached or even exceeded with a high transfusion rate.
CONCLUSION
Blood transfusion in children generally follows the same rules
as in adults, but some indications, risks, or techniques are specific
to children in view of their physiologic differences. The choice of
a blood component should be related to the clinical situation,
bearing in mind the relative risk versus benefit for the child. Blood
transfusion has become relatively safe, but there are still associated
risks. Although blood transfusion is inevitable under certain
circumstances, blood-sparing techniques, including homologous
transfusion and pediatric cell savers, have been developed to limit
the exposure to transfused blood.
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28. Hess JR,. Greenwalt TG Storage of red blood cells: new approaches.
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31. Hogman CF, Meryman HT. Red blood cells intended for transfusion:
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48. Silliman CC, Ambruso DR, Boshkov LK. Transfusion-related acute lung
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49. Bux J, Sachs UJ. The pathogenesis of transfusion-related acute lung injury
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51. Rouger P, Le Pennec PY, Noizat-Pirenne F. Immunologic risk analysis of
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52. Heddle NM. Pathophysiology of febrile nonhemolytic transfusion
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53. Transfusion Task Force. Amendments and corrections to the Transfusion
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55. Tobian AA, King KE, Ness PM. Transfusion premedications: a growing
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56. Hume HA, Preiksaitis JB. Transfusion associated graft-versus-host
disease, cytomegalovirus infection and HLA alloimmunization in
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58. Williamson LM, Stainsby D, Jones H, et al. The impact of universal
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59. Dzik WH. New technology for transfusion safety. Br J Haematol. 2007;
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61. Dzik WH. Emily Cooley Lecture 2002: transfusion safety in the hospital.
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71. King KE, Shirey RS, Thoman SK, et al. Universal leukoreduction
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74. Ketchum L, Hess JR, Hiippala S. Indications for early fresh frozen plasma,
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76. OShaughnessy DF, Atterbury C, Bolton Maggs P, et al. Guidelines for
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77. Stainsby D, Jones H, Asher D, et al. Serious hazards of transfusion: a
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Perioperative Blood Sparing

Techniques in Pediatric Patients
Dale F. Szpisjak and Catherine Paquet
INTRODUCTION
Although allogeneic blood transfusion is a life-saving therapy, it is
not without risk. Nucleic acid testing technology has markedly
improved the safety of the contemporary blood bank regarding the
transmission of viral diseases (HIV, hepatitis B and C, human T-cell
lymphotrophic virus [HTLV], West Nile virus).1 Nevertheless, risks
such as hemolytic transfusion reaction, bacterial infection, alloimmunization, and transfusion-related acute lung injury remain.
Strategies to avoid the risks associated with blood transfusion
include preoperative autologous donation (PAD), washing and
re-infusion of intraoperative cell salvage blood (CSB), acute
normovolemic hemodilution (ANH), induced hypotension (IH),
and the use of pharmacologic adjuncts such as erythropoietin, antifibrinolytics, and recombinant Factor VIIa (rFVIIa). This section
concludes with a discussion regarding the pediatric Jehovahs
Witness patient.
PAD
Although a report on the use of PAD predated the HIV epidemic,2
the concerns about the transmission of viral diseases increased
interest and utilization of this technique.3 Application to the pediatric patient population is challenging consequent to their smaller
size, poor cooperation, lack of randomized, controlled trials
demonstrating benefit, and increased costs relative to allogeneic
blood.4 Regardless of these challenges, there is evidence of benefit
and the emotional peace of mind that avoiding allogeneic transfusion gives patients and their parents must not be ignored.
Indications for PAD include surgical procedures in which more
than 25% of the patients blood volume is expected to be lost.5
Other indications include patients with rare blood types or those
who are difficult to cross-match as a consequence of alloimmunization.6 This technique has been applied frequently in orthopedic surgery2,79 but has also been utilized in heart,10,11 abdominal,5
urologic,5 and craniosynostosis12 surgery. Contraindications
applicable to the pediatric population include hemoglobin less
than 11 g/dL, bacteremia at the time of donation, active seizure
disorder, or significant cardiopulmonary disease such as cyanotic
heart disease, poorly controlled hypertension, or aortic stenosis.6
The volume of blood obtained at each donation is variable.
Target donation volumes range from 5 to 15 mL/kg.5,12 Mayer and
coworkers reported one donation of 20 mL/kg.5 Although this was
a violation of their donation protocol, there was no complication
in that patient. To avoid hypovolemia during donation from
patients who weigh less than 25 kg, intravenous fluid replacement
should be considered.5,1012 Oral iron supplementation is also
54
C H A P T E R
indicated.5,8,11 The number of units obtained is limited by the

patients starting hematocrit and time available before surgery.
Donation should not occur within 3 days of surgery because this
increases the risk of preoperative anemia, allowing little time for
the patient to produce new erythrocytes. Concurrent administration of erythropoietin8 or freezing the blood for storage may
increase the number of units obtained,11 but both add expense to
the process. Phlebotomy failure rates on first attempt range from
10 to 18%.5,12,13
Obtaining PAD blood is not without risk. Sedation or general
anesthesia may be required to obtain patient cooperation.12,14 The
incidence of donor reactions, although not often reported, varies
from 2.5 to 9.9%.2,9,11 They include dizziness, nausea, vomiting,
hypertension, and vasovagal reactions. Another concern is
inducing anemia by blood donation; subsequently, the blood
cannot be used for transfusion because of bacterial infection or
some other mishap during the storage process. The literature is
silent regarding the incidence of this complication; however, the
former has occurred in the authors experience.
The efficacy of PAD is measured by determining the rates
at which patients avoid allogeneic transfusion. Murray and
colleagues reported that 90% of PAD donors undergoing scoliosis
surgery avoided allogeneic transfusion, but the PAD group had
more idiopathic than neuromuscular scoliosis patients and were
older and larger, which may have led to a selection bias.7 In
Silvergleids series, 88% of the patients were transfused with
only autologous blood.9 Masuda and associates series of heart
surgery patients avoided allogeneic transfusion in 94% of their
cases (N = 80), but blood availability was facilitated by donation
at the time of cardiac catheterization and freezing the PAD blood
for storage to increase the donation period.11 Komai and coworkers also studied heart surgery patients and reported that 85% of
single-unit donors and 93% of two-unit donors avoided allogeneic
blood, but these patients also received erythropoietin at the
time of donation.10 Longatti and colleagues used PAD and ANH
in 11 children (aged 323 mo) undergoing craniosynostosis
surgery.12 Six of 7 patients who participated in both PAD and ANH
avoided allogeneic blood, whereas 2 patients donating only PAD
required allogeneic blood. Regis and associates combined PAD
with biweekly 10,000 U of erythropoietin in 23 patients and
compared them with historical controls that donated only PAD.8
They found that only 1 patient receiving erythropoietin required
allogeneic transfusion compared with 9 of 28 controls. In this
study, 36% of the patients who did not receive erythropoietin
could not participate in the PAD program secondary to anemia.
The use of PAD does help avoid exposure to allogeneic blood
in pediatric patients. It has been used in infants that weigh as little
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as 6.8 kg and as young as 3 months.12 Although administering

erythropoietin during the donation period improves the rates of
participation and avoidance of allogeneic blood, this is at increased
cost and lacks evidence from either randomized controlled trials
or large case series. Despite this, the intangible benefit such as the
peace of mind it provides patients and their parents must not be
overlooked.
INTRAOPERATIVE CSB
Intraoperative CSB is a form of autotransfusion in which shed
blood is collected, washed, and transfused back to the same patient.
Obtaining CSB is a multistep process. The shed blood is collected
and anticoagulated by aspiration through double-lumen suction
tubing that simultaneously mixes the blood with an anticoagulant
solution. The anticoagulant is either heparinized normal saline
(30,000 U/L) or citrate-phosphate-dextrose solution. After a
sufficient amount of blood has been collected, it is pumped into a
spinning centrifuge where the collected particles separate based
on density. As heavier particles (erythrocytes) enter the centrifuge,
lighter particles (e.g., leucocytes, platelets, plasma, irrigation fluid,
cellular debris) are displaced from the centrifuge. This technique
increases the hematocrit of the collected blood to the range of
45 to 60%.15 After the erythrocytes are concentrated, they are
washed by pumping sterile normal saline into the centrifuge
while it is spinning. The washing process removes cellular debris
and eliminates nearly all of the anticoagulant.16 Wash volume
recommendations range from three to six times the centrifuge
volume. After washing, the centrifuge is stopped and the blood is
pumped to a holding bag where samples can be drawn for qualitycontrol assays. The blood is then drained from the holding bag to
a transfer bag for administration to the patient.
There are two basic types of centrifuges: those based on Latham
bowl technology and the rotating disk type. The main difference
between the two is the priming volume, which highlights two
major limitations when applying this technology to pediatric
patients: the volume of shed blood required to fill the bowl and
the time required to collect and process it. These devices
concentrate erythrocytes to a hematocrit of 45 to 60%. Pediatric
centrifuge bowls are available in 55-, 70-, and 125-mL sizes. Filling
a 55-mL bowl to a hematocrit of 50% would require a red cell
volume of 27.5 mL. This would correspond to the red cell volume
contained in a blood loss of 92 mL with a hematocrit of 30%. The
blood loss required to fill the 70- and 125-mL bowls are
correspondingly higher (140 and 250 mL, respectively). It is
difficult to collect enough shed blood from a small patient to
completely fill the centrifuge bowl and process it in time to avoid
the need for an allogeneic transfusion. Partially filling is not
recommended, given concerns about inadequate removal of
cellular debris.17,18 This priming volume limit can be overcome by
the use of rotating disk devices, which require smaller red cell
priming volumes (18 mL according to Freseniuss product
information) and can process CSB faster than the Latham bowl
devices.15
CSB is indicated when the need for allogeneic blood is anticipated. It has been used in orthopedic,13,19 neurosurgical,14,2025
and cardiac26 surgical procedures. Contraindications include
surgical procedures in which aspiration of contaminants cannot
be avoided. The contaminants include topical procoagulants
(avitene, surgical, Gelfoam), povidone-iodine (Betadine), topical
antibiotics, methylmethacrylate, bowel contents, infected fluid,
oxymetalazone, or compounds that would hemolyze erythrocytes.27 The use of CSB in obstetrics is controversial secondary to
the risk of amniotic fluid embolism.2832 It should not be used in
patients with pheochromocytoma because catecholamines are not
adequately removed.33 The use of CSB in surgery for malignancy
is controversial because of the theoretical possibility of transfusing
viable cancer cells that could become metastases. Although this
risk is reduced by filtration of processed CSB with a leucocyte
depletion filter before transfusion,3436 there are no published
clinical trials on the safety of this technique in children.
The efficacy of CSB has been questioned when scoliosis
patients participate in PAD programs.13,37 Simpson and coworkers
reported that CSB decreased the need for allogeneic transfusion
only in patients older than 16 years.13 There was also a trend
toward CSB efficacy when blood loss exceeded 2000 mL. Similarly,
Siller and colleagues found no difference in allogeneic exposure
when patients participated in a PAD program.37 Although allogeneic blood exposure was the same as in controls who did not have
CSB, the controls had donated more units of PAD. Although PAD
may meet the patients transfusion requirements, CSB may be
useful in patients with blood loss that exceeds the blood available
from PAD.
Nicolai and associates studied CSB in 22 patients with cerebral
palsy undergoing hip surgery.19 The CSB group (N = 11) received
a total of only 2 units of allogeneic blood, compared to 20 units in
the control group.
The us of CSB technology in infants is difficult because of
the volume of blood that must be collected for processing. Several
authors have investigated the application of this technology to
infants undergoing surgical correction of craniosynostosis.14,1925
Jimenez and Barone24 studied infants (mean age 7 mo, mean
weight 8.7 kg) and reported that 33% of the patients given CSB
did not require allogeneic blood, but the study group was small
(N = 18) with historical controls. Decreased exposure to allogeneic
blood has been demonstrated when a multimodal approach
to autotransfusion was applied. Velardi and coworkers combined
erythropoietin, PAD, and ANH with CSB in 13 patients (median
age 8 mo [range 632 mo], weight 614 kg).14 All patients received
erythropoietin, ANH, and CSB. Only 4 patients participated in
the PAD portion of the protocol. Allogeneic blood was needed
in 2 patients, neither of which donated PAD. Krajewski and
colleagues in a randomized, prospective study of infants having
craniosynostosis surgery (mean age5 mo, range 38 mo)
compared erythropoietin and CSB (N = 41) with controls who did
not receive either.25 They found that only 5% of the study group
required allogeneic blood compared with 100% of the controls.
Although the use of CSB is limited by patient size, the use of
small centrifuge bowls or rotating disk centrifuge technology
increases the likelihood that an adequate amount of blood will be
collected for processing. A multimodal approach that combines
CSB with erythropoietin, PAD, and ANH decreases patient exposure to allogeneic blood, although implementing this approach
requires time, money, and the supporting infrastructure.
ANH
ANH is the process of withdrawing whole blood from the
patient while maintaining isovolemia through the simultaneous
administration of crystalloid or colloid solution. This process
ideally occurs before the commencement of surgically induced
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blood loss. The theory supporting this technique is that conservation of red cell mass should occur because the blood lost during
the surgical procedure would have a lower red cell mass than what
would have been lost without ANH. Upon completion of the surgical procedure, the sequestered whole blood would be transfused,
in reverse order of acquisition, back to the patient in an attempt to
correct the anemia while reducing exposure to allogeneic blood.
The physiologic compensation for the acute reduction of oxygencarrying capacity includes increased cardiac output and decreased
systemic vascular resistance. Because young children have a
limited ability to increase stroke volume, the cardiac output increases through an increase in heart rate. This increase in cardiac
output and myocardial oxygen demand under anemic conditions
is well tolerated by children who do not have atherosclerotic
disease that limits the application in adults.38 However, the high
concentration of fetal hemoglobin may limit release of oxygen
because of its lower P50 (oxygen pressure of whole blood at 50%
oxygen saturation) value.38
Although ANH is often discussed in terms of saving erythrocytes, the withdrawn blood also contains plasma and platelets.
Another theoretical advantage of ANH is the conservation of
blood elements that would otherwise be lost, decreasing blood
loss through improved hemostasis. Friesen and associates39
demonstrated improved coagulation test in 16 infants undergoing
cardiopulmonary bypass (CPB) with prebypass ANH of 15 mL/kg.
However, there was no difference in postoperative hematocrits and
all patients were exposed to allogeneic blood. The study was not
powerful enough to determine a difference in fresh frozen plasma
(FFP) and platelet exposure. Hence, this theory awaits confirmation in larger trials.
The indications and contraindications for ANH have been
summarized by Murto and Splinter.40 Indications include a
preoperative hematocrit greater than 35%, expectation that 20% or
more of the patients blood volume can be withdrawn without
exceeding the predefined transfusion trigger, and an expected
blood loss of 15% or greater of blood volume. (The last indication
is disputed in Weiskopf s mathematical model,41 which maintains
that expected blood loss must exceed 70% of the blood volume to
prevent exposure to unit of allogeneic blood.) It is also indicated
in patients with rare blood types, patients who are difficult to
cross-match, patients who refuse transfusion, and patients who
are unable to participate in a PAD program. ANH may be
acceptable to Jehovahs Witness patients.42
Contraindications include end-organ dysfunction (cardiac,
pulmonary, renal, central nervous system), hemoglobinopathies,
clotting disorders, pre-existing anemia, hemodynamic instability,
polycythemia, emergency surgery, or surgery in which rapid and
massive blood loss is anticipated.
Potential complications include end-organ damage should
oxygen carrying capacity be compromised, infection if collection
bags become contaminated, and anemia should a mishap with the
withdrawn blood prevent its transfusion to the patient.
A limitation of this technique pertains to logistics (difficulty
obtaining vascular access, size of patient, ensuring a proper mixture
of whole blood and anticoagulant). Although phlebotomy with
large-bore needles or central catheters is relatively straightforward
in adults, this can be very challenging in small patients. Several
studies document overcoming this via phlebotomy with an arterial
line.43,44 The usual ratio of citrate-phosphate-dextrose anticoagulant solution is 14 mL/100 mL of whole blood. This may
require modification of standard 450-mL-capacity blood donation
Perioperative Blood Sparing Techniques in Pediatric Patients
863
collection bags that contain 64 mL of the anticoagulant. Calculation

of the volume to be withdrawn depends on the starting and target
hematocrits. Mild hemodilution targets a hematocrit of 25 to 30%,
whereas moderate hemodilution targets a hematocrit of 20 to 25%.
Severe hemodilution is defined as a hematocrit lower than 20%.40
The volume to be withdrawn is calculated from the following
equation:
Hcti Hctt EBV
Hctavg
where, HCTi = initial hematocrit, HCTt = target hematocrit,
HCTavg = average hematocrit, and EBV = estimated blood volume
of the patient.
The units of blood should be weighed while they are being
withdrawn to precisely regulate their volume. By convention,
1 mL of whole blood is presumed to weigh 1 g. While blood is
being withdrawn, it should simultaneously be replaced with a
balanced salt solution (3 mL/1 mL blood withdrawn) or colloid
solution (1 mL/1 mL withdrawn).
ANH is usually well tolerated by healthy patients with physiologic reserve. The compensatory responses to ANH include
decreased blood viscosity, which decreases systemic vascular
resistance. The decreased viscosity increases tissue blood flow and
compensates for the decreased oxygen capacity. Cardiac output
increases, but the myocardium is presumed to be the organ most
vulnerable to hypoxemic ischemia because of its near maximal oxygen extraction at baseline state.45,46 Despite the ability
of healthy patients to mount compensatory responses to the
anemia induced by ANH, the safe lower limit of oxygen-carrying
capacity has yet to be established. Although global indicators of
adequate perfusion such as lactate and mixed venous oxygen
saturation have been used in a study of extreme ANH in
adolescents undergoing scoliosis surgery,47 these are not indicators
of specific end-organ perfusion and do not establish the safety
of extreme ANH.
Another major limitation regarding ANH is that there are few
studies48,49 establishing the efficacy of this therapy as the sole blood
conservation strategy in pediatric patients. That other blood
conservation strategies (PAD, CSB) are employed is not surprising.
But, as mentioned in section on PAS and Intraoperative CSB, even
if this were the only blood conservation strategy employed,
mathematical modeling41 predicts that the surgical blood loss must
exceed 70% of the patients blood volume for ANH to be effective.
Although smaller blood loss will result in a higher postoperative
hematocrit with ANH, there would be no need for allogeneic
exposure and, therefore, no efficacy.
Several studies have evaluated the efficacy of ANH when
combined with other blood conservation strategies. Meneghini
and coworkers studied ANH (target hematocrit 25%) with erythropoietin therapy in 16 infants undergoing craniosynostosis
surgery (age 59 mo, weight 69.5 kg) compared with 9 historical
controls.44 Erythropoietin (300 U/kg) was administered twice per
week for 3 weeks with oral iron supplementation. The ANH
volume withdrawn was 18 mL/kg and was replaced with hydroxyethyl starch. Eleven of 16 infants in the EPO/ANH group did not
receive allogeneic blood, whereas 7 of 9 controls did. Longatti and
colleagues used ANH and PAD in 11 children (age 323 mo)
undergoing craniosynostosis surgery.12 Six of 7 patients able to give
both donations avoided allogeneic blood, whereas 2 patients
donating only PAD required allogeneic blood. Velardi and
coworkers, using a multimodal no allogeneic blood protocol
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combining PAD, CSB, and erythropoietin with ANH, demonstrated a 15% exposure to allogeneic blood in a study of 13
infants undergoing craniosynostosis surgery.14 By contrast, an
earlier study using only ANH in craniosynostosis repair did not
show efficacy.50
In summary, ANH is an attractive blood-sparing technique
from a theoretical standpoint, but it is challenged by several
considerations, including potential difficulties with phlebotomy
and few well-powered studies demonstrating efficacy in children.
Although it may be useful in combination with PAD, erythropoietin, and CSB, this awaits confirmation in large, well-controlled
studies.
IH
IH is the technique of deliberating lowering the patients blood
pressure with the goal of decreasing the driving pressure for blood
loss in the surgical field. In theory, pediatric patients should be
better able to tolerate IH than adults because they do not have
atherosclerotic disease that may limit end-organ perfusion. IH is
commonly used in spine surgery and maxillofacial51 surgery and
may be employed with other blood-sparing techniques (PAD,
ANH, CSB). Combining IH with ANH may be hazardous, especially during spine surgery, given the association with postoperative vision loss that occurs even in pediatric patients who
presumably do not have atherosclerotic disease.52 Analysis of spine
surgery data in the American Society of Anesthesiologists Visual
Loss Registry demonstrates that postoperative vision loss was
associated with IH (40% of the patients) and a median hematocrit
of 25.5%.53 Although the majority of patients were adults, one
patient was as young as 19 years. Given these concerns, it may be
wise not to use IH and ANH simultaneously.
ERYTHROPOIETIN
Multiple case reports document the use of erythropoietin
as an adjunct to blood-sparing techniques in pediatric surgery.8,10,14,23,25,44,5457 The aim is to increase the hematocrit in order
to facilitate PAD or ANH or as a treatment for pre- or postoperative anemia. Erythropoietin is a useful but expensive strategy,
studies are small and only one was a randomized, controlled trial.25
Doses have varied widely, ranging from 50 U subcutaneously.
every other day55 to 10,000 U subcutaneously weekly for 3 weeks.8
Iron supplementation should occur simultaneously to ensure that
erythrocyte production is not limited by baseline iron stores.
Contraindications to erythropoietin therapy include uncontrolled
hypertension, hypersensitivity to human albumin, or hypersensitivity to mammalian cellderived products. Patients receiving
this medication should have blood counts monitored closely to
determine the therapeutic effect and ensure that polycythemia
does not occur, thereby increasing the risk of thrombosis. Given
the wide range of doses reported, expert hematology consultation
is recommended to ensure that doses are appropriate, modified as
needed, and effect monitored.
CARE OF THE PEDIATRIC

JEHOVAHS WITNESS
A belief of the Jehovahs Witness (JW) faith is that receiving
allogeneic blood, specifically erythrocytes, plasma, leucocytes, or
platelets, is forbidden. This prohibition also applies to PAD blood.

