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ASSociAtE EditorS

Luciano Gattinoni
Università degli Studi di Milano,
Policlinico di Milano, Italia
Massimo Antonelli
Università Cattolica Sacro Cuore,
Policlinico Gemelli, Roma, Italia
Antonio Pesenti
Università degli Studi di Milano Bicocca,
Ospedale San Gerardo, Italia

vol. 2 • n° 2 • 2010 SEction EditorS

n intEnSivE cArE
Luciano Gattinoni
Università degli Studi di Milano, Policlinico di Milano, Italia
EditorS in chiEf n AnESthESiA
Fabio Guarracino
Alberto Zangrillo Azienda Ospedaliera Universitaria Pisana, Pisa, Italia
Università Vita-Salute San Raffaele n vASculAr SurgEry
Milano, Italia Roberto Chiesa
Università Vita-Salute San Raffaele, Milano, Italia
roland hetzer n cArdiAc SurgEry
Deutsches Herzzentrum Berlin, Germany Ottavio Alfieri
Università Vita-Salute San Raffaele, Milano, Italia
n cArdiology
Official Journal of Giuseppe Biondi-Zoccai
Università degli Studi di Torino, Italia
School of Anesthesiology n clinicAl cArdiology
and Intensive Care Alberto Margonato
Università Vita-Salute San Raffaele, Milano, Italia
Cattedra di Anestesia e Rianimazione
Università Vita-Salute San Raffaele n invASivE cArdiology
Milano, Italia Stephan Dreysse
Deutsches Herzzentrum Berlin, Germany
n intErvEntionAl pEdiAtric cArdiology
Endorsed by Peter Ewert
Deutsches Herzzentrum Berlin, Germany
ITACTA n EchocArdiogrAphy
(Italian Association Michele Oppizzi
of Cardiothoracic Anaesthesiologists) Università Vita-Salute San Raffaele, Milano, Italia n mEtAboliSm
Dionisio Colella
Deutsches Herzzentrum Berlin, Germany Università degli Studi di Tor Vergata, Roma, Italia
n nEw tEchnologiES
WEb Site Federico Pappalardo
Università Vita-Salute San Raffaele, Milano, Italia n in hoSpitAl EmErgEnciES
Luca Cabrini
Università Vita-Salute San Raffaele, Milano, Italia
n nurSing
Mariano Fichera
Università Vita-Salute San Raffaele, Milano, Italia
n hEmAtology
Andreas Koster
Deutsches Herzzentrum Berlin, Germany
n pEEr-to-pEEr communicAtion
Edizioni Internazionali srl Michael John
Università Vita-Salute San Raffaele, Milano, Italia
Divisione EDIMES n imAging
Via Riviera 39 - 27100 Pavia Università Vita-Salute San Raffaele, Milano, Italia
Tel. 0382526253 r.a. - fax 0382423120 n futurE EvEntS
E-mail: George Silvay
The Mount Sinai School of Medicine
EXEcutivE Editor
Massimiliano Nuzzi
Università Vita-Salute San Raffaele, Milano, Italia

John T. Apostolakis
Cleveland Clinic, OH, US
Elena Bignami
Università Vita-Salute San Raffaele, Milano, Italia
Segreteria di redazione Tiziana Bove
Università Vita-Salute San Raffaele, Milano, Italia
Lara Sussani
Cattedra di Anestesia e Rianimazione Maria Grazia Calabrò
Università Vita-Salute San Raffaele, Milano Università Vita-Salute San Raffaele, Milano, Italia
Via olgettina, 60 - 20132 Milano
Nicola Colangelo
Tel. +39 02 26436158
fax +39 02 26436152 Università Vita-Salute San Raffaele, Milano, Italia Michele De Bonis
Università Vita-Salute San Raffaele, Milano, Italia
wEb Site Francesco De Simone Università Vita-Salute San Raffaele, Milano, Italia

direttore responsabile Gian Franco Gensini

Paolo E. zoncada
Università degli Studi di Firenze, Italia
Giuseppe Giardina
Registrazione Tribunale di Milano
Università Vita-Salute San Raffaele, Milano, Italia
n. 532 del 26 novembre 2009
James L. Januzzi
The Journal is indexed in
Harvard University, Massachusetts General Hospital, US
GooGLE SCHoLAR, HInARI, Giovanni Landoni
InDEX CoPERnICUS Università Vita-Salute San Raffaele, Milano, Italia
ISSn (onLInE): 2037-0512 Kevin Lobdell
ISSn (PRInTED): 2037-0504 Sanger Heart and Vascular Institute, Charlotte, NC, US
Stampa Giovanni Marino
Jona Srl Università Vita-Salute San Raffaele, Milano, Italia
Paderno Dugnano (MI)
Andrea Morelli
Università degli Studi “La Sapienza”, Roma, Italia
Stefano Romagnoli
Ospedale Careggi, Firenze, Italia
Antonio Emilio Scala
Dean, Università Vita-Salute San Raffaele, Milano, Italia
Anna Mara Scandroglio
Edizioni Internazionali srl Università Vita-Salute San Raffaele, Milano, Italia
Divisione EDIMES
Via Riviera 39 - 27100 Pavia Università degli Studi “La Sapienza”, Roma, Italia
Tel. 0382526253 r.a. - fax 0382423120
E-mail: Emiliano Vitalini
Ospedale San Camillo Forlanini, Roma, Italia
in Intensive Care
Cardiovascular Anesthesia

Endorsed by

ConTEnTS 3

n EditoriAl
preventing mortality in cardiac surgery with anesthetic drugs and techniques.
there is need for a consensus conference ...................................................................................................................................................................5
G. Landoni, A. Zangrillo

n rEviEw ArticlE
the edge-to-edge technique for mitral valve repair ..................................................................................................................................7
M. De Bonis, O. Alfieri

glucose metabolism in cardiovascular surgery ............................................................................................................................................ 19

C. Lazzeri, S. Bevilacqua, F. Ciappi, C. Pratesi, G. F. Gensini, S. Romagnoli

n originAl ArticlE
high-sensitivity c-reactive protein (hs-crp) and tumor necrotizing factor-alpha
(tnf-α) after on- and off- pump coronary artery bypass grafting ..................................................................... 27
H. Javadzadegan, N. Nezami, K. Ghobadi, A. Sadighi, A.A. Abolfathi, N.D. Nader

A new method for managing emergency calls................................................................................................................................................. 35

G. Landoni, L. Cabrini, O. Fochi, A. Zangrillo

day admission for thoracic aortic surgery ........................................................................................................................................................... 40

G. Silvay

transoesophageal echocardiography during coronary artery bypass procedures:

impact on surgical planning............................................................................................................................................................................................................... 43
F. Guarracino, C. Cariello, L. Tritapepe, L. Doroni, R. Baldassarri, A. Danella, M. Stefani

n cASE rEport
bullet embolisation from injured inferior cava vein to the right ventricle ...........................................51
A. Zenelaj, M. Brati, M. Kerci

n imAgES in mEdicinE
penetrating chest trauma: the role of emergency echo.................................................................................................................. 55
F. Guarracino, R. Baldassarri, C. Vullo, M. Stefani

n pApErS, poStErS, prESEntAtionS:

communicAting thE biomEdicAl SciEncES
once upon a time there was a congress................................................................................................................................................................... 57
M. John
Arresto cardiaco
HIE Encefalopatia Ischemica Ipossica
Danno vertebrale traumatico
Danno celebrale traumatico
Mantenimento organi per donazione

SEDA S.P.A. Telefono +39 02 48424.1

Via Tolstoi, 7 Fax +39 02 48424290
20090 Trezzano sul Naviglio (Mi) -

Certificato UNI EN ISO 9001:2000

in Intensive Care
Cardiovascular Anesthesia

Endorsed by

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 77-79

Ethics and methodology,
not bureaucracy
G. Landoni, A. Zangrillo
Department of Anesthesia and Intensive Care, Università Vita-Salute San Raffaele, Milan, Italy

we have a dream that within ten years, patients admitted to teaching

hospitals will long to be enrolled in “researcher driven”*randomized
clinical trials. Patients will be fully aware of the reduced complica-
tion rates and the improved outcomes that occur in patients invol-
ved in randomized clinical trials, the so-called “Hawthorne effect”.
we have a dream that within ten years scientists will not have to
spend months waiting for ethics committee approval and will not
have to raise thousands of Euros in funds to carry out their research.
on the contrary, they will have a 50% salary increase as they are
spending their creative and enthusiastic energies to perform clinical
trials (at present, hospitals receive several thousand Euros from the
Ministry of Health for each published article, yet the clinical scienti-
st generally knows nothing about it).
Although both “company driven” and “researcher driven” research
are important and useful, the differences are striking. Unfortunate-
ly, patients, medical doctors and legislators do not seem to be fully
aware of these differences. one reason for this might be the influen-
ce of international insurance, pharmaceutical and quality-control
Today, a clinical scientist who wants to compare two forms of treat-
ment that have routinely been used in clinical practice for around 20

*for this editorial the following definitions will be used: “company driven” trials include
phase I, II (III) trials on new drugs with safety issues and economical implications; “rese-
archer driven” trials include phase (III) IV trials on “old” drugs (“generics”) or techniques
used in various combinations, or for new indications with no safety issues or economical
implications. The clinical scientist has no conflict of interest with the drug company. Patient
management is carried out using the best available treatment, the only difference being ran-
domization to treatment or control; “in between” trials include phase (II) III (IV) trials that
resemble the “researcher driven” type, but are actually “company driven”.

Corresponding author:
Giovanni Landoni, M.D.
Department of Cardiothoracic Anesthesia and Intensive Care
Università Vita-Salute San Raffaele
Via olgettina, 60 - 20132 Milano, Italy

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2


78 years, two slightly different dosages of the same drug, or use a safe
drug at a lower dosage with slightly different indications is obliged
1) prepare hundreds of pages of documentation (most of the time
not in English, but in a language not generally used by the scien-
tific community);
2) wait from six to twelve months for ethics committee approval
(which at times never arrives);
3) pay a Contract Research organization (CRo) for the quality mo-
nitoring of the study;
4) pay a CRo for the pharmacovigilance of the study (even if the
drug has been used in clinical practice for 20 years on millions of
5) pay specific insurance for all patients enrolled in the study.

Considering that it can take from one to two years to receive a grant
(from its ideation to its funding) and that protocol approval takes a
year, we are generally forced to observe our ideas while they agonize
under the weight of bureaucracy and fundraising requirements.
we have a dream that within ten years the same clinical scien-
tist will have his idea approved by an ethics commission made up
of peers and patients after only a few weeks and will randomize
hundreds of patients in just a few days using established multicen-
ter networks without costs or bureaucracy. In Italy, for example, we
have more than 100 cardiac surgery centers that perform around
40,000 cardiac surgery operations every year. It would be simple and
cheap to compare inotropic or vasoconstrictor agents in perioperati-
ve cardiac failure; to identify if the widespread use of diuretics in the
management of acute renal failure is useful, useless, or dangerous, to
compare anesthesia techniques and drugs, or investigate preventive
measures or curative drugs for the prevention or treatment of car-
diological, nephrological, or neurological complications. We would
need networking, a simple national web-based database and regular
meetings (either online or in person).
In intensive care the situation is almost grotesque. Most patients are
unconscious and therefore cannot provide written informed con-
sent, which means they cannot benefit from inclusion in researcher
driven randomized clinical trials according to the interpretation of
many ethics committees. As a result, critically ill patients have no
evidence-based medicine guidelines to support the life-saving treat-
ment they are receiving.
Hospitals that carry out clinical research perform better than those
that do not. Patients (and Patients’ Associations) should ask to be-
come involved in “researcher driven” trials. They should go to those
hospitals where “researcher driven” trials are performed and ask to

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

Ethics and methodology, not bureaucracy

be enrolled in ongoing trials. In fact, patients enrolled in “researcher 79

driven” clinical trials have improved outcomes, irrespective of the
assigned treatment or control. This so-called “Hawthorne effect”
can be explained, in part, by the superior knowledge and skill of
the medical doctors/departments where research is performed and
by the additional attention that all the medical and nursing staff
dedicates to these patients. “Research driven” trials should involve
every patient that is admitted to a high-standard hospital. There is
so much to discover and each patient should be studied and benefit
from inclusion in randomized protocols.
Two factors limit this extraordinary opportunity: bureaucracy and
ignorance. International and European laws in this field are excel-
lent where “company driven” trials are concerned, but limit “rese-
archer driven” trials and thus, indirectly, kill thousands of patients
every year.
of course, clinical research has to be studied at Universities and Ma-
ster Courses and clinical scientists need to possess strong methodo-
logy and should receive incentives to disclose any conflict of interest.
What we all need is Ethics and methodology, not bureaucracy.
our dream is to reach this objective within 10 years. We believe we
can do it and we are certain that all of our patients will benefit gre-
atly from it.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

Papers, Posters,
the biomedical sciences

Enrolment for one-day courses

organised on a weekly basis from September 2010

• Methodology and basic statistics

• Impact Factor, H index, Scopus, Pubmed and Google Scholar
• The point of view of the author, reviewer, editor
• How to review a paper
• Without publication your discoveries will remain in your laboratory or in your ward and will be
unknown to the rest of the biomedical community. Remember that it is your duty to contribute to the
construction of an ever-growing biomedical database that will hopefully develop clinical and surgical
techniques, therefore improving the health and lives of your patients.
• How is it possible to be captivating and interesting when communicating scientific data? Science is
serious, but there is no reason why it should be boring.

Prof. Michael John · Università Vita-Salute San Raffaele, Milan

Prof. Giovanni Landoni · Università Vita-Salute San Raffaele, Milan

For details contact Lara Sussani (

in Intensive Care
Cardiovascular Anesthesia

rEviEw ArticlE
Endorsed by

major themes for 2009 in
cardiothoracic and vascular anesthesia
J. Fassl¹, H. Riha², H. Ramakrishna³, N. Singh4, T. Wyckoff4, C. Roscher4,
J.G.T. Augoustides4
¹Department of Anesthesiology and Critical Care, University of Basel; Switzerland;
²Department of Anesthesiology and Intensive Care Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech
Republic; ³Department of Cardiac Anesthesia, Mayo Clinic, Scottsdale, Arizona, USA;
Department of Anesthesiology and Critical Care, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 81-91

The hybrid operating room is the venue for transcatheter therapy with the convergence of three specialties:
cardiac surgery, cardiovascular anesthesiology, and interventional cardiology. Transcatheter aortic valve re-
placement is proof that cardiac specialists have embraced the endovascular revolution. Since pharmacologic
and ischemic myocardial conditioning are safe and effective, they are currently the focus of multiple trials.
Angiotensin blockade, anemia and endoscopic saphenous vein harvesting worsen outcome after coronary
artery bypass grafting (CABG). Although off-pump CABG is equivalent to on-pump CABG, it may improve
outcomes in high-risk groups. Although percutaneous coronary intervention (PCI) significantly decreases
mortality after myocardial infarction, the evidence is less convincing for intra-aortic balloon counterpulsa-
tion. Even though prasugrel was recently approved for platlet blockade in PCI, it may be superceded by ti-
cagrelor. Although PCI and CABG appear equivalent for multivessel coronary disease, CABG lowers revascu-
larization rates and also has superior outcomes in diabetics and the elderly. Hetastarch and n-acetylcysteine
both increase bleeding and transfusion in cardiac surgery. factor VII can treat life-threatening bleeding, but
its safety requires further evaluation. Since eltrombopag and romiplostim stimulate platelet production, they
may have a future role in hemostasis after cardiac surgery. Even though fenoldopam, atrial natriuretic peptide
and sodium bicarbonate are nephroprotective, further trials must confirm these findings. Intensive insulin
therapy offers no further outcome advantage and significantly increases hypoglycemic risk. The past year has
witnessed the advent of a new clinical venue, new devices, and new drugs. The coming year will most likely
advance these achievements.

Keywords: hybrid operating room, transcatheter aortic valve replacement, transcatheter mitral valve repair, isch-
emic preconditioning, pharmacologic conditioning, levosimendan, volatile anesthetics, angiotensin-converting en-
zyme inhibitors, anemia, hetastarch, coronary artery bypass grafting, endovascular saphenous vein graft harvesting,
percutaneous coronary intervention, intra-aortic balloon counterpulsation, sodium bicarbonate, atrial natriuretic
peptide, fenoldopam, intensive insulin therapy, prasugrel, ticagrelor.


This article is the first of its kind for this

journal, and we thank the editorial board
Corresponding author:
John G.T. Augoustides MD, fASE, fAHA for the invitation to review the highlights
Associate Professor of 2009 in cardiothoracic and vascular an-
Cardiothoracic Section
Anesthesiology and Critical Care esthesia. The dominant themes for 2009
Dulles 680, HUP
3400 Spruce Street
will initially be outlined in the introduc-
e.mail: tion of this article and then subsequently
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
J. Fassl, et al.

