(Roberto W. Dal Negro, Richard Hodder (Auth.), Rob

Long-Term Oxygen Therapy
Roberto Walter Dal Negro • Richard Hodder

Editors
Long-Term Oxygen
Therapy
New Insights and Perspectives
Forewords by Marc Miravitlles and Dario Olivieri
123
Roberto Walter Dal Negro Richard Hodder†
Lung Unit and Department Divisions of Pulmonary and Critical Care
of Internal Medicine University of Ottawa
ULSS 22 Regione Veneto The Ottawa Hospital-Civic Campus,
Bussolengo Hospital Ottawa, ON, Canada
Verona, Italy
The Editors and Authors wish to thank VitalAire Italia Spa for the contribution to this book
ISBN 978-88-470-2579-0 ISBN 978-88-470-2580-6 H%RRN
DOI 10.1007/978-88-470-2580-6
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To Rick, a distinguished scientist full of humanity:
when a good friend of mine disappears, part of my life is missing
Foreword
When cure is not an option, there is no doubt that the main outcome of treatment
of a chronic and debilitating disease is to improve survival. This is also true for
chronic respiratory diseases, such as – but not limited to – chronic obstructive pul-
monary disease (COPD). Despite the recent advances in pharmacotherapy, no new
drug, neither bronchodilators nor anti-inflammatory agents, have been shown to
prolong survival in COPD; however, since the early 1980s we know that the use of
long-term oxygen therapy (LTOT) in patients with COPD and hypoxemia prolongs
life in compliant patients.
For the last 30 years, LTOT has been irreplaceable in patients with severe COPD
and resting hypoxemia. However, research has continued and other indications of
LTOT have emerged. In addition, the criteria and systems of delivery for LTOT
have improved and the evaluation of patients both before and during therapy have
also been further developed.
It is believed that aspects related to LTOT belong to the respiratory specialist. It
is true that most of the research and the management of patients under this therapy
is carried out by pulmonologists. Nevertheless, this is an example of a necessary
interaction between the pulmonologist, community doctor, respiratory therapist and
healthcare institutions to provide an adequate network to help patients under this
type of long-term and costly treatment. Last but not least, we cannot forget the
expectations and needs of the patients under LTOT. It is crucial to provide the ade-
quate delivery systems to improve compliance and help the patients to preserve
their quality of life, which, in many cases, can be severely impaired.
In this context, it has been a pleasure to welcome the initiative of this book enti-
tled Long-Term Oxygen Therapy. New Insights & Perspectives, edited by two great
and recognized experts, Dr. Dal Negro and Dr. Hodder. This is a very comprehen-
sive and up-to-date book covering all aspects that clinicians, researchers and health-
care professionals need to know about LTOT. The authors are an impressive list of
vii
viii Foreword
specialists, mainly Italian but with recognition well beyond their country, and with
known expertise in the field. I find the initiative to gather together all aspects relat-
ed to this form of therapy, starting from the patient candidate for LTOT, to the
expected outcomes of treatment, particularly interesting. Moreover, one section of
the book is dedicated to a review of the role of all sectors involved in LTOT: the
lung physician, general practitioner, caregivers, healthcare institutions and even the
role of the media. Of course, a whole section is dedicated to the needs and perspec-
tives of patients.
I want to congratulate Dr. Dal Negro and Dr. Hodder for gathering together this
outstanding group of authors and developing this book, which will provide infor-
mation to all readers interested in the state of the art of LTOT. I am also sure that
reading this book will alert readers to some aspects that still need more research and
questions that, after 30 years, still remain unanswered. In an era when there is a
great proliferation of scientific journals online and information circulates extreme-
ly fast on the internet, it is clear that we need references to search for valid knowl-
edge, the knowledge that has been elaborated and filtered by real experts. This is
the role of this book, and the interested reader can find in its pages everything that
needs to be known about this important therapy for our respiratory patients.
I only wish that future publishers will continue this important contribution to the
respiratory field.
Marc Miravitlles
Pulmonologist and Senior Researcher
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)
Hospital Clínic, Barcelona
Foreword
Have you ever wondered just how important the patient’s perspective is to ensure
success with long-term oxygen therapy (LTOT)? It is widely known that in chron-
ic diseases, patient compliance is essential for a positive outcome - the treatment
will not be effective if you do not take your medicine. LTOT, however, is more com-
plex and demanding than just taking a pill. The treatment is day and night and
requires the use of sophisticated machinery and cooperation between the patient
and his/her healthcare providers. The patient’s perspective is very important since
his/her commitment to the therapeutic regimen needs to be guaranteed in order to
reach therapeutic goals.
The work by Roberto Dal Negro and Richard Hodder focuses on the importance
of patient well-being and compliance as well as the value of encouraging the patient
to actively participate in his/her care to ensure optimal therapeutic outcomes. A
potential candidate for LTOT must be identified and involved in the decision-mak-
ing process. The following multidimensional parameters must be carefully evaluat-
ed in the patient: pulmonary, cardio-circulatory, metabolic and neuromuscular.
Furthermore, the patient’s psychological and cognitive profile must be defined and
carefully considered. Recent studies have underscored the diversity in patient per-
spectives when facing the prospect of LTOT and the discomfort it may incur in their
daily life.
The patient must feel appropriately surrounded by competent healthcare providers
who are ready to intervene as necessary. The caregivers must all be on the same wave-
length. The general practitioner must work in collaboration with the pulmonologist
by transferring care of the patient back and forth as necessary. Importantly, healthcare
centres need to be available and sensitive to the patient’s needs according to the situ-
ation at hand. The media can play an important role in sensitising society to the seri-
ous problems these patients face and the importance of prompt social and medical
intervention.
ix
x Foreword
This brilliant and up-to-date book by Dal Negro and Hodder does not limit itself
to citing general principals and guidelines for LTOT, but rather delves deep into the
various modes of oxygen administration and the details of managing LTOT treat-
ments. LTOT is a standard outpatient therapy complete with benefits and limita-
tions, but there is also the potential for tele-control of the patient’s condition and
parameters, thereby facilitating the evaluation of the effects of therapy.
Based on these premises, the outcomes that the authors expect, stated at the end
of the technical and methodological chapters, are reasonable. Clinical outcomes
based on the patient that can be objectively documented. Outcomes that consider
not only respiratory function but also the patient’s quality of life, including human-
istic aspects. The work concludes with a general vision of the impact of LTOT on
the patient’s needs.
Anxiety, depression, antisocial behaviour and somatoform conditions are the con-
ditions most commonly reported in patients with chronic obstructive pulmonary dis-
ease (COPD) and chronic respiratory insufficiency. Moreover, the discomfort men-
tioned by patients being treated for COPD with LTOT ranges from dyspnoea and lim-
itations on mobility due to the oxygen device to the stigma of a poor body image.
Unfortunately, these factors lead many patients to stay home and contribute to self-
isolation and subsequent depression.
While several of these aspects may already have begun prior to starting LTOT,
they tend to worsen with time and interfere with lifestyle and physical activity. The
discouraged patient thereby justifies his/her reluctance to use oxygen and subse-
quent non-adherence to therapy. This behaviour degenerates with time and in rela-
tion to the patient’s dependence on treatment. The patient’s effort to accept treat-
ment varies over time, generally increasing as the disease progresses. The patient’s
sense of frustration increases accordingly and he/she realizes that they are increas-
ingly dependent on oxygen therapy in order to feel better.
In conclusion, the complexity of these factors makes the issue of LTOT extreme-
ly important and current for both the patient and physician. This work is timely and
current considering the periodic updates in the literature on COPD and its treatment
with LTOT. A wholehearted thanks to all the authors and editors for their efforts in
creating this excellent work.
Dario Olivieri
Professor of Respiratory Medicine
Department of Clinical Science
University of Parma (Italy)
Contents
1 The Patient Candidate for Long-Term Oxygen Therapy . . . . . . . . . . 1

Roberto W. Dal Negro and Richard Hodder†
Section I The Multidimensional Evaluation of Patients
2 Lung Function Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

Cleante Scarduelli
3 Cardiovascular and Metabolic Indices . . . . . . . . . . . . . . . . . . . . . . . . . 45

Andrea Corsonello, Claudio Pedone, Simone Scarlata
and Raffaele Antonelli Incalzi
4 Chronic Obstructive Pulmonary Disease (COPD):

Neuromuscular Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Cristina Deluca, Ebba Buffone, Elena Minguzzi
and Maria Grazia Passarin
5 The Psychological and Cognitive Profile . . . . . . . . . . . . . . . . . . . . . . . 67

Sonia Dal Ben and Fernanda Bricolo
6 Nutritional Deficiencies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Roberto Aquilani, Federica Boschi and Evasio Pasini
7 Gender-Related Differences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
Paola Turco
Section II The Cooperating Roles
xi
xii Contents
8 Home LTOT: The Role of the Caregiver . . . . . . . . . . . . . . . . . . . . . . . 89

Roberta Barian and Stefano Bertacco
9 The General Practitioner (GP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

Germano Bettoncelli
10 The Cooperating Roles: The Lung Physician . . . . . . . . . . . . . . . . . . . 105

Silvia Tognella
11 The Health Institutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

Paola Pisanti
12 The Role of Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

Daniel Della Seta
13 Systems for Oxygen Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Carlo Castiglioni
Section III Models for LTOT Management
14 Standard Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

Eugenio Sabato, Saverio Sabina and Carlo G. Leo
15 Tele-Control at Home . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

Roberto W. Dal Negro
16 The Value of a Systemic Accreditation Path . . . . . . . . . . . . . . . . . . . . 185

Massimo Dutto and Nicoletta Palese
Section IV The Outcomes
17 Clinical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

Claudio Micheletto
18 Humanistic Outcomes and Quality of Life . . . . . . . . . . . . . . . . . . . . . 211

Mauro Carone and Sabina Antoniu
19 The Economic Impact of Long-Term Oxygen Therapy . . . . . . . . . . . 221

Lorenzo G. Mantovani, Marco Cristiani and Gianluca Furneri
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Contributors
Raffaele Antonelli Incalzi Chair of Geriatrics, University Campus Bio Medico,

Rome, Italy
Sabina Antoniu Pulmonary Disease University Hospital, University of Medicine and

Pharmacy, Grigore T Popa Iasi, Iasi, Romania
Roberto Aquilani Service of Metabolic-Nutritional Pathophysiology and of Clin-

ical Nutrition, Scientific Institute of Montescano, “S. Maugeri Foundation”, Pavia,
Italy
Roberta Barian ULSS22 Bussolengo, Lung Disease Department, Orlandi Hospital,

Bussolengo (VR), Italy
Stefano Bertacco ULSS22 Bussolengo, Lung Disease Department, Orlandi Hospi-

tal, Bussolengo (VR), Italy
Germano Bettoncelli General practitioner, Ospitaletto, Italy
Federica Boschi Department of Drug Sciences, University of Pavia, Pavia, Italy
Fernanda Bricolo Psychologist and Psychotherapist, Verona, Italy
Ebba Buffone Neurology Unit, Department of Internal Medicine, Orlandi Hospital,

Mauro Carone Salvatore Maugeri Foundation, Institute for Research and Care, Di-
vision of Pulmonary Disease, Scientific Institute of Cassano, Cassano delle Murge
(BA), Italy
xiii
xiv Contributors
Carlo Castiglioni Medical Director VitalAire, Milan, Italy
Andrea Corsonello Unit of Geriatric Pharmacoepidemiology, Italian National Re-

search Center on Aging (INRCA), Cosenza, Italy
Marco Cristiani Charta Foundation, Milan, Italy
Sonia Dal Ben Psychologist and Psychotherapist, Verona, Italy
Roberto W. Dal Negro Lung Unit and Department of Internal Medicine, ULSS 22
Regione Veneto, Bussolengo Hospital, Verona, Italy
Daniel Della Seta Journalist, Rome, Italy
Cristina Deluca Neurology Unit, Department of Internal Medicine, Orlandi Hospi-

Massimo Dutto Bureau Veritas Health Department, Milan, Italy
Gianluca Furneri Charta Foundation, Milan, Italy
Richard Hodder† Divisions of Pulmonary and Critical Care, University of Ottawa,

The Ottawa Hospital-Civic Campus, Ottawa, ON, Canada
Carlo G. Leo Health Technology Assessment Unit, National Council of Research –

Institute of Clinical Physiology, Lecce, Italy
Lorenzo G. Mantovani Faculty of Pharmacy, Federico II University of Naples,

Naples, Italy
Claudio Micheletto Respiratory Unit, Department of Medicine, Mater Salutis Hos-

pital, Legnago (VR), Italy
Elena Minguzzi Neurology Unit, Department of Internal Medicine, Orlandi Hospi-

Nicoletta Palese Bureau Veritas Health Department, Milan, Italy
Evasio Pasini Scientific Institute of Lumezzane, “S. Maugeri Foundation”, Brescia,

Italy
Contributors xv
Maria Grazia Passarin Neurology Unit, Department of Internal Medicine, Orlandi

Hospital, Bussolengo (VR), Italy; New affiliation: Neurology Unit, Department of
Neurosciences, Bufalini Hospital, AUSL Cesena (FC), Italy
Claudio Pedone Chair of Geriatrics, University Campus Bio Medico, Rome, Italy
Paola Pisanti Head Office for Health Planning, Italian Ministry of Health, Rome,
Italy
Eugenio Sabato Pulmonary Unit, ASL BR, Brindisi, Italy
Saverio Sabina Health Technology Assessment Unit, National Council of Research

– Institute of Clinical Physiology, Lecce, Italy
Cleante Scarduelli Cardio-pulmonary Rehabilitation Unit, Cardio-thoracic-vascu-

lar Department, C. Poma General Hospital, Mantova, Italy
Simone Scarlata Chair of Geriatrics, University Campus Bio Medico, Rome, Italy
Silvia Tognella Lung Unit, ULSS22 Regione Veneto, Bussolengo Hospital, Verona,
Italy
Paola Turco Research & Clinical Governance, Verona, Italy

The Patient Candidate
for Long-Term Oxygen Therapy 1
Roberto W. Dal Negro and Richard Hodder†
1.1 A Brief History of Oxygen Therapy
Very little oxygen existed when our earth was formed approximately 4.6 billion years
ago, but atmospheric oxygen gradually increased over time and for the past 100 mil-
lion years the atmospheric concentration of oxygen has been similar to what we en-
joy today. Nowadays, we take oxygen for granted as something that supports day-
to-day life and as a life-saving therapy when needed, but the history of clinical oxy-
gen therapy and particularly of long-term oxygen therapy (LTOT) is a relatively re-
cent phenomenon [1-3].
The concept of oxygen as a therapeutic agent evolved from the work by several
physiologists of the 17th century. Oxygen was first identified in 1772 in Sweden by
Scheele (who called it fire air), and was independently isolated from heating mer-
curic acid by Joseph Priestly in England in 1774. Priestly hinted at possible thera-
peutic properties of this dephlogisticated air when he speculated that: It might be par-
ticularly salutary to the lungs in certain morbid cases when the common air would
not be sufficient to carry off the phlogistic putrid effluvium fast enough. Not long af-
ter, Antoine Lavoisier named the gas oxygen.
Oxygen was apparently first used as a therapeutic agent by Thomas Beddoes in
the early 1800s at his Pneumatic Institute in Bristol, England [4], and until the ear-
ly 20th century it was popular as potential therapy for a wide range of disorders in-
cluding cholera, syphilis, hysteria and infertility, occasionally being administered by
enema. However, when no consistent positive results were observed, enthusiasm for
oxygen therapy diminished, until in the 1920s, when it was recognized that oxygen
R.W. Dal Negro ()

Lung Unit and Department of Internal Medicine, ULSS 22 Regione Veneto
Bussolengo Hospital
Verona, Italy
e-mail: rdalnegro@alice.it
R.W. Dal Negro and R. Hodder (eds.), Long-Term Oxygen Therapy, 1

DOI: 10.1007/978-88-470-2580-6_1, © Springer-Verlag Italia 2012
2 R.W. Dal Negro, R. Hodder
Chronic Hypoxemia
PaO2 < 60 mmHg (7.99)
Tissue
Stimulation CNS Peripheral Pulmonary

of erythropoiesis hypoxia vasodilation vasoconstriction
Helpful Harmful Helpful Harmful Harmful Helpful Helpful Harmful

tO2 carrying tblood viscosity tdrive to breathe t/FVSPQTZDIJBUSJD t$)' JTDIFNJB t heart rate, t*NQSPWFE t1VMNPOBSZ
capacity tmicrovascular t*NQSPWFE102 1$02 disturbance dysrhythmias cardiac output V/Q matching hypertension
rheology t*ODSFBTFEXPSL t O2 delivery t*NQSPWFE102 t3JHIUIFBSU
of breathing strain
Fig. 1.1 Consequences of chronic hypoxemia
deficiency could result in serious physiological derangements (Fig. 1.1) and that these
could be partially reversed by breathing supplemental oxygen. Paralleling these ob-
servations, it became possible to commercially produce oxygen using the fractional
distillation of liquid air, and to measure the oxygen saturation of blood.
Subsequently, the famous physiologist J. B. S. Haldane used oxygen to treat chlo-
rine gas poisoning during World War I and advocated its use in other respiratory dis-
orders [5]. In Edinburgh, in 1921, the Canadian, Jonathan Meakins, successfully used
oxygen therapy to reverse oxygen desaturation in the blood of patients with pneu-
monia [6]. Following the publication of his observations, oxygen therapy became the
standard practice for pneumonia.
In the United States, Alvin Barach first used oxygen to reverse hypoxemia in the
1920s and recognized the potential role of continuous oxygen therapy to treat patients
with hypoxemic chronic obstructive pulmonary disease (COPD) [7]. Outpatient use
of oxygen was investigated by Cotes in 1956 in the UK [8] and by Barach [9] in the
US in 1959. Domiciliary use of oxygen to reduce polycythemia and pulmonary hy-
pertension was studied in detail in the late 1960s, and the potential for increasing
longevity with oxygen in COPD was first demonstrated in 1970 by Neff and Petty
[10]. The two landmark studies on the role of supplemental oxygen in severely hy-
poxemic COPD patients, the British Medical Research Council (MRC) [11] and the
US National Institutes of Health’s nocturnal oxygen therapy trials (NOTT) [12] were
published in 1980-1981, and have subsequently formed the basis of current LTOT
programs throughout the world. The medical community has subsequently embraced
LTOT and it has been estimated that there are likely over a million patients receiv-
ing some form of this therapy worldwide [13-14].
1 The Patient Candidate for Long-Term Oxygen Therapy 3
1.2 Rationale for LTOT
The consequences of living with chronic hypoxemia can be adaptive, as in healthy

individuals living at high altitude [15-16], or harmful, for example in patients with
lung disease and other comorbidities (Fig. 1.1) [12, 15-19]. Thus, the rationale for
providing chronically hypoxemic patients with LTOT is to slow down, prevent, or
reverse those maladaptive consequences that can lead to reduced functioning, health-
related quality of life (HRQoL), and longevity. Furthermore, given the widespread
biological actions of oxygen, additional benefits of LTOT might exist including:
changes in ventilatory control, alterations in pulmonary blood flow, modulations of
gene expression and cellular phenotype [16], and modulation of systemic inflamma-
tion [19-20] and lung remodelling in response to injury [16, 21-22].
Only a few therapies have been shown to prolong survival in patients with advanced
COPD [18, 22], including LTOT [11-12, 23], smoking cessation [24], influenza [25]
and pneumococcal [26] vaccination, non-invasive ventilation for acute exacerbations
of COPD [27], lung volume reduction surgery in selected patients [28], and possi-
bly sustained bronchodilator therapy [29-31]. Of these interventions, LTOT has the
greatest overall impact. The precise reasons for improved longevity with LTOT are
unknown and likely multifactorial, as discussed earlier. We know for example, that
early LTOT can reduce pulmonary hypertension [11-12, 32-35], and improve exer-
cise capacity [35-42], all of which could contribute in various ways to prolonging
life expectancy [18, 32-33, 43]. In addition to hypoxemia, other predictors of survival
in COPD patients receiving LTOT include age, disease progression, frequency of
COPD exacerbations, COPD phenotype [44], reduction in pulmonary hypertension
[35, 45], improvement in maximum oxygen consumption during exercise [35], hy-
percapnia, anemia [46] and the presence of co-morbid illnesses [11, 23, 47-49]. Tra-
ditionally, untreated hypoxemic COPD has been felt to be associated with polycythemia
with its attendant potentially harmful consequences of pulmonary hypertension, re-
duced cerebral blood flow, and increased risk of thromboembolic disease (Fig. 1.1)
[19]. However, more recent observations have suggested that polycythemia may be
less of a problem than anemia in COPD [46]. In one large series, a hematocrit > 55%
was observed in only 8.4% of patients with severe COPD, perhaps because these pa-
tients were all on LTOT [46]. Anemia of chronic disease may be prevalent in advanced
COPD as a reflection of systemic inflammation [46, 50-51], or as a consequence of
occult renal failure and impaired production of erythropoietin that has been ob-
served in elderly patients with COPD [52]. By improving oxygen delivery to all tis-
sues in hypoxemic patients, LTOT has the potential to correct altered hemoglobin lev-
els. Indeed, in a 3-year telemetric study of patients with severe hypoxemic COPD,
LTOT use was associated with a normalization of hemoglobin in both polycythemic
and anemic patients [50].
From the patient’s perspective, it is possible that in addition to improving survival,
Table 1.1 Factors affecting clinical response to LTOT

Pulmonary disease factors
• Severity of hypoxemia
• Chronicity of hypoxemia
• Nature of lung disease (e.g. COPD, pulmonary fibrosis, etc.)
• Presence/absence of pulmonary hypertension
Oxygen therapy factors
• Dose of LTOT
• Adherence to LTOT
• Ambulatory oxygen prescribed and used or not
• Portable oxygen device weight/ease of use
• Side effects of LTOT (e.g. headaches, dry nasal mucosa, uncomfortable cannulas, device noi-
se, self-image, etc.)
• Complications of LTOT (e.g. burns, tripping over oxygen tubing, exaggerated hypercapnia, etc.)
Patient factors
• Co-morbid disease (e.g. heart, arthritis, psychological factors, sleep-related illness, etc.)
• Nutritional status
• Anemia
• Perception of breathlessness
• Role of hypoxemia in causing breathlessness
• Social and living situation
• Availability and strength of caregiver support
• Adherence to regular exercise program
Healthcare delivery factors
• Availability of pulmonary rehabilitation
• Access to respiratory educators
• Availability of collaborative self-management/chronic disease management program
LTOT might be useful in improving other patient-centred outcomes such as exercise

capacity, sleep quality, fatigue, rate of COPD exacerbations, and the need for hospi-
talization. Chronic hypoxemia has a direct negative influence on HRQoL and neu-
ropsychiatric functioning (e.g. cognition, mood, etc.) [17, 53-56], but only a few stud-
ies on how LTOT might improve these important outcomes have been done and re-
sults are conflicting. In patients with advanced COPD and resting hypoxemia, some
studies have detected no benefit from LTOT on HRQoL [57-59], or neuropsychiatric
functioning [54, 60-61], while others suggest a positive influence on either HRQoL
[54, 62-63], or neuropsychiatric functioning [12,57, 64-67]. A few investigators have
looked at the effects of outpatient LTOT on these outcomes in COPD patients with
isolated exertion-related hypoxemia, again with some studies showing small improve-
ments in neuropsychiatric functioning or HRQoL [64], whereas others have not
[62,68-69].
Not all patients appear to respond well to LTOT. This is not surprising as, in ad-
dition to the degree of hypoxemia, it is likely that several interacting variables are
involved in influencing the clinical response to LTOT (Table 1.1), both in real life
and in clinical trials. It is not clear for example, what levels of chronic, non-life threat-
ening, hypoxemia will provoke significant tissue hypoxia and subsequent organ dys-
function, as this will modulated by other variables such as the presence of co-mor-
bid illness, hemoglobin levels, cardiac output, the health of the microvasculature, ad-
herence with LTOT, adherence with regular exercise, the availability of pulmonary
rehabilitation and educational and psychosocial support etc. Indeed, the values of PO2<
55 mmHg, and PO2< 59 mmHg with cor pulmonale or polycythemia, that form the
basis of most current LTOT guidelines arose not from the results of the NOTT [12]
and MRC [11] trials, as these were not dose finding trials, but rather from the rea-
sonable a priori assumptions of trial entry criteria made by the investigators. Nev-
ertheless, the longevity data from the NOTT and MRC trials described below sug-
gest that these blood gas criteria do identify a population of COPD patients likely to
benefit from LTOT and it would indeed seem prudent to intervene with LTOT for pa-
tients with this degree of hypoxemia. Little formal work on predicting specific he-
modynamic responses to LTOT has been done, but there is some evidence that in hy-
poxemic COPD patients, a reduction in pulmonary artery pressure and an improve-
ment in maximum oxygen uptake during exercise testing as predictors of increased
longevity with LTOT in these patients [35, 45]. Because such observations are im-
practical, LTOT indications will remain based on broader clinical outcomes such as
longevity and possibly increased exercise capacity. Whether patients with worse or
lesser degrees of hypoxemia would benefit from LTOT is an area awaiting future re-
search.
1.3 The Enduring Legacy of the MRC and NOTT Oxygen Trials
All LTOT guidelines have been derived from two relatively small, non-blinded clin-
ical trials conducted over 30 years ago in a highly selected group of significantly hy-
poxemic patients with severe COPD [11-12]. The MRC trial [11] attempted to an-
swer the question of whether some oxygen therapy was better than no oxygen ther-
apy, and the NOTT trial [12] investigated whether continuous oxygen therapy was
better than only nocturnal oxygen therapy. Both trials studied the effect of low flow
oxygen in predominantly elderly (NOTT: ~ 65 years old; MRC: ~ 58 years old), most-
ly male patients with advanced COPD and resting daytime hypoxemia (NOTT: mean
PO2 51 mmHg, PCO2 43 mmHg, FEV1 29% predicted; MRC: mean PO2 50 mmHg,
PCO2 54 mmHg, FEV1 0.70 L). NOTT studied 203 patients for a mean duration of
19.3 months (investigators stopped the trial at 38 months feeling it unethical to re-
strict oxygen to nocturnal use only), and the MRC trial reported on 87 patients over
a 5-year follow-up. Oxygen dosing was different between the two trials. In the NOTT
trial oxygen at 1-4 L/min was taken for ≥ 19 hours per day in the continuous group
and for ≤ 13 hours per day in the nocturnal group, whilst the MRC oxygen group used
oxygen for 15 hours per day, usually at 2 L/min.
Taken together (Fig. 1.2), the results of these two trials confirmed that low flow
100
NOTT O2 19 h
90
NOTT O2 12 h
80 MRC O2 15 h
70 MRC No O2
Cumulative percent survival
60
50
40
30
20
10
0
10 20 30 40 50 60 70
Time (months)
Fig. 1.2 Survival results of MRC and NOTT long-term oxygen trials. Adapted from [63, 157]
supplemental oxygen for > 15 hours per day improves 5-year survival from 25-41%
in patients with advanced COPD who have resting daytime hypoxemia defined as a
PO2< 55 mmHg (7.33 kPa), or a PO2 55-59 mmHg (7.33 - 7.87 kPa) plus evidence
of hypoxic organ dysfunction such as cor pulmonale or a hematocrit > 55%. These
results have been concisely summarized by DC Flenley [70] in reference to hypox-
emic COPD patients as: “…no oxygen is bad….oxygen for some of the time is bet-
ter….but oxygen for most of the time is best of all”. Largely due to ethical consider-
ations, it is difficult to imagine that we will ever repeat placebo-controlled LTOT tri-
als in patients with significant hypoxemia (i.e. resting daytime PO2< 55 mmHg) re-
gardless of the underlying cause of the hypoxemia.
Despite modern management strategies for COPD, it remains a progressive illness
and so it is logical to expect that the impact of LTOT will diminish with time in in-
dividual patients. Indeed, an uncontrolled 12-year LTOT observational trial in patients
similar to those studied in the NOTT and MRC trials demonstrated a 5-year survival
of 62% (better than NOTT, MRC), but only a 26% 10-year survival [23].
As noted earlier, while based upon sound reasoning, the fixed limit for a qualify-
ing PO2< 55 mmHg is somewhat arbitrary, and it is quite possible that some individ-
uals with milder degrees of hypoxemia may benefit from LTOT. A placebo-controlled
trial investigating the role of LTOT in COPD patients with milder hypoxemia (rest-
ing daytime PO2 of 56-65 mmHg) has reported that over ≥ 3 years, LTOT did not pro-
vide longevity benefits [71-72]. Similarly, a trial of nocturnal LTOT in COPD patients
with mild resting daytime hypoxemia and isolated nocturnal hypoxemia was unable
to demonstrate improved longevity, nor did nocturnal oxygen slow down either the
progression of pulmonary hypertension, or the time to the onset of significant day-
time hypoxemia requiring full LTOT. Although neither of these trials was powered
to show a statistical effect of LTOT on survival, taken together they suggest that COPD
patients without significant daytime hypoxemia are unlikely to live longer with
LTOT, at least based upon group mean data. This hypothesis currently under active
investigation (see below).
1.4 Current LTOT Guidelines and Selection of Patients for LTOT
Providing LTOT is an expensive therapy [73-78] with a real potential for abuse by
inappropriate prescription [78-85]. Thus, in order to limit its use to those most like-
ly to benefit, most countries offering LTOT follow prescribing guidelines based up-
on the MRC and NOTT studies [86]. A sample of various guidelines is shown in Table
1.1 and reveals only minor inconsistencies [47, 86-90]. However, some guidelines
do suggest a possible role for LTOT in circumstances not currently supported by sol-
id evidence-based data and it is these areas that define the need for further large-scale
studies. An algorithm representative of the commonly used approach to screening and
prescribing LTOT is shown in Figure 1.3. Many, perhaps the majority, of LTOT pre-
scriptions are initiated when patients are hospitalized for an exacerbation of COPD.
Despite the fact that many funding agencies require a reassessment of the patient’s
Potential LTOT candidate

tDPNQBUJCMFEJTFBTFB
tTUBCMFPOPQUJNBMNFEJDBMUIFSBQZ
Confirmed hypoxemia
t10NN)H L1B
t10NN)H oL1B

QMVTDPSQVMNPOBMFPSIFNBUPDSJU
Long-Term Oxygen Therapy PO2 > 60 mmHg (8.0 kPa) plus

tHPBM40
tEVSBUJPOIEBZJODMVEJOHTMFFQ low SO2 % with sleep/exerciseb
tUJUSBUF0EPTFUPQSFWFOUIZQPYFNJB tHPBMTMFFQFYFSDJTF40
EVSJOHTMFFQFYFSUJPO tJNQSPWFEFYFSDJTFDBQBDJUZTBGFSTMFFQ
Regular re-evaluation of medical

therapy and O2 requirements
B &YJTUJOHFWJEFODFPOMZTVQQPSUTTFWFSF$01% CVUJTDPNNPOMZFYUSBQPMBUFEUPPUIFSEJTFBTFT
C $POUSPWFSTJBMCVUDPNNPOQSBDUJDFXJUIPOMZSFMBUJWFMZXFBLTVQQPSUJOHFWJEFODFoNPSFSFTFBSDIOFFEFE
Fig. 1.3 LTOT selection algorithm

Table 1.2 Clinical criteria for selecting potential LTOT candidates

Degree GOLD ATS/ERS NICE AIPO
of hypoxemia
(FIO2 = 0.21)
Severe PaO2 < 55 mmHg PaO2 < 55 mmHg PaO2 < 55 mmHg PaO2 < 55 mmHg
(7.33 kPa) (7.33 kPa) (7.33 kPa) (7.33 kPa)
or SpO2 ≤ 88% or SpO2 ≤ 88%
Moderate PaO2 of 55 PaO2 of 55 PaO2 of 55 PaO2 of 55
to 59 mmHg to 59 mmHg to 59 mmHg to 60 mmHg
(7.33-7.87 kPa) (7.33-7.87 kPa) (7.33-7.87 kPa) (7.33-7.99 kPa)
or SpO2 of 89% or SpO2 of 89% or SpO2 of 89% plus at least one
plus at least one plus at least one plus at least one of the following
of the following of the following of the following criteria:
criteria: criteria: criteria: • hematocrit
• pulmonary • cor pulmonale • pulmonary > 55%
hypertension • peripheral hypertension, • signs
• peripheral oedema • peripheral of pulmonary
oedema • hematocrit oedema hypertension
• hematocrit > 55% • secondary • signs of hypoxia
> 55% polycythemia (peripheral
• *nocturnal oedema of right
desaturation heart failure,
for more than mental decline)
30% of sleep • *ischemic heart
failure
Normoxemia No recommendation *PaO2 ≥ 60 mmHg No recommendation *Intermittent
at rest (7.99 kPa) oxygen may be

or SpO2 >90% indicated for:
plus severe • desaturation
nocturnal (SpO2 < 90%)
desaturation for more than
and lung-related 30% of sleep
dyspnoea • in presence of
responsive exercise-related
to oxygen desaturation
*not currently evidence-based.
GOLD, Global Initiative for Obstructive Lung Disease; ATS, American Thoracic Society;
ERS, European Respiratory Society; NICE, National Institute for Health and Clinical Excellence;
AIPO, Italian Association of Hospital Pulmonologists.
ongoing need for supplemental oxygen once stable post hospital discharge, some ev-
idence suggests that this is not done in a majority of cases [91-94]. This underlines
the important role for collaborative self-management and integrated care which em-
phasizes good communication and cooperation amongst the various healthcare pro-
fessionals and agencies involved in providing LTOT in the context of chronic dis-
ease management [95-101].
When selecting patients for possible LTOT, clinicians (and patients) need to ap-
preciate that dyspnoea alone is insufficient to justify a prescription for oxygen [102]
Table 1.3 Clinical criteria for selecting patients for LTOT