The JW believes that a transfusion jeopardizes the patients status
in the next life and may also jeopardize their status within their
faith community. This absolute prohibition does not seem to apply
to other components of blood (globulin fractions, albumin,
erythropoietin), where the decision to use those products is left
to the individual.58
Patients who have reached the legal age of majority and are
mentally competent are free to refuse blood transfusion or any
other therapy, even if it results in death. However, these rights
of autonomy and self-determination do not apply to children
who are not emancipated minors and, therefore, unable to give
informed consent. This creates an ethical dilemma for the physician caring for the children of JW parents when transfusions
may be indicated and the parents refuse. The approach to these
situations depends on the nature and urgency of the surgical
procedure.
If an emergency transfusion is indicated and the parents refuse,
it may be necessary to obtain a court-ordered transfusion. Every
hospital needs policies and procedures in place both to inform JW
parents59 and to minimize the time required to obtain the court
order when the patient is in extremis.42 For elective surgery, it
is essential to have a preoperative conference with the parents
that includes the surgeon, anesthesiologist, patient (depending
on maturity), and perhaps an elder (liaison officer) of their JW
community who is well informed not only on the spiritual issues
but also the medicolegal issues and hospitals policy. It is important
to be nonconfrontational in order to reach a consensus rather than
telling parents that they have no choice, for the latter may provoke
the parents into canceling surgery altogether.47
Before elective surgery, the patients hematocrit should be
optimized. This should include oral iron therapy42 and erythropoietin,54,60 assuming the patient will accept the latter. PAD is not
usually an option for the JW patient because many insist that the
blood, even their own, must remain in continuous circuit.60
Intraoperative techniques to consider include IH, hypothermia,61
CSB,62 ANH,61 and rFVIIa.62 Discussing these techniques with
the patient preoperatively is essential to ensure that they are
acceptable. Including an elder from their faith may be very helpful
in clarifying the acceptability of adjuvant techniques to the
JW patient.
Case reports describe the anesthetic management of pediatric
JW patients who did not receive allogeneic blood. Ross and
colleagues described the use of ANH and postoperative erythropoietin in a 4-year-old 16-kg girl who underwent excision of a
bilateral Wilms tumor.54 Postoperative hematocrit was 9% and
it increased to 14% after return of ANH blood. Digeria and
associates described the management of a 6-year-old injured in
a motor vehicle accident who, after crystalloid resuscitation,
had a preoperative hematocrit of 18%.55 The lowest hematocrit
value was 12% but increased to 31% by postoperative day 20 with
erythropoietin treatment. Rosengart and coworkers used preoperative erythropoietin in a 23-month-old JW child who underwent a Manouguian procedure with CPB that included aprotinin
and CSB.56 The lowest hematocrit on bypass was 16%. Discharge
hematocrit was 37% and no allogeneic blood was used. In two
pediatric liver transplant patients (ages 6 and 30 mo), Jabbour and
colleagues used preoperative erythropoietin, iron, folic acid, and
multivitamins.57 Intraoperative management included ANH, CSB,
aprotinin, and DDAVP (desmopressin [1-deamino-(8-D-arginine)
vasopressin]. One patient also received rFVIIa. Both patients also
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865
received postoperative erythropoietin. Postoperative hematocrit

was 29% in both patients. No allogeneic blood products were
transfused.
transfusion. The subgroup with the higher reduction in blood loss

were the patients experiencing excessive perioperative blood loss
(>1092 mL/24 h).
PHARMACOLOGIC THERAPY
-Aminocaproic Acid
Desmopressin
Epsilon-aminocaproic acid (EACA) is a synthetic antifibrinolytic

derived from lysine. It competitively blocks the binding of plasmin
to fibrin by occupying the lysine-binding sites on plasminogen,
thus inhibiting fibrinolysis.80 It is indicated in the treatment of
excessive bleeding resulting from systemic hyperfibrinolysis and
has been studied mostly in the context of cardiac surgery.8183
EACA can be administered orally or intravenously. After oral
administration, the peak plasma concentration is reached within
approximately 1 hour. When administered intravenously, each
gram of medication should be diluted in 50 mL to avoid hypotension, bradycardia, and arrhythmia. The pediatric dosage
consists of an intravenous bolus of 100 mg/kg, followed by a continuous infusion of 33.3 mg/kg/h. The maximum dosage should
not exceed 18 g/m2/d. Its elimination half-life is approximately
2 hours.
A large portion of EACA is not metabolized and 40 to 65% of
the dose is excreted unchanged in the urine. It may accumulate
in patients with reduced renal function; therefore, a reduced
dose should be used in these patients. Its administration is not
recommended in neonates because benzyl alcohol is used as a
preservative and has been associated with metabolic acidosis and
death in these patients. There are a limited number of randomized
studies with EACA, but a potential for increased risk of postoperative myocardial infarction was reported in adults.84
In a prospective study with historical controls,85 a loading dose
of 100 mg/kg followed by an infusion of 10 mg/kg/h decreased
blood loss and transfusion in patients undergoing spinal fusion
for idiopathic scoliosis. Florentino-Pineda and coworkers performed a randomized, double-blinded study in 36 patients with
idiopathic scoliosis and demonstrated no change in blood loss
between groups, although postoperative and total perioperative
blood losses were lower in the EACA group.86 The need for
autologous transfusion postoperatively was also less.
Hyperfibrinolysis was successfully treated with EACA in
20 adults undergoing liver transplantation, after reversal of fibrinolysis was demonstrated in vitro. No thrombotic complications
were associated with the use of EACA.87 A randomized study of
EACA for pediatric liver transplantation has yet to be published.
Four randomized studies in children undergoing cardiac
surgery demonstrated a benefit with EACA that was associated
with a lower requirement for blood transfusion in three of
these studies.82,83,88,89 In 1974, it was reported that 75 mg/kg of
EACA followed by an infusion of 15 mg/kg/h reduced blood loss
in cyanotic children undergoing cardiac surgery.83 Rao and
colleagues demonstrated in a study of 170 patients that EACA
given in three boluses of 100 mg/kg to cyanotic infants and
children decreased blood loss at 24 hours.89 It also decreased the
need for erythrocyte and platelet transfusions, the time for sternal
closure, and the re-exploration rate. EACA given as three boluses
of 100 mg/kg was shown to be equivalent to low-dose aprotinin
with regard to blood loss and erythrocyte or platelets transfusions
during cardiac surgery in 300 cyanotic children.82 There was also
a trend toward improved effectiveness with the combined use
of aprotinin and EACA. EACA and aprotinin were compared in
Desmopressin is a synthetic analogue of the antidiuretic hormone

arginine vasopressin. Desmopressin, as opposed to vasopressin,
retains minimal vasopressor activity linked to V1 receptor agonist
action. The antidiuretic effect is related to its strong V2 receptor
agonist activity. It also increases von Willebrands factor (vWF)
release and Factor VIII levels, most likely by release from storage
sites in the vascular endothelium and hepatocytes, respectively.
These effects occur in patients with high, normal, or low levels of
these factors.
Desmopressin does not affect platelet count or aggregation,
but it enhances platelet adhesion to the vessel wall. These two
mechanisms result in a shortened activated partial thromboplastin
time and bleeding time. Administration of desmopressin also
causes a release of plasminogen activator, resulting in plasmin
formation. This plasmin is inactivated in the plasma by a protease
inhibitor and will not result in increased fibrinolysis.63
Indications for desmopressin include central diabetes insipidus
and control of bleeding secondary to trauma or minor surgical
procedures in patients with hemophilia A, type I von Willebrands
disease, or uremia. The dose is 0.3 g/kg intravenously administered preoperatively over 10 to 30 minutes64 and will increase
factor levels two- to fivefold.65 Tachyphylaxis may occur if repeated
doses are given at short intervals (<24 h) to patients with hemophilia, presumably from depletion of Factor VIII stores.65
The time to peak levels is 30 to 60 minutes after intravenous
injection or 90 to 120 minutes after subcutaneous or intranasal
administration. It is metabolized to inactive components mainly
in the liver and kidneys.66 Elimination half-time is about 3 hours
when injected intravenously, and it is excreted primarily in the
urine. Factor VIII plasma half-life is 5 to 8 hours, whereas vWF
plasma half-life is 8 to 10 hours.63 Possible side effects include
facial flushing, nausea, headache, and mild increases in diastolic
blood pressure and heart rate. Severe hyponatremia and seizures
following water retention are of special concern with desmopressin use.65 There is also an increased risk of arterial thrombosis.
A meta-analysis published in 1999 reported a nearly 2.4-fold
increased risk of perioperative myocardial infarction during
cardiac surgery with desmopressin compared with placebo.67
Although an early study demonstrated reduced blood loss and
erythrocyte transfusion in posterior spinal fusion,68 subsequent
studies failed to show benefit in patients with idiopathic or
nonidiopathic scoliosis.6972 Desmopressin also failed to reduce
blood loss or transfusion requirements during elective partial
hepatectomy.73
Salzman and associates demonstrated that desmopressin
injection after termination of CPB reduced blood loss and
transfusions during complex cardiac surgery.74 However, further
studies did not reproduce these results in either adult or pediatric
patients.7578 A meta-analysis published by Cattaneo79 analyzed
17 randomized, double-blind studies including a total of 1171
patients undergoing cardiac surgery. Desmopressin lowered
postoperative blood loss by 19%, but did not affect the rate of
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a meta-analysis of adult populations.90 It revealed identical

reductions of total blood loss and total postoperative transfusions.
EACA use was also compared with tranexamic acid and no
significant difference in the outcome was noted between these
two groups.88
Tranexamic Acid
Tranexamic acid is an antifibrinolytic medication approximately
10 times more potent than EACA. It is a synthetic derivative
of lysine.91 Activity of its trans-isomer was described in 1964 and
utilization in pediatrics was reported in 1967 for a urologic
procedure.92 It acts by competitive blockade on lysine-binding sites
of plasminogen, which results in a block of the interaction between
plasmin and lysine residues located on the fibrin surface. This
results in delayed fibrinolysis and blood clot dissolution.91 It is also
a noncompetitive inhibitor of plasmin at high doses, and it may
also increase the expression of glycoprotein Ib (GPIb) receptors
on platelets.93
Tranexamic acid is indicated in patients with hemophilia or
von Willebrands disease undergoing tooth extraction to prevent
bleeding. The recommended dose is 7 to 10 mg/kg intravenously
preoperatively and is repeated every 6 to 8 hours after the surgery.
It is also used to treat excessive bleeding resulting from surgical
hyperfibrinolysis, gastrointestinal hemorrhage, menorrhagia, or
postpartum hemorrhage.91
Peak plasma concentration is reached within 3 hours after
oral administration. After an intravenous injection, elimination
half-life is approximately 2 hours. Nearly all (95%) of the dose is
excreted unchanged in the urine.91 There is a risk of accumulation
with renal disease and, therefore, an adjustment of dosage interval is required. There are potential gastrointestinal side effects,
including nausea, cramping, and diarrhea, when taken orally.
Disturbance of color vision is an indication of toxicity and mandates discontinuing this medication. It may cause hypotension if
given more rapidly than 100 mg/min intravenously. The incidence
of intravascular thrombosis was not shown to be superior with
tranexamic acid compared with control group.84
In adults undergoing total knee arthroplasty, a dose of 10 to
15 mg/kg of tranexamic acid was shown to decrease total blood
loss, the number of patients requiring allogeneic blood transfusion, and the number of transfused erythrocyte units. No
increased risk of thromboembolic complication was noted.9496
Three pediatric studies9799 evaluated tranexamic acid efficacy
during posterior spinal fusion for scoliosis. Two of them included
patients with both primary and secondary scoliosis. Neilipovitz
and associates randomized patients to receive an initial bolus of
10 mg/kg of tranexamic acid, followed by either a maintenance
infusion of 1 mg/kg/h or placebo.97 They demonstrated a diminution in the total amount of blood transfused perioperatively in the
tranexamic acid group, despite this group having more patients
with secondary scoliosis and a smaller body mass, two factors
associated with higher blood loss. In another study, a bolus of
100 mg/kg of tranexamic acid, followed by a maintenance infusion
of 10 mg/kg/h was used.98 In the tranexamic acid group, intraoperative bleeding was decreased by 41% compared with placebo
group (1230 535 mL vs 2085 1188 mL, P < .01). The reduction
in blood loss was more significant in patients with secondary
scoliosis, and these patients had a lower mean total transfusion
volume. A retrospective study of 56 patients with Duchenne
muscular dystrophy demonstrated reduced blood loss, blood
transfusion, and CSB transfusion in the tranexamic acid group

using a bolus of 100 mg/kg with a maintenance infusion of
10 mg/kg/h.99
Tranexamic acid use for craniofacial surgery has also been
reported.100 Twenty infants were randomized to receive either
tranexamic acid 15 mg/kg intra- and postoperatively or to be
controls. Although a smaller amount of bleeding was found in the
tranexamic acid group, there was no significant difference in the
amount of blood transfused.
This antifibrinolytic medication was also studied in adult
orthotopic liver transplantation,101 where it decreased intraoperative blood loss, blood products requirements, and donor
exposure. Tranexamic acid was also superior to EACA in reducing
the need for transfusion during orthotopic liver transplantation.102
To date, no randomized study has been published on tranexamic
acid use during pediatric liver transplantation.
The benefit of using tranexamic acid was confirmed in adult
patients undergoing cardiac surgery with CPB.103 A study of
88 pediatric patients demonstrated a lower blood loss and transfusion rate with a bolus of 50 mg/kg of tranexamic acid in the
subgroup of patients with cyanotic conditions.104 Four prospective,
randomized studies in pediatric cyanotic patients demonstrated a
decreased blood loss and need for transfusion with tranexamic
acid88,105107 with one demonstrating a lower re-exploration rate
with the use of three 10-mg/kg boluses.107 Bolus doses ranged
between 10 mg/kg and 100 mg/kg in these studies. Reid and
coworkers studied 44 children undergoing repeat sternotomy.108
The tranexamic acid group received two boluses of 100 mg/kg
followed by an infusion of 10 mg/kg/h; this group had decreased
blood loss at 24 hours postoperatively, decreased total blood
transfusion volume, and decreased sternal closure time compared
with the placebo group. Chauhan and colleagues evaluated the
efficacy of different tranexamic acid regimens: a single bolus of
50 mg/kg, a bolus of 10 mg/kg followed by a continuous infusion
of 1 mg/kg/h, three boluses of 10 mg/kg (at anesthesia induction,
at initiation of CPB, and after protamine dose), and two boluses of
20 mg/kg (at anesthesia induction and after protamine dose).106
All were compared with a control group. The group given three
boluses of 10 mg/kg had the best results, followed by the group
given two boluses of 20 mg/kg. In another study, tranexamic acid
was compared with EACA and no significant difference in
outcome was noted between these two groups.88 Tranexamic acid
has also been compared with aprotinin, in addition to the combination of both drugs.105 There was no difference in blood loss or
transfusion requirements at 24 hours. In addition, no benefit was
found when both drugs were used in combination.
Its efficacy during adult liver transplantation is established.
None of the randomized, controlled trials has shown a higher
incidence of thromboembolic complication. A meta-analysis of
23 studies that included 1407 patients failed to demonstrate any
difference in the rate of arterial and venous thrombosis or in the
mortality.109 Although these data from the adult patient population
are reassuring, tranexamic acid has not been studied in the
pediatric liver transplant population.
Aprotinin
Aprotinin is a nonspecific protease inhibitor isolated from bovine
lung tissue. Its use during pediatric cardiac surgery was first
described in 1970.110 A prospective, randomized study in 1987
reported a decreased blood loss and transfusion requirements with
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aprotinin use during adult cardiac surgery.111 The mechanism of

action is not fully elucidated. It has antifibrinolytic activity via
direct inhibition of plasmin and kallikrein, and it also inhibits
proteases from the coagulation cascade that are activated by the
CPB circuit and the surgical stimulus. Consequently, thrombin
and the intrinsic coagulation pathway are inhibited. Aprotinin
contributes to preservation of platelet function and also attenuates
the inflammatory response in a dose-dependent manner. Other
mechanisms such as reduction of oxidative stress are under
investigation.112
Before its worldwide withdrawal in 2008, aprotinin was
indicated for patients at high risk of bleeding or receiving blood
transfusion undergoing CPB in the course of coronary artery
bypass grafting, liver transplantation,113 and major orthopedic
surgery.114,115 A recent poll conducted via a mailed questionnaire
to 546 cardiac anesthesiologists and surgeons about the clinical
consequences of the suspension of the license for aprotinin
on patients undergoing cardiac surgery was reported. In all, 285
(52%) responded, the majority of respondents (61%) felt it had not
had any effect, 29% of respondents felt the suspension of the
license for aprotinin had had a detrimental effect on patient care,
and 2% an extremely detrimental effect. In conclusion, although
the majority of respondents felt that the suspension of the license
for aprotinin had no effect, almost a third felt it had negatively
affected the care of patients undergoing cardiac surgery.116
The activity of aprotinin can be expressed in kallikreininactivating unit (KIU), milligrams, or European pharmacopeia
unit (EPhU). One KIU is the amount of aprotinin that decreases
the activity of 2 biologic kallikrein units by 50%. One milligram
of aprotinin is equivalent to 7143 KIU and 1 106 KIU equals
500 EPhU. In vitro, a plasma concentration of 50 KIU/mL of
aprotinin is necessary to inhibit plasmin and 200 KIU/mL to
inhibit kallikrein activity.117 An in vivo plasma concentration
of 125 KIU/mL, achieved with the low-dose aprotinin regimen,
is a plasma concentration at which plasmin is 90% inhibited.112
A high aprotinin regimen is used to target higher plasma concentration and, hence, optimal plasmin and kallikrein inhibition. The
high-dose aprotinin regimen in the pediatric literature corresponds approximately to a loading dose of 240 mg/m2 followed by
a continuous infusion of 56 mg/m2/h, or a loading dose of 30,000
to 40,000 KIU/kg followed by a continuous infusion of 7000 to
20,000 KIU/kg/h.118120
Aprotinin undergoes glomerular filtration, re-absorption by
the proximal tubules, and gradual metabolism by lysosomal
enzymes in the kidney. It is eliminated primarily by the kidneys.
The distribution and elimination half-life are approximately
0.3 to 0.5 hours and 5 to 8 hours, respectively.121 The plasma halflife is approximately 150 minutes.
Aprotinin is associated with hypersensitivity reactions
presenting as skin rashes and a risk of anaphylaxis, mostly upon
re-exposure. The incidence of anaphylaxis can vary from 0.4% up
to 4% depending of the time elapsed since previous exposure.122
The risk is higher between the 4th and the 30th day after the
previous exposure and declines after 6 months.122,123 Aprotininspecific immunoglobulin G antibodies have been detected in 26 to
47% of patients treated with aprotinin in the previous 6 months.
The administration of an intravenous test dose is recommended
for all patients.121 Adequately designed prospective studies failed
to show an augmentation of the risk of graft thrombosis or thromboembolic complications with aprotinin treatment in adults.124,125
However, the multicenter IMAGE (International Multicenter
867
Aprotinin Graft Patency Experience) trial, published in 1998,