82 explored in depth in the in the body of the recent trials. Although prasugrel appears
article. Transcatheter valve therapy in the likely to replace clopidogrel, the future of
emerging environment of the hybrid op- oral thienopyridine platelet blockade may
erating room (oR) will likely disseminate be moving to direct and reversible blockade
even more globally, as further approvals with ticagrelor, pending the results of large
from regulating agencies are obtained in trials currently in progress.
new countries and for new devices. The With these advances in platelet blockade,
venue for these breakthrough technologies the role of PCI may continue to expand in
will likely increasingly be the hybrid oR, the management of multivessel coronary
best understood as merging the advantages artery disease (CAD). Although PCI ap-
of the cardiac catheterization laboratory pears equivalent to CABG for multivessel
and the operating room. This new peri- CAD in select groups, it still has a signifi-
operative venue will continue to facilitate cantly higher risk of revascularization and
novel interventions as specialists embrace adverse outcomes in diabetics and patients
the unfolding endovascular revolution in >65 years old. It is likely that the inter-
cardiovascular medicine. ventional management of CAD will be
Perioperative myocardial conditioning of integrated in the hybrid oR in the future
the myocardium has gained increasing at- search for the best combined approach to
tention as trials consistently demonstrate CAD.
enhancement of clinical outcomes after Since bleeding and transfusion after car-
cardiac surgery with exposure to volatile diac surgery independently predict adverse
anesthetics, levosimendan and ischemia, outcome, the impaired hemostasis associ-
both local and remote. It is likely that these ated with hetastarch and n-acetylcysteine
perioperative techniques will gradually be is concerning. The perioperative safety
integrated into the conduct of cardiotho- of factor VII in severe bleeding requires
racic and vascular procedures, as the out- further study. The advent of the throm-
come advantages are demonstrated in ad- bopoeitin agonists such as eltrombopag
equately powered trials with meaningful and romiplostim offers the opportunity
clinical end-points. In contrast, periopera- to boost preoperative platelet levels which
tive exposure to angiotensin blockade and may have a clinical niche in the cardiac
anemia independently predict adverse out- surgical patient.
come after coronary artery bypass graft- Similarly to bleeding and transfusion, re-
ing (CABG). The outcome advantages of nal dysfunction independently predicts ad-
off-pump CABG appear to be confined to verse outcome after cardiac surgery. Pilot
high-risk patients. Endoscopic saphenous data suggest that fenoldopam, atrial natri-
vein harvesting may increase the risks of uretic peptide and sodium bicarbonate may
coronary graft thrombosis to worsen clini- be nephroprotective after cardiac surgery.
cal outcomes after CABG. In contrast, the Although further trials are indicated to ex-
aggressive management of ST-elevation plore their efficacy and safety, the search
myocardial infarction (STEMI) with per- for nephroprotective agents in our special-
cutaneous coronary intervention (PCI) ty is a priority, given the outcome impor-
consistently improves outcomes across tance of maintaining renal function peri-
multiple trials. The indications for intra- operatively.
aortic balloon counterpulsation in STEMI In a similar fashion, ongoing trials have ex-
have recently been questioned as the out- plored the safety and efficacy of periopera-
come advantages are not substantial in tive glucose management. Although goal

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

major themes for 2009 in cardiothoracic and vascular anesthesia

glucose level ≤180 mg/dL enhance clinical fective multidisciplinary teamwork in the 83
outcome after adult cardiac surgery, these hybrid oR setting (9-13).
outcome advantages are not universal. The hybrid oR will likely also significantly
Tighter glucose control for levels in the impact the interventional management of
range of 80-110 mg/dL not only does not CAD (14). A recent trial (n=366) demon-
offer any clinical advantage but substan- strated that completion angiography after
tially increases the risk of hypoglycemia. CABG in a hybrid oR allowed diagnosis of
graft inadequacies in 12% of cases. These
lesions were all corrected there and then
trAnScAthEtEr vAlvE in the hybrid oR with either PCI or sur-
intErvEntionS gical revision. The hybrid oR has brought
advanced fluoroscopy to the intraoperative
Aortic valve management of CAD with significant ef-
Transcatheter aortic valve implantation fect. This is analogous to the effect of TEE
(TC AVI) is a major innovation in our on the conduct of cardiac surgery, where
specialty and consequently has received the ability to image the structures of inter-
considerable attention (1-4). This technol- est and receive immediate feedback has
ogy will generalize further in the USA if fundamentally altered our specialty for-
the landmark PARTnER trial (Placement ever (15, 16).
of AoRTic TranscathetER Valve Trial:
full details available at www.clinicaltrials. Mitral valve
gov, last accessed March 2nd 2010) demon- Transcatheter mitral valve therapy has re-
strates significant outcome improvement. cently progressed far beyond balloon val-
It is essential that the anesthesia team vuloplasty for mitral stensosis and these
thoroughly understands the entire TC AVI many of the novel therapies are currently
procedure as their focused and integrated in clinical trials (17-19). Transcatheter
participation is essential for the success Alfieri mitral valve repair is now possible
of this challenging procedure, including with an array of technologies that enable
transesophageal echocardiography (TEE) leaflet edge-to-edge union. Percutane-
(5-8). The major phases in the conduct of ous mitral annuloplasty is also possible
TC AVI each have their complications (9- through stenting of the coronary sinus that
11). Vascular access may be complicated by is closely related to the mitral annulus. It is
arterial rupture, apical tearing, and aortic likely that these 2 therapeutic approaches
dissection. Malsizing of the aortic prosthe- may be combined in the future to signifi-
sis may be complicated by valve emboliza- cantly enhance the durability of the repair,
tion, aortic annulus rupture and aortic dis- as evidenced by the surgical approach (20).
section. Errors in rapid transvenous ven- furthermore, the hybrid operating room
tricular pacing may allow ventricular ejec- will likely become their natural venue as
tion to interfere with balloon valvuloplasty cardiothoracic surgeons master these in-
and subsequent valve deployment. Errors novative approaches that have established
in aortic prosthesis positioning may be their safety and efficacy in clinical trials
complicated by valve prolapse, valve embo- (21). Indeed, it is logical that dual trans-
lization, coronary occlusion as well as rup- catheter aortic and mitral valve interven-
ture of the aortic root and left ventricular tions will be possible in the near future
outflow tract. The successful management once the individual technologies have en-
of complications depends on rapid and ef- tered clinical practice.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

J. Fassl, et al.

84 pEriopErAtivE conditioning has mostly been evaluated in small trials.

for myocArdiAl protEction Recent meta-analysis (cumulative n=933:
22 trials) confirmed its outcome benefits
Volatile anesthesia after cardiac surgery: protection against
Volatile anesthetics have been demonstrat- ventricular arrhythmias (odds ratio 0.11;
ed to condition the myocardium protec- 95% confidence intervals 0.04-0.29;
tively to better tolerate ischemia-reperfu- P=0.001) and inotrope sparing (odds ratio
sion (22, 23). The outcome importance of 0.34; 95% confidence interval 0.17-0.68;
this important characteristic of our volatile P=0.002) (29).
anesthetics was investigated in a massive Given the cumulative benefits of this in-
multicenter Italian CABG cohort study tervention, its perioperative safety and
(n=34 310: 64 centers) (24). Exposure efficacy should be further evaluated in ad-
to volatile anesthesia significantly low- equately powered clinical trials (29, 30).
ered perioperative mortality (P=0.035),
especially if there was prolonged duration Remote ischemic conditioning
(P=0.022) or if the volatile agent was iso- Remote ischemic preconditioning is de-
flurane (P=0.039). These positive findings fined as ischemic myocardial protection
add more weight to the argument that the following brief ischemia of a remote tissue
contemporary cardiac anesthetic should and has mainly been studied in small clini-
include a volatile component for optimal cal trials (31). Recent trials have confirmed
outcome (25). that this technique significantly reduced
the release of cardiac injury biomarkers
Levosimendan after PCI as well as both noncardiac and
Levosimendan is a calcium-sensitizing ino- cardiac surgery (32-36).
dilator that may exert beneficial outcome These promising data have generated the
effects when administered as soon as pos- mandate for a family of perioperative tri-
sible after anesthetic induction, including als (n=40: full details available at www.
reduced troponin release (P=0.0003) and, last accessed March 15th
hospital stay (P=0.05) (26, 27). A recent 2010). If the promise from the pilot trials
meta-analysis (cumulative n=440: 10 is consistently demonstrated across this
trials) confirmed that levosimendan ex- latest trial set, then this technique will
posure significantly reduced mortality af- gradually enter the mainstream of clinical
ter cardiac surgery (odds ratio 0.35; 95% practice.
confidence interval 0.18-0.71; P=0.003)
(28). These encouraging observations have SurgicAl mAnAgEmEnt
spawned multiple clinical randomized tri- of coronAry ArtEry diSEASE
als across both in adult and pediatric heart
surgery to more fully explore perioperative The dangers of perioperative
benefits due to levosimendan (full details angiotensin blockade
available at, last ac- Angiotensin-converting enzyme inhibitor
cessed March 17th 2010). (ACEI) therapy has already been highlight-
ed as an independent predictor for signifi-
Ischemic conditioning cant perioperative hypotension (37-39).
Although ischemic preconditioning con- A large observational study (n=10 023
fers significant ischemic tolerance to the CABG patients: 1996-2008) demonstrated
myocardium, its perioperative application that preoperative ACEI exposure signifi-

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

major themes for 2009 in cardiothoracic and vascular anesthesia

cantly increased mortality (P=0.04), re- ed that this technique was safe and effec- 85
nal dysfunction (P=0.0002), atrial fibril- tive as it did not independently predict ad-
lation (P<0.0001), and inotropic support verse outcomes (49).
(P<0.0001) (40) furthermore, recent data Consequently, adequately powered ran-
indicate that the perioperative vasoplegia domized trials are required to resolve this
associated with ACEI is dose-dependent controversy. These trials may have limited
(41). Based on these recent observations, subject enrollment as patients may be re-
it is reasonable to discontinue ACEI be- luctant to be randomized to endoscopic
fore CABG, as is currently recommended saphenous vein harvesting, given its well-
in noncardiac surgery (42). The vasoplegia known outcome disadvantages.
associated with ACEI exposure has been
managed successfully with vasopressin The controversy about the pump
given either prophylactically or therapeuti- in CAbG
cally (43, 44). Since the maturation of off-pump CABG,
its comparison with on-pump CABG has
The dangers of preoperative anemia been an ongoing question (50). A mas-
A massive observational trial (n=10 025: sive cohort comparison (n=63.047:
1998-2007 demonstrated that preoperative n=48.658 on-pump CABG; n=14.389 off-
anemia independently predicts mortality pump CABG) demonstrated no significant
after elective CABG (45). furthermore, it differences in perioperative mortality and
also independently predicts postoperative stroke with the off-pump cohort experienc-
renal dysfunction (46). ing clinically marginal increases in hospi-
These observations should trigger a great- tal length of stay and cost (51).
er focus with a new set of trials in cardiac A second cohort comparison (n=14.766
surgery to test the safety and efficacy of from 1997-2007: n=7.083 off-pump CABG;
preoperative hemoglobin augmentation n = 7.683 on-pump CABG) demonstrated
with interventions such as erythropoietin. that the off-pump technique preferential-
ly reduced mortality in high risk patients
The controversy about endoscopic (P=0.005) (52). These ‘real-world’ analy-
saphenous vein graft harvesting ses suggest that the CABGtechniques ap-
Endoscopic saphenous vein harvesting has pear equivalent, except in high-risk subsets
entered mainstream clinical practice due to where the off-pump technique may offer
its cosmetic and wound advantages. Since outcome advantages.
there may be more manipulation with this The controversy in CABG was further ex-
technique, there is conceptually the dan- plored in a recently published randomized
ger of venous endothelial trauma and pos- trial (n=2203) (53). This trial demon-
sible loss of long-term patency (47). In a strated that after one year, the off-pump co-
large observational CABG study (n=1753 hort had significantly worse outcomes and
in endoscopic harvest group; n=1247 in graft patencies.
open harvest group) endoscopic venous This trial has multiple limitations in its de-
harvesting significantly increased the risks sign, including multiple confounders such
of death, myocardial infarction or repeat as surgical inexperience, operative risk, and
revascularization (hazard ratio 1.22; 95% aprotinin exposure (54-56). In summary,
confidence interval 1.101-1.47; P=0.04) this randomized trial reflects the off-pump
(48). In contrast, a larger single center learning curve and its findings should be
study (n=5825: 1998-2007) demonstrat- confined to that domain.

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J. Fassl, et al.

86 pErcutAnEouS coronAry decreased mortality in STEMI managed

intErvEntion with primary fibrinolysis (95% confidence
interval 16%-20%; P<0.0001). The evi-
PCI for myocardial infarction dence supporting IABP in STEMI is weak
Although primary PCI is effective in STE- at best.
MI, its efficacy in ‘real-world’ settings is
still debated. (57). To address this concern, The new platelet blockers prasugrel
a recent meta-analysis included random- and ticagrelor
ized trials (n=8140: 23 trials) and obser- Prasugrel is a novel thienopyridine that
vational studies (n=185.900: 32 studies) blocks platelets more reliably than clopdo-
(58). Compared to fibrinolysis, primary grel. Both these agents block the adenos-
PCI reduced mortality in randomized tri- ine diphosphate P2Y12 receptor and both
als (odds ratio 0.66; 95% confidence inter- requires biotransformation in the liver to
val 0.51-0.82) and in observational studies form the active drug metabolites (61). In
(odds ratio 0.77; 95% confidence interval acute coronary syndromes, prasugrel was
0.62-0.95). In the set of observational stud- superior to clopidogrel for ischemic reduc-
ies, primary PCI had no significant long- tion (hazard ratio 0.81i; 95% confidence
term clinical outcome benefits. This meta- interval 0.73-0.90; P<0.001), but at the
analysis suggests that the substantial ben- expense of bleeding risk (hazard ratio
efits of PCI in STEMI are relevant in clini- 1.32; 95% confidence interval 1.03-1.68;
cal practice beyond the domain of strictly P=0.03) (62).
controlled randomized trials. A multicenter global randomized trial
furthermore, PCI should be routinely un- (n=3534) also demonstrated the superior-
dertaken within 6 hours after fibrinolyis. A ity of prasugrel over clopidogrel in STEMI,
recent randomized trial (n=1.059) dem- based on the composite endpoint of cardio-
onstrated that this approach significantly vascular death, MI or stroke (hazard ratio
decreased the incidence of an adverse out- 0.68; 95% confidence interval 0.54-0.87;
come endpoint (relative risk 0.64; 95% P=0.0017) (63). An important periopera-
confidence interval 0.47-0.87; P=0.004), tive observation from this trial was that
defined as a composite of death, reinfarc- prasugrel significantly increased bleeding
tion, recurrent ischemia, congestive heart after CABG (P=0.0033).
failure, or cardiogenic shock within 30 The thienopyridines, clopidogrel and
days (59). prasugrel, bind irreversibly to the plate-
let ADP P2Y12 receptor after hepatic bio-
Intra-aortic balloon pump therapy transformation and are therefore indirect
in myocardial infarction irreversible platelet inhibitors (64). The
Although intra-aortic balloon counter- novel thienopyridine, ticagrelor, binds di-
pulsation (IABP) has been recommended rectly to the platelet ADP P2Y12 receptor
for STEMI with cardiogenic shock, the and requires no hepatic activation (64). In
evidence supporting this recommendation acute coronary syndromes (n=18.624),
was examined in a recent meta-analysis ticagrelor was superior to clopidogrel,
(60). In the analysis of 7 randomized tri- based on the composite endpoint of cardio-
als (n=1.009), IABP did not improve out- vascular death, MI or stroke (hazard ration
come, and significantly increased stroke 0.84; 95% confidence interval 0.77-0.92;
and bleeding. In the analysis of 9 obser- P<0.001) (65). Ticagrelor did not signifi-
vational studies (n=10.529), IABP only cantly increase bleeding after CABG in this

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

major themes for 2009 in cardiothoracic and vascular anesthesia

large trial. Given these positive outcome surgery (71). This trial demonstrated no 87
effects, this drug will likely disseminate significant reduction in surgical re-explora-
throughout clinical practice. tion (P=0.42), mortality (P=0.90), and a
trend towards increased stroke (P=0.09).
PCI or CAbG for multivessel coronary In a randomized adult cardiac surgical trial
artery disease (n=172), exposure to factor VII significant-
A large single center observational trial ly reduced surgical re-exploration (P=0.03)
(n=3.720: 2004-2005) demonstrated that and allogeneic transfusion (P=0.01) with
at 3 years PCI significantly increased death no significant increase in serious adverse
(hazard ratio 1.62; 95% confidence inter- events (72). further trials are required to
val 1.07-2.47) and MI (hazard ratio 1.65; more adequately explore the safety and ef-
95% confidence interval 1.15-2.44) (66). ficacy of this hemostatic intervention in car-
In a larger pooled analysis (n=7.812: diac surgery with massive bleeding.
10 trials), CABG was superior to PCI for
mortality reduction only in 2 subgroups, Can the kidney be protected after
namely diabetics (hazard ratio 0.70; 95% cardiac surgery?
confidence interval 0.56-0.87; P=0.014) The search for nephroprotective strategies
and the elderly (hazard ratio 0.82; 95% in cardiac surgery is ongoing. In a small
confidence interval 0.70-0.97; P=0.002) randomized trial (n=92), fenoldopam sig-
(67). further trials are required to explore nificantly reduced the risk of renal replace-
the survival benefits of CABG in multives- ment therapy (P=0.037) (73). A larger
sel CAD. randomized trial (n=504) demonstrated
that perioperative atrial natriuretic peptide
Perioperative bleeding and transfusion is nephroprotective (P<0.0001) and sig-
Excessive bleeding after cardiac sur- nificantly reduces postoperative complica-
gery significantly increases the risks of tions (P=0.0208) (74). In a pilot random-
prolonged mechanical ventilation, pro- ized trial (n=100), perioperative sodium
longed stay in the intensive care unit stay bicarbonate infusion significantly reduced
(P<0.001), and death (P<0.001) (68). renal injury after on-pump cardiac surgery
Volume resuscitation with the artificial (odds ratio 0.43; 95% confidence interval
colloid hetastarch in off-pump CABG 0.19-0.98; P=0.043) (75). These promis-
(n=156: I liter of hetastarch versus I liter ing nephroprotective agents are currently
of albumin) significantly increased medias- being further evaluated in more than 50
tinal bleeding (P<0.001), transfusion risk randomized trials (full details available
(P=0.012), and transfusion dose (packed at, last accessed
red blood cells P=0.017; fresh frozen plas- March 19th 2010).
ma P=0.009; and, platelets (P=0.013) In contrast, a large trial (n=563) impli-
(69). Although n-acetylcysteine can be cated pentastarch exposure as a significant
nephroptotective perioperatively, it can predictor of renal dysfunction after cardiac
significantly increase mediastinal bleed- surgery (odds ratio per mL/kg 1.08; 95%
ing (P=0.008), red blood cell transfusion confidence interval 1.04-1.12; P=0.001).
P=0.02) and the risk of receiving≥5 units This trial also demonstrated that this
of red blood cells (P=0.005) (70). nephrotoxicity is dose-dependent with a
A recent meta-analysis (cumulative n=298: threshold value of 14 ml per kilogram body
5 trials) explored the safety and efficacy of weight (76). Given the current focus on
factor VII therapy for hemostasis in cardiac the importance of renal function in adult

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

J. Fassl, et al.

88 cardiac surgery, it is likely that the ongo- outcome after CABG. off-pump CABG
ing clinical development of perioperative with experienced perioperative teams may
nephroprotective interventions will re- improve outcomes in high-risk patients.
main a priority. Endoscopic saphenous vein harvesting
may compromise graft patency. The man-
Does tight glucose control matter? agement of STEMI should almost always
Tight perioperative management of glucose include PCI, but the evidence for IABP in
remains controversial in cardiac surgery this important disease is far less conclu-
(77). In a recent large randomized trail in sive.
critically ill adults (n=6.014), intensive The novel platelet blockers prasugrel and
insulin therapy significantly increased ticagrelor are likely to transform current
mortality (odds ratio 1.14; 95% confidence practice of antiplatelet therapy in cardio-
interval 1.02-1.28; P=0.02) and severe hy- vascular diseases. Although PCI is a rea-
poglycemia (P<0.001) (78). sonable option in multivessel CAD, CABG
Recent meta-analysis of intensive insulin offers a survival advantage in diabetics and
therapy in the intensive care unit (n=13 the elderly. Hetastarch and n-acetylcyste-
567: 26 trials) has demonstrated that this ine may worsen bleeding and transfusion
intervention decreased mortality in the in cardiac surgery. Although factor VII can
surgical intensive care unit (relative risk arrest massive bleeding, further trials are
0.63; 95% confidence interval 0.44-0.91) required to explore its safety. Recent ran-
but not in medical (relative risk 1.0; 9%% domized trials have shown that fenoldo-
confidence interval 0.78-1.28) or mixed in- pam, atrial natriuretic peptide and sodium
tensive care units (relative risk 0.99; 95% bicarbonate are significantly nephropro-
confidence interval 0.86-1.12) (79). The tective in cardiac surgery. Although peri-
Society of Thoracic Surgeons recommends operative glucose management (goal glu-
insulin infusion to maintain perioperative cose level ≤180 mg/dL) improves outcome
glucose levels below 180 mg/Dl (80). in adult cardiac surgery, this benefit is not
universal across all hospital settings. More
intensive insulin therapy is not indicated
concluSionS since it does not improve outcome and car-
ries a significant hypoglycemic risk. The
The hybrid operating room is likely to be- year 2009 has witnessed major advances
come the ideal venue for transcatheter car- cardiothoracic and vascular anesthesia
diovascular therapy. Transcatheter aortic with new devices, new clinical venues, and
valve implantation will gradually encour- new drugs.
age further innovations as the revolution
in transcatheter management of cardiovas- No conflict of interest acknowledged by the authors.
cular diseases matures. Myocardial condi-
tioning with volatile anesthetics and levo-
simendan significantly protect the heart
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operative trials. Perioperative angiotensin tic valve implantation: a case series. J Cardiothorac
blockade and anemia significantly worsen Vasc Anesth 2009; 23: 286-291.