• Confirmed diagnosis of a disease capable of causing chronic hypoxemia
• Optimized medical therapy
• Disease stability
• Confirmed smoking cessationa
• Confirmation that supplemental oxygen reverses hypoxemiab
• Confirmation that supplemental oxygen confers clinical benefit if provided for improving
exercise capacityc
a Not mandatory in all jurisdictions; b Not always rigorously documented;
c Not universally required.
and that certain other clinical criteria should be confirmed (Table 1.2). Even in pa-
tients with COPD and significant resting hypoxemia, there is only mixed evidence
that supplemental oxygen will relieve breathlessness when such patients are at rest
[57-58, 60, 102-105]. There is even less evidence supporting the use of LTOT to treat
resting breathlessness in patients without significant resting hypoxemia [102, 106],
although one recent systematic review has suggested that LTOT may improve symp-
toms in this type of patient and that oxygen prescription should be individualized [105].
On the other hand, there is good evidence that oxygen therapy will reduce exertion-
related breathlessness in COPD patients with both resting and isolated, exertion-re-
lated hypoxemia (see below) [41, 102, 107-109]. In this regard, clinicians should be
aware that prescribing LTOT without an outpatient facility can have a tendency to
reinforce sedentary lifestyles in patients by forcing them to stay indoors [110, 111].
COPD clinical practice guidelines are somewhat vague in making recommenda-
tions regarding continued smoking and the prescription of LTOT [112-113]. Smok-
ing prevalence in patients on LTOT is poorly studied, but is probably in the range of
20-30% and physicians must advise prospective LTOT patients on the safety hazards
of this practice [112]. Despite the fact that 38-43% of patients in the original MRC
and NOTT LTOT trials continued to smoke [11-12], it is generally believed that con-
tinued cigarette smoking may negate the benefits of LTOT in COPD by virtue of in-
creasing carboxyhemoglobin levels and so limiting the desired oxyhemoglobin and
hematocrit responses [114], as well as contributing to COPD progression and open-
ing the door for fire-related injuries [115] (Table 1.3).
Despite a lack of firm supporting evidence, these MRC/NOTT inspired LTOT guide-
lines have been extrapolated for use in hypoxemic patients with diseases other than
COPD such as interstitial lung disease [116-118], bronchiectasis [119], cystic fibro-
sis, kyphoscoliosis [120], chronic congestive heart failure, etc., and this seems rea-
sonable, particularly because it is unlikely that any large scale, placebo-controlled
clinical trials of LTOT will ever be conducted in hypoxemic patients from these groups.
One recent survey in Italy is representative of the worldwide experience and has doc-
umented the relative infrequency of LTOT prescriptions for conditions other than
COPD over the past 2 decades (Fig. 1.4) [121].
1,3% 0,9%
2,6% 2,4%
2,6% 2,1%
2,9% 2,7%
3,6% COPD
3,9%
6,9% Lung fibrosis
6,1%
Thoracic dysmorphisms
Pulmonary embolism
TB sequelae
Cancer
Pneumoconiosis
80,6% 81,4%
Fig. 1.4 Most common reasons for prescribing LTOT in Italy from 1990-2004 (n= 2204)114 and
updated to 2011
1.5 The Patient’s Perspective on LTOT
The responses of patients facing the prospect of LTOT are very individualized, as can
be seen from the following quotes taken from typical patients using LTOT for ad-
vanced COPD [122-125]:
“For me, emphysema is gasping old men on oxygen. What a way to live!”
“One of the main reasons I quit smoking is that I didn’t want to end up on oxygen.”
“I feel like everybody is staring at me….I just feel like a freak”
“I think I feel like it’s shameful because I have to do it because I smoked”
“If you know it’s there, you seem to relax, but if you say to yourself: “I have no oxy-
gen”, then you start to panic…”
“You have to use it in moderation. If you’re going to use it all the time, you’re go-
ing to become dependent on it…”
“I thought oxygen would confine me. But I proved it didn’t. It freed me. I could golf
and travel again!”
“Oxygen is my life support system. Without it, I’d die.”
“Oxygen is no big deal. It’s like any other piece of clothing that I wear all day, every
day. It’s become part of my life.”
Clearly, many patients appear to be conflicted when LTOT is recommended and ac-
ceptance of LTOT should not be taken for granted. Some patients welcome LTOT
because they perceive it to be a therapy that will help them live longer and more ac-
tive lives. Such well-informed patients recognize that LTOT can be liberating by open-
ing up new opportunities for them to increase activities of daily living (ADL), both
basic and instrumental. They thus see LTOT as an enabling therapy that will help them
to regain a measure of lost independence and social interaction, and so provide an

opportunity to lead more normal lives. Some will experience reduced breathlessness
with ADL and exercise and will thus become more motivated to adhere to prescribed
exercise training. Even if LTOT is not used as prescribed, many patients are reassured
by the fact that it is available if needed (i.e. for breathlessness) [122] and this may
help to reduce the likelihood of panic attacks and so improve their quality of life.
Other patients may react negatively to a prescription for LTOT and far from wel-
coming it as a hopeful new therapy, an oxygen prescription may be seen as a sign of
advanced disease and that the end of life is near [123-124, 126-127]. This forced
glimpse into their own mortality and the realization that they will forever be tethered
to an oxygen source, can have a significant depressing effect on patients that elimi-
nates any optimism that their lives will get better [122, 126, 128]. This may be es-
pecially true for patients who feel confined indoors to a stationary oxygen device,
so that LTOT can in fact create suffering by forcing them to make compromizes to
their lifestyles that represent significant losses of independence, autonomy and self-
perception [125-127]. LTOT is also perhaps the most visible of chronic therapies and
exposes the patient’s illness for all to see. It should therefore not be surprising that
some patients, especially those with minimal social support, may react to the disabil-
ity imposed by advanced COPD and the need for LTOT, by withdrawing from oth-
ers in an attempt to hide their disability. Such a state of invisible disability can threat-
en their self-esteem when they must invent explanations for their lack of social in-
teraction that do not acknowledge their illness [129]. They may feel ashamed of hav-
ing to rely upon others and paradoxically, have trouble in gaining recognition because
of their self-imposed isolation and concealment of their disease.
Thus patients prescribed LTOT may easily become conflicted by wanting to main-
tain mastery over their disease and take advantage of the liberating potential of
LTOT, but at the price of having to accept dependency on oxygen therapy [122, 126].
This fear of dependency on oxygen may be an explanation for the common obser-
vation of poor adherence with LTOT, especially ambulatory oxygen (see below) [59,
125]. Healthcare professionals may play an unwitting role in poor patient adherence
to LTOT, if they do not fully appreciate that using LTOT can be a profound challenge
for some patients and fail to support and advise them adequately [126]. Indeed, cli-
nicians enthusiastic for the benefits of LTOT often discover that convincing patients
that LTOT can be liberating for them is not always a simple matter.
Many of the challenges facing patients starting LTOT can be solved by good com-
munication between healthcare professionals and patients and their caregivers. Sad-
ly, this may not be the reality for most, as patients frequently report that they had on-
ly a single brief conversation about LTOT with their physicians at the time of initial
prescription [125]. All involved healthcare professionals need to appreciate the chal-
lenges faced by patients starting LTOT (which will be highly individualized) and should
regularly re-evaluate and reassess the patient’s success or concerns with adjusting to
LTOT and should encourage patients to discuss any problems they may be experi-
encing with this new therapy. Many of these challenges will be psychosocial in na-
ture and clinicians must be prepared for this type of dialogue. Such discussions
should also include the patient’s caregivers, because a major factor influencing the
patient’s response to LTOT is the degree of caregiver support, whether it be from fam-
ily, friends, or healthcare professionals. Enthusiastic and available caregivers can help
patients to realize that LTOT is not stigmatising, but rather that it can be liberating
by opening up new opportunities for them to re-engage with society, thus improving
their quality of life. Other resources to help patients adjust to LTOT and get the most
from this valuable therapy include discussions with other patients who have done well
with LTOT, perhaps at the local lung association or pulmonary rehabilitation program,
or if available, with respiratory educators as part of a collaborative self-management
program for COPD [95, 99-100, 130].
1.6 Adherence to LTOT
Adherence to LTOT is an important issue, as there is good evidence that in chroni-

cally hypoxemic patients with COPD, the longevity benefits of LTOT are unlikely
to be realized unless it is taken for at least 15 hours per day [12, 23]. In a 12-year
follow-up study of LTOT, survival was directly related to adherence to LTOT [23].
Survival at 5 years was 59% and 20% in patients who adhered or not to LTOT > 15
hours/day, respectively. At 10 years, survival was 20% in those who adhered to
LTOT and 0% in those who did not. Failure to prescribe LTOT to hypoxemic COPD
patients upon discharge from hospital has also been shown to be a risk factor for fre-
quent COPD exacerbations requiring readmission to hospital [131].
Data on adherence to LTOT is not always easy to obtain accurately. Measuring
adherence to any therapy is subject to error and LTOT is no exception [59, 84, 132-
135]. Patient responses to questionnaires tend to overestimate oxygen usage; meas-
uring the time of oxygen concentrator use does not track whether the patient was ac-
tually using the oxygen [136] and weighing portable oxygen devices will be affect-
ed by the set flow rates, which patients can manipulate. Notwithstanding these chal-
lenges, several studies of adherence to LTOT have been done and it is clear that de-
spite advice to patients that LTOT can prolong life, adherence to LTOT is not guar-
anteed [76, 125, 135,137-138]. One review of adherence to LTOT in Europe revealed
only a 26-55% adherence with oxygen for the prescribed number of hours per day
[76]. Results from a study of over 900 patients in France are typical and demonstrat-
ed that only 45% of hypoxemic COPD patient were using LTOT for > 15 hours/day
as had been prescribed [139]. Ambulatory oxygen was underused in this study, with
the majority only using oxygen while resting and only 4% of patients using it out-
side the home. This might have reflected the fact that lightweight portable oxygen
devices were not readily available in this 1996 study. The benefits of ambulatory LTOT
have been questioned by several investigators, at least in part because of observed
poor adherence with this method [59, 64, 68, 140-141]. A Canadian study reported
an average use of outpatient oxygen of only about 15 minutes/day [59], whereas a
recent study in the United States observed that outpatient oxygen was used for only
2.5 hours/day, but its use to enhance ADL was not investigated [141]. On the other
hand, other investigators have observed increased oxygen use if outpatient oxygen
has been prescribed [59, 76, 133, 142].
Several risk factors for poor adherence to LTOT have been identified [135, 137].
One potential cause of observed poor adherence to LTOT is poor prescribing prac-
tice by clinicians. Despite clear prescribing guidelines, many physicians fail to em-
phasize the importance of taking oxygen for at least 15 hours/day [80, 135, 139, 143].
For some patients, poor adherence to LTOT reflects inadequate communication or
teaching from healthcare professionals about the importance, goals, and practical as-
pects of LTOT [85, 125, 144]. For example some clinicians may emphasize that LTOT
is mainly to relieve breathlessness rather than to increase longevity and if patients
remain symptomatic, adherence will suffer. Inappropriate or missed opportunities for
LTOT prescription were more common in the early years following the landmark
NOTT and MRC trials, but this has improved as the cost to providers forced increased
regulation and adherence to prescribing guidelines [135].
Patient attitudes to LTOT discussed earlier will also affect adherence to this ther-
apy. While many patients will rationalize and accept the need for LTOT, some may
choose only to use it intermittently, in the false belief that they can become addict-
ed to oxygen [122, 145], or that it will lose its beneficial effects if taken too often.
For others, intermittent use of oxygen reflects a form of denial of disease and the con-
sequences of chronic hypoxemia, often with a desire to continue smoking cigarettes
[85, 139]. They may also want to test the waters to prove to themselves that they are
not dependent on oxygen. Still other patients will see oxygen only as a therapy to
treat breathlessness and will not take it when resting comfortably [125, 146]. Some
patients will choose not to take full advantage of outpatient oxygen for fear of being
embarrassed by exposing their disability in public [129]. Others, particularly those
with advanced disease or the elderly may find heavy portable devices too onerous to
carry or use [125, 127, 141]. Patients with advanced disease may become depressed
and develop a sense of hopelessness with all forms of therapy, including LTOT
[147]. For other patients, poor adherence to LTOT may reflect poor perceived ben-
efit (i.e. relief of breathlessness), a sense of restricted autonomy, cost, unwillingness
to stop smoking, noisy devices, or complications and side effects of nasal cannulas,
including appearance, headaches, uncomfortable nasal cannulas, loss of sense of smell
or taste, or dry and bleeding nasal mucosa [127, 139].
In one large survey, factors associated with good adherence to LTOT included the
presence of advanced disease; an initial prescription for oxygen > 15 hours/day; suc-
cessful smoking cessation; education on LTOT by a nurse or respiratory therapist;

advice to use oxygen for all ADL, and absence of complications/side effects of
LTOT [139]. The value of good and open communication between patients, health-
care professionals and caregivers cannot be overemphasized if LTOT is to be suc-
cessful [126, 135, 148]. Discussions should include the rationale, importance and prac-
ticalities of LTOT, and in particular, the fact that LTOT is not being prescribed to re-
lieve breathlessness, but rather to improve survival and that adherence with the > 15
hours/day prescription is vital [148]. Prescription of ambulatory, lightweight portable
oxygen devices, perhaps including an oxygen conserving device may facilitate bet-
ter adherence to LTOT, but proving this assumption has been somewhat challenging
(see below) [59, 76, 133, 141-142]. Discussions should be had with clear and sim-
ple language, adapted to the patient’s ability to comprehend the issues. Ideally this
should be done in the context of a collaborative self-management approach to chron-
ic disease management, with supportive follow-up if personnel resources permit
[95, 100-101, 126, 130, 144, 146, 149-150]. Caregivers should also be participants
in these discussions [151].
1.7 Complications of LTOT
Reported burn injury associated with LTOT is rare, as oxygen itself is not explosive,
but will support combustion, for example if oxygen tubing ignites from cigarette use
[112, 115, 152-153]. Falls from tripping over oxygen tubing may occur, especially
in the elderly. Safe storage of pressurized oxygen cylinders is important to prevent
damage and possible explosive release of the oxygen regulator, and care to avoid liq-
uid oxygen burns when filling portable devices is also warranted. While oxidative
stress may occur in response to low flow oxygen therapy [154-156], and changes con-
sistent with oxygen toxicity have been seen in biopsy specimens of COPD patients
dying while on LTOT [157], these are currently felt to be mild in degree and unlike-
ly to promote disease progression or death. The low oxygen concentrations usually
used with LTOT are unlikely to promote the absorptive atelectasis and worsening shunt
fraction that may be seen with high flow oxygen [158-159].
A commonly expressed concern about supplemental oxygen therapy in patients
with COPD is secondary worsening of hypercapnia and this may on occasion lead
to under-prescription of LTOT and to uncorrected hypoxemia, which is a much
greater concern. While some degree of hypercapnia may occur in response to LTOT
in some patients, this is generally not due to suppression of the so-called hypoxemic
drive to breathe, but rather to alterations in ventilation/perfusion matching and the
Haldane effect [160-162]. This is of little clinical consequence in the stable COPD
patient on LTOT [163] and may even be a positive adaptive response that acts to re-
duce work of breathing in these patients. Interestingly, in a recent telemetric study
of hypoxemic COPD, LTOT use was associated with reductions in PCO2 from 49.4
mmHg to 45.9 mmHg at three years, particularly in patients who had baseline poly-
cythemia, which also normalized in response to LTOT [50].
1.8 LTOT: Unanswered Questions and Future Research
The mortality data in hypoxemic patients with advanced COPD based on the NOTT
and MRC trials has formed the basis for LTOT prescribing for almost 30 years. While
some questions regarding the generalisability of these results remain [22], for ethi-
cal reasons, additional placebo-controlled trials in this patient group will not be con-
ducted. Since publication of these landmark clinical trials, little research has been
done to further refine our knowledge about the indications for LTOT, its mechanisms
of action and the best patient-centred outcomes to follow. Indeed, as discussed ear-
lier, the precise reasons for increased survival in the NOTT [12] and MRC [11] tri-
als of LTOT are not known. In both of these trials, there was a positive association
between survival and the duration of oxygen use. If this is the key to increased
longevity, then perhaps LTOT for 24/7 should be rigidly prescribed and enforced. On
the other hand, perhaps longevity reflected the fact that LTOT prevented hypoxemia
during times of particular hypoxemic stress such as sleep or exertion, and that LTOT
should be targeted to these periods. Perhaps LTOT promoted increased exercise ca-
pacity and increased physical activity and it was this result alone, or an associated
reduction in COPD exacerbations and reduced hospitalizations that contributed to the
observed increased survival [43, 164] (Table 1.3).
In 2005, The National Heart Lung and Blood Institute (NHLBI) convened a work-
shop on LTOT to define important areas for future research [22]. Workshop par-
ticipants commented that there have only been 4 randomized trials of survival with
LTOT [11-12, 23, 71], involving a total of only 501 subjects, and yet millions of
patients have received this therapy which costs billions of dollars annually [22].
This workshop recommended a few areas for focused research designed to explore
ways to optimize LTOT from the patient care and cost effectiveness perspectives
(Table 1.4).
1.8.1 LTOT for COPD Patients with Only Mild Resting

Daytime Hypoxemia
A trial of LTOT in COPD patients with only mild hypoxemia at rest during the day
was negative, but LTOT was only taken for a mean of 13.5 hours/day [71]. Perhaps
this duration of LTOT was too low and a duration approaching 24 hours/day might
show a benefit in this patient group. Perhaps other patient-centred outcomes such as
Table 1.4 Suggested areas for future research in LTOT

National Heart Lung and Blood Institute recommendations for focused research in COPD
1. Role of ambulatory LTOT in COPD patients with isolated exertion-related hypoxemia
2. Role of LTOT in COPD patients with isolated sleep-related hypoxemia not due to OSAa
3. Role of LTOT in COPD patients who are only mildly hypoxemic at rest
4. Value of individualized LTOT prescriptions based upon data taken at rest, and with exertion and
sleep in COPD patients who have significant resting daytime hypoxemia
5. Effect of lightweight portable oxygen devices on outcomes in COPD
Additional areas where LTOT research is needed

1. Role of ambulatory oxygen in patients with significant resting daytime hypoxemia
2. Role of LTOT in patients without COPD (IPF, bronchiectasis, kyphoscoliosis, neuromuscular
disease, chronic CHFb)
3. Role of LTOT in hypoxemic patients with varying stages of airflow obstruction
4. Relationship between LTOT and oxidative stress and COPD progression in COPD patients with
mild hypoxemia
5. Role of comorbid illness in modulating response to LTOT in COPD
6. Defining effective strategies to enhance adherence with LTOT
a OSA, obstructive sleep apnoea; b CHF, congestive heart failure.
HRQoL, neuropsychiatric functioning, exercise capacity, or the frequency of COPD

exacerbations, which were not measured in this trial, might improve in response to
LTOT in this mildly hypoxemic group. Perhaps there are subgroups of patients with
mild hypoxemia such as those with pulmonary hypertension, poor exercise capaci-
ty, frequent exacerbations or co-morbid cardiac disease, who might respond best to
LTOT. A clinical trial investigating LTOT in this mildly hypoxemic group of COPD
patients is currently underway (Table 1.5).
1.8.2 LTOT for COPD Patients with Isolated Exertion-Related

Hypoxemia
The value of supplemental oxygen to treat exertion-related hypoxemia in patients who

do not manifest resting daytime hypoxemia is controversial [28,38-39, 47, 71, 102,
106, 165-171], perhaps because not all patients with COPD and breathlessness man-
ifest hypoxemia during exertion and perhaps because many patients do not seem to
use this therapy very frequently [42, 59, 62, 64, 68, 140, 172-175]. Nevertheless, sup-
plemental oxygen during exertion/exercise has been shown to hasten recovery from
exercise-induced dynamic hyperinflation [36, 41, 170], increase exercise endurance
capacity [28, 38-42, 71, 107, 165, 176-178] and may improve HRQoL by promot-
ing increased mobility and thus independence [64]. Indeed, it is common practice to
use intermittent LTOT to assist exercise training during pulmonary rehabilitation for
patients with and without resting hypoxemia in order to reduce the patient’s ventila-
tory loads and so permit increased exercise intensity and duration [179] and perhaps
Table 1.5 Suggested areas for future research in LTOT

Trial Details
Long-Term Oxygen Treatment (LTOT) in Factors affecting survival over 3 years in
Chronic Obstructive Pulmonary Disease: COPD patients with hypoxemia at rest or with
Factors Influencing Survival (NCT00871962) sleep/exercise
(France: ANTADIR)
Effectiveness of Long-Term Oxygen Therapy Primary outcome survival. Observation up to
in Treating People With Chronic Obstructive 4.5 years of COPD patients with normal or
Pulmonary Disease (The Long-term Oxygen mild resting hypoxemia who desaturate with
Treatment Trial [LOTT]) (NCT00692198) exercise
(United States: NHLBI)
The COPD on Oxygen Patient Management Investigate the effect of a structured disease
European Trial (COMET) (NCT01241526) management program vs usual care on
(France, Germany, Italy, Spain) frequency of hospitalization over 2 years in
COPD patients on LTOT
LTOT in COPD Patients With Moderate Investigate whether aggressive therapy for
Chronic Hypoxemia and Chronic Heart COPD and CHF will obviate need for LTOT in
Failure (NCT00668408) (Italy) COPD patients with CHF and PO2 55-65
mmHg who receive either LTOT or no
supplemental oxygen. Primary endpoint is
mortality over 3 years
The International Nocturnal Oxygen (INOX) Nocturnal oxygen vs sham oxygen in COPD
Trial (NCT01044628) (Canada, France, patients not qualifying for LTOT, but who have
Portugal) sleep-related SpO2% < 90% for more than
30% of sleep time. Mortality over 3 years
also the safety of exercise [180]. Despite these observations, not all investigators have
been able to demonstrate improvements in training effects during pulmonary reha-
bilitation with supplemental oxygen in COPD [172, 181-183].
The rationale for efforts to improve exercise capacity for all patients with COPD
is self-evident. Increased physical activity has been shown to be associated with im-
proved blood pressure and diabetes control, improved psychological health, re-
duced COPD exacerbations and the risk of hospitalization [43, 164, 184]. In addi-
tion, as exercise capacity is related to mortality in COPD [185-187], achieving im-
proved exercise tolerance might possibly lead to increased longevity [164, 186] as
well. Providing ambulatory LTOT to patients with isolated exertional hypoxemia
might also have other benefits such as promoting mobility outside the home, thus
increasing patient independence, social interaction, improved activities of daily liv-
ing and HRQoL. In addition, if isolated exertional hypoxemia is itself harmful (e.g.
by promoting oxidative damage, cardiac dysrhythmias, etc.), then LTOT might al-
so be beneficial for this group of patients [180]. The role of LTOT in COPD patients
with isolated exertional hypoxemia is currently being investigated in 2 multicentre
clinical trials (Table 1.5).
1.8.3 LTOT for COPD Patients with Isolated Nocturnal Hypoxemia

Without OSA
Conventional LTOT in patients with resting, daytime hypoxemia compulsorily in-

cludes the sleeping hours and so corrects sleep-related hypoxemia. However, the po-
tential role of LTOT in patients with isolated nocturnal hypoxemia is unclear. Pa-
tients with COPD who are normoxemic while awake can develop nocturnal, sleep-
related hypoxemia, unrelated to sleep apnoea [34, 188-191] and it has been suggest-
ed that mortality is higher in these individuals [192]. Indeed, 9 of the 64 deaths in
the NOTT trial occurred during sleep [12]. Some have postulated that the progres-
sion of COPD to pulmonary hypertension, right heart failure and death may be de-
pendent on the severity of oxygen desaturation occurring during sleep time [193-
198], and this is supported by observations of sleep-related hypoxemia causing
acute increases in pulmonary artery pressure [199-200], as well as significant car-
diac dysrhythmias [201-203]. Nocturnal desaturation may also cause poor sleep qual-
ity, with excessive daytime somnolence and reduced HRQoL [188-189, 191]. Evi-
dence of the effect of supplemental oxygen on sleep quality in COPD is mixed, with
one study showing improved sleep architecture [191], but another showing no ben-
efit on sleep arousals nor total sleep time [189]. Just as for isolated exertion-relat-
ed hypoxemia, nocturnal hypoxemia may also be harmful by promoting oxidative
stress and progressive lung damage.
Only a few trials have attempted to assess the effectiveness of nocturnal only LTOT
in patients with daytime normoxemia who do not qualify for conventional LTOT [34,
72, 204]. In a small 3-year, double-blind, randomized, controlled trial using a sham
oxygen concentrator as control, Fletcher demonstrated that in patients with a day-
time PO2> 60 mmHg, there was a small but statistically significant reversal of pro-
gressive pulmonary hypertension in response to nocturnal oxygen, but no survival
benefit [34]. A group of French investigators conducted a two year open-label, ran-
domized, controlled trial of nocturnal LTOT in 76 patients with COPD and daytime
PO2 56 – 69 mmHg and found no differences in survival, pulmonary artery pressures,
nor the need to progress to continuous LTOT [72]. In the third trial, no effect of noc-
turnal LTOT on HRQoL was observed in a small 6 week period crossover trial of 19
patients with daytime normoxemia [204]. Thus, while some have recommended
nocturnal only LTOT for such patients (Table 1.1) [86], the benefit of this strategy
has yet to be confirmed and if ineffective, may represent a significant unnecessary
cost to any healthcare system supporting its use. The role of nocturnal only LTOT in
patients with daytime normoxemia is currently the subject of an international clini-
cal trial (Table 1.5).
If isolated nocturnal hypoxemia is proved clinically important, screening for this
may require overnight oximetry [205]. However, simple observation of SO2% dur-
ing a six minute walk test (6MWT) may also be useful in this regard [206-207]. It
has been recently demonstrated that in patients with COPD and a daytime PO2 of ~70
mmHg, an SO2% ≤ 88% during a 6MWT was predictive of nocturnal SpO2% < 90%
for at least 30% of sleep time in 10/21 patients tested [207]. In a similar study, the
time to oxygen desaturation (SO2% < 90%) during the 6MWT was predictive of the
risk of nocturnal desaturation in patients with COPD and a daytime PO2 60-70
mmHg [206]. No nocturnal desaturation was noted in patients who desaturated af-
ter 3.5 minutes during the 6MWT, but 74% of patients who desaturated during the
first minute had nocturnal hypoxemia.
1.8.4 Individualized LTOT Prescriptions Based on Resting, Exertion

and Sleep Observations
It is possible that the benefits of LTOT seen in the NOTT and MRC trials accrued
not from reversing resting hypoxemia, but rather from preventing damage or harm
from additional hypoxemia related to sleep or exertion. Furthermore, there is some
evidence from a systematic review that LTOT may have a favourable effect on breath-
lessness and other symptoms, at least for some patients with COPD [105], suggest-
ing that there may be subgroups of patient who might respond to individualized
oxygen prescriptions. Development of automated devices that adjust oxygen flow
rates based upon the patients activity, time of day or even measured SpO2% will
offer the potential of personalized LTOT that might improve and expand the ben-
efits of LTOT, while minimising cost from inappropriate prescription and perhaps
also the risk of oxygen-induced oxidative damage from overdosing when not nec-
essary [165].
1.8.5 Effect of Lightweight Portable Oxygen Devices on Outcomes

in COPD
Many ambulatory oxygen devices are bulky, heavy and cumbersome to use and so
may discourage patients from increasing physical activity and mobility and the many
benefits that can accrue from being more active [43,164]. Although lighter, portable
devices are available, they tend to be more expensive and may not be available to all
potential users of LTOT. The COPD Clinical Research Network of the NHLBI has
recently completed a small trial investigating the influence of lightweight portable
oxygen devices on adherence and activity levels of COPD patients with advanced
COPD (FEV1 31% predicted, resting PO2 52 mmHg) [141]. Use of conventional 22
lb E-type oxygen cylinders on a wheeled cart was compared to use of 3.4 lb alumini-
um cylinders in a carrying bag. In this group of patients with advanced COPD, over
6 months, the lightweight oxygen devices had no influence on either the duration of
oxygen use or patient activity. Stationary oxygen use averaged 17.2 h/day and out-
patient use ranged from 1.4 – 2.5 h/day and decreased over the 6 months of obser-
vation regardless of device type. These results suggest that improved educational ef-
forts aimed at increasing outpatient oxygen use are warranted.
Additional potential areas for research in LTOT include the following:
1.8.6 Role of Ambulatory Oxygen in Chronically Hypoxemic

Patients on LTOT
It makes intuitive sense that chronically hypoxemic patients who qualify for LTOT
ought to benefit from outpatient oxygen using portable devices compared to those
who remain tied to stationary oxygen devices, and many of the arguments in favour
of outpatient LTOT for patients with isolated exertional hypoxemia discussed ear-
lier should also apply to chronically hypoxemic patients. Ambulatory oxygen should
promote exercise, thus leading to improved exercise capacity, which in turn should
promote mobility outside the home, more independence and social interaction and
improved activities of daily living, all of which lead to a better HRQoL and possi-
bly increased longevity [43, 164, 185-187, 208]. Although cross-sectional data does
confirm that COPD patients with better exercise capacity have better long-term out-
comes [185], it has been difficult to prove that better exercise capacity necessarily
leads to increased physical activity [43, 187].Nevertheless, in COPD, increased lev-
els of physical activity do seem to be associated with increased longevity [164, 186,
208]. Ten year survival was observed to be 75% in one group of COPD patients who
rated their physical activity as high, compared to 45% in patients reporting low lev-
els of activity [164]. In another study, COPD patients on LTOT had a 4 year sur-
vival of 35% if they reported regular outdoor activity, compared with 18% in those
who were more sedentary [208]. In addition, there some evidence from small stud-
ies that exertion-related hypoxemia is associated with reduced longevity in COPD
[186, 209-210] and an analysis of the original NOTT data showed that patients who
could take advantage of ambulatory oxygen by improving their exercise levels had
better survival and fewer hospitalizations compared to those who used only station-
ary oxygen and had lower activity levels [111]. Finally, HRQoL is closely linked to
exercise capacity in COPD which tends to decrease with time [185, 211-212], and
although not well investigated, there is some data suggesting that LTOT, particular-
ly when combined with pulmonary rehabilitation and maintenance may prevent this
deterioration in exercise endurance capacity in certain patients with COPD [39, 65,
165, 213-214].
In short term studies, many investigators have clearly demonstrated that provid-
ing supplemental oxygen during exercise to significantly hypoxemic patients with
advanced COPD reduces dyspnoea and improves exercise endurance capacity [41,
103, 107, 109]. Mechanisms responsible for this improvement include reduced dys-
pnoea, slower breathing rates promoting reduced dynamic hyperinflation with ex-
ertion, reduced lactate acidosis, all of which act to reduce ventilatory limitation [107,
179, 136, 37]. However, most investigators have been unable to demonstrate that the
benefits of supplemental oxygen seen in the laboratory can be translated to real life,
with several trials failing to show that the addition of outpatient oxygen to COPD
patients with resting hypoxemia could improve exercise capacity, breathlessness, or
HRQoL [59, 106, 173, 175]. As discussed earlier, this may reflect the reality that
many, if not most, COPD patients prescribed ambulatory oxygen, remain relative-
ly sedentary and do not use portable oxygen much at all [42, 59, 62, 64, 141, 172,
175, 215]. Reduced exertion-related breathlessness and improved exercise capaci-
ty have also been reported in response to supplemental oxygen in patients with pul-
monary fibrosis, but long-term implications of these observations are unknown
[109, 116-118].
1.8.7 The Role of Short-Burst Oxygen Pre or Post Exertion
Most specialists do not recommend so-called short-burst oxygen therapy (SBOT) for
use either pre or post-exercise in non-hypoxemic patients with COPD [83, 107, 168-
169, 171, 174, 216-217], although some jurisdictions will fund such use [168, 217-
218]. Little gains in oxygen saturation are to be expected from pre-emptive oxygen
breathing in patients who are not significantly hypoxemic at rest, and most studies
of this practice have been negative [216, 219-222]. In practice, most patients using
SBOT use it after exertion in an attempt to reduce breathlessness and enhance recov-
ery [166, 218]. In one study of 100 patients receiving SBOT by cylinder oxygen, pa-
tients were observed to use oxygen before exertion (26%), during exertion/exercise
(19%), post exertion (87%) and at rest (46%) [218]. Investigators in this observation-
al study suggested that considerable cost savings would accrue by changing from cylin-
ders to oxygen concentrators. While most studies do not support SBOT use, one tri-
al did demonstrate accelerated reduction in exercise-induced hyperinflation with
post-exertion oxygen therapy [170].
Despite a lack of supporting evidence, many patients with access to SBOT report
subjective benefit, perhaps reflecting a placebo effect, and indeed, in one double blind-
ed study of air versus oxygen, observed shortened recovery time from exertion as-
sociated with activities of daily living with oxygen compared to air, but 75% of pa-
tients reporting benefit could not distinguish breathing air from oxygen [166]. On the
other hand, some patients may genuinely benefit from breathing supplemental oxy-
gen following exertion [36, 170], while others may be experiencing a reflex reduc-
tion in breathlessness from the cooling sensation of gas flow (air or oxygen) to the
face or nostrils [223-224], although this has been disputed [168]. Ideally, prescrip-
tion of SBOT for use before, after or during exertion should probably be individual-
ized on the basis of single blinded trials with air versus oxygen and using some ob-
jective endpoints such as recovery time, duration of exercise, time spent out of doors
and breathlessness with exertion. Although labour-intensive, such trials would serve
to limit this expensive therapy to those who will likely benefit and to signal the need
for greater efforts at collaborative self-management education in those who remain
breathless, but who do not benefit from this form of LTOT.
1.8.8 The Influence of Co-Morbidities in COPD on the Response

to LTOT
COPD does not occur in isolation and most patients with this disease also suffer co-
morbid illness [48-49, 225-228]. Indeed, it has been postulated that COPD is itself
a systemic disease, or at least leads to systemic illness [228-229] and so has many
potential phenotypes [230]. Comorbidities (e.g. cardiac disease, metabolic syn-
drome, osteoporosis, arthritis, low or high BMI, etc) are very likely to affect prog-
nosis and outcome in patients with COPD [47, 226, 231-232] and have not been ad-
equately controlled for in the LTOT trials to date. Furthermore, it is unknown whether
LTOT can modulate co-morbid illness such as cardiac or metabolic disease in hypox-
emic patients with or without COPD.
COPD clinical practice guidelines should probably be re-written to address the
particular needs of COPD patients with various comorbidities, including how their
presence will affect pharmacological and non-pharmacologic management strategies
[233]. There is increasing evidence that treatment of co-morbid illness may reduce
mortality in COPD patients [234] and this emphasizes the need for additional clini-
cal trials to investigate the potential role for LTOT in hypoxemic patients with and
without comorbid illness, and the effect of comorbid illness on the response of the
COPD patient to LTOT. Currently there is one clinical trial investigating the role of
LTOT in patients with co-existing COPD and congestive heart failure (Table 1.5).
1.9 Summary
LTOT has dramatically altered the outlook for many patients with significantly hy-
poxemic COPD and has the potential to further improve life quality and duration for
others not currently included in prescription guidelines. Future directions in LTOT
research are needed to better identify which patients are most likely to benefit from
this therapy, how adherence with LTOT can be enhanced, which clinical outcomes
are most likely to be modifiable, how it can be most efficiently and cost/effectively
delivered and how the presence of comorbid illness affects clinical response.
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Section I
The Multidimensional Evaluation of Patients
Lung Function Parameters
2
Cleante Scarduelli
Scientific evidence for the therapeutic benefits of long-term oxygen therapy (LTOT)
in patients with hypoxemia due to chronic obstructive pulmonary disease (COPD) is
based on two landmark prospective randomized clinical studies published about thirty
years ago [1-2].
What is the diagnostic and prognostic role of pulmonary function tests (PFTs) to-
day in patients with advanced COPD, and how can we use them for the correct in-
dication of LTOT?
In this chapter we shall try to answer these questions.
2.1 Role of PFTs in the Diagnostic and Prognostic Evaluation

of COPD
Spirometry should be undertaken in all patients suspected of or having COPD [3].

A clinical diagnosis of COPD should be considered in any patient who has dyspnoea,
chronic cough or sputum production, and/or a history of exposure to risk factors for
the disease [3]. It is important to make a confident diagnosis of COPD and to rule
out other diseases that may involve similar symptoms.
Spirometry is the gold standard for diagnosing COPD and monitoring its progres-
sion but should be performed using techniques that meet published standards [4]. It
is the best standardized, most reproducible, and most objective measure of airflow
limitation available [3]. Ideally, the principles of clinical decision-making should be
C. Scarduelli ()
Cardio-pulmonary Rehabilitation Unit
Cardio-thoracic-vascular Department
C. Poma General Hospital
Mantova, Italy
e-mail: cleante@libero.it

36 C. Scarduelli
applied to the interpretation of the results of PFTs, where the post-test probability of
disease is estimated after taking into consideration the pre-test probability of disease,
the quality of the test results, the effects of false positive and false negative interpre-
tations and finally, the test results themselves and how they compare with reference
values [5].
Spirometry measurements and interpretation should be performed in accordance
with published references values [5]. A recent publication by the ATS/ERS task force
on the standardisation of lung function testing suggests that forced expiratory vol-
ume in one second (FEV1) is referred to vital capacity (VC) rather than forced vital
capacity (FVC) in defining an obstructive pulmonary defect [5]. An obstructive
ventilatory defect is a disproportionate reduction of maximal airflow from the lung
in relation to the maximal volume that can be displaced from the lung. It implies air-
way narrowing during exhalation and is defined by a reduced FEV1/VC level below
the 5th percentile of the predicted value [5].
The slowing of the expiratory flow is most obviously reflected in a concave
shape on the flow-volume curve. Quantitatively, it is reflected in the proportionally
greater reduction in the instantaneous flow measured after 75% of the FVC has been
exhaled (FEF 75%) or in mean expiratory flow between 25% and 75% of FVC than
in FEV1 [5]. The presence of a post-bronchodilator (e.g. 400 μg salbutamol)
FEV1/FVC < 0,70 confirms the presence of a flow limitation that is not fully re-
versible [3].
Using the fixed ratio (FEV1/FVC) is particularly problematic in older adults since
the ratio declines with age, leading to the potential for labelling healthy older adults
as having COPD. So post-bronchodilator reference values in this population are ur-
gently needed to avoid potential overdiagnosis [3].
Both FEV1 and FVC predict all causes of mortality independent of tobacco
smoking, and abnormal lung function in smokers identifies a subgroup of them at in-
creased risk of lung cancer and cardiovascular disease and mortality [3, 6-7]. In the
Lung Health Study in 5,887 COPD patients (mean FEV1 74% predicted; mean
FEV1/FVC 63% predicted) it was observed that every 10% decrease in FEV1 was
associated with a 14% increase in all causes of mortality and a 28% increase in car-
diovascular mortality [7].
Moreover, it has recently been demonstrated that abnormal lung function defined
either as FVC, or FEV1/FVC below the lower limit of normal, is associated with a
significantly increased risk (HR 2.31) of heart failure among older adults [8]. D. D.
Sin, in a population based-study and a systematic review of the literature, has found
strong epidemiologic evidence to indicate that reduced FEV1 is a marker of cardio-
vascular mortality independent of age, gender, and smoking history [9]. PFTs are es-
sential in assessing COPD severity which is based on patient symptoms, the sever-
ity of spirometric abnormality, and the presence of complications such as respiratory
failure, right heart failure, weight loss, and hypoxemia [3].
2 Lung Function Parameters 37
Disease severity is classified according to the Global Initiative for Chronic Ob-
structive Lung Disease (GOLD) in four spirometric stages based on post-bron-
chodilator FEV1:
• stage I mild: FEV1/FVC < 0,70; FEV1 ≥ 80% predicted;
• stage II moderate: FEV1/FVC < 0,70; 50% ≤ FEV1 < 80% predicted;
• stage III severe: FEV1/FVC < 0,70; 30% ≤ FEV1 < 50% predicted;
• stage IV very severe: FEV1/FVC < 0,70; FEV1 < 30% predicted or < 50% pre-
dicted plus chronic respiratory failure [3].
However, there is only a weak correlation between FEV1, symptoms and impair-
ment of a patient’s health-related quality of life, for this reason formal symptomatic
assessment is also required [3]. There are several validated questionnaires to assess
symptoms in patients with COPD. GOLD recommends the use of the modified British
Medical Research Council questionnaire (mMRC) or the COPD Assessment Test
(CAT). The mMRC questionnaire only assesses disability due to breathlessness,
whereas the CAT has a broader coverage of the impact of COPD on the patient’s daily
life and well-being [3].
The measurement of lung volumes is not mandatory in identifying an obstructive
defect. It may, however, help to disclose an underlying disease and its functional con-
sequences [5]. For example, an increase in Total Lung Capacity (TLC), Residual Vol-
ume (RV), or the RV/TLC ratio above the upper limits of natural variability may sug-
gest the presence of emphysema, or other obstructive diseases, as well as the degree
of lung hyperinflation [5].
Decline in lung function is evidenced by periodic spirometry measurements every
year. Spirometry should be performed if there is an increase in symptoms or a com-
plication. Other PFTs, such as diffusing capacity (DLCO), inspiratory capacity and
lung volumes are not essential in routine assessment but can provide information
about the overall impact of the disease and can be useful in resolving diagnostic un-
certainties and assessing patients for surgery [3].
Mixed abnormalities (obstructive and restrictive) are characterized by the coex-
istence of physiological characteristics of both obstructive (FEV1/VC) and restric-
tive (TLC) defects below the 5th percentiles of their relevant predicted values [5].
These mixed abnormalities can be found in patients with COPD and other co-mor-
bidities (for example congestive heart failure and post pleura-pulmonary TB).
Using a modified GOLD classification system of COPD (using pre-bron-
chodilator FEV1 stratification of disease severity) and adding a restricted category
(FEV1/FVC > 70% and FVC < 80% predicted) in a large population of 15,759 adult
participants, aged 43-66 years at baseline, in the ARIC study the GOLD stages of
COPD were associated with higher mortality in up to 11 years of follow-up [10].
In this study 1,242 (8%) subjects died and the rate of death varied from 5.4/1,000
among normal subjects to 42.9/1,000 among subjects with GOLD stage 3 or 4
COPD [10].
38 C. Scarduelli
1.0
0.8 Quartile 1
Quartile 2
Probability of survival
0.6
Quartile 3
0.4
0.2 Quartile 4
P < 0.001
0.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52
Time (months)
Fig. 2.1 Kaplan-Meier survival curves for the four quartiles of the BODE. Quartile 1 is a score of 0
to 2; quartile 2 is a score of 3 to 4; quartile 3 is a score of 5 to 6; and quartile 4 is a score of 7 to 10.
Survival differed significantly between the four groups (p < 0.001). From [15]. © Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society
After adjusting for covariates, all GOLD categories, along with the restricted cat-
egory, predicted a higher risk of death: GOLD 3 or 4, hazard ratio (HR) 5.7; GOLD
stage 2 HR 2.4; GOLD stage 1 HR 1.4; GOLD stage 0 HR 1.5; and restricted HR 2.3
[10]. Additionally this study demonstrated that the presence of respiratory symptoms
predicts higher mortality at every level of lung function impairment, including sub-
jects with normal lung function [10].
A large body of data has been accumulated in patients classified using GOLD
spirometric grading systems (1 = mild; 2 = moderate; 3 = severe; 4 = very severe).
These show an increase in the risk of exacerbations/year (1 = unknown; 2 = 0.7-0.9;
3 = 1.1-1.3; 4 = 1.2-2), hospitalizations/year (1 = unknown; 2 = 0.11-0.20; 3 = 0.25-
0.3; 4 = 0.4-0.54) and 3-year mortality (2 = 11%; 3 = 15%; 4= 24% ), with worsen-
ing of airflow limitation [3, 11-13].
Several variables, including FEV1, exercise tolerance assessed by walking dis-
tance, symptoms, weight loss, reduction in arterial oxygen tension, frequent exacer-
bations, hospitalisations from COPD exacerbations and composite indices, identify
patients at increased risk for mortality [14]. The BODE (Body Mass Index, obstruc-
tion, dyspnea and exercise assessed by walking distance over six minutes) method
gives a composite score (from 0 to 10), which is a better predictor of subsequent sur-
vival than any component alone, and its properties as a measurement tool are under
investigation [15] (Fig. 2.1).
2.2 Role of PFTs in the Indication of LTOT
Arterial blood gas (ABG) measurements should be performed, in stable patients with
FEV1 < 50% predicted or with clinical signs suggestive of respiratory failure or right
heart failure, while breathing room air [3].
The inspired oxygen concentration (FiO2%) should be noted and this aspect is of
particular importance if the patient is using an oxygen-driven nebulizer. The devel-
opment of respiratory failure is indicated by PaO2 < 8.0 kPa (60 mmHg) with or with-
out PaCO2 > 6.7 kPa (50 mmHg) in arterial blood gas (ABG) measurements made
while breathing air at sea level.
Screening patients by pulse oximetry and assessing ABG in those with oxygen sat-
uration (SaO2) < 92% is a useful way of selecting patients for ABG [3]. Severe hypox-
emia at rest during daytime hours in stable patients with COPD has been demonstrated
to be a marker of mortality [16-17]. Improved survival with the use of supplemental
oxygen (> 15 hours/day) in hypoxemic patients was demonstrated in two landmark stud-
ies published in the early 1980s [1-2]. The beneficial effect of supplemental oxygen on
survival in the Nocturnal Oxygen Therapy Trial (NOTT) was so large that the trial was
prematurely terminated and required only 200 subjects [1]. LTOT is generally indicated
in patients with very severe COPD (stage IV) who have [3]:
• PaO2 at or below 7.3 kPa (55 mmHg) or SaO2 at or below 88% with or without
hypercapnia (evidence B); or
• PaO2 between 7.3 kPa (55 mmHg) and 8 kPa ( 60 mmHg) or SaO2 ≤88% if there
is evidence of pulmonary hypertension, peripheral oedema suggesting congestive
heart failure, or polycythemia (hematocrit > 55%) (evidence D).
A decision about the use of LTOT should be based on the resting PaO2 values re-
peated twice or more over three weeks in a stable patient [3]. Many COPD patients
are hypoxemic at discharge from hospital after an exacerbation of their underlying
respiratory disease but about 30-38% of them improve their PaO2 values by optimis-
ing medical management to the extent that they no longer fulfil selection criteria for
LTOT [18-19].
It has been reported that reassessment of the indication to LTOT after three
months of clinical stability is advisable in order to reduce the number of patients who
would be eligible for LTOT soon after an episode of exacerbation [20]. There is no
evidence that LTOT is warranted in other forms of chronic respiratory failure when
arterial blood gas criteria are similar to those established for COPD.
Current data do not support the use of LTOT in patient populations that do not meet
the above criteria [3, 14]. Because supplemental oxygen therapy is so effective in pa-
tients with severe, resting daytime hypoxemia, it might be expected that oxygen ther-
apy would improve survival in subjects with less severe daytime hypoxemia.
Despite this widespread impression there are only two small trials in COPD pa-
tients with less severe daytime hypoxemia (PaO2 56-65 mmHg or more without signs
40 C. Scarduelli
of pulmonary hypertension, congestive heart failure, polycythemia) that showed no