revealed an increased risk of coronary graft thrombosis, mostly
secondary to a higher risk in a subgroup of patients from one
single center.126 The multicenter study done on 4374 patients by
Mangano and associates demonstrated an increased risk of
myocardial infarction and stroke in adult patients undergoing
primary cardiac surgery.127 Another multicenter study performed
on 2331 high-risk surgical patients was terminated early because
of a higher mortality from a cardiac cause in the group receiving
aprotinin.128 Jaquiss and coworkers found no difference in the risk
of thrombosis in 865 pediatric patients treated with high-dose
aprotinin,123 but large randomized studies are lacking for the
pediatric population. Concern about renal toxicity was raised
by two recent studies. Mangano and associates found a twofold
rise in renal dysfunction or dialysis among patients undergoing
primary or complex coronary artery surgery.127 In a retrospective
study of 898 patients undergoing cardiac surgery, Karkouti and
colleagues showed an increased rate of renal dysfunction in those
receiving aprotinin.129 A database review of 657 pediatric patients
reported an increased incidence of renal dysfunction and dialysis
in aprotinin-treated patients, but the association with aprotinin
was not significant after adjustment for other variables.130 No large
randomized pediatric study has evaluated the presence of renal
toxicity with aprotinin use.
Aprotinin had a blood-sparing effect during pediatric
craniofacial surgeries, decreasing the need for blood transfusion
for 3 days postoperatively.131 Aprotinin was also studied during
posterior spinal fusions in adolescents with idiopathic scoliosis.132
The aprotinin group demonstrated a 41% reduction in blood loss
and a tendency to receive fewer blood transfusions. High-dose
aprotinin was also evaluated in a group of patients mostly with
neuromuscular disease or undergoing reoperation (i.e., groups at
higher risk for bleeding).133 Patients given aprotinin had significantly less blood loss, lower need for transfusion, and smaller
blood loss collected with intraoperative cell salvage. In a study
of 60 adult patients undergoing anterior and posterior spinal
fusions,134 the half-dose aprotinin regimen reduced total blood
loss and transfusion requirements compared with the EACA
group or the control group.
Aprotinin was reported to reduce exposure to allogeneic
blood transfusion and the need to reoperate because of bleeding
in adults undergoing cardiac surgery.135 To date, 14 randomized
studies have been published in the pediatric cardiac surgery
literature.82,105,118120,136144 A variety of dose regimens, patient sizes,
diagnoses, types of surgery, and transfusion triggers are included
in these studies. The bolus doses varied between 10,000 to 50,000
KIU/kg, the prime doses between 10,000 to 40,000 KIU/kg, and in
10 studies, a maintenance infusion of 3500 to 25,000 KIU/kg/h
was administered. Five of these randomized trials demonstrated a
decrease in bleeding,82,105,136,143,144 and 5 demonstrated a decrease
in at least one measure of transfusion82,105,118,136,140 with aprotinin
treatment. Two of these studies were in patients exclusively with
cyanotic heart conditions.82,105 Three studies demonstrated a
decrease in the time to chest closure in the aprotinin group.82,105,120
A meta-analysis of randomized, controlled trials in pediatric
cardiac surgery confirmed that aprotinin reduced the proportion
of children receiving erythrocyte or whole blood transfusions
during surgery by 33%, although an effect on the total volume of
blood transfused or blood lost postoperatively was not demonstrated.137,145 Wippermann and associates demonstrated in a
randomized, double-blind study in 34 infants and children that
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the group treated with aprotinin required less inotropic support

postoperatively.137
Smaller patients are at risk of massive bleeding. Mossinger
and coworkers performed a randomized, double-blind study of
60 patients weighting less than 10 kg undergoing primary corrective congenital cardiac surgery.136 The group receiving aprotinin
had less blood loss (13.5 mL/kg/h vs 19.4 mL/kg/24h, P < .05) and
fewer erythrocyte (13% vs 47%, P < .05) and cryoprecipitate
(3% vs 31%, P < .05) transfusions. Boldt and colleagues studied
60 patients undergoing different procedures.141 The patients were
randomized to five small groups: weight less than 10 kg or over
10 kg, aprotinin or no aprotinin, and one group undergoing major
intrathoracic vascular surgery without CPB. No improvement in
platelet function or reduction in blood loss was found with the use
of aprotinin, and all patients treated with aprotinin were given
more erythrocyte and plasma transfusions. Dietrich and associates
studied 60 patients weighing less than 10 kg undergoing primary
corrective congenital cardiac surgery with CPB of duration less
than 120 minutes.143 The patients were randomized to receive lowdose aprotinin, high-dose aprotinin, or no aprotinin. Attenuation
of hemostatic activation during CPB and less blood loss at 6 hours
with the high-dose aprotinin regimen were found, although there
was no difference in the amount of blood lost at 24 hours.
Patients undergoing repeat cardiac surgery are also at increased
risk for bleeding. Miller and coworkers studied 45 infants and
children undergoing repeat sternotomy for various cardiac procedures.120 They were randomized to low-dose aprotinin, highdose aprotinin, or no aprotinin. Although there was no difference
in the amount of blood transfused at 24 hours, there was a 22 to
46% reduction in the post-CPB coagulopathy and a shorter time
for sternum closure in the high-dose aprotinin group. In another
study, 61 infants and children were randomized to low-dose aprotinin, high-dose aprotinin, or placebo.118 Both aprotinin groups
had smaller amounts of erythrocytes, platelets, and plasma transfusion postoperatively and reduced allogeneic blood exposure.
There was no difference in the amount of transfusion between the
low-dose and the high-dose aprotinin regimens.
Studies have also investigated the efficacy of aprotinin during
different cardiac procedures.136,138,143,146 In a study described
previously in which aprotinin treatment was beneficial, a subanalysis of the four major diagnoses was performed: ventricular
septal defect, complete atrioventricular septum defect, transposition of the great arteries, and tetralogy of Fallot.136 Aprotinin
did not show benefit in any of these diagnoses; however, the
subgroups were small. Davies and colleagues randomized 42 infants and children to aprotinin or placebo.138 The patients were
stratified into three groups: infants undergoing major open
heart surgery with hypothermia, low-flow, and nonpulsatile
CPB; children between 1 and 5 years old undergoing major reconstructive open heart surgery with hypothermia and intermittent
low-flow CPB; and children undergoing repeat heart surgery. No
beneficial effect of aprotinin was shown in any group. In a prospective, observational study of 168 children, Carrel and associates
demonstrated decreased blood loss, decreased blood transfusion,
and decreased fibrinolysis postoperatively in the group undergoing repair of transposition of great arteries with high-dose
aprotinin.146 This effect was not seen in the groups undergoing
repair of ventricular septal defect or tetralogy of Fallot.
Various aprotinin doses have been used. Five studies assessed
the efficacy of high- versus low-dose aprotinin regimen in the
pediatric population.105,118120,146 Two demonstrated decreased
blood loss143 or blood transfusion120 with the high-dose regimen

only, although the amount of blood lost at 24 hours was not
significantly decreased in these studies. Another study demonstrated a lower rate of transfusion and donor exposure with both
low-dose and high-dose aprotinin.118 Carrel and associates146
demonstrated the benefit of high-dose aprotinin only in the group
undergoing repair of transposition of great arteries. Boldt and
coworkers randomized 42 infants and children weighing less
than 20 kg to low-dose aprotinin, high-dose aprotinin or no
treatment.119 There was no benefit of either dose of aprotinin on
the amount of blood loss, blood transfusion, or platelet function.
The low-dose aprotinin group received more plasma transfusions
than either the high-dose or the control group.
Aprotinin was compared to other antifibrinolytics. Bulutcu and
associates demonstrated in 98 children that tranexamic acid or
aprotinin reduced blood loss, the need for blood transfusion, and
the time for chest closure to a similar extent.105 The combination
of these two medications was not superior to the use of either one
alone. Low-dose aprotinin was equivalent to EACA in reducing
blood loss and erythrocyte or platelets transfusion. The combination of these two drugs had a trend toward slight improvement
in effectiveness.82
It is difficult to reach strong conclusions from these pediatric
studies in cardiac surgery. More studies with more rigid methodology and well-defined transfusion criteria are needed. Furthermore, aprotinin has been withdrawn worldwide after publication
in May 2008 of a multicenter study that was terminated early
secondary to a higher mortality with aprotinin use.128
Recombinant Activated Factor VII

rFVIIa is a recombinant preparation of activated human
coagulation Factor VII. It is thought to act at the site of injury by
binding to tissue factor, which is released into the circulation
after an injury. This would lead to thrombin formation and,
subsequently, activation of platelets, contributing to the clot
formation.80 rFVIIa inhibits fibrinolysis owing to activation of
thrombin-activatable fibrinolysis inhibitor.147 rFVIIa use was
approved in 1999 for the treatment of bleeding in patients with
hemophilia A or B with known inhibitors to Factor VIII or IX.148
It is also indicated for patients with Factor VII deficiency. The dose
used for these indications is 90 to 120 g/kg intravenously. There
are few randomized studies of off-label use of rFVIIa mainly
investigating bleeding during surgical procedures and after trauma.
However, most of the literature represents case reports or case
series. The risk of thromboembolic event in patients without hemophilia is unknown. In the majority of studies published
to date, there was no significant difference in the frequency
of thromboembolic events in patients receiving rFVIIa, although
sample sizes are small.149 However, a trend toward higher risk
for strokes and myocardial infarctions was seen in a trial of
rFVIIa use after intracerebral hemorrhage (7% for rFVIIa vs 2%
placebo).150
rFVIIa has a median half-life of 2.7 hours in adults, but it may
be reduced during active bleeding. Frequent dosing intervals of
2 to 3 hours is necessary to maintain adequate blood concentrations, contributing to the high cost of treatment with this medication.88 Pediatric pharmacokinetics data are limited, but the
half-life of rFVIIa is less at approximately 1.3 hours and the clearance more in children than in adults. This implies that the children
might require higher dosages.151,152
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rFVIIa treatment at doses between 20 and 100 g/kg

intravenously had no effect on blood transfusion requirements in
adults undergoing partial hepatectomy.153,154 Two studies evaluated
doses of rFVIIa ranging from 20 to 120 g/kg intravenously, but
both failed to show decreased blood loss or erythrocyte transfusion intraoperatively during liver transplantation.155,156 However,
one of these studies demonstrated a reduction in the proportion
of patients requiring erythrocyte transfusion.155 In another study,
a small cohort of seven pediatric patients had reversal of their
coagulopathy after a single dose of rFVIIa ranging from 37 to
148 g/kg after liver graft reperfusion.157
A pilot study of patients undergoing complex, noncoronary
cardiac surgery did not demonstrate any difference between
rFVIIa and placebo groups.158
One randomized study evaluated rFVIIa treatment in 143 blunt
trauma and 134 penetrating trauma cases.159 The treatment
was initiated with a dose of 200 g/kg intravenously, followed by
100 g/kg 1 hour later, and 100 g/kg 3 hours later or similar
boluses with placebo. This treatment was started after transfusion
of the eighth unit of red cells. In the patients with blunt trauma
and rFVIIa treatment, a reduction in the number of red cells units
transfused by 2.6 units and lower requirement for massive
transfusion were noted. In the penetrating trauma patients, there
was no difference with rFVIIa treatment.
The number of well-designed, prospective, randomized studies
of rFVIIa treatment is small. Furthermore, there is little evidence
supporting its off-label use. Although reports demonstrate its
efficacy under off-label conditions, robust data establishing dose,
efficacy, and risk are required before this expensive therapy will
become a standard in resuscitation care.160,161
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101. Boylan JF, Klinck JR, Sandler AN, et al. Tranexamic acid reduces blood
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102. Dalmau A, Sabate A, Acosta F, et al. Tranexamic acid reduces red cell
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104. Zonis Z, Seear M, Reichert C, et al. The effect of preoperative tranexamic
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107. Chauhan S, Bisoi A, Modi R, et al. Tranexamic acid in paediatric cardiac
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acid versus placebo in decreasing blood loss in pediatric patients
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109. Molenaar IQ, Warnaar N, Groen H, et al. Efficacy and safety of
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110. Gralnick HR: Epsilon-aminocaproic acid in preoperative correction of
haemostatic defect in cyanotic congenital heart-disease. Lancet. 1970;1:
12041205.
111. Royston D, Bidstrup BP, Taylor KM, et al. Effect of aprotinin on need
for blood transfusion after repeat open-heart surgery. Lancet. 1987;2:
12891291.
112. McEvoy MD, Reeves ST, Reves JG, et al. Aprotinin in cardiac surgery: a
review of conventional and novel mechanisms of action. Anesth Analg.
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113. Soilleux H, Gillon MC, Mirand A, et al. Comparative effects of small
and large aprotinin doses on bleeding during orthotopic liver transplantation. Anesth Analg. 1995;80:349352.
114. Janssens M, Joris J, David JL, et al. High-dose aprotinin reduces blood
loss in patients undergoing total hip replacement surgery. Anesthesiology.
1994;80:2329.
115. Capdevila X, Calvet Y, Biboulet P, et al. Aprotinin decreases blood loss
and homologous transfusions in patients undergoing major orthopedic
116. McMullan V, Alston RP. The effect of the suspension of the licence for
aprotinin on the care of patients undergoing cardiac surgery: A survey
of cardiac anesthesiologists and surgeons opinions in the United
Kingdom. J Cardiothorac Vasc Anesth. 2010;24:418421.
117. Royston D. High-dose aprotinin therapy: a review of the first five years
experience. J Cardiothorac Vasc Anesth. 1992;6:76100.
118. DErrico CC, Shayevitz JR, Martindale SJ, et al. The efficacy and cost of
aprotinin in children undergoing reoperative open heart surgery. Anesth
Analg. 1996;83:11931199.
119. Boldt J, Knothe C, Zickmann B, et al. Comparison of two aprotinin
dosage regimens in pediatric patients having cardiac operations.
Influence on platelet function and blood loss. J Thorac Cardiovasc Surg.
1993;105:705711.
120. Miller BE, Tosone SR, Tam VK, et al. Hematologic and economic impact
of aprotinin in reoperative pediatric cardiac operations. Ann Thorac
Surg. 1998;66:535540.
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121. Davis R, Whittington R. Aprotinin. A review of its pharmacology and

therapeutic efficacy in reducing blood loss associated with cardiac
surgery. Drugs. 1995;49:954983.
122. Dietrich W, Ebell A, Busley R, et al. Aprotinin and anaphylaxis: analysis
of 12,403 exposures to aprotinin in cardiac surgery. Ann Thorac Surg.
2007;84:11441150.
123. Jaquiss RD, Ghanayem NS, Zacharisen MC, et al. Safety of aprotinin use
and re-use in pediatric cardiothoracic surgery. Circulation. 2002;106:
I90I94.
124. Levy JH, Pifarre R, Schaff HV, et al. A multicenter, double-blind,
placebo-controlled trial of aprotinin for reducing blood loss and the
requirement for donor-blood transfusion in patients undergoing repeat
coronary artery bypass grafting. Circulation. 1995;92:22362244.
125. Lemmer JH Jr, Stanford W, Bonney SL, et al. Aprotinin for coronary
bypass operations: efficacy, safety, and influence on early saphenous vein
graft patency. A multicenter, randomized, double-blind, placebocontrolled study. J Thorac Cardiovasc Surg. 1994;107:543551.
126. Alderman EL, Levy JH, Rich JB, et al. Analyses of coronary graft patency
after aprotinin use: results from the International Multicenter Aprotinin
Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg.
1998;116:716730.
127. Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin
in cardiac surgery. N Engl J Med. 2006;354:353365.
128. Fergusson DA, Hebert PC, Mazer CD, et al. A comparison of aprotinin
and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;
358:23192331.
129. Karkouti K, Beattie WS, Dattilo KM, et al. A propensity score
case-control comparison of aprotinin and tranexamic acid in hightransfusion-risk cardiac surgery. Transfusion. 2006;46:327338.
130. Szekely A, Sapi E, Breuer T, et al. Aprotinin and renal dysfunction after
pediatric cardiac surgery. Paediatr Anaesth. 2008;18:151159.
131. DErrico CC, Munro HM, Buchman SR, et al. Efficacy of aprotinin in
children undergoing craniofacial surgery. J Neurosurg. 2003;99:287290.
132. Khoshhal K, Mukhtar I, Clark P, et al. Efficacy of aprotinin in reducing
blood loss in spinal fusion for idiopathic scoliosis. J Pediatr Orthop.
2003;23:661664.
133. Cole JW, Murray DJ, Snider RJ, et al. Aprotinin reduces blood loss during
spinal surgery in children. Spine. 2003;28:24822485.
134. Urban MK, Beckman J, Gordon M, et al. The efficacy of antifibrinolytics
in the reduction of blood loss during complex adult reconstructive spine
surgery. Spine. 2001;26:11521156.
135. Laupacis A, Fergusson D, Drugs to minimize perioperative blood loss in
cardiac surgery: meta-analyses using perioperative blood transfusion as
the outcome. The International Study of Peri-operative Transfusion
(ISPOT) Investigators. Anesth Analg. 1997;85:12581267.
136. Mossinger H, Dietrich W, Braun SL, et al. High-dose aprotinin reduces
activation of hemostasis, allogenic blood requirement, and duration of
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137. Wippermann CF, Schmid FX, Eberle B, et al. Reduced inotropic support
after aprotinin therapy during pediatric cardiac operations. Ann Thorac
Surg. 1999;67:173176.
138. Davies MJ, Allen A, Kort H, et al. Prospective, randomized, double-blind
study of high-dose aprotinin in pediatric cardiac operations. Ann Thorac
Surg. 1997;63:497503.
139. Seghaye MC, Duchateau J, Grabitz RG, et al. Influence of low-dose
aprotinin on the inflammatory reaction due to cardiopulmonary bypass
in children. Ann Thorac Surg. 1996;61:12051211.
140. Herynkopf F, Lucchese F, Pereira E, et al. Aprotinin in children
undergoing correction of congenital heart defects. A double-blind pilot
study. J Thorac Cardiovasc Surg. 1994;108:517521.
141. Boldt J, Knothe C, Zickmann B, et al. Aprotinin in pediatric cardiac
operations: platelet function, blood loss, and use of homologous blood.
Ann Thorac Surg. 1993;55:14601466.
142. Boldt J, Zickmann B, Schindler E, et al. Influence of aprotinin on the
thrombomodulin/protein C system in pediatric cardiac operations.
J Thorac Cardiovasc Surg. 1994;107:12151221.
143. Dietrich W, Mossinger H, Spannagl M, et al. Hemostatic activation
during cardiopulmonary bypass with different aprotinin dosages in
pediatric patients having cardiac operations. J Thorac Cardiovasc Surg.
1993;105:712720.
144. Huang H, Ding W, Su Z, et al. Mechanism of the preserving effect of
aprotinin on platelet function and its use in cardiac surgery. J Thorac
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145. Arnold DM, Fergusson DA, Chan AK, et al. Avoiding transfusions in
children undergoing cardiac surgery: a meta-analysis of randomized
trials of aprotinin. Anesth Analg. 2006;102:731737.
146. Carrel TP, Schwanda M, Vogt PR, et al. Aprotinin in pediatric cardiac
operations: a benefit in complex malformations and with high-dose
regimen only. Ann Thorac Surg. 1998;66:153158.
147. Lisman T, Mosnier LO, Lambert T, et al. Inhibition of fibrinolysis by
recombinant factor VIIa in plasma from patients with severe hemophilia
A. Blood. 2002;99:175179.
148. Hedner U. Factor VIIa in the treatment of haemophilia. Blood Coagul
Fibrinolysis. 1990;1:307317.
149. Levy JH, Fingerhut A, Brott T, et al. Recombinant factor VIIa in patients
with coagulopathy secondary to anticoagulant therapy, cirrhosis, or
severe traumatic injury: review of safety profile. Transfusion. 2006;46:
919933.
150. Mayer SA, Brun NC, Begtrup K, et al. Recombinant activated factor VII
for acute intracerebral hemorrhage. N Engl J Med. 2005;352:777785.
151. Lindley CM, Sawyer WT, Macik BG, et al. Pharmacokinetics and
pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther.
1994;55:638648.
152. Erhardtsen E. Pharmacokinetics of recombinant activated factor
VII (rFVIIa). Semin Thromb Hemost. 2000;26:385391.
153. Lodge JP, Jonas S, Oussoultzoglou E, et al. Recombinant coagulation
factor VIIa in major liver resection: a randomized, placebo-controlled,
double-blind clinical trial. Anesthesiology. 2005;102:269275.
154. Shao YF, Yang JM, Chau GY, et al. Safety and hemostatic effect of
recombinant activated factor VII in cirrhotic patients undergoing partial
hepatectomy: a multicenter, randomized, double-blind, placebocontrolled trial. Am J Surg. 2006;191:245249.
155. Lodge JP, Jonas S, Jones RM, et al. Efficacy and safety of repeated
perioperative doses of recombinant factor VIIa in liver transplantation.
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156. Planinsic RM, van der MJ, Testa G, et al. Safety and efficacy of a single
bolus administration of recombinant factor VIIa in liver transplantation
due to chronic liver disease. Liver Transpl. 2005;11:895900.
157. Markiewicz M, Kalicinski P, Kaminski A, et al. Acute coagulopathy after
reperfusion of the liver graft in children correction with recombinant
activated factor VII. Transplant Proc. 2003;35:23182319.
158. Diprose P, Herbertson MJ, OShaughnessy D, et al. Activated recombinant
factor VII after cardiopulmonary bypass reduces allogenic transfusion in
complex noncoronary cardiac surgery: randomized double-blind
placebo-controlled pilot study. Br J Anaesth. 2005;95:596602.
159. Boffard KD, Riou B, Warren B, et al. Recombinant factor VIIa as
adjunctive therapy for bleeding control in severely injured trauma
patients: two parallel randomized, placebo-controlled, double-blind
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160. Alten JA, Benner K, Green K, et al. Pediatric off-label use of recombinant
factor VIIa. Pediatrics. 2009;123:10661072.
161. Jen H, Shew S, Recombinant activated factor VII use in critically ill
infants with active hemorrhage. J Pediatr Surg. 2008;43:22352238.
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55
Outpatient Anesthesia
Daniel Vischoff and Sophie Saindon
INTRODUCTION
Ambulatory surgery was considered as a revelation of the 1990s,
but in fact, it is much older. The first description is traced to
Dr. James H. Nicoll, a surgeon from the Royal Hospital for Sick
Children in Glasgow, who made a presentation to the British
Medical Association, published in 1909, about his experience of
8988 operations over a period of 10 years.1 The span of operations
performed was wide and included surgical treatment of tuberculosis of bones, joints, and glands; clubfeet; cleft lips and palates;
spina bifida; pyloric stenosis. His paper does not discuss morbidity
and mortality, which must have been substantial by our standards
as hinted in the discussion following the presentation when
Dr. A. Fullerton from Belfast questioned the responsibility of the
surgeon if a child operated for a hernia as an outpatient should die
from sepsis or other causes!
Nowadays, because of patient preferences and economic
pressures, almost two thirds of procedures in children are done
on an outpatient basis.
The major prerequisite to shift procedures from inpatient to
outpatient is that no compromise be made in the patients safety.
Outpatient anesthesia has many advantages:
Minimal separation of the child from her or his parents and her
or his normal environment may reduce behavioral changes
caused by separation and hospitalization.
Diminished risk of nosocomial infections.
Maintenance of an active role for the parents in the care of their
child, their role often being lost with hospitalization.
General and financial benefit for the family unit, which is less
disrupted than with hospitalization.
Cost reductions for the institution.
More beds and personnel available to satisfy hospitalization
needs.
It also has its limitations, which can be summarized as a

transfer of responsibilities and costs from the hospital to the family
or caregivers.
Outpatient surgery can be performed in hospitals or in freestanding facilities. Both have advantages and limitations. The
major limitation of free-standing facilities is the lack of rapid and
direct access to a hospital. Therefore, they must have policies and
arrangements with hospitals for patients who need hospitalization
because of surgical or anesthetic complications.
The purpose of this chapter is to examine the setting most
appropriate for effective and safe outpatient anesthesia: selection
of patients and procedures, information and preparation of patients
and family, anesthetic considerations, postoperative manage-
C H A P T E R
ment, discharge criteria, prevention of complications, and evaluation of results.
SELECTION CRITERIA
The Procedure
Each facility must establish a list of suitable procedures. In 1964, a
British surgeon, Rex Lawrie,2 published a list of criteria that still
form the basis of modern criteria.3
1. No intracranial, intrathoracic, or major intra-abdominal
surgery.
2. Minimal risk of anesthetic or surgical complications (e.g.,
bleeding).
3. Simple nursing care that can be provided by parents.
4. Simple postoperative medication such as analgesics and
antiemetics.
5. No major limitation on the childs activities.
Table 551 presents a list of the most commonly performed
outpatient procedures at Sainte Justine Hospital, Montreal. They
are usually short procedures of less than 2 hours, but the duration
of procedure is not by itself a limitation to outpatient surgery.
Adenotonsillectomy has been questioned as a suitable outpatient
procedure, but its safety has been well documented,4,5 and it has been
performed at our institution since the mid-1980s. Many publications
focus on primary hemorrhage as being the main complication to
consider in determining the suitability of an outpatient procedure.
However, many patients scheduled for adenotonsillectomy have
obstructive respiratory symptoms and require special precautions.
Obstructive sleep apnea is discussed under Obstructive Sleep Apnea
Syndrome, later in this chapter. The frequency of bleeding
requiring re-intervention is less than 0.1%.6 Early hemorrhage usually
happens during the first 4 hours. Therefore, these patients go to the
recovery room for the initial observation period and then to the day
care unit. After a minimum stay of 4 hours, they can be discharged
home; those bleeding or necessitating a re-intervention will be
hospitalized. Late hemor rhage usually occurs at home on
postoperative days 5 to 7.
The Family
Parents must be responsible people wanting to play a role in their
childs operation and they must be available. They should also live
in a radius of approximately 30 miles or a 1-hour drive from a
hospital.
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TABLE 55-1. Procedures Commonly Done on an