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in Intensive Care
Cardiovascular Anesthesia

rEviEw ArticlE
Endorsed by

post cardiac arrest therapeutic
hypothermia in adult patients, state
of art and practical considerations
P.F. Beccaria1, S. Turi1, M. Cristofolini2, S. Colombo1, C. Leggieri1,
F. Vinciguerra1, A. Zangrillo1
Department of Anaesthesia and Intensive Care, Università Vita-Salute San Raffaele, Milano, Italy;

Department of Anaesthesia and Intensive Care, Ospedale Santa Chiara, Trento, Italy

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 93-103

The importance of therapeutic hypothermia in selected categories of patients has been widely demonstrated.
Laboratory, animal, and human studies permitted to understand the molecular mechanisms underlying cool-
ing and its importance in preventing the ischemia/reperfusion injury of the brain. The development of new
technologies offered the possibility to reach the desired temperature effectively and rapidly, reducing related
side effects. nevertheless, the application of systematic protocols of cooling has not been adequately reached
in many hospitals. In this paper the most recent findings regarding hypothermia, its physiological bases and
ways of application are reviewed.

Keywords: therapeutic hypothermia, cardiac arrest, ischemia-reperfusion injury, neuroprotection, cooling, re-

out-of-hospital cardiac arrest claims cooling methods, apart from some farsee-
225,000 lives each year in the United States ing and lonely voices as Peter Safar (3), the
and a similar number in Europe, accounting curtain falls over therapeutic hypothermia
for about half of all deaths due to cardiovas- (TH) in the following decades.
cular disease (1). Even when resuscitation After almost forty years of oblivion, inter-
efforts are successful, recovery is too often est in cooling was rekindled in the early
limited by post-anoxic encephalopathy. 1980s by the positive results from animal
The interest regarding hypothermic thera- experiments suggesting that neurological
py to protect brain after cardiac arrest start- outcome could be improved by using mild
ed in late ’50s of the past century and the to moderate hypothermia (31°C-35°C)
first publication dates 1959 (2). rather than deep hypothermia (30°C), with
In spite of promising evidences, mostly be- far fewer and less severe side effects (4-6).
cause of the absence of simple and reliable following the promising results obtained
from laboratory and animal models, in
2002 two important randomized multicen-
Corresponding author: tric studies on humans were realized (7, 8).
Paolo federico Beccaria
Department of Anaesthesia and Intensive Care, In the first, the European Hypothermia af-
Università Vita-Salute San Raffaele
Via olgettina, 60 - 20132 Milan, Italy
ter cardiac arrest study group enrolled 275
email: patients, with 137 patients randomly as-
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
P.F. Beccaria, et al.

94 signed to the hypothermia group and 138 of presumed cardiac etiology, active induc-
to the normothermia group. (i.e., the group tion of hypothermia was beneficial (class
that received standard care after resusci- IIa). Similar therapy may be beneficial for
tation). The study included only patients patients with non-Vf arrest out of hospital
who had been resuscitated after witnessed or for in-hospital arrest (class IIb).
out-of-hospital cardiac arrest due to ven- Although eight years passed from the origi-
tricular fibrillation (Vf) that were random- nal publications and several studies clari-
ly assigned to undergo TH (target bladder fied many mechanism of TH and described
temperature, 32°C to 34°C) over a period feasibility and efficacy of different cooling
of 24 hours or to receive standard treat- methods (10, 11), this therapeutic approach
ment with normothermia. The tempera- is far from being extensively and widely
ture was maintained at 32°C to 34°C for used in everyday practice.
24 hours from the start of cooling, followed In a survey carried out in 2005 in the US
by passive rewarming, which was expect- (12), of 265 physician (practicing emer-
ed to occur over a period of 8 hours. This gency medicine, critical care and cardiol-
study demonstrated that systemic cooling ogy) who were asked if they had ever used
increases the chance of survival and of a fa- TH after cardiac arrest, 87% answered
vorable neurological outcome, as compared no. Among reasons for non-use they men-
with standard normothermic life support tioned not enough data to support TH,
without significant differences in terms of non-inclusion in ACLS protocol or techni-
complications in the two groups. cal difficulties.
In the second study 77 patients who re- While a recent survey carried out on all
mained unconscious after resuscitation UK intensive care units showed that 85%
from out of hospital cardiac arrest were of departments considered TH as a part of
randomly assigned to treatment with hy- post cardiac arrest management with a ma-
pothermia (33° C core body temperature jor implementation in use on the last three
for 12 hours) or normothermia. In the TH years (13), another recent review under-
group 49% survived with a good outcome lined that an informal online survey of car-
(home or rehabilitation facility discharge) diology conference attendees showed that
compared with the 26% (P=0.046) of the 20% of respondents were even aware of the
normothermia group. American Hospital Association guidelines
Considering these results, the 2005 Ameri- (14).
can Heart Association guidelines for car- Many studies tried to identify the reasons
diopulmonary resuscitation and post resus- why, despite scientific evidence, TH fa-
citation support concluded that clinicians tigues to reach a routinely utilization. A
should not actively rewarm hemodynami- recent study conducted on a 43 Canadian
cally stable patients who spontaneously de- hospital network identifies some pivotal
velop a mild degree of hypothermia (33°C) elements: lack of familiarity and availabil-
after resuscitation from cardiac arrest (9). ity of concrete TH protocols, availability
The same guidelines state that mild hypo- of equipment, equipment costs, and higher
thermia may be beneficial to neurologic workload demands for emergency nurses
outcome and is likely to be well tolerated are the most perceived barriers. Awareness
without significant risk of complications. of these general, individual and local bar-
In a select subset of patients who were riers may improve adherence to evidence-
initially comatose but hemodynamically based practice (15).
stable after a witnessed Vf cardiac arrest Moreover, the majority of out-of-hospital

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

post cardiac arrest therapeutic hypothermia

cardiac arrest patients nowdays are con- Promising data come from the utilization of 95
ducted to emergency medical services with bispecrtal index (BIS) and suppression ra-
non-Vf (pulseless electrical activity, asys- tio during TH as an early predictor of neu-
tole) as the initial cardiac rhythm, for this rologic outcome (23, 24).
reason, clinicians have to decide whether for the future, larger prospective studies
or not to use TH in this patient group, con- are needed to re-assess the validity of tradi-
sidering the feasibility, possible benefit, and tional clinical, biochemical and instrumen-
potential adverse side effects of hypother- tal outcome predictors in patients treated
mia in patients with neurological injury with hypothermia and the identification of
who have been resuscitated from non-Vf good outcome predictors is of paramount
cardiac arrest (16). importance.
Some studies tried to evaluate feasibility and
efficacy of TH in other medical emergency
situations and with cardiac arrest presenta- mEchAniSmS of Action
tion rhythms different from Vf (17-19), al-
though some authors believe that it will be Animal and laboratory findings during
difficult to find significant evidence due to 1980s and 1990s allowed a better knowl-
the low incidence and poor outcome of this edge of the molecular mechanisms under-
condition. As Bernard maintains, these tri- lying hypothermia, helping to define ad-
als would require a very large sample size to equate strategies of cooling and to prevent
detect a significant change in an important possible side effects.
outcome measure such as survival with In the 1950s and 1960s, when the first
good neurological function. procedures of cooling were realized, it was
Bernard et al suggest that, considering the presumed that the beneficial effects of hy-
few adverse effects related to the use of hy- pothermia were related to the reduction of
pothermia and their relatively easy man- brain metabolic requests (25). Although
agement, it would appear reasonable for this statement is correct (a decrease in ce-
clinicians to cool most patients with sus- rebral metabolism by 6% to 10% for each
pected neurological injury following pro- grade of body temperature reduction has
longed cardiac arrest, whatever the initial been observed) this is not the unique in-
cardiac rhythm (20). volved mechanism (26).
Since a recent retrospective study (21) con- Brain damages after a cardiac arrest may be
ducted on 491 patient shows no significant considered as a model of ischemia-reperfu-
improvement in neurologic outcomes in sion injury. Animal and laboratory findings
patients whose initial rhythm was different during ’80s and ’90s showed an increase in
from Vf, further prospective studies are apoptosis, a dysfunction in mitochondrial
needed to clarify whether TH is effective activity, and an alteration in ion pump
also in asystole and pulseless electrical ac- function controlling the influx of calcium
tivity or not. into cells (27). During cooling an inhibition
Another key point for the future is the iden- of caspase enzyme activation, a prevention
tification of poor and good outcome predic- of mitochondrial dysfunction, a decreased
tors after TH post cardiac arrest. Glasgow overload of excitatory neurotransmitters,
Coma Scale monitoring and particularly and a modification of intracellular ion con-
motor response from third day after cardiac centrations were observed, (28, 29). Im-
arrest remains a powerful tool to predict mune system is also activated in the injured
outcome of patients treated with TH (22). brain. one hour after the ischemic insult

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

P.F. Beccaria, et al.

96 an increase of inflammatory molecules (in- the brain and in other sites reproducing the
terleukin-1, tumor necrosis factor alpha) natural haemostasis of vasoactive agents
released by microglia, endothelial cells and (38).
astrocytes is detectable (26). This phe- In some patients, during the post-ischemic
nomenon is associated to chemotaxis and phase, it is also detectable an epileptic ac-
complement system activation facilitating tivity, probably associated to the ongoing
neutrophil, macrophages and monocytes brain damage. Hypothermia is associated to
passage trough the endothelium (30). a reduction in the convulsive activity, pro-
numerous animal experiments and some viding an adequate neuro-protection (39).
clinical studies showed that hypothermia Hypothermia increases the expression of
suppresses ischemia-induced inflammatory the so called immediate early genes, which
reactions and release of pro-inflammatory are a part of the protective cellular stress
cytokines and decreases the production of response to injury, and stimulates the in-
nitric oxide, which is a key agent in the duction of cold shock proteins, which can
development of post-ischemic brain injury protect the cell from ischemic and traumat-
(31). In addition, hypothermia can impair ic injury (40). Ischemia-reperfusion also
neutrophil and macrophage function, re- leads to substantial rises in cerebral lactate
ducing white blood cell count (32). levels that are shown to be reduced during
Another mechanism of damage is related cooling (41). The importance of the protec-
to the increase of free radicals such as su- tive effect of hypothermia on the brain can
peroxide, peroxynitrite, hydrogen peroxide, also be deduced by the observation that fe-
and hydroxyl radicals that play an impor- ver is associated with an increase risk for
tant role in determining whether injured adverse outcome, worsening mortality in
cells will recover or die (33). Cooling seems brain injures (42).
to reduce the production of free radicals and
to mitigate the damage, allowing the cells a Cooling strategy
better recovery after injury. This function Thanks to a better knowledge of hypother-
and the ability in preserving the integrity of mia mechanisms a rationale approach and
blood-brain barrier also determine a reduc- management of cooling strategy was es-
tion of cerebral edema and the consequent tablished and three main phases identified
intracranial hypertension (34). (43).
In addition, brain glucose utilization is af- The first is the induction phase, with the
fected by ischemia-reperfusion, and there target to reach a mild hypothermia (a core
is evidence suggesting that hypothermia temperature between 32°C-34°C), as soon
can improve brain glucose metabolism; in as possible. Some animal experiments
particular the ability of the brain to utilize suggest that neuro-excitotoxicity can be
glucose (35). blocked or reversed only if the treatment
A disruption in equilibrium of vaso-active is initiated in the very early stages of the
substances such as endothelin, thrombox- neuro-excitatory cascade (44). other stud-
ane A2 (TxA2), and prostaglandin I2, fol- ies have reported somewhat wider time
lowing an ischemic or traumatic event, can frames, ranging from 30 minutes to up to 6
lead to vasoconstriction, hypoperfusion, hours (45). The possibility of reaching hy-
and thrombogenesis in injured areas of the pothermia in the field for out-hospital car-
brain (36, 37). diac arrest is still object of debate. one not
Several studies showed how hypothermia adequately powered trial demonstrated a
affects the local secretion of these agents in trend toward a better neurological outcome

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

post cardiac arrest therapeutic hypothermia

when cooling was started out-of-hospital (32°C-34°C), cardiac output decreases by 97

with 4°C saline rapid infusion (17), and 25% to 40%, mainly due to a decrease in
preliminary data from the PRInCE study heart rate; since metabolic decrease exceeds
showed that cooling before RoSC with a cardiac output reduction, overall circula-
nasal cooling device is feasible, and in se- tory system result unchanged or improved.
lected groups of patients allowed higher At 32°C heart rate usually decrease around
neurologically intact survival rate when 40-45 beats per minute and when heart
compared with TH started in hospital (19). rate is allowed to decrease, systolic function
The second phase is the maintenance one, usually increases. Conversely myocardial
with the aim to maintain core temperature contractility decreases when chronotrop-
as close as possible to the target (maximum ic agents are administrated or a pacing is
fluctuation 0,2-0,5 0C). placed; if an increase in heart rate is nec-
The third phase is the rewarming period, essary rewarming the patient to a slightly
which consists in a slow and controlled re- higher temperature may be sufficient. oc-
turn to normothermia (0,2-0,3 0C/h). This currence of malignant arrhythmias is de-
phase starts 24 hours after hypothermia in- scribed only for severe hypothermia (53,
duction and ends when the patient reaches 54).
normothermia. Slow de-cooling avoids vio- The increase in venous return induced by
lent hemodynamic fluctuations and electro- hypothermia can lead to activation of atrial
lytes disorders and prevent hypoglycemia natriuretic peptide and a decrease in the
due to increased insulin sensitivity. More- levels of anti-diuretic hormone leading to
over some studies (46, 47) suggest that rap- a marked increase in diuresis, which may
id rewarming could reverse some protective lead to hypovolemia, renal electrolyte loss,
effects of hypothermia while a significant and hemoconcentration with increased
decrease in jugular venous oxygen satu- blood viscosity (55). Hypovolemia is the
ration during rapid rewarming of patient most frequent cause of haemodinamic in-
following cardiac surgery is demonstrated stability during the induction phase, its pre-
(48, 49), and the incidence and severity of vention and prompt treatment is of pivotal
jugular bulb desaturation may be lessened importance (56).
by a slower rewarming. Hypothermia also induces electrolytic dis-
Each TH phase is characterized by physi- orders: during the induction phase potas-
ological changes. Shivering is a protective sium and magnesium levels decrease due to
strategy activated by human organism in urinary loss and intracellular shift. While
contrast to temperature loss and leads to an electrolytes correction may prevent ar-
undesirable increase in metabolic rate and rhythmias, it is necessary to consider that
oxygen consumption (50). in the rewarming phase electrolytes move-
Its prevention and aggressive treatment ment occur in the opposite direction (57).
requires subsequent steps: a rapid cooling In cooled patients a reduction in metabo-
below 34°C, magnesium administration, lism is also observed. Caloric intake and
adequate sedation and analgesia, and even- mechanical ventilation should be decreased
tually neuromuscular blockade (51). Some in order to balance o2 and Co2 and to avoid
authors describe benefits from skin warm- alterations that can worse the ischemic/re-
ing during cooling (52). Shivering preven- perfusion injury (58).
tion and treatment is of paramount impor- A decreased insulin secretion and, in many
tance to avoid TH benefits loss. patients, a moderate (and sometimes se-
During mild to moderate hypothermia vere) insulin resistance is observed. This

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

P.F. Beccaria, et al.