survival benefit for continuous oxygen therapy [21-22]. However, this issue is the
main topic of study by the ongoing Long-Term Oxygen Treatment Trial, which plans
to enrol 1,134 patients and follow them for 4.5 years to assess a potential benefit in
survival or hospitalization rates [23].
The two most controversial aspects of LTOT are its use in patients who desatu-
rate during exercise or develop nocturnal oxygen desaturation [14, 23].
There are important challenges in evaluating the effectiveness of LTOT during ac-
tivity in patients with COPD: a) lack of uniform criteria for defining exertional de-
saturation and b) lack of standardized exercise protocols [23].
Threshold values for oxygen desaturation vary from 88% to 90% and relative de-
clines from 2% to 5% in published investigations. Some studies require maintenance
of oxygen saturation by pulse oximetry (SpO2) below a threshold value for a speci-
fied interval of time varying between 0.5 and 5 minutes [23]. The techniques for in-
ducing exertion vary from activities of daily living to incremental maximal cycle er-
gometry [23].
It has been shown that COPD patients with moderate hypoxemia at rest (PaO2 60-
70 mmHg) do not experience desaturation during routine daytime activities or at night
if they do not desaturate during the first 3.5 minutes of the Six Minute Walk Test
(6MWT) [24]. So the 6MWT may be a useful test to screen patients with moderate
hypoxemia at rest who are at risk of desaturate during exercise or during the night [24].
Lower FEV1 (0.89 L) and DLCO (7.1 mL/min/mmHg) have been shown to iden-
tify COPD patients with PaO2 at rest > 55 mmHg, who desaturate during exercise
form those who do not desaturate (FEV1 1.44 L; DLCO 15.3 mL/min/mmHg) [25].
It has been shown that about half of COPD patients with SpO2 ≤ 95% desaturate
during the 6MWT while only 16% of those with SpO2 > 95% desaturate during the
6MWT [26]. Exertional desaturation in COPD is caused by ventilation/perfusion mis-
matching, diffusion limitation, shunting and reduced oxygen content of mixed venous
blood [14].
Several studies have suggested that exertional desaturation may be associated with
poor prognosis in patients with COPD [22]. Although exertional desaturation in pa-
tients with COPD and resting normoxemia appears to predict a poor prognosis, the
effects of LTOT on survival in this group have not been prospectively studied in a large
population [23]. The 6MWT is useful to evaluate the increase in exercise tolerance
with supplemental oxygen, which in one study increased form 391 +/- 36 m to 450
+/- 29 m [27]. The mechanism for the improvement in exercise performance with sup-
plemental oxygen is increased endurance time, reduced respiratory rate and dynamic
hyperinflation during exercise in COPD patients with mild hypoxemia [28].
Patients with COPD can develop nocturnal oxygen desaturation (NOD) even when
oxygen is adequate during wakefulness (PaO2 > 60 mmHg). The most severe episodes
of NOD occur during rapid eye movement sleep with a reported prevalence of 27%
[23]. However, there are no accepted standards for the level or duration of desatura-
tion that define NOD in patients with COPD [23]. NOD is more pronounced among
patients with low baseline oxygenation, it may be more severe than desaturation dur-
ing maximum exercise [14].
The only accurate method for detecting NOD in patients without severe daytime
hypoxemia is to obtain overnight oximetry. Retrospective data suggest decreased sur-
vival in patients with NOD and only a few studies examined the impact of nocturnal
supplemental oxygen therapy on mortality in patients with COPD and NOD [23].
Higher pulmonary arterial pressure values have been found in COPD patients with
daytime PaO2 ranging from 60 to 70 mmHg and NOD defined as oxygen saturation be-
low 90% for > 30% of the sleep time [29] In patients with mild to moderate daytime
hypoxemia (PaO2 56-69 mmHg) and associated NOD, no improvement in survival was
noted with nocturnal oxygen therapy for two years [30]. Based on limited available data
it is unknown whether LTOT affects survival in patients with COPD and isolated NOD
[23]. It has been reported that most COPD patients do not suffer from overnight desat-
uration despite not increasing their usual LTOT prescription overnight [31].
LTOT is one of the few interventions that improve survival in COPD patients and
its inclusion criteria and effects have been reported in two randomized clinical trials
about thirty years ago [1-2].
Current guidelines for LTOT refer to the inclusion criteria of the NOTT or MRC
trial and presume that only patients who meet these criteria will benefit from LTOT
[1-3]. However, today we know that there are some uncertainties regarding LTOT (pa-
tients with COPD and moderate hypoxemia, exercise induced desaturation and
NOD) [14, 23]. The pulmonologist evaluating a patient with possible indication to
LTOT is still faced with the task of integrating the results of PFTs with clinical data
(for example, comorbidities) that were not represented in the two landmark clinical
trials [1-2], together with the above reported unanswered questions regarding the ef-
ficacy and cost-effectiveness of LTOT [14, 23].
References
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poxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 93:391-398
2. Report of the Medical Research Council Working Party (1981) Long term domiciliary oxygen
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bidities. Eur Resp J 166:333-339
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moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis
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13. Jenkins CR, Jones PW, Calverley PM et al (2009) Efficacy of slameterol/fluticasone propionate
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placebo-controlled TORCH study. Respir Res 10:59
14. Make B, Krachman S, Panos RJ et al (2010) Oxygen Therapy in advanced COPD: In Whom
does it work? Seminars in Resp and Crit Care Med 31:334-342
15. Celli BR, Cote CG, Marin JM et al (2004) The body-mass index, airflow obstruction, dyspnea,
and exercise capacity index in chronic obstructive pulmonary disease. N Eng J Med 350:1005-
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chronic airflow limitation. Am J Med 74:249-255
18. Levi-Valensi P, Weitzenblum E, Pedinelli JL et al (1986) Three month follow-up of arterial blood
gas determination in candidates for LTOT. Am Rev Respir Dis 133:547-551
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scription of oxygen to patient with chronic lung disease hypoxic at discharge from hospital.
Respir Med 95:582-587
20. Guyatt GH, Nonoyama M, Lacchetti C et al (2005) A randomized trial of strategies for assess-
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hypoxemia. Thorax 52:674-679
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of endurance in COPD patients with reversible hypercapnia. Respiration 71:342-347
23. Stoller JK, Panos RJ, Krachman S et al (2010) Oxygen therapy patients with COPD: current
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ing distance test predicts 24-hour oximetry in COPD patients with PO2 between 60 and 70
mmHg. Resp. Med 102:1026-1032
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and exercise endurance in nonhypoxemic COPD patients. Eur Resp J 18:77-84
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time to reconsider the guidelines? Thorax 61:779-782
Cardiovascular and Metabolic Indices
3
Andrea Corsonello, Claudio Pedone, Simone Scarlata,
and Raffaele Antonelli Incalzi
3.1 Introduction
Patients on long-term oxygen therapy (LTOT) are commonly plagued with cardiovas-
cular and metabolic problems. Indeed, they are usually ex-smokers and are affected
by conditions such as COPD or pulmonary fibrosis carrying an important cardiovas-
cular risk [1]. Furthermore, physical inactivity per se and vitamin D deficiency, both
highly prevalent in hypoxemic COPD patients [2], negatively affect glucose metabo-
lism and have a proinflammatory effect [3]. Older age also – the mean age of LTOT
patients being 74 years [1] – qualifies as a risk factor for cardiovascular and metabolic
conditions. Furthermore, hypoxemia induces hemodynamic and metabolic changes
with important clinical effects (see next section). Finally, exacerbations of baseline res-
piratory conditions impact both the cardiovascular and metabolic status, with impor-
tant effects on the inherent markers. We will summarize first the cardiovascular and
metabolic effects of hypoxemia and try to distinguish them from problems related to
the underlying respiratory conditions and related comorbidity. Then we will review
the main diagnostic indices and how they fluctuate as a consequence of exacerbations,
new comorbidities and pharmacologic interventions. The final section will be devoted
to a very practical choice of indices useful for every day clinical practice.
3.2 Hypoxemia: Overview of Cardiovascular

and Metabolic Effects
The human organism adapts to hypoxia by downregulating the metabolic demand.

Both protein translation and Na-K-ATPase activity are depressed. ATP production
R. Antonelli Incalzi ()

Chair of Geriatrics, University Campus Bio Medico, Rome, Italy
e-mail: r.antonelli@unicampus.it

46 A. Corsonello et al.
decreases because hypoxia lowers the activity of the electron transport chain. This
limits the overproduction of reactive oxygen species during hypoxia and slows the
rate of oxygen depletion to prevent anoxia [4].
Hypoxemia qualifies as an atherogenic condition. Indeed, it has been proven to en-
hance glucose uptake by macrophages in the atherosclerotic plaque, to promote an-
giogenesis, cytokine production and low density lipoprotein oxidation [5]. On the
other hand, hypoxemia redirects myocardial metabolism from NEFA oxidation to gly-
colysis and has important cardioprotective effects by promoting angiogenesis, NO
synthesis and extracellular matrix remodelling [6]. It also depresses the cerebral me-
tabolism, and, at least in the rat experimental model, the hippocampus is the region
of the brain that is most vulnerable to the effects of concurring ischemia and hypoxia
[7]. This probably explains the high prevalence of defective secondary memory in hy-
poxemic COPD patients [8]. By contrast, very mild hypoxia physiologically occurs
in the Central Nervous System and seems beneficial as it promotes the replication and
differentiation of neural stem cells [9].
Hypoxemia exerts a vasodilator effect on the systemic and a vasoconstrictor ef-
fect on the pulmonary circulation. These effects are aimed at improving tissue oxy-
genation and, by curtailing blood flow to poorly ventilated pulmonary areas, at op-
timising the ventilation/perfusion ratio. Hypoxia-induced systemic vasodilation is
mediated by NO and prostaglandins [10], and is reduced by severe atherosclerosis
or the use of COX-inhibitors. Pulmonary vasoconstriction, in turn, depends upon sev-
eral mechanisms which are independent from autonomic nerves [11].
Hypoxia impairs osteoblast metabolism and replication, while enhancing osteo-
clast activity; furthermore, by creating a local acid milieu, hypoxia promotes bone
reabsorption to buffer acidity [12]. These effects concur with other factors (physical
inactivity, nutritional problems, low vitamin D levels, etc.) to explain the high preva-
lence of osteoporosis in LTOT patients [13].
Hypoxia has been shown to promote the synthesis of proinflammatory adipokines
in the visceral adipose tissue [14], but it is unclear to what extent this effect is rele-
vant in explaining the inflammatory and catabolic status frequently found in LTOT
patients. Hypoxia also affects liver metabolism and promotes fibrosis and steatosis
[15]. Furthermore, it promotes insulin resistance [16].
3.3 Warning 1: LTOT Is Not a Panacea
LTOT should not be considered a complete remedy for hypoxemia or a means of pre-
venting its abnormal effects. Indeed, LTOT is tailored to at-rest needs and may be in-
adequate to changing needs during physical exercise or sleep. Even supplementary oxy-
gen during exercise, despite preventing the surge in IL6 serum levels and oxidative
stress, cannot smooth the basal inflammatory status in COPD patients [17]. Further-
3 Cardiovascular and Metabolic Indices 47
more, the inorganic phosphate/phosphocreatine ratio in the exercising muscle remains

higher in hypoxemic subjects than in control subjects despite oxygen supplementation,
which is consistent with less efficient oxidative muscular metabolism [18].
Furthermore, sleep disorders such as OSA and CHF, which are both very common
in LTOT patients, frequently disrupt the architecture of sleep and cause nocturnal hy-
poventilation and, thus, hypoxemia despite LTOT. For instance, OSA has been re-
ported to reach a 15-20% prevalence in the population aged over 65 years [19], i.e.
in the age bracket to which the vast majority of LTOT patients belong; it is often un-
recognized due to age-related changes in its clinical presentation [20]. As a conse-
quence, even if optimally corrected at rest, hypoxemia may recur at times and have
multiple negative effects.
3.4 Warning 2: Hyperoxia Also Has Untoward Effects
The correction of hypoxemia should aim at providing a SaO2 level ≥ 95%, which, due
to the sigmoid-shaped curve of hemoglobin saturation in oxygen, corresponds to PaO2
in the 60-65 mmHg range. Increasing the inspired fraction of oxygen over the min-
imal PaO2 level, associated with SaO2 > 95%, will expose the patient to the risk of
hypercarbia, but also to the less appreciated but clearly harmful effects of hyperoxia.
Indeed, hyperoxia causes systemic, e.g. cerebral and cardiac, vasoconstriction and an
ensuing risk of critical ischemia [21]. Furthermore, ad libitum provision of O2 to pa-
tients with exacerbated COPD in pre-hospital settings has been shown to increase the
need for care and mortality [22]. Accordingly, mainly in the acute care setting, any
effort should be made to tailor FiO2 and, in ventilated patients, the ventilation param-
eters to obtain the optimal SaO2 level with the lowest FiO2.
Other cardiovascular and metabolic effects of hypoxemia will be shortly referred
to in the two sections on the relevant indexes.
3.5 Cardiovascular Indices
Preclinical indices, i.e. indices of cardiovascular dysfunction in the absence of overt car-
diovascular disease, are impaired to varying degrees in respiratory diseases. This is true
for flow-mediated dilation, the intima-media thickness of the internal and common
carotid arteries, pulse wave velocity and myocardial relaxation. The pathophysiological
meaning and clinical implications of these abnormalities are summarized in Table 3.1.
Serum BNP and, with slower kinetics, NT-proBNP increase as a consequence of
left ventricular stretching, and are a clue to detecting CHF coexisting with chronic hy-
poxemia. However, selected respiratory conditions also can account for a moderate rise
in these markers. Among these are right ventricular overload, chronic pulmonary
Table 3.1 Selected cardiovascular indices affected by chronic hypoxemia

Index Meaning Effect of hypoxemia
FMD An index of endothelial Decreased in COPD
function. FMD depression has
negative, albeit variable,
prognostic meaning
IMT An index of atherosclerosis Hypoxemia per se is an
heralding cardiovascular atherogenic condition. Moreover,
events LTOT patients have an important
risk profile for atherosclerosis
PWV An index of arterial stiffness, Increased in COPD. Hypoxia
predicts cardiovascular events further decreases arterial elasticity
NT-proBNP An index of left ventricular RV overload can mildly increase
stretching typically increased NT-proBNP
in CHF patients
Troponin An index of myocardial Increased in 1 out of 4 patients
damage with COPD exacerbation, mainly
in the context of severe hypoxemia
or tachyarrhythmias
ECG: right P wave, Indexes of RA/RV overload, Signs typically seen in patients
S1S2S3 or S1Q3, RVH portend a poor prognosis with severe hypoxemia
PAP (echocardiographic Reflects pulmonary vascular Typically increased in patients with
measure) resistances, but technical severe hypoxemia
problems frequently hamper
the recording
Peak filling rate Explores left ventricular early Directly decreased by hypoxemia
of the left ventricle diastolic filling as well as by ventricular
(radionuclide interdependence
cardiography)
Tei’s index An index of overall RV Can be impaired prior to the onset
(echocardiographic function disclosing overload of chronic hypoxemia
measure) even before hypertrophy or
dilatation occurs
GFR Renal function Frequently depressed despite
normal creatinine in hypoxemic
patients due to sarcopenia and,
then, low muscular dismissal of
creatine
6’WT An index of overall Hypoxemia accelerates decline of
performance performance. Response to LTOT is
an index of quality of LTOT.
FMD, flow-mediated dilation; IMT, intima-media thickness; PWV, pulse wave velocity;
NT-proBNP, N-terminal pro-brain natriuretic peptide; ECG, electrocardiography; RVH, right
ventricular hypertrophy; RA, right atrium; RV, right ventricle; PAP, pulmonary arterial pressure;
GFR, glomerular filtration rate; 6’WT, Six Minute Walk Test.
hypertension and pulmonary embolism; furthermore, renal failure and atrial fibrilla-
tion, which are both highly prevalent in LTOT patients, as well as older age, can in-
crease BNP/NT-proBNP [23]. Accordingly, a very scrupulous interpretation of BNP
and NT-proBNP increase in the context of LTOT is needed.
Serum troponin is a marker of myocardial damage. Both severe hypoxemia and
tachyarrhythmias likely account for a mild, but prognostically ominous, increase in
serum troponin during acute COPD exacerbations [24].
Depressed glomerular filtration rate (GFR) can also be considered a preclinical vas-
cular index because it heralds cardiovascular mortality [25]. Furthermore, GFR val-
ues in the 60-30 ml/min/m2 of body surface are frequently associated with normal
serum creatinine [26], due to the frequently coexisting sarcopenia (see chapter by
Aquilani). The origin of renal failure complicating COPD is related to vascular kid-
ney disease and several nephrotoxic effects of smoking. Hypoxia per se further im-
pairs renal function: in a COPD population, microalbuminuria had a 24% prevalence,
comparable to that found in type 2 diabetes, and only hypoxemia and systolic blood
pressure as independent correlates [27]. The general endothelial dysfunction or in-
creased glomerular permeability mediated by hypoxemia-driven cytokines might ex-
plain this association. Given that microalbuminuria portends an ominous prognosis
in the general and special populations [28], efforts should be made to recognize and,
if possible, treat it. Indeed, it has been reported to be reversible in normal subjects
exposed to high altitude hypoxia [29] and, in non-COPD populations, with ACE-in-
hibitors or angiotensin-blocker treatment [30].
A procoagulant status, seemingly multifactorial in origin, has been reported to
characterize COPD, with high fibrinogen serum levels and hypoxia-driven platelet
hyperaggregation being central to this condition [31]. Lower leg phlebitis and pul-
monary embolism have been reported to be more prevalent than expected in COPD
patients, mainly during exacerbations [32]. In COPD patients, hypoxia has been
shown to have selected procoagulatory and proinflammatory effects [33].
Selected indexes of cardiac ischemia, such as proAVP and proANP, have been re-
ported to increase in the context of pneumonia and to have important prognostic im-
plications [34]. It is not known whether hypoxemia affects proANP and proAVP
serum levels; the risk of hypoxemia-related myocardial dysfunction (see next section)
suggests that proAVP and proANP may be increased in LTOT patients. Testing this
hypothesis would enable the correct use of these markers in the event of pneumonia
in a LTOT patient.
Optimal LTOT is expected to prevent the hypoxia-related rise in pulmonary vas-
cular resistance (PVR). However, this goal is frequently missed because of exercise-
related and nocturnal hypoxemia, the pulmonary vasoconstrictor effect of hypercar-
bia, and structural and irreversible pulmonary vascular damage. Furthermore, selected
conditions requiring LTOT, e.g. several types of secondary fibrosis or chronic throm-
boembolic pulmonary disease, per se cause pulmonary hypertension.
The RV adapts to pressure overload less efficiently than to volume overload [35].
Tricuspid regurgitation frequently complicates pulmonary hypertension and con-
tributes with hypoxemia and hypercarbia to cause splanchnic congestion and lower
leg oedema [36]. Thus, a CHF-like clinical pattern may characterize respiratory pa-
tients with severe hypoxemia, but LTOT may not completely reverse leg oedema if
pulmonary hypertension and hypercarbia persist.
The LV diastolic relaxation is variously impaired. Hypoxia per se hampers early,
ATP-dependent, protodiastolic relaxation [37]. The RV dilatation and the leftward
bulging of the interventricular septum further limits LV filling [38]. Interestingly, at
least in the rat heart, the right ventricle seems to be more vulnerable to the hypox-
emic oxidative stress because the hypoxia-driven glycolytic shift is less efficient than
in the left one [39]. Both ECG and echocardiography can provide important indexes
of right ventricular dysfunction in hypoxemic patients [40-41] (Table 3.1).
Working in a condition of no or very low volume reserve, the heart cannot adapt
to effort or an emotion-related increase in demand. This in itself dramatically limits
the response to the exercise and, then, the possibility of exercising. Furthermore, the
metaboreflex, by increasing the sympathetic tone and, then, decreasing blood flow
to the lower leg, aims at improving the consumption of O2 by the respiratory mus-
cles [42]. Thus, the lower leg cannot adapt to physical effort due to the early onset
of a feeling of exhaustion and muscle pain. In conclusion, effort limitation in LTOT
patients is mainly related to non-respiratory conditions, i.e. to heart and lower leg dys-
function. Accordingly, performance in the Six Minute Walk Test should be consid-
ered an index of overall adaptation and not of respiratory adaptation to exercise.
A summary of cardiovascular indexes characterising LTOT patients, with special
emphasis on clinically useful indexes, is provided in Table 3.1.
3.6 Metabolic and Inflammatory Indices
The association of LTOT and metabolic dysfunction largely depends upon the res-
piratory conditions requiring LTOT. Indeed, metabolic syndrome has been reported
to be highly prevalent in populations with restrictive lung disease, but not in those
with COPD [43]. This likely reflects the high proportion of abdominal obesity in the
restricted population. In COPD, instead, the prevalence of metabolic syndrome de-
clines for increasing GOLD stage [44], likely reflecting the hypoxia-related rise of
malnutrition.
The same is true for diabetes mellitus: its prevalence is strictly related to restric-
tive lung disease and, in COPD populations, decreases as the GOLD stage rises [45].
However, it is worth noting that restrictive lung disease has been reported to precede
the onset of diabetes in population studies [46], as if unknown diabetogenic factors
(e.g. spillover of inflammatory mediators from the lung) characterized restricted pa-
Table 3.2 Selected metabolic and inflammatory indices affected by hypoxemia

Index Meaning Effect of hypoxemia
Fibrinogen Procoagulant status Increased mainly during exacerbations
HOMA An index of insulin resistance Resistance increased in restrictive, but
not in obstructive lung disease.
Role of hypoxemia: uncertain
CRP An index of systemic inflammation, Increased mainly in hypoxemic COPD
marks patients at special risk
of cardiovascular events
IL-8 An index of systemic inflammation Frequently increased in severe COPD
ESR A marker of inflammation or anemia Increased in the context of anemia or,
less predictably, COPD exacerbation
DEXA A marker of bone mineral density Frequently depressed in COPD even
prior to the onset of hypoxemia
Vitamin D Many important biological actions, Very commonly depressed in
e. g. anti-inflammatory, hypoxemic COPD
insulin-sensitising
HOMA, homeostasis model assessment; CRP, C-reactive protein; IL-8, interleukin-8;
ESR, erythrocyte sedimentation rate; DEXA, dual-energy X-ray absorptiometry.
tients. The dramatic reduction of mobility in LTOT patients is per se a risk factor for
diabetes, whereas the progressive loss of appetite might have a protective effect. On
the other hand, hypoxemia has complex effects on metabolism in addition to promot-
ing growth hormone resistance and accelerated catabolism of thyroid hormones
[47]. It is difficult to weigh the effects of hypoxemia in the context of so many con-
founding variables. Selected metabolic and inflammatory indices are summarized in
Table 3.2
In COPD, the prevalence of an atherogenic serum lipid profile is not higher than
expected on an purely epidemiological basis and, in patients receiving LTOT, lower
than expected [31]. This finding likely reflects the effects of malnutrition and hyper-
catabolism on lipid metabolism.
An important association between COPD and thyroid dysfunction has been ob-
served in a large epidemiological study in a geriatric population in Sweden [48]. Ac-
cordingly, an atherogenic serum lipid profile should always cast the suspicious of co-
existing hypothyroidism.
C-reactive protein (CRP) is a negative prognostic marker in the general popula-
tion and, mostly, in populations with cardiovascular and metabolic diseases [49]. It
has been reported to affect COPD patients with increased cardiovascular mortality
[50]. In a COPD population aged 65 and over, serum CRP levels increase with COPD
severity, but it briskly peaks at pathological values with the passage from III to IV
GOLD stage [51], suggesting a causal role of hypoxemia. Indeed, hypoxemia pro-
motes the production of cytokines such as TNF-alpha and IL8, which induce the liver
synthesis of CRP [52]. However, the hepatic synthesis of CRP is genetically con-
trolled; thus, a straightforward correlation between hypoxemia and CRP is unlikely.
The erythrocyte sedimentation rate (ESR) is higher than normal in a minority of
patients with stable COPD, and anemia is the usual explanatory factor, whereas hy-
poalbuminemia, likely reflecting malnutrition and systemic inflammation, is more fre-
quently associated with increased CRP [51]. Other metabolic markers, e.g.
adipokines, are influenced by hypoxemia [53], but the available knowledge is too lim-
ited to provide solid results.
3.7 Which Indices Should be Routinely Used?
Most of the previous cardiovascular and metabolic indexes lie in the field of exper-
imental medicine, although some of them look as promising biomarkers. The work-
Table 3.3 A proposal of cardiovascular and metabolic indices to be used in LTOT patients
Index Use
NT-proBNP To screen coexisting CHF
BNP For the differential diagnosis (cardiac vs respiratory) of acute onset or
acutely worsened dyspnoea
Vitamin D To exclude deficiency and, in the event of a confirmatory answer,
to guide replacement
GFR Identifying concealed renal failure is mandatory to tailor the dosage
of renally cleared drugs to the glomerular filtration rate
Troponin To monitor the course of severe COPD exacerbations
ECG: RA/RV overload To identify patients at greatest risk of death: optimize LTOT
and the remaining therapy
Echocardiogram: Worsening of these indexes is consistent with poor quality LTOT
PAP, Tei’s index increasing RV overload or pulmonary disease worsening despite
optimal LTOT and overall therapy
Echocardiogram: LV To exclude LV systolic dysfunction (unlikely for normal NT-proBNP)
kinetics and relaxation and to screen for the highly prevalent LV diastolic dysfunction.
Optimizing LTOT is expected to improve LV relaxation through
several mechanisms
6’WT An effective index of overall performance status. Changes in the
walked distance exceeding or even approaching the minimal clinically
significant difference help recognize worsening health status
NT-proBNP, N-terminal pro-brain natriuretic peptide; BNP, brain natriuretic peptide;
GFR, glomerular filtration rate; RA, right atrium; RV, right ventricle; PAP, pulmonary arterial
pressure; LV, left ventricle; 6’WT, Six Minute Walk Test; CHF, congestive heart failure.
up with LTOT patients requires that a few indexes be measured and followed up as
indicators of the quality of care. A tentative list of indexes is presented in Table 3.3.
3.8 Conclusions
Recording and analysing selected metabolic and cardiovascular indices can be a clue
to concealed comorbidity or poor-quality O2 therapy. Furthermore, it can disclose res-
piratory or non-respiratory acute events which, in hypoxemic patients, are frequently
atypical or oligosymptomatic in their presentation [54]. Accordingly, a judicious use
of these indexes will assist the practising physician with a potentially precious guide
to optimize O2-therapy in the context of the multidimensional view of such a com-
plex patient.
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Chronic Obstructive Pulmonary Disease
(COPD): Neuromuscular Implications 4
Cristina Deluca, Ebba Buffone, Elena Minguzzi
and Maria Grazia Passarin
Oxygen is necessary for the correct functioning of the whole nervous system, includ-
ing its peripheral component, muscles and nerves. Although there are some data in
the literature showing that the lack of oxygen impairs this correct functioning of mus-
cles and nerves, as we will illustrate, to the best of our knowledge there are no data
regarding whether oxygen therapy may prevent and reverse this damage.
4.1 COPD and Neuropathy
4.1.1 First Description of Neuropathy in COPD
The first suggestion that COPD could be associated with neuropathy came from a
study by Appenzeller et al. [1], who demonstrated clinical and electrophysiological
evidence (slowed peroneal motor conduction velocities) in seven patients with
COPD and wasting. However, since the study preselected patients with malnutrition,
which is a well-known cause of metabolic and axonal neuropathy, it could not state
that COPD was a direct cause of neuropathy. Moreover, neuropathic symptoms im-
proved in these patients after treatment of malnutrition and COPD, again making it
impossible to disentangle the two possible aetiologies. Nonetheless, this study has
the merit of first arousing the issue of neuropathy in COPD.
M.G. Passarin ()

Neurology Unit, Department of Internal Medicine, Orlandi Hospital
Bussolengo (VR), Italy.
New affiliation
Neurology Unit, Department of Neurosciences, Bufalini Hospital, AUSL
Cesena (FC), Italy
e-mail: mgpassarin@ausl-cesena.emr.it

58 C. Deluca et al.
4.1.2 Almitrine and Neuropathy in COPD
In 1985 some studies reported patients with COPD who had developed peripheral neu-
ropathy while they were receiving treatment with almitrine, which is an agonist of aor-
tic and carotid chemoreceptors [2-3]. Chedru et al. [2] described four patients with
COPD who developed sensory polyneuropathy within four to seven months after be-
ginning treatment with almitrine; moreover, the symptoms began to improve after one
to two months after stopping the treatment, data which was interpreted as the time as
necessary for axonal regeneration. Gherardi et al. [4] performed a nerve biopsy study
on eight patients treated with almitrine, presenting with the characteristic association
of sensory peripheral neuropathy with a recent body weight loss. The nerve biopsies
showed axonal damage affecting myelinated fibres, predominantly large ones and to
a lesser degree unmyelinated fibres, as well as some degree of segmental demyelina-
tion. When the nerve biopsy was delayed after withdrawal of the drug, marked axonal
regeneration was observed. Moreover, micro-angiopathy was observed in five patients
suffering from chronic hypoxemia. The Authors concluded that although the mecha-
nism causing the neuropathy remained obscure, hypoxia was a strong contributor.
These data led to a reconsideration of the previous studies which had shown an
association between COPD and neuropathy [1, 5]. Suggett et al. [6] hypothesized that
almitrine unmasked latent neuropathy and did not have an actual direct neurotoxic
effect. Chedru et al. [2] also hypothesized that almitrine could enhance a latent con-
dition, since only a minority of patients treated with almitrine actually developed
polyneuropathy. Many studies later addressed this safety issue and suggested the use
of a low dose of almitrine and the monitoring of patients during treatment [7-8].
4.1.3 Subclinical and Clinical Characteristics of Neuropathy in COPD
4.1.3.1 Axonal
The prevalence of neuropathy in COPD has been reported in a wide range of 36%
to 80%, which probably depends on different patient selections and methods. How-
ever, all the studies found that the prevalence of subclinical neuropathy is much higher
than the clinical prevalence.
Although all studies excluded patients with known causes of neuropathy (diabetes
mellitus, alcoholism, malnutrition, etc.), they differed in the selection according to
COPD severity and patient age (which actually is another known factor affecting
nerve function). All the studies had the difficulty of eliminating the additive risk fac-
tors for neuropathy such as smoking, malnutrition and drug use, which are all frequent
in COPD.
All studies addressed nerve conduction velocity and amplitude, both motor and
sensory, but they differed both in the amount of studied nerves (for easily entrapped
4 Chronic Obstructive Pulmonary Disease (COPD): Neuromuscular Implications 59
nerves, like the median and peroneal nerves, one might argue that the damage might
be due to the entrapment and not to a true toxic-hypoxic mechanism) and in the in-
clusion of electromyographic data.
Valli et al. [9] were the only authors who found mainly electromyographic abnor-
malities (explored by means of needle electromyography) and they interpreted them
as indicative of anterior horn cell disease, also considering the greater susceptibility
of the spinal cells to anoxia and the relative resistance of the peripheral nerve [10].
However, these abnormalities may also have been caused by cervical and lumbar
spondylosis.
Neuropathies consist of two main types, which are identified by different electro-
physiological abnormalities. The axonal type manifests electrophysiologically as a
decrease in the amplitude of the nerve potentials, whereas the demyelinating type is
associated with a decrease in nerve conduction velocity. Neuropathy in COPD is
mainly axonal. Ozge et al. [11] found axonal neuropathy prevalence (low amplitudes
rather than slow conduction velocities) to be 53%. The authors explained these data
by means of the experimental study by Nukada et al. [12] on galactose neuropathy
in which it was hypothesized that chronic hypoxia was the reason for endoneural hy-
poxia and axonal degeneration.
Faden et al. [13] found that the most consistent abnormality was a reduction in the
amplitude of the sensory action potential, indicating axonal damage. The amplitude
of the potential, differently from the conduction velocity parameter, is not affected by
room temperature, thus excluding confounding factors responsible for the alteration.
Although the amplitude of sensory potential is affected by age, in the study by Faden
et al. [13] this factor was excluded because the control group was age-matched.
Jarratt et al. [14] showed that the main electrophysiological alteration was a de-
crease in nerve potential amplitude, consistent with an axonal damage, whose origin
is usually metabolic or toxic.
Jann et al. [15] found low amplitude of both motor and sensor nerve potentials with
only slight decrease in nerve conduction velocity in COPD patients, thus indicating
that the neuropathy was axonal.
4.1.3.2 Sensory
The neuropathy in COPD is mainly subclinical; in the minority of cases when it is
clinically manifest, the symptoms are mainly sensory [13, 14, 16].
4.1.3.3 Lower limbs