Outpatient Basis
Specialty
Procedure
General surgery
Herniorraphy/hydrocelectomy
Orchiopexy
Excision of masses (e.g., cyst, lymph node,
breast mass)
Muscle biopsy
Incision + drainage: abscess
Laryngo-, tracheo-, bronchoscopy
Esophagoscopy, esophageal dilation
Foreign body extraction (respiratory,
digestive)
Hematology: bone marrow
sampling/aspiration, intrathecal
injections, lumbar puncture
Gastroscopy, colonoscopy
Cystoscopy
Diagnostic radiology: CT scan, MRI
Interventional radiology
Cardiac catheterization
Transesophageal echography
Hypospadias repair
Testicular biopsy
Circumcision
Hydrocelectomy
Tonsillectomy, adenoidectomy (see text)
Myringotomy and tube insertion
Closed reduction of nasal fractures
Extraction, restoration
Examination
Lachrymal duct probing and intubation
Strabismus
Excision of chalazion, cyst
Otoplasty
Excision of skin lesion, nevus
Scar revision
Benign malformations (e.g., syndactyly,
polydactyly, amniotic bands)
Closed reductions of fractures
Arthroscopy
Hardware removal
Cast changes
Pulsed dye laser
Skin lesion: condyloma, biopsy
Diagnostic/
therapeutic
procedures
Urology
ENT
Dental
Ophthalmology
Plastic surgery
Orthopedic
surgery
Dermatology
CT = computed tomography; ENT = ear, nose, and throat; MRI, magnetic

resonance imaging.
The Patient
Physical status: patients should be American Society of Anesthesiologists (ASA) physical status 1 and 2, the majority of units accepting ASA 3 patients as long as they are stable and well controlled.
Special Risk Factors

Prematurity/Age
The expremature infant (<37 wk gestation) is at increased risk of
respiratory and cardiovascular complications.710 The factors
TABLE 55-2. Factors Increasing the Risk of Apnea in

Former Preterm Infants
Gestational age
Growth and development
Conditions related to prematurity: bronchopulmonary
dysplasia, subglottic stenosis, residual lung disease
Other medical conditions: heart diseases, central nervous
system disease, endocrine or metabolic disease
Apnea and bradycardia, caffeine treatment
Anemia (hematocrit 30%)
Peri-operative complications: hypoglycemia, hypoxia,
hypocalcemia, hypothermia, sepsis
Data from references.10, 11, and 16.
studied and shown to increase the risk are listed in Table 552 and
should warrant either a postponement of surgery or an admission.11,12
All patients who are admitted and monitored can be discharged
after 12 hours free of apnea,10 usually the next morning. Caffeine
can be prescribed at a dose of 10 mg/kg intravenosly in addition
to monitoring for apnea and bradycardia.13 If the patient is already
being treated with caffeine, it should be continued. Spinal anesthesia without sedation seems to be associated with less apnea than
general anesthesia,11 but further prospective studies with a large
number of infants are needed to confirm it.14
For otherwise healthy expremature infants, the risk of apnea
is low but is not zero.14 Clinicians seeking an apnea risk of 1% as
a qualification for outpatient surgery must wait until 54 weeks
postconceptional age (PCA) for infants born at 35 weeks gestation
and until 56 weeks PCA for 32 weeks gestation after the conclusions of the combined analysis by Ct and coworkers.14 The
authors and others will wait until 60 weeks PCA to treat the ex
premature infants as outpatient because of case reports of apnea
until this age.9 The literature always emphasizes that these infants
must be treated on a case-by-case basis. Economic constraints may
influence the final decision.
The incidence of apnea after general anesthesia in full-term
infants without any disease is unknown, but cases have been
reported.15,16 Although some authors accept these infants as outpatients at 42 weeks PCA, each department has to define its own
policy because of an absence of consensus in the literature.
Upper Respiratory Infection

Upper respiratory infection (URI) is particularly frequent in the
young child, and it is not always possible to find a symptom-free
period. URI increases perioperative respiratory complications
such as laryngospasm, bronchospasm, and desaturation episodes
without increasing long-term consequences.17 It is our policy to
proceed with outpatient anesthesia if the child has only a runny
nose, whereas signs of an active infectious process (temperature
> 38C, rales, colored nasal discharge or sputum, malaise) are a
contraindication to elective surgery. Other criteria that were
shown to be linked with a higher risk of anesthetic complications
are history of prematurity or reactive airway disease, surgery
involving the airway, exposure to tobacco smoke, and use of an
endotracheal tube.18 Clinicians have to make everyday decisions,
and following strict guidelines is not always in the best interest
of the patient. As Ct wrote in an editorial, Good judgment,
common sense clinical experience and informed consent always
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take precedence in making the decision to proceed with a specific case.19
Outpatient Anesthesia 875
With the increasing incidence of obesity in children, the

pediatric anesthesiologist will meet more and more patients
with type 2 diabetes.
Asthma
Well-controlled asthma is not a contraindication to outpatient
anesthesia, whereas poorly controlled asthma alone or combined
with signs of URI or lower respiratory infection is. Asthmatic
children should have their treatment continued or slightly increased in the perioperative period, depending on the usual
behavior of their disease. Preoperative treatment with a agonist
may be useful, even if the patient is asymptomatic, because of the
risk of provoking airway irritation during anesthesia induction
and emergence.20
Sickle Cell Disease

Children with sickle cell disease are always under the care of
a hematologist and should most often be treated as inpatients,
after appropriate hematologic preparation. For certain minor
procedures, some sickle cell patient can be outpatients if good
hydration and analgesia are confirmed before discharge.25 Patients
with sickle cell trait do not differ from normal patients and can be
treated on an outpatient basis.
Malignant Hyperthermia
Heart Conditions
Patients with heart murmurs should be investigated before coming
to surgery, functional murmurs requiring no special precautions.
Patients with heart diseases or malformations can qualify as outpatients if they are stable, well-controlled, and given a prophylactic
antibiotic therapy as recommended by the American Heart
Association (AHA).21 The prophylaxis must be prescribed well in
advance of surgery to avoid delays and omissions. The prophylaxis
can be given orally 30 to 60 minutes before the start of surgery
in most situations. If the intravenous route is selected, the AHA
recommends a 30-minute interval between administration and
beginning surgery. Because of difficulty with intravenous access in
children, the authors and others22 feel it is reasonable to administer
the antibiotics at induction of anesthesia as soon as the intravenous
line is secured, except for vancomycin, which needs a longer
infusion time. This practice is not part of the AHA guidelines.
Seizures
Seizures are a frequent occurrence in young children and do
not contraindicate outpatient anesthesia as long as the patient is
well-controlled and stable. Regular doses of medication should
be taken with clear fluids before and after surgery. When nausea
and vomiting prevent a normal schedule of oral administration,
an intravenous therapy must be prescribed until oral intake has
resumed.
Mental Handicap
These children often present with pathologies that would mandate
inpatient status, but their heavy reliance on parents and usual
environment makes proceeding as an outpatient a safe choice as
long as all considerations pertaining to associated diseases (cardiac,
neurologic) are addressed.
Diabetes Mellitus
Type 1 diabetes is one of the most frequent chronic disease in
children in developed countries.23 Although traditionally described
as unstable and not eligible for outpatient surgery, type 1 diabetic
patients can have same-day surgery for minor procedures if strict
criteria are respected: children older than 5 years who have undergone surgery early in the day, who have no associated comorbidity,
who have consumed a normal meal without vomiting, and who
have a normal or slightly high blood glucose discharge on the same
day may be considered.24
Children with a proven or suspected history of malignant hyperthermia can be treated as outpatients as long as they receive a
trigger-free anesthesia, regional or general, have an uneventful
procedure, and are observed for 3 hours postoperatively.26
Obstructive Sleep Apnea Syndrome

Sleep-disordered breathing exists as a continuum of severity
ranging from partial airway obstruction producing primary
snoring, through intermediate conditions (upper airway resistance
syndrome), to continuous episodes of complete airway obstruction
or obstructive sleep apnea. Obstructive sleep apnea syndrome
(OSAS) occurs in children of all ages but more commonly in
children from 2 to 7 years of age. The prevalence may be higher
among African American individuals than among white individuals.27 Signs of OSAS are sleep disturbances, failure to thrive,
and behavioral problems. Diurnal fatigue, the hallmark of adult
OSAS, rarely occurs in pediatric OSAS.28
Physical examination is important to evaluate airway structures,
but findings are often normal even in severe OSAS.
Anesthesiologists are mostly preoccupied by the potential
complications after adenotonsillectomy in this population. Polysomnograhy is the gold standard for diagnosing sleep apnea.29
Because it is expensive, time-consuming, and not widely available,
most children come to surgery without any diagnostic study. What
can we do to ensure optimal anesthetic management of these
children? First, we must determine which patients are suitable
for same day surgery. Children younger than 3 years, those with
severe OSAS, failure to thrive, recent URI, or associated medical
conditions (Down syndrome, craniofacial disorders, and genetic/
metabolic/storage disease) are not candidates for outpatient surgery.30 Otherwise healthy children older than 3 years who come
to surgery for mild obstructive symptoms can be discharged if the
immediate postoperative course is uneventful. In 2006, the ASA
published Practice Guidelines for the Perioperative Management of
Patients with Obstructive Sleep Apnea.31 They do contain clinical
criteria that can be used do identify patients with OSAS in the
absence of a sleep study. These criteria have a high degree of
sensitivity, therefore a low specificity, meaning that some patients
may be treated more aggressively than would be necessary if a
sleep study were available.
PREOPERATIVE PREPARATION
Screening of outpatients is usually made by the surgical staff
with consultations to the appropriate specialists including the
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anesthesiologist in case of abnormal findings. Many centers

advocate assessment of all significantly abnormal patients in a
preadmission clinic. This practice, although useful, requires an
additional visit to the hospital. To decrease last-minute cancellations related to acute problems (e.g., fever, cough, skin eruption),
a telephone call to the parents 1 to 2 days before surgery appears
most effective.
The routine preoperative evaluation of outpatients is the same
as for inpatients and includes a history and physical examination
with special attention to past surgical or anesthetic experiences.
It can be done up to 3 months in advance and brought up to date
on the day of surgery.
Laboratory tests are ordered to detect unsuspected conditions
that may alter the conduct of anesthesia or surgery or to satisfy
institutional or legal criteria.32 However, preoperative evaluation is
not an effective period for screening.32,33
The American Academy of Pediatrics, the ASA, and the
American College of Surgeons make no definite recommendations
for preoperative testing.33 It is safe, logical, and economical to
individualize the laboratory tests ordered based on the patients
history, physical examination, and intended surgical procedure.
Significant anemia is rare in otherwise healthy, well-nourished
patients. Its incidence in pediatric surgical patients may vary
between 0.5 and 9%,34,35 being relatively higher in infants younger
than 1 year or with chronic illness. Furthermore, only a small
number of anemic patients have their surgery postponed and,
although it is difficult to diagnose mild degrees of anemia by
clinical evaluation of children, the results of the tests have little
influence on patient management.35 Most anesthesiologists and
surgeons are not concerned about mild degrees of anemia and
inconsequential abnormalities of urine analysis.33 Coagulation
testing is not recommended as a routine before Aden tonsillectomy
by the American Academy of Otolaryngology-Head and Neck
Surgery.
Therefore, routine laboratory tests should be kept to a minimum. A suckling test is prescribed for all at-risk ethnicity patients.
A positive suckling test should be followed by hemoglobin
electrophoresis. Whether a routine pregnancy test should be
ordered for every menstruating female has to be decided by each
institution based on the frequency of pregnancies and medicolegal
concerns. Although teenage pregnancy represents 13 to 23% of
total pregnancies in the United States,32 its incidence may be very
different in other countries.
1. Light meals, milk and formula are emptied slowly from the
stomach and the fasting interval should be 6 hours. Toast and
cereals are considered a light meal. Meals that include fried,
fatty foods or meat prolong gastric emptying and mandate a
fasting period of 8 hours41 or more.42
2. Breast milk: the gastric-emptying time for this nutrient is
approximately 48 minutes whereas it is 78 minutes for formula.43
A study comparing by ultrasound the gastric antral surface in
children younger than 5 years has shown that the gastric volume
returned to fasting values 165 minutes after breast milk
ingestion.44 Therefore, a 4-hour fasting period after breast milk
is adequate.
3. Clear fluids include water, electrolytes solutions, fruit juices
without pulp, carbonated beverages, clear tea, and black coffee.
Many studies show that there are no differences in gastric
residual volume or pH between those patients who fast 8 hours
and those who fast 2 to 3 hours after clear liquids ingestion.37,39
When allowed to drink clear fluids until 2 hours before the
scheduled time of anesthesia, patients are less thirsty, less
hungry, and more comfortable than those fasting for longer
periods.37,45 Carbohydrate-containing fluids have the same
effect as water on gastric volume and pH,38 but they diminish
the hunger sensation46 and lower the risk of preoperative hypoglycemia.36 Because of the difficulty in predicting the exact time
of surgery, the authors encourage children to drink up to
3 hours before induction of anesthesia.
PREOPERATIVE FASTING
PREMEDICATION
Fasting from midnight is neither appropriate nor justified for

children because it can lead to dehydration, hypotension at
induction, asymptomatic hypoglycemia,36 and discomfort. Fasting
prescriptions must take into consideration the scheduled time of
surgery, the patients age, and the differences in gastric-emptying
time after ingestion of solids or clear liquids while never neglecting
the patients safety. Studies have shown that children may have a
residual gastric volume greater than 0.4 mL/kg with a pH less than
2.5 and that the number in this group is not reduced by prolonged
fasting.37,38 Up to 76% of children have a sufficient volume of acidic
gastric contents at induction to cause chemical pneumonitis, and
yet the clinical syndrome is rare.37 The incidence of aspiration is
up to threefold greater in children than in adults (9/10,000 vs
3/10,000).39 Fortunately, should aspiration occur, it has been shown
Anxiety before surgery is a common clinical phenomenon and is

a concern for every pediatric anesthesiologist. Even a healthy child
scheduled for a minor procedure can be terrified. Although the
majority of adult patients receive sedative premedicants, most
anesthesiologists are familiar with the screaming and resistance
that often occur when an unsedated young child is taken away
from his or her parents for surgery.47 The time between the
patients arrival at the hospital and the scheduled time of surgery
is often very short in a well-organized outpatient surgery clinic.
It is useful to prepare the child and the family beforehand by
explaining to them the sequence of events. This usually starts at
the surgeons office, but more often, hospitals offer presurgical
preparation programs in which the child can either tour the
operating rooms or watch a video describing all the different steps
TABLE 55-3. Fasting Recommendations Before Scheduled

Time of Anesthesia for Healthy Patients of All Ages
Undergoing Elective Procedures
Ingested Material
Minimum Fasting Period, h
Clear liquids
Breast milk
Infant formula
Nonhuman milk
Light meal
2
4
6
6
6
From reference 41.
that there is no serious morbidity in the immediate postoperative

period after elective procedures in patients younger than 18 years.40
We endorse the ASA guidelines for fasting before elective
surgery41 (Table 553).
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before and after the operation. Special pamphlets or books can
also be distributed 1 to 2 weeks before the operation to help reduce
the anxiety. The parents should be part of this psychological
preparation because their anxiety can be transmitted to the child
and augment the childs fear.48
Especially for outpatient surgery, most of the children have
no previous hospital experience. Others may come on a regular
basis for special procedures such as radiotherapy, gastrointestinal
endoscopies, and laser treatment in dermatology and can either
be confident, afraid, or scared depending on their previous experiences. Many children exhibit negative behavioral responses after
surgery (nightmares, eating disturbances, new-onset enuresis).49
Both sedative premedicants and parental presence during induction of anesthesia are currently used to prevent this occurrence.
Since about 2000, the trend among pediatric anesthesiologists in
the United States is to give sedative premedication more often and
to younger children and to allow the parents to be present more
often in the operating room or in the postanesthesia care unit
(PACU).50 The decision to use premedication or parental presence
must be individualized. Many parents ask to be present, especially
if they have already been present at a previous induction.
Somebody must be available to escort the parents after induction
or at anytime when the anesthesiologist asks them to leave.
Generally, infants younger than 6 months separate easily from
parents, go into the arms of the anesthesiologist or the nurse
without crying, and usually do not require sedation. Children
older than 4 years who are reluctant to separate from parents or to
accept the facemask will benefit either from premedication or
from parental presence at induction.51 But only the presence of a
calm parent will benefit the child; the presence of an anxious
parent will not.48,52 Children younger than 4 years seem to be more
anxious during induction in the presence of their parents.51
When medication is needed, the oral route of administration is
usually easily accepted by most children. The nasal, intrarectal, or
intramuscular routes are not used in routine pediatric anesthesia
(except for some very uncooperative, agitated children).
Midazolam
In a North American survey, 96% of all respondents who
premedicate use oral midazolam.50 The medication can be drawn
from the injectable preparation (oral dose 0.5 mg/kg), but because
of the bitter taste of the solution, it is judicious to dilute it in apple
juice, carbonated beverages, or flavored acetaminophen (15
20 mg/kg). The latter provides early postoperative analgesia.
Cherry-flavored syrup of midazolam (2 mg/mL) has been
marketed. When given orally, midazolam is effective in 10 to 30
minutes53 and does not prolong the stay in the PACU,54 but there
are some reports that emergence can be briefly delayed.55 There
are less postoperative behavioral disturbances after premedication
with midazolam,56 but up to 14.5% of children may still exhibit
anxiety and lack of compliance during induction. The children
younger than 4 years and highly emotional may not respond well
to midazolam.57
Ketamine
Ketamine is traditionally administered parentally. It can also be
used orally as a premedication (6 mg/kg mixed with a cola-flavored
clear liquid 2025 min before induction).58 It offers clinical
characteristics similar to midazolam. When ketamine is given
orally, there are no psychedelic symptoms.59 The combination of

ketamine and midazolam increases the success of premedication,59
but doses must be reduced.
Oral Transmucosal Fentanyl Citrate