98 can lead to hyperglycaemia and/or a signifi- curs but they normalize once normothemia
cant increase in doses of insulin required is reached.
to maintain glucose levels within an accept- In table 2 a list of laboratory and instru-
able range (59). mental tests we use in our department to
Despite standard coagulation tests will monitor and prevent changes, side effects
show no abnormalities unless they are per- and potential complications due to TH.
formed at the patient’s actual core temper-
ature, due to effects on platelet count and Cooling methods
function, kinetics of clotting enzymes and After having identified patient to cool and
other steps in the coagulation cascade, hy- excluded conditions that contraindicate
pothermia produces a mild bleeding diathe- TH (Table 1), clinicians should start cool-
sis (60-64). ing as soon as possible and should consider
Hypothermia begins to affect platelet func- the different options to get the target tem-
tion only when temperature decrease be- perature.
low 35°C, and other coagulation factors are needs for other procedures such as percu-
affected when temperature decrease below taneous coronary intervention shouldn’t
33°C (60-64); the risk of clinically signifi- delay cooling, as TH during percutanue-
cant bleeding induced by hypothermia in ous transluminal coronary angioplasty is
patients who are not already actively bleed- shown to be feasible and safe (69).
ing is very low.
Drugs clearance is affected by cooling, the table 1 - Indications and contraindications to thera-
half-life is increased and higher plasmatic peutic hypothermia.
concentrations are achieved with the same indicAtionS:
doses (64). This must be kept on mind •• Return of Spontaneous Circulation (RoSC) af-
while administrating sedatives, analgesics, ter cardiac arrest (any rhythm of presentation,
any location)
neuromuscular blockade agents or other re- •• Coma (does not open eyes to pain, does not fol-
quired medicaments. low verbal command)
Multiple evidences show that hypothermia •• Age ≥18
can suppress epileptic activity (65-67), even
if during TH antiepileptic medicaments are •• Time from RoSC >6 h
administered for patient sedation, continu- •• other possible causes for coma (stroke, intoxi-
ous EEG monitoring is recommended when cation, head trauma, hypoglicaemia, seizures)
seizures or non-seizures epileptic activity is •• Significant pre-existing neurologic impairment
•• Systolic arterial pressure <90 mmHg despite
suspected, especially when muscle relaxant fluids and vasopressors
are required for shivering control. •• Refractory Ventricular Arrhythmia
Hypothermia impairs immune functions •• Pre-existing coagulopaty or severe bleeding
and inhibits various inflammatory re- (Disseminated Intravascular Coagulation, se-
vere thrombocytopenia, liver failure)
sponses, increasing the risk of infections noTE: anticoagulant and antiplatelet therapy
(68). Incidence of pneumonia is described are not a contraindication
to increase in some cases, particularly for •• Pregnancy
prolonged hypothermia and some authors •• Sepsis
•• Known pre-existing terminal illness
suggest prophylactic treatments. Appropri-
ate attention must be taken in wound care SuSpEnd cooling protocol whEn:
(68). •• sepsis or pneumonia
other minor alteration, like transient im- •• refractory haemodynamic instability
•• severe refractory arrhythmia
paired bowel function or amylase count oc-

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

post cardiac arrest therapeutic hypothermia

table 2 - Timetable for laboratory and instrumental tests in use in our institute. 99
time from th induction (h) 0 2 8 12 16 24 36 48 72
Blood Urea nitrogen Creatinine ⊗ ⊗ ⊗ ⊗
Albumin, Proteinaemia ⊗ ⊗ ⊗ ⊗
Creatine Phosphokinase ⊗ ⊗ ⊗ ⊗ ⊗ ⊗
Aspartate Transaminase
Alanine Transaminase Lactate ⊗ ⊗ ⊗ ⊗ ⊗ ⊗
dehydrogenase bilirubin
Creatine Kinase Myocardial
⊗ ⊗ ⊗ ⊗ ⊗ ⊗
Band isoenzyme, Troponin
Coagulation tests ⊗ ⊗ ⊗ ⊗
Amylase, lipase ⊗ ⊗ ⊗
Lactate ⊗ ⊗ ⊗ ⊗
Complete Blood Count ⊗ ⊗ ⊗ ⊗
Arterial Blood Gas
⊗ ⊗ ⊗ ⊗ ⊗ ⊗ ⊗ ⊗
+ electrolytes + glycaemia
Electrocardiography ⊗ ⊗ ⊗ ⊗ ⊗ ⊗
Echocardiography ⊗ ⊗
Chest X-Ray ⊗ ⊗

(continuous when needed)
Evoked potential ⊗
Computed Tomography scan
(if need to exclude other causes ⊗
for coma)

first of all a temperature probe must be po- trolled rewarming is to integrate different
sitioned. The site chosen to measure core cooling methods.
temperature is of key importance. Pulmo- Administration of cold fluids in the induc-
nary artery catheter is the gold standard for tion phase is a common, practical, effective,
core temperature detection but risks linked safe and cheap procedure. A rapid bolus of
to the procedure must be considered; oe- 20-30 ml/kg 4°C isotonic saline solution is
sophageal and bladder probes are less pre- effective in decreasing temperature and its
cise and slower in detecting temperature use is supported by multiple evidences in
changes but widely used due high correla- pre-hospital setting as in emergency depart-
tion to core temperature, relative simple po- ment (70-74).
sitioning and few side effects. Modern cooling devices work in a con-
Tympanic probes are also used, particu- trolled feedback manner, continuously
larly indicated for out-of-hospital measure- measuring patient’s temperature and con-
ments, they are quick and easy to place, sequently changing the temperature of the
may reflect brain temperature but readings cooling elements (catheters, pads, or blan-
sometimes may be inaccurate. kets).
The best way to achieve rapid cooling, tem- Intravascular cooling devices permit to
perature maintenance and a slow and con- achieve a tight temperature control but are

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

P.F. Beccaria, et al.

100 affected by risks and complications of cen- ers. Extensive and rapid diffusion of pro-
tral venous catheterization (75, 76). tocols and process issues, further training
Surface cooling devices allow a good tem- and more studies in this field are essential
perature control, are well tolerated and key points for new developments and TH
relative safe because of the infrequency of application increasing.
overcooling and lack of vascular catheter-
ization complications and are useful for No conflict of interest acknowledged by the authors.
maintenance of normotermia after cooling
(70). Both this kind of devices represent, at rEfErEncES
the moment, the best and preferred choice
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hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

in Intensive Care
Cardiovascular Anesthesia

rEviEw ArticlE
Endorsed by

volatile anaesthetic myocardial
protection: a review
of the current literature
E. Lin, J.A. Symons
Department of Anaesthesia and Perioperative Medicine, Alfred Hospital, Monash University; Melbourne, Australia

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 105-109

Ischaemic preconditioning is a powerful innate adaptive phenomenon whereby brief periods of sublethal isch-
aemia result in marked tolerance to subsequent lethal ischaemia. Halogenated anaesthetics have been shown
to mimic ischaemic preconditioning, modifying and attenuating ischaemia reperfusion injury.
This review aims to present the current animal and human data, discuss the possible mechanisms of action
and review the clinical evidence for volatile anaesthetic-induced myocardial protection.
There is class Ia evidence for the myocardial protective properties of sevoflurane and desflurane in low risk
patients undergoing coronary artery bypass grafting surgery.
These volatile anaesthetics have been shown to improve clinical outcomes and health economics following
cardiac surgery, reducing intensive care and hospital stay. The evidence for the benefit of volatile anaesthetics
in non-cardiac surgery is less robust and further large randomized controlled trials are required to elucidate
this question.

Keywords: volatile anaesthetics, myocardial protection, ischaemic preconditioning, mechanisms, cardiac anaes-
thesia, outcomes.

introduction Mechanism of myocardial protection

Ischaemic preconditioning is a powerful in-
There is strong evidence for volatile anaes- nate adaptive phenomenon discovered by
thetic induced myocardial protection in ex- Murry and colleagues (1), whereby brief
perimental studies. periods of sublethal ischaemia results in
Despite this weight of evidence in animal marked tolerance to subsequent lethal isch-
studies, the translational into human trials aemia. Halogenated anaesthetics have been
has borne less consistent results. shown to mimic ischaemic precondition-
This review aims to present the current an- ing, modifying and attenuating ischaemia
imal and human data, discuss the possible reperfusion injury (2).
mechanisms of action and review the clini- Two periods of ischaemic preconditioning
cal evidence. have been described; early or classical pre-
conditioning that occurs immediately, and
induces potent protection that lasts one to
Corresponding author: two hours.
Joel A Symons, MD
Department of Anaesthesia and Perioperative Medicine, Late preconditioning or the second win-
Alfred Hospital, Monash University
Victoria, 3800 - Melbourne, Australia
dow of preconditioning occurs 24 hours
e.mail: after the initial stimulus, induces a less pro-
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
E. Lin, J.A. Symons

106 nounced cardio-protection, but lasts for up ly separate these two protective effects of
to 72 hours (3). volatile anaesthetics on the myocardium.
Early and late preconditioning probably This is best demonstrated by the fact that
involves different signalling pathways that studies have also suggested the maximum
have yet to be fully elucidated. Early pre- protection is yielded by the administration
conditioning is thought to involve opening of volatile anaesthetics throughout the op-
mitochondrial ATP dependent potassium erative procedure (18).
channels (4-9), increasing mitochondrial
reactive oxygen species (4, 10, 11), decreas- Clinical evidence in cardiac surgery
ing cytosolic and mitochondrial calcium Since 1985, when freedman and colleagues
loading (12), protection of endothelial (19) reported that enflurane could im-
coronary cells by mediating nitric oxide prove post-ischemic myocardial recovery,
release (13) and by suppressing neutrophil there has been extensive research into the
activation and the neutrophil-endothelium potential benefits of anaesthetic myocar-
interactions that cause myocardial dysfunc- dial protection in both animal and human
tion (14, 15). models. The majority have been performed
Pathways of late preconditioning involve on patients undergoing CABG (coronary
attenuation of nuclear factor kB (nfkB), artery bypass grafting). Unfortunately, to
activation and reduced expression of tu- date, these studies have been observational
mour necrosis factor k (Tnfk), interleu- in nature or if randomized have been too
kin 1 (IL1), intracellular adhesion mol- small and underpowered to identify effects
ecules, enoS, a reduction of the hyper- on significant outcomes such as myocardial
contraction that follows reperfusion and infarction and mortality. Studies have gen-
activation of anti-apoptotic kinases (Akt, erally used surrogate markers for myocardi-
ERK 1-2) (2). al protection such as the cardiac troponins
Volatile anaesthetics have been shown in a as a measure of myocardial injury.
number of animal ex vivo and in vivo ex- To date there have been 3 meta-analyses
periments to be able to precondition the performed including only randomized con-
myocardium in a similar way to classical trolled trials (RCTs) to try and answer the
ischaemic preconditioning. Similarly, vol- question does volatile anaesthesia improve
atile anaesthetics have the ability to post- outcomes in coronary surgery?
condition the myocardium whereby ex- Yu and Beattie performed the first meta-
posure to volatiles during the reperfusion analysis in 2006 (20). The authors identi-
period also protects the myocardium (16). fied 32 randomized studies involving 2841
There is now increasing evidence that vola- patients. Volatile anaesthetics included hal-
tile anaesthetics can induce late precondi- othane, enflurane, isoflurane, sevoflurane
tioning, raising the potential of myocardial and desflurane and were administered in
protection that persists after the exposure any combination of the pre-bypass, during
in the operating theatre (16, 17). bypass and post-bypass periods. When com-
In addition to the ability to precondition pared with intravenous anaesthetics, those
the myocardium, all volatile anaesthet- who were exposed to volatile anaesthetics
ics induce a dose dependent decrease in had an observed reduction in mortality that
myocardial contractility, decrease myocar- did not reach statistical significance (oR,
dial oxygen demand and therefore improve 0.65; 95% CI 0.36-1.18). furthermore, re-
myocardial oxygen balance during isch- moving studies that used halothane or en-
aemia. It is often difficult to experimental- flurane in their study protocols also failed

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

volatile anaesthetic myocardial protection

to show a statistically significant reduction ics throughout the entire procedure. only 107
in mortality. Similarly, no statistical differ- a few of the RCTs were of high quality and
ence was seen in the incidence of AMI be- all the studies included numbers that were
tween groups. However, post hoc analysis too small to allow for assessment of impor-
of patients that received sevoflurane or des- tant clinical outcome variables such as AMI
flurane showed that these patients experi- and death.
enced significantly less Troponin I leakage Data pooling and analysis showed that
than patients receiving intravenous anaes- when compared with intravenous anaes-
thesia. thesia, sevoflurane and desflurane were
Symons and Myles performed a similar associated with significant reductions in
meta-analysis in 2006 (21). They identified the rates of all major clinical outcome vari-
27 randomized studies including 2979 pa- ables. Volatile anaesthesia significantly re-
tients comparing volatile with non-volatile duced the degree of troponin I leakage (oR
anaesthesia for CABG. Volatile anaesthetics 0.47; 0.29, 0.76). Importantly, the risk of
again included halothane, enflurane, isoflu- all-cause mortality and AMI was also sig-
rane, sevoflurane and desflurane and were nificantly reduced by volatile anaesthesia
administered during pre-bypass, bypass and (oR 0.31; 0.12,0.80 and oR 0.51; 0.32,0.84
post-bypass periods. There was no signifi- respectively). furthermore, the use of sevo-
cant difference between volatile and non- flurane and desflurane was associated with
volatile anaesthetic groups with respect to a significant reduction in the duration of
death, myocardial infarction, myocardial mechanical ventilation, length of ICU stay
ischaemia or ICU length of stay. However, and time to hospital discharge.
patients randomized to receive volatile an- Though this represents strong class Ia evi-
aesthetics had significantly higher cardiac dence for myocardial protection with mod-
indices, lower troponin I concentrations, ern volatile anaesthetic agents in patients
reduced requirement for inotropic support, undergoing CABG, results from a large ob-
shorter duration of mechanical ventilation servational study published in 2007 are not
and shorter length of hospital stays than quite so conclusive. Data from a retrospec-
those randomized to receive intravenous tive Danish database of 10,535 patients un-
anaesthetics. The results indicated that dergoing cardiac surgery with sevoflurane
volatile anaesthetics may indeed be able to or propofol anaesthesia showed no differ-
change outcomes in cardiac surgery. ence in overall post-operative mortality or
More recent animal evidence suggests that myocardial infarction (28). The group sur-
sevoflurane and desflurane display more mise that both propofol and sevoflurane
prominent cardioprotection than the older have different cardioprotective properties.
halogenated anaesthetics (22-26). This lead Sub-group analysis revealed that in patients
to the most recent meta-analysis performed undergoing non-coronary cardiac surgery,
by Landoni and colleagues in 2007 (27). sevoflurane was superior to propofol whilst
Their group identified 22 randomised stud- propofol was superior to sevoflurane in
ies involving 1922 patients where compari- patients with severe ischaemia, cardiovas-
sons of the modern volatile anaesthetics cular instability or those requiring urgent
sevoflurane and desflurane were made with surgery. This finding may reflect the anti-
intravenous anaesthesia in CABG surgery. oxidant properties of propofol and the isch-
Most studies were performed on patients aemic preconditioning effect of unstable
undergoing on-pump CABG and most au- angina negating the myocardial protection
thors administered the volatile anaesthet- offered by volatile anaesthesia.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

E. Lin, J.A. Symons

108 Clinical evidence in non-cardiac surgery 2. Landoni G, Bignami E, oliviero f, zangrillo A.

Landoni and colleagues performed a meta- Halogenated anaesthetics and cardiac protection
in cardiac and non-cardiac anaesthesia. Ann Card
analysis of RCTs comparing sevoflurane or Anaesth 2009; 12: 4-9.
desflurane anaesthesia with intravenous 3. Yellon DM, Downey JM. Preconditioning the myo-
anaesthesia in adult patients undergoing cardium: from cellular physiology to clinical cardi-
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4. de Ruijter W, Musters RJ, Boer C, et al. The car-
nine studies and over 6000 patients were dioprotective effect of sevoflurane depends on pro-
included in the analysis but firm conclu- tein kinase C activation, opening of mitochondrial
sions could not be made due to the low K+ATP channels, and the production of reactive
incidence of cardiovascular events in both oxygen species. Anesth Analg 2003; 97: 1370-
groups. 1376.
5. Hanouz J-L, Yvon A, Massetti M, et al. Mechanisms
nevertheless, the most recent American of desflurane-induced preconditioning in isolated
College of Cardiology/American Heart As- human right atria in vitro. Anesthesiology 2002;
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of volatile anaesthetic agents during non- 6. Hara T, Tomiyasu S, Sungsam C, et al. Sevoflurane
protects stunned myocardium through activation of
cardiac surgery in patients at risk for AMI
mitochondrial ATP-sensitive potassium channels.
(Class IIa, level B) (30). Anesth Analg 2001; 92: 1139-1145.
7. nakae Y, Kohro S, Hogan QH, Bosnjak zJ. Intra-
cellular mechanism of mitochondrial adenosine tri-
concluSionS phosphate-sensitive potassium channel activation
with isoflurane. Anesth Analg 2003; 97: 1025-1032.
8. zaugg M, Lucchinetti E, Spahn DR, et al. Volatile
There is class Ia evidence for the myocardi- anesthetics mimic cardiac preconditioning by prim-
al protective properties of sevoflurane and ing the activation of mitochondrial KATP channels
desflurane in low risk patients undergoing via multiple signalling pathways. Anesthesiology
2002; 97: 4-14.
coronary artery bypass grafting surgery. 9. zaugg M, Lucchinetti E, Spahn DR, et al. Differen-
The modern volatile anaesthetics have tial effects of anesthetics on mitochondrial KATP
been shown to improve clinical outcomes channel activity and cardiomyocyte protection. An-
and health economics following cardiac esthesiology 2002; 97: 15-23.
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robust and further large randomized con- of preconditioning by isoflurane in rabbits: a direct
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No conflict of interest acknowledged by the authors. 2002; 96: 125-133.
13. novalija E, fujita S, Kampine JP, Stowe Df. Sevo-
flurane mimics ischaemic preconditioning effects
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hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2


20133 Milano - Piazza Carlo Donegani, 1
DIVISIONE OSPEDALIERA: Viale Europa, 28 - Milano Oltre 2 - 20090 Segrate
Tel. - Fax - E-mail:
in Intensive Care
Cardiovascular Anesthesia

originAl ArticlE
Endorsed by

fenoldopam to prevent renal
replacement therapy after cardiac
surgery. design of the fEno-hSr study
G. Landoni¹, T. Bove¹, D. Pasero², M. Comis³, S. Orando4, F. Pinelli4, F. Guarracino5,
A. Corcione6, N. Galdieri6, M. Zucchetti7, E. Maglioni8, B. Biagioli8, G. Pala9,
M. Frontini10, F. Caramelli11, B. Persi12, M. Renzini13, F. Paoletti13, L. Lorini14,
A. Morelli15, G. Alvaro16, R. Bianco17, D. Pittarello17, A. Manzato10, G. Pedersini10,
A. Mizzi¹, N. Lojacono3, P. Leoncini3, T. Iovino6, C. Cariello5, R. Baldassarri5,
A.M. Camata12, G. Padua9, G. Frascaroli11, S. Leonardi7, E. Bignami¹, A. Zangrillo¹
¹ Università Vita-Salute San Raffaele, Milano; ²A.O.U. San Giovanni Battista, Torino; ³A.O. Ordine Mauriziano, Torino;
A.O.U. Careggi, Firenze; 5A.O. U. Pisana, Pisa; 6A.O. Vincenzo Monaldi, Napoli; 7A.O. Riuniti Papardo-Piemonte, Messina;
A.O.U. Senese Policlinico S. Maria alle Scotte, Siena; 9Ospedale Civile SS. Annunziata, Sassari; 10A.O. Spedali Civili di Brescia,
Brescia; 11A.O.U. Policlinico S. Orsola-Malpighi, Bologna; 12Ospedale Regina S. Maria dei Battuti, Treviso;
A.O. di Perugia - Ospedale S. Maria della Misericordia, Perugia, 14Ospedali Riuniti di Bergamo, Bergamo;
Università La Sapienza - Policlinico Umberto I, Roma; 16A.O. Mater Domini Germaneto, Catanzaro;
A.O. di Padova, Padova

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 111-117

introduction: Acute kidney injury requiring renal replacement therapy is a serious complication following
cardiac surgery associated with poor clinical outcomes. Until now no drug showed nephroprotective effects.
fenoldopam is a dopamine-1 receptor agonist which seems to be effective in improving postoperative renal
function. The aim of this paper is to describe the design of the fEno-HSR study, planned to assess the effect
of a continuous infusion of fenoldopam in reducing the need for renal replacement therapy in patients with
acute kidney injury after cardiac surgery.
methods: We’re performing a double blind, placebo-controlled multicentre randomized trial in over 20 Italian
hospitals. Patients who develop acute renal failure defined as R of RIfLE score following cardiac surgery are
randomized to receive a 96-hours continuous infusion of either fenoldopam (0.025-0.3 µg/kg/min) or placebo.
results: The primary endpoint will be the rate of renal replacement therapy. Secondary endpoints will be:
mortality, time on mechanical ventilation, length of intensive care unit and hospital stay, peak serum creati-
nine and the rate of acute renal failure (following the RIfLE score).
conclusions: This trial is planned to assess if fenoldopam could improve relevant outcomes in patients un-
dergoing cardiac surgery who develop acute renal dysfunction. Results of this double-blind randomized trial
could provide important insights to improve the management strategy of patients at high risk for postoperative
acute kidney injury.

Keywords: fenoldopam, cardiac surgical procedures, acute renal failure, cardiac surgery, anesthesia, renal replace-
ment therapy.