Nowak et al. [17] showed that neuropathy in COPD was more pronounced in the
lower than in the upper limbs.
Faden et al. [13] also found impaired nerve conduction more commonly in the lower
extremities as compared with the upper extremities; accordingly, in the four patients
with clinical neuropathy, the signs (slight sensory and reflex changes, without mus-
60 C. Deluca et al.
cle weakness or wasting) were found in the lower extremities only. Jarratt et al. [14]
found conduction abnormalities much more frequently in the leg than in the arm.
4.1.4 Entrapment Neuropathies
Many types of neuropathy are associated with an increased incidence of entrapment

neuropathy, which usually affects the median nerve at the wrist (carpal tunnel syn-
drome) and the peroneal nerve at the fibular head. Pfeiffer et al. [18] found an in-
creased tendency for entrapment neuropathies in chronic hypoxemia.
Moore et al. [5] found 7% clinical neuropathy and 58% subclinical neuropathy in
COPD patients; however, since the two nerves they explored were the median and
peroneal nerves, which are easily compressed, one might argue that this high preva-
lence was due to entrapment and not to pure toxic-hypoxic neuropathy.
4.1.5 Hypoxemia Is the Main Cause of Neuropathy in COPD
As regards the correlation between the severity of neuropathy and hypoxemia, Ozge
et al. [11] divided their COPD patients into two groups according to the severity of
hypoxemia: PaO2 < 60mmHg as group I and PaO2 ≥ 60 as group II. The prevalence
of neuropathy in COPD was 71% in group I and 42% in group II, so that the preva-
lence of neuropathy was statistically higher in group I, i.e. in patients whose hypox-
emia were more severe.
The authors found no association between the prevalence of symptoms (muscle
weakness, sensory symptoms such as paresthesia, dysesthesia and pain) and the sever-
ity of hypoxemia. On the other hand they found a statistical association between the
prevalence of symptoms and electrophysiologically diagnosed polyneuropathy, es-
pecially for hypoxemic patients (p = 0.04). Moreover they showed a correlation be-
tween the severity of airway obstruction and neuropathy (p = 0.001), thus suggest-
ing that neuropathy may be more frequent in advanced COPD when the expiratory
flows are decreased and blood oxygenation impaired. On the other hand, the dura-
tion of COPD was not significantly correlated with neuropathy.
Pfeiffer et al. [18] also found that the rate and severity of neuropathy correlated
with the severity of chronic hypoxemia. Three out of 20 patients with mild hypox-
emia (PaO2 less than 15 mmHg below normal) had polyneuropathy as compared with
15 out of 36 with severe hypoxemia (PaO2 more than 30 mmHg below normal (rates
different at the 10% level)). PaO2 and age were the only variables discriminating be-
tween patients with and without peripheral neuropathy.
Nowak et al. [17] also showed that the prevalence of polyneuropathy in COPD pa-
tients whose mean (standard deviation, SD) arterial PO2 was 59 (9) mmHg and mean
ratio of forced expiratory volume in the first second to vital capacity (FEV1.0/VC)
was 42 (12%), increased with severity of hypoxemia (p less than 0.05), thus suggest-
ing that chronic hypoxemia may contribute to neuropathy. In accordance with data
from Pfeiffer et al. [18], Nowak et al. [17] found that age and the degree of hypox-
emia were predictors to differentiate between COPD patients with and without PNP.
Jarratt et al. [14] in their multicenter electrophysiological and clinical study
found that the patients in all subgroups of peripheral neuropathy were more hypox-
emic although not significantly so.
Oncel et al. [19] found that left sural nerve’s sensory nerve action potential am-
plitude was correlated positively with FEV(1)% (r = 0.425; p = 0.009).
Diabetic neuropathy is characterized by endoneurial vessels alterations which com-
promise the delivery of nutrients and oxygen to nerve fibres resulting in impaired ax-
onal transport (which requires energy) and causing axonal degeneration. Chronic hy-
poxemia may work in a similar manner in causing nerve damage [20]. Stoebner et
al. [21] investigated whether in COPD patients with neuropathy there was a relation-
ship between neuritic lesions (axonal degeneration and secondary demyelination) and
vascular lesions in endoneurial vessels. They analysed nerve biopsies in COPD pa-
tients and normal controls and they found that in COPD patients the endoneurial struc-
ture of microvessels was altered in that the basal membrane was thickened and the
lumen was narrowed; moreover these structural alterations in COPD patients corre-
lated with hypercapnia. The authors therefore concluded that the microangiopathy in
peripheral nerves in patients with COPD appears to be essentially related to hypoxia
and reduction in blood flow, as in diabetic neuropathy.
4.1.6 Cigarette Smoking as a Contributing Causative Factor
Faden et al. [13] investigated the pathophysiological role of smoking in neuropathy

associated with COPD and found a correlation between cigarette consumption and
electrophysiologic alterations. Control subjects had a significantly lower cigarette con-
sumption than COPD patients (p < 0.0001). Moreover, sensory nerve function and
smoking history were significantly correlated for all the sensory nerves tested (ulnar,
median, radial and sural nerves). The authors found the strongest correlation between
cigarette consumption and sensory nerve function for the sural nerve (Spearman rank
correlation coefficient, r = .68, p < 0.01), followed by the ulnar (r = .48, p < 0.01),
median (r = 0.41, p < 0.05) and radial (r = 0.38, p < 0.05) nerves. Nicotine receptors
have been shown on the axons and terminals of many motor and sensory nerve fibres,
and since nicotine at high doses may acutely affect sensory and neuromuscular
transmission [22], it might be the neurotoxin responsible for COPD associated neu-
ropathy. Kayacan et al. [23] found that distal latency of sural nerve significantly cor-
related with cigarette consumption.
62 C. Deluca et al.
On the other hand, Ozge et al. [11] found contrary results, in that they showed more
neuropathy in the non-smokers COPD patients (nine of smoker patients had neuropa-
thy, whereas 7 of 11 who were non-smokers had neuropathy (p < 0.005)), thus sug-
gesting that cigarette smoking is not a causative factor on its own.
4.1.7 COPD Treatment Also Improves Neuropathy
Appenzeller et al. [1] showed that the neuropathic symptoms improved in COPD pa-
tients after treatment of malnutrition and COPD, but since malnutrition and COPD
were treated at the same time it was not possible to distinguish which was the main
factor.
Jann et al. [15] found that the improvement of respiratory function was associated
with slight but progressive improvement of neuropathic symptoms; moreover also
electrophysiological parameters significantly improved within one year.
4.2 COPD and Myopathy
4.2.1 Hypoxemia Is the Main Cause of Myopathy in COPD
In COPD patients skeletal muscle dysfunction and muscle wasting are common and
involve the quadriceps muscles in particular [24]. Muscle biopsies show muscle fi-
bre atrophy and alteration of fibre type [25]. Reduced muscle strength is predictive
of increased healthcare use and increased mortality. Although malnutrition, disuse at-
rophy and steroid use may all contribute to muscle dysfunction, probably the main
causative factor is chronic hypoxemia [24]. Actually, not only normal subjects ex-
posed to chronic hypoxemia show a reduction in muscle strength and composition
[26], but in chronically hypoxemic COPD patients muscle dysfunction is partially im-
proved by supplemental oxygen [27]. Hypoxia can lead to skeletal muscle dysfunc-
tion by contributing to systemic inflammation which may cause muscle protein
degradation via the ubiquitin/proteasome system [25]. Skeletal muscles can also be
damaged by oxidative stress which occurs when there is an imbalance between the
amount of reactive oxygen species produced in normal aerobic metabolism and the
antioxidant defence mechanisms, which can be both enzymatic (superoxide dismu-
tase) and nonenzymatic (glutathione). Chronically hypoxemic COPD patients have
evidence of increased oxidative stress, especially after physical exercise.
Recent studies have shown that the expression of myogenic genes in COPD mus-
cles is reduced [28] and that in cachectic COPD patients the ability to induce the ex-
pression of myogenic genes in response to training is reduced [29]. It has been hypoth-
esized that the lack of expression of myogenic genes depends on the over-activation
of the NF-kB pathway induced by systemic inflammatory signals created in the lung.
Vogiatzis et al. [29] showed that, in COPD patients with muscle biopsies, COPD mus-
cles are not capable of activating NF-kB targets after physical training.
A very recent study challenged this idea that muscle wasting in COPD is corre-
lated to systemic inflammation [30]. These authors discovered that the expression of
chromatin modification enzymes, which are known to control muscle differentiation,
is altered in COPD muscles and most importantly is correlated with oxygen avail-
ability. These data suggest that an epigenetic mechanism regulated by tissue hypoxia
may be the main factor responsible for muscle wasting in COPD.
4.2.2 Steroids and Muscles
Steroids are a known factor causing myopathy. However, the steroid dose is actually
the main factor which can influence the degree of alterations in muscles.
Amaya-Villar et al. [31] investigated COPD patients admitted to intensive care
units because of acute exacerbations, and who developed acute quadriplegic myopa-
thy. What they found was that the total dose of corticosteroids was significantly higher
in patients with myopathy compared with the patients who did not developed it, thus
indicating that the total dose of corticosteroids is a factor associated with occurrence
of myopathy after the administration of corticosteroids. Certainly other factors con-
tribute to the development of acute myopathy in COPD patients admitted in ICU, like
the severity of illness at admission and the development of sepsis, but while these are
hardly modifiable factors, the total dose of steroids administered is not.
Pouw et al. [32] investigated whether long-term low-dose steroid administration
has the same effect as high-dose steroids. They compared parameters of muscle en-
ergy metabolism and muscle qualitative morphology in stable severe COPD patients,
who never received maintenance treatment with oral glucocorticosteroids, with
COPD patients using low-dose oral prednisolone for more than a year.
The authors found no difference in musclular high energy phosphate levels and in
oxidative and glycolitic enzyme capacities. Likewise, no differences in parameters of
muscle morphology were found between COPD patients who never received steroids
and those who had been taking long-term low-dose steroids in the previous year.
4.2.3 Cigarette Smoking and Myopathy in COPD
Although the role of cigarette smoking as a cause of neuropathy has not yet been fully
established, its role in muscle skeletal dysfunction has recently been shown [33]. Since
inflammation and oxidative stress are known to contribute to muscle dysfunction in
COPD patients and oxidants contained in cigarette smoke may induce adverse effects
64 C. Deluca et al.
by means of oxidative phenomena, the authors explored oxidative stress and inflam-
mation in the quadriceps of human smokers and in the diaphragm and limb muscles
of guinea pigs chronically exposed to cigarette smoke. Protein oxidation levels were
increased in the quadriceps of smokers and patients with COPD and in the respiratory
and limb muscles of guinea pigs exposed to cigarette smoke, whereas muscle inflam-
mation was not increased either in humans or in rodents exposed to cigarette smoke.
4.3 Conclusions
It appears that damage to muscles is more severe than impairment of the nerves in
COPD patients, the nerve damage often being subclinical and the muscle wasting be-
ing correlated to re-hospitalization and death.
Anyway, both nerve and muscle impairment are mainly related to chronic hypox-
emia. Studies are therefore needed to investigate whether oxygen therapy, especially
long-term oxygen therapy, may prevent and reverse this damage.
References
1. Appenzeller O, Parks RD, MacGee J (1968) Peripheral neuropathy in chronic disease of the res-
piratory tract. Am J Med 44:873-880
2. Chedru F, Nodzenski R, Dunand JF et al (1985) Peripheral neuropathy during treatment with
almitrine. Br Med J (Clin Res Ed) 290(6472):896
3. Gherardi R, Louarn F, Benvenuti C et al (1985) Peripheral neuropathy in patients treated with
almitrine dimesylate. Lancet 1:1247-1250
4. Gherardi R, Baudrimont M, Gray F, Louarn F (1987) Almitrine neuropathy. A nerve biopsy study
of 8 cases. Acta Neuropathol 73:202-208
5. Moore N, Lerebours G, Senant J et al (1985) Peripheral neuropathy in chronic obstructive lung
disease. Lancet 2(8467):1311
6. Suggett AJ, Jarratt JA, Proctor A, Howard P (1985) Almitrine and peripheral neuropathy.
Lancet 2:830-831
7. Allen MB, Prowse K (1989) Peripheral nerve function in patients with chronic bronchitis re-
ceiving almitrine or placebo. Thorax 44:292-297
8. Winkelmann BR, Kullmer TH, Kneissl DG et al (1994) Low-dose almitrine bismesylate in the
treatment of hypoxemia due to chronic obstructive pulmonary disease. Chest 105:1383-1391
9. Valli G, Barbieri S, Sergi P et al (1984) Evidence of motor neuron involvement in chronic res-
piratory insufficiency. J Neurol Neurosurg Psychiatry 47:1117-1121
10. Gelfan S, Tarlov IM (1956) Physiology of spinal cord, nerve root and peripheral nerve compres-
sion. Am J Physiol 185:217-229
11. Ozge A, Atiş S, Sevim S (2001) Subclinical peripheral neuropathy associated with chronic ob-
structive pulmonary disease. Electromyogr Clin Neurophysiol 41:185-191
12. Nukada H, Dyck PJ, Low PA et al (1986) Axonal caliber and neurofilaments are proportion-
ately decreased in galactose neuropathy. J Neuropathol Exp Neurol 45:140-150
13. Faden A, Mendoza E, Flynn F (1981) Subclinical neuropathy associated with chronic obstruc-
tive pulmonary disease: possible pathophysiologic role of smoking. Arch Neurol 38:639-642
14. Jarratt JA, Morgan CN, Twomey JA et al (1992) Neuropathy in chronic obstructive pulmonary
disease: a multicentre electrophysiological and clinical study. Eur Respir J 5:517-524

15. Jann S, Gatti A, Crespi S et al (1998) Peripheral neuropathy in chronic respiratory insufficiency.
J Peripher Nerv Syst 3:69-74
16. Agrawal D, Vohra R, Gupta PP, Sood S (2007) Subclinical peripheral neuropathy in stable mid-
dle-aged patients with chronic obstructive pulmonary disease. Singapore Med J 48:887-894
17. Nowak D, Brüch M, Arnaud F et al (1990) Peripheral neuropathies in patients with chronic ob-
structive pulmonary disease: a multicenter prevalence study. Lung 168:43-51
18. Pfeiffer G, Kunze K, Brüch M et al (1990) Polyneuropathy associated with chronic hypoxemia:
prevalence in patients with chronic obstructive pulmonary disease. J Neurol 237:230-233
19. Oncel C, Baser S, Cam M et al (2010) Peripheral neuropathy in chronic obstructive pulmonary
disease. COPD 7:11-16
20. Mayer P, Dematteis M, Pépin JL et al (1999) Peripheral neuropathy in sleep apnea. A tissue
marker of the severity of nocturnal desaturation. Am J Respir Crit Care Med 159:213-219
21. Stoebner P, Mezin P, Vila A et al (1989) Microangiopathy of endoneurial vessels in hypoxemic
chronic obstructive pulmonary disease (COPD). A quantitative ultrastructural study. Acta Neu-
ropathol 78:388-395
22. Simpson LL, Curtis DR (1974) Neuropoisons: their pathophysioogical actions. New York,
Plenum Press, Vol. 2, pp 61-97
23. Kayacan O, Beder S, Deda G, Karnak D (2001) Neurophysiological changes in COPD patients
with chronic respiratory insufficiency. Acta Neurol Belg 101:160-165
24. Kent BD, Mitchell PD, McNicholas WT (2011) Hypoxemia in patients with COPD: cause, ef-
fects, and disease progression. Int J Chron Obstruct Pulmon Dis 6:199-208. Epub 2011 Mar 14
25. Kim HC, Mofarrahi M, Hussain SN (2008) Skeletal muscle dysfunction in patients with
chronic obstructive pulmonary disease. Int J Chron Obstruct Pulmon Dis 3:637-658
26. Wüst RC, Degens H (2007) Factors contributing to muscle wasting and dysfunction in COPD
patients Int J Chron Obstruct Pulmon Dis 2:289-300
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ity in chronic obstructive airways disease. Thorax 43:965-971
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2010 Aug 5
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induced oxidative stress: A role in chronic obstructive pulmonary disease skeletal muscle dys-
function. Am J Respir Crit Care Med 182(4):477-88. Epub 2010 Apr 22
The Psychological and Cognitive Profile
5
Sonia Dal Ben and Fernanda Bricolo
In recent years, several studies have been conducted to investigate and measure the
cognitive power of patients suffering from chronic obstructive pulmonary disease
(COPD). This topic was becoming of increasing interest because chronic hypoxemia
has been progressively regarded as a crucial risk factor for possible cognitive dysfunc-
tion. From a general point of view, patients suffering from COPD do not show a sig-
nificant decrease in their cognitive functions, unless severely hypoxemic [1].
In the general population, a loss in cognitive function is typical for individuals who
have dementia due to their advanced age, or Alzheimer’s or Parkinson’s disease.
To be diagnosed, dementia requires the presence of a clinical syndrome which
should be defined on the basis of certain criteria and symptoms (DSM IV) [2].
5.1 Diagnostic Criteria for Alzheimer’s-Induced Dementia
A. The occurrence of multiple cognition disorders, such as:

1) loss of memory (reduced ability to learn new information or to remember
information previously acquired);
2) one (or more) of the following cognitive disorders:
a) aphasia (a speech disorder);
b) apraxia (difficulty performing motor activities despite the integrity of motor
function);
c) agnosia (inability to recognize or identify any object despite the integrity of sen-
sorial function);
S. Dal Ben ()

Psychologist and Psychotherapist
Verona, Italy
e-mail: sonia.dalben@yahoo.it

68 S. Dal Ben, F. Bricolo
d) difficulty with executive functions (namely planning; organising; ordering in

sequence; abstracting).
B. Any of the A1 or A2 criteria if caused by a reduced social or working function rep-
resenting a significant decline when compared to previous performances;
C. The occurrence of a progressive decline in cognitive function;
D. Any of the A1 or A2 criteria unrelated to the following conditions:
1) other CNS difficulties causing progressive loss of memory and cognitive functions
(i.e. vascular disease of the brain, Parkinson’s disease, Huntington’s disease, sub-
dural hematoma, non-hypertensive hydrocephalus; brain cancer);
2) systemic disease known to cause dementia (i.e. hypothyroidism; lack of vitamin
B12 or folic acid, lack of niacin, hypercalcaemia, neurosyphilis, HIV infection);
3) effects of drugs;
E. difficulties occurring not only during a delirium-related condition.
5.2 Diagnostic Criteria for Dementia Resulting

from Other Causes
A. The presence of multiple cognitive disorders occurring in both the following con-
ditions:
1) loss of memory (reduced ability to learn new information or to remember infor-
mation previously acquired);
2) one (or more) of the following cognitive disorders:
a) aphasia (a speech disorder);
b) apraxia (difficulty performing motor activities despite the integrity of motor
function);
c) agnosia (inability to recognize or identify any object despite the integrity of sen-
sorial function);
d) difficulty with executive functions (namely planning; organising; ordering in
sequence; abstracting).
B. Any of the A1 or A2 criteria if caused by a reduced social or working function rep-
resenting a significant decline when compared to previous performances;
C. difficulties occurring not only during delirium;
D. difficulties occurring not only during a delirium-related condition.
At present, what is known about so-called brain aging is contaminated by the pres-
ence within the group of elder healthy patients studied from the point of view of in-
dividuals with a certain amount of difficulty in a pre-clinical phase: in other words,
individuals in the early stages of the disease (preceding the clear disease), who are
difficult to recognize even with sophisticated diagnostic tools.
In the past, several clinical definitions were used for subclinical cognitive impair-
ment related to aging, such as: benign forgetfulness [3]; age-associated memory im-
5 The Psychological and Cognitive Profile 69
pairment (AAMI) [4]; age-associated cognitive impairment (AADI) [5]: all these con-
ditions were usually identified as disorders (isolated or multiple) without any evolu-
tion, and presumed to belong to the context of the physiological aging.
More recently, the normality of these conditions has been questioned. In fact, it
has been documented that elderly people alone (not those with dementia, but indi-
viduals with some mild cognitive disorders only) were at higher risk to develop de-
generative dementia when compared to normal tests in the general population [6].
Further definitions have been proposed in order to define sub-clinical cognitive
dysfunction when related to pathological conditions, such as: mild cognitive disor-
der (as coded by the ICD-10 or MCI), or mild neuro-cognitive disorder (as coded by
the DSM IV) [3,7-8].
In particular, the term Mild Cognitive Impairment (MCI) is presently used in eld-
erly individuals who are well preserved in terms of their ability to cover the major-
ity of actions during their daily living, but with sub-clinical, isolated impairment that
is possibly at risk for developing Alzheimer’s disease. This term has been introduced
to define the transition between normal aging and dementia. The hypothesis support-
ing this concept is that patients who develop dementia pass through a transitional
phase of mild cognitive impairment that is characterized by the impairment of an
unique cognitive area, affecting memory function in the majority of cases [9].
According to Petersen et al. [9], the diagnosis of MCI is based on the presence of
the following conditions: a) subjective memory disorders; b) limited memory per-
formances compared to other individuals of the same age and educational degree; c)
impairment not affecting the working and social activities of subjects, and their daily
life; d) normality of all other cognitive functions; e) lack of dementia; f) in the ab-
sence of other conditions possibly underlying a memory impairment (such as: depres-
sion, endocrine diseases, etc.). These criteria tend to select a subset of individuals
whose general cognitive functions are similar to those of normal control subjects,
while their memory functions are similar to those of mild Alzheimer’s patients [13].
Furthermore, other studies showed that these subjects have an altered metabolism of
the protein precursor of amyloid, which is very similar to that measured in subjects
suffering from Alzheimer’s disease [10]; moreover, they are also characterized by the
presence of atrophy of the medial structures of the temporal lobes, which is quite sim-
ilar to that of patients with mild Alzheimer’s disease [11].
Cognitive functions are:
1. executive functions (attention, problem solving, planning and programming, cog-
nitive organization; reasoning);
2. language (verbal speech, comprehension);
3. memory (short-term, long-term, work);
4. practice (ideomotor, ideative, visual-constructive).
They were investigated using different variables:
• age (mainly > 60 years);
• socio-economic status;
• educational level;
• pathological phenotypes (diabetes, depression, cardiovascular diseases, Alzheimer’s,
Parkinson’s, etc.).
In the majority of international studies, the most accredited tests for assessing cog-
nitive functions are:
1. Mini Mental State Examination (MMSE) [12];
2. Trial Making Test A and B (TMT) [13];
3. Clock Drawing Test or the Clock Test [14].
These tests have been used for research, but mainly on their own, and never all to-
gether.
5.3 The impact of Anxiety and Depression in COPD Subjects

During LTOT
Several studies have shown that anxiety and depression can frequently occur in COPD
patients and during LTOT, even if he ability to affect COPD and its outcomes
(namely, the exacerbation or hospitalization rate; and survival) still remains to be clar-
ified. Nevertheless, data now available tend to indicate that both these conditions can
effectively impair the course of COPD [15-16]: in particular, the probability of sur-
vival proved much better in females in a good mood than in depressed females [17].
Furthermore, in subjects previously depressed in whom COPD occurred later, it was
confirmed that both the hospitalization rate and mortality improved significantly when
the mood was better [18].
Recent studies carried in subjects with chronic respiratory failure managed with
LTOT tend to emphasize that a bad mood leads to a worse quality of life in these con-
ditions [19]. For these reasons, it is very important that these individuals can main-
tain their activities as much as possible, and can participate actively in rehabilitation
programs and programs of psychological support.
Symptoms of anxiety and depression were investigated using the Hospital Anx-
iety and Depression scale in 701 COPD patients admitted to a respiratory rehabil-
itation program, and several indices were collected (such as: clinical signs; lung func-
tion; exercise tolerance; comorbidities; smoking habit; long-term oxygen use; use
of anti-depressants) [20]. Data from this study proved that the degree of dyspnoea,
a BMI value <21, and the female gender are the most important risk factors for de-
pression [20].
Even if symptoms of anxiety and depression are described as commonly occur-
ring in COPD, the true prevalence is variable indeed because both dyspnoea and bad
mood can lead to anxiety per se, but can also be directly related to the structural dam-
age induced by COPD primarily [21]. In other words, if LTOT tends to cause a lower
independency of individuals following this particular therapeutic regimen (and the

related procedures), it may also depend on their original respiratory limitation and
on the corresponding level of their health status [22].
Despite some studies emphasising that the degree of dyspnoea of severe COPD
patients in LTOT can be directly affected by their anxiety and depression profile, other
studies suggest that the unique result achievable in these individuals by means of the
psychological approach consists in lowering their dyspnoea perception, because
their original anxiety and depression state do not change significantly with the psy-
chological support [23].
5.4 The Cognitive Function in Severe COPD and LTOT
Some studies indicate that cognitive functions can improve during LTOT. In partic-
ular, it has been documented that severe COPD patients tend to improve substan-
tially their cognitive function some weeks after the start of assisted ventilation due
to severe exacerbation [24]. Moreover, unlike patients with mild hypoxemia, those
who are highly hypoxemic significantly improved in their quality of life during
LTOT [25].
In a recent study, the cognitive function of COPD patients in LTOT was compared
to that of healthy individuals of the same age, and the Short Test of Mental Status to-
gether with Transcranial Doppler Ultrasonography were used [26]. After three
months of LTOT, the cognitive performance of COPD patients improved significantly
and became equal to that of matched healthy controls.
From this point of view, some gender-related results were found following LTOT:
in fact, it has been shown that the cognitive decline of females receiving LTOT is
faster when compared to that of healthy women of the same age, and of men; more-
over, females in LTOT tend to feel more limited and claim lower physical perform-
ance due to LTOT [27].
As mentioned above, it should be pointed out that both the decline in cognitive
function and the extent of oxygen effects on cognition are generally suggested as di-
rectly related to the extent of hypoxemia and to the clinical severity of COPD [28-
29]. When neuro-psychological measurements are carried out by means of the
MMSE, it has been shown that physical activity is able to improve both hypoxemia
and cognitive functions, while cigarette smoke tends to impair these functions, par-
ticularly after a 20-year duration of smoking habit [30]. Furthermore, it has been sug-
gested that some cognitive functions can be much more impaired than others (namely,
attention), and some specific morpho-functional studies also suggest that the brain
zones involved are likely to be the same as those that lead to impairment in
Alzheimer’s disease [29].
5.5 Personal Experience of Cognition Measurement in COPD

and LTOT
The aim of our project was to investigate the prevalence of cognitive impairment in
current smokers with COPD receiving LTOT, compared to healthy individuals. A pre-
liminary cohort of 132 subjects (74 males; mean age 71.5 years ± 12.1 SD) was stud-
ied: 45 individuals were current smokers admitted to the smoking cessation program;
48 were COPD patients hospitalized for severe exacerbation, and 39 were severe
COPD following a LTOT regimen at home.
All subjects were investigated by means of the Clock Drawing Test, the Mini
Mental State Examination (MMSE) and the Trial Making Test A and B: the use in
the same subjects of all questionnaires currently available for measuring cognition
had never been tried before, the MMSE being the most frequently used in the ma-
jority of studies.
Even though much younger than others (mean age: 53 years) and with a lung func-
tion much more preserved, smokers had a pathological Clock Drawing Test score in
6.7% of cases.
In COPD, the cognitive function was more frequently and heavily impaired: the
Clock Drawing Test score was ≤ 6 in 43.2% of cases, while the Mini Mental State
Examination score was ≤ 27 in 32.9% of cases, but ≤ 24 in 20.4% of cases. Further-
more, the Trial Making Test score was ≥ 94 (test A) in 36.4% of cases, and ≥ 283 (test
B) in 55.7% of cases.
When compared to the corresponding values for healthy subjects, main data
emerging were that the cognitive performance assessed by means of the TMT-A test
in COPD subjects was significantly impaired in all ages of life, and particularly in
the decades 40-49 and 50-59 years: the mean scores were 48.9 ± 23.6sd in COPD vs
72.2 ± 24.9sd in healthy controls (p < 0.015), and 53.8 ± 26.3 SD in COPD vs 73.7
± 34.5 SD (p < 0.006), respectively. Also the TMT-B score (which is a much more
strict score for evaluating cognition) was significantly impaired in COPD patients
aged 40-49 years compared to healthy controls of the same age (mean score 11.8 ±
53.9 SD vs 163.2 ± 97.5 SD, p < 0.015). As mean scores measured in COPD of these
two decades correspond to those of healthy controls twenty years older, this evidence
clearly contributes to support the aging affect of COPD (of at least twenty years, in
this case), particularly in younger people (Fig. 5.1).
As with the cognitive impairment of subjects admitted for severe exacerbation and
of those managed with LTOT, subjects in the latter group were more compromized
(three out of four cognitive scores were more impaired) even if the prevalence of their
impairment was quite lower than that of exacerbated individuals.
Finally, no relationship was seen between any single parameter of lung function
(such as: FEV1; PaO2; PaCO2) and the level of cognitive decline measured in these
subjects by means of all the most specific tests, universally used for these purposes.
110
100
90 P < 0.015 P < 0.006
80
TMT-A score
70
60
50
40
0 41-50 51-60 61-70 71-89

Age (years)
Fig. 5.1 Changes in the TMT-A score by age in healthy controls (●) and in COPD patients (●),
together with the significance of statistical comparisons (t test). The trends highlight the aging effect
of COPD
In conclusion, the overall cognitive state measured in subjects suffering from

COPD (and also smokers) is significantly lower than in healthy individuals of the
same age, particularly in the 5th-6th decade of life. This feature puts light on the dan-
gerous effect of COPD in terms of a subject’s cognition impairment, and the posi-
tive effects of chronic oxygen supplementation still needs to be clarified in all the clin-
ical stages of COPD.
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17. Crockett AJ, Cranston JM, Moss JR, Alpers JH (2002) The impact of anxiety, depression and
living alone in chronic obstructive pulmonary disease. Qual Life Res 11:309-316
18. Ng TP, Niti M, Tan WC et al (2007) Depressive syptom and Chronic obstructive pulmonary dis-
ease. Arch Intern Med 167:60-67
19. Janssens JP, Rochat T, Frey JG et al (1997) Health related quality of lie in patients under long
term oxygen therapy: a home based descriptive study. Respir Med 91:592-602
20. Janssen DJ, Spruit MA, Leue C, Gijsen C, Hameleers H, Schols JM, Wouters EF, Ciro network
(2010) Symptom of Anxiety and Depression in COPD patients entering pulmonary rehabilita-
tion. Chronic Respir Dis 7:147-57
21. Hill K, Geist R, Goldstein RS, Lancasse Y (2008) Anxiety and depression in end-stage COPD.
Eur Respir J 31:667-677
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living in patients with severe chronic obstructive pulmonary disease on long-term oxygen ther-
apy. Eur Respir J 10:1552-1555
23. Michiaki M et al (1996) Relationship between dyspnea in daily life and psycho-physiological
state in patients with chronic obstructive pulmonary disease during long-term domiciliary
oxygen therapy. Intern Med 35:453-458
24. Ambrosino N, Bruletti G, Scala V et al (2002) Cognitive and perceived health status in patients
with chronic obstructive pulmonary disease surviving acute or chronic respiratory failure: a con-
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Nutritional Deficiencies
6
Roberto Aquilani, Federica Boschi and Evasio Pasini
Patients with Chronic Obstructive Pulmonary Disease (COPD) on Long-Term Oxy-

gen Therapy (LTOT) may suffer from nutritional deficiencies that negatively affect
their functional and life prognosis.
For clinical purposes it is convenient to consider extensive nutritional deficiencies
in COPD as consisting of: 1) a real shortage of certain nutrients, and/or 2) alterations
of the principal muscle metabolic activities.
6.1 Nutritional Deficiencies
To date, documented nutritional deficiencies in COPD are:

• reduced muscle and/or plasma amino acid content;
• low mineral/electrolyte content;
• impaired muscle balance between muscle antioxidant levels and reactive oxygen
substances (ROS).
The causes of nutritional deficiencies in COPD, particularly in patients on LTOT,
are multifactorial and include: poor nutritional intake, when associated with in-
creased energy expenditure; systemic inflammation; hypoxemia; anabolic hormone
insufficiency; sympathetic overdrive, and atrophy of the muscles. These mechanisms,
either alone or more commonly in various combinations, are particularly notable in
emphysema-type pulmonary insufficiency (“pink puffers”), and in elderly subjects
with COPD.
F. Boschi ()
Department of Drug Sciences, University of Pavia
Pavia, Italy
e-mail: federica.boschi@unipv.it

76 R. Aquilani et al.
A. Reduced muscle and/or plasma amino acid contents

Patients with emphysema may have reduced concentrations of muscle amino acids
glutamate and glutamine [1]. Impaired muscle glutamate can follow decreased mus-
cle transport capacity of amino acids and possibly hypoxia, the latter even in the form
of recurrent episodes [1-2].
Given that alterations in muscle glutamate and glutamine concentrations are as-
sociated with increased muscle glycolytic activity [1], systemic inflammation may
be regarded as one of the most important factors affecting muscle amino acid con-
centrations.
Reduced muscle glutamate and glutamine levels may also be relevant to patients
with emphysema-type COPD, particularly in those on LTOT, since low glutamate re-
duces the synthesis of cellular antioxidant glutathione (GSH) [1] and therefore in-
creases the sensitivity of skeletal muscle to oxidative stress leading to additional mus-
cle deterioration.
Low muscle glutamine may lower the release of glutamine from muscle leading
to lower glutamine levels in the plasma. This therefore causes an important dysfunc-
tion of the immune system. Indeed, glutamine is as important (or even more so) as
glucose for the proliferation of all immune cells, particularly lymphocytes and
macrophages [3]. As a consequence, the susceptibility to any infection is greatly in-
creased in COPD patients. To the best of our knowledge, no studies at present exist
addressing the therapeutic possibility of improving muscle glutamate and glutamine
contents.
B. Low mineral/electrolyte stores [4-5]

Abnormalities of serum electrolytes can impair cellular functionality which can in
turn change muscle concentrations, even in supportive respiratory muscles.
In clinical practice, serum sodium and potassium are routinely measured, whereas
magnesium and calcium, which also affect muscle contraction, are less frequently de-
termined. In addition to poor dietary intake and the systemic use of corticosteroids,
reduced serum levels of magnesium may occur due to physical activity-induced per-
spiration; episodes of dyspnoea; infections, and high temperature, namely during hot
summers. Also calcium serum levels may be low in patients with poor dietary intake,
and particularly when on systemic corticosteroid therapy. However, the most impor-
tant and frequent factor reducing calcium intestinal absorption is represented by the
insufficient intake of vitamin D, namely when subjects have low exposure to sunlight.
C. Impaired muscle balance between muscle antioxidant levels and reactive

oxygen substances (ROS)
Oxidative stress contributes to muscle wasting. Patients with COPD have oxidative
stress which is higher that normal and an increased oxidized/reduced glutathione ra-
tio [6-7].
6 Nutritional Deficiencies 77
Cigarette smoke [8], inflammation [9], and infections [10] are the main oxidant
factors when considering the COPD altered oxidant-antioxidant balance.
The lung is a site of important antioxidant/oxidant reactions, and it is suggested
by the rich antioxidant defenzes within the lung, including both enzymatic and non-
enzymatic systems [11-12].
The most important systems of enzymatic antioxidants are: superoxide dismutase
(SOD), which degrades O-2, and the glutathione (GSH) redox system, which blocks
H2O2 activity. GSH is particularly important for the lung epithelial lining fluids where
concentrations are 100 times higher than those found in plasma [13-14]. GSH forms
intermolecular disulphide non-radical end product-oxidized glutathione (GSSG)
when exerting its antioxidant capacity. GSH also acts as a co-factor for enzymes
which decrease oxidative stress [11-12, 15].
Of the non-enzymatic factors that could function as antioxidants, vitamin E, ß-
carotene, vitamin C, uric acid, flavonoids and bilirubin are the most important. Con-
sidering patients on LTOT, adequate antioxidant capacity is of paramount impor-
tance as oxygen administration can cause lung damage by inducing oxidative
stress [16-17].
Increased oxidant substances and decreased antioxidant ones may be present in
both skeletal muscle and plasma of patients with COPD. Peripheral skeletal muscles
in resting patients with muscle weakness and wasting due to COPD have a higher pro-
duction of ROS as suggested by their antioxidant capacity which is also higher than
in normal subjects [18]. Concomitant reduced vitamin E levels may also be present
[18]. Low GSH concentrations may follow reduced levels of muscle glutamate, which
is an important substrate in the synthesis of GSH [1].
A comprehensive picture in total plasma antioxidant activity has been described
in patients with COPD at rest [19]. In particular, low plasma vitamin E levels were
found in these subjects [20], and low vitamin E can contribute to increase exercise-
induced oxidative stress [20]; changes in the morphology of skeletal muscles [21] as-
sociated with necrosis of type I muscle fibers [22], and an enhanced susceptibility
of sub-cellular membranes to oxidative damage [23].
6.2 Metabolic Deficiencies in COPD Patients
Reduced concentrations in energy-rich compounds (ATP, phosphocreatine) follow-

ing impaired energy metabolism in skeletal muscles may be a characteristic of
COPD patients. This condition is even clearer during exercise [24].
The quadriceps femoris muscle in COPD individuals has low concentrations of
glycogen [25], whose degradation contributes to provide cell glucose molecules for
energy production. Most probably, reduced energy formation in COPD is caused by
enhanced anaerobic energy metabolism and reduced aerobic energy metabolism. Sev-
eral studies have shown increased muscle lactate concentrations in COPD patients
[26]. A recent investigation found that ambulatory subjects with COPD and sarcope-
nia were in a state of hyperlactatemia [27] even if receiving oxygen.
Probably, both enhanced anerobic metabolism and impaired aerobic metabolism
are caused by abnormalities of the enzymes deputed to sustain the two metabolic cy-
cles. Indeed, in skeletal muscles of COPD subjects, the contents of phosphofructok-
inase and lactodehydrogenase, both enzymes of anaerobic metabolism, are high [28],
whereas the contents in citrate synthase, succinate dehydrogenase aerobic enzymes
of the Krebs cycle are significantly lower than in normal subjects [29].
Adequate muscle energy formation is essential for exercise tolerance and protein
synthesis, hence for tissue maintenance and storage in COPD subjects. Until recently,
treatments to steadily reduce anaerobic metabolism and improve aerobic metabolism
in order to boost energy production were not available. In this respect, there is a mis-
conception of the role played by O2 administration in subjects on LTOT. Whereas
acute oxygen administration improves exercise capacity in COPD [30], the ability of
LTOT to retrieve alterations in muscles of COPD patients is disappointing. The im-
provement of muscle oxidative energy metabolism may be only limited during oxy-
gen administration [31], whereas it disappears altogether when patients are breath-
ing room air. Under these conditions, COPD patients on LTOT have a lower muscle
aerobic capacity associated with a low intracellular pH and a slow creatinphosphate
recovery compared with normal subjects.
Recently, a preliminary study carried out on COPD patients with sarcopenia and
LTOT has showed that 2-month oral supplementation with essential amino acids
(EAAs) can significantly reduce plasma hyperlactatemia compared with a placebo-
controlled group [27]. Interestingly, reduced plasma lactate was associated with an
increased FAT free mass (+3.6 kg) and increased daily life physical activity (+78 %),
neither of which were observed in the control group.
Finally, a similar study [32] carried out on cachectic subjects supplemented with
EAAs showed similar results. EAAS supplemented subjects improved their fat free
mass (+1.5 kg) and their Six Minute Walk Test. The authors of both studies explained
the results as a consequence of EAAs which act within the aerobic metabolic cycle
(Krebs) as a surrogate substrate for energy formation.
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6 Nutritional Deficiencies 79
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struct Pulmon Dis 5:29-39
Gender-Related Differences
7
Paola Turco
Chronic respiratory diseases are leading causes of morbidity and death worldwide;
in particular, chronic obstructive pulmonary disease (COPD) causes the highest im-
pact on patients and health systems.
The relationship between gender and COPD still is a fairly complex and debated
matter, in particular when concerning patients who were admitted to long-term oxy-
gen therapy (LTOT).
Independently of the general assumption that oxygen can provide clear benefits
in terms of survival as assessed long ago by two landmark studies [1-2], the precise
mechanisms of these effects are not clarified, and conflicting results emerge partic-
ularly when studies are oriented to determine the possible role of gender in induc-
ing those benefits, thus leading to difficult and uneven interpretations.
Inflammatory lung diseases are showing an increasing prevalence, morbidity and
mortality in women: in the case of COPD, values measured in females are progres-
sively approaching those in males. Although COPD had been described as more com-
mon in men, it has been also suggested for a while that women may be at increased
risk of developing more severe COPD and mortality [3-4].
Concerning the susceptibility to exacerbations as the possible cause of reduced sur-
vival in COPD, a recent study confirmed that, in general, more frequent exacerba-
tions are associated with the greater clinical severity and impairment of health sta-
tus, an elevated white-cell count, and a history of gastro-oesophageal reflux [5], the
latter condition possibly representing a potential link with gender as it shows the high-
est prevalence in women. In this study, sex was associated with exacerbation fre-
quency, but it was further combined with other variables. The enhanced bronchial hy-
perresponsiveness of female smokers has also been suggested as a factor influencing
their susceptibility to COPD, probably due their smaller airways [6].
P. Turco ()
Research & Clinical Governance, Verona, Italy
e-mail: turcop@libero.it