Oral transmucosal fentanyl citrate (OFTC) is prepared by
dissolving precise amounts of fentanyl in a sucrose solution and
making it resemble a lollipop, which comes in a range of formats
to allow 15 to 20-g/kg doses. Onset of action is similar to that of
midazolam (2030 min) and the effect lasts 30 minutes, but
fentanyl does not lead to better cooperation or less anxiety in
children. To be effective, fentanyl must be absorbed through
the oral mucosa and the child should be supervised because
swallowing decreases its effect owing to first-pass metabolism
through the liver. Frequent side effects such as pruritus (70% of
patients) and postoperative nausea and vomiting (PONV; 64%)60
or the moral reluctance of some anesthesiologists to use a medication in the form of a lollipop limit the applicability of this
method in pediatric surgical outpatient procedures. Occasional
respiratory depression with arterial oxygen desaturation (12% of
patients)60 require its administration in a monitored care setting.
Clonidine
Clonidine in a 4-g/kg oral dose causes sedation and decreases
requirements for postoperative analgesia.61 Its slow onset of action
(must be given at least 45 min before surgery) makes it an unusual
choice for outpatients. Although clonidine can be associated with
moderately increased sedation during the first 24 postoperative
hours (appreciated by certain parents),62 it does not delay discharge from the PACU or hospital.63
Analgesic Creams
Analgesic cream (EMLA [eutectic mixture of local anesthetics],
Synera, or Ametop) must be part of the preparation of the child if
an intravenous induction is planned. To be effective, EMLA cream
must be applied under an occlusive dressing for at least an hour
and the Synera patch is effective after 20 to 30 minutes. They
should be applied to two potential sites for intravenous induction
in case the first venipuncture is not successful and can be put on
at home by the parents. The absence of pain at injection does not
eliminate the fear of the needle itself.
INDUCTION OF ANESTHESIA
The basic principles for anesthesia induction do not differ whether
the patient is an outpatient or an inpatient. The ideal agent for
outpatient surgery should produce a rapid and smooth induction;
a rapid emergence; a prompt recovery and a short PACU stay;
minimal side effects such as restlessness, nausea, vomiting, drowsiness, and pain; and allow rapid discharge. The choice of the agent
and the technique is based on the needs of each individual patient
and the preference of the anesthesiologist.
Inhalation Induction
Inhalation induction is a popular choice among pediatric
anesthesiologists. The two agents most suitable for inhalation
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induction are halothane and sevoflurane. Although isoflurane can

sometimes be used, its pungency makes it difficult to administer
because of respiratory side effects. Desflurane is not used for
induction because of a high incidence of airway complications and
involuntary movements.64,65
Sevoflurane
Sevofluranes pleasant smell and low blood-gas partition coefficient
(0.68%) make it the agent of choice for mask induction. It is the
least irritating agent and offers hemodynamic stability. These
characteristics allow a smooth, safe, and rapid induction. The
technique can be by stepwise increases of inspired concentrations
with 1.5 to 2% increments every three to five breaths up to 7 to 8%
in a mixture of oxygen (30%) and nitrous oxide (70%). Induction
can be hastened by beginning with a circuit primed with 8% of
sevoflurane in 70% nitrous oxide with no adverse respiratory or
hemodynamic side effects.66,67 Even at this high inspired concentration, it cannot be used as a single-breath technique in children
but it is faster than incremental doses of sevoflurane in children.66
The addition of nitrous oxide to high concentrations of sevoflurane
tends to decrease the incidence of excitement during induction.
Because sevoflurane offers cardiovascular and hemodynamic
stability, there is no need for routine intravenous atropine.68,69
Halothane
A smooth and rapid induction can be obtained by 0.5% increments
every three to five breaths (4%) in a combination of oxygen (30%)
and nitrous oxide (70%). The usual side effects are bradycardia and
hypotension because of the myocardial depressant effect of
halothane, especially in relatively hypovolemic patients owing to
a prolonged fast. Their prevention or treatment is intravenous
atropine (0.01 mg/kg)7072 as soon as the intravenous line is
secured. With an inspired concentration of halothane at 4% during 2 to 3 minutes, it is possible to intubate the trachea without a
muscle relaxant.
Because of the hemodynamic stability offered by sevoflurane and its wide use, the use of halothane has progressively
decreased since about 2000, prompting manufacturers to stop its
production.
laryngeal mask airway (LMA). The injection of propofol (4 mg/kg)

with remifentanil (34 g/kg) allows a smooth intubation without
the use of a muscle relaxant.76 The use of intravenous atropine is
strongly recommended to prevent bradycardia when propofol is
used in children,73 especially in association with remifentanil.76
Pain at injection is minimized by using a large vein or by injecting
lidocaine 0.2 mg/kg intravenously either directly or mixed with
propofol.77 After induction, propofol can be used for maintenance
of anesthesia in a continuous infusion, making it a most suitable
agent for anesthesia in remote locations or in unfamiliar settings.
Thiopental
Children require relatively large doses of thiopental (57 mg/kg)
to ensure rapid induction of anesthesia.78,79 Recovery time is
slightly prolonged when thiopental is used for induction instead
of propofol.73
Intramuscular Induction
It is unpleasant and fortunately rare that a struggling child cannot
be managed either by appropriate premedication or by inhalational or intravenous induction. Ketamine is the most suitable
drug available for intramuscular use. Sedating doses of 4 to
6 mg/kg should be given in a monitored care setting and higher
doses (610 mg/kg) are induction doses. Because of the increase
of salivary secretions, an antisialagogue is recommended when
ketamine is administered. By using the more concentrated solution, the volume of drug injected is reduced and the muscle pain
is diminished.
MAINTENANCE OF ANESTHESIA
The recent introduction of short-acting anesthetic agents, muscle
relaxants, and analgesics with a rapid onset and a short duration
of action has contributed to the rapid expansion of outpatient
surgery. The association of general anesthesia with local or regional analgesia offers a rapid and comfortable emergence from
anesthesia, allowing a short PACU stay and early discharge from
hospital.
Intravenous Induction
Inhalation Agents
Given the choice, some children may prefer an intravenous

induction, especially if skin analgesia is provided with a local
anesthetic skin preparation or with subcutaneous lidocaine
infiltration.
Isoflurane
Isoflurane is not the ideal agent for induction but is a good choice
for maintenance because it allows a rapid emergence and recovery.
Its price makes it economical to use especially if one uses low fresh
gas flow.
Propofol
Propofol is used very often for outpatient anesthesia and for procedures outside the operating room. Even if propofol is currently
still not recommended for children younger than 3 years, most
pediatric anesthesiologist use it for infants and young children
because it offers a safe and smooth induction with a low incidence
of side effects.73 The dose for induction in unpremedicated
children is 2.5 to 3 mg/kg,74,75 but it has to be increased to 3 to
4 mg/kg for infants 1 to 6 months old.75 Propofol induction produces respiratory depression and apnea74 and depresses laryngeal
reflexes more than thiopental, allowing easy placement of a
Sevoflurane
Sevoflurane can be used for induction and maintenance
of anesthesia. The minimum alveolar concentration (MAC) of
sevoflurane is 2.5% for patients aged from 6 months to 12 year and
3.2 to 3.3% for infants younger than 6 months.80 The additive effect
of nitrous oxide on MAC is less in children than in adults.80 For
economical reasons, the fresh gas flow must be minimized by
using a circle system. Because of the potential nephrotoxicty of
compound A, the package label in the United States prohibits the
use of sevoflurane in rebreathing systems with flow rate less than
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1 L/min, in Canada with flow rates less than 2 L/min; in many
countries, there is no flow rate restriction.81 The occurrence of
emergence agitation after sevoflurane anesthesia is a common
phenomenon and a major disadvantage of this agent for maintenance of anesthesia. Its incidence varies according to its definition and its cause remains obscure. Pain is not the only factor,
because postanesthesia agitation has been observed even when
pain was efficiently treated. Although this period of agitation is
self-limited, resolving without pharmacologic intervention over
time,82 various treatments have been proposed (e.g., benzodiazepines, clonidine, and dexmedetomidine).
Desflurane
Desflurane has the lowest blood solubility (0.42) of all agents,
allowing for a rapid emergence. It can easily be introduced after
induction with another agent. In one study, when used for maintenance and emergence, mask-administered desflurane did
not provoke airway irritability by contrast with the irritability
seen at induction.83 The relationship between age and the MAC
of desflurane in infants and children is similar to that reported for
halothane and isoflurane. For all three inhalational agents, MAC
increases with age, reaching a maximum value during infancy and
decreasing thereafter.64 The MAC of desflurane peaks in infants
6 to 12 months of age (9.9%) and decreases with advancing age to
reach 8% in children aged 2 to 12 years.64 Postanesthesia agitation
has been described with desflurane.84
Halothane
Halothane is not a good choice for maintenance of anesthesia
because of its hemodynamic and cardiac side effects. Halothane
will perhaps disappear; many manufacturers have stopped producing it.
Intravenous Agents
Propofol
Propofol can be used for total intravenous anesthesia for outpatient pediatric surgery. In prolonged procedures, recovery
becomes less predictable than with inhalation agents. The infusion
rate for maintenance should be increased 25 to 50% compared
with adults,85 and doses as high as 300 to 500 g/kg/min may be
needed to suppress movement in children if used alone.73,86 These
doses are used during the early part of maintenance and are
gradually decreased to 150 g/kg/min. When used for magnetic
resonance imaging or other painless procedures, a dose of 100 g/
kg/min effectively prevents children from moving.87 For short
procedures, propofol maintenance allows a rapid and smooth
emergence and decreases PONV if used without nitrous oxide.
However, propofol may be associated with apnea or airway
obstruction and should be used only with appropriate monitoring
and by professionals skilled in airway management.
When propofol is used for successive procedures, one must be
careful to prevent contamination by changing syringes and lines
between each patient and using strict aseptic techniques.88
Remifentanil
Remifentanil is an opioid analgesic that can be used for outpatient
surgery as an adjunct to either propofol in total intravenous
anesthesia or to inhalation anesthesia. Its rapid plasma clearance

by plasma esterases produces an elimination that is independent
of rate or duration of infusion. The dose of remifentanil to maintain spontaneous ventilation depends on the age of the child;
younger children, especially those younger than 3 years, tolerate
higher dose of remifentanil.89 Because of the variations in doses,
the respiratory rate of the patient is a reliable indicator of
increasing opioid effect.90 The association of propofol and remifentanil provides effective conditions for many procedures under
deep sedation or anesthesia while maintaining spontaneous
ventilation. With a 200 g/kg/min rate of propofol infusion, the
dose of remifentanil infusion varies between 0.35 g/kg/min (for
children < 3 years old) to 0.16 g/kg/min for older children.89
Care must be taken to provide early postoperative analgesia for
painful procedures, because there are no residual analgesic effects
of remifentanil. The advantage of this ultrashort-acting opiate is
that it can be used without increasing the incidence of nausea
and emesis.91
Outpatient anesthesia does not preclude the use of muscle
relaxants. Among the nondepolarizing agents, any short-acting
drug may be used (rocuronium, cisatracurium, atracurium) as
long as its effect has terminated or been antagonized at the end of
the procedure.
AIRWAY MANAGEMENT
There are many options for airway management in outpatient
anesthesia. Facemask is a good option for short procedures. For
longer operations or when the anesthesia provider must have both
hands free, the LMA92 is a useful tool. It has numerous applications
in outpatient anesthesia.93 It is less irritating for the airway than an
endotracheal tube; it is, therefore, an interesting tool in cases of
asthma or URIs. Indication for intubation does not differ between
outpatients and inpatients. With careful technique and the use of
correct-size tubes, the incidence of croup is low.94 The general use
of uncuffed tubes in young children is challenged because cuffed
endotracheal tubes may diminish the need for repeated laryngoscopy and reduce the leak of anesthetic gases in the operating
room without being associated with an increased incidence of
postintubation croup.95
ANALGESIA
The need for intraoperative and postoperative analgesia depends
upon the nature of procedure and not upon whether the child is
an outpatient or an inpatient. Postoperative pain concerns should
be addressed before and during the operation in order for the
patient to have a pain-free emergence and recovery, especially
when the newer short-acting anesthetic agents are used. Therefore,
when started intraoperatively, long-acting analgesics are an adjunct to general anesthesia and prolong the analgesia even after
discharge from hospital. Whenever possible, the use of local analgesia or regional blocks combined with general anesthesia will
permit lower inhaled concentrations of agents intraoperatively and
less need for opioids postoperatively. Medications given in the
PACU should be given in small intravenous doses and monitored
closely.96 If the intramuscular route is chosen, it should be used
while the child is still asleep to avoid injection-related pain and
fear. When needed, it may be useful to give a dose of the oral
analgesic planned for home administration before discharge to test
its effectiveness and tolerability.
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Opioid Agents
Nonopioid Agents
Although initial doses may be chosen by general guidelines, the

effective dose of opioid agents must be titrated to avoid relative
overdose.
Nonopioid agents are used to treat mild to moderate pain or as an

adjunct to opioid agents for more severe pain. All the nonopioid
agents have a ceiling effect and escalating the dose does not
provide more analgesia.99
Morphine
Morphine is the gold standard to which all other opioids are
compared. Increments of 0.05 mg/kg intravenously are given every
10 to 15 minutes until pain is controlled. The relief of tension,
anxiety, and pain usually results in drowsiness and sleep, which
mandate nurse surveillance in the PACU. Common side effects
include frequent nausea and vomiting, occasional pruritus
(especially around the nose), and urinary retention. The feared
respiratory depression occurs gradually, with warning signs
(sedation), and is treated with naloxone (12 g/kg intravenously).
Fentanyl
Fentanyl is usually injected during the operation, and its analgesic
effect may continue until arrival in the PACU. Intraoperative doses
vary according to the surgical procedure and usually 1 to 2 g/kg
intravenously can be injected every hour if necessary.
Sufentanil
Sufentanil can be used for outpatient anesthesia. It is 5 to 10 times
more potent than fentanyl. It must be diluted if used in small
pediatric patients.
Remifentanil
Remifentanil is such an ultrashort-acting analgesic agent that,
when used in the operating room, postoperative analgesia must
be started before awakening to prevent a painful and agitated early
emergence.
Meperidine
Meperidine use is still popular in North America mainly for
intramuscular injections during surgery or in the PACU as a last
resort when intravenous access is lost and oral medication is not
an option. The effective intravenous dose is 0.5 mg/kg every 10 to
15 minutes until pain is controlled or 1 mg/kg intramuscularly
every 3 hours.
Codeine
Codeine is commonly prescribed as oral analgesic (0.51.0 mg/kg
every 4 hours orally).
It is available in tablets or syrup, facilitating its administration
to small children usually in combination with acetaminophen. The
analgesic effect begins 20 minutes after ingestion.
Some literature has shown that codeine metabolism to morphine shows significant genetic variation.97 Some individuals are
poor metabolizers; little of the administered codeine will be
converted to morphine, resulting in poor analgesia. At the other
end of the spectrum, some individuals are extensive metabolizers;
increasing the conversion of codeine to morphine may result in
unexpected adverse effects.98 Therefore, even if codeine is widely
prescribed, it might not be the ideal agent.
Acetaminophen
Acetaminophen (paracetamol) is the most commonly used mild
analgesic in children. The usual oral dose is 10 to 15 mg/kg
prescribed every 4 hours (maximum 100 mg/kg/day100). It is effective in 40 to 60 minutes. The effective rectal dose is controversial
but ranges between 20 and 40 mg/kg.101 Propacetamol is an intravenous drug corresponding to a water-soluble precursor of
paracetamol with the same properties. One gram of propacetamol
is the equivalent of 500 mg of paracetamol.102 A dose of 30 mg/kg
intravenously has been shown to be effective.103 Its rapid injection
may lead to a temporary decrease of blood pressure and a slight
irritation at the site of injection.102
Non-Steroidal Anti-Inflammatory drugs

KETOROLAC: Ketorolac can be given intravenously, intramuscularly, or orally. It is as effective as morphine for mild and
moderate pain and is associated with less emesis.104 The loading
dose is 0.5 to 1.0 mg/kg intravenously, effective in 45 minutes. The
main disadvantage of ketorolac is its effect on platelet aggregation,
and it has been shown to increase bleeding after tonsillectomy
when the drug was administered before incision.105 It is also
contraindicated for patients with hepatic or renal failure.
IBUPROFEN: Ibuprofen at doses of 10 mg/kg every 6 hours (orally

or rectally) provides good analgesia and reduces the need for
opiates.106,107 Its anti-inflammatory property is useful in dental
surgery.
ACETYLSALICYLIC ACID: Acetylsalicylic acid has been abandoned in pediatrics because of its possible role in Reyes syndrome, its effect on platelet function, and its gastric irritant
properties.
Local and Regional Anesthesia

Regional anesthesia combined with general anesthesia decreases
the dose of the agent used for general anesthesia, allows a faster
emergence, and provides a pain-free recovery, early ambulation,
and discharge from hospital. The anesthesiologist can choose the
type of block and the drugs according to surgical procedure and
to her or his skill, but the technique should have minimal side
effects or interference with motor function.
Caudal Block
Caudal block is used in single shots for outpatients. It provides
analgesia for circumcision, hypospadias repair, herniorraphy,
orchiopexy, and some orthopedic procedures on the lower
extremities. Many anesthesiologists prefer to place the block
before the start of surgery in order to obtain both an adjunct to
general anesthesia and postoperative pain relief. It has been shown
that, for short-duration procedures, the timing of caudal block
does not affect the duration of analgesia.108 The time to micturition
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is a concern for ambulatory surgery because it can delay hospital

discharge. Some children can take longer than 8 hours to void after
a caudal injection of bupivacaine, but postoperative voiding is
neither a necessary nor a practical criterion for discharge from day
surgery.109 Bupivacaine 0.25% is used in children who are not yet
walking, but to avoid motor weakness in older children, bupivacaine 0.125% is used. Analgesia lasts 4 to 6 hours. Some information is available on the use of the newer local anesthetics for
caudal analgesia. When 0.2% ropivacaine, 0.25% levobupivacaine,
and 0.25% bupivacaine were compared, postoperative analgesia
was the same but there was a slight reduction in motor blockade
in the ropivacaine group.110112 The use of additives to caudal local
anesthetics has been extensively discussed. Although clonidine,
ketamine, and midazolam increase the duration of analgesia, their
routine use in outpatients is still controversial.113
Pain is a reality, a consequence of surgery more than a complication. It has a tremendous role in postoperative behavior in
children. Negative behavior related to pain affects half of the
patients on the day of surgery and, in 10%, can last up to 2 to
4 weeks longer than the duration of pain itself.121 Significant predictors of behavioral changes in children are age younger than 3 to
4 years, severe postoperative pain, persistent low-grade pain at
home, and previous bad experience of health care.121 Therefore,
emphasis must be placed on pain prevention. The use of opioids
or local anesthetics intraoperatively should provide analgesia in
the postoperative period and a regular administration (as opposed
to an as-needed regimen) schedule of oral analgesics should
prevent pain recurrence at home.
Penile Block
Nausea and Vomiting
Penile block is the ideal technique for circumcision and other

minor surgery of the penis. It may not be effective for hypospadias
repair if the surgery involves the base of the penis. Many techniques have been described, but the safest and most reliable is
the subpubic approach.114 Two injections are made below the
iliac branches of the pubic bone, 0.5 to 1 cm lateral to the midline
with a caudal traction of the penis. Use of a short-bevel needle
allows the anesthesiologist to clearly feel Scarpas fascia. After
piercing the fascia, 0.1 mL/kg of bupivacaine 0.25% to 0.5%
without epinephrine is injected on each side (maximum 5 mL
per side).
A review of 10,772 children undergoing day surgery found that

PONV was the fourth most common reason for unplanned
hospital admission following pain, surgical complications, and
surgery late in the day.124 The usual incidence is from 10 to 35%,
but it can reach 70 to 80% after surgical procedures such as strabismus125 or tonsillectomy.126
Anesthetic factors that have been shown to increase the risk
of PONV are the use of volatile agents, nitrous oxide, intra- and
postoperative use of opioids. Four independent risk factors were
identified in a pediatric population of 1257 children aged 0 to
14 years undergoing various types of surgery under general
anesthesia without antiemetic prophylaxis: duration of surgery
longer than 30 min, age older than 3 years, strabismus surgery,
and a positive history of PONV in the children or their close
relatives
Several antiemetic medications have been used with variable
efficacy. Ondansetron and other serotonin receptor antagonists
along with dexamethasone are the most reliable agents.127 Children
who are at moderate or high risk for POV should receive combination therapy with two or three prophylactic drugs from different
classes.128 Antiemetic doses for prophylaxis of vomiting are shown
in Table 554. When PONV occurs postoperatively, treatment
should be administered with an antiemetic from a pharmacologic
class different from the one initially given. If no prophylaxis was
given, the recommended treatment is a low-dose serotonin
antagonist. Propofol appears to decrease PONV best when it is
used during induction and maintenance, being more effective
when nitrous oxide is omitted.129 It is ineffective as an antiemetic
in subhypnotic doses in children.130 Because of the U.S. Food and
Drug Administration (FDA) blackbox warning for droperidol,
many are reluctant to use this drug (the dose is 1015 g/kg).
Ilioinguinal and Iliohypogastric Nerve Block

Ilioinguinal and iliohypogastric nerve block is commonly used for
herniorraphy or orchidopexy. It can be done by the surgeon under
direct vision of the nerve during the operation. In cases in which
the nerve is not visible, bupivacaine 0.25% (maximal dose
1 mL/kg) instillation in the wound is equally effective.115 Pain relief
is similar whether the nerve block is administered either by
the anesthesiologist using a percutaneous approach or by the
surgeon.116 It has also been shown that these nerve blocks are as
effective as caudal blocks for controlling postoperative pain.117,118
Upper and Lower Extremity Blocks