Corresponding author: Acute renal failure (ARf) is a common as
Giovanni Landoni, M.D. well as life threatening complication in pa-
Department of Anaesthesia and Intensive Care,
Università Vita-Salute San Raffaele tients undergoing cardiovascular surgery
Via olgettina, 60 - 20132 Milan, Italy
(1-3). Despite improvements in intensive care treatments and dialysis technology,
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
G. Landoni, et al.

112 the mortality associated with acute renal son to best medical therapy, fenoldopam us-
failure requiring renal replacement therapy age reduces the risk of RRT (34/525 [6.5%]
(RRT) remains unacceptably high, though in the fenoldopam group vs 59/569 [10.4%]
once discharged from hospital long-term in the control arm, oR=0.54 [0.34-0.84],
mortality is low with satisfactory quality p=0.007).
of life in patients discharged from hospital In a second meta-analysis (8) 13 clinical
alive (4). studies comparing fenoldopam to placebo
However no drug showed nephroprotective or standard treatment in cardiovascular
properties translating into a reduction in surgery were included.
the incidence of renal replacement therapy The studies enrolled a total of 1.059 patients
and mortality in a cardiovascular setting (528 received fenoldopam and 531 placebo
(5). or best available treatment). fenoldopam
fenoldopam mesylate is a benzazepine dosage varied across studies, being always
derivative and a dopamine A-1 (DA-1) re- >0.03 µg/kg/min and most often 0.1 µg/
ceptor agonist that seems to be effective kg/min, reaching 0.3 µg/kg/min in a single
in improving postoperative renal function study.
(5). fenoldopam exerts hypotensive effects All but 2 studies had a ≥24 hours fenoldo-
characterized by a decrease in peripheral pam infusion, with 5 studies reporting ≥2
vascular resistance, with increased renal days of continuous application. overall
blood flow, diuresis and natriuresis; all analysis showed that, in comparison to
these effects are primarily related to acti- best medical therapy, fenoldopam was as-
vation of DA-1 receptors. other beneficial sociated with a significant reduction in the
renal effects of fenoldopam could be related rates of all major endpoints. Specifically,
to other pharmacological properties that fenoldopam usage reduced the risk of RRT
are still under investigation such as an anti- (30/528 [5.7%] in the fenoldopam group
inflammatory effect (6). vs 71/531 [13.4%] in the control arm;
A meta-analys (7) of 16 randomized con- oR=0.37 [0.23-0.59], p<0.001, number
trolled trials including 1290 patients (622 needed to treat =13) and of in-hospital
receiving fenoldopam and 668 receiving mortality (28/501 [5.6%] in the fenoldo-
placebo or best available treatment, mostly pam group vs 55/503 [10.9%] in the con-
low dose dopamine) was recently conduct- trol arm (oR=0.46 [0.29-0.75], p=0.02,
ed. five trials were performed in cardiac number needed to treat =19).
surgery, three in vascular surgery, two in Several studies suggested that fenoldopam
liver and one in renal transplants, while could have a nephroprotective action in
five trials were performed in the intensive a cardiac surgery setting, even when it is
care unit (ICU) either in selected patients used before surgery (9-12), but they were
with sepsis (two studies) or in the overall not powered enough to detect an improve-
ICU population. ment in clinical relevant outcomes, such as
fenoldopam dosage varied across studies, the need for renal replacement therapy or
between 0.025 µg/kg/min and 0.3 µg/kg/ mortality.
min (in one study), mostly being adminis- Scientific literature is not unanimous about
tered at a dosage of 0.1 µg/kg/min. All but 2 the protective properties of fenoldopam,
studies had a >12 h fenoldopam infusion, and there are also studies which showed
with 8 studies reporting ≥2 days infusion no improvement with administration of
(median duration 48 h). fenoldopam in high-risk patients undergo-
overall analysis showed that, in compari- ing cardiac surgery (13).

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

fenoldopam and renal replacement therapy

mEthodS postoperative increase in serum creatinine 113

and/or diuresis <0,5 ml/kg/h for 6 hours)
Study aim (Table 1).
Based on previous concerning the admin- Conversely, the following exclusion criteria
istration of fenoldopam in patients at high will be applied: previous unusual response
risk for ARf (14), we are planning to ini- to fenoldopam, glaucoma, expected ICU
tiate a large (1000 planned patients) mul- stay less than 24 hours after randomization,
ticentre, prospective, randomized, double- RRT already started or planned before ran-
blind, placebo controlled clinical study en- domization, “do not resuscitate” patients,
rolling patients undergoing cardiac surgery participation in other randomized studies
who will develop acute renal dysfunction. (within the previous 30 days), fenoldo-
our aim is to confirm the promising results pam administration within the previous 30
of the cited meta-analyses and to add evi- days, preoperative RRT or dialysis.
dence based medicine to the supposed re-
nal protective properties of fenoldopam in Study procedure
critically ill patients (7, 8). All patients planned to undergo cardiac sur-
gery who won’t have exclusion criteria will
Patients selection be approached by a member of the research
We will enroll consecutive patients under- team to sign the informed consent. failure
going cardiac surgery who will develop an to obtain a signed informed consent will
acute renal failure after cardiac surgery. make the patient ineligible for the study.
Candidates for this study meeting the fol- Treatment assignment between fenoldo-
lowing criteria will be included: patients pam and placebo will be determined by a
who are able to understand and sign an in- randomization in a ratio of 1:1. Randomiza-
formed consent, aged 18 years or older, un- tion will be performed by centrally provided
dergoing cardiac surgery who will develop, sealed opaque envelopes. To ensure that al-
during the ICU stay an acute renal dysfunc- most equal number of patients will receive
tion designed as “R” of RIfLE score (50% either treatment, randomization blocks of

table 1 - RIFLE score for acute renal failure.

gfr* criteria uo† criteria
Risk increased creatinine x1.5 Uo† <0.5 ml/kg/min
or GfR* decrease >25% for 6 hours
Injury increased creatinine x2 Uo† <0.5 ml/kg/min
or GfR* decrease >50% for 12 hours
failure increased creatinine x3 Uo† <0.3 ml/kg/min for 24 hours
or GfR* decrease >75% or anuria for 12 hours
or creatinine ≥4 mg/dl
(acute rise of ≥0.5 mg/dl)
Loss Persistent ARf#=complete loss
of renal function >4 weeks
ESRD End-stage renal disease
* Glomerular filtration Rate
† Urine output
Acute Renal failure

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

G. Landoni, et al.

114 table 2 - A clinical score to predict acute renal failure urine output greater than 0.5 ml/kg/h, no
after cardiac surgery according to Thakar et al. (15). intravenous inotropic or vasopressor ther-
risk factor points apy aside from dopamine 5 µg/kg/min, and
female gender 1 no seizure activity. Criteria for hospital
discharge will be hemodynamic as well as
Congestive heart failure 1
respiratory recovery, the presence of clean
Left ventricular ejection fraction and dry incisions, afebrile condition, nor-
mal bowel movement, and independent
Preoperative use of Intra Aortic ambulation and regular oral nutrition.
Balloon Pump
Preoperative data will be collected according
Chronic obstructive Pulmonary
1 to the clinical score to predict ARf suggested
Disease by Thakar et al. (15) (Table 2), the Continu-
Insulin-requiring diabetes 1 ous Improvement in Cardiac Surgery Study
Previous cardiac surgery 1 score (CICSS) by Chertow et al. (16) (Table
3), the Simplified model to predict postop-
Emergency surgery 2
erative dialysis by Mehta et al. (17) (Table
Valve surgery only 1
Coronary Artery Bypass table 3 - The Continuous Improvement in Cardiac
Graft + valve Surgery Study score (CICSS) by Chertow et al. (16).
other cardiac surgeries 2 points
Preoperative creatinine 1.2 to Valvular surgery 3
<2.1 mg/dl Estimated creatinine clearance ml/min
Preoperative creatinine ≥2.1 mg/dl 5 ≥100 0
80-99 2
60-79 3
20 patients will be used. fenoldopam and 40-59 5
placebo (normosaline) will be identical in <40 9
shape, color, appearance and size.
Intra aortic ballon pump prior 5
Enrolled patients will be randomized in the to surgery
ICU after the development of an ARf de- Prior heart surgery 3
fined as “R” of RIfLE score, to a placebo or
nYHA* functional class 4 2
fenoldopam (Corlopam - Cephalon, Roma,
Italy) continuous infusion. Starting dose Peripheral vascular disease 2
will be 0.1 µ/kg/min (ranging from 0.025 Left ventricular ejection fraction <0.35 2
to 0.3 µg g/kg/min, according to mean ar- Pulmonary rales 2
terial pressure). Since the renal protective Chronic obstructive pulmonary disease 2
effect of fenoldopam seems to be related to Systolic blood pressure
the dose, it will be suggested to administer
120-139 0
at least 0.1 µg/kg/min.
140-159 0
The infusion will be maintained for 96
<120 and valvular surgery 2
hours or until the patient’s ICU discharge. <120 and CABG† 0
Transfer out of the ICU will be performed ≥ 160 and valvular surgery 0
with Spo2 ≥94% at an fio2 ≤0.5 by face- ≥ 160 and CABG† 3
mask, adequate cardiac stability with no Abbreviations
hemodynamically significant arrhythmias, * new York Heart Association
† Coronary Artery Bypass Graft
chest tube drainage less than 50 ml/h,

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

fenoldopam and renal replacement therapy

table 4 - The Simplified model to predict postoperative 4), and the Simplified Renal Index score 115
dialysis by Mehta et al. (18). by Wijeysundera et al. (18) (Table 5). Tele-
Score phone-based interviews will be performed at
Last serum creatinine (mg/dl) 1 month and 1 year after the procedure.
0.5 5
1.0 10 Study endpoints
1.5 15 The primary endpoint will be the rate of
2.0 20 RRT (continuous venous-venous hemofil-
2.5 25 tration or hemodialysis, according to center
3.0 30 guidelines and protocols). The theoretical
3.5 35 need for RRT will be documented as well as
4.0 and higher 40 defined as the presence of one of the follow-
Age ing parameters and symptoms: serum creati-
<55 0 nine >6 mg/dl during hospital stay; clinical
55-59 1 presentation of uremia, including altered
60-64 2 mental status, itching and/or severe nausea
65-69 3 and vomiting; hypoxia (oxygen saturation
70-74 4 <90% with fio2>=40% unresponsive
75-79 5 to diuretics); wedge pressure >25 mmHg;
80-84 6 hyperkalemia (>6.5 mmol/l or >6.0 after
85-89 7 treatment with cation-exchange resine; met-
90-94 8 abolic acidosis with bicarbonate levels ≤10
95-99 9 mEq/l inspite of endovenous bicarbonates
>100 10 administration. Secondary endpoints will
Surgery be represented by: mortality (in-hospital
CABG* only 0 mortality and telephone follow-up), time
Abbreviations on mechanical ventilation (hours), length
* Coronary Artery Bypass Graft
† new York Heart Association of ICU and hospital stay (days), peak serum
creatinine (mg/dl) and the rate of ARf (fol-
table 5 - A simplified predictive index for renal re- lowing the RIfLE score definition).
placement therapy after cardiac surgery suggested by
Wijeysundera et al. (18). Statistical analysis and sample
variable points size calculation
Estimated glomerular filtration rate 31- 1 An independent clinician investigator with
60 mL/min extensive experience in designing, con-
Estimated glomerular filtration rate 2 ducting and analysing clinical trials, not
≤ 30 mL/min involved in patient management, will be
Diabetes mellitus requiring medication 1 responsible for the statistical analysis. Data
Left ventricular ejection fraction ≤ 40 1
will be stored electronically and analysed
by means of the Epi Info 2002 (CDC), SPSS
Previous cardiac surgery 1
11.0 (SPSS), and STATA 9.0 (STATA) soft-
Procedures other than isolated coronary 1 wares, when appropriate. All data analysis
artery bypass graft or isolated atrial
septal defect repair will be carried out according to a pre-es-
tablished intention-to-treat analysis plan.
non elective procedure 1
Dichotomous data (including the primary
Preoperative intra-aortic balloon pump 1 outcome) will be compared by using a two-

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

G. Landoni, et al.

116 tailed chi2test with the Yates correction or rESultS

fisher’s exact test when appropriate. Con-
tinuous measurements will be compared During the present study we will expect
using the Mann-Whitney U test. Two-sided that fenoldopam would reduce the need for
significance tests will be used throughout. RRT in patients at risk for ARf after cardi-
Data will be presented as medians (25th and ac surgery and allow a faster recovery and
75th percentiles) or as means (± standard a better outcome. our trial should work out
deviation - SD). Regarding the primary end- clear recommendations regarding fenoldo-
point sample size, with an expected need pam administration in a cardiosurgical set-
for RRT of 5% in the treatment group vs ting to improve outcomes and reduce hospi-
10% in the control group (7, 8), aiming for a tal costs. Improved survival of critically ill
0.05 alpha and 0.80 power, a total of 870 pa- patients undergoing cardiac surgery would
tients will have to be enrolled (435 patients be the most relevant implication of this
per group). This number will be increased study. Reduction in cost per patient will be
by 15% (leading to a total of 1000 patients) striking, since acute renal failure and renal
in order to take into account potential pro- replacement therapy prolong intensive care
tocol deviations. All 1000 patients will be and hospital stay.
analysed according to the intention-to-treat
principle, beginning immediately after ran-
domization. Two interim analyses will be diScuSSion
carried out during the course of this study,
after randomizing 250 and 500 patients. nephroprotection in patients with or at
risk of ARf is a topical matter in cardiac
Monitoring of the study anesthesia. Many studies (9-12) and meta-
Monitors will verify adherence to required analyses (7, 8) appeared in literature sug-
clinical trial procedures and confirm accu- gesting a protective effect by fenoldopam in
rate collection of data and will follow the patients undergoing cardiac procedures.
Good Clinical Practice (GCP) guidelines. Roasio et al showed that an infusion of 0.1
Study monitoring and follow-up, from the µg/kg/min of fenoldopam administered for
initial set-up to final reporting, will be ful- 48 hours in patients with acute renal injury
filled according to current national and In- after cardiac surgery reduced the need for
ternational requirements. RRT in a single-center case-matched study.
However, literature is not unanimous and
Ethical issues data from large, multicentre, randomized
The drug is safe and has been used as an trials powered enough to detect a differ-
antihypertensive drug in clinical practice ence in clinical relevant outcomes are lack-
for more than 15 years. We might prob- ing. We will conduct a large multicentre
ably observe more hypotensive episodes in randomized study comparing fenoldopam
the treatment group but once being aware to a placebo in patients undergoing cardiac
of this potential side effect it shouldn’t be procedures who will develop an ARf to ad-
problematic to detect and manage these dress the question whether the administra-
episodes in the ICU. no interference with tion of this drug might influence patients’
the subject privacy is planned. Data will outcome after cardiac surgery.
be stored in an electronic database without 30.000 cardiac surgical interventions
indicating the name of the patients (a nu- are performed in Italy every year (and
meric code will be used). 1.000.000 in the world). Since acute renal

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

fenoldopam and renal replacement therapy

failure develops in 2-10% of this popula- 6. Aravindan n, natarajan M, Shaw AD. fenoldopam 117
tion, up to 3000 patients in Italy (100.000 inhibits nuclear translocation of nuclear factor kap-
pa B in a rat model of surgical ischemic acute renal
in the world) could benefit from the results failure. J Cardiothorac Vasc Anesth 2006; 20: 179-
of this study every year. This will be the 186.
first multicentre randomized controlled tri- 7. Landoni G, Biondi-zoccai GG, Tumlin JA, et al.
al comparing the effects of fenoldopam to Beneficial impact of fenoldopam in critically ill pa-
tients with or at risk for acute renal failure: a meta-
placebo after cardiac surgery. analysis of randomized clinical trials. Am J Kidney
This study is powered enough to highlight Dis 2007; 49: 56-68.
potential advantages deriving from fenoldo- 8. Landoni G, Biondi-zoccai GG, Marino G, et al.
pam administration in patients that are at fenoldopam reduces the need for renal replacement
high risk for postoperative acute renal dys- therapy and in-hospital death in cardiovascular sur-
gery: a meta-analysis. J Cardiothorac Vasc Anesth
function. 2008; 22: 27-33.
9. Cogliati AA, Vellutini R, nardini A, et al. fenoldo-
Funding, conflicts of interest pam infusion for renal protection in high-risk car-
The project is funded by the Italian Ministry of Health. diac surgery patients: a randomized clinical study. J
Funding source had no influence on the study design. We Cardiothorac Vasc Anesth 2007; 21: 847-850.
do not have any commercial interest with drug compa- 10. Caimmi PP, Pagani L, Micalizzi E, et al. fenoldopam
nies producing the drugs that will be used in this study. for renal protection in patients undergoing cardio-
pulmonary bypass. J Cardiothorac Vasc Anesth
Acknowledgements 2003; 17: 491-494.
A. Vavassori14, D. Colella18, A. Davi2, P. De Vico18, 11. Barr Lf, Kolodner K. n-acetylcysteine and fenoldo-
D. Dini4, A. Gavina11, G. Grillone11, f. Liuzzo16, pam protect the renal function of patients with
R. Lobreglio2, M. Lupo2, L. Marchetti8, G. Marino1, chronic renal insufficiency undergoing cardiac sur-
V. Salandin12, I. Virzo1, R. Vozzo16, P. zuppelli1, gery. Crit Care Med 2008; 36: 1427-1435.
M. Conte19, P. Del Sarto20, B. Martinez21, G. Paternos- 12. Halpenny M, Lakshmi S, o’Donnell A, et al.
ter22, G. Ricciardi23, M. falco24, A. Gratarola25 fenoldopam: renal and splanchnic effects in pa-
ospedali Riuniti di Bergamo, Bergamo; 18A.o. Universi- tients undergoing coronary artery bypass grafting.
taria Policlinico Tor Vergata, Roma; 19Città di Lecce Hospi- Anaesthesia 2001; 56: 953-960.
tal GVM Care & Research, Lecce; 20ospedale Pasquinucci, 13. Bove T, Landoni G, Calabrò MG, et al. Renopro-
Massa; 21A.o. Universitaria Santa Maria della Misericordia, tective action of fenoldopam in high-risk patients
Udine; 22Casa di Cura Villa Verde, Taranto; 23A.C.o. San undergoing cardiac surgery: a prospective, double-
filippo neri, Roma; 24European Hospital, Roma; 25A. o. blind, randomized clinical trial. Circulation 2005;
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111: 3230-3235.
14. Tumlin JA, finkel KW, Murray PT, et al. fenoldo-
pam mesylate in early acute tubular necrosis: a ran-
rEfErEncES domized, double-blind, placebo-controlled clinical
trial. Am J Kidney Dis 2005; 46: 26-34.
1. Landoni G, Roberti A, Boroli f, et al. Mitral valve 15. Thakar CV, Arrigain S, Worley S, et al. A clinical
surgery and acute renal failure. Eur J Anaesthesiol score to predict acute renal failure after cardiac sur-
2007; 24: 100-101. gery. J Am Soc nephrol 2005; 16: 162-168.
2. Landoni G, Bove T, Crivellari M, et al. Acute renal 16. Chertow GM, Lazarus JM, Christiansen CL, et al.
failure after isolated CABG surgery: six years of ex- Preoperative renal risk stratification. Circulation
perience. Minerva Anestesiol 2007; 73: 559-565. 1997; 95: 878-884.
3. Bove T, Calabrò MG, Landoni G, et al. The incidence 17. Mehta RH, Grab JD, o’Brien SM, et al; Society of
and risk of acute renal failure after cardiac surgery. J Thoracic Surgeons national Cardiac Surgery Data-
Cardiothorac Vasc Anesth 2004; 18: 442-445. base Investigators. Bedside tool for predicting the
4. Landoni G, zangrillo A, franco A, et al. Long-term risk of postoperative dialysis in patients undergo-
outcome of patients who require renal replacement ing cardiac surgery. Circulation 2006; 114: 2208-
therapy after cardiac surgery. Eur J Anaesthesiol 2216.
2006; 23: 17-22. 18. Wijeysundera Dn, Karkouti K, Dupuis JY, et al.
5. Schetz M, Bove T, Morelli A, et al. Prevention of Derivation and validation of a simplified predictive
cardiac surgery-associated acute kidney injury. Int J index for renal replacement therapy after cardiac
Artif organs 2008; 31: 179-189. surgery. JAMA 2007; 297: 1801-1809.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