82 P. Turco
The active role of female hormones has been suggested also in COPD [7]. Actu-
ally, even in cases of cigarette smokers, women develop COPD after smoking fewer
cigarettes per lifetime and are two or three times more likely to require hospital ad-
mission than male patients [8].
In animal models, female lungs were described as more susceptible to oxidant
damage in response to cigarette smoke [9, 10]. Moreover, in humans it has been sug-
gested that the female sex hormone oestradiol contributes to oxidative stress and
greater airway injury via an increased metabolism of cigarette smoke to generate ox-
idants/oxidizers [11].
Regarding the survival of COPD patients, in general terms it can depend on sev-
eral factors including the extent of the intrinsic tissue damage within the lungs; the
presence of one or more comorbidities (such as: pre-existing cardiovascular and or
metabolic diseases; the occurrence of cardiac complications of COPD – i.e. cor pul-
monale or embolic events; sarcopenia; obesity; vascular brain insults, lung cancer);
environmental and socio-economic conditions.
Sex-related differences as predictors of survival during LTOT were investigated
in 404 COPD patients (201 men) registered in the national register of Sweden between
1987 and 1989: the cohort represented 90% of all patients entering LTOT in the pe-
riod. Lung function and performance status predicted survival during LTOT in men,
while a poor performance status and the use of oral steroids did so in women. More-
over, steroid use was related to increased mortality in women (RR 2.13; 95% CI 1.38-
3.29, p < 0.001). In patients not receiving oral steroids, women had a better survival
rate than men. Finally, an increased susceptibility to the side effects of oral steroids
was suggested as the possible explanation of this difference [12].
Sex-related differences were further investigated in a very large population (n =
9,759) of subjects admitted to LTOT between 1986 and 1993. Their basic diseases
were: COPD; chronic interstitial pneumonia; sequelae of tuberculosis. In this study,
the gender effect on survival was confirmed, and mean survival in women was longer
than in men, regardless of the original respiratory disease (by 0.41 years in COPD; 1.84
years in tuberculosis sequelae, and 0.78 years in interstitial pneumonia), thus suggest-
ing that women have a better prognosis than men when admitted to LTOT. Neverthe-
less, no clear explanation of this significant difference was hypothesized [13].
Females experienced longer survival than males also in a real-life study carried
out on five hundred and five patients with hypoxic COPD (249 males and 256 fe-
males) receiving oxygen via concentrators. In this study, a survival advantage was de-
scribed for females using oxygen for at least 19 h/day [14].
A few years ago, a seven-year prospective cohort study on 435 COPD outpatients
(184 females and 251 males) produced quite different conclusions in terms of mean
survival of women receiving long-term oxygen [15]. Despite the non-significant trend
for increased mortality for women emerging from unadjusted analyses (p < 0.07), af-
ter adjusting for potential risk factors (age, pack-years, PaO2, BMI, and FEV1) fe-
7 Gender-Related Differences 83
85 Mean expectancy for females
80 Mean expectancy for males
75
Age (years)
70
65
0 M F M F
When entering LTOT At the end of LTOT
Fig. 7.1 Male and female ages when entering LTOT and at the end of LTOT compared to the cor-
responding mean national expectancy of life
males on LTOT resulted at a significant higher risk of death (HR 1.54; 95% CI 1.15-
2.07, p < 0.004). Despite similar initial survival rates, those discrepancies in survivals
emerged only after the first three years of follow-up, without any difference in clin-
ical and therapeutic management between men and women. It has been suggested that
some differences in criteria for selecting patient populations may possibly explain
these results which are not in agreement with those from other studies [10-12, 16-
17]. In this study, data on adherence to LTOT and on patients’ true smoking status
were not collected during the observational period, as they could have affected the
results. Another factor which can help to explain the above mentioned discrepancies
between different studies is also represented by the wide range of rules for indica-
tions to start LTOT in the cohorts of subjects investigated.
The particular topic of possible differences in survival between males and females
has been further investigated during LTOT at home in a cohort of 309 patients
whose overall mean age when they entered tele-LTOT was 70.7 years ± 13.7 SD, and
the mean duration of LTOT was 6.1 years. Firstly, females (30.4% of subjects) usu-
ally entered LTOT an average of two years later than males. In 2005, mean crude data
on the mortality of LTOT subjects showed that survival was shorter than expected in
both males and females when compared to that of the general population (national
data). In particular, even if females on LTOT were apparently older than males (78
vs 76 years) at the end of LTOT, when their survival was compared to the national
mean life expectancy (78 years for males and 82.5 years for females), females
proved to die much earlier [18] (Fig. 7.1). These data are in agreement with those by
Machado et al., which were obtained in an equivalent sample of subjects, though for
a shorter duration [15].
84 P. Turco
Days 1500
1000
500
0 M F M F
LTOT standard care LTOT telemetric
Fig. 7.2 Mean survival in the standard care and tele-LTOT groups by gender
In 2009, a wider cohort of patients (n = 886) admitted to LTOT at home over the
last ten years due to very severe chronic obstructive respiratory disease (COPD) was
investigated in terms of survival (no. of days since entering the LTOT program) [19].
Subjects were divided into two subsets well matched for sex, age, lung function and
daily oxygen consumption: group A were patients managed according to a standard
protocol for home assistance, and group B were patients managed according to a tele-
metric protocol for their daily monitoring at home [20]. Daily oxygen use was 1.97
L/min for an average of 16.6 h/day in group A, and 1.92 L/min for an average of 16.6
h/day in group B (p = ns). Males were more represented in both groups with a male/fe-
male ratio of 2:1. In standard care, the mean survival was of 482.6 days ± 273.9 SD,
while in tele-LTOT it was 1239.6 days ± 382.1 SD, p<0.01: in other words, survival
was 2.5 times longer in this group (Fig. 7.2).
As described in previous studies, the two groups proved different in terms of oc-
currence of fatal acute events: the incidence of acute cardiac and/or cardio-respira-
tory relapses rapidly leading to death was significantly higher during standard care
(33.0 vs 17.3%), as well as that of fatal lower tract respiratory infections (LTRI) (21.1
vs 11.3%). The groups proved equal in terms of the incidence of deaths due to can-
cer and metabolic causes.
Interestingly, concerning possible gender-related differences in outcomes, females
in standard care (n = 74) showed a significant shorter survival than males (n = 144),
such as of 368.5 days ± 181.4 SD and 538.8 days ± 346.2 SD, respectively (p < 0.01),
while males (n = 134) showed a significant shorter survival than females (n = 51) dur-
ing tele-LTOT, such as of 1166.4 days ± 556.1 SD and 1433.7 days ± 656.3 SD, re-
spectively (p < 0.01) (Fig. 7.2) [19].
7 Gender-Related Differences 85
Survival of patients affected by very severe COPD admitted to tele-LTOT had

never been investigated previously on the basis of the specific model for their man-
agement at home. Data from this study showed that the organizational model of man-
agement and intervention can also play a crucial role in favouring gender-related dis-
crepancies in main outcomes, in particular in terms of respiratory infectious
complications and survival. As the two subsets of patients were well matched for the
main risk factors, it has been speculated that both a different psychological approach
of females to procedures required by the tele-LTOT protocol at home and their greater
acceptance of the multi-parametric telemetric remote control may likely contribute
substantially to explaining these gender-related differences in the model performance.
In conclusion, the gender dependency of outcomes in very severe COPD during
long-term oxygen treatment has been frequently assessed, and females, who were
originally more susceptible than males to COPD, also seem conditioned by other fac-
tors (interventional models; personality profile, etc.), which can further affect the
length of their survival.
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Section II
The Cooperating Roles
Home LTOT: The Role of the Caregiver
8
Roberta Barian and Stefano Bertacco
The qualitative improvement of health services in favour of severe chronic individ-

uals represents an essential and crucial point in order to offer a level of assistance high
enough to fit patients’ increasing and evolving needs.
In the context of this cultural evolution, the continuous improvement in the effi-
cacy and efficiency of health services should be pursued, and particularly aimed at
improving patients’ quality of life; to consolidating their degree of awareness and in-
dependence, to promoting their social activities and relationships [1]. However, as re-
ported in other chapters of this book, this process, which is adapted to the needs of
patients suffering from chronic and disabling respiratory diseases, should be supported
by expert health professionals.
The role of specialist nurses has greatly increased in the last decades, and it has
gradually become essential for educational programs, as far as supporting a true and
effective self management at home for this kind of patients and their families (Fig.
8.1). Particular attention should be paid to the role of families in this context because
they are increasingly involved in the daily management of their disabled relative(s),
and at least one member of the family usually acts as the single caregiver [2].
In general terms, the caregiver is a person who takes care of other individuals who
are unable to care for themselves independently, responding to their physical, psy-
chological and social needs [3].
This supporting role can be covered by different persons in real life.
In the majority of cases, the home caregiver is one member of the patient’s fam-
ily, who is usually an inexperienced person that must become suddenly able to deal
with one of his or her relatives who became sick, and has to face a lot of previously
unknown health problems. He/she must ensure a constant and continuous care over-
S. Bertacco ()
ULSS22 Bussolengo, Lung Disease Department, Orlandi Hospital
e-mail: sabertacco@ulss22.ven.it

90 R. Barian, S. Bertacco
The caregiver
The patient The family
Fig. 8.1 Continuous education of patients

and caregivers improves their awareness
Continuity in specialist care at home of the disease, adherence to oxygen treatment
and continuity of care
coming personal fears and difficulties related to his/her new and changing role, even
if suffering economic losses, reducing free time, and increasing the daily stress. In par-
ticular, when the home caregiver is a member of the family, he/she is exposed to a high
risk of stress because he/she has to change his/her own life-style dramatically [4].
The impact on his/her social and personal life, the duty to withdrawal or substan-
tially change previous consolidated behavioural uses, the sense of emotional deple-
tion, insufficient sleep, and tiredness are some of the aspects that frequently lead the
care-giver to feel inadequate and often incompetent for the new task. On the other
hand, for obtaining the expected therapeutic results, severe chronic respiratory dis-
ease usually necessitates frequent drugs and/or continuous oxygen administration to-
gether with other therapeutic procedures that can induce substantial changes in the
lifestyle of the caregivers. Taking care, every day, of a person with a severe disabil-
ity sustained by a chronic, debilitating and progressive disease often associated with
elderly, may be physically and emotionally exhausting for caregivers, and financially
costly [5].
In other circumstances, this role is covered by a person who takes care of the pa-
tient but on the basis of an employer-employee relationship: in other words, he/she
is a worker dedicated to that patient, and consequent emotional and physical burden
will be much lower when compared to that of a family member involved in the same
activities [3]. In these cases, the degree of the professional standard required of the
caregiver varies according to the patient’s disability and the procedures needed at
home (such as: frequent bronchial aspirations; feeding through gastric cannulas; con-
tinuous mechanical ventilation; continuous monitoring by means of special equip-
ment, etc.), and the level of pay corresponds to this [6].
A quite different role is that of the specialist caregiver who works within the Lung
Unit: he/she is devoted to managing all educational contacts with chronic respiratory
patients and their home caregivers, to support them, and find a solution for all criti-
cal aspects related to their therapeutic plans: in other words, this kind of caregiver is
a true professional interface between the lung physician and the patient or his/her fam-
ily. When compared to the lung physician, the specialist caregiver should be regarded
as the other side of the same coin in the management of chronic, disabling disease.
8 Home LTOT: The Role of the Caregiver 91
From a general point of view, the caregiver is able to greatly affect patients’ aware-
ness and acceptance of the disease, their adherence to therapy, their emotional sta-
tus and their long-term vision of the problems. Frequently there is a gap between pa-
tients’ expectations and the achievement of the therapeutic goals. Usually, these goals
are not aimed to cure the patient, but rather to improve his/her general health status
and to prevent acute serious events [7]. Then the caregivers interact with the patients’
lives and supports them to gain a central role in their disease management, particu-
larly in the case of chronic respiratory disease. In fact, patients often just want to add
quality to their life rather than merely prolong life.
It is not obvious at all that the family is able or wants to help the family member
who is sick because sometimes the family balance can be completely deranged by the
unexpected occurrence of a disabling illness. On the other hand, when caregivers who
do not speak the same language as the patient, or are not sufficiently aware, or moti-
vated and specialized, they do not add any value to the patient’s care and management,
and the family system starts to become chaotic. The patient feels alone and abandoned
in these conditions and this particular psychological state may damage his/her adher-
ence to long-term therapy. Thus, only a professional and specialist caregiver is able
to act as an irreplaceable positive stimulus and psychological support for the patient.
Nevertheless, it can also happen that the caregiver is a regular worker who takes
personal care without sharing any empathy with the patient: in these conditions, the
caregiver may be perceived as an intrusive person who actually enters the patient’s
own home and contributes to subtracting and taking up space [8]. It is essential, there-
fore, that he/she is approved of not only by the disabled person but also by his/her
partner or family.
The existence of a good, consolidated relationship between the patient and
his/her caregiver is of great value in terms of their willingness to cooperate and ad-
here to the planned therapeutic protocols, even if further action is required in order
to optimize the effectiveness of disease management, in particular:
• simple therapeutic schemes;
• a good physician-nurse-patient relationship;
• continuous education of the patient and caregiver;
• periodic controls of treatment comprehension in the long term [9].
The training of home caregivers can be carried out by lung physicians, specialist
nurses and technicians. If the roles and responsibilities of each member of the net-
work are not defined precisely, the major risk is that the caregiver does not know who
to contact when help is required. Actually, there is consolidated evidence that proper
training of caregivers leads to a substantial drop in adverse events with treatments.
The caregiver should correspond to a project that can fulfil all the patient’s needs
adequately. It is also necessary to propose educational plans that take into account
the gradual transfer of therapeutic skills from health professionals to patients, thus
promoting their autonomy, active collaboration, and self management.
The utility and need of continuous and appropriate education has become even
more obvious when considering that healthcare is increasingly moving towards a
home-based model: this is the vision that our Lung Unit has also been supporting as
a strategic choice for a considerable time.
In our model of assistance, many of our patients, particularly those to be managed
for LTOT, enter a domiciliary hospitalization program. Obviously, the education
program for patients and their home caregivers is usually based on discussing the dis-
ease and the related therapeutic strategies in these cases. They must learn how to rec-
ognize the early clinical signs of an impaired respiratory condition, such as the occur-
rence of desaturation, tachypnoea, cyanosis, and sweating [10]. However, considering
that they usually do not perform any significant effort and also often have dyspnoea
at rest (which is a typical sign of their severe disability) sometimes breathlessness may
not be sufficiently perceived as a dangerous clinical change in these subjects [11].
Other signs that should be identified by the caregiver are those usually associated
with nocturnal hypoventilation, such as: fatigue, disturbed sleep, nightmares and
headaches (in particular just after waking), anxiety, confusion, loss of appetite and
of weight [12]. Finally, they have to learn that the presence of a weak voice and dif-
ficulty in coughing and expelling bronchial secretions indicate that the respiratory
muscles are losing their strength [13].
All these messages confirm the growing need for continuing and proper educa-
tion in favour of these individuals in order to enable early recognition and manage-
ment of the main symptoms of possible respiratory deterioration at home, together
with many other challenging aspects related to the severe chronic condition.
Despite the main outcomes (such as: hospitalizations; exacerbations, etc.), each
program locally in use is also aimed at achieving other specific outcomes (even hu-
manistic), and several actions might be activated correspondingly. Our model, which
has been in use for some time for LTOT management at home, requires a specific
training program for the correct use of devices and accessories used at the patient’s
home [14]. On the other hand, the home will change from being a private space to a
public space where drugs, devices, interfaces, etc. will take the place of objects re-
lated to the previous domestic life of the patient [8].
At the start of the therapeutic program, all patients receive a form to fill in prop-
erly at home in order to collect clinical and behavioural data periodically: this form
provides lung physicians and institutional nurses with several indices to match to other
parameters (such as: pulse oximetry, oxygen consumption, and heart rate) centralized
to our Lung Centre via the telemetric contacts with all patients’ homes [15] (see the
chapter on the telemetric model in this book), which are very helpful for the contin-
uous improvement of the educational program itself.
Training on the use of metered-dose and powder inhalers, adherence to pre-
scribed therapies, essential nutritional advice, and, if the patient can walk, the use of
the portable oxygen tank (the stroller), are also included as further essential topics
Table 8.1 Who manages patients treated with LTOT at home?

2004 2011
Who is the caregiver? 53.5% partner 53.3% partner
How old is the caregiver? 54.9 (SD 12.8) 76.2 (SD 8.7)
Table 8.2 When do you use oxygen during the day?

Patient response Caregiver response
2004 2011 2004 2011
Morning 2.8% 3.1% 3.1% 3.1%
Afternoon 4.6% 3.7% 4.9% 4.0%
Night 7.9% 8.5% 7.3% 8.7%
Oxygen after meal Always Sometimes Never
Caregiver 35.9% 31.3% 32.8%
Patient 30.5% 23.2% 41.5%
in the educational program. Obviously, the compliance of patients and caregivers is

monitored continuously in order to achieve the maximum control of the disease, and
data are collected systematically.
When these LTOT patients enter the domiciliary hospitalization program, all their
educational and medical protocols are strictly planned as with regular hospitalization
[9]. A dedicated survey based on a specific questionnaire to fill in twice a year started
several years ago and is aimed at investigating the basic point of view of patients (and
their caregivers) when admitted to the tele-LTOT program at home, and how these per-
spectives can change over time during their domiciliary LTOT experience.
Data from this survey have pointed out that the daily management of patients
treated with LTOT is essentially carried out by close relatives rather than employed
personnel (Table 8.1), and, within the family, the person most involved is usually the
patient’s partner (53.3% of cases).
In the program for managing LTOT patients, the activity of specialist nursing in
the last years has been specifically aimed at obtaining the best possible adherence to
oxygen prescription, both in terms of hours/day and flow/minute. As reported in Table
8.2, it is still evident that oxygen therapy is mostly carried out during the afternoon
and at night, and this evidence was independently confirmed by the patient and the
caregiver. In addition, both patients and caregivers claim that oxygen is also frequently
needed after meals. In particular, concerning the adherence to prescribed daily oxy-
gen, both patients and their care-givers confirm that the mean daily duration of oxy-
gen intake is quite high in our protocol: at least 15.0 hours/day were claimed by the
patients and 15.8 hours/day confirmed by the caregiver, respectively.
Table 8.3 The current awareness of the therapeutic role of oxygen

Yes 68.3% 71.8%
No 13.4% 21.9%
I don’t know 18.3% 6.3%
Table 8.4 How many times per day do you go outside?

Periodically 32.9% 35.9%
Regularly once a day 45.1% 40.8%
Never 22.0% 23.3%
Table 8.5 Are you using the stroller when you go outside?
Always 30.5% 28.1%
Sometimes 25.6% 28.1%
Never 42.7% 40.6%
Furthermore, due to long-lasting nursing programs, in the last years there has been
a further increase in the number of patients who correctly respond at home to respi-
ratory distress by increasing their daily duration of oxygen assumption. However, de-
spite our repeated recommendations, some patients (23.4%) still respond first to res-
piratory distress by increasing oxygen flow only, without any previous oximetrical
confirmation.
Another crucial point in specialist nursing delivered to LTOT patients is concern-
ing their acceptance and use of the oxygen stroller. As the appropriate use of the
stroller has the potential to increase the patient’s autonomy, the action of nursing is
aimed at encouraging the use of this type of device both inside and outside the pa-
tient’s home, and making the patient’s manifest disability well accepted. However,
the current awareness of the therapeutic role of oxygen rapidly and greatly increased
in recent years and the use of this type of device in real life has became much more
tolerated and accepted in our society (Table 8.3).
Nevertheless, the majority of LTOT patients seem to be sufficiently integrated in
their social environment as more than 70% of them are daily leaving their homes while
using oxygen: unfortunately, there is also a residual proportion of patients, such as the
most disabled ones, who never leave their home (as they cannot) and do not use the
portable oxygen device at all (Tables 8.4 and 8.5). Despite patient claims, the corre-
sponding caregiver usually gives a less optimistic vision of this particular aspect.
Table 8.6 Who usually refills the stroller with oxygen?

2004 2011 2004 2011
One relative 33.0% 43.8% 41.7% 22.2%
The patient himself/herself 25.0% 37.5% 33.0% 55.6%
Other 41.7% 0% 24.0% 0%
When the causes for not using portable oxygen are further investigated, the per-
centage responding I do not feel comfortable has dropped over the years, and patients’
and caregivers’ opinions tend to coincide perfectly (19.5% and 21.8%, respectively).
However, this reason remains the principal cause for not using the portable device;
other causes are: the weight of the portable device (13.4% and 10.9%, respectively);
its size (4.9% and 1.6%, respectively), and the procedures required for managing the
device (1.9% and 6.3%, respectively). It is rewarding that the great majority of LTOT
patients assert that they do not have any problem in using and managing their
strollers, and it is regularly checked and certified by the specialist nurse.
In the past, all the procedures related to stroller management were traditionally the
responsibility of the caregiver in the majority of cases. The educational programs
aimed to increase self-management in patients produced appreciable results from this
point of view as an increasing proportion of patients have progressively acquired suf-
ficient skill to manage the device by themselves (Table 8.6): in particular, they
proved able to read and interpret the display messages; to check the oxygen reserve
available in the stroller, and refilling the device with oxygen (Table 8.6). When com-
pared to the past, the personal empowerment is substantially increased, and the role
of other unqualified persons disappeared.
These data confirm that, independently of all other therapeutic options, the edu-
cational approach to LTOT patients and their care-givers still remains absolutely im-
portant in the context of the effective management of these chronically disabled res-
piratory subjects. Moreover, a great proportion of both patients and caregivers are
absolutely in favour of integrated actions intended to improve their knowledge of the
disease, and several centres are developing specific initiatives, which also enable a
break from the daily burden for disabled persons and their attendants.
In conclusion, the good feeling between the patient and his/her caregiver repre-
sents a cornerstone in the management of LTOT at home as much as with the corre-
spondent lung physician, who represents the institutional setting of care. These in-
tegrated, though delicate, relationships are absolutely crucial for improving patients’
awareness of the disease and their adherence to therapeutic protocols (which are in-
creasingly detailed and complex), and for optimising the majority of long-term clin-
ical and social outcomes.
References
1. Farina M, Tognella S (2005) Continuing quality improvement in the management of H-LTOT.
In: Dal Negro RW, Goldberg AI (eds) Home Long-Term oxygen treatment in Italy: the addi-
tional value of telemedicine. Springer, Milan, pp 151-162
2. Petty TL, Casaburi R (2000) Recommendations to the fifth Oxygen Consensus Conference. Writ-
ing and Organizing Committees. Respir Care 45:957-961
3. Grimaldi V, Fabbrini F (2007) Proposta di uno strumento per misurare il carico assistenziale del
caregiver di un paziente oncologico in fase terminale a domicilio. Rivista Italiana di Cure Pal-
liative 1:51-58
4. Rossi Ferrario S (2005) L’impatto sociale, l’individuo, la famiglia ed il caregiver. Alir 42:10-
11
5. Miyashita M, Yamaguchi A, Kayama M et al (2006) Validation of the Burden Index of Care-
givers (BIC), a multidimensional short care burden scale from Japan. Health Qual Life Outcomes
4:52
6. Van Pelt DC, Milbrandt EB, Qin L et al (2007) Informal caregiver burden among survivors of
prolonged mechanical ventilation. Am J Respir Crit Care Med 175:167-73
7. Solèr M, Michel F, Perruchoud AP (1991) Long-term oxygen therapy for cor pulmonale in pa-
tients with chronic obstructive pulmonary disease. Respiration 58(Suppl 1):52-56
8. Wiles JL (2003) Informal caregivers’ experiences of formal support in a changing context. Health
and Social Care in the Community 11:189-207
9. Dal Negro RW, Turco P (2005) Telemedicine and HLTOT in Italy: a 20 year experience. In: Dal
Negro RW, Goldberg AI (eds) Home Long-Term Oxygen treatment in Italy: the additional value
of telemedicine. Springer, Milan, pp 69-83
1:681-685
11. Crockett AJ, Cranston JM, Moss JR, Alpers JH (2001) Survival on long-term oxygen therapy
in chronic airflow limitation: from evidence to outcomes in the routine clinical setting. Intern
Med J 31:448-454
poxemic chronic obstructive lung disease: a clinical trial. Ann Intern Med 93:391-398
13. Chailleux E, Fauroux B, Binet F, Dautzenberg B, Polu JM (1996) Predictors of survival in pa-
tients receiving domiciliary oxygen therapy or mechanical ventilation. A 10-year analysis of AN-
TADIR Observatory. Chest 109:741-749
14. Dal Negro RW, Barian R, Cadinu R, Turco P (2009) Perceived quality in patients with severe
respiratory failure on home LTOT with telemonitoring. Multidisciplinary Respiratory Medicine
4:182-186
15. Dal Negro RW (2000) Long term oxygen tele-home monitoring, the Italian perspective. Chest
Companion Book, pp 247-249
The General Practitioner (GP)
9
Germano Bettoncelli
9.1 Introduction
In recent years there has been a constant and gradual increase in respiratory diseases
involving severe repercussions in terms of human, healthcare and economic costs. In
particular, chronic obstructive diseases, and especially chronic obstructive pul-
monary disease (COPD), are among the main causes of compromized respiratory
function, which often leads to respiratory insufficiency. Despite improved knowledge
of the etiopathogenetic mechanisms of these diseases and the availability of many
drugs and other forms of highly effective treatment nowadays, such as rehabilitation
therapy, we unfortunately still do not have the means of stopping the slow but in-
evitable decline of the disease with any certainty. Even today the only two methods
shown to be capable of prolonging life in patients with COPD are smoking cessation
and long-term oxygen therapy (LTOT) [1-3], even though it is still not clear how oxy-
gen produces this beneficial effect.
The role of general practitioners (GPs) in managing such patients is generally re-
garded to be decisive for the balanced use of healthcare resources, both because most
patients are cured in primary care settings and because the high prevalence of dis-
ease in the population coincides with the wide geographical spread of the general
practice studies. If GPs have a special role in monitoring at-risk populations and pre-
venting disease, especially, with the help of practice nurses, in the smoking cessation,
intervention in favour of early diagnosis, staging and implementation of a rational and
personalized care plan is just as important. Today there are ways of offering patients,
if not the certainty of recovery, at least the prospect of slowing the development of
G. Bettoncelli ()
General practitioner
Ospitaletto, Italy
e-mail: gerbet@alice.it

98 G. Bettoncelli
the disease and an acceptable quality of life. These objectives can be achieved
through integrated and coordinated action from all professionals involved at various
points in caring for patients with COPD, and this integration becomes more impor-
tant as the patient’s condition worsens and the complexity of care requirements grows.
9.2 Overview of the Problem
Respiratory insufficiency is a fundamental turning point in a patient’s clinical history.

Frequently such conditions arise slowly, allowing patients to adjust gradually and thus
reducing their real perception of the disease. Even doctors, in some cases, may not
recognize promptly the emergence of the problem if, where there is no suspicion, it
is not specifically investigated. In other cases the occurrence of an acute episode, such
as the exacerbation of COPD, may trigger respiratory insufficiency, often leading to
admission to hospital. In such cases, diagnosis may be made earlier.
In Italy, evaluation of the need for LTOT and its prescription as another form of res-
piratory care, is usually carried out by specialists. They are also responsible for inform-
ing patients and their families of this important decision, as well as the reasons for and
consequences of such intervention. At the end of this initial moment, appropriate com-
munication between specialists and GPs who later provide care at home is of great im-
portance. When discharge from hospital, the stability status should be suitably eval-
uated from a clinical, psychological and emotional point of view, as well as the
availability of home-based care with the support of local services, the presence of care-
givers who are instructed and trained in the patient’s needs, and the certainty of an ap-
propriate family environment (Fig. 9.1). Before discharge the GP must be informed
Discharge of LTOT patients

4 basic steps
Evaluation
Information, education and training
Home care plan
Discharge
Home care and monitoring

Fig. 9.1 Planning discharge of LTOT patients
9 The General Practitioner (GP) 99
Table 9.1 Patient information on LTOT

The patient is helped to understand the goal of LTOT and of keeping blood oxygen levels within
the limits of normal to minimize damage caused by tissue hypoxia. This leads to:
• improved quality of life
• improved health
• increased survival
• reduced admission and hospitalization rates
of the patient’s clinical conditions, the reasons for LTOT, the type sources for admin-
istration and the procedures required to guarantee normal supply of everything nec-
essary. It is not rare, especially in early phases, that such treatment causes consider-
able psychological discomfort in many patients and extreme difficulty in acceptance,
which may even lead to refusal of the decision. In this case the role of the GP is im-
portant as he/she, due to his/her knowledge of the patient and the social and family
reality, may help to explain the importance of the decision and the expected benefits,
thus helping to overcome both the idea of oxygen therapy as an emblem of a termi-
nal disease and the embarrassment of being seen in public (Table 9.1).
Management of LTOT patients at home must be as comfortable as possible, guar-
anteeing, where necessary, the coordination of all those who are involved at various
levels (nurses, rehabilitation therapists, psychologists, pulmonologists, etc.).
9.3 Method of Regional Supply of Oxygen Therapy
It is important for GPs to be aware of the various means of supplying oxygen at home.
Considered as a life-saving drug, the administration of medicinal oxygen in Italy
is financed by the National Healthcare Service following an initial prescription by pul-
monary specialists. The possible methods of supplying oxygen therapy to patients at
home include:
a) Compressed gas storage in cylinders, for patients who require occasional breath-
ing support (e.g., some patients with asthma, heart disease or terminal diseases).
In such cases oxygen is stored in high-pressure cylinders with a geometric capac-
ity of 7 or 14 litres, corresponding to a quantity of gas equal to 1,200 or 3,000 litres,
respectively. This type of medicinal gaseous oxygen is dispensed regionally by pub-
lic and private pharmacies, which are legally bound to stock them;
b) Electrically powered oxygen concentrators that enrich the patient’s surroundings
with oxygen;
c) Liquid oxygen stored in chilled tanks, introduced in Italy in the early 1990s, is the
option of choice in this country for LTOT patients at home with chronic respira-
tory insufficiency due to COPD [4]. Liquid oxygen is supplied to patients using a
system of medical devices that includes: a basic cryogenic container with a geo-
100 G. Bettoncelli
Approval Visit to pharmacy

Prescription of prescription Completion of GP’s by patient with prescription
by specialist by local health part of prescription in order to obtain medicinal
authority oxygen supplies
Delivery of treatment to the patient’s home Order placed by pharmacy

by the supplier, following checks by the pharmacist with the company that
at the pharmacy as to the quality and quantity will deliver medicinal oxygen
to be administered to the patient’s home
Fig. 9.2 Procedure for the supply of liquid oxygen at home (Source: Federfarma 2000)
metric capacity of between 20 and 45 litres of oxygen, equal to a quantity of gas

of between 15,000 and 40,000 litres; a small portable cylinder (it holds 164-170
litres and weights about 1.3-1.6 kg). The portable container provides greater auton-
omy for the patient, as it makes it possible to live in a way that is closer to normal
in terms of social relations and possible work activities (e.g. household activities).
The only warning to pay attention to concerns the natural evaporation of liquid oxy-
gen from the containers.
The availability of cryogenic containers and later of electric concentrators of oxy-
gen made it possible for LTOT to be introduced in Italy about 25 years ago, and it is
now used by about 65,000 patients.
Unfortunately in Italy a double system of oxygen distribution still remains, by di-
rect agreement or via pharmacies, and this is highly wasteful whether it is supplied
to the National Healthcare System or to patients who require further medical prescrip-
tions (Fig. 9.2).
9.4 Evaluation and Monitoring of Patients Using LTOT at Home
GPs must schedule regular controls for patients receiving LTOT that can be performed
in the doctor’s surgery or at the patient’s home, depending on the patient’s conditions.
During these visits the clinical conditions must be evaluated, and in particular:
• peripheral saturation using pulse oxymeter (to be maintained above 90% except
in patients with COPD);
• respiratory frequency and use of accessory muscles (frequency and depth);
• presence of bronchial secretions and the patient’s ability to expel them;
• cyanosis of the mucosa and nail beds;
• heart rate and blood pressure;
• state of consciousness (confusion or stupor may indicate hypercapnia);
• cardiocirculatory conditions;
• condition of the mucosa of the oral and nasal cavities, and possible dryness;
• presence of cutaneous lesions on the face caused by the mask.
The GP may initially verify treatment efficacy according to the patient’s colour,
mental lucidity, heart rate and breathing effort. Data from instruments and blood gas
analyses are very important in understanding a patient’s real breathing conditions.
Moreover, it is important that the supply system in particular is checked:
• Masks, nasal cannulas and connections which, unless otherwise necessary, should
be replaced on a weekly basis. The connections, as few of which as possible should
be used to reduce the risk of loss, should be long enough to allow for patient mo-
bility. No lubricating grease or oils are used on the washer in order to avoid the
danger of fire.
• Humidifiers (bubbling) must contain the right amount of distilled water so that they
are free of calcareous deposits and sediments that may hamper the supply of oxygen.
Patients must receive adequate instructions for using the stroller and refilling the
main cylinder regularly and correctly (holding the stroller upright at all times). They
must also control the amount of oxygen contained in the cylinder.
It must be checked that patients are maintaining oxygen supply for the prescribed
period and that the flow rates are respected, adjusting them according to whether the
patient is asleep, awake or using physical effort.
9.5 Risks Involved with Oxygen Therapy
The GP must understand that oxygen administration must always be carefully con-
trolled, especially in subjects with COPD in whom respiratory centres are less sen-
sitive to CO2 stimulus and are indirectly activated by hypoxic stimulus of the carotid
glomera. Therefore, improved PaO2 may be associated with reduced ventilation
with consequent deterioration of hypercapnia (leading to hypercapnic coma). High
oxygen concentrations over long periods can induce aspecific toxic effects due to
changes in cell enzyme activity. In rare cases oxygen toxicity has also been indicated
with concentrations below 24%. In the lungs mucocilliary activity and macrophagic
function may be reduced, hyaline membranes may form and pulmonary vasodilation
may occur. Systemically, the possible complications are systemic vasoconstriction and
reduced erythropoiesis and cardiac output.
9.6 The Main Issues for Managing LTOT Patients at Home
GPs may deal with certain issues when managing LTOT patients, which are not al-
ways easy to resolve. It is essential that the GP knows his/her own role within an in-
tegrated assistance model.
102 G. Bettoncelli
1. First, it is his/her responsibility to form a diagnostic suspicion of respiratory in-

sufficiency – which, if it is not done perceptively, may lead to admission to hos-
pital or specialist consultation – based on symptoms, objective examination and,
where possible, measurement of arterial saturation. Patients admitted due to new
acute episodes must be controlled again approximately one month after discharge
to check whether LTOT is really necessary.
2. The decision to implement LTOT is to be made by the specialist. However, before
therapy begins, an appropriate exchange of information must take place with the
GP so that the reasons behind the decision are understood, the patient’s discharge
conditions known and the care plan shared.
3. The GP must be suitably informed as to the main oxygen supply systems, their
maintenance, prescription methods and the refurnishing of supplies at the patient’s
home.
4. It is the GP’s task to facilitate the patient’s return home by interacting with all care
providers and checking that all necessary social and healthcare support has been
set up. He/she must closely ensure that the patient is not exposed to cigarette smoke
and, if patients receiving LTOT continue to smoke, to neutralize therapy and ex-
plain the risks of fire.
5. Promoting patient motivation is essential for the success of LTOT. It is important
to establish therapy goals and discuss them with the patient, providing written in-
formation too. For patients who have trouble accepting their condition and the need
for oxygen therapy, the GP must use his/her own persuasive powers to convince
the patient (and his/her family) of the benefits of treatment. In particular, the pa-
tient must understand the importance of using oxygen during physical activity out-
side the home. The GP must check that the patient takes appropriately all the med-
icines prescribed for his/her condition.
6. A regular control program must be available for the patient, integrated with spe-
cialists who, if necessary, should also be available to visit the patient at home. Spe-
cialist control of patients is indicated one-to-two months after institution of
LTOT, with determination of PaO2 and PaCO2. In stable conditions the controls
must be carried out at least once a year [5]. Where possible, telemonitoring sys-
tems, which nevertheless do not exclude the GP’s role, should be arranged. Spe-
cialists must provide indications in particular on the management of patients with
sporadic hypoxemia and oxygen therapy at night.
7. During regular visits to the patient, the GP must evaluate the clinical conditions,
collecting data on the patient’s medical history that relevant to his/her symptoms
and to the ability to carry out daily activities in a satisfactory way. In particular,
the nutritional status (BMI), infections, the rehabilitative physical activity program
and cor pulmonale must be evaluated. It should also be checked whether oxygen
is being administered for long enough, which is often not the case. Even when the
patient is able to attend visits at the doctor’s surgery, it is good for the doctor to
sometimes go to the patient’s house to check the oxygen supply systems and as-
sess the overall living conditions in terms of fire prevention.
9.7 Integrated Management Procedures
In the near future a sharp increase in low-, medium- and high-intensity respiratory as-
sistance at home is to be expected. Home management of patients is usually complex,
as with cases requiring LTOT, leading to close integration between GPs, specialists,
nurses and all those involved in providing assistance at various levels. This integra-
tion is based on a common analysis of the patient’s care needs, the available resources,
the establishment of a care plan, and the implementation and regular control of such
a plan. In this scenario, communication between those involved is a fundamental re-
quirement and today the availability of new respiratory telemedicine technologies is
a great advantage. The aims of an integrated care network are:
• to verify diagnosis and patient monitoring;
• to discharge the patient early with protection;
• to reduce admission rates;
• to reduce early diagnosis of new acute episodes and complications;
• to optimize care (personal, continuous care);
• to improve quality of life;
• to limit costs.
References
1:681-685
3. Bateman NT, Leach RM (1998) Acute oxygen therapy. British Medical Journal 317:798-801
4. Majani U, De Cristofaro L, De Felice A et al (1995) Direttive AIPO per la ossigenoterapia a lungo
termine (OLT) nei pazienti affetti da insufficienza respiratoria cronica secondaria a broncopneu-
mopatia cronica ostruttiva. Rassegna di Patologia dell’Apparato Respiratorio 10:334-344
5. McDonald CF, Crockett AJ, Young IH (2005) Adult domiciliary oxygen therapy. Position
statement of the Thoracic Society of Australia and New Zealand. MJA 182:621-626
The Cooperating Roles:
The Lung Physician 10
Silvia Tognella
The primary goal of oxygen therapy is to correct and improve alveolar and/or tissue
hypoxia. Therefore, any disorder causing hypoxia is a potential recommendation for
oxygen administration.
The aim of oxygen therapy is to maintain PaO2 at > 60 mmHg (8.0 kPa) or arte-
rial oxygen saturation (SaO2) ≥ 90% [1]; these oxygen levels have been found to be
a strong survival predictor and are considered high enough to allow adequate oxy-
gen delivery to peripheral tissues and preservation of the function of vital organs [2].
If the term drug means any substance prepared for therapeutic use for any disease,
then oxygen must be considered a drug. As a medication, oxygen therapy needs ad-
equate prescription to be really effective and to avoid its potential side effects: at very
high concentrations, oxygen is toxic for lung tissues [3], and an increasing ventila-
tion/perfusion mismatch can represent a risk for hypoventilation [4].
The role of lung physicians in the management of oxygen therapy is not easy to
determine. The lung physician is in fact the first manager of a complicated puzzle,
in which it is important to ensure the adequate prescription in terms of flow per minute
and hours per day to each patient (Fig. 10.1). Other crucial aspects to face are: the
choice of the most appropriate system of delivery and the most convenient interfaces
for the best compliance and adherence to the program, procedures for effective
monitoring, and the healthcare costs.
S. Tognella ()
Lung Unit, ULSS22 Regione Veneto
Bussolengo Hospital
Verona, Italy
e-mail: stognella@ulss22.ven.it
106 S. Tognella
Fig. 10.1 The role of lung physician in the management of LTOT at home
10.1 Prescription
10.1.1 Strategies for Oxygen Delivery
There are several different ways to use oxygen. It’s very important that an expert lung
physician combines the appropriate and correct prescription for each different clin-
ical situation and setting, fulfilling specific rules.
1. Short-term high-dose oxygen is used for acute situations, such as: pneumonia, lung
embolism or asthma attack. This kind of oxygen supplementation has been in-
cluded in many guidelines as acute treatment and is usually prescribed in a hos-
pital setting [5]. In this protected care setting it is also important to pay very care-
ful attention to patients with chronic obstructive pulmonary disease (COPD) or
global respiratory insufficiency with CO2 retention, in which high doses of oxy-
gen may be a true risk for blood acidosis and related serious consequences. The
lung physician should support patients in order to optimize oxygen effects for an
adequate period of time, to stimulate self-management [6], to avoid possible side
effects and drop-outs from the therapeutic plan, and also to find the correct tim-
ing to wean the patient from oxygen therapy.
2. Home continuous long term oxygen therapy (H-LTOT) for patients with chronic
respiratory failure.
10 The Cooperating Roles: The Lung Physician 107
90
80
70
60
50
40
30
20
10
0
COPD Fibrosis Kyphoscoliosis Pulmonary Neoplasm Others
embolism
Fig. 10.2 Distribution of different causes of H-LTOT in the last twenty years
As previously reported in this book, H-LTOT is acknowledged as a treatment able