Blocks of the upper and lower extremity can be done under
ultrasound guidance or with the use of a nerve stimulator.
In experienced hands, these blocks are safe119 and offer ambulatory
patients excellent analgesia.
COMPLICATIONS
AND HOSPITALIZATION
Major problems are rare after ambulatory anesthesia in children.
Most complications are transient and managed before discharge:
somnolence, nausea and vomiting, fever, and respiratory incidents
(cough and stridor). At home, the complications, which tend to
last a few days, are pain, loss of appetite, and behavioral changes
(regressive daytime behavior, sleep disturbances, new-onset
enuresis).120122
Complications severe enough to require hospitalization have
an incidence of around 1 to 2%,123,124
Pain
TABLE 55-4. Antiemetic Doses for Prophylaxis of

Postoperative Vomiting in Children
Drug
Dose
Dexamethasone
Dimenhydrinate
Granisetron
Odansetron
Perphenazine
150 g/kg
0.5 mg/kg
40 g/kg
50100 g/kg
70 g/kg
From reference 128.
Maximum
5 mg
25 mg
0.6 mg
4 mg
5 mg
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Allowing instead of requiring children to drink clear liquids

before discharge decreases the incidence of vomiting.131
Croup
The incidence of postintubation croup in children is around 1%,94
but the incidence of severe croup necessitating hospitalization is
12 times lower at 0.08%.123 The most common cause is a tightfitting tube without an air leak at 30 to 40 cmH2O.
Croup usually begins immediately after extubation, and always
within 3 hours, which is the mandatory observation period after
extubation. Most cases are mild and need only humidified oxygen
for a short period. For more severe cases, racemic epinephrine
2.25% (0.5 mL diluted in saline 4.5 mL) or epinephrine 1:1000
5 mL132 is administered via a facemask. The effect lasts for 1 hour,
and the child should be observed 4 hours after treatment.3 Those
who are symptomatic at rest or need repeated doses of epinephrine
are the most severe cases and should be hospitalized. Less severe
cases are allowed to go home with appropriate parental counseling
(observation, humidified air, and avoidance of irritants).
DISCHARGE INSTRUCTIONS
At the end of the procedure, patients go first to the PACU and,
after initial recovery to the short-stay unit (SSU). With the use of
the new agents and different techniques, patients can bypass the
PACU to go directly to the SSU where they are cared for by the
nurse and the parents, allowing a reduced nurse-to-patient ratio.
There is no mandatory stay length in the SSU except for certain
conditions: depressant medication administration (90 min),
inhaled epinephrine (4 h), tracheal intubation (3 h), and adenotonsillectomy (4 h).
To be discharged home, patients must fulfill specific criteria
to avoid the need of further medical treatments, but drinking131
or voiding109 is not mandatory.
When the child is ready to leave, he or she should be accompanied by a responsible adult who is not the driver of the car.133
Parents must be given written instructions about home care,
the operation, and its sequel in the following days; the care of the
incision or operative site; the diet and level of physical activity
allowed; and a prescription for analgesic medication. Also included is the telephone number of a responsible person from the
outpatient facility or those of the surgeon and the anesthesiologist
as well as instructions concerning follow-up visits.
EVALUATION OF PATIENT
AND FAMILY SATISFACTION
Every outpatient unit must have several mechanisms to evaluate its
performance and the satisfaction of its patients.
To assess efficiency, there must be an ongoing evaluation of all
cancellations because they are counterproductive, annoying to
parents, and stressful to patients. A retrospective study showed a
global cancellation rate of 7.7% including 4.5% after arrival at the
hospital.133 Hospitalization rate should also be monitored because
it represents a measure of outcome, a control of quality, and a
reflection of inadequate preoperative evaluation. All patients (or
parents) should be contacted by telephone the day after surgery
to evaluate satisfaction and to detect problems.
Because major complications after ambulatory surgery are

uncommon, statistically useful studies to assess outcome are very
difficult and should be replaced by studies about minor morbidity.
Although these studies are scarce, they show that pain and PONV
are experienced by a large number of patients and are still undertreated.121
FUTURE TRENDS
Outpatient surgery is safe, economical, and highly desired by
patients and their parents. Boundaries concerning medical conditions and types and duration of operations are being pushed a little
more everyday. New agents/techniques will allow for improved
operating conditions and a faster pain-free recovery and discharge
as long as analgesia is established before awakening. Doctors must
prescribe an effective schedule for pain relief medication and incite
the parents to follow it. Our future challenge is to reduce the minor
morbidity.
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ditions Pradel; 1993. pp 533
115. Casey WF, Rice LJ, Hannallah RS, et al. A comparison between
bupivacaine instillation versus ilioinguinal/iliohypogastric nerve block
for postoperative analgesia following inguinal herniorraphy in children.
116. Trotter C, Martin P, Youngson G, et al. A comparison between
ilioinguinal-iliohypogastric nerve block performed by anaesthetist or
surgeon for postoperative analgesia following groin surgery in children.
117. Hannallah RS, Broadman LM, Belman AB, et al. Comparison of caudal
and ilioinguinal/iliohypogastric nerve blocks for control of postorchiopexy pain in pediatric ambulatory surgery. Anesthesiology. 1987;
66:832834.
118. Splinter W, Roberts DJ. Prophylaxis for vomiting by children after
tonsillectomy: dexamethasone versus perphenazine. Anesth Analg.
1997;85:534537.
119. Giaufre E, Dalens B, Gombert A.: Epidemiology and morbidity of
regional anesthesia in children: a one-year prospective survey of the
French-Language Society of Pediatric Anesthesiologists. Anesth Analg.
1996;83:904912.
120. Kotiniemi LH, Ryhnen PT, Valanne J, et al. Postoperative symptoms at
home following day-case surgery in children: a multicentre survey of
551 children. Anaesthesia. 1997;52:963969.
121. Kotiniemi LH, Ryhnin PT, Moilanen IK. Behavioural changes in
children following day-case surgery: a 4-week follow-up of 551 children.
Anaesthesia. 1997;52:970976.
122. McGraw T, Kendrick A. Oral midazolam premedication and postoperative behaviour in children. Paediatr Anaesth. 1998;8:117121.
123. Patel RI, Hannallah RS. Anesthetic complications following pediatric
ambulatory surgery: a 3-yr study. Anesthesiology. 1988;69:10091012.
124. Awad IT, Moore M, Rushe C, et al. Unplanned hospital admissions
in children undergoing day-case surgery. Eur J Anaesthesiol. 2004;21:
379383.
125. Abramowitz MD, Oh TH, Epstein BS, et al. The antiemetic effect of
droperidol following outpatient strabismus surgery in children.
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126. Litman RS, Wu CL, Quinlivan KJ. Gastric volume and pH in infants
fed clear liquids and breast milk prior to surgery. Anesth Analg. 1994;79:
482485.
127. Splinter WM, Roberts DJ. Dexamethasone decreases vomiting by
children after tonsillectomy. Anesth Analg. 1996;83:913916.
128. Gan TJ, Meyer TA, Apfel CC, et al. Society for Ambulatory Anesthesia
guidelines for the management of postoperative nausea and vomiting.
Anesth Analg. 2007;105:16151628.
129. Watcha MF, Simeon RM, White PM, et al. Effect of propofol on the
incidence of postoperative vomiting after strabismus surgery in pediatric
outpatients. Anesthesiology. 1991; 75:204209.
130. Zestos MM, Carr AS, McAuliffe G, et al. Subhypnotic propofol does not
treat postoperative vomiting in children after adenotonsillectomy. Can
J Anaesth. 1997;44:401404.
131. Schreiner MS, Nicolson SC, Martin T, et al. Should children drink before
discharge from day surgery? Anesthesiology. 1992;76:528533.
132. Waisman Y, Klein BL, Boenning DA, et al. Prospective randomized
double-blind study comparing L-epinephrine and racemic epinephrine
aerosols in the treatment of laryngotracheitis (croup). Pediatrics.
1992;89:302306.
133. Johnson GG. Day care surgery for infants and children. Can Anaesth Soc
J. 1983;30:553557.
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Sedation and Anesthesia

for Procedures Outside
Operating Theaters
Jonathan H. Smith, Kar-Binh Ong, and Michael R. J. Sury
INTRODUCTION
Caring for children outside operating theaters has become a
fast-growing concern of anesthetists. Many children need minor
procedures rather than surgery and, if these are painful or frightening, particularly if they have to be repeated, the suffering that
they can cause is an appreciable problem that clinicians are finding
difficult to manage. Nevertheless, tools and services are available
to help. Although it is true that anesthesiologists have the expertise
to use potent short-acting drugs, this is not enough to solve the
problem because it is not always appropriate or applicable. Pediatricians and nurses need both advice and practical help to provide
a comprehensive service that brings together all the methods,
pharmacologic and behavioral, to reduce distress.
Behavioral methods of calming children could, indeed, be
the major growth area for pediatric anesthesia, not as scientific
advance, but rather application of principles that are not new but
are largely not taught in a specific sense nor used. Applying simple
psychological tools could allow the more logical management
of distressed children. The prevention and amelioration of fear
should be part of any pediatric syllabus. To that aim, this chapter
addresses the subject beyond the narrow confines of anesthesia
drugs. Sedation during intensive care is not discussed and neither
is the sedation management of children with psychiatric problems.
The chapter has two sections: general issues and specific sites
outside theaters.
GENERAL ISSUES
Scope and Demand
In major pediatric hospitals, many anesthetic procedures takes
place outside operating theaters, perhaps as much as 30% of the
total number. If the number of sedations is added to this estimate,
the importance of the subject, if only in numerical terms, becomes
more striking. Further, there will be children who deserve sedation
or anesthesia who, for practical and regrettable reasons, may not
receive it.
The specialties that have increased their demand since about
2000 include
Painless imaging.
Insertion of long-term venous access.
Intrathecal chemotherapy.
Gastroenterologic endoscopy.
Cardiac angiography.
Considerable expansion in each of these has caused strategic

changes as well as specific developments in pharmacologic techniques. Two other areas deserve prominence. Dental care in uncooperative children is well known to be difficult, and more recently,
the demand for sedation and analgesia for minor injuries within
emergency departments has also increased.
Children are unlikely to cooperate with procedures that cause
distress from fear or pain. Cooperation not only is unlikely because
of age but also is further reduced by illness, hunger, thirst, and
pain. It is likely to be even more difficult in children with underlying behavioral problems such as attention deficit disorder, autism,
learning difficulties, and congenital problems such as Down syndrome. Many children requiring imaging are in these categories.
Anesthesia is a crucial component in the portfolio of techniques necessary for these services. Nevertheless, anesthesia
resources are limited and special planning will be required to
maximize their efficient use. Fortunately, anesthesia is not always
necessary.
Appropriateness
Restraint of children is a taboo subject. In the United Kingdom,
the Royal College of Nursing has published guidelines that specify
how and when children can be protected.1 Gentle cuddling of
children to prevent them moving may be appropriate, but the use
of strapping, such as a papoose board, is no longer acceptable.
Given that restraint is not an option, techniques should be suited
to both the procedure and the child. For example, usually a simple
intravenous cannula can be inserted with a combination of local
anesthesia and distraction, whereas complex cardiac angiography
in a sick child needs monitored controlled ventilation and conventional anesthesia.
Table 561 shows the range of management techniques available; their appropriateness will depend upon several factors
including the degree of discomfort, the longevity of the procedure,
and the ability of the child to cooperate.
Behavioral Techniques
Many procedures can be managed by behavioral methods alone.
Play specialists are particularly adept at calming children and, in
some instances, remove the need for any sedation or anesthesia.2
Psychologists can also contribute with hypnotic techniques that
can be useful in verbal children.3,4 The importance of both of these
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Sedation and Anesthesia for Procedures Outside Operating Theaters
TABLE 56-1. Techniques

These techniques should be available for procedures
(the appropriate use of local anesthesia is assumed):
Behavioral techniques
Systemic analgesia
Anxiolysis
Conscious sedation
Deep sedation
Dissociative sedation
Minimal anesthesia
Conventional anesthesia
Intensive care
professional groups should not be underestimated. Standard
techniques such as play, distraction, and guided imagery are valuable, and hypnosis is potentially useful even in small children.5
Behavioral methods are helpful only with active participation of
the child and are not meant to trick the child into false expectations; they enable the development of coping strategies and work
best in combination with brief informational preparation. Nevertheless, distraction can be applied to even small children who may
be content to avoid thinking about, or giving attention to, the
unpleasant procedure they are about to undergo. Toys, games, and
books are useful in the early phase of calming children and, if they
are helpful, their positive effect can be reinforced to either reduce
or remove the need for pharmacologic intervention. In general,
although this is difficult to prove, children who cope without the
need for drugs are happier.6
Behavioral techniques are time-consuming yet, if they are
successful, the investment is surely invaluable for children with
chronic illnesses or for those who may need to return for further
procedures. Many hospitals do not have play specialists because
of the perception that they are not cost-effective and that nursing
skills are adequate. Whereas experienced nurses maybe equally
skilled, play specialists release nurses for more appropriate tasks.
The calming effect of a respected play specialist on a busy ward
full of stressed children, parents, and nurses can be impressive.
Anesthesiologists should work with play specialists, and both
should assess the value and limitations of behavioral methods for
a planned procedure. Play specialists can ease the stress before
introducing sedation or anesthesia, and therefore, close communication with anesthesia services is ideal.
Hypnosis is potentially useful for older children.7 Indeed, distraction and calming techniques used in young children have a
principle in common with hypnosis. Both involve the concentration of the child being moved from the cause of distress to a
subject of pleasure. The methods by which this is achieved vary
but all need the childs cooperation, not necessarily explicit, to take
part in what could be described as a fantasy. In some fortunate
children, their imagination and powers of concentration are
extremely effective and can be harnessed to prevent them thinking
about and experiencing the distress of a procedure.
Anesthesia Versus Sedation

Several differences are important. The crucial difference is not
related to the drugs, but to the expertise of the user. An anesthesiologist can choose the drug and use it to its best advantage,
whereas untrained practitioners must avoid drugs that are likely to
cause airway and breathing side effects. Sedation drugs, therefore,
887
have to be safe enough for untrained (or insufficiently trained)

practitioners. Sedation drugs tend to be weak or impotent, slowacting, long-lasting, and unreliable (depending, of course, upon
the procedure intended). By contrast, anesthesiologists can choose
anesthesia drugs because these are potent, short-acting, fast-onset
and offset, and always succeed. An anesthesiologist should be
able to manage all the acute predictable effects of the drugs on the
airway, the breathing, and the circulation. In addition, subanesthetic doses of anesthesia drugs can be used initially and increased
if necessary.
There is a perception among anesthesia professionals that
sedation is less safe because nonanesthesiologists may not be able
to manage airway obstruction or apnea. However, the public and
nonanesthesiologists tend to believe that sedation is a safer option
because they wish to avoid the need for airway and breathing
support. There are little data to support either view, and it is likely
that safety depends upon several factors including the procedure,
the drugs, the practitioner, and the patient group. For example,
sedation in elderly patients having gastrointestinal endoscopy has
a reputation for mortality, but it is unreasonable to believe that
sedation of children for painless imaging is similar.
The availability of personnel is influential. Even in many firstworld hospitals, there are insufficient anesthesiologists to provide
a comprehensive service for all procedures, and it follows that
others must deliver sedation and they need training to use safe
and effective protocols.8,9
Definitions
Standard definitions8,1012 (Table 562) are useful but, unfortunately, are imperfect in common scenarios. These and other
controversial definitions are discussed under Definitions.
Conscious or Moderate Sedation

Conscious sedation is a safe and useful concept for cooperative
adults but not for most children, especially if they are sick. In an
uncooperative child, sedation rarely changes a no to a yes. It is
generally accepted that true conscious sedation is unlikely in
most clinical scenarios, but there are exceptions. The ability of a
child to rouse depends to some extent upon the stimulus applied.
Whenever spoken word is inappropriate, such as in infants or
nonverbal children, a nonpainful stimulus is useful. Nevertheless,
rousing the child makes the procedure more difficult. The term
moderate sedation is preferred in the current literature because it
does not assume consciousness but rather that the patient is easily
rousedusually by communication but also by other similar appropriate light stimulus.13 Nevertheless, conscious sedation remains
a common term.14,15
Deep Sedation
In the 1990s, deep sedation was generally considered as being a
sleep state from which a patient was not easily roused. In the
United Kingdom, it was not an accepted term because the state was
considered to have the same potential for hypoxia as anesthesia.
In the United States, a state of deep sedation was accepted and
defined as a state from which the patient is not easily roused but
that it may be accompanied by a partial or complete loss of
protective reflexes and includes the inability to maintain a patent
airway independently. There were adverse events, and so the U.S.
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TABLE 56-2. Standard Definitions

These are standard definitions used by American Society of Anesthesiologists10 and the Scottish Intercollegiate Guidelines Network.8
Minimal sedation (anxiolysis) is a drug-induced state during which patients respond normally to verbal commands. Although
cognitive function and coordination may be impaired, ventilatory and cardiovascular functions are unaffected.
Moderate sedation/analgesia (conscious sedation) is a drug-induced depression of consciousness during which patients respond
purposefully to verbal commands, either alone or accompanied by light tactile stimulation (reflex withdrawal from a painful
stimulus is not a purposeful response). No interventions are required to maintain a patent airway, and spontaneous ventilation is
adequate. Cardiovascular function is usually maintained.
Deep sedation/analgesia is a drug-induced depression of consciousness during which patients cannot be easily roused but respond
purposefully following repeated or painful stimulation. The ability to maintain ventilatory function independently may be
impaired. Patients may require assistance in maintaining a patent airway, and spontaneous ventilation may be inadequate.
Cardiovascular function is usually maintained. In the United Kingdom, deep sedation is considered to be part of the spectrum of
general anesthesia.
General anesthesia is a drug-induced loss of consciousness during which patients are not rousable, even by painful stimulation.
The ability to independently maintain ventilatory function is often impaired. Patients often require assistance in maintaining a
patent airway, and positive-pressure ventilation may be required because of depressed spontaneous ventilation or drug-induced
depression of neuromuscular function. Cardiovascular function may be impaired
insurance companies forced hospitals to ensure that deep sedation was managed to the same standards as for anesthesia. Thus,
standards of care have become similar in the United Kingdom
and the United States, yet there is a difference in the personnel.
In the United Kingdom, only anesthesiologists can use techniques
deeper than conscious sedation, whereas this is not so in the
United States.
Now, deep sedation is an accepted term across the globe, but
there are still difficulties or circumstances in which the term does
not fully describe the sedation. It may be unreasonable to use a
term that tries to describe sedation under one headingif that is
true, and there are different types of sedation that are deeper than
minimal sedation, then the following definitions may be useful.
In any event, they describe the sedation state related to the
drug technique rather than compliance to an overall concept of
deep sedation.
Sleep Sedation
Children do not lie still for painless imaging unless they are asleep.
Although it is true that it should be possible to rouse the sleeping
child if necessary, trying to prove this during the procedure itself
is counterproductive. Nevertheless, whatever the depth, sleep must
be safe. A working definition of sedation that is deep enough to
cause sleep is a technique in a state of depression of the nervous
system such that the patient is not easily roused but which has a
safety margin wide enough to render the loss of airway and breathing reflexes unlikely.11,16 This could be called sleep sedation
because the depth is uncertain unless the child is tested with
a stimulus.
Minimal Anesthesia
Low-doses of potent short-acting anesthetics can cause sleep that
is unlikely to have appreciable airway effects and from which
recovery is rapid. In many articles, authors have called these techniques deep sedation, but this is unsatisfactory because unintended
anesthesia is likely, albeit briefly, in a proportion of children.
Nevertheless, this is different from conventional anesthesia that
needs airway support. The term light anaesthesia17 could be used
but, as for sleep sedation, once the child is asleep, it is unhelpful
to test his or herr conscious level. Techniques are described,
and are now commonplace, that begin with a brief anesthetic

followed by a sleep maintained by low doses from which the child
may be easily roused. These techniques could be called minimal
anaesthesia.18
Dissociative Sedation
Ketamine provides a unique unconscious state, and it is argued
that a separate definition is justified. In low doses, ketamine causes
trancelike dissociation in which the eyes may be open, vital
reflexes are present, and there is sufficient analgesia to manage
minor painful procedures. It causes amnesia. Surgery can be managed under higher doses that may still preserve protective airway
reflexes, spontaneous breathing, and cardiovascular stability.
It is argued that ketamine has a margin of safety so wide that nonanesthesiologists can use it, provided they have the necessary
training.19
Assessment and Monitoring

of Consciousness
Observational Scales
The concept of consciousness is illusive, and several observational
scales have been developed to describe it. In order for a scale (or
tool) to be practical, the number of levels within a scale should be
limited so that the observer can make repeated and frequent
scores. Scales with 5 or 6 are popular but the descriptors may not
be adequate for all situations and, therefore, validity and reliability
may be poor. This is a recognized difference between the detailed
scales used by psychologists and the practical scales of clinical
medicine. There are many clinical scales and, as a rule, each was
designed for a different scenario. Two widely used validated scales
are the Observers Assessment of Alertness/Sedation20 and the
University of Michigan Sedation21 scales, but only the latter was
developed for children and specifically for painless imaging. For
painful procedures, scales vary from a modified Ramsay scale that
has eight levels22 to much more complicated and time-consuming
scales that are useful in psychological research.23,24 Examples of
sedation scales used in other scenarios are the COMFORT25 in
intensive care and the modified Glasgow Coma Scale26 in children
with coma.
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889
Within a scale, there are two descriptors of any level: the