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in Intensive Care
Cardiovascular Anesthesia

originAl ArticlE
Endorsed by

perioperative evaluation
of primary hemostasis in patients
undergoing mitral valve repair
F. Pappalardo¹, P. Della Valle², G. Maj¹, A. Franco¹, A. Lattuada3,
G. Landoni¹, A. Zangrillo¹, A. D’Angelo²
¹Department of Anesthesia and Intensive Care, Università Vita-Salute San Raffaele, Milan, Italy;
²Coagulation Service and Thrombosis Research Unit, Università Vita-Salute San Raffaele, Milan, Italy;
³Coagulation Service and Thrombosis Research Unit, Ospedale Sacco, Milan, Italy

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 119-127

introduction: no data exist on the prevalence of primary hemostatic defects and acquired von Willebrand
disease in mitral valve prolapse with severe regurgitation.
methods: Primary hemostasis was evaluated by PfA-100, von Willebrand factor Antigen (vWf:Ag) and Ris-
tocetin cofactor (vWf:RiCof) assays in a prospective observational trial. Sixty-five consecutive patients with
mitral regurgitation (study group) or aortic stenosis (control group) who were operated for mitral valve repair
or aortic valve replacement were enrolled in the study.
results: There were no differences in Closure Time in the two groups at all time points. The concentration
of plasma vWf: Ag was within normal limits in all patients preoperatively; after surgery, a significant increase
was observed in both groups from baseline (199 +/- 144 mcg/dL vs. 295 +/-141 mcg/dL in the study group,
p=0.002; 243 +/- 141 mcg/dLl vs 338 +/- 154 mcg/dL in the control group, p=0.009).
The ratio of vWf:RiCof to vWf:Ag was slightly decreased preoperatively in both groups (ratio= 0.91) and
showed a marked increase in the postoperative period (ratio=0.22) as, probably, new hemostatically effective
large multimeric forms of vWf were released.
conclusions: Patients who present for surgery with a valvular pathology with high shear stress have some
degree of primary hemostasis defect; nevertheless, the potent stimulus of surgery and the correction of the
underlying disease allow quick restoration of vWf activity and normalization of PfA-100.

Keywords: von Willebrand, mitral surgery, aortic surgery, platelect function, cardiac surgery.

introduction tions. Similarly, patients with other cardiac

defects might occasionally exhibit such ab-
Acquired von Willebrand syndrome in high normality.
intracardiac shear stress conditions, such Platelet and blood clotting activation has
as aortic stenosis (1-8), ventricular septal been shown in patients with mitral valve
defect (9) and patent ductus arteriosus (10), prolapse but no data exist on the prevalence
has been clearly defined in its epidemiol- of primary hemostatic defects and acquired
ogy, pathophysiology and clinical correla- von Willebrand disease in mitral valve pro-
lapse with severe regurgitation (11).
Corresponding author: The fluid dynamics of a regurgitant valve
federico Pappalardo, MD
Department of Cardiovascular Anesthesia and Intensive Care are, in many ways, similar to the fluid dy-
Università Vita-Salute San Raffaele
Via olgettina, 60 - 20132 Milan, Italy
namics of a stenotic valve; however, the
e.mail: anatomy of the regurgitant orifice and the
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
F. Pappalardo, et al.

120 dynamics of the regurgitant flow are com- All patients signed an informed consent,
plex and not fully understood. The shape according to the Declaration of Helsinki,
and the direction of the regurgitant jet de- after approval of the protocol by the Ethics
pends on multiple factors, including the Committee of our Institution.
anatomy and orientation of the regurgitant
orifice, the driving force across the valve, PFA-100
and the size and compliance of the receiv- The PfA-100 provides an ex vivo quanti-
ing chamber. tative measure of platelet function under
Given these facts, we hypothesized that pri- high shear conditions simulating primary
mary hemostasis defects could be a feature haemostatic events following vascular in-
in patients with mitral valve prolapse. jury.
Aim of this study was to evaluate the prev- The platelet function analyzer (PfA-100,
alence of primary hemostasis disorders in Dade Behring, Inc, Deerfield, Ill.) performs
patients with severe mitral regurgitation analyses on citrated whole blood samples
due to prolapse without an history of path- (Vacutainer tubes, Becton Dickinson; ci-
ological mucocutaneous bleeding, by means trate 129 mmol/L; 3.8%) and measures the
of PfA-100 and to define their pathophysi- time needed for a platelet plug to form after
ology and clinical implications. activation of platelets by collagen and aden-
osin diphosphate (CADP, 50 μg) or collagen
and epinephrine (CEPI, 10 μg). The sample
mEthodS is aspirated under constant negative pres-
sure through a 200 μm capillary into a small
65 consecutive patients undergoing open reservoir, by passing through an 150 μm
heart surgery for valve operations were opening coated with collagen/epinephrine
prospectively evaluated; 41 patients under- (CEPI) or collagen/ADP (CADP). As blood
went mitral valve repair for severe mitral contacts the collagen-coated membrane,
regurgitation (study group), 24 of them un- the platelet agonist (epinephrine or ADP)
derwent aortic valve replacement for severe is solubilized, resulting in platelet stimula-
aortic stenosis (control group). 5 patients tion. The test terminates when the devel-
were excluded from the analysis for postop- oped primary hemostatic plug obstructs
erative re-exploration with evident source the opening. The instrument provides the
of surgical bleeding. Closure Time (CT) parameter, indicating
Patients were not included if operated on the time duration of the test: results are ex-
urgency-emergency priority or with a mini- pressed in seconds, with a maximum test
mally invasive approach or had chronic time of 300 seconds. Any value greater
atrial fibrillation. no patient received war- than that is reported as non closure. our as-
farin or antiplatelet drugs within 7 days says were performed with CADP cartridges
before surgery; patients on intravenous in order to remove the effect of antiplatelets
heparin had it stopped at least 6 hours pre- acting on ADP receptors.
operatively. Patients were not considered All PfA-100 measurements were performed
eligible if the preoperative platelet count within 30 minutes of sample collection.
was <80,000 x 109/l, if they had preopera-
tive PT and/or APTT ratios >1.2 or if they Patients’ management
had a history of hematological or hepatic Prior to institution of cardiopulmonary by-
disease (e.g., active hepatitis or cirrhosis), pass (CPB), patients received intravenous
or chronic renal failure requiring dialysis. porcine heparin (300 IU/kg of body weight)

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

primary hemostasis in patients undergoing mitral valve repair

and, during CPB, additional doses (5000 to Buckberg’s protocol. Mild-to-moderate 121
IU), if required, to maintain the activated hypothermia was employed (mean internal
clotting time (ACT) >480 sec. (ACT II, temperature: 31.4°C).
Medtronic, Minneapolis, Mn, USA). ACT Shed mediastinal blood suction and left
measurements were carried out 2 minutes heart venting were actively performed with
after heparin administration and every 20 two separated roller pumps. Additionally,
minutes thereafter. After termination of blood was aspirated from the operative
CPB and surgical hemostasis, heparin was field with a vacuum suction device (D745,
neutralized with protamine sulphate (1:1 Dideco, Mirandola, Italy), processed in a
ratio). All patients received an intraopera- cell saver (Compact-A, Dideco, Mirandola,
tive infusion of tranexamic acid (1g in 20 Italy), and then reinfused after closure of
minutes before skin incision, followed by the chest.
a continuous infusion of 400 mg/h until
completion of surgery) according to our in- Laboratory assays
stitutional protocol. Blood samples were collected from a radi-
At the end of the surgical procedure, pa- al arterial catheter by means of a two-sy-
tients were transferred to the Intensive ringe technique. The first syringe was used
care unit (ICU). Postoperative blood loss to withdraw 10 ml of blood and then the
was collected in a graduated reservoir con- sample was obtained in the second syringe.
nected to a closed evacuation system (Ar- Sample time points were as follows:
gyle, Aqua-seal, Sherwood Medical, Tul- A) preoperatively (Baseline);
lamore, Ireland). B) before heparin administration (Pre-hep);
C) after removal of the aortic crossclamp
Cardiopulmonary bypass circuit (Unclamp);
Extracorporeal circulation was instituted D) 4 minutes after the administration of
in all patients by draining blood by grav- protamine (Post-prota);
ity into an open venous reservoir (Avant E) at ICU arrival (ICU-arrival);
Reservoir, Dideco, Mirandola, Italy), and f) 4 hours after ICU arrival (ICU-4h);
by driving it by means of a roller peristal- G) the morning following surgery (ICU-
tic pump (Caps, Stöckert Instruments, Mu- 18h).
nich, Germany) through a heat exchanger Blood samples were collected in siliconized
integrated with a hollow fiber membrane Vacutainer tubes (Becton Dickinson, Plym-
oxygenator (Avant D903, or Avant D903 outh, UK) containing tri-sodium citrate
Ph.i.s.i.o., Dideco, Mirandola, Italy) and (0.19 M); within 1 hour from blood collec-
through an arterial filter (D734 MICRo tion, platelet poor plasma was obtained by
40, Dideco, Mirandola, Italy) back into the centrifugation for 20 minutes at 2000 RPM
patient at a mean flowrate of 2.4 l/min/m2. at room temperature.
The same custom pack of PVC/silicone tub- Plasma aliquots of platelet-poor plasma (0.4
ing (Dideco, Mirandola, Italy) was used for mL) were snap-frozen with methanol and
all patients. The circuit was primed with dry ice and finally stored at –80 °C until
1500-ml Ringer lactate solution, 100 mL assayed.
Mannitol 18%, and 5000 IU porcine hepa-
rin. Intermittent cold blood cardioplegia Assay methods
(4°C) was infused by means of a heat ex- Von Willebrand factor Antigen (vWf:Ag)
changer (D720 Helios C, Dideco, Mirando- was determinated by commercially avail-
la, Italy) and two roller pumps, according able ELISA assays (Asserachrom vWf, Di-

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

F. Pappalardo, et al.

122 agnostica Stago, Asnier sur Seine, france). Differences were considered statistically
Ristocetin cofactor activity (vWf:RiCof) significant in case p-values were lower than
was measured by commercially available ly- 0.05.
ophilized platelet reagents (Dade-Behring, Statistical analyses were performed using
Marburg, Germany) using an automated the SPSS Statistical Package version 11.5.1
coagulometer (ACL 9000; Instrumenta- (SPSS Inc, Chicago, USA).
tion Laboratory, Lexington, Massachusset,
USA) (12).
All results are the mean of the two determi- rESultS
nations and expressed as IU/dL of plasma.
The authors had full access to the data and Patients’ demographics were similar in the
take responsibility for its integrity. All au- two groups (mitral valve repair/study group
thors have read and agree with the manu- vs aortic valve replacement/control group).
script as written. Platelet count and hematocrit did not differ
between the two groups at all time points
Statistical analyses (Figure 1 and 2)
Descriptive data are expressed as mean There were no differences in Closure Time
standard deviation or median with inter- in the two groups at all time points (Fig-
quartile range (IQR) as appropriate ac- ure 3): the median closure time at baseline
cording to the skewedness of the observed was above the normality range (less than
distribution. Statistical significance of the 118 sec.) in both groups (146 sec. [106-299,
difference between continuous variables 25th-75th percentile] in the study group vs
was assessed by using a Student t-test or a 183 sec. [128-299, 25th-75th percentile] in
Mann-Whitney U-test as appropriate. Com- the control group, p=0.22); only three
parison of proportions was performed by patients in the control group exhibited a
Chi-Square or fisher Exact tests as appro- “normal” CT preoperatively (12%) vs 14
priate. All reported p values are two tailed. patients (38%) in the study group. five pa-

Control group
P = 0.6 Study group
P = 0.5 P = 0.7
P = 0.8
P = 0.9


Baseline Unclamp ICU arrival ICU-4h ICU-18h

figure 1 - Time course of platelet count (t-test) mean ± SD.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

primary hemostasis in patients undergoing mitral valve repair

Control group
Study group

P = 0.9 P = 0.7

P = 0.6
30 P = 0.7 P = 0.4

Baseline Unclamp ICU arrival ICU-4h ICU-18h

figure 2 - Time course of hemostasis: (%) (t-test) mean ± SD.

tients in the control group had non closure 18 hours postoperatively (163sec. [109.5-
(CT >300 sec.) preoperatively. 299, 25th-75th percentile] vs 83sec. [66-
Preoperative CT increased following hepa- 112, 25th-75th percentile], p<0.001) (Table
rin administration and again with initiation 1); similarly the haematocrit and plate-
of CPB. fifteen minutes after protamine let count decreased. These variables were
sulphate administration, CT returned to inversely related to CT at all time points
near baseline values. (PLT p<0.001, r=-0.424; Hct p<0.003,
Median (CT) of all patients significantly r=-0.353 at ICU arrival (Spearman test).
decreased from baseline at ICU arrival and The concentration of plasma vWf:Ag was

Control group
Study group
P=0.01 P=0.09

P = 0.2
P = 0.7
P = 0.1 P = 0.5
P = 0.7

Baseline Post-epa Post-plegia Unclamp Post-prota ICU arrival ICU-4h

figure 3 - Closure Time (Mann-Whitney) median (25th-75th percentile).

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

F. Pappalardo, et al.

124 table 1 - Time course of Platelet Function Analyzer Closure Time [median (25th – 75th percentile)] in the overall
25th percentile median 75th percentile p
Baseline 109.5 163 299
Pre-hep 132.75 185 299.75 0.389
Post-hep 120 163 299 0.112
Post-CPL 205.5 293 299 < 0.001
Unclamp 151.5 256.5 300 0.009
Post-prota 106 151 247 0.109
ICU arrival 63.5 78 90 < 0.001
4h after ICU arrival 62 79 102 < 0.001
18h after ICU arrival 66 83 112 < 0.001

within normal limits in all patients preop- groups (ratio=0.91; normal range greater
eratively. (VWf:Ag) levels did not differ than 0.7) and showed a marked increase in
at all time points in the two groups; after the postoperative period (ratio= 0.22) as,
surgery, a significant increase was observed probably, new hemostatically effective large
in both groups from baseline (199+/-144 multimeric forms of vWf were released.
mcg/dL vs 295+/-141 mcg/dL in the study The correlations between CT and vWf:Ag
group, p=0.002; 243+/-141 mcg/dL vs and vWf:RiCof could not be calculated be-
338+/-154 mcg/dL in the control group, cause of a number of patients had an infi-
p=0.009) (Figures 4, 5 and 6). nite CT (>300 sec.). However, our results
The ratio of vWf:RiCof to vWf:Ag was indicate that, on the whole, the prolonga-
slightly decreased preoperatively in both tion of the CT was inversely proportional

600 P < 0.001 600

P = 0.009

500 500
P = 0.155
vWF (mcg/dL)

vWF (mcg/dL)

400 400

300 300

200 200

100 100

Baseline Unclamp ICU-arrival Baseline Unclamp ICU-arrival

figure 4 - von Willebrand Factor Antigen concen- figure 5 - von Willebrand Factor Antigen con-
tration: time course in the overall study population. centration: time course in the control group.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

primary hemostasis in patients undergoing mitral valve repair

found to be both sensitive (90-100%) and 125
specific (88-95%) in the detection of von
P = 0.009
500 Willebrand disease (13-16).
P = 0.932 our study shows that patients with mitral
valve regurgitation due to prolapse have
vWF (mcg/dL)

high intracardiac shear stress which is re-
300 sponsible for the development of defects of
primary hemostasis, which can be detected
200 by means of PfA-100.
Despite these biological alterations, how-
100 ever, these patients do not show any patho-
logical mucocutaneous or surgical bleed-
Baseline Unclamp ICU-arrival ing, confirming the discrepancy between
the low frequency of bleeding symptoms
figure 6 - von Willebrand Factor Antigen con- and the high prevalence of hemostatic ab-
centration: time course in the study group. normalities in this setting. This subclini-
cal defect of primary hemostasis is quickly
to the level of vWf:Ag and of vWf:RiCof corrected by valve replacement due to the
(Figure 3). quick restoration of vWf levels; however
Postoperative bleeding did not differ in the it is responsible for a higher postoperative
two groups (280 ml [220-400, 25th-75th per- bleeding in those patients with the most se-
centile] vs 300 ml [180-400, 25th-75th per- vere deficiencies.
centile]) and no significant correlation was The PfA-100, however, is a sensitive, spe-
detected between nor preoperative or post- cific and reproducible test which might be
protamine CT and postoperative mediasti- useful to screen patients preoperatively to
nal drainage. However, among the patients identify those who could benefit from cor-
population, five patients had no formation rect diagnosis and appropriate therapy to
of the platelet plug at baseline (CT>300 or reduce their complications.
non-closure): this subgroup showed a sta- High shear rates prevail in stenotic valves:
tistically significant higher postoperative under these conditions, large molecular
bleeding as compared to the rest of other weight multimers of vWf are changed in
patients (350 ml [240-400, 25th-75th percen- shape and exposed to the action of, which
tile] vs 220 ml [180-290, 25th-75th percen- results in their proteolysis. High molecu-
tile]), p=0.05) which was related to CT at lar weight multimers of vWf are the most
baseline (r=0.441, p=0.035). effective in platelet mediated hemostasis.
no patients suffered of any thromboembol- Platelet adhesion to the subendothelial ma-
ic complication. trix of injured arterial vessels wall requires
adhesion of platelets to subendothelially lo-
cated vWf and of plasma vWf to subendo-
diScuSSion thelial collagen. In addition, vWf enhances
the adhesion of platelets to fibrin clots and
Patients with high intracardiac shear stress stabilizes coagulation factor VIII (17-20).
have a certain degree of proteolysis of high Although aortic stenosis is a relevant in
molecular weight vWf and such a condi- vivo model of shear stress induced cleav-
tion may contribute to the increased risk of age of vWf with resultant loss of its larg-
postoperative bleeding. PfA-100 has been est multimers, fluid dynamics of mitral re-