to affect (i.e., increase) both the survival and the quality of life of patients with se-
vere COPD and chronic hypoxemia. This statement is based upon a large body of
science that began in the mid-1960s and became firmly established by two major
controlled clinical trials in COPD patients: the Nocturnal Oxygen Therapy Trial
(NOTT) and the British Medical Research Council (MRC) [7-8]. Later, H-LTOT
was also recommended in respiratory failure caused by other pulmonary diseases,
such as kyphoscoliosis, lung fibrosis and pulmonary embolism. Nevertheless, in
our experience too (Fig. 10.2), COPD remains the major cause of chronic hypoxia
requiring H-LTOT [9].
Until now oxygen prescription has been included in the COPD guidelines of the
main worldwide scientific societies, such as the American Thoracic Society
(ATS), the European Respiratory Society (ERS), and the Thoracic Society of Aus-
tralia and New Zealand [10, 11].
3. Intermittent home use for patients with frequent episodes of respiratory failure. Data
indicating that the intermittent prescription of oxygen for episodic hypoxia has a clin-
ical value in these cases are still controversial and any clearly show what is still miss-
ing. In any case, the primary aim of oxygen therapy when prescribed for intermit-
tent use is to improve both the patient’s mobility and psychological profile, and to
reduce the disease impact [11-12]. The second point, even if no evidence-based data
are available, is to avoid hypoxia-related conditions, namely secondary polyglobu-
lia and pulmonary hypertension. No specific indications are given by any Italian na-
tional guidelines on how to evaluate proper oxygen supplementation in these patients.
4. Palliative indications. Palliative oxygen therapy is widely used for the treatment
of dyspnoea in individuals with a life-limiting illness who are ineligible for long-
term oxygen therapy.
108 S. Tognella
The role of oxygen therapy for palliation of dyspnoea is also unclear [13-15], and
in particular there is conflicting evidence on patients with lung cancer who are not
significantly hypoxemic. The few studies published on this topic do not clearly
demonstrate that oxygen relieves dyspnoea in these patients. The consensus achieved
amongst lung physicians is that supplemental oxygen should not be used when the
oxygen saturation at rest is within the normal range. Otherwise, some patients with
significant hypoxemia can benefit from oxygen therapy; in these cases, it is impor-
tant to focus on two crucial points: 1) oxygen is not the therapy for dyspnoea, but
it should be regarded as a part of the integrated palliative care for dyspnoea in end-
stage respiratory conditions; 2) even in these patients, it is important to identify a
specific therapy protocol, with respect for social and healthcare costs.
10.1.2 Flows and Duration
The primary goal of the lung specialist in prescribing oxygen is the identification of
the oxygen delivery flow that is most adequate and fitting to the patient’s needs, with-
out any side effects.
The appropriateness of oxygen flow is usually assessed through the oxygen en-
richment test [16]. The first arterial blood analysis should be done after 30 minutes
at rest and while breathing room air. Arterial gas analyses will then be repeated for
increasing oxygen flows until an arterial PaO2 of 65 – 75 mmHg (8.7 - 10 kPa) is
reached, but avoiding PaCO2 increments that may induce dangerous pH modifica-
tions. The goal is also to reach a minimum PaO2 level of 60 mmHg (8 kPa), as this
value is a strong survival predictor [2]: this value is regarded as a real threshold in
acute as well as chronic respiratory failure.
Of course, during the initial phases of an acute condition, oxygen represents a con-
tinuous therapy and its duration will be decided according to the course of the clin-
ical condition; when stabilized, a gradual weaning from oxygen is presumable or pos-
sible. Weaning should be considered when the patient becomes comfortable and
oximetry returns to acceptable values: in these cases, weaning can be gradually at-
tempted by discontinuing oxygen or lowering its concentration over a fixed period
and re-assessing the clinical parameters and SpO2 periodically.
Based on the original MRC & NOTT studies [7-8], continuous oxygen therapy has
been recommended in patients with chronic respiratory failure for at least 14-18 hours
per day. One further problem is represented by nocturnal oxygen therapy. First of all,
it is important to distinguish isolated episodes of hypoxemia during sleep (due to hy-
poventilation or worsening ventilation–perfusion inequalities in patients with obstruc-
tive or fibrotic lung diseases) from hypoxemia associated with sleep apnoea (caused by
upper airway obstruction, obesity, or hypoventilation syndrome). When nocturnal hy-
poxemia occurs in patients eligible for H-LTOT, it is important to recommend supple-
mental oxygen therapy during sleep as part of the 14/18-hours/day program, whereas
apnoea syndromes generally require other forms of therapy (such as continuous posi-
tive airway pressure or nocturnal ventilation) rather than supplemental oxygen only.
The role of the lung physician is to suspect such isolated nocturnal hypoxemia in
patients whose arterial oxygen tension is too high to prescribe continuous oxygen ther-
apy while awake, but who have daytime drowsiness, daytime hypercapnia, poly-
cythemia, pulmonary hypertension or right heart failure. Although data are insufficient
at present for rigorous recommendations in this kind of subject (and further specific
studies are needed), the current consensus is that nocturnal oxygen therapy may be rec-
ommended in patients whose nocturnal arterial oxygen saturation falls below 88% and
who demonstrate evidence of any hypoxia-related conditions, or in patients whose oxy-
gen saturation repeatedly falls below 88% over a third of the night [11].
Several patients with advanced respiratory diseases may also show the occurrence
of exercise-induced respiratory failure: it has been reported that large-scale oxygen
desaturation can be measured during usual daily life activities, such as walking, eat-
ing, or washing [17]. For these reasons it is also important to check whether the oxy-
gen prescription is adequate during exercise using the Six Minute Walk Test or the
cardiopulmonary exercise test.
10.1.3 Delivery System and Interfaces
Starting from the patient’s clinical and social conditions and from the oxygen pre-
scription (flow per minute and hours/day), the lung physician should choose the ap-
propriate delivery system and interfaces for the patient.
As reported in a separate chapter of this book, there are three different systems for
home oxygen delivery: 1) high-pressure cylinders; 2) liquid oxygen systems; 3) oxy-
gen concentrators.
In a real-life setting, the complexity of the puzzle is to combine clinical require-
ments with the patient’s social environment without forgetting the economic context
of oxygen treatment. For example, for the same oxygen prescription in terms of
flow/minute and hours/day, different delivery systems may be recommended if the
patient is completely immobilized or still not disabled and walking, such as oxygen
concentrators rather than liquid oxygen with a portable tank. It should be noted that
since the beginning of the present century several companies are producing differ-
ent models of portable oxygen concentrators which are already available on the mar-
ket. It is important to know that in most cases the oxygen flow is limited to 1-3 L/min
with these devices, and that they use some version of pulse flow or on-demand flow
in order to deliver oxygen only when the patient is inhaling.
Moreover, if the patient’s environmental and social conditions, and the home set-
ting are not presumed safe enough for managing the liquid reserve tank, the lung
110 S. Tognella
physician should not prescribe this particular delivery system. In order to prevent any
risk of fire, it is very important to inform the patient that this system should be po-
sitioned at least 1.5 meters away from any smoker, flames, electrical appliances and
inflammable products. Oxygen itself is not an inflammable gas, but accelerates the
rate of combustion of other materials. Furthermore, as liquid oxygen can easily be
absorbed by porous materials (such as wood, rubber foam, etc), it may therefore cause
sudden combustion in particular conditions [18].
Nowadays, numerous interfaces are available for oxygen therapy [19]. The most
frequently used are: nasal cannulas, nasal catheters, simple oxygen masks, Venturi
masks and reservoir masks. One of the principal aims of the lung physician’s job is
to find the most fitting interface for each patient, by weighing both efficacy and ef-
fectiveness in order to optimize adherence to oxygen therapy, patient comfort and
costs.
• Nasal cannulas are the most simple, cost-effective and accepted interface. Only
very brief training is required, but the FiO2 delivered is not accurate enough [20]
and can represent a true clinical problem in cases of elevated oxygen flows, due
to the induced dryness of nasal mucosa and/or possible epistaxis.
• When compared to nasal cannulas, nasal catheters are more stable and enable de-
creased oxygen dispersion and respiratory work; nevertheless, they often need to
be fixed to the patient’s skin with plasters, and oxygen humidification is also re-
quired for avoiding mucus plugs production. For these reasons they are very un-
comfortable and are avoided for long-term domiciliary use.
• Simple facial oxygen masks are a good alternative to nasal cannulas, in particu-
lar for high-delivery oxygen flows, and are mainly used in hospitalized patients.
The mask is useful in patients who are strictly mouth breathers, as well as some
patients with extreme nasal irritation or nose bleeding [21]. Nevertheless, they have
some disadvantages when compared to nasal cannulas: they do not allow for eat-
ing or talking and they increase the anatomical dead space; moreover, they are less
attractive than nasal cannulas.
• Reservoir facial masks are supplied by a reservoir in which oxygen flows at 8 to
10 L/min, so that the patient inhales high oxygen concentrations. When this
mask is tightly sealed to the patient’s face it can be very uncomfortable and thus
poorly tolerated. Moreover, higher oxygen concentrations also create a greater risk
of CO2 retention.
• Venturi facial masks allow oxygen administration at fixed and established oxygen
concentrations and are more frequently used in hospitalized subjects. They can be
also used at home, but in rare cases, for short periods of treatment, and under a
very strict medical control: in fact, if not used in the right way, they can cause a
significant increase of carbon dioxide.
In a real-life setting it is important that the lung physician who prescribes oxygen
knows the main aspects of each medical interface in order to define the best thera-
peutic protocol for the patient. It is possible to combine different interfaces: for ex-
ample, in patients requiring high oxygen flows for many hours, the most comfortable
interfaces during eating are nasal cannulas, which can also be an alternative to facial
masks, particularly during sleep.
10.2 Monitoring
Proper monitoring of oxygen therapy is recommended to ensure adequate oxygena-

tion and to save precious oxygen from wasting.
As mentioned above, the dose of oxygen should be calculated carefully, and oxy-
gen partial pressure should be measured in the arterial blood.
In patients with acute respiratory failure managed in a hospital setting, arterial
blood gases are easily measured several times, particularly during the first hours of
oxygen delivery.
Repeated measurements of arterial blood gases (ABG) may be difficult to assess
for several reasons, firstly because they require sequential blood withdrawals from
an artery. Collecting blood from an artery is more painful for the patient than from
a vein because arteries are deeper and protected by nerves. In the Intensive Care Unit,
if several blood samples are requested, an arterial catheter may be positioned in the
artery in order to collect blood whenever needed.
When performing the arterial gas analysis, further crucial aspects attain specifi-
cally to the pre-analytical phase of the measurement, such as: the choice of the right
syringe for collecting blood, the storage and transport of specimens, and the good
quality control of analysers [22].
Pulse oximetry (PO) is a simple, rapid, non-invasive and reliable method for mon-
itoring oxygen therapy. The use of pulse oximetry makes it possible to know the pa-
tient’s heart rate and oxygen saturation, even if there are potential problems to be
aware of with this method, such as: the interference of nail dyes, the role of dyshe-
moglobins and other pigments [23], the occurrence of motion artefacts, the role of
hypotension, vasoconstriction, skin thickness, temperature and anemia [24].
It is important to point out that ABG and PO are complementary tests for the ef-
fective monitoring of patients with respiratory failure: lung physicians can use both
of them with the aim of arranging the best protocol for each patient.
In our experience, the monitoring protocol consists of different phases:
1. ABG, mainly used for diagnostic purposes, for defining the context of respiratory
failure, and during the early phase control of acute in-patients;
2. oxygen enrichment test, with at least two ABG tests (with and without oxygen)
for precise oxygen titration;
3. home (tele)-monitoring of oxygen saturation and heart rate for the remote control
and monitoring of severe respiratory patients;
112 S. Tognella
4. periodical ABG for outpatients managed in a domiciliary setting: the length of in-
tervals between ABGs should be defined by the lung physician according to the
patient’s clinical conditions.
10.3 Adherence and Compliance
In general terms, it is not difficult to obtain the patient’s adherence to oxygen ther-
apy during acute respiratory failure: in this condition, it is usually the patient who asks
for oxygen.
Otherwise, some problems can occur when oxygen therapy lasts for month or
years. Patients with chronic respiratory failure admitted to H-LTOT need specific ed-
ucational protocols to ensure an adequate degree of compliance to the physician’s pre-
scription both in terms of oxygen use and other pharmacological options.
The complexity of H-LTOT protocols firstly depends on the number of people ac-
tively involved: not only patients and lung physicians, but also the patient’s caregivers,
GP and the specialist nurse.
As patients and their caregivers may have serious difficulties in carrying out even
the simplest of daily activities, it is absolutely important to provide them with ade-
quate education (Fig. 10.3).
A full and specific nursing protocol allows the patient to cope with the disease,
to adhere more easily to the medication procedures, to learn how to solve routine daily
problems, and also to manage unscheduled critical situations. Patients who enter H-
Fig. 10.3 Different actors actively involved in the educational approach to H-LTOT
Fig. 10.4 The crucial role of nursing in H-LTOT, acting as a double interface between patients,
families and lung physicians
LTOT must have access to as much information as possible to participate more ac-
tively and to take responsibility for their own disease management.
For more than twenty years our Respiratory Department has opted for the at-home
management of patients with severe respiratory failure as Hospitalized Outpatients.
As reported elsewhere in this book, our model consists of a telematic integrated sys-
tem which measures, transmits and monitors daily in real time certain vital signs and
parameters from various specific devices located at the patient’s home and central-
ized in the Lung Unit. Until now, our program has recruited 1,192 patients on H-
LTOT, 580 of them (65.5% males) being monitored and managed according to the
tele-Home Hospitalization protocol.
Even if the lung physician is the crucial figure in defining medical and educational
strategies, the nursing staff are devoted to actively sharing, reinforcing and provid-
ing educational principles to patients and caregivers effectively (Fig. 10.4). In the H-
LTOT therapeutic strategy, the role of nursing is absolutely crucial, firstly because
nurses are the professionals with the largest cultural background for facing the pa-
tient’s needs/problems, and for understanding their motivational and behavioural re-
quests; secondly, because patients and caregivers immediately perceive that nurses
are the most confidential professionals and the person to contact without any shame
or embarrassment, without any fear or perplexity for sharing opinions freely regard-
ing their health perceptions.
Based on the experience gained in these years, we have realized that the most rel-
evant nursing messages for patients are personal and behavioural aspects that can
greatly affect their adherence to the therapeutic program, and that need to be fre-
quently and periodically refreshed, clarified, and updated: in particular, how to man-
age certain technicalities for oxygen delivery at home, certain nutritional aspects, cer-
tain methods for administering concomitant respiratory medication, and certain
aspects of their social life, etc.
114 S. Tognella
As a central figure of the system, the nurse should collect all possible information,
and then elaborate and share the most relevant messages to the patient and lung physi-
cian. In other words, the nursing role acts as a double interface between the patient
(and his/her caregiver) and the lung physician, who is able to filter and evaluate all
their requests.
This approach to H-LTOT has been confirmed as a useful and effective instrument
for managing severe respiratory patients at home for some time [25]. Patient satis-
faction, the perception that there is a common better knowledge to share, and the sig-
nificant drop in hospital admissions and in the duration of the hospital stays, greatly
contributed to reinforce our conviction about the true long-term effectiveness of the
H-LTOT program even if our strategies are continuously reviewed and implemented
in order to improve as much as possible all actions intended to produce even better
clinical outcomes and to enable an even better economic convenience.
10.4 Particular Clinical Needs During LTOT
It is important to point out that it is possible to perform the great majority of all other
clinical procedures in LTOT patients when needed, including bronchial endoscopy.
Obviously, it is important to have a specialist but also a multidisciplinary approach
in these cases: in particular, bronchoscopy should be performed with ventilation sup-
port (CPAP or BPAP) and with anesthesiological support if needed [26].
References
1. Celli BR, MacNee W, ATS/ERS Task Force (2004) Standards for the diagnosis and treatment
of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23:932-946
2. Skwarski K, MacNee W, Wraith PK, Sliwinski P, Zielinski J (1991) Predictors of survival in
patients with chronic obstructive pulmonary disease treated with long-term oxygen therapy.
Chest 100:1522-1527
3. Deneke SM, Fanburg BL (1982) Oxygen toxicity of the lung: an update. Br J Anesth 54:737-
749
4. Calverley PM (2000) Oxygen-induced hypercapnia revisited. Lancet 356:1538-9
5. Bernard GR, Artigas A, Brigham KL et al (1994) The American-European Consensus Confer-
ence on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am
J Respir Crit Care Med 149:818-824
6. Bourbeau J, Christodoulopoulos P, Maltais F et al (2007) Effects of SFC on airway inflamma-
tion in COPD: a randomised controlled study. Thorax 62: 938-943
7. Kvale PA, Cugell DW, Anthonisen NR et al (1980) Continuous or nocturnal oxygen therapy in
hypoxemic chronic obstructive lung disease. Ann Intern Med 93:391–398
therapy in chronic hypoxic cor pulmonale complicating chronic bronchitis and emphysema.
Lancet 1:681–686
9. Tognella S (2005) LTOT outcomes: patient’s and doctor’s perspectives. In: Dal Negro RW, Gold-
berg AI (eds) Home long-term oxygen treatment in Italy. Springer, Milan, pp 119-132
10. Celli BR, MacNee W, committee members (2004) Standards for the diagnosis and treatment of
patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 23:932–946
11. McDonald CF, Crockett AJ, Young IH (2005) Adult domiciliary oxygen therapy. Position
statement of the Thoracic Society of Australia and New Zealand. MJA 182:621–626
12. Petty TL (1998) Supportive therapy in COPD. Chest 113:256S-262S
13. Uronis HE, Abernethy AP (2008) Oxygen for relief of dyspnea: what is the evidence? Curr Opin
Support Palliat Care 2:89-94
14. Booth S, Anderson H, Swannick M et al (2004) The use of oxygen in the palliation of breath-
lessness. A report of the expert working group of the scientific committee of the association of
palliative medicine. Respiratory Medicine 98:66-77
15. Abernethy AP, McDonald CF et al (2010) Effect of palliative oxygen versus room air in relief
of breathlessness in patients with refractory dyspnoea: a double-blind, randomised controlled
trial. The Lancet 376:3784-3793
16. Facchin F, Trevisan F (2005) From national to regional criteria for H-LTOT. In: Dal Negro RW,
AI Goldberg (eds) Home long-yerm oxygen treatment in Italy. Springer, Milan, pp 27-42
17. Soguel Schenkel N, Burdet L, de Muralt B, Fitting JW (1996) Oxygen saturation during daily
activities in chronic obstructive pulmonary disease. Eur Respir J 9:2584-2589
18. Battaglia E, Amaducci S (2005) Systems for Oxygen delivery. In: Dal Negro RW, Goldberg AI
(eds) Home long-term oxygen treatment in Italy. Springer, Milan, pp 43-58
19. Amaducci S, Battaglia E (2005) The interfaces. In: Dal Negro RW, Goldberg AI (eds) Home
long-yerm oxygen treatment in Italy. Springer, Milan, pp 59-68
20. McCoy R (2000) Oxygen-Conserving Techniques and Devices. Respir Care 45:95-104
21. ATS Statement (1995) Standards for the Diagnosis and Care of Patients with Chronic Obstruc-
tive Pulmonary Disease. Respir Crit Care Med 5:s77-s120
22. Burnett RW, Covington AK, Fogh-Andersen N et al (1994) Recommendations on whole blood
sampling, transport, and storage for simultaneous determination of pH, blood gases, and elec-
trolytes. International Federation of Clinical Chemistry Scientific Division. J Int Fed Clin Chem
6:115–120
23. Ralston AC, Webb RK, Runciman WB (1991) Potential errors in pulse oximetry III: Effects of
interference, dyes, dyshemoglobins and other pigments. Anesthesia 46:291–295
24. Sinex JE. Pulse oximetry: Principles and limitations. The American Journal of Emergency Med-
icine 17:59-66
25. Bisato R, Turati C (2005) The changing role of nursing in teletric LTOT at home. In: Dal Ne-
gro RW, Goldberg AI (eds) Home long-term oxygen treatment in Italy. Springer, Milan, pp 95-
100
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tic bronchoscopy in hypoxemic patients. A randomized double-blind study using a new device.
The Health Institutions
11
Paola Pisanti
The operations of the Italian health system require a complex organization, which
must ensure the proper coordination and smooth running of all the components (hu-
man resources, facilities and equipment).
The Italian National Health Service (INHS) is structured on three main different
levels (central, regional and local).
The central government and the Ministry of Health, in particular, determine the
INHS targets and the most important measures to be implemented. They determine
which services are to be guaranteed to citizens in conditions of uniformity, and al-
locate to the regions and autonomous provinces the financial resources derived from
taxation funds and allocated by Parliament.
The 19 regions and 2 autonomous provinces plan healthcare activities and organ-
ize services in relation to the needs of the population. They appoint managers of both
Local Health Unit Agencies and Hospital Agencies, coordinate their actions, super-
vise the attainment of results and intervene in cases of mismanagement.
The local structure of healthcare includes community healthcare at home and at
work, district healthcare and hospital care.
The Local Health Agencies are also responsible for the daily management of the
health services and are in charge of providing primary care, including contracts with
general practitioners (GPs), provision of occupational health services, health educa-
tion, disease prevention, pharmacies, family planning, child health and information
services. The Local Health Agencies are the mainstay of the INHS. These agencies,
known as Aziende Sanitarie Locali, are run by managers appointed by the President
of the Government of the region or autonomous province to which the agency be-
longs. They have full autonomy for organizational, administrative, financial, account-
P. Pisanti ()
Head Office for Health Planning, Italian Ministry of Health
Rome, Italy
e-mail: p.pisanti@sanita.it
118 P. Pisanti
Fig. 11.1 Italian National Health Service’s Structure
ing, managerial and technical issues, and must operate within the limits of the yearly
health budget determined by the regional government (Fig. 11.1).
As for as the structure of the Italian population and the role of the INHS at the end
of April 2010, the population amounted to 60,418,711 (sixty million, four hundred
and eighteen thousand, seven hundred and eleven) people. Living conditions have im-
proved and there has been an increase in people aged 65 years and above, who now
represent 20.2% of the population.
The population of seniors may reach 20.3 million by 2051.
In others words, in 2051 people aged over 64 will amount to 33% of the population.
Beyond that, the number of very old people may increase, in fact the very elderly
(people aged 85 and above), may reach 7.8% of the overall population.
The data clearly show that 30% of over-65s do not suffer from any severe disease,
20% have a chronic disease that does not significantly impact their physical and cog-
nitive functions, and 50% have multiple chronic morbidity, which results in a mobil-
ity impairment for daily activities in 40% of this 50%. This demographic change re-
quires the end of the vision that focused on the hospital rather than the territory, which
characterized the 20th century.
Hence it gives rise to new issues in health, social and economic fields, which lead
us to rethink health strategies, especially concerning the management of chronicity
and the prevention of disability.
This change has also caused the transition from an organ approach to a holistic
approach. Hence we are taking care of the person and not only of the disease.
The elderly with chronic disease are people who have specific needs.
11 The Health Institutions 119
The function of patients is not connected only to their diseases; rather, it is the re-
sult of their relation with their economic, social, environmental and neuropsycholog-
ical conditions. The health system has to promote integration between early treatment,
care and socio-medical services.
Above all it is necessary to use a multi-dimensional evaluation that focuses on the
person and the complexity of the patient.
The creation of specific assistance and therapeutic pathways allows us to inden-
tify a frail aged person and after that to improve their quality of life by reducing dis-
ability, which is an approach that at the same time reduces hospitalization, promot-
ing the employment of home healthcare, and saves money in the socio-health context.
Italian health policy is moving towards the provision of continuous assistance
based on functional integration between hospital, territory and social services.
This is why such services need to be organized with the help of different institu-
tions and social figures to promote old age protection.
The efficiency of the policies lies in their ability to organize services and integrated
pathways that, firstly, have the promotion of aging hand-in-hand with good health,
and secondly allow for the containment and/or reduction of disabilities to promote
prolonged self-sufficiency.
In a nutshell: quality of life.
The health system must change to meet an demand for assistance that is new and
different, as demand is characterized by long-term help, continuity in treatment and
the use of a strategy and measures that tend to stabilize the pathological situation as
a means of improving patients’ quality of life.
It is of the utmost importance to define a care model or models based on integrated
management that relies on GPs, specialists and other health workers, and those not
involved in the care of respiratory disease patients.
The reality of respiratory diseases causes human, social and economic damage but
the magnitude of the threat is not one that has been ignored by the Italian Ministry
of Health. We have paid particular attention to it; being committed to programs that
improve the rights of all people and paths that guarantee uniformity and continuity
of those rights.
In the course of our work we constantly bear in mind three fundamental aspects
when considering improvements in respiratory patients’ rights:
• international guidelines and recommendations;
• national guidelines and recommendations;
• analysis of the population’s health needs.
Moving on to the national context, it is important bear in mind that two national
regulatory instruments changed the role of the Ministry of Health.
The first is the amendment of Title V of the Italian constitution that entrusts to the
Italian state the duty of establishing general care principles and to the regions the ap-
plication of these principles in the organization of health facilities.
120 P. Pisanti
The Italian state changed from being an organizer and manager of services to the
guarantor of equitable access to care nationally.
The second is the Prime Ministerial Decree dated 29 November 2001 that pre-
scribes basic levels of care and encourages regions to develop National Health Uni-
form Services.
Decree No. 270 dated 28 July 2000 provides additional resources to be deployed
in the treatment/care of more extensive health problems.
Decree No. 272 dated 28 July 2000 focuses in particular on children suffering from
chronic illnesses.
In general, we believe that is important to maintain the following priorities for
chronic diseases:
• to support the distribution and development of tools, such as multidimensional as-
sessment;
• to guarantee continuous assistance;
• to develop and qualify forms of integrated home assistance;
• to guarantee, at every stage of care, rehabilitation pathways through the implemen-
tation of specific diagnostics;
• to identify, in particular, the family as the centre of the network in the double role,
and to involve the voluntary sector giving families the instruments to acquire an
ethical and managerial culture that allows them to work with reliability, clarity and
efficiency.
In particular the 2003-2005 National Health Plan outlines new ways of deploy-
ing healthcare based on the following principles:
• continuous care over longer periods;
• integration of health and social services deployed in highly diverse care situations
(integrated continuous care).
Furthermore, the development of a new type of care is prescribed, based on a mul-
tidisciplinary approach which aims to create the necessary machinery to integrate so-
cial and health services deployed both by current and future health professionals.
This plan emphasizes:
1. the role of the citizen and the management of the INHS;
2. participation in planning and evaluation;
3. the passage from informed consent to empowerment;
4. development of association.
The 2006-2008 National Health Plan has singled out the major pathologies: res-
piratory diseases, cancers, diabetes and heart conditions.
As far as preventative activities are concerned, the guidelines highlight the impor-
tance of the following actions.
Regarding the therapeutic stage, follow-up and rehabilitation, the plan underlines
the importance of promoting the qualification of services and operative units to im-
prove both the quality and accessibility by developing the use of national and inter-
national guidelines and shared protocols. Furthermore, focusing on the main health
services provided by hospitals is recommended, by dedicating buildings furnished
with the most modern technology.
What do we do on a territorial level?
The answer is to push integrated home care in a special way for people affected
by respiratory failure with the availability of respiratory monitoring tools.
What do we do at the hospital level?
Remember the efficiency of intensive respiratory therapy units in the management
of critical respiratory patients, with the possibility of implementing non-invasive in-
tensive respiratory therapy and a notable improvement in quality of life, the possi-
bility of reducing the number of occupied beds in intensive care wards and a reduc-
tion in the management costs of patients with respiratory failure.
When planning our actions, we have tried above all to understand the needs of pa-
tients by highlighting gaps in assistance.
In Italy these gaps regard the continuity of assistance, incomplete adherence to me-
dicinal therapy, family problems and difficulties in communication between pa-
tients and medical staff and between medical staff (Fig. 11.2).
As for as long-term oxygen therapy (LTOT) in Europe, more than 500,000 peo-
ple are receiving it (> 15 hours per day). This intervention, which is generally pre-
scribed for patients with very severe COPD, has been shown to increase survival in
patients with chronic respiratory failure.
Fig. 11.2 Context. Property of Paola Pisanti

122 P. Pisanti
Table 11.1 Patients receiving long-term oxygen therapy

Country No. of patients Source
Austria 8,000 (96 per 100,000) Distributor
Czech Republic 2,520 (24 per 100,000) Linde
France 100,000 (155 per 100,000) Ministry of Health and Solidarity
Ireland (195 per 100,000) National respiratory framework
Italy 62,000 (104 per 100,000) Distributor
Portugal 24,360 (229 per 100,000) Respira survey (estimated)
Serbia 250-300 in Belgrade 100 in other towns Estimated
UK 90,000 (in England and Wales) Department of Health
EFA Book on Chronic Obstructive Pulmonary Disease in Europe. Sharing and Caring
Table 11.2 Monthly cost (US dollars)

USA 400
The Netherlands 500
Spain 90
Italy 225
France 550
Canada 300
Wijkstra PJ et al (2001)
LTOT for patients with severe COPD increases survival and has a beneficial im-
pact on pulmonary hemodynamics, hematological characteristics, exercise capacity,
lung mechanics and mental state. The number of patients receiving LTOT is an in-
dicator of the efficiency of national healthcare systems; it can also provide additional
information about the presence of severe COPD cases in a given country. Table 11.1
shows the number of patients on LTOT in the countries surveyed. The difference in
LTOT data among countries may depend on the different sources of data. It would
be interesting to investigate whether these findings correlate with the incidence of the
severity of COPD, in particular with GOLD stage, i.e. severe.
In Italy about 60,000 people are under LTOT (> 15 hours per day) and the cost is
about 250,000,000 euros per year.
The cost to the healthcare system for LTOT patients are mainly due to exacerba-
tions and subsequent hospitalizations, and range from 225 US dollars in Italy to 550
US dollars in France (Table 11.2).
Oxygen therapy is reimbursed in Austria, France and the Netherlands, and is free
in Italy and Serbia. In Austria, the public health insurance system prefers to pay for O2
concentrators, and in Germany, oxygen equipment does not always conform to the pre-
scription. In the Czech Republic liquid oxygen is provided mostly for patients await-
ing lung transplantation, and liquid oxygen therapy is given only to patients who are
mobile.
In Portugal, access to oxygen therapy is difficult because of administrative prac-
tices in some regions, but may improve after the publication in 2009 of a public ten-
der. In Serbia, oxygen therapy is based on well-defined criteria, and the social insur-
ance system pays for oxygen concentrators. A pulmonary municipality service
provides oxygen at home. The home oxygen service has recently improved greatly
in the UK and patients now have access to home oxygen and cylinders, which
makes it easier for them to leave the house.
Particular attention is required for those travelling by air with oxygen therapy. In
fact, people using oxygen therapy can travel by air provided their doctor agrees.
EC Regulation 1107/2006, which contains an updated Code of Practice regarding
the carriage of disabled and reduced mobility passengers, requires airlines to provide
necessary assistance without any additional costs.
However, regulations about oxygen use on planes differ from country to country
and from airline to airline, and can be complicated. See the European Lung Founda-
tion website for detailed information on the requirements of airlines operating in Eu-
rope (www.european-lung-foundation.org).
In Italy GPs have a central role in the diagnosis and management of patients with
respiratory diseases. They are responsible for early diagnosis, and they refer the pa-
tient to the pulmonary specialist. Importantly, most of the management could be done
by GPs, especially in cases of mild or moderate respiratory disease. Above all, GPs
should give patients messages about positive lifestyle changes, and evaluate patients’
personal risks as they change over the years. Moreover, GPs should also be actively
involved in patient education and re-education programs.
Usually, the first healthcare professional that a patient with respiratory symptoms
sees is the GP (see The role of the general practitioner). It is the GP who will refer
the patient to a specialist if necessary. Good coordination between the GP and the pul-
monary specialist is a prerequisite for effective management of patients with respi-
ratory disease.
Suggested Reading
Piano Sanitario Nazionale 2003-2005
Piano Sanitario Nazionale 2006-2008
EFA Book on Chronic Obstructive Pulmonary Disease in Europe. Sharing and Caring
Facts and policies about the Italian National Health Service (INHS)
Wijkstra PJ et al (2001) International approaches to the prescription of long-term oxygen therapy.
The Role of Media
12
Daniel Della Seta
12.1 Introduction
The aim of this detailed account is clear: to stimulate debate on the importance of cor-
rect information regarding the management of patients who require long-term oxy-
gen therapy, considering the psychological approach to this and the relevance of the
message, and thus attempting to sensitize public opinion to help patients in under-
standing the course of their disability.
In recent years, with the proliferation of communication media, the environment
in which journalists and information users work has changed radically.
The profession of communication remains highly coveted, but jobs are scarce and
the skills are often in precise fields. It is not unusual that journalists come up against
a large amount of unknown content, at which point they follow the editor’s instructions
in order to gather stories and interviews. Unfortunately this can lead to confusion.
The role of the journalist is to transform and clarify themes or arguments that
sometimes may not be popular or understood by the wider public. Even profession-
als who have grasped the importance of correct communication and wish to improve
their work do not always know how to improve.
In the rapid history of sociology and communication, a little-known Trentino pro-
fessor called Francesco Fattorello stands out as a true pioneer for his far-sightedness
and ability: he was the author of The Social Technique of Information [1], written
along simple lines that must be learned by communications specialists well before
taking up the pen or microphone. The rules are simple, but are still unknown to many
who work in the media sector.
D. Della Seta ()