stimulus used to challenge consciousness and the response
achieved by that stimulus. It is obvious that the stimulus is crucial
and that the depth of consciousness results from a balance between the arousal stimulus and the sedation. Moreover, in the
absence of stimulation, sedation can become too deep.
Sedation drugs often have a long and unpredictable recovery
profile, and it is important to decide when it is safe for close
observation to end. This will depend upon the drugs used, but it
is wise, for most drugs, to wait both for at least 2 hours and until
the child is increasingly active. A test of sleepiness has been
proposed whereby the childs ability to remain awake is tested by
observing her or him in a quiet, darkened room.27 The length of
time chosen will depend upon the situationfor example, in
infants recovering from chloral hydrate, if they can stay awake
for 20 minutes, they are highly likely to meet all other discharge criteria.
Monitors of Consciousness
Monitors of consciousness may be categorized as either indirect or
direct. Indirect monitors include pulse oximetry and capnography
that indicate respiratory depression associated with sedation. Pulse
oximetry is mandatory for all sedated and anesthetized children.
Capnography is extremely useful,28 and a good waveform can
be obtained if a soft catheter is placed in a nostril. Current
capnographs have a low aspiration rate through narrow tubing so
that more accurate and sensitive estimations are possible. Simple
butterfly tubing is soft enough for the nose (Figure 561), but
purpose-made tubing systems are available that combine both the
delivery of oxygen and the aspiration of tidal gas29 (Figure 562).
Electrocardiography (ECG) and noninvasive blood pressure
should be applied if possible.
Heart rate variability (HRV) is related to autonomic activity
and is a potential monitor of anesthetic depth (in adults). It encompasses several mathematical expressions of the variation of
the time difference between successive ECG R-waves. If a steadystate respiratory rate sequence is analyzed over as little as
20 seconds, underlying autonomic rhythms can be quantified, but
Figure 56-2. Capnoline tubing on a babys face. These nasal

cannulae incorporate two separate tubes. One delivers oxygen
to the upper lip through perforations and the other is used for
capnography.
as yet, the technique is currently only a research tool.30,31 It is likely
that the mechanical effect of breathing has a greater effect on HRV
than conscious level and will obscure the signal caused by the
autonomic control of heart rate from the brainstem. Moreover, the
evidence for the mechanisms of HRV control by the autonomic
nervous system is poor.
Direct measurement of brain function using processed
electroencephalography (EEG) or auditory evoked potentials
(AEPs) is of limited value because of both theoretical and practical
limitations. Processed EEG such as bispectral index (BIS) or
entropy change in natural sleep as well as sedation, and neither
have been adequately validated in small children. With experience,
monitors such as BIS may assist in monitoring consciousness level
in some techniques22,3234 including propofol35 but do not seem to
help with sevoflurane36 or ketamine.
None of these monitors should predict, with certainty, whether
or not an individual will move in response to a physical stimulus
because movement is caused by activity of the spinal cord and does
not necessarily involve higher cerebral centers of consciousness.37
Recommendations
Figure 56-1. Butterfly tubing used for capnography. The needle is

discarded and the remaining soft tubing is suitable for insertion
into the nose
In 1992, the Royal Colleges recommended two principles of

safety: (1) if a patient is unable to respond to a verbal command,
then he or she should be managed by an anesthetist and (2) that
techniques by nonanesthesiologists should carry a margin of
safety wide enough to render unintended loss of consciousness
unlikely.14 Meanwhile, the United States accepted the concept of
deep sedation but now, in effect, the safety standards are similar
because it requires the same standards of care as for anesthesia.38
In the United States, the Joint Commission have produced guidance on sedation and anesthesia that matches the output from
both the Academy of Pediatrics and the American Society of
Anesthesiologists (ASA).
In the United Kingdom, in 2002, the Scottish Intercollegiate
Guidelines Network published a clinical guideline, and its updated
2004 version is available on the Internet. It contained most of
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the available evidence but was mainly a statement of opinion

and, as such, was a guideline. A new guideline is currently being
developed by the National Institute of Clinical Excellence and
Health (NICE) that aims to bring together the evidence to support
effective and safe practice across all specialties and services that
need to sedate children.
Sedation of children for dental procedures has long been a
problem. In the United Kingdom, there are guidelines (published
by SIGN is a publishing company, the British Society of Paediatric
Dentistry, and the Department of Health) to advise that any
sedation in children younger than 16 years, other than nitrous
oxide alone, should be undertaken only in a hospital setting.39
Nevertheless, there is a continuing demand for alternative sedation
techniques that combine potent drugs in subanesthetic doses.40
These have been termed alternative conscious sedation techniques,
but it remains to be seen whether there is serious risk of accidental
anesthesia. The details of one tragic case has been already been
published.41
In 2001, the Academy of Medical Colleges responded to reports
of unacceptable mortality in adult patients having esophagogastroscopy.9 In summary, they are
Safe sedation techniques should be defined for each specialty.

Organizations should ensure that staff receive sedation training.
Hospitals should appoint two lead consultants (an anesthetist
and a nonanesthetist) to lead and support sedation services.
Such an approach seems sensible and could apply to pediatric

practice.
Sedation Protocols for Nonanesthesiologists

In a report of 95 sedation disasters, in which there were 51 deaths
and 9 cases of permanent neurologic damage, the most common
avoidable factors were an obvious failure to apply basic standards
of monitoring and airway management.42 It is hoped that, if
sedationists conform to a protocol, this would help to prevent
mistakes and accidents and to prepare for known complications.
In a review of over 30,000 sedation records from centers conforming to safety standards, rates (per 10,000) of other complications
were as follows: unexpected apnea,24 stridor, or laryngospasm 4.3,
and significant desaturation 157. Because there were no deaths
and only 1 child required cardiopulmonary resuscitation, this is
evidence to suggest that expected complications can be managed
successfully by nonanesthetists.43
Principles of Safety and Success

The principles of safety and success in sedation are in conflict. For
example, a low dose will be safer than a high dose but will not be
as successful. Likewise, a hungry child will not sleep easily but a
recent meal increases the risk of aspiration. Table 563 itemizes some
principles for the design of protocols for nonanesthesiologists. The
most important factors for both safety and success are the judgment
and the skill of the staff. With the exception of nitrous oxide sedation
(see Dentistry/sedation), all sedated and anesthetized patients must
be monitored with pulse oximetry (at least) and have someone
assigned to give undivided care. That person must be trained for
all common eventualities and make a contemporaneous record of
her or his observations. Suitable assistance must be available to help
prevent or manage complications. Full resuscitation expertise
must be available within the hospital or unit.
TABLE 56-3. Principles for Design of Safe and Successful

Sedation Protocols
Success
Experienced staff
Minimize the distress of the procedure
Selection of children
Choose effective drugs/techniques
Quiet and child-friendly environment
Safety
Experienced staff
Enforce contraindications to sedation
Safe drugsdo not exceed maximum doses
Recovery and discharge criteria
Good facilities and equipment
Patient Assessment and Common

Contraindications to Sedation
The most important safety factor in any protocol is the assessment of fitness for sedation. Many children have contraindications to conventional sedation techniques and should be
managed by an anesthetist instead. Table 564 presents contraindications published by SIGN, and Table 565 is a more
detailed list appropriate for painless imaging and used by the
authors.
Fasting
Children should be fasted for any sedation technique in which
pulmonary aspiration is possible (Table 566). In emergency
departments, these fasting rules may not be appropriate either
because stomach emptying cannot be relied upon or the procedure
is too urgent. It is unreasonable to delay sedation (or anesthesia)
in some circumstances and the emergency medicine specialists
have developed guidance for minimizing risk. In their view, the
risk of using effective sedation and analgesia in unfasted children
may be justified.44
TABLE 56-4. SIGN Contraindications to Sedation
in Children
Children with any of these contraindications should not
normally be sedated:
Abnormal airway
Raised intracranial pressure
Depressed level consciousness
History of sleep apnea
Respiratory failure
Cardiac failure
Neuromuscular disease
Bowel obstruction
Active respiratory tract infection
Known allergy or adverse reaction to sedative
Child too distressed despite adequate preparation
Older child with severe behavioral problems
Consent refusal by parent or patient
From reference 8.
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TABLE 56-5. Common Contraindications to Sedation

for Painless Imaging
TABLE 56-6. Appropriate Intake of Food and Liquids

Before Elective Sedation
Airway Problems
Any actual or potential airway obstruction (e.g., snoring or
stridor, blocked nose, small mandible, large tongue).
NB: Both the amount and the type of foods ingested must be
considered when determining an appropriate fasting period.
Apneic Spells
Related to brain damage or previous drug treatment.
Ingested Material
Respiratory Disease
SpO < 94% in air.
2
Respiratory failure (high respiratory rate, oxygen treatment).
Inability to cough or cry.
High Intracranial Pressure
Drowsiness.
Headache.
Vomiting.
Epilepsy
Generalized convulsions requiring rectal diazepam within the
last 24 h OR rectal diazepam used more frequently than once
in 2 weeks.
Previous adverse reaction to sedation (i.e., exacerbation of
seizures).
Children requiring resuscitation during a convulsion within
the last month.
Children who not only have convulsions but also have other
major neurologic or neuromuscular disease: such as apneic
spells or hypotonia as part of global neurologic disease; intracranial hypertension owing to cerebral tumor or encephalitis.
Generalized convulsions with cyanosis more frequent than
once per day.
Children who have had a convulsion < 4 h before sedation.
Failure to regain full consciousness and mobility after a recent
convulsion.
Risk of Pulmonary Aspiration of Gastric Contents

Abdominal distention.
Appreciable volumes draining from nasogastric tube.
Vomiting.
Severe Metabolic, Liver, or Renal Disease

Requiring intravenous fluids or dextrose.
Jaundice or abdominal distention.
Requiring peritoneal or hemodialysis.
SpO2 = oxygen saturation of hemoglobin monitored with pulse oximetry.

From reference 16.
Painful Versus Painless Procedures

Sedation for painful procedures is much more difficult than for
painless scans, and it is reasonable to separate sedation management into these two groups. Painful procedures in uncooperative
children are ideally managed by anesthesiologists who can use
potent short-acting drugs. By contrast, the majority of children
will keep still for painless imaging with behavioral or sedation
techniques and, only if this fails or if the child is not fit for
sedation, is anesthesia essential.
Sedation Failure
Standard doses may not be effective in some children, and if
doses are increased, there should be a limit to prevent accidental
891
Clear liquids: water, fruit juices without

pulp, carbonated beverages, clear tea,
black coffee.
Breast milk.
Infant formula.
Nonhuman milk: because nonhuman
milk is similar to solids in gastricemptying time.
Light meal: a light meal typically consists
of toast and clear liquids. Meals that
include fried or fatty foods or meat may
prolong gastric-emptying time.
Minimum
Fasting Period, h
2
4
6
6
6
www.asahq.org/publicationsAndServices/NPO.pdf
anesthesia. Consequently it is wise to accept a failure rate and

to delay the procedure and to try again with either a different
technique or anesthesia. There was a rule in the past that the
combination of sedation and anesthesia was potentially dangerous because of prolonged unconsciousness. This is almost certainly not true for modern short-acting agents such as propofol
or sevoflurane. In many situations, the child needs the procedure
and cannot wait for the following day. Sedationists may need
to call for anesthesia assistance early rather than use high doses of
sedation that remains ineffective and could, in combination with
anesthesia, delay recovery.
Resources
Training
People are the most important resource and they should be
deployed within a team. It is common for practitioners to focus
on the what or how of sedation but it is the who that is most
important. The management of children for stressful procedures should be included in training syllabuses. Some organizations have recommended training but have not specified what
is to be taught; emergency department physicians in the United
States45 and dentists in the United Kingdom15 are among the first
to lead the way forward in training and credentialing. There
are courses or conferences on sedation, but they tend to focus
on knowledge rather than practical skills. Practical airway skills
and management of unconscious children are reliably taught
in the operating theater but, if this is not possible, resuscitation
courses remain the only useful source of teaching relevant skills.
Simulation is a tool that could be developed but is limited to the
management of complications rather than technique. Three
scenarios could be practiced: airway obstruction, anaphylaxis, and
cardiac arrest.
Courses that teach how to assess a sick child are also important.
Qualification and registration also need to be considered. One
potential route to progress is through individual specialties
applying safe standards of care by credentialing their members
and/or their service departments. It will be a challenge for the
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anesthesia profession to help other specialties to deliver a safe and

effective service.
Experienced nurses with a background of anesthesia, intensive
care, or accident and emergency can be formed into teams. They
can be taught locally by tutorials in resuscitation and practice in
airway and intravenous skills on anesthetized children. Skills will
need to be revalidated regularly. The most crucial aspect of safety
is teamwork.16,4648
TABLE 56-7. Anesthesia Considerations in Magnetic

Resonance Imaging
Remote Location of MRI Scanner
Help is not immediately available.
Is there adequate space for conduct of anesthesia?
Are there adequate recovery facilities?
Lack of Access to Patient
Ability for rapid removal of patient from scanner in an
emergency.
Remote monitoring of patient is essential.
Equipment and Facilities

The equipment and monitoring should be equal to that used for
anesthesia except for the presence of an anesthesia machinethis
may be necessary to manage failed sedation. The facilities will vary
according to the procedure. Painless imaging requires a quiet area
to induce sleep and it is best sited close to the scanner to minimize
disturbing the child during transfer. In other situations, sedation
is undertaken in the procedure room itself and will need sufficient
space for staff involved. A recovery area, of suitable size, needs
qualified staff and should not be isolated. Some centers have
developed mobile services for the wards49 and others utilize
intensive care units.50
Distressing procedures should be undertaken in a procedure
room and not in the bed area so that the child can be comforted
by returning to his or her own space (i.e., their place of safety).
Economics
For painless imaging, there is no doubt that anesthesia is faster
than sedation and, therefore, more efficient. In terms of cost per
session, anesthesia is probably cheaper per patient but only if a
comparison is made with similar patients. The cost is related to
personnel (equipment should be similar and drugs costs are small
by comparison), and anesthesia is cheaper only if the patient
throughput is efficient.
Yet, either anesthesia resources may not be available or the
procedures themselves may not justify the expense. In many
situations, the need for anesthesia can be minimized by offering
behavioral and sedation techniques to suitable children. Assessment of children several days before the procedure allows planning and preparation.
SPECIFIC SITES OUTSIDE THEATERS

RadiologyPainless Imaging
There is a heavy demand for painless diagnostic imaging
techniques and the main problem is the requirement for the
child to be sufficiently immobile for long enough.18 Some children
will lie still with encouragement and practice or with behavioral
techniques2 but many will need sedation or anesthesia. Many short
investigations can be successfully completed under sedation.
However, if the procedure is lengthy ot requires special positioning
of the child (e.g., arms up) or physiologic interventions such as
breath-holds, an anesthetic is more appropriate. Anesthesia is
also usually safer if the child is ASA status 3 or 4.51
Special Considerations for

Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) scanners are often situated
in remote locations away from the main operating rooms,
Strong Magnetic Field Continuously Present

Only MR-safe or MRcompatible equipment is allowed in
the scanner.
Monitoring equipment should be MR-compatible. Artifacts
from the magnet may be significant.
Anesthetic machines, vaporizers, and gas cylinders should be
compatible.
Personnel
A nominated consultant anesthetist should be responsible.
Before entering the scanner room, all staff must be screened
and informed of local protocols.
There should be a clear protocol that defines the actions that
should be taken in the event of a clinical emergency.
MR = magnetic resonance; MRI = magnetic resonance imaging.
so help may not be immediately available. Most scanners are

built as a long narrow tunnel and are very noisy during scanning.
This design can cause claustrophobia and restricts access to the
patient. MRI scanners have a strong magnetic field and apply
radiofrequency pulses. In response, tissue atoms change alignment
and emit radiofrequency waves that are processed into images
by a computer. The normal magnetic field at the surface of the
earth is 0.5 to 1.0 Gauss (G), and common MRI scanners produce a magnetic field that vary in strength from 0.5 to 3.0 Tesla
(T; 1 T = 10,000 G). Equipment within the scanning room
should, therefore, be either MR-safe (does not pose a safety
hazard to patients or personnel but may not function normally
and may interfere with the scan) or MR-compatible (functions
normally and does not interfere with the scanning equipment;
it may not be safe, however).52 Failure to check equipment can lead
to objects being pulled into the scanners core and injury to
the patient or staff.53,54 There are several problems to consider
before performing sedation or anesthesia; these are summarized
in Table 567.
INTRAVENOUS CONTRAST: Gadolinium is the MR contrast and

rarely causes anaphylaxis. It is contraindicated in children with
renal failure.
Anesthesia for MRI, Nuclear Medicine,

and Computed Tomography
Whatever the imaging modality, there are general considerations.
Airway: The method of airway maintenance selected depends

on patient factors and imaging requirements. A natural airway technique (i.e., no artificial airway device) can be successfully used in many children for both MRI and computed
tomography (CT) scans. However, interventions such as chin
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lift, the insertion of an oropharyngeal airway, or lateral positioning may be required.55,56 These children maintain spontaneous respiration and receive oxygen via nasal cannulae while
anesthesia is maintained with a propofol infusion. This technique is not suitable for children with pre-existing airway obstruction, sleep apnea, enlarged tonsils, or if the scan is lengthy.
Sevoflurane has been used in a large series of children to cause
minimal anesthesia57 and such a technique may be applicable
also in small infants.29,58 The laryngeal mask airway (LMA)
device is MR-safe; however, there may be a small metal spring
in the pilot balloon that causes scan artifact if it is not held away
from the patient with tape. Common indications for tracheal
intubation include a risk of aspiration of gastric contents, failure
to maintain an adequate airway with a laryngeal mask, or if positive-pressure ventilation is indicated.
Breathing: Spontaneous respiration can be maintained for
many scans but a sequence of breath-hold maneuvers may be
requested. During cardiac MRI, the breath-hold sequences are
numerous and prolonged so care must be taken to ensure that
adequate ventilation and oxygenation are re-established each
time. In infants and small children, spontaneous breathing
movements can cause movement of the head and cerebral image
artifact; controlled ventilation may be necessary in these
circumstances.
Circulation: Most diagnostic CT and MRI scans are relatively brief so that intravenous fluids are rarely indicated.
All patients having cardiac MRI scans should receive intravenous fluids because these scans can take between 60 and
120 minutes and many of these patients tolerate hypovolemia
poorly.
Sedation for Diagnostic CT and MRI

Younger children will not lie still for long enough to facilitate most
diagnostic MRI or CT scans. Sleep must be induced either naturally or chemically.
MRI and Intensive Care Patients

Children requiring intensive care are a particular challenge in the
MRI scanner.59 Most pediatric intensive care unit (PICU) ventilators are neither MR-safe nor -compatible. Therefore, children
requiring high inspired oxygen concentrations, high levels of
positive end-expiratory pressure (PEEP), or specialized ventilatory
strategies such as high-frequency oscillation may become hypoxic
when transferred to the MR-compatible ventilator. A risk assessment should be made before the patient is transferred to the MRI
unit. Placing the patient on a ventilatory strategy equivalent to the
MRI unit for a trial period on the PICU gives a good indication as
to whether the patient will remain stable or not. Any chest drains
and closed tracheal suction systems in place need to be assessed as
to their compatibility for the MRI scanner.
Invasive monitoring such as arterial pressure transducers may
need to be briefly disconnected for transfer and then reconnected
via a long extension line and the transducer placed in the control
room (the most modern MR-compatible monitoring systems can
measure intravascular pressures invasively). Similarly, any continuous infusion devices such as syringe drivers must be checked
for MR-compatibility and, if necessary, a long extension line
inserted and the syringe driver placed in the control room
(MR-compatible syringe drivers are available). These maneuvers
often require the brief cessation of the inotropic drugs, which
some patients tolerate poorly. Planning and communication are
required before the patient is collected from the intensive care
unit. Ideally, the patients bedside nurse should accompany her or
him to the scanner with the anesthetist so continuity of care can
be maintained.
893
Natural sleep: Infants younger than 6 months will reliably sleep

long enough for a scan to be completed if they are fed and then
kept warm in the feed and wrap technique.18
Chloral hydrate and triclofos: Chloral hydrate and triclofos are
oral sedative-hypnotic drugs that are metabolized to trichloroethanol. Chloral has an unpleasant taste and can also cause gastric irritation. Triclofos is better tolerated but has a longer onset.
At doses of 50 to 100 mg/kg (maximum 1 g), 95% of children
less than 15 kg will reliably lie still for MRI scans.16 Despite
having a wide margin of safety, these drugs can cause airway
obstruction, respiratory depression, prolonged recovery, and
gastrointestinal effects.6064
Barbiturates: Pentobarbital is a short-acting barbiturate that can
be given orally at doses of 2 to 4 mg/kg (maximum 8 mg/kg) or
intravenously (titrated up to 5 mg/kg). Although pentobarbital
can cause respiratory depression, the overall adverse event rate
is less than with chloral hydrate and successful sedation rates
are similar.65 Thiopentone is an intravenous anesthetic agent
that induces potent respiratory depression and should not
be given via this route for sedation. Rectal absorption of
thiopentone (2550 mg/kg) is rapid and reliably produces
sedation adequate for imaging.66
Benzodiazepines: Benzodiazepines alone are not sufficiently effective to cause sleep long enough for imaging. Midazolam is the shortest acting of all the benzodiazepines and
can be given orally (0.5 mg/kg), rectally (0.250.5 mg/kg),
nasally (0.2 mg/kg), or intravenously (by careful titration).
Its effects of anxiolysis, amnesia, and sedation occur within
2 to 3 minutes of intravenous injection or within 10 to 20 minutes if given by the other routes. With all routes of administration, respiratory depression is a risk and this is much greater
if there has been concomitant administration of an opioid
drug or other respiratory depressant. The nasal administration
causes a painful burning sensation because of the low pH of the
solution.
Flumazenil: Paradoxical reactions can occur and can be
treated with intravenous flumazenil.6770 Incremental doses
of 10 g/kg intravenously will cause direct antagonism of all
the benzodiazepines and lead to rapid reversal of their effects.
Abrupt withdrawal of benzodiazepines may provoke seizures
if there is an underlying seizure disorder or benzodiazepines
dependence. Resedation can occur because the half-life of
flumazenil is much shorter than that of the benzodiazepines.
Dexmedetomidine: This 2 receptor agonist causes sedation
similar to natural sleep. It has been used with success for
sedation of children for MRI and CT scans.7173 The effective
induction dose is 2 to 3 g/kg infused intravenously over
10 minutes. A maintenance infusion is necessary (12 g/kg/h).
Children are asleep and probably rousable during scanning.
The overall success rate is over 90%. Moreover, the timing of
the sedation effect is reliable, making this drug a realistic
alternative to propofol (single-drug technique) for painless
imaging. Its cardiovascular effects are variable in the
sense that bradycardia has been reported, albeit with blood
pressure remaining in the normal range. Treatment with
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glycopyrrolate increases the heart rate but causes potentially

dangerous hypertension (personal communication from
Dr. K. Mason, Boston). The combination of dexmedetomidine
with ketamine is a potentially useful combination that may be
investigated in the future74 (personal communication from
Dr. J. Tobias, Columbus, Ohio).
Interventional Radiology
The diagnostic and therapeutic role of the interventional radiology
(IR) department is now firmly established in most hospitals. Since
about the 1990s, the range of procedures performed in the IR suite
has expanded and now involves every organ system (Table 568).
Many of the patients will have significant pathology and, therefore,
need a thorough history and clinical examination in their
preoperative assessment. Specific problems are discussed with
individual procedures.
TABLE 56-8. Procedures Performed in the Interventional
Radiology Suite
Respiratory
Bronchography
Tracheal/bronchial dilation and stenting
Bronchoscopy
Bronchial alveolar lavage
Lung biopsy
Drainage of pleural collections
Cardiovascular
Vascular access
PICC
Tunneled central line insertion (Hickman, port-A-Cath)
Venous thrombosis stenting
Inferior vena caval filter insertion
Diagnostic angiogram
AVM Embolization