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

F. Pappalardo, et al.

126 gurgitation are also characterized by high of vWf has large variations, as it is influ-
shear stress. enced by ABo blood type, Lewis blood type
These anomalies measured with PfA-100 race and age (25).
were reversed by surgical correction of the Moreover, the plasma level of vWf tran-
regurgitant valve on the first postoperative siently increases in response to a variety
day, a finding which is consistent with the of physiological conditions including trau-
12-to-20-hour half-life of vWf in vivo. ma, surgery, atherosclerosis, inflammatory
The correction of PfA-100 abnormalities states and β-adrenergic stimulation.
after surgical repair or replacement of the
diseased valve indicates that the passage
of blood through the diseased valve causes concluSionS
a disturbance of flow, thereby generating
high shear stress and turbulence, may be In conclusion, mitral regurgitation second-
responsible, at least in part, for a height- ary to prolapse is responsible for a certain
ened vWf proteolysis. However, the overall degree of proteolysis of high molecular
imbalance of primary hemostasis is usually weight vWf as shown by abnormal shear
mild and the PfA-100 abnormalities are not induced platelet aggregation. This defect of
an accurate predictor of a bleeding tenden- primary hemostasis is quickly corrected by
cy, unless non closure is present (21). valve repair due to the prompt restoration
froom et al. (22) reported their evaluation of vWf levels and this condition is not as-
of vWf in mitral valve prolapse: they con- sociated with an increased risk of bleeding,
clude that there is a relationship between except for those patients with the most se-
mitral valve prolapse and low levels of vere deficiencies.
vWf:Ag. However, vWf:Ag levels are nor- on the basis of these data, postoperative
mal in those patients with mitral valve pro- bleeding after mitral valve repair should
lapse and heart failure, as it may account prompt a search for other causes than von
for an increased release of vWf. Willebrand disease.
Slaughter et al. (23) have investigated the In addition, our observation confirms the
PfA-100 in CABG patients: they showed discrepancy between the low frequency of
that an impaired ADP mediated platelet ag- bleeding symptoms and the high prevalence
gregation is not corrected after surgery in of hemostatic abnormalities in the setting
17 of 19 patients. Moreover, they reported heart valve disease. Although aortic steno-
that 80% of patients having CABG with sis and mitral regurgitation are a relevant
abnormal chest tube output had prolonged in vivo model of shear-stress induced cleav-
PfA-100 measurements 15 minutes after age of vWf with resultant loss of its largest
administration of protamine sulphate. multimers, the diagnosis of von Willebrand
Raman et al. (24) identified 16 bleeders syndrome should be restricted to those pa-
after CABG: in 15 of those whose bleed- tients who have bleeding.
ing was controlled by platelet transfusion, Shear induced platelet aggregation is sig-
PfA-100 after protamine sulphate was pro- nificantly increased after cardiac surgery,
longed. They suggested a potential role for but the role that this phenomenon might
PfA-100 measurements to help identify play in the development of postoperative
which patient could benefit from platelet thromboembolic complications remains to
transfusion after CABG. be addressed.
Several limitations of our study should be
acknowledged. first, plasma concentration No conflict of interest acknowledged by the authors.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

primary hemostasis in patients undergoing mitral valve repair

rEfErEncES 14. Kundu SK, Heilmann EJ, Sio R, et al. Character- 127
ization of an in vitro platelet function analyzer,
1. Vincentelli A, Susen S, Le Tourneau T, et al. Ac- PfA-100. Clin Appl Thromb Hemostas 1996; 2:
quired von Willebrand syndrome in aortic stenosis. 241-9.
n Engl J Med 2003; 349: 343-349. 15. Mammen Ef, Comp PC, Gosselin R, et al. PfA-100
2. Yoshida K, Tobe S, Kawata M. Acquired von Wille- system: a new method for assessment of platelet dys-
brand Disease Type IIA in patients with aortic valve function. Semin Thromb Hemost 1998; 24: 195-202.
stenosis. Ann Thorac Surg 2006; 81: 1114-1116. 16. Cattaneo M, federici AB, Lecchi A, et al. Evaluation
3. Pareti fI, Lattuada A, Bressi C, et al. Proteolysis of the PfA-100 system in the diagnosis and thera-
of von Willebrand factor and shear stress-induced peutic monitoring of patients with von Willebrand
platelet aggregation in patients with aortic valve ste- disease. Thromb Haemost 1999; 82: 35-39.
nosis. Circulation 2000; 102: 1290-1295. 17. Mannucci PM. Treatment of von Willebrand’s Dis-
4. Sadler JE. Aortic stenosis, von Willebrand factor, ease. n Engl J Med 2004; 351: 683-694.
and bleeding. n Engl J Med 2003; 349: 323-325. 18. Mohri H. Acquired von Willebrand syndrome: its
5. Goldsmith IR, Blann AD, Patel RL, Lip GY. Effect pathophysiology, laboratory features and manage-
of aortic valve replacement on plasma soluble P-se- ment. J Thromb Thrombolysis 2003; 15: 141-149.
lectin, von Willebrand factor, and fibrinogen. Am J 19. Reiter RA, Knöbl P, Varadi K, Turecek PL. Changes
Cardiol 2001; 87: 107-110. in von Willebrand factor-cleaving protease (AD-
6. King RM, Pluth JR, Giuliani ER. The association of AMTS13) activity after infusion of desmopressin.
unexplained gastrointestinal bleeding with calcific Blood 2003; 101: 946-948.
aortic stenosis. Ann Thorac Surg 1987; 44: 514-516. 20. Matsui H, Sugimoto M, Mizuno T, et al. Distinct and
7. Anderson RP, McGrath K, Street A. Reversal of aor- concerted functions of von Willebrand factor and
tic stenosis, bleeding gastrointestinal angiodyspla- fibrinogen in mural thrombus growth under high
sia, and von Willebrand syndrome by aortic valve shear flow. Blood 2002; 100: 3604-10.
replacement. Lancet 1996; 347: 689-690. 21. Buyukasik Y, Karakus S. Goker H, et al. Rational use
8. Warkentin TE, Moore JC, Morgan DG. Aortic ste- of the PfA-100 device for screening of platelet func-
nosis and bleeding gastrointestinal angiodysplasia: tion disorders and von Willebrand disease. Blood
is acquired von Willebrand disease the link? Lancet Coagul fibrinolysis 2002; 13: 349-353.
1992; 340: 35-37. 22. froom P, Margulis T, Grenadier E, et al. Willebrand
9. Gill JC, Wilson AD, Endres-Brooks J, Montgomery factor and mitral valve prolapse. Thromb Haemost
RR. Loss of the largest von Willebrand factor mul- 1988; 60: 230-231.
timers from the plasma of patients with congenital 23. Slaughter Tf, Sreeram G, Sharma AD, et al. Re-
cardiac defects. Blood 1986; 67: 758-761. versible shear-mediated platelet dysfunction during
10. Rauch R, Budde U, Koch A, et al. Acquired von Wil- cardiac surgery as assessed by the PfA-100 platelet
lebrand syndrome in children with patent ductus function analyzer. Blood Coagul fibrinolysis 2001;
arteriosus. Heart 2002; 88: 87-88. 12: 85-93.
11. Martini f, zuppiroli A, Gori A, et al. Platelet and 24. Raman S, Silverman nA. Clinical utility of the plate-
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valve prolapse. Thromb Res 1996; 83: 299-306. procedures involving extracorporeal circulation. J
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for ristocetin cofactor activity using an automated 25. nitu-Whalley IC, Lee CA, Brown SA, et al. The role
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13. Kundu SK, Heilmann EJ, Sio R, et al. Description disease and its relationships with von Willebrand
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Semin Thromb Hemost 1995; 21: 106-112. 9: 298-302.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

Nei nostri farmaci equivalenti
c’è tanta scienza
quanta negli originatori.
Nei nostri farmaci equivalenti
c’è tanta scienza
quanta negli originatori.
in Intensive Care
Cardiovascular Anesthesia

cASE rEport
Endorsed by

inter-hospital extracorporeal
life support
G. Redaelli¹, A. Annoni¹, R. Caruso², F. Formica³, V. Meroni¹, L. Avalli¹
¹Cardiac Surgical ICU, ²Perfusion Service, ³Cardiac Surgical Department, San Gerardo Hospital, Monza, Italy

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 131-134

A 60-year-old man with history of hypertension and unspecified left ventricular dysfunction had chest pain at
home at 9 am. At 1 pm he was transported to a peripheal hospital and treated for acute myocardial infarction.
At 4.30 pm, despite pharmacological and intra aortic balloon pump support , the extreme hemodynamic insta-
bility and the echocardiographic signs forced the doctors in charge to contact the “extracorporeal membrane
oxygenation team” of our Intensive Care Unit. The team, that in our hospital is composed of an intensivist,
a cardiac surgeon, a perfusionist and a nurse, reached the hospital at 5.15 pm and performed a percutaneous
cannulation of right femoral artery and left femoral vein connecting the patient to the extracorporeal mem-
brane oxygenation circuit. At 6.30 pm the patient on extracorporeal membrane oxygenation was transferred
by ambulance to the Cardiac Surgery Intensive Care Unit of San Gerardo Hospital in Monza. on day 20 he was
transferred back to the original hospital without neurological deficits, with normal renal function and normal
blood gas analysis.

Keywords: extracorporeal membrane oxygenation, cardiogenic shock, cardiac arrest.

introduction vice than by standard treatment with IABP

Cardiogenic shock is the leading cause of In this investigation we report our experi-
death for patients with acute myocardial ence of using extracorporeal membrane ox-
infarction who reach the hospital alive. ygenation (ECMo) to resuscitate a 60-year-
It affects about 6 to 8% of patients with old man with critical left main coronary
acute myocardial infarction. (1) Despite artery disease complicated by acute myo-
the advantages of early intra-aortic balloon cardial infarction (AMI) and cardiogenic
pump (IABP), fibrinolysis, percutaneous shock. The connection of patient to ECMo
coronary intervention or coronary arterial circuit was performed in an hospital other
bypass graft , once shock is diagnosed, the than ours and the patient was then trans-
mortality remains high (about 50%) with ported to our hospital on ECMo with an
half of death occurring during the first 48 Advanced Care Mobile Unit.
hours. (2).
Some studies suggested that haemodynam-
ic and metabolic parameters could be more cASE rEport
effectively reversed by ventricular assist de-
A 60-year-old man with history of hyper-
Corresponding author: tension and unspecified left ventricular
Gianluigi Redaelli, MD
Cardiac Surgical Intensive Care Unit dysfunction started to have chest pain at
San Gerardo Hospital
Via Pergolesi, 33 - 20052 Monza, Italy
home at 9 am. His medications included
e.mail: beta-blockers, a sartanic and a tiazidic di-
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
G. Redaelli, et al.

132 uretic. He waited more than four hours at bolus). At 4.30 pm the doctors in charge de-
home before calling for help. At 1.30 pm cided to call our extracorporeal membrane
he alerted the emergency department (118) oxygenation (ECMo) team, composed of
and the advanced life support team found four figures (intensivist, cardiac surgeon,
him awake, hypotensive, symptomatic and perfusionist and nurse by cardiac surgi-
with ECG signs of extensive antero-lateral cal care unit). At 5.15 pm we reached the
AMI. Morphine and apirine were admin- peripheral hospital and, being the patient
istered, dopamine infusion started and the hemodinamically unstable , we decided for
patient was transferred to the nearest pe- ECMo implantation. Percutaneous can-
ripheral hospital having a coronary care nulation of right femoral artery with a 17
unit, ten kilometres from our hospital. french cannula and of left femoral vein
At 2 pm during the angiographic study he with a 21 french cannula was performed.
developed severe cardiogenic shock unre- The perfusionist prepared and primed the
sponsive to catecholamine (dopamine 20 circuit and at 5.40 pm the patient was con-
mcg/kg/min) and requiring IABP support nected to ECMo with blood flow3.5 L/min,
(1:1). The angiographic study showed dis- gas flow 3 L/min and fio2 0.6 with rapid
tal occlusion of left main coronary artery hemodynamic stabilization, reduction of
and the cardiologist performed angioplasty amines, recovery of diuresis and normal-
on left anterior descending and circum- ization of blood gas parameters (pao2 457
flex coronary artery and positioned a bare mmHg, paCo2 29 mmHg, pH 7.48, lactates
metal stent on left main and left anterior 1,9 mmol/L, BE -1,2 mmol/L). The reopro
descending arteries administering heparin infusion was interrupted at the beginning
bolus 7500 IU and continuous infusion of of the manoeuvre and we had no hemor-
reopro. ragic complications. At 6.30 pm the patient
The procedure was successful and obtained on ECMo was transferred by ambulance to
a good revascularization, but the TIMI the cardiac surgery intensive care unit of
score was 1 (the patient had severe hypo- San Gerardo Hospital in Monza. The trans-
tension despite high-dose norepinephrine). port required 20 minutes for a distance of
At 3.30 pm the patient had a bradi-asystolic about 10 kilometres and was uneventful.
cardiac arrest treated with 20 minutes ad- The patient was maintained sedated, with
vanced life support algorithms including continuous perfusion of muscle relaxant
tracheal intubation and transvenous pac- and, for the first 24 hours therapeutic hy-
ing. pothermia was applied for brain protection.
After the resuscitation manoeuvres, the pa- With total ECMo support he was hemo-
tient was still in cardiogenic shock refrac- dynamically stable without catecholamine
tory to high amines dosage (dopamine 16 support. Monitoring included arterial, cen-
mcg/kg/min plus adrenaline 0.14 mcg/kg/ tral venous and pulmonary artery catheter.
min), IABP, pacing, mechanical ventilation: Hemodynamic data were: arterial blood
systolic blood pressure was 90 mmHg, heart pressure 150/60 mmHg, heart rate 80 beats,
rate 100 beats per minute, anuria, pao2 53 sinus rhythm, central venous pressure 12
mmHg, paCo2 60 mmHg, pH 7.04, lactates mmHg, wedge pressure 15 mmHg, pulmo-
>6 mmol/L and base excess -14 mmol/L. nary artery pressure 29/18 mmHg, cardiac
An echocardiography examination showed output 2,5 L/min, venous oxygen satura-
the presence of contractile reserve (i.e. tem- tion 72%. A transesophageal echocardiog-
porary improvement of ejection fraction raphy showed an ejection fraction of 10%
and arterial pressure during epinephrine under full ECMo blood flow. Dobutamine
inter-hospital extracorporeal life support

5 mcg/kg/min was started to assure aortic ing high PEEP and interruption of heparin 133
valve opening. and clopidogrel. Ecodoppler was performed
Intravenous infusion of heparin had an ac- to exclude the presence of thrombosis in
tivated clotting time of 180-200 seconds. the main vessels.
Aspirin and clopidrogel were started with- on day 8 the patient developed an hyper-
out loading dose. tensive crisis with pulmonary oedema with-
on day 1 echocardiography showed aki- out changes in ECG or cardiac regional wall
nesia of apex and anterior wall, severe hy- motion with high pulmonary pressures re-
pokinesia of septum and lateral wall, no quiring mechanical ventilation with PEEP
valvular defects. Daily evaluations of legs 15cmH2o, high fio2 and inhalatory nitric
perfusion were performed with clinical pa- oxide for 48 hours.
rameters and/or arterial doppler. We never negative water balance and infusion of cal-
found any problem of leg perfusion in this cium-sensitizer because of the evidence of
case. diastolic dysfunction at echicardiography-
on day 4, because of relative hypertension, were performed. ACE-inhibitor and beta-
we started infusion of calcium-sensitizer blockers were introduced. on day 11 the
and weaning from ECMo gradually reduc- patient was extubated and on day 13 we in-
ing blood flow at 2 L/min for 12 hours and troduced digoxin for prevention/treatment
then 1 L/min for others 12 hours while of .congestive heart failure (4).
monitoring hemodinamic parameters and on day 20 he was transferred back to the
cardiac performance and dimensions with hospital he came from. At discharge from
Swan-Ganz catheter and echocardiogra- our unit the patient was awake, without
phy. on day 5 the patient was weaned from neurological deficits, hemodynamically
ECMo with IABP (1:1) and dobutamine 10 stable, in sinus rhytm, receiving ACE-in-
mcg/kg/min. hibitor and beta-blocker, with normal renal
The cannulae were removed with only ex- function and normal blood gas analysis.
ternal compression for hemostasis. After The equipment used during the transpor-
removal of ECMo cannulae the patient de- tation included: an usual Advanced Care
veloped hyperdynamic shock (cardiac out- Mobile Unit coordinated by our 118 depart-
put 11 L/min, blood pressure 80/40 mmHg) ment; a portable ECMo circuit (Figure 1)
requiring norepinephrine for 24 hours. We and a transport ventilator “oxylog 3000
treated this hyperdynamic shock as a septic (Draeger, Lubeck, Germany). The portable
one, performing cultural examination and ECMo circuit is composed by Rotaflow
starting empiric antibiotic therapy with centrifugal blood pump, Rotaflow console
meropenem. and permanent life support system (Ma-
on day 6 we removed IABP and started ni- quet, Jostra Medizintechnik AG, Hirrlin-
trates. Echocardiography without ECMo gen, Germany); cannulae Bio-Medicus
and IABP support showed persisting aki- (Medtronic inc., Minneapolis, Mn). The
nesia of apex and anterior wall with good transport of ECMo_system was made with
recovery of septal and lateral wall motion the “Mobile Heart-Lung Machine (HLM)
and an ejection fraction of 30%. holder HKH 8800 (Maquet, Jostra Mediz-
on day 7 linezolid was added to meropenem intechnik AG, Hirrlingen, Germany)” (5).
because of fever and elevation of leukocytes In our Unit we have an “ECMo-bag” con-
and inflammation indexes. The same day taining devices for cannulation and emer-
the patient had bronchial bleeding and de- gency assistance of intensive patients ready
terioration of blood gas parameters, requir- for use.
G. Redaelli, et al.


figure 1 - ECMO circuit with membrane oxygenator and centrifugal pump mounted on a specially
designed multifunctional holder Steering and control unit including battery pack.