Journalist
Rome, Italy
e-mail: ddellaseta@tiscali.it
126 D. Della Seta
What has changed today compared to twenty years ago? There are new opportu-
nities to reach users, readers and internet surfers, who themselves are the patients of
today and possibly tomorrow. It is possible to talk and interact immediately, even with
personal smartphones, without violating the privacy that appears, on the other hand,
to be severely eroded. Politics has made substantial use of this: the President of the
United States, Barack Obama, has successfully initiated a new means of communi-
cation to guarantee much greater audiences that in meetings and to distribute his own
political message, with the possibility of opening debates, forums and new places of
virtual exchange where replies can be received quickly.
And why not take advantage of new experiences in a range of areas? Medicine
would not lack courage in this respect. Nevertheless, by adhering to traditional mass
communication, which generally means promoting knowledge via television, radio
and newspapers, inaccuracies are greater, errors more widespread, and advice is given
by experts who are interviewed by colleagues who do not know the subject.
This is how we trust the words of the presumed expert, an incorrect (and horri-
ble) term that means nothing and does not justify years of specialisation and hard work
by those who can more correctly be called specialists or technicians. They are given
a microphone or notebook at the beginning to record their assessment and thus dis-
pel any doubt, thinking about muddling their way through with a cue that it is only
the beginning of the journey, without knowing that this may instead trigger a real and
genuine panic, even in indifference to reading and explaining what the television or
last-minute testimonial did not say.
It is not necessary to yield to the flattery of satisfaction or to improvisation, but
to point to skill and real knowledge of the problems, diseases, solutions and territory,
aware that a correct psychological approach to the subject and patients can direct the
interested public and thus promote a good service. This is a warning that applies to
doctors themselves, who are often too present in radio and television broadcasts.
In qualified writings we also find a lack of understanding of the news. Insufficient
time or knowledge of scientific material, and occasionally some improvisation cause
unthinkable damage to the transmission of the message.
The abused expressions, I read it in the newspaper ... they said it on the TV ... I
heard it on the radio ..., unfortunately stay in the public’s ears like an absolute truth,
incapable of being refuted.
The internet, i.e. the web, that great network that provides access to anyone and makes
it possible to read up on general themes and arguments, deserves a separate discussion.
Medicine does not avoid forums, chat or blogs, all of which are new ways to read any
type of news, which is very often written and published without adequate resources. The
reliability of such news items must be verified by checking the original sources, if pos-
sible primary, qualified sources. This is a requirement for professional journalists who
understandably have a duty to provide the details of their communication.
Remember the African virus campaigns, on avian flu and widespread disease from
12 The Role of Media 127
the Far East, or killer flu, which in recent years have filled page after page in the news-
papers, causing alarm in the population each week, only to disappear suddenly from
the front pages of general or specialized magazines after a while, relegated to the In
Brief section or even forgotten about, once the presumed phase of interest is over, if
not built upon.
Sometimes information manages even to create a health emergency, as in 1997
with the DBM (Di Bella method) for curing cancer, or in 1996 with the UROD
method of quickly detoxifying those with substance addictions. In 1984 the scien-
tist Robert Gallo, in one of the first worldwide conferences on AIDS, stressed that
controlling the disease would depend on both medical and clinical methods, as well
as information from the media. If the information is correct and useful for the pub-
lic, and not sensational, it will guarantee a positive result. Today everyone knows
that the slogans If you know it, avoid it or Don’t die of ignorance refer in particular
to prevention campaigns. This highlights the importance and role of journalists.
Health, well-being and the search for a good quality of life are widely discussed
by specialists, and are now key factors in our daily lives. In 2001 the daily, weekly
and monthly Italian newspapers about medical and scientific matters recorded a per-
centage interest of 16.7%, equivalent to 8 million readers. In 2005, the percentage rose
to 19%, or 9.2 million readers. Today the increase is constant and indicates the birth
(and death) of a new title on the subject.
In 2001, Eurisko announced an important fact on Italian television: science pro-
grams are watched by 6.5 million people on the small screen, equivalent to 13.6%.
By 2005 this had increased to 18.3%, and 8.8 million people were considered poten-
tial viewers. With the exhaustion of programs like those that created a style and at-
tracted a different public to the subject of science, an assessment of the overall sce-
nario is no longer possible since the arrival of digital television, due to the proliferation
of channels and themed programs.
In fact, it is not television, radio or the newspapers that do not cover healthcare
subjects – in terms of both good and bad health – that are related to health and well-
being. These are the best ways for specialists, doctors, opinion editors and re-
searchers, who have repeatedly been given the chance to explain the terms of the ques-
tions, to achieve optimal confirmation of their publicity and image. And we live in
a society of image. In terms of content, we may expect themes that are hard to trans-
form and understand, that are uncomfortable or do not usually make the news.
Social communication campaigns have been assertive in recent years. However,
their abundance has caused a certain level of disorientation among the public. We are
referring to journals dedicated to understanding how to combat a particular disease,
or those written for the prevention of unknown or rare diseases. There are now dozens
of scientific societies, specialist associations or patient associations, which, whilst
lacking coordination, promote study days, congresses, presentations and even large-
scale initiatives involving institutions and the communication media.
128 D. Della Seta
Every Sunday football players exit the stadium tunnel for the playing field wearing a
white shirt containing a written message, but often they do not grasp the significance be-
yond the slogan. And yet they are often a new testimonial in campaigns against such dis-
eases. This alone does not come freely, and it is a useful way to make the problem known.
In both the public and private sectors, social communication has an important
strategic role. For Rai, the largest cultural body in Italy, the bureaucratic route is not
always simple or realistic, but with the patronage of the Ministry of Health and other
state bodies (such as the Social Secretariat) it helps to provide a campaign that is con-
sidered important for television and radio slots. In such cases, individual stories are
particularly appropriate for general television programs that reflect on current human
and everyday difficulties. But personal experience must be part of a news story, an
initiative, a tangible event that links generations pedagogically.
There remains about: who trains the communicators and journalists? An ad hoc
training course for specialist or sector journalists is essential so that they develop the
need to closely understand the reality of what they intend to write about, especially
in view of social aspects that involve the media, patients and the state via the national
healthcare service.
Medical and scientific communication is only a specialisation for journalists and
graduates in scientific information, but it is a real sector within medicine, since be-
haviour, lifestyle and individual choices all depend on it. A pedagogical role and eth-
ical reflection must be recognized in terms of everything that may depend on the ef-
fectiveness of preventive strategies, our well-being, and healthcare. Relapse is
important and has a social, ethic and economic aspect.
In 1996 in France, the Bioethics Committee issued a Recommendation to journal-
ists, a document with thirteen points outlining precise and concrete guidelines. At this
time there were 26,000 journalists, of whom, to understand the scope of the meas-
ure, over 3,000 were sports journalists and only 180 were scientific journalists.
Medical news was superficial and confusing. The importance of the skill and the ped-
agogical role of scientific journalism became clear, along with the ethical dimension
of professional training. The document concluded with these words. It is important
to consider that the target public of scientific information is not an indistinct and
amorphous mass. They are patients, their families, associations and doctors ... and
all those who think about who creates and distributes the information.
Journalism does not always take into account the ethical dimension of the profes-
sion. Scientific news is often poorly delivered, appearing on the front page only if it
is unusual or curious. News items are distorted or badly understood, translated from
misleading titles, sometimes absurd and used to alarm, deceive or create false hope.
Everything in practice is put at the same level, i.e. both documented and imagined
facts. However, it is vital that the patient knows the limits, potential risks and con-
tradictions of surgery and/or medical treatment, as well as the difference between one
type of therapy and another.
There is a particular phenomenon in Italian journalism whereby it is not facts that

become words, but very often words that are transformed into facts. It is a virtual form
of communication in which we talk of something that in reality does not exist ... an in-
formation-disinformation, in which only the sensational makes the news (Umberto Eco).
12.2 From Citizen to User: Health Communication
Discussing health today is a necessary warning for all levels of society, insofar as we
live with mass communication, with the resulting benefits, including a widespread
ability to transmit news, but also with the risk of a culture of sensation. Health sen-
sations can be broadcast lightly, but can also create in citizens, who are generally lack-
ing a health culture and not able to comprehend the related economic logic, the illu-
sion that health is an acquirable individual good, like any other consumable good, i.e.
a good that confers a resulting social status [2].
The gap between market communication and public communication is thus grow-
ing. It is easier, for those not suffering from disease, to accept information on prod-
ucts and services to be acquired individually in the field of health or the promise of
a happiness pill, instead of receiving institutional information intended to improve
collective health and healthcare education.
With the widespread availability of scientific information, surgical medical
progress, the increase in media exposure has lead to great expectations among the pub-
lic and the desire to be an active player in choices affecting own interests. In partic-
ular, this desire is shown when a citizen becomes a client-user of the healthcare struc-
ture, and, when expressing healthcare needs, demonstrates the greatest need of
understanding and being understood. However, very often the bulk of information
with which the public is bombarded does not correspond to an effective cultural
growth, but only to a large and confused search for solutions that are perceived to be
effective, if not life-saving. The public’s ability to determine their own health is cer-
tainly connected with economic possibilities, and depends on their level of health lit-
eracy, which means the ability to understand and make decisions in this area. Free
choice and awareness are, in fact, closely connected and depend on knowledge. Those
with greater health needs, such as the elderly, are often unable to understand and act
accordingly.
12.3 Doctor-Patient Communication
Communication between doctors and patients is at the heart of the communication

process. Since this relationship is all often too pediatric, it is necessary to turn it into
a relationship between adults. It is worth abandoning shyness and blind trust in doc-
130 D. Della Seta
tors and learning to make just requests. In fact, those who visit the doctor only have
something to lose when they begin unnecessary treatment or do not fundamentally
understand the benefits and risks. Until a few years ago, the doctor-patient relation-
ship was characterized by a situation of total dependence from patients, who passively
trusted their doctors, who in turn made decisions according to an outdated paternal-
istic model.
The profound change in this relationship has had important repercussions on meth-
ods for evaluating the effects of treatment. In fact, by no longer considering the pa-
tient as an object of treatment but as an active subject in the treatment process, care
is assessed not merely from the doctor’s point of view (based only on normalisation
of parameters and symptoms, or prolonging survival), but also from the patient’s point
of view, taking into account the effect that the disease and treatment have on patients
as individuals in a social and cultural context, with needs, aspirations, human rela-
tions and feelings. In other words, it has become necessary to assess the disease and
treatment as well as the patient’s quality of life.
The medical profession, through its culture, training and role, represents a diverse
group from a vast public. Therefore, a series of detailed studies have created a com-
plex process known as a transactional analysis. This explains the role of the doctor
in carrying out communication duties. Factors that affect the doctor-patient relation-
ship are behaviour, languages, listening, location and work setting.
Doctor-patient communication is often ineffective, difficult to understand or im-
peded not only by psychological barriers but also organizational barriers. For exam-
ple, the lack of connections and communication between various structures and care
levels may lead to confusion, loss of time and inefficiency. Studies on doctor-patient
communication show that both doctors and patients have problems and demands that
can be related to communicative dysfunction. Patients complain of poor understand-
ing of the terminology used, difficulty in expressing their own thoughts, and a sense
of frustration and dismay in their relationships with healthcare institutions. Doctors,
on the other hand, speak of insufficient intellectual relationships based on the simple
passage of information. The communication process between healthcare profession-
als and patients therefore plays a key role in each preventive or therapeutic procedure,
in each decision regarding health, and in each program to evaluate efficiency.
Today health is more than ever a priority for mass communication, and is essen-
tial in relationships between mass media and the public because of the great interest
aroused in many respects. We can each recognize ourselves in health problems and
warnings about sometimes excessive health needs and wishes, with a stratification
that depends of social, personal, cultural, territorial and physical differences. Health,
in fact, is a primary good for everyone: constitutionally protected, it has varying im-
plications, including economic ones.
Communication can make those who are not experts in medical subjects change
their behaviour in terms of lifestyle, diet and structural health choices, and can change
doctors’ decisions and requests for certain diagnostic and care services, with undeni-
able economic implications. In one scenario in which health resources are constantly
diminishing, the expense must be appropriate and the importance of the economic im-
plications of communication itself must be clear. Health communication means focus-
ing attention on health quality, seeking to better explain the thread of a complex mo-
saic: thus information and communication become an integrated science.
12.4 Long-Term Oxygen Therapy
Explaining long-term oxygen therapy means, for those who do not know the subject,
imagining a scenario in which these patients live, almost hidden, although they so nu-
merous as to create a hub of exchange and experience.
How can we translate the possibility of living without dyspnoea? As well as acute
disease, numerous chronic respiratory diseases (such as COPD, pulmonary fibrosis
and cystic fibrosis) can lead to persistent hypoxemia, with consequent dyspnoea. To
understand this, it is as if the patients are living at 5,000 metres above sea level: every-
thing, even the smallest of movements, can be demanding. Prolonged oxygen defi-
ciency can seriously harm the organs and cardiocirculatory system.
We cannot explain the technicalities of the functioning and indications of oxygen
therapy, but we can certainly try to understand the dynamics and translate the corre-
sponding logic and problems. Patients who cannot satisfy their oxygen needs through
breathing constantly require integrated support, particularly with effort, since their
biological structures cannot store oxygen.
We therefore think only of transmitting a message that can reach most patients.
Considerable attention must be paid to terminology. There are many ways to admin-
ister oxygen: even the simplest of them requires an explanation of how to apply the
oxygen mask that covers the nose and mouth and releases the gaseous mix directly
into the nostrils (use of nose clips), as well as the mechanics of breathing. In more
serious cases, oxygen therapy must be maintained by endotracheal intubation, in or-
der to connect the airways directly with the apparatus to determine differences in pres-
sure with a pump, and in order to check lung expansion.
But how is such treatment explained without prior knowledge? Use of oxygen ther-
apy is not indicated only for respiratory insufficiency, but is also necessary for rare
eventualities and conditions, such as carbon monoxide poisoning. Some patients in
very serious conditions have been saved, in the event of CO poisoning, by the admin-
istration of pure oxygen in a hyperbaric chamber (pressure above normal), which in-
creases the quantity of gas transported to the plasma. In those with myocardial in-
farction the use of oxygen therapy is now routine practice too.
But in our specific case of patients with chronic pulmonary diseases that require
not occasional treatment but continuous oxygen administration for several months or
132 D. Della Seta
years, detailed information is required so that patients can understand their disease.
Clearly, transmission of the concept of normal life becomes complicated in these
cases, despite such treatment.
Home-based oxygen therapy is often discussed. Progress has enabled the use of
equipment and administration methods that allow patients to continue with oxygen
therapy at home, outside the hospital, in order to live a normal life. Various methods
of administration have been studied that enable subjects with chronic respiratory in-
sufficiency to continue with treatment at home with relatively unobtrusive and easy-
to-use equipment, allowing them to lead an acceptable life. In specific cases, the spe-
cialist may prescribe a trans-tracheal catheter that is inserted and attached to the
trachea with minimal surgery and cannot be seen under clothing.
All this is part of a patient’s personal history and sometimes difficult life experi-
ences: but we talk of life, and this is significant in many cases.
The message must include the real aspects of the problem. A few years ago we met
various COPD patients. In interviews with medical television programs, we wanted
to issue two messages.
First, to explain a patient’s typical day: the difficulties, discomfort, mobility issues,
use of equipment, and the burden of the oxygen reserve container for use outside the
home. A flexible tube enables the flow of oxygen from the container to the nose. Pa-
tients– remembering the image – usually inhale oxygen through suitable nose clips.
I asked how technology and new materials have made this more comfortable. The an-
swer I received was that such a system is economical and easy to manage. Nose clips
are not fixed like a watertight diving mask, so some of the oxygen is wasted. The in-
terrupted airflow sometimes carries a risk of mucosal dryness, which can be resolved
with the application of creams. Many patients find the nose clips esthetically unat-
tractive, but solutions have been found to this problem too: oxygen administration may
in fact be achieved by apparently normal nose clips to make the handicap less obvi-
ous. It is, however, important to remember that the advantage of treatment is greater
than the esthetic disadvantages.
In particular, I recall the experience of one patient who explained to me with ob-
vious pride and in detail how liquid oxygen is used. Liquid oxygen evaporates us-
ing a coil, transforming itself into a gas and – I was told with an expression possi-
bly of bewilderment or discomfort – how 850 litres of gas could be obtained from
one litre of liquid oxygen, with a calculated consumption rate of 2 litres per minute,
as well as how the content of a tank of 44 litres lasted about a fortnight. However,
some patients did not familiarize themselves with the equipment and were ashamed
to use it in public as the nose clips were rather garish. There were other effects: phys-
ical, such as dry nasal mucosa, and emotive, as well as doubts on the ability to re-
tain social relations as the lifeblood of daily existence.
On the other hand, the love of life, the relationship with healthcare professionals,
the secure approach of specialists, the regularity of controls, and the warning from
those who, having committed errors due to their own weakness, have issued a mes-
sage, specifically to young people, so that they can preserve their own health. Look-
ing out, despite everything in life, is an important message.
Since long-term oxygen therapy increases life expectancy and improves quality
of life in patients with chronic respiratory insufficiency, this strategy therefore helps
those who must undergo it by illustrating in particular the positive results, so that it
is more readily acceptable and the corresponding criticism is easier to tolerate.
Finally, we must mention the economic aspects: we have noted the methods of re-
imbursement for the costs of long-term oxygen therapy, which in certain countries
are the full responsibility of the social security system and in others are covered by
insurance policies.
12.5 Listening: the First Expression of Love is Based

on Communication. Sociology and Medicine
The first service owed to a person is to listen; the beginning of love and interest in a
person is to learn to listen; listening can heal whereas a lack of it can cause very deep
wounds and the failure of communication.
A culture of non-listening now prevails: we no longer know how to be silent, to
be with ourselves and others; we have neither the time nor the desire to listen. Our
days are made up of shouting and yelling; it is a life without silence, without listen-
ing, without dialogue, without joy, as this comes from both afar and within.
Listening means accepting the other unconditionally, even differences that enrich
and do not divide, as well as sharing feelings with the other, being positive and not
letting oneself get down, and especially not transmitting this.
Each form of communication has its grammar: the issuer, the message, the code,
the means, the context and the intention, the receiver and the confirmation. But there
can also be discomfort: from the issuer there can be superficiality, distraction, lack
of awareness and clarity; from the receiver there can be prior understanding, haste,
superficiality, deafness, worry, inability to listen and prejudice.
By renewing the thread the links tradition with the theory of Prof. Fattorello, we
can say that communication works when the receiver has understood correctly what
the issuer wanted to say. Communication therefore arrives and does not depart. If we
can conclude that deep listening requires some attention: a lack of self and prejudice
and complete patience.
In each encounter there is no determined value for what is said nor in the content
or solutions offered, but in particular there is a relationship created by a climate of
authentic listening.
We all form a happy link in the chain of life. We all have value in life. If spring
has so much value it is because it has been entrusted with it by winter. Communica-
134 D. Della Seta
tion is spring, the happy beginning of discovery and conquest of someone. It is the
instrument that allows us to find it in various ways and with various results, only if
we know how to express the best in us, not by ourselves but by the other, and we will
be so much more capable of interacting with our interlocutor; we shall have so much
more success with our words.
If a word enters another person with its value and leaves a sign, it is because some-
one knew how to speak and has given the best of him/herself.
References
1. Fattorello F (2005) Teoria della tecnica sociale dell’informazione. QuattroVenti Editrice, Ur-
bino
2. Valleca S (1998) Comunicazione per la salute. Masson Editrice
Systems for Oxygen Delivery
13
Carlo Castiglioni
13.1 Oxygen Prescription and Distribution
Oxygen is a drug that is prescribed by a specialist and administered to patients with

respiratory diseases following the guidelines that several scientific societies have com-
piled and in accordance with the legislation in force in the country where the ther-
apy is to be given. The oxygen supplier is responsible for guaranteeing that the oxy-
gen therapy devices given to the patients are capable of providing an amount of
oxygen consistent with the treatment prescribed by the doctor.
Long-term oxygen therapy (LTOT) should be accompanied by specific training of
the patient and caregivers on the use and maintenance of devices for respiratory ther-
apy, with particular reference to the risks caused by improper use of these devices.
13.2 Oxygen as a Drug
Oxygen is considered a medicinal product when: it is presented as having curative

or prophylactic properties against human or animal diseases and is administered to
a human being or animal with a view to establishing a medical diagnosis or restor-
ing, correcting or modifying the human’s or animal’s organic functions (Legislative
Decree No. 178/91, Art. 1, Subsection 1).
Directive 2001/83/EC issued by the European Parliament and Council on 6 No-
vember 2001, published in the European Official Gazette No. 311 of 28 November
2001, which came into force on a European level on 18 December 2001, represents
the completion of the path that led oxygen to be considered a drug.
C. Castiglioni ()
Medical Director VitalAire, Milan, Italy
e-mail: carlo.castiglioni@airliquide.com
136 C. Castiglioni
The published text did not, however, specify a definite term for its implementa-
tion: consequently, while in some countries such as France, Germany and Spain, the
directive was applied unamended within a short period of time, in Italy, its applica-
tion was delayed until the publication of Legislative Decree No. 219/06 of 24 April
2006 and Legislative Decree No. 274/07 of 29 December 2007, which implemented
the directive but with a few amendments to adapt it to the specific Italian context so
the relevant registration procedure (MA) was not completed until 1 January 2010.
In conclusion, oxygen is subject to the community standard for medicinal prod-
ucts for human use and may therefore be dispensed exclusively by companies that
have applied for and obtained a Marketing Authorization (MA), while the dispen-
sation regulations are national and follow the methods laid down in each country for
the prescription of medicinal products.
The special features of oxygen as a drug with regard to its packaging, transporta-
tion and use has obliged the health authorities and manufacturers to develop specific
delivery and service methods. Due to its chemicophysical properties, oxygen may be
dispensed in gaseous form or liquid form. From the clinical point of view, the two
forms are equivalent, but the methods of transport and delivery differ.
Gaseous oxygen is normally used in emergency clinical situations and is contained
in cylinders of various sizes; the smaller ones may be purchased by the patients them-
selves at the chemist’s.
Liquid oxygen is used principally for long-term treatment mainly due to the fact
that cryogenic containers support longer treatment than the contents of the gas cylin-
ders. The use of liquid oxygen obliges the manufacturer and MA holder to deliver
the cryogenic container to the patient’s home.
In many cases, home delivery services have changed over time, the scope of their
activities expanding to include providing patients and their relatives with technical
information on the use of the product and even providing the support of professional
healthcare operators to train them to use the product, to assist with the control of the
respiratory failure and check compliance with therapy.
Irrespective of the dispensing device, the oxygen is administered to the patient us-
ing devices such as nasal cannulas or masks, while the gas must be duly humidified.
The oxygen sources that may be used at the patient’s home are therefore:
Gaseous oxygen cylinders

Gaseous oxygen is only used occasionally at the patient’s home as the cylinders have
a capacity that limits the duration of therapy.
Gaseous oxygen cylinders must be white and have a white cap.
Cryogenic liquid oxygen containers

These containers are made up of a base unit and a portable unit (stroller), which pro-
vides the patient with autonomy of 3-5 hours away from home.
13 Systems for Oxygen Delivery 137
Liquid oxygen is one of the most commonly used methods of providing oxygen
therapy and enables therapy to be administered both at home and away from home.
While gaseous and liquid oxygen are subject to the quality criteria (GMP) laid
down by the medicinal product regulatory authorities, the oxygen produced by con-
centrators depends on the specific regulation of each individual device.
Oxygen concentrators
Concentrators represent an economical oxygen source, currently the most widely used
in Europe.
Concentrators support oxygen concentrations ranging from 20 to 95%. The mo-
lecular sieve holds back the nitrogen present in the ambient air and allows the oxy-
gen to flow into the container, which is connected (via a humidifier and flowmeter)
to the patient’s supply system.
The device is electric so it must have a back-up system that enables it to function dur-
ing a power failure and an oxygen cylinder is normally also provided for emergencies.
13.3 Oxygen Therapy Service
13.3.1 Oxygen Therapy Service with Oxygen Cylinders
13.3.1.1 Installation of the Equipment

When the oxygen equipment is installed for the first time at home, the patient or care-
giver should be given the information they need to enable them to use the equipment
safely.
The supplier should:
• provide the patient with an operating manual written specifically for the users of
the device and containing all the necessary operating instructions;
• give adequate training to the patient and the caregiver;
• implement a formal program to ensure that training has been successful;
• make sure that the oxygen dispensing devices are used safely;
• give indications on where to position and store the cylinders;
• check that the length of the tube leading from the device to the patient is less than
15 m (Fig. 13.1)
• give the patient a written communication that may be sent to the insurance com-
pany informing it of the presence of oxygen at the patient’s home and, where ap-
plicable, in the patient’s car (if the portable unit is used);
• give him/her an emergency telephone number that is operative 24 hours a day;
• give the patient, during the initial supply, a list of all the instruments provided with
the cylinder and any consumable device that has to be replaced or replenished pe-
riodically.
138 C. Castiglioni
Fig. 13.1 Maximum distance between the Fig. 13.2 Oxygen containers must be placed
patient and the oxygen source in ventilated rooms
13.3.1.2 Storing the Oxygen Cylinders

If the patient needs more than one cylinder, the supplier must decide how the cylin-
ders should be stored and check that a suitable area is available in the patient’s home
to make sure that the patient would not be at risk in case of an accident (check to be
made by the supplier).
In order to carry out these checks, the supplier must know the number of cylin-
ders to be supplied periodically, i.e. the oxygen flow prescribed and the daily dura-
tion of therapy (the number of oxygen cylinders supplied should be consistent with
the patient’s actual needs. An excessive number of cylinders may lead to a reduced
rotation, thus increasing the risk of accidents).
At the patient’s home, the cylinders should be:
• kept to the minimum number required;
• kept in a safe place with limited access;
• kept outdoors preferably, if a large number of cylinders are required;
• kept away from flames or places where people smoke;
• kept in ventilated rooms (not kitchens or garages) (Fig. 13.2);
• securely positioned to avoid all risk of falling;
• kept in different places from empty cylinders.
13.3.1.3 Handling the Cylinders

When handling the cylinders (to replace an empty cylinder with a full one), the pa-
tient or caregiver should:
• wear protective gloves and safety shoes;
• use a trolley to move them from one room to another;
• make sure that their gloves and hands are clean and that no creams, oils or other
forms of grease are used during handling;
• take care to avoid knocking them against obstacles or dropping them;

• avoid rolling the cylinders on the floor (the valves could open accidentally);
• avoid gripping the handwheel to avoid the risk of the valve opening accidentally
(grip the protective cap or the body of the cylinder);
• avoid applying any additional marks or labels to the cylinders until authorized to do so.
13.3.1.4 Preparing the Cylinders for Therapeutic Use

For cylinders with no integrated regulator and flowmeter valve, the patient or care-
giver should be instructed:
• to check that the pressure regulator and flowmeter are suitable for use;
• to check that the surfaces of the pressure regulator and valve are clean and that the
gaskets and airtight washers are in good condition. If the washer is damaged, the
cylinder should not be used (call the supplier);
• to make sure that the pressure regulator is securely fixed to the valve of the cylin-
der by applying an appropriate force;
• not to open the valve until the pressure reducer and the flowmeter are firmly con-
nected and set to their zero or minimum flow position;
• to make sure that the humidifier is present and functions properly.
13.3.1.5 Starting Therapy with Oxygen Cylinders

Before using any kind of cylinder, the patient, a relative of his or the caregiver should
be instructed to:
• make sure that nobody is smoking near the device during oxygen administration;
• set the pressure reducer and flowmeter to their zero or minimum flow position (Fig.
13.4 and Fig. 13.5);
• stand opposite the reducer outlet and open the cylinder valve slowly (Fig. 13.3);
• if the handwheel is not present, use a spanner approved by the manufacturer to
open the valve (to determine whether a valve is opened or closed, open the valve
slowly as far as it will go and then turn back by a quarter of a turn). Leave the span-
ner in the valve of the cylinder so that the spanner is available in an emergency;
Fig. 13.3 Opening the cylin- Fig. 13.3 Opening the cylin- Fig. 13.5 Set the flowmeter
der valve der reducer on the required flow
140 C. Castiglioni
• check the high-pressure gauge on the built-in regulating valve and/or reducer to
make sure there is enough gas in the cylinder to complete therapy (Fig. 13.3);
• check that oxygen flows out of the nasal cannulas or tubes (by opening the valve
of the pressure gauge) when they are disconnected from the mask or other device,
by immersing the outlets in a glass of water. Flow will be indicated by the presence
of bubbles;
• check for leaks between the cylinder valve and the flowmeter reducer connected
to it. Leaks may be indicated by a hissing sound in which case a more accurate
check should be made as described in the following section;
• check that the flowmeter works properly (Fig. 13.5);
• make sure that the oxygen tube is correctly connected to the nasal cannula and the
humidifier, then regulate the flow according to the doctor’s prescription.
13.3.1.6 Checking for Leaks During the Use of Oxygen Cylinders

During the use of oxygen cylinders, leaks may occur between the valve of the cylin-
der and the pressure regulator. This problem is normally accompanied by a hissing
sound. Having connected the regulator to the cylinder, a check for leaks should be
made before proceeding to use the cylinder.
If a leak occurs between the valve and the cylinder or from the regulating valve,
the latter should be closed immediately, providing that this can be done safely, and,
in any case, the supplier should be informed immediately.
Cylinders with integrated regulator and flowmeter valves: some oxygen cylinders
have a valve incorporating a reducer and flowmeter so that the latter does not have
to be removed and applied to a new cylinder. This enables the cylinder to be used im-
mediately and prevents the gas being emitted violently.
For cylinders with no integrated valves, if there is a leak between the valve of the
cylinder and the regulator, the patient or caregiver should be instructed to avoid tak-
ing any action while the device is under pressure.
With a view to finding leaks, the patient should be trained to:
• close the valve of the cylinder and check for a leak by observing the gauge on the
pressure regulator connected;
• notice the indication of a leak by a drop in the pressure gauge reading;
• release the pressure from the device connected by opening the flowmeter to emit
any trapped gas into the atmosphere; remove the device and check the condition
of the gasket and the airtight washer;
• inform the supplier if the gasket or airtight washer show signs of wear or damage.
The gasket may only be replaced by authorized staff;
• reconnect the pressure regulator tightening the connection with moderate force and
check for leaks as described above;
• never use adhesive tape or other compounds to plug a leak;
If the leak cannot be plugged, separate the cylinder in question from the others and
inform the supplier of the defect found. If the flowmeter regulator shows signs of dam-
age, make sure that it is returned to supplier.
13.3.1.7 Precautions to Be Taken After Using Oxygen Cylinders

The patient, a relative or the caregiver should be instructed to avoid emptying the
cylinders below the residual pressure level, as indicated by the pressure indicator. The
supplier is responsible for informing the patient or relative of the residual pressure
level at which the cylinder should be replaced.
After using the cylinder, the patient or caregiver should be instructed to:
• close the valve of the cylinder with the appropriate force;
• release the pressure of the reducer/flowmeter connected by selecting a flow and
letting the gas out into the atmosphere;
• regulate the flow to zero on the reducer/flowmeter connected;
If the cylinder is empty, remove the reducer/flowmeter connected, reassemble it
on a new cylinder and store the empty one in a suitable place;
Keep the valve of the cylinder closed even when it is empty and to be returned to
the supplier.
13.3.2 Oxygen Therapy Service with Liquid Oxygen Containers
13.3.2.1 Initial Installation of the Devices

When installed for the first time at home, the patient or caregiver should be given the
information they need to use the equipment safely (Fig. 13.6). Each base module has
an LED or LCD display indicating the oxygen content of the container (Fig. 13.7 and
Fig. 13.8), which enables the patient to check and duly inform the supplier when the
level drops below ¼.
To start oxygen therapy, the patient should install the condensation beaker, con-
nect the humidifier to the oxygen outlet and fill the beaker with distilled water, con-
nect the chosen dispensing device and set the prescribed flow.
Fig. 13.6 Container for liquid Fig. 13.7-13.8 LCD or LED display indicator
oxygen
142 C. Castiglioni
The supplier should:

• provide the patient with an operating manual written specifically for the users of
the device and containing all the necessary operating indications;
• give adequate training to the patient and the caregiver;
• implement a formal program to check that training has been successful;
• give indications on where to position and store the device;
• check that the length of the tube leading from the device to the patient is less than
15 m (care should be taken to avoid twisting the tube so as not to restrict the flow
and in some cases it may have to be fixed to stop it getting crushed);
• give the patient a written communication that may be sent to the insurance com-
pany informing it of the presence of oxygen at the patient’s home and, where ap-
plicable, in the patient’s car (if the portable unit is used);
• give him/her an emergency telephone number that is operative 24 hours a day;
• give the patient, during the initial supply, a list of all the instruments provided with
the container and any consumable device that has to be replaced or replenished
periodically.
13.3.2.2 Preparing and Checking the Device

Whenever the base unit (Fig. 13.6) of liquid oxygen is provided to the patient, the sup-
plier must check that:
• the outer surfaces of the base unit and the portable unit are clean and undamaged.
The inspection should include a check for dents on the container and its lid;
• the filling connector is clean, in good condition and free of leaks;
• the condensation tank is clean and empty;
• the oxygen outlet is clean and in good condition;
• the flow control valve works properly;
• the level indicator works properly, including its battery, if present;
• the containers have no cold stains, which are signs of freezing;
• the device is free of leaks (except for leaks from the safety valve, designed for this
purpose in a non-defective container);
• the base unit is correctly marked;
• the containers have not exceeded the ten-year validity period on the basis of the
periodic checks laid down by the ADRlRID;
• the portable unit fits securely into the base unit without any leaks;
• the portable unit has an air release valve that is easy to use;
• any non-conformity is dealt with promptly, replacing the container where necessary.
• at every delivery, the supplier must also check that:
- the disposable accessories are available;
- the base unit is clean and that the humidifier is in good condition (especially the
connection between the water container and the lid of the humidifier); the pa-
tient, a relative or the caregiver should, in any case, be instructed on how to
clean/reset them, in accordance with the specific instructions provided by the

manufacturer.
Every day:
• remove the humidifier and rinse it under running water;
• top up with the necessary amount of distilled water;
• reconnect the humidifier to the support;
• wipe the points connecting the main unit to the portable unit with a dry cloth.
Every week:
• remove the humidifier and any residual water;
• wash the humidifier with cold water and liquid detergent in order to remove any
lime scale present;
• rinse, dry and reposition.
13.3.2.3 Precautions for High Flows

The storage of an excessive number of full liquid oxygen devices at the patient’s home
increases the potential risk of accidents. The supplier should therefore determine the
size and number of base units actually required by the patient, considering the flow
prescribed by the doctor and the frequency of delivery.
For patients who need higher than average oxygen flows (i.e. flows of > 6 litres
per minute), it may be necessary to provide other oxygen back-up systems or alter-
natively to use a single container that ensures the necessary flow, providing the base
unit does not freeze.
If the prescribed flow exceeds the flow capacity of a single container or freezes
it, two or more containers may be connected to meet the patient’s needs. In some
cases, it is also possible to provide a portable unit designed specifically for high flows.
13.3.2.4 Storing the Containers at the Patient’s Home

Liquid oxygen containers should always be stored indoors in suitable rooms; the
rooms best suited to the installation of the devices at the patient’s home are gener-
ally the living room and bedroom.
In order to ensure that they are stored safely in the patient’s home, a relative or
the caregiver should bear in mind that:
• the liquid oxygen devices periodically release small quantities of gaseous oxygen
and so the containers should be kept in a well-ventilated area to avoid oxygen
building (not be stored in small or closed areas such as cabinets);
• the equipment should always be kept at a distance of at least 1.5 metres from:
- electrically-powered devices such as televisions, air conditioners and hair dryers;
- the devices should always be kept at a distance of at least 2-3 metres from fires
and bare flames;
144 C. Castiglioni
- ovens or other heat sources with bare flames.

When choosing where to store the devices in the patient’s home, it should be borne
in mind that the containers should not be positioned:
• in corridors or near doors;
• where they may obstruct the patient or caregiver in their movements;
• where they may get knocked or overturned.
13.3.2.5 Using the Liquid Oxygen Containers

The main precautions to be taken when using liquid oxygen devices are based on the
following considerations:
• as most accidents associated with the use of these devices are caused by tobacco
smoke, patients and their relatives should be informed of the risks created by smok-
ing near an oxygen dispensing device and should therefore be instructed not to
smoke at all (we recommend the use of NO SMOKING symbols and signs) (Fig.
13.9);
• avoid touching the frozen surfaces of the device and all risk of contact between
the liquid oxygen or frozen tubes and your skin or non-protective clothing when
using the devices (in the case of a cold burn, immerse the part of the body con-
cerned in warm water and seek medical advice);
• never apply oil or grease to the oxygen devices as these materials burn vigorously
in oxygen-enriched environments (Fig. 13.10);
• never use Vaseline, face or hand cream with oil-based ingredients: The supplier
should advise the patient only to use oil-free creams suitable for use with oxygen
to prevent the nostrils drying up and, during administration, to make sure that the
equipment is clean, paying particular attention to the filling connectors (if pres-
ent, apply the connector covers when the device is not in use);
Fig. 13.9 Smoking should be prohibited where Fig. 13.10 Do not use oils or grease on the oxy-
oxygen is used gen containers
• do not use the portable unit under a cloth or clothing and only transport it in en-
closures specifically designed for this purpose (the enclosure must provide ade-
quate ventilation and be compatible with oxygen);
• keep the device in a well ventilated room to avoid creating an oxygen-enriched at-
mosphere; keep it away from combustible material and protected from heat
sources which could speed up the dispersion of oxygen from the container;
• take care to avoid dust and/or ice blocking the air release valve, the connections
and the safety devices;
• handle the devices with care and avoid knocking and dropping them;
• if the base unit has to be moved, use a base with wheels (specifically designed for
each kind of container and supplied by the service company) (only use on flat sur-
faces to avoid the risk of it overturning); never take the base unit up or down steps:
the container should be transported exclusively by the supplier, using equipment
designed for this purpose. If there is a lift, it may be used only if the container is
safe and has no gas leaks, or it no other persons are present in the lift;
• always keep the container in an upright position (unless it is specifically designed
for other positions) and out of the reach of children;
• do not apply any additional mark or label to the device unless authorized to do so;
• never attempt to repair any of the components of the device;
• never place objects on the top of the base unit or apply pressure to the filling con-
nector as this could be accidentally activated, causing oxygen to be released into
the environment;
• close the flowmeter when not in use, even for short periods of time, to avoid cre-
ating an oxygen-enriched atmosphere;
• make sure that the oxygen tube and the accessories are correctly connected and
the humidifier correctly assembled to prevent leaks;
• make sure that the oxygen tube does not get twisted or flattened by heavy objects;
• make sure that the oxygen tube leading from the container to the patient is less than
15 metres long to ensure that a satisfactory flow of oxygen is maintained and to
prevent condensation forming in the tube due to reduced oxygen flow;
• check that oxygen flows out of the nasal cannulas or tubes when they are discon-
nected from the mask or valve-operated device by immersing the outlets in a glass
of water: a flow will be indicated by the presence of bubbles. Select only the flow
prescribed by your doctor;
It is also indispensable that the supplier makes sure that the patient or caregiver
is duly informed of all emergency measures and, in particular, of the following rules:
• If the container has a major liquid oxygen leak, move away from the cloud of
vapour and the immediately surrounding area, open windows and outside doors,
evacuate the area and contact the supplier immediately;
• If a fire starts in the presence of a liquid oxygen container, evacuate the area im-
mediately and call the fire brigade. It is important to inform the firefighters of the
146 C. Castiglioni
presence of oxygen in the patient’s house even if there is no fire; if clothes catch
fire in an oxygen-enriched atmosphere, use water to put out the flames since sim-
ply suffocating the flame caused by oxygen-enriched materials is not enough to
put the fire out; in the case of cold burns, immerse the part of the body concerned
immediately in warm water and seek medical advice;
13.3.2.6 Filling the Portable Unit

Cryogenic containers for liquid oxygen therapy at the patient’s home come with a
portable unit that may be filled by the patient. The portable unit should be filled with
great care (Fig. 13.11). Before proceeding to fill it, check that the base unit contains
at least ¼ of its full capacity.
In particular, the main safety measures to be taken in this phase are:
1. the portable unit should be clean and the humidity absorbing pad, if present, should
be clean and dry;
2. the level indicator should work properly, including the battery, if present;
3. the filling connectors of both containers should be checked before filling to make
sure that they are clean and dry to prevent the device malfunctioning as a result
of freezing;
4. the portable unit should be perfectly in line with the filling connector on the base
unit without any leaks and the discharge valve of the portable unit should be easy
to operate;
5. the discharge valve should be opened and closed rapidly to remove any ice that
has formed during the filling operation; if a minor leak of liquid oxygen occurs
when the portable unit is detached from the base unit, it should be immediately
reattached to the base unit; this procedure is useful to remove ice or any other ob-
struction in the filling connector: in this way, when the portable unit is detached
subsequently, the leak should no longer occur;
6. if the portable unit cannot be separated easily from the base unit, excessive force
should not be applied as the containers could be frozen together (do not use a hair
dryer or other heat sources to try and melt the ice). Simply leave the containers
connected for a short period of time with the discharge valve of the portable unit
closed to allow the filling connector to warm up and the ice to melt so that the con-
tainers may subsequently be separated with ease;
7. the filling connector should be checked before use and kept dry if moisture is pres-
ent before filling the portable unit. When both devices are operating, moisture may
form on the exposed surfaces of contact of the device due to condensation and this
could freeze causing components such as valves or filling connectors to lock in
their open or closed position;
8. if a major oxygen leak occurs in both containers, you should move away from the
container and air the room by opening doors and windows; the portable unit should
never be used when it is connected to the base unit;
Fig. 13.11 Filling the portable container
9. at the end of the filling operation, the portable unit should be detached from the
base unit and placed upright on a clean, flat surface.
The supplier should make sure that the patient or caregiver is capable of filling the
portable unit correctly and safely; this should be done during initial installation. The
patient should be requested to carry out a practical test, which involves filling the
portable unit under the supervision of the operator from the service company.
13.3.2.7 Transporting Containers Away from the Home

Transportation of oxygen therapy devices (cylinders and liquid oxygen containers)
by the supplier is regulated by the ADR standard for the transportation of hazardous
goods by road.
For these aspects, reference should be made to the EIGA guideline implemented
in Italy through the Assogastecnici – Medicinal Gas Group guideline entitled Prepa-
ration and management of vehicles for the supply of medicinal oxygen for home care.
This standard lays down no particular specifications for the transportation of oxy-
gen containers by the patient by car or in other private vehicles.
Nevertheless, this transport entails potential risks for which the following safety
measures should be taken:
• only the quantity of product necessary to complete the journey should be transported;
• smoking in the vehicle is strictly prohibited;
• the patient, driver and all other occupants of the vehicle should be adequately
trained on how to handle the containers during use in the vehicle and the safety
measures to be taken in the event of an accident; it is important to stress the risks
associated with an oxygen-enriched atmosphere inside the vehicle;
• the containers should be kept in an upright position (unless specifically designed
for other positions) and securely fixed so that they remain in position in case of
a sudden jolt or impact;
148 C. Castiglioni
• the devices should preferably not be kept on the passenger seat of the car with not
in use;
• the flow valve should be kept closed when the device is not in use;
• the device should not be used in the vehicle when filling up with fuel;
• the devices should not be left unattended inside the vehicle;
• the vehicle should be adequately ventilated, preferably by opening at least one win-
dow (the outside air ventilation system should also be selected instead of recycling
the air inside the vehicle);
The patient’s vehicle should preferably be equipped with an antistatic tape to re-
duce the risk of static electricity forming. If means of public transport, such as buses,
trains, ships or aeroplanes, are used, the patient should apply to the transport com-
pany for a permit to be able to transport and use oxygen containers. If more than one
patient under oxygen therapy are present in the same place (e.g. in a restaurant or ho-
tel), they should inform the owner/manager of the restaurant or hotel of the precau-
tions to be taken when oxygen is used.
13.3.2.8 Oxygen Therapy Service with Oxygen Concentrators