Cerebral angiogram
Cerebral AVM or aneurysm embolization
Gastrointestinal System
Endoscopy and esophageal dilation
Abdominal angiogram
Insertion of feeding tubes
Percutaneous gastrostomy
Nasogastric/jejunal
Percutaneous biopsy (liver or tumor)
Drainage of abdominal collection/fluid
Renal System
Renal biopsy
Nephrostomy Insertion
Renal artery stenting/Dilation
Musculoskeletal and Cutaneous

Joint injections
Bone and soft tissue biopsies
Cystic mass sclerosis
AVM = arteriovenous malformation; PICC = peripherally inserted central catheter.
Respiratory Procedures
BRONCHOGRAM/BRONCHOSCOPY, TRACHEAL/BRONCHIAL
DILATION, AND STENTING: Many children requiring these
procedures will have presented in early life with stridor and
respiratory distress and may have had reconstructive tracheal
surgery. Occasionally, multiple procedures are necessary within a
short period of time.
Preoperative evaluation is essential to determine the current
situation of the child, and there may be some element of noisy
breathing and respiratory distress. The parents are usually able to
give an indication if their child is currently in a stable state or is
working harder than normal. If the child is working much harder
and is relying on nebulized adrenaline to maintain an airway, a
period of postprocedure intensive care should be arranged.
It is our practice to prescribe atropine (40 g/kg orally) as
premedication to help control secretions. Usually, a dynamic study
is required so an anesthetic technique that maintains spontaneous
ventilation is preferred. A careful inhalational induction with
sevoflurane in oxygen allows the anesthetist to assess the airway as
the childs sedation deepens and permits maximum oxygenation
as the child is induced. Once intravenous access is obtained,
topical lidocaine (3 mg/kg) is sprayed onto the larynx and an
LMA is inserted. Spontaneous respiration is then maintained
throughout the study. Some children will have such severe airway
obstruction that tracheal intubation and positive-pressure ventilation are required. Specially adapted angle pieces are available
that allow a flexible fiberoptic bronchoscope to be passed down
the LMA or tracheal tube with minimal leakage of the fresh gas
flow. During the study, varying levels of PEEP can be applied to the
airways and an assessment of collapsibility of the large airways
made. Balloon dilation and stenting involve a brief period of total
airway obstruction so that the patient should be preoxygenated
before balloon inflation.
Postprocedure, the patient may require intravenous dexamethasone 0.25 mg/kg, nebulized adrenaline, and supplemental
oxygen if there is residual airway obstruction or increased work of
breathing. A distressed, crying child also generates turbulent flow,
which can increase airway resistance further. The optimal position
for recovery for a small child may, therefore, be sitting in the
comfort of his or her parents arms. If the larynx has been sprayed
with lidocaine, the child should remain nil by mouth for at least
2 hours afterward.
Diagnostic flexible bronchoscopy is performed without a bronchogram for assessment of respiratory conditions such as cystic
fibrosis, bronchiectasis, hemoptysis, and as postlung transplant
follow-up. Bronchography and bronchoscopy are dynamic studies
and require the previously described anesthetic technique. A
bronchoalveolar lavage may cause a transient period of increased
oxygen requirement and respiratory distress postoperatively.
Occasionally, continuous positive airway pressure (CPAP) or
tracheal intubation and positive-pressure ventilation are required.
Postlung transplant patients require regular transbronchial
biopsies. A biopsy has a risk of pneumothorax, so a plain chest
radiograph should be taken.
Cardiovascular Procedures
VASCULAR ACCESS PROCEDURES: Modern pediatric medical and
surgical care is dependent on reliable intravenous access for
repeated diagnostic sampling and therapy. Multiple attempts at
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peripheral intravenous access are distressing for the child, so that

early insertion of secure central venous access is important. If
intravenous access is likely to be required for more than about 7 to
10 days, a tunneled device or a peripherally inserted central
venous catheter (PICC) is indicated.
PICCS: These 3- to 6-French-diameter lines are usually inserted

via peripheral veins in the upper limbs; however, veins on the
lower limbs or scalp can be used. Ultrasound guidance can be used
to identify suitable peripheral veins, and a central tip position
should be confirmed with fluoroscopy at the time of insertion.
Cooperative older children are able to lie still for PICC insertion. Topical anesthetic cream can be used to cover the peripheral
puncture site. Uncooperative children will need a standard general
anesthetic technique.
CENTRAL VENOUS ACCESS: Children requiring long-term venous
access should have a tunneled central line (such as a Hickman line)
or a subcutaneous reservoir device (such as a port-A-Cath) placed.
These devices are inserted most commonly via the internal jugular
veins, but the common femoral and subclavian veins can be used.
The line is then accessed at a site distal from the venous puncture.
Placement of tunneled lines requires a general anesthetic for
the majority of children. After induction, the child is positioned on
the imaging table with the head in extension and rotated to one
side (if the internal jugular route is planned). During cannulation,
there is a risk of air embolism, which is increased if the child is
self-ventilating. It is our standard practice, therefore, to intubate
the trachea and ventilate the lungs with positive pressure during
these procedures.
Venous puncture itself is not painful but the subcutaneous
tunneling performed during the procedure can result in a significant cardiovascular response despite infiltration of the area
with local anesthesia. A short-acting opioid such as fentanyl or
remifentanil may be needed to cover the period of tunneling
intraoperatively.
Central Nervous System Procedures

CEREBRAL ANGIOGRAM: The patients may present electively or
may be suffering from significant intracranial pathology. Patients
with significant pathology may have varying levels of consciousness, raised intracranial pressure, dehydration, and cardiovascular
instability. A baseline neurologic status should be recorded.
If any intervention is planned during the angiogram, there is a
risk of intracranial bleeding so cross-matched blood should be
available. Moyamoya disease and the vein of Galen aneurysmal
malformation (VGAM) are two conditions that require special
attention.
General anesthesia is indicated for all cerebral angiograms
because absolute stillness is required. A neurostable anesthetic
technique should be chosen and the maintenance of an adequate
cerebral perfusion pressure ensured. Positive-pressure ventilation
with an end-tidal carbon dioxide within normal limits is usual.
Embolization of any vascular malformations may then be performed if necessary. These procedures may be long, so particular
care must be taken with positioning, padding of pressure points,
temperature regulation, and fluid maintenance (a urinary catheter
may be needed). Postoperatively, an early assessment of the neurologic status of the patient is essential so large doses of longacting opioid drugs should be avoided.
895
MOYAMOYA DISEASE: The peak incidence of this disease is in

the first decade of life. A progressive occlusion of the internal
carotid arteries can present with transient ischemic attacks,
seizures, and neurologic deficits. Cerebral blood flow depends on
a proliferation of collateral vessels at the base of the skull. The
appearance of these vessels on angiogram is described as a puff of
smoke or Moyamoya in Japanese. Flow through these collateral
vessels is precarious so the anesthetic management is to avoid
hypocapnia, hypercapnia, hypotension, hypovolemia, hypoxia,
and hypothermia.75
VGAM: A true VGAM is a rare abnormality in which multiple

feeding arteries drain directly into the embryonic precursor of the
vein of Galen. The resulting large arteriovenous pouch may
present as high output cardiac failure in the neonatal period or as
progressive macrocephaly, hydrocephaly, and neurologic deficits
later.76 Only 2.5% of patients have a spontaneous thrombosis of a
VGAM and, because only 50% are neurologically intact, embolization is indicated in most cases.77 The anesthetic management
should aim for cardiovascular stability. Inotropic support may be
required in the neonatal period, and therefore, central venous and
arterial line placement should be considered. Intensive care is
often required after embolization to allow a period of stability.
Gastrointestinal/Renal Procedures
ENDOSCOPY AND ESOPHAGEAL DILATION: These patients will
have a history of difficulty in feeding or swallowing related to
esophageal strictures. There is commonly a history of previous
esophageal surgery for tracheal esophageal fistula, esophageal
atresia, or caustic substance ingestion. Patients with severe epidermolysis bullosa also present with dysphagia and can be a particular
challenge to the anesthetist.78 Balloon dilation is performed by
passing a guidewire past the stricture under radiologic guidance,
and then sliding a balloon over the wire to the area requiring
dilation. The balloon is then inflated under radiologic guidance.
Often multiple procedures are required over a long period of
time so the child and her or his parents will have a personal
preference for a particular anesthetic technique. Almost always,
an endotracheal tube is required to prevent aspiration and this
should be firmly secured, because dislodgment during endoscopy
is possible.
INSERTION OF FEEDING TUBES/PERCUTANEOUS GASTROSTOMY:

Nasogastric feeding tubes are usually inserted blindly on the ward
or under a general anesthetic given for another procedure.
Occasionally, a Silastic nasoduodenal or nasojejunal tube is
required for mid- to long-term feeding. These procedures require
x-ray screening to confirm correct positioning. Alternatively,
a percutaneous endoscopic gastrostomy (PEG) is placed. Both
techniques require the passage of an endoscope and subsequent
manipulation. A general anesthetic technique with tracheal
intubation protects the airway and allows accurate placement of
the tubes.
LIVER/RENAL/ABDOMINAL MASS BIOPSY: The use of ultrasound

guidance for biopsies of abdominal organs or masses is now
standard practice. Older children may tolerate these procedures
awake with analgesia supplied by topical local anesthetic cream
and then local infiltration. Nitrous oxide (50%) is also a valuable
technique for cooperative children. Uncooperative children will
require a general anesthetic. Breath-holds are no longer necessary,
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so a spontaneously breathing technique with an LMA is acceptable.

Postbiopsy, the child must be observed closely for signs of hemorrhage because bleeding from the puncture site can occur.
ABDOMINAL ANGIOGRAM/RENAL ARTERY STENTING: Diagnostic

abdominal angiogram requires absolute stillness and breathholding maneuvers that require the patient to be anesthetized,
paralyzed, and ventilated. A tracheal tube is preferred to am LMA
because even small amounts of air introduced into the gut during
ventilation can degrade the quality of the images. Occasionally, gut
motility needs to be reduced by the administration of glucagon.
Renal artery stenting is performed in children with hypertension
secondary to renal artery stenosis. During general anesthesia, the
blood pressure should be kept to within 25% of the preprocedure
values. There is a risk of arterial rupture during ballooning and
stenting so adequate intravenous access and cross-matched blood
should be available.
NEPHROSTOMY: Ultrasound- or x-rayguided percutaneous

nephrostomy is usually indicated for an acutely obstructed kidney
and is a temporary measure until a definitive drainage procedure
can be performed. If the patient is a neonate, the obstructed
kidney is failing, or there are signs of infection and sepsis, the
procedure should be performed urgently. The procedure is usually
short and noninvasive and can be performed with the patient tilted
into the lateral position, but occasionally, the prone position is
necessary. If turned prone, the patient should be intubated and
ventilated, the eyes and face padded, and the abdomen free to
move with ventilation.
Miscellaneous Procedures
JOINT INJECTIONS, BONE AND SKIN BIOPSIES: All these are rapid,
noninvasive procedures. Children with juvenile rheumatoid
arthritis (Stills disease) can be a particular challenge. Careful
positioning is required and airway management may be made
difficult by temporomandibular joint and cervical spine involvement.79
SCLEROSIS
OF
SKIN LESIONS: A variety of cystic and vascular
skin lesions are suitable for treatment with sclerosing agents.

A preprocedure MRI scan is performed to map the extent of any
lesion. Some lesions can extend into the airway or thoracic cavity,
making anesthesia potentially difficult; these cases should be
reviewed with the radiologist before starting. Lymphangioma,
such as cystic hygromas, are responsive to sclerosis with OK-432
(a lyophilized incubation mixture of group A Streptococcus
pyogenes of human origin). Venous malformations are treated with
sodium tetradecyl sulfate, a detergent-based sclerosant. Both of
these treatments can be painful, so adequate postoperative analgesia should be available. Significant systemic complications
are rare; the most common problems are fever and local skin
pigmentation.
Cardiac Catheterization and MRI

Much of the diagnostic work of the cardiac catheter laboratory is
now done in the echocardiography laboratory and cardiac MRI
suite. However, there has been an expansion in the interventional
procedures performed in the catheter laboratory (Table 569) that
includes the development of imaging by MRI.
TABLE 56-9. Procedures Performed in the Cardiac

Catheter Laboratory
Balloon valvotomy
Balloon angioplasty/Stent insertion
Aortic coarctation
Pulmonary artery stenosis
Right ventricular outflow tract conduit stenosis
Closure of holes and aberrant vessels
Atrial septal defect
Ventricular septal defect
Patent ductus arteriosis
Aortopulmonary collateral vessels
Atrial septostomy
Transposition of great arteries
Hypoplastic left heart
Severe pulmonary hypertension
Electrophysiology studies and radiofrequency catheter ablation
Recurrent arrhythmias
Diagnostic studies
Pulmonary hypertension studies
Hypertrophic obstructive cardiomyopathy
Pulmonary valve replacement
Anesthesia and Sedation for

Cardiac Catheterization
Many of the modern diagnostic and interventional cardiac
catheter techniques require the patient to be absolutely still for
a prolonged period of time. In addition, the hemodynamic studies
require reproducible and consistent physiologic conditions such
as inspired oxygen concentrations, arterial carbon dioxide tension,
and systemic vascular resistance as well as needing breath-holding
procedures. General anesthesia with endotracheal intubation and
positive-pressure ventilation gives the anesthetist the most control
over these variables and is our technique of choice.80
Complications of Cardiac Catheterization

Adverse events occur more frequently during cardiac catheterization than during anesthesia for other procedures.81 Children
at particular risk are those younger than 1 year and those with
significant pulmonary hypertension.8183 In addition to specific
high-risk cases, each intervention has a number of predictable
complications, which are discussed in the following sections.
NEONATES AND INFANTS: These children may present with ductdependent, unbalanced circulations, with lethal cardiac lesions
that need urgent therapeutic interventions. They are, therefore,
high-risk cases and should be discussed fully with the cardiologists before starting. The immature myocardium is particularly
sensitive to the negative inotropic effects of volatile anesthetic
agents, so they should be used with caution. In infants with a
significant right-to-left-shunt, inhalational induction may take
longer than usual.
PULMONARY HYPERTENSION: Children with baseline suprasystemic pulmonary arterial pressures are at increased risk of
a major complication such as cardiac arrest and pulmonary
hypertensive crisis.8284 The conduct of anesthesia in these patients
is crucial, and there are two plausible mechanisms of circulatory
collapse from which the outcome is reputed to be poor. Pulmonary
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hypertension is a common feature of children after cardiac surgery

both in the operating theater and in intensive care and is probably
caused by a primary rise in the pulmonary vascular resistance
(PVR) and secondary ventricular failure. Hypercarbia, acidosis,
and hypoxia all increase PVR. A second mechanism is a primary
ventricular failure in the presence of fixed high PVR. Certainly,
anesthesia can reduce cardiac contractility, and hypoxia and
hypotension will reduce cardiac oxygenation. Severe pulmonary
hypertension causes right ventricular expansion that can squash
the left ventricle. Further right ventricular expansion can critically
reduce cardiac output. If this is the mechanism (it is rational but
unproved), it is crucial to maintain systemic blood pressure and
oxygenation to preserve the function of the right ventricle to
prevent it expanding. Maintaining anesthesia with minimal
doses is wise; under these circumstances, level of consciousness
monitoring may be helpful.84,85 Ketamine is also a potentially
useful drug in these situations, and there is evidence supporting its
use in pulmonary hypertension.86 A careful anesthetic technique
with tracheal intubation and positive-pressure ventilation allows
most control of the physiologic variables. Inhaled nitric oxide and
intravenous prostacyclin should be available for acute exacerbations; however, not all patients will respond.
HYPERTROPHIC OBSTRUCTIVE CARDIOMYOPATHY: Hypertrophic obstructive cardiomyopathy (HOCM) is a familial disorder characterized by left ventricular hypertrophy because of
outflow tract obstruction. The patients suffer from arrhythmias,
syncope, myocardial ischemia, and eventual cardiac failure. The
anesthetic management should aim to avoid sympathetic stimulation while mai

2011 Pediatric Anesthesia - Bissonnette

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To All the Children of the World We Care For

Dean B. Andropoulos, MD, MHCM [106]

Associate Professor of Anesthesiology

Professor of Anesthesiology and Pediatrics

Swati Agarwal, MD [67]

Asim Ali, BASc, MD, FRCSC [102]

Kanwaljeet J. S. Anand, MB BS, DPhil, FAAP,

Brian J. Anderson, MB ChB, PhD, FANZCA,

Christian Apitz, MD [7]

Glen S. Van Arsdell, MD [94]

Karim Ashenoune, MD, PhD [63]

Hanan Azzam, MD [82]

Mette M. Berger, MD, PhD [124]

Gilles Boulay, MD [1]

Professor of Anesthesia and Critical Care Medicine

Facult de Mdecine, AP-HP

Marc-Andr Bernath, MD, MER [124]

Nathalie Bourdaud, MD [53, 112]

Dominique A. Bettex, MD [73]

Universit Paris Descartes

Kenneth M. Brady, MD [15]

Bruno Bissonnette, MD [6]

David A. Blacoe, MbChB, MRCP(UK), FRCA [128]

Christopher M. Bolton, MB BS, FANZCA, PhD [122]

Peter D. Booker, MB, BS, MD, FRCA [23, 95]

Alain Borgeat, MD, PhD [44]

Adrian Bsenberg, MB ChB, FFA(SA) [47,49,132]

Karen A. Brown, MD, FRCP(C) [62]

Stephen C. Brown, MD, FRCPC [16]

David Buckley, MBBChB, FANZCA, FCICM [42]

Sabine Kost-Byerly, MD [66]

Xavier Capdevila, MD, PhD [45]

Pierre Carli, MD [68]

Brian Chanpong, DDS, MSc [126]

Professeur dAnesthsiologie et de Ranimation Chirurgicale

Clinical Assistant Professor

Alison S. Carr, MB BS, FRCA, MSc,

Michael J. Casas, DDS, Dip.Paed, MSc, FRCD(C) [125]

Pierre-Guy Chassot, MD, PhD [73]

Farha Abd El-Aziz El-Chennawi, MD [82]

Associate Professor of Dentistry

Neroli Chadderton, BHB, MBChB, FANZCA [23]

Olivier Choquet, MD [45]

Tristan M. B. de Chalain, MSc, MB Ch.B, FCS(SA),

George A. Chalkiadis, MB BS, FANZCA,

John Chandler, FDSRCS, FCARCSI [10]

Associate Professor of Anesthesia

Howard M. Clarke, MD, PhD, FRCS(C),

John G. Coles, MD, FRCSC [105]

Mario J. da Coneicao, MD, PhD [34]

Bairbre Connolly, MB BCh, BAO, FRCSI, MCh,

Isabelle Constant, MD, PhD [75]

Robin G. Cox, MB BS, MRCP(UK), FRCA, FRCPC [36]

Peter N. Cox, MBChB, DCH, FFARCS (UK),

Mary Cunliffe, MB BS, FRCA, FFPMRCA [91]

Sharon L. Cushing, MD, MSc, FRCS(C) [98]

Souhayl Dahmani, MD, PhD [19]

Andrew Davidson, MBBS, MD, FANZCA [77]