diScuSSion lation performed either by the cardiac sur-

geon or the intensive care specialist.
The details of our “ECMo project” are
available online at and are inclusive of in- No conflict of interest acknowledged by the authors.
clusion and exclusion criteria, flowcharts,
duties of the emergency department (118), rEfErEncES
background and reasons that justify the 1. Seyfarth M, Sibbing D, Bauer I, et al. A ran-
project that offers to the surrounding hos- domized clinical trial to evaluate the safety
pitals that have no cardiac surgery and no and efficacy of a percutaneous left ventricu-
expertise with ECMo the possibility of a lar assist device versus intra-aortic balloon
prompr referral. pumping for treatment of cardiogenic shock
Within this project and till July 2009 the caused by myocardial infarction: J Am Coll
ECMo team was activated 7 times: in five Cardiol 2008; 52: 1584-1588.
cases no intervention was needed (we were 2. Thiele H, Sick P, Buodriot E, et al. Random-
ized comparison of intra-aortic balloon sup-
on stand-by for elective dangerous proce-
port with percutaneous left ventricular assist
dures in catheter laboratories). The first pa- device in patients with revascularized acute
tient with cardiogenic shock who received myocardial infarction complicated by cardio-
ECMo in the peripheral hospital and trans- genic shock. Eur Heart J 2005; 26, 1276-1283.
port to our hospital died in our intensive 3. Baughman KL, JarchoJA. Bridge to life-car-
care unit on day 2 for intestinal infarction diac mechanical support. n Eng J Med 2007;
due to important extracardiac arteriopathy. 357: 846-849.
The second patient is described in details in 4. Hood WB Jr, Dans AL, Guyatt GH, et al. Digi-
this case report and had good recovery. talis for treatment of congestive heart failure
in patients in sinus rhythm. Cochraine Data-
overall, before july 2009, our experience
base Syst Rev 2004; CD002901.
with ECMo for cardiac assistance included 5. Matthias Arlt, Alois Philipp, Markus zim-
57 cases, 35% of them performed outside mermenn, et al. first experience with a new
in the emergency department, in the cath- miniaturized life support system for mobile
eterization laboratory or in other hospitals. percutaneous cardiopulmonary bypass. Re-
and all of them with percutanoeus cannu- suscitation 200877; 345-350.
in Intensive Care
Cardiovascular Anesthesia

imAgES in mEdicinE
Endorsed by

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 137-138

A “four-leaf clover” aortic valve
A. Grimaldi, E. Collu, A. Castiglioni, G. La Canna, M. De Bonis, E. Bignami,
G. Melisurgo, O. Alfieri
Department of Cardiothoracic and Vascular Surgery, Università Vita-Salute San Raffaele, Milan, Italy

A 75-year-old man with acute worsening

of heart failure symptoms and a clinical
history of prior rheumatic fever, presented
with blood pressure 150/60 mmHg and a
high-pitched diastolic murmur in the aor-
tic area.
A preliminary Transthoracic exam showed
severe aortic regurgitation (vena contracta
width >7 mm) (Figure 1) and moderate
mitral regurgitation due to rheumatic leaf-
lets retraction.
A three-dimensional reconstruction of
short axis aortic view showed a four leaflets
valve with a significant central tip malcoap-
tation (Figure 2, Panel A).
A Transesophageal exam confirmed a quad- figure 1 - The Standard Transthoracic approach
ricuspid valve with four cusps approximate- shows a severe aortic insufficiency (vena contracta
ly of equal size (Hurwitz and Roberts Type width >7 mm).
A) (Figure 2, Panel B).
The peculiar spatial arrangement allowed
the cusps leading edges to malcoaptate caus-
ing a severe aortic regurgitation.
no anomalous origin of coronary ostia was
The surgical inspection confirmed the di-
agnosis (Figure 3) and the aortic valve was
successfully replaced with a biological pros-
normally shaped aortic valve has three
leaflets according to a regular cono-trunkal
embryological ripartition into aortic and
pulmonic valve and development of three

figure 2 - Panel A. Transthoracic Three-Dimen-

Corresponding author:
Antonio Grimaldi, MD
sional echocardiographic reconstruction of the
Department of Cardiothoracic and Vascular Surgery four-leaf clover aortic valve. Panel B. The Stand-
Università Vita-Salute San Raffaele
Via olgettina 60 - 20132 Milan, Italy
ard Transesophageal aortic short axis view shows
e.mail: the symmetrical central tip malcoaptation.
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
A. Grimaldi, et al.

138 small pads of mesenchymal tissue. Any

eventual deviation from the symmetric ar-
rangement can lead to leaflets number or
position abnormalities (1).
According to autopsy series the prevalence
of quadricuspid aortic valve ranges be-
tween 0,008 and 0,033% (2) and the valve
malformation can be alone or associated
to other congenital cardiac defects (3); in
10% of cases a displacement of coronary
ostia or a single coronary artery can be de-
tected (4).


1. fernandez B, Duran AC, Matire A, et al. new em-

bryological evidence for the formation of quadricus-
pid aortic valves in the Syrian hamster. J Comp Path
1999; 121: 89-94.
2. feldman B, Khandernia B, Warnes C, et al. Inci-
dence, description and functional assessment of iso-
lated quadricuspid aortic valves. Am J Cardiol 1990;
65: 937-938.
3. Suzuki Y, Daitoku K, Minakawa M, et al. Congeni-
tal quadricuspid aortic valve with tetralogy of fal-
lot and pulmonary atresia. Jpn J Thorac Cardiovasc
Surg 2006; 54: 44-46.
figure 3 - At surgical inspection the quadri- 4. Robicsek f, Sanger PW, Daugherty HK, Montgom-
cuspid aortic valve appears to be made up of four ery CC. Congenital quadricuspid aortic valve with
cusps approximately of equal size. No anomalous displacement of the left coronary orifice. Am J Car-
coronary ostia were detected. diol 1969; 23: 288-290.

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

in Intensive Care
Cardiovascular Anesthesia

pApErS, poStErS, prESEntAtionS:

communicAting thE biomEdicAl SciEncES Endorsed by

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia 2010; 2: 139-141

leave nothing to chance:
using English to navigate
your presentation
M. John
Professor of Applied English, Faculty of Medicine, Università Vita-Salute San Raffaele Milan, Italy

I have already spoken about the need to presentation without too many problems.
prepare attractive slides to transmit your You have probably ‘borrowed’ words, phras-
discoveries, procedures and statistics dur- es and structures already when you have
ing an oral presentation at a peer-to-peer written papers. There is nothing wrong
congress. I have also already mentioned with that. So, let’s start.
the fact that during your presentation you
should not hold notes in your hand and 1. the polite opening
simply read a written text to your audience. I am honored to speak here today...
This would be terribly boring for them and Thank you so much for inviting me to speak...
would not reflect positively upon your abil- 2. the topic and aim of the presentation
ities as a speaker. The aim of my presentation is...
Remember, you do not need notes in any My talk mainly deals with...
case as all of your relevant data should be
present in the concise and clear bullet points 3. the structure of the presentation
written in your slides, which you then ex- First of all, I’ll give you an overview of our
pand upon and develop during your talk. procedure...
Let’s be honest, you should know what you Then, I’d like to touch on...
are talking about as far as your medical spe- Following this, we’ll be examining...
cialty is concerned. Finally, we’ll take a closer look at...
However, you might have a few more prob-
lems with the English language. Maybe you 4. navigating forward
are not a native speaker. Maybe your Eng- So, after my introduction let’s take a look at...
lish is not fluent. Maybe you are convinced Now this brings me to a very interesting point...
that your English is the worst on the plan- I’d like to proceed with some examples of...
et! This will make you nervous when you
5. branching out
have to speak in a language that is not your
I want to take a moment to talk about...
own to describe complex, maybe even con-
Another thing we cannot ignore concerning
troversial, procedures and theories.
this topic is...
We are therefore going to have a look at some
phrases that will help you get through the 6. returning to the main theme
I’d like now to return to the main theme of my
Corresponding author:
Prof. Michael John presentation...
Università Vita-Salute San Raffaele, Milan, Italy
Via olgettina 48 - 20132 Milan, Italy
Now let’s go back to the central theme of my
e.mail: talk...
hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2
M. John

140 7. in conclusion Taking all of these factors into account...

Finally, I want to mention...
My presentation is drawing to its close... 10. the take-home message
We might therefore conclude that... The bottom line of our study is...
What I want you to remember is...
8. describing your slides
As you can see in this slide... 11. thanks and closure
What we are looking at here is... Thank you for your attention...
In this slide, I want to draw your attention to... Thanks for listening...
In the upper/lower part of the image you can see...
To illustrate my point I’d like you to focus on of course, what comes next is often con-
this graphic... sidered the most difficult, although in my
opinion it is also the most fruitful, part of
9. Summarizing any presentation: ‘What questions do you
To sum up... have?’
In summary, what I have tried to show you is... More about that next time!

Questions from the readers

1 is it better to use the present tense

or the past tense when writing a
ent tense to tell your readers what the pa-
per is about. Use the simple past to describe
background information and to give an over-
view of your methods.
The main tense used in a biomedical paper is The Methods should be written in the simple
the simple past The word ‘simple’ is impor- past tense.
tant as compound tenses, such as the present The simple past should also be used in the
perfect, should be avoided unless absolutely The Discussion uses the simple present to
necessary. put your results and conclusions into con-
However, the simple present is also used as text, but you will also use the simple past
you can see below. tense at times when you are referring to pre-
In the Introduction you should use the pres- vious work in the field.

2 how is the medical history inter-

view (anamnesis) carried out in
4. Past Medical History (PMH) (including
major illnesses, any previous surgery/op-
erations, any current ongoing illness, e.g.
A doctor typically asks questions to obtain 5. Review of systems (RoS) Systematic
the following information about the patient: questioning about different organ systems
1. Identification and demographics: name, 6. family diseases - especially those relevant
age, height, weight to the patient’s chief complaint
2. The “chief complaint (CC)” - the major 7. Childhood diseases - this is very impor-
health problem or concern, and its time tant in pediatrics
course (e.g. chest pain for past 4 hours) 8. Social history (medicine) - including
3. History of present illness (HPI) - details about living arrangements, occupation, mari-
the complaints, enumerated in the CC tal status, number of children, drug use

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

“once upon a time there was a congress...”

(including tobacco, alcohol, other recre- 10. Allergies - to medications, food, latex, and 141
ational drug use), recent foreign travel, other environmental factors.
and exposure to environmental pathogens Sexual history, obstetric/gynecological
through recreational activities or pets history etc.*
9. Regular and acute medications (including (* Wikipedia)
those prescribed by doctors, and others
obtained over-the-counter or alternative for more detailed information visit http://

“Questo è il sesto di una serie di articoli sull’argomento.

Potete indirizzare domande (in italiano o in inglese) a e vedrete le
risposte pubblicate su questa rubrica”.

‘This is the sixth of a series of articles on this topic.

Send any questions to who will answer them as part of this column’

hSr proceedings in intensive care and cardiovascular Anesthesia 2010, vol. 2

in Intensive Care
Cardiovascular Anesthesia

futurE EvEntS
Endorsed by

calendar for future meetings
intensive care, Surgery and cardiovascular Anesthesia

2010 2011
June 28th. first Consensus Conference on Reduction of Mortality January 12-15. Annual Meeting Society for Technology in Anes-
in Cardiac Anesthesia and Intensive Care. Milano, Italy. for thesia. Las Vegas, nevada. for information, contact: Society for
information, contact:, Website: www.hsrpro- Technology in Anesthesia, 6737 W. Washington Street, Suite 1300, Milwaukee, WI 53214. Email:
June 29 - July 2. The 11th Annual Congress of Asian Society for January 16-21. 29th Annual Symposium: Clinical Update in Anes-
Vascular Surgery. Kyoto, Japan. for information, contact: thesiology, Surgery and Perioperative Medicine with Interna- tional faculty and Industrial Exhibits. St. Martin, french West
September 9-11. Czech national Congress Society of Anesthesiolo- Indies. for information, contact: Helen Phillips, The Mount Sinai
gists in Critical Medicine. zlin, Czech Republic. for information, School of Medicine, one Gustave L. Levy Place, Box 1010, new
contact: Guarant, Ms. R. Somolova, opletolova, 22 11000 Prague York, nY 10029. Email:
1. Email: January 31 - february 2. 47th Annual Meeting Society of Thoracic
September 11-15. 24th Annual Meeting of the European Association Surgeons. San Diego, CA. for information, contact: Email: sts@
for Cardio-thoracic Surgery. Geneva, Switzerland. for informa-
tion, contact: EACTS, 3 Park Street, Windsor, Berkshire SL41LU, february 13-16. 40th Annual Meeting of the German Society for
UK, Email: Thoracic and Cardiovascular Surgery. Stuttgart, Germany. for
September 21-24. 12th International Congress of Cardiothoracic and information, contact: Executive Secretary GSTCVS Langerbeck-
Vascular Anesthesia. Beijing, China. for information, contact: Virchou Haus Luisenstr 58/59, 10117 Berlin, Germany. Email:
Email:, Website:
September 30 - october 2. 2nd International Meeting on Aortic Di- february 24-27. International Conference on Pre-Hypertension and
seases. Liege, Belgium. for information contact: Department of Cardio Metabolic Syndrome. Vienna, Austria. for information,
Cardiovascular and Thoracic Surgery CHU Liege, 4000 Liege, Bel- contact: Paragon Conventions, 18 Avenue Louis – Casai, 1209
gium. Email:, Website: www.chuliege. Geneva, Switzerland. Email: March 22-25. 31st International Symposium on Intensive Care and
october 2-5. Australian Society of Anaesthetists 69th national Scien- Emergency Medicine. Brussels, Belgium. for information, con-
tific Congress Melbourne 2010. Melbourne, Australia. for infor- tact: Eramus University Hospital, Route de lennik 808, B-1070
mation, contact: Website: Brussels, Belgium, Email:,
october 9-13. 23rd Annual Congress European Society of Intensive Website:
Care Medicine. Barcelona, Spain. for information, contact: ESI- April 29-May 4. 33rd Annual Meeting and Workshops Society of Car-
CM, 40 Avenue Joseph Wybran, 1070 Brussels, Belgium. Email: diovascular Anesthesiologists. Savannah, GA. for information, contact: SCA, Po Box 11086, 2209 Dickens Road, Richmond, VA
october 16-20. American Society of Anesthesiologists Annual Mee- 23230, Website:
ting. San Diego, CA. for information, contact: ASA, 520 n. nor- May 11-15. 58th Annual Meeting Association of University Anesthe-
thwest Highway, Park Ridge, IL 60068, Website: www.ASAhq. siologists. Philadelphia, PA. for information, contact: AUA, 520
org n. northwest Highway, Park Ridge, IL 60068, Email: dionne@
December 10-14. Sixty-fourth Postgraduate Assembly, new York
State Society of Anesthesiologists. new York, nY. for informa- october 15-19. American Society of Anesthesiologists Annual Me-
tion, contact: nYSSA, 85 fifth Avenue, new York, nY 10003, eting. Chicago, Il. for information, contact: ASA, 520 n. north-
Email: west Highway, Park Ridge, IL 60068, Website:
December 17-18. 4th International Congress: Aortic Surgery and november 7-8. Surgery of the thoracic aorta. Bologna, Italy. for in-
Anesthesia “How to do it”. Milano, Italy. for information, con- formation contact: noema, Via orefici 4, 40124 Bologna, Italy.
tact: S. Grassi, San Raffaele Congress Centre, Via olgettina 58, Email:, Website: www.noemacongres-
20132 Milano, Italy, Email:; Website: aor-
March 25-30. 15th World Congress of Anesthesiologists. Buenos
Aires, Argentina. for information, contact: Website: www.

HSR Proceedings in Intensive Care and Cardiovascular Anesthesia welcomes announcements of interest to physicians, re-
searchers and others concerned with cardiothoracic and vascular anesthesiology, medicine, pharmacology and related areas.
All copies are reviewed and edited for style, clarity and length. Information should be addressed to: George Silvay, M.D.,
Ph.D., Editor, Professor of Anesthesiology, Department of Anesthesiology, Mount Sinai Medical Center, 1 Gustave L. Levy
Place, Box 1010, new York, nY 10029-6574. E-mail:
Ossimetro Cerebrale / Somatico InvOS™*
Reflecting the color of life
Somanetics: un parametro vitale di qualità
Unico ossimetro in commercio al tempo stesso cerebrale e somatico, il Sistema Cerebrale / Somatico INVOS effettua il
monitoraggio delle variazioni di saturazione regionale di ossigeno (rSO2), rivelando in modo semplice e diretto l’insorgere di
complicanze ischemiche. Il Sistema Cerebrale / Somatico INVOS consente di applicare fino a quattro sensori contemporaneamente
su aree specifiche, di rilevare precocemente problemi di ossigenazione in tempi spesso più rapidi rispetto ai parametri vitali
sistemici, e di intervenire tempestivamente.

Modalità di monitoraggio a due o quattro canali:

• R
afforza il monitoraggio cerebrale con l’introduzione
del monitoraggio somatico
• I dentifica e permette di gestire in maniera più precisa
problemi di ossigenazione regionale
• P
ossibilità di posizionare fino a quattro sensori per
ottenere, in modo non invasivo, dati sull’ossigenazione
da zone di maggior interesse
• F
ornisce dati più oggettivi da utilizzare per un
trattamento personalizzato del paziente

Altri vantaggi:
rSO2 cerebrale e somatica: una guida in
• Display più ampio per una più facile lettura
• U
scita video ad un secondo monitor remoto per una
tempo reale alla perfusione e agli interventi
Cerebrale sinistro
migliore visibilità da parte dell’intero personale di Intubato Cerebrale destro
Somatico sinistro (peri-renale)
cura 80
Inizio CEC Somatico destro (peri-renale)

Fine CEC
• Download dei dati più facile tramite porta USB 70

• Impostazioni utente migliorate

• I ndicatore di potenza del segnale per riflettere meglio
Soglia di desaturazione somatica
le interferenze 50

Raffreddamento, aumento
Vent CO2, FiO2 e anestetici
Soglia di desaturazione cerebrale
Indicazioni per l’uso:
Il Sistema INVOS è progettato per monitorare e misurare direttamente, 30
etCO2 etCO2
in modo continuo e non invasivo, le variazioni di saturazione regionale 40 28
cerebrale dell’emoglobina in un individuo. Poiché l’emoglobina nel campo
20 2 unità di CGR
del sensore è costituita dal 75% circa di sangue venoso, dal 20% di
Clampaggio aortico totale Rimozione del clampaggio aortico totale
sangue arterioso e dal 5% di sangue capillare, l’interpretazione clinica Ipotensione
delle letture è coerente con quella di una misura venosa.Il dispositivo 16:16 16:46 17:16 17:46 18:16 18:46 19:16 19:46 20:16 20:46
è destinato all’uso per tutti quei pazienti che presentano un rischio di
squilibri nell’ossigenazione cerebrale. Il dispositivo deve essere utilizzato
esclusivamente da personale medico specializzato.Il dispositivo può
inoltre essere utilizzato per il monitoraggio aggiuntivo di supporto della
saturazione di emoglobina in una regione di tessuto muscolare scheletrico
al di sotto del sensore di un individuo a rischio di stati ischemici per flusso
ridotto o assente.

Controindicazioni: Nessuna.
™* Somanetics, INVOS e “Reflecting the color of life” sono marchi registrati di Somanetics Corporation.
COVIDIEN, COVIDIEN con logo e simbolo ™ sono marchi registrati di Covidien AG o delle sue consociate.
© 2007 Covidien AG o sue consociate. Tutti i diritti riservati. C-MN-SurgRealities/IT

Covidien Via Rivoltana, 2/d +39 02 703171 [t]

Italia SpA 20090 SEGRATE (Mi) +39 02 703 173 17 [f]
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4 th I N T E R N A T I O N A L C O N G R E S S



Il PPI differente dall’origine

Depositato presso l’AIFA in data 26/01/2010

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