When planning the installation of oxygen concentrators at the patient’s home, the area
in which the equipment is to be installed should be checked to make sure that the risk
of an accident with the oxygen is minimal for the patient and caregiver. For patients
receiving home care, this check should be carried out by the person installing the con-
centrators.
When a concentrator is installed for a new patient, the entire oxygen administra-
tion circuit, including cannulas for oxygen therapy and distribution tubes, should be
new. The humidifier should be replaced or disinfected, if it can be reused, and the an-
tibacterial filter and dust filter should be replaced between one patient and the next
following the instructions given by the manufacturer.
When choosing the place where the concentrator and its accessories are to be in-
stalled, the patient, relative or caregiver should be instructed to:
• keep the concentrator at a distance of at least 3 metres from bare flames;
• keep the concentrator at a distance of at least 1.5 metres from heat sources and elec-
trical devices;
• avoid installing the concentrator near curtains, padded armchairs or any other ma-
terial;
• leave a space of at least 15 cm around the concentrator to allow air to circulate;
• avoid installing the concentrator in a kitchen or garage where oils or grease may
be stored or used;
• avoid installing the concentrator in such a way that the air inlet or outlet of the con-
centrator could be obstructed in any way;
• keep and use the concentrator in an upright position;
• position the concentrator near a power outlet to avoid using extensions;
• position the concentrator close enough to the patient for him/her to hear the
alarm if it is activated.
In addition, great care should be taken to choose a suitable place for the spare
cylinders given to the patient in case the concentrator malfunctions or there is a power
failure. The general rules for the storage and use of medicinal oxygen cylinders are
set forth earlier in this document.
13.3.2.9 Using Oxygen Concentrators

The supplier should make sure that the patient, relative and/or caregiver are adequately
instructed on how to use the concentrator. Training must include all operational as-
pects of the device, including the cleaning, maintenance and general safety informa-
tion on the use of oxygen in the patient’s home. The supplier should leave a copy of
the manufacturer’s operating manual for the specific concentrator supplied. The train-
ing of the patient, relative and/or caregiver should include an explanation of the mean-
ing of the labels and symbols applied to the device by the manufacturer.
General precautions:
• multiple sockets should not be used to power the device (Fig. 13.12);
• extensions should not be used;
• solvents should not be used to clean the surfaces of the concentrator;
• the air filter should be cleaned periodically by rinsing it under running water;
• the humidifier should be removed, rinsed and refilled with distilled water every day.
The patient should make sure that:
• nobody smokes near the device during administration of the oxygen therapy;
• if a humidifier is used, the container is unscrewed, filled (as indicated in the in-
structions of the humidifier) and fitted to the concentrator again;
• all the equipment is connected correctly so as to avoid leaks; the tubes and con-
nectors are in good condition;
• if the patient requires a greater flow than that emitted by a single concentrator, the
supplier should supply a device that can connect to several containers so that the
Fig. 13.12 Check the electrical system

when using the concentrators
150 C. Castiglioni
patient receives the amount prescribed by the doctor. When more than one device
is used to administer the prescribed flow to the patient, it is very important to po-
sition the devices close together, reducing to a minimum the length of tubes between
the containers. It may be necessary to use tubes with a larger diameter than nor-
mal so as to avoid excessive pressure drops. When multiple containers are used to
administer higher flows, further attention should be paid to prevent a backflow of
water from the humidifier from one container to another.
13.3.2.10 Filling the Oxygen Cylinders from the Oxygen Concentrators

Some concentrators may be used to fill medicinal oxygen cylinders at a high pres-
sure. This method of filling cylinders with oxygen compressed by a concentrator is
not recommended unless specific risk assessments have been made and the patient
is trained and his competence verified.
The requirements for filling cylinders at a high pressure are regulated by national
and international legislation and great care should be taken to ensure that all require-
ments are met before allowing healthcare operators or patients to fill cylinders from
an oxygen concentrator.
13.4 Risks of Oxygen Use
13.4.1 General Risks
Following the installation of the oxygen therapy equipment, the patient and/or care-
giver should be trained on the procedures to be followed if an accident takes place:
accidents may include an interruption in the flow, a fault in the container, refusal by
the patient or the equipment being involved in a fire.
The probability of these problems occurring is low providing the equipment has
been installed correctly and the patient and caregivers have received adequate train-
ing.
Most serious accidents that take place during oxygen therapy are caused by the
patient or caregiver smoking (Fig. 13.9).
In case of a fire, the patient should be instructed to:
• contact the fire brigade immediately and inform them of the presence of oxygen
therapy equipment;
• move away and isolate the equipment but only if this can be done safely;
• the patient should leave the house immediately, if possible.
If a major oxygen leak occurs as a result of the cylinder being dropped and the
pressure regulator getting broken, or between the valve of the cylinder and the reg-
ulator or a major leak of liquid oxygen occurs from a cryogenic container, the patient
or caregiver should:
• close the valve of the cylinder or container for the liquid oxygen only if this can
be done safely;
• make sure that the doors and windows are open to ventilate the room;
• contact the supplier immediately.
(If a cylinder or cryogenic container is dropped, even if there is no apparent dam-
age, the supplier should be informed immediately).
If the oxygen concentrator heats up more than usual, the power source should be
isolated and the supplier should be informed immediately. If the patient cannot sus-
pend the administration of oxygen until the electrical problem has been solved, he
should use the emergency cylinder.
In any case, the patient should be advized to contact the supplier whenever he/she
suspects that the oxygen therapy equipment is faulty or malfunctioning.
During the oxygen therapy, specific precautions should be taken according to the
method of administration.
During the initial installation of the equipment, the patient (and/or caregiver)
should be informed of the risks associated with the use of oxygen.
In order to prevent an excessively oxygen-enriched atmosphere forming, the
rooms in which the cylinders, cryogenic containers and concentrators are positioned
should be adequately ventilated.
It should be borne in mind that oil and grease burn vigorously in an oxygen-en-
riched environment so a fire may start if the equipment is contaminated with oil or
grease (oils, creams, ointments, etc.), so the oxygen therapy equipment should:
• be handled carefully with clean hands and tools;
• only be used with products approved for use with oxygen if the patient has to use
creams, ointments or oils to avoid his/her nostrils drying up.
1. It should be borne in mind that combustible materials burn more vigorously and
at a higher temperature in an oxygen-enriched atmosphere, so:
a. never smoke while the oxygen dispenser is being used;
b. do not allow anybody to smoke in the room or near a patient receiving oxygen
therapy;
s. keep potential sources of ignition away from the place where the cylinders are kept;
d. avoid heat sources (including cigarettes) gas cookers, toys, electrical devices
and bare flames in rooms that could be saturated with oxygen.
2. Materials such as clothes and sheets are excellent oxygen absorbers and burn rap-
idly if saturated and exposed to a source of ignition. These materials retain oxy-
gen for some time even after the oxygen source is removed so the following in-
structions should be respected under all circumstances:
a. air clothes and/or sheets if you suspect that they have been exposed to oxygen
(clothes should be aired for at least 15 minutes and sheets should be ventilated
for 30 minutes before they may be moved safely close to a possible source of
ignition);
152 C. Castiglioni
b. never cover the oxygen therapy device with any material and do not place it near
curtains;
c. never use the oxygen therapy equipment if it is covered with a cloth or clothes,
if containers or bags are used to transport it, they should be designed to pre-
vent an oxygen-enriched atmosphere forming;
d. to prevent accidental increases in the concentration of oxygen in the air, the pa-
tient and relatives should be instructed how to turn off the oxygen dispensing
source when it is not in use.
Only specially trained persons may use the oxygen therapy equipment (the
equipment should be kept out of the reach of children).
13.4.2 Risks Associated with the Use of Compressed Oxygen
There are some specific risks associated with the administration of oxygen from com-
pressed gas cylinders. They are mainly due to conditions of high pressure and the
weight of the cylinders themselves:
1. great care should be taken to make sure the valves of the cylinders are closed when
not in use to avoid leaks and creating hyperoxygenated areas; it is important that
the rooms in the patient’s house where the cylinders are stored are well ventilated;
2. the energy stored in a compressed oxygen cylinder is very high and it should be
borne in mind that this pressure rises with temperature, so the cylinders should be
kept away from heat sources;
3. it is also important to check that the flow regulating valve is assembled correctly and
set to its zero/minimum flow position before opening the valve of the cylinder;
4. the valve should be opened very slowly so as to avoid adiabatic compression,
which could cause a fire;
5. great care should be exercized in storing oxygen cylinders and they should be se-
cured to a stable support to eliminate the risk of them falling.
13.4.3 Risks Associated with the Use of Liquid Oxygen
The risks associated with the supply of medicinal liquid oxygen to patients are mainly
due to the low temperature of liquefied gas, so the following precautions should be
taken:
1. liquid oxygen necessarily has an extremely low temperature (-183 °C, a volume
of liquid oxygen under standard pressure conditions, when vaporized, produces
approximately 873 volumes of gaseous oxygen at 15°C) at standard atmospheric
pressure: contact with the cold surfaces of the equipment (e.g. valves, tubes, joints,
etc.) may cause severe cold burns and frostbite, great efforts should therefore be
made to avoid coming into direct contact with the liquid oxygen and/or the cold
parts of the equipment without wearing personal protective equipment;
2. moisture may build up on the exposed surfaces of the equipment containing liq-
uid oxygen, thus forming ice and blocking components such as valves and joints
open or closed, if the moisture penetrates into the liquid oxygen tubes or the equip-
ment it freezes thus compromising the operation of components such as safety
valves or control valves and creating a potentially hazardous faulty condition;
3. due to its low temperature, liquid oxygen constantly absorbs heat through the walls
of the container which causes it to vaporize and turn into gaseous oxygen. The sur-
plus gaseous oxygen is automatically dispersed but it is important to keep the liq-
uid oxygen containers in a well-aired room away from combustible materials and
protected against exposure to heat sources;
4. the density of the gas released at a low temperature by the cryogenic container is
higher than that of the air so the oxygen will tend to accumulate on the floor if the
room is poorly aired.
13.4.4 Risks Associated with the Use of Oxygen Concentrators
Although concentrations dispense oxygen at a relatively low pressure and flow rate,
the general precautions for using oxygen should be taken with great care. With spe-
cific reference to concentrators, the risks are mainly due to the fact that they receive
electrical power.
The following rules should also be respected:
1. during operation of the oxygen concentrator, take care when connecting the de-
vice to the power outlet to avoid the risk of an electric shock;
2. during maintenance of the oxygen concentrator or filling of the humidifier, the de-
vice should always be turned off and detached from the power outlet;
3. the concentrator should never be used in the bathroom or similar rooms.
13.5 Travelling with Oxygen
Patients receiving oxygen therapy may now travel freely at least in the main Euro-
pean countries. In fact, all the leading oxygen manufacturers and distributors provide
support to patients from overseas.
In order to have a sufficient supply of oxygen, the journey should be planned some
time in advance (every company has its own procedures and different methods of ac-
tivating this service) so the person who wishes to use the service should contact the
customer service of the company that supplies him/her at home.
In any case, oxygen may now be transported by car using a portable unit (called
154 C. Castiglioni
a stroller) and the same applies to rail transport (for journeys of over 3 hours, the pa-
tient should ask the company that supplies him/her with oxygen at home to provide
an additional stroller that may be used when the first one runs out).
The patient may continue to take oxygen after embarking on a ship providing the
travel agency that organized the journey is informed.
Travelling by air is a little more complicated. In fact, most airline companies do
not allow the use of liquid oxygen on their aeroplanes to the point that they even vi-
olate the rules of the aeronautical registers, which generally allow the use of liquid
oxygen on the aeroplane for medical purposes.
A patient wishing to organize a journey for which he/she must necessarily take an
aeroplane should book the flight well in advance and inform the airline company that
he/she is under home oxygen therapy, in which case the airline company will be re-
sponsible for supplying the oxygen required by the patient during the flight.
13.6 Oxygen Therapy Devices
Medical oxygen therapy devices comprise all devices that connect the patient to the
oxygen source and dispense oxygen. These devices may be applied to the face
(masks), the nostrils (cannulas and glasses) or inserted into the pharynx (probes).
Other devices are designed to humidify the oxygen and connect the devices.
13.6.1 Cannulas
Nasal cannulas (also called nasal glasses) are made of anti-allergy synthetic mate-
rial, are disposable, of a standard length and positioned in the nostrils. The position
is maintained by passing the supply tube over and behind the ears, in some models
using an elastic mechanism that simulates the structure of spectacles (Fig. 13.13)
Nasal glasses are the most widely used and best tolerated administration system.
As these devices supply oxygen to the front of the nostrils, the precise amount of
oxygen inhaled is unknown and they certainly cannot be used with high gas flows
(maximum flow of 6 L/min).
Nasal glasses lose their efficacy if the patient breathes with his/her mouth open.
These devices are widely used (they are inexpensive), easy to use even without any
specific experience and above all comfortable for the patient even if they may cause
sores at the points of contact (nostrils and ears) and dryness of the nasal mucus in-
duced by the flow of oxygen (the humidifier is useful).
They should in any case be used with care in that during sleep they may move out
of position.
Much has been done from the aesthetic point of view, in fact, some frames of
Fig. 13.13 Nasal cannulas
glasses conceal the oxygen dispenser inside them so that it is virtually invisible.
Advantages: medical device inexpensive, comfortable and generally well toler-
ated by the patient.
Disadvantages: extremely variable FIO2 value, irritation of nasal mucus.
13.6.2 Masks
Masks are also made of anti-allergy synthetic material (vinyl polychloride), are dis-
posable and represent an alternative to the nasal glasses even when oxygen has to be
dispensed at high flow rates.
The mask enables the O2 to mix with the ambient air that penetrates through the
side openings. The simplest masks have a metal rim that enables the mask to be
adapted to the shape of the patient’s face.
They are positioned over the face so that the mask fits against the skin around the
nose and mouth and are held in the correct position by a system of elastic bands (Fig.
13.14).
The latest masks are made of materials that readily fit to the structure of the face
and have drastically reduced the pressure sores that were often caused by these devices.
Masks are divided into standard, child, adult and extra-large types, masks with a
reservoir bag and Venturi masks.
156 C. Castiglioni
Fig. 13.14 Standard mask Fig. 13.15 Venturi mask
Advantages: useful for patients who breathe exclusively through their mouths
Disadvantages: variable FIO2 value, cannot be worn while eating, poorly tolerated
during sleep.
13.6.2.1 Venturi Mask

A standard, anatomical, anti-allergy and disposable mask. This mask has a hole to
which is connected a tube with a diameter of about 2 cm with a valve at the end for
modifying the concentration of the O2 administered. The mask is then connected by
a tube, also disposable and made of anti-allergy material, to an O2 source.
This type of mask may be used to supply fixed FIO2 flows (L/min) with different
percentages of O2 indicated by specific colour codes (each colour corresponds to a
precise oxygen concentration so as to guarantee the prescribed FIO2) (Fig. 13.15).
It is useful in cases of hypoxemia with sufficient ventilation as in the case of
chronic obstructive pulmonary disease in which ventilation is sustained by the hy-
poxia. It is also useful in patients who breathe through the nose and mouth or preva-
lently through the mouth.
Advantages: dispenses a precise oxygen concentration
Disadvantages: rather uncomfortable like all masks, cannot be worn while eating.
13.6.2.2 Mask with a Reservoir Bag

It is a disposable mask made of anti-allergy synthetic material and equipped with a
bag (reservoir) that enables some of the oxygen that would be lost in the exhaling
phase, as it is supplied continuously, to be recovered (Fig. 13.16).
This mask permits partial, low-flow rebreathing and the reservoir allows some the
exhaled air to be inhaled again.
Advantages: used to administer high FIO2 levels > 40 % (up to 90 %).
Fig. 13.16 Mask with a reservoir bag
Disadvantages: uncomfortable and, like all masks, cannot be worn while eating. It
is not indicated for chronic obstructive pulmonary disease in that
it may increase the PaCO2 pressure (thus causing hypercapnia).
13.6.3 Probes
Oxygen therapy probes are normally inserted through a nostril (after lubrication) into
the pharynx. With respect to masks and cannulas, probes reduce the dead space and
the volume in which the oxygen is mixed with the exhaled air.
They have the advantage of being more stable than glasses and masks, as well as
reducing the dead space, but they are not well tolerated by the patient.
These devices are generally disposable and made of anti-allergy synthetic mate-
rial. The supply conditions vary according to the guidelines and agreements between
the public health authority and the service providers.
These inhalation systems are made of various materials so the patient may choose
the system that is most comfortable (although it must be latex free).
13.6.4 Humidifiers
Humidifiers are containers, the latest of which are made of plastic, in which the oxy-
gen dispensed by the supply source (gaseous cylinder, liquid oxygen container, con-
centrator) is made to flow through a tank in which there is a small amount of distilled
water.
The oxygen bubbling through this water is enriched with moisture and warms up
before reaching the patient’s airways.
A humidifier is required in that oxygen tends to dry the mucous membranes and
if the therapy is administered for a long period, it may lead to epithelial damage with
158 C. Castiglioni
the formation of a crust and bleeding of the mucus in the nasopharyngeal region. In
this case, use can be made of products based on hyaluronic acid or carboxymethyl glu-
can in a gel or solution (nasal spray) to lubricate and humidify the mucous membranes.
The humidifiers are to be cleaned and disinfected periodically in that they may be
contaminated by bacteria that could cause bronchial relapses or pneumonia in eld-
erly and debilitated patients.
Suggested Reading
Linee guida AIPO 1995 su OLT (2005) Rassegna di Patologia dell’Apparato Respiratorio 1:334-
344
Miselli M (1995) Ossigenoterapia. In: Miselli M (ed) Assistenza al paziente domiciliare. Roma, Il
Pensiero Scientifico Editore
Petty TL, O’Donohue WJ Jr (1994) Further recommendations for prescribing, reimbursement, tech-
nology development, and research in long-term oxygen therapy. (Fourth Oxygen Consensus Con-
ference, Washington DC, October 15-16, 1993. Am J Respir Crit Care Med 150:875-877
American College of Chest Physicians (1999) Clinical indications for non invasive positive pres-
sure ventilation in chronic respiratory failure due to restrictive lung disease, COPD and noc-
turnal hypoventilation. A Consensus Conference Report. Chest 116:521-534
McCoy R (2000) Oxygen Conserving Techniques and Devices. Respir Care 45:95-103
Petty TL, Casaburi R (2000) Recommendations of 5th Oxygen Consensus Conference. Respir Care
45:957-961
Kacmarek R (2000) Delivery Systems for Long-Therm Oxygen Therapy. Respir Care 45:84-92
Murgia A, Scano G, Palange P, Corrado A et al (2004) Linee guida per l’ossigenoterapia a lungo
termine (LTOT) – aggiornamento 2004. Rassegna di Patologia dell’Apparato Respiratorio
19:206-219
Dunne PJ (2009) The Clinical Impact of New Long-term Oxygen Therapy Technology. Respir Care
54:1100-1111
National Clinical Guideline Centre (2010) Chronic Obstructive pulmonary disease: management of
chronic obstructive pulmonary disease in adults in primary and secondary care. London – Na-
tional Clinical Guideline Centre http://guidance.nice.org.uk/CG101/guidance/pdf/English (7.6
– pp 241-253)
Section III
Models for LTOT Management
Standard Care
14
Eugenio Sabato, Saverio Sabina and Carlo G. Leo
The care of patients requiring oxygen begins with access to long-term oxygen ther-
apy (LTOT). Figure 14.1 shows three different modalities depending on the context
in which such access is required by the pulmonologist. Diagrams show that all the path-
ways illustrated arrive at a common activity: delivery of the LTOT program. Thus this
chapter focuses on the description of a model that, by ensuring continuity of care, rep-
resents the standard of care for LTOT management. The goal of this paradigm is to
bring health services closer to the population, make them more accessible and inte-
grated with the hospital, and improve their coordination and continuity in every area.
14.1 Beyond Critical Issues: a Reference Model
Oxygen is a drug, and therefore should be prescribed with due care and in the quan-
tities required. Regarding home oxygen therapy, international recommendations [1]
indicate that the duration of administration should be closer to 24 hours. Mularski and
colleagues [2] report, with specific reference to the American situation, that the ap-
propriate use of oxygen in chronic obstructive pulmonary disease (COPD) patients
could reduce annual mortality by about 50% [3]. These COPD patients in advanced
stages of the disease are the most common candidates for LTOT. Appropriate use of
oxygen also reduces the risk of hospitalization [4].
Appropriate prescription and accurate information about the method of adminis-
tration to enhance patient compliance are therefore important critical issues in the
LTOT process. Katsenos and Constantopoulos [5] report that doctors often prescribe
oxygen for less than 15 hours per day, that effectiveness and prescription compliance
E. Sabato ()
Pulmonary Unit, ASL BR
Brindisi, Italy
e-mail: sabatoeugenio@gmail.com
162 E. Sabato et al.
Fig. 14.1 Access to the LTOT program according to a specialist visit suggested by the GP, b hospi-
tal discharge, c follow-up of chronic respiratory patient
14 Standard Care 163
are associated with pulmonologists rather than general practitioners (GPs), that only
60% of prescriptions are appropriate, that half of patients do not receive written in-
structions on the use of equipment and nearly two-thirds of them are not informed
about the importance of LTOT. In addition, Mason and Suntharalingam [6] note that
the inappropriate prescription of LTOT leads to an increase in morbidity and can gen-
erate unjustified costs for the purchase of oxygen. All these critical aspects need to be
managed and resolved through the identification and adoption of methods and actions
aimed at increasing adherence to LTOT. This process of analysing problems and find-
ing solutions makes it possible to define a model of care. Previously identified criti-
cal issues can be overcome by implementing several courses of action: training all in-
dividuals involved in the process, improving doctor-patient communication, and
defining responsibilities and pathways related to the prescription.
For training it is necessary to develop educational aimed at healthcare profession-
als (GPs, pulmonologists, nurses, physiotherapists) as well as patients and caregivers1.
Introducing specific training programs can have a significant impact on both ap-
propriate prescription and compliance [7]. For healthcare professionals it is crucial
to attend continuing education programs focused on primary and respiratory care and
oxygen therapy equipment [3]. These programs enhance interaction and communi-
cation between healthcare professionals and patients/caregivers, emphasising the im-
portance of LTOT and the correct use of related equipment. Given the complexity and
multiplicity of the actions required to use these devices properly, training programs
focusing on them should be provided [8]. It has been shown [9] that patients receiv-
ing LTOT often have unjustified fears that can adversely affect their adherence to the
program. Moreover, as noted by Tiep and Carter [10], due to its bulk, oxygen equip-
ment can become a critical issue for patients and can discourage participation in re-
habilitation programs.
Communication strengthens the relationship of trust between doctor and patient,
facilitating collaboration [11]. This establishes a more balanced relationship between
them in managing decisions [12], and consequently leads to greater adherence to the
prescribed care program [13-15].
With regard to the skills and pathways of the prescription, the British Thoracic So-
ciety (BTS) guidelines [16] indicate that all patients requiring LTOT must be evalu-
ated by pulmonologists. In fact, Mason and Suntharalingam [6], based on their
analysis, report that inappropriate prescription of oxygen in COPD patients occurs
in about half (46%) of all prescriptions and that this inappropriateness can be attrib-
uted in most cases (78%) to GPs.
The model must consider actions and methods aimed at overcoming another im-
portant problem: the lack of continuity of care. By extending the definition given by
1 The word caregiver refers to non-professional figures who participate in the healthcare process.
Usually they are members of the patient’s family.
MeSH to chronicity, this can be expressed as healthcare delivered continuously

from the first contact until death.
This definition can be translated into the need for regular and structured follow-
up, which Howard and colleagues [17] maintain increases adherence to LTOT. The
follow-up mainly provides frequent and programmed pulmonary examinations in or-
der to monitor the patient’s status and reduce the flow of oxygen [18]. In addition,
follow-up involves the above mentioned continuous training program.
Therefore, it is evident that, in order to better manage patients receiving LTOT, the
greatest effort must be to create a multidisciplinary team trained in pulmonary disciplines.
14.2 Application of the Reference Model
LTOT patient care is more effective the more closely it adheres to the care process con-
sidered in the model. In fact, while the model must necessarily consider each individ-
ual involved in the care process, its application must consider them as a whole in a vi-
sion of rationalising available resources and enhancing the patient’s quality of life.
14.2.1 Pulmonary Service in the Territory
As previously mentioned, it is essential to start with the creation of a multidiscipli-

nary team with specific training in pulmonary issues, before implementing care, re-
habilitation and education pathways.
The LTOT patient must be managed in his/her territory (e.g. patient’s home, out-
patient department, etc.). Thus the team must be able to operate in the territory and it
must have an institutional setting specifically designed to ensure interventions and the
resources needed to implement them: this is the pulmonary service in the territory
(PST). The PST is the ideal context in which to secure outpatient services, respiratory
home care service (HRCS) for non-ambulatory patients, and the implementation of
continuing education programs for all stakeholders involved in the care process.
14.2.1.1 Outpatient Service

Ambulatory LTOT patients can use the outpatient service for pulmonary examina-
tions. The examination includes:
• blood gas analysis;
• spirometry;
• blood pressure check;
• monitoring of patient compliance with the prescribed therapy;
• regulation of oxygen flow;
• pulmonary report for GPs.
At the end of the examination LTOT is prescribed and/or confirmed and/or mod-
ified, specifying the flow and the number of hours deemed appropriate.
14.2.1.2 RHCS (Respiratory Home Care Service)

Non-ambulatory patients are treated by the RHCS team, which goes to the patient’s
home. The team is usually composed of at least one pulmonologist and another health-
care professional (nurse and/or physiotherapist). A telephone appointment is made be-
fore the visit. Sometimes only the nurse visits the patient. After the relevant examina-
tion (pulse oximetry, blood pressure, evaluation of general condition, etc.), the nurse
compiles a report used by the pulmonologist to assess the appropriate requirements. If
the visit is aimed at reducing oxygen flow, then the pulmonologist must be present.
During home examinations, in addition to the above-listed activities the efficiency
of the LTOT equipment supplied to the patient is monitored and attention is paid to
determining the critical issues for caregivers in managing patients who receive oxy-
gen therapy.
It is important to specify that the team is not the principal clinical reference for
the patient, but is the specialized unit that advises the GP, who is the only official ref-
erence for the patient.
In the first few months following the patient’s admission to a LTOT program, the
RHCS team performs frequent home visits in order to better understand the patient’s
clinical situation. It is during this period that the main problems emerge: difficulty
in self-managing the therapy, adapting to the prescribed treatment or managing the
equipment supplied.
The resolution of these problems allows implementation of highly customized pro-
grams for respiratory care to which pulmonary rehabilitation programs are added, if
necessary. This assistance is based on the activation of a network of territorial care
services that can operate only if there are well-defined integration protocols. In par-
ticular, the network nodes, with their specialized areas, are presented in Table 14.1.
At the end of the examination, the team establishes the time intervals between vis-
its, depending on the patient’s clinical stability and the compliance of caregivers.
Table 14.1 Nodes of the territorial network and related activities

Actor (node) Activity
RHCS team 1) prescribes oxygen therapy
2) contacts the GP to prescribe home healthcare
GP 1) requests home healthcare
Home healthcare l) delivers respiratory rehabilitation and medical therapy
team 2) informs GP and RHCS pulmonologist on the patient’s condition
Oxygen equipment 1) verifies the compatibility of the patient’s home with the oxygen equipment
company 2) fills out a technical report on home-equipment compatibility
Moreover, at the patient’s home a prescription sheet for oxygen therapy is also re-
leased.
In order to meet care needs through increasing degrees of protection, it is also ap-
propriate to provide progressive levels of intensity of care:
a. Low-intensity healthcare regime: for clinically stable patients treated with oxy-
gen therapy who still do not require Home Mechanical Ventilation (VRD). In this
regime tracheotomized patients receiving LTOT are treated without mechanical
ventilation.
b. Medium-intensity healthcare regime: for clinically stable patients who require in-
vasive or non-invasive mechanical ventilation by tracheotomy < 16 h/day and LTOT.
Most important is the training of caregivers for patients on oxygen therapy. Train-
ing courses should be held in the same pulmonology centres (hospital and/or terri-
torial service) where the patients are treated.
Moreover, caregivers and patients must be initially informed and educated by the
hospital pulmonology team and subsequently by the territorial pulmonology team.
14.2.2 Hospital-Territory Integration
As shown in Fig. 14.1, the collaboration between different subjects, each with her/his
own skills and responsibilities, enables a patient’s admission to the LTOT program.
Similarly, the network of territorial health services ensures the delivery of a customized
program. In order to obtain a comprehensive vision of the LTOT patient and guaran-
tee continuity of care, these two aspects, so far analysed separately, must become nodes
of the same network. In the method of admission described in Fig. 14.1c, integration
is guaranteed by the fact that the same subject prescribes access and delivers the pro-
gram. In the other two methods it is necessary to involve, in addition to oxygen ther-
apy, accompanying the patient to the LTOT program. In particular, in the case described
in Fig. 14.1b this accompaniment is represented by a protected discharge. Furthermore,
this configuration also allows a planned admission to be managed.
In order to facilitate the return home of the patient, all the cooperative procedures
between the hospital and territorial services must be activated. Hospital discharge of
the patient should be made only when it is found that the home care plan is totally
efficient. Similarly, both the hospital and territorial pulmonology teams should agree
on follow-up and planned admissions, as well guaranteeing emergency hospitaliza-
tions at any time.
14.2.2.1 Participants and Activities of the Integration Process

The hospital-territory integration model must be implemented through the creation of
a network of services for patients in LTOT, which is necessary for determining an inte-
grated care pathway. The following tables describe the participants and services involved
Table 14.2 Actors and services involved in the care network

Actors and services Description
GP The patient’s main reference and for this reason must
be informed about everything relating to the patient
Case Manager Works to satisfy patient’s needs; intervenes
in the relationship with the caregiver, the institutions
and the medical staff; removes obstacles; plans, monitors
and evaluates the projects to be implemented; ensures
appropriate use of resources; plans training events
Caregiver The patient’s main assistant who thus must be involved
in the training program regarding use of equipment
PST on the whole (physicians, Intervenes in all integration activities between territory
nurses, physiotherapists) services and hospital
Pulmonary Hospital Unit Requests LTOT and guarantees the integration activities
– PHU – (physicians, nurses, between hospital and territory services. Provides training
physiotherapists) for patients and caregivers
Local Health District (LHD) Prescribes LTOT and manages all administrative
procedures regarding oxygen delivery
Oxygen Equipment Company (OEC) Delivers oxygen cylinders to patient’s home
in the care network (Table 14.2) and their activities to implement the integration process
in both the case of protected discharge and planned hospitalization (Table 14.3).
14.3 Conclusions
The healthcare pathway described above shows the multiple relationships between
the actors involved (health professionals, caregivers, institutions and companies) and
the various levels at which these interactions occur: support, training, information.
All these relationships represent a complex system. In the logic of systems, a system
is complex if it is not constituted merely by the sum of its components, but also by
an intricate high level of interconnection [19]. Analysing, rationalising and manag-
ing a complex system requires:
a. the contribution of various disciplines, each of which can read a part of the complex-
ity as well as a overall view. Thus the contribution must be provided not only by
health professionals involved in the healthcare pathway, but also by professionals
with training in activity analysis, rationalization and representation of organizations;
b. the participation of various institutions that have missions closely related to the
problem object of analysis;
c. the use of tools for representing and managing the complexity. These tools should
be based on international standards and shared by the scientific community.
Table 14.3 Participants and activities in the integration program

Action Actors Relation between main actor Objective
Main Actor Partecipant and partecipant
1 HHN CM At least three days before patient
discharge HHN makes contact with
CM and sends a report with clinical
and personal data of patient,
caregiver and GP
PO: to ensure
2 HHN Patient/ HHS submits the report for GP and
protected
caregiver the oxygen therapy request for LHD
discharge
3 HHN OEC If the case of non-ambulatory
patients HHS arranges the evaluation
of critical issues for RHCS
admission
4 HHN Physicians, HHS plans the weekly training PO: to ensure
nurses, program for patients and caregivers protected
physiotherapists discharge
of PHU
SO: to offer
5 Physicians, Patients and Guarantee the training program a training
nurses, caregivers program on
physiotherapists LTOT, managing
of PHU of equipment,
PST
6 CM GP CM sends a report to the GP

7 LHD Patients and/or LHD authorizes LTOT and provides
caregivers a list of OECs
8 Patients and/or OEC Patients and/or caregiver identifies
caregivers the company and requests oxygen
9 OEC Patient, LHD OEC verifies the compatibility
between patient home and OP: to ensure
equipment, then prepares a technical protected
report for LHD discharge
10 OEC PHU OEC provides equipment needed for
the training of patients and caregiver
11 HHN Patient HHN delivers to the patient request
for blood gases and pulmonary
examination and advises her/him to
contact the PST
12 OEC Patient OEC provides the service to the OP: oxygen
patient delivery
13 CM Patients and/or CM contacts the patient/caregiver OP: to deliver
caregivers the territorial
health care
program
(continued)
Table 14.3 (continued)

Action Actors Relation between main actor Objective
Main Actor Partecipant and partecipant
SO: to
understand
the patient
condition
14 CM PST CM informs the pulmonologist PO: to deliver
pulmonologist and plans an examination as soon the territorial
as possible after the patient’s health care
discharge program
15 CM Physicians, CM plans for the training program PO: to deliver
nurses, the territorial
physiotherapists health care
of PST program
16 CM patients and/or CM contacts patients and caregivers SO: to offer a
caregivers for training training program
on RHCS, PST,
17 Physicians, Patients and/or Guarantee the training program emergency
nurses, caregivers management,
physiotherapists scheduling of
of PST examinations
and equipment
management
18 PST physician Patient Visit the patient and evaluate PO: to ensure
and/or nurses the need for a planned admission a personalized
healthcare
program
19 PST physician Patient and/or Physician prepares and delivers
caregiver, the accompaniment letter
HHN, case for hospital admission in triplicate PO: to ensure
manager planned hospital
admission
20 CM HHN CM plans the admission together
with HHN
PO, principal objective; SO, secondary objective; CM, case manager; HHN, hospital head nurse;
LHD, local health district; OEC, oxygen equipment company; PHU, pulmonary hospital unit;
PST, pulmonary service in the territory; RHCS, respiratory home care service
The complexity of the pathway for LTOT patients reveals the need for a techni-
cal and methodological shift – from the supply of good performance to the ability to
design and manage integrated care processes. Mono-disciplinary approaches are dis-
carded in favour of multi-disciplinary ones that allow for a multifactorial analysis of
needs. A unified approach that meets all the patient’s needs becomes possible only
by integrating responsibilities and resources [20]. If an overall view of the combina-
tion of care and needs is recognized, then this integration becomes the model of or-
ganization of the care process.
References
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BMJ 323:625-628
Tele-Control at Home
15
Roberto W. Dal Negro
In most evolved public health organizations, Long-Term Oxygen Treatment (LTOT)

has long been a consolidated therapeutic strategy for patients suffering from chronic
respiratory failure (CRF), and equates to an unavoidable portion of public health plan-
ning [1].
The continuous progressive ageing of populations and the ever increasing preva-
lence of chronic respiratory diseases has helped to suggest new scenarios in order to
match specific services to people’s requirements regardless of the ever decreasing
availability of resources. Although the richest countries have had the chance to in-
vest more than 10% of their IGP in public health programs in the past, in more re-
cent times they have gradually had to optimize their specific investments by favour-
ing the most cost-effective programs, and those of the highest value in social terms.
This is of particular value for the strategic approach to pathologies, i.e. chronic
respiratory diseases, that are characterized by long-term chronicity, long-lasting
loss of productivity and disability, occurrence of several exacerbations, frequent hos-
pitalization, and a dramatic burden and social impact.
In the past, the interventional models for managing LTOT at home were based on
usually inadequate numbers of health professionals - doctors and nurses - who had
to face an excessive number of patients, their activities being substantially supported
by groups of volunteers (sometimes organized in local dedicated organizations), who
contributed with the periodic contact with these patients and their families, and fre-
quently replaced institutional roles. Obviously, this approach to LTOT led to a large
amount of fragmented local experience, each consisting of a relatively small num-
ber of patients; moreover, the routine management was highly affected by paternal-
ism, the outcomes were highly uneven, and results often not comparable.
R.W. Dal Negro ()

Lung Unit and Department of Internal Medicine, ULSS 22 Regione Veneto
Bussolengo Hospital
Verona, Italy
e-mail: rdalnegro@alice.it
172 R.W. Dal Negro
Since the end of 1980s, the economic resources for public health have progres-
sively decreased, and the true cost-effectiveness of choices has become mandatory
in health planning, even for interventional LTOT protocols.
Chronic respiratory failure (in its hypoxic and/or hypoxic-hypercapnic clinical
manifestation) is an interesting test bed for novel interventional health models in-
tended to optimize the allocation of resources and measure the expected clinical ben-
efits for patients and the public health system.
The increasing difficulties in effectively managing and monitoring an ever grow-
ing number of CRF patients distributed within large territories who require LTOT at
home stimulated the introduction of protocols based on innovative electronic tech-
nologies enabling daily telemetric contacts with patients at home, and their interac-
tive remote control, almost independently of the amount of staff involved. At that time,
telemedicine was in fact defined as “the approach that can provide, though remote,
the advantages of a specialist organization and equipment, and special short-term
expertise at the patient’s home when needed”.
The very first release of a pioneer system dedicated to the daily telemetric mon-
itoring of LTOT patients at home was engineered in Verona, Italy, in 1990 (with the
support of the Veneto Regional Government and of the National Research Council
– NRC), and based on the wide use of liquid oxygen: liquid oxygen was preferred
to other systems because it was considered the most convenient for both patients (i.e.,
in terms of the quality of the oxygen delivered; environmental noise; personal costs
due to long-term power use; patient autonomy and mobilization) and institutions (i.e.,
the health opportunity delivered to LTOT patients and their families; health and so-
cial costs). Furthermore, the equipment for the liquid oxygen delivery enabled spe-
cific technical implementations that allowed for the precise remote control of oxy-
gen consumption by patients at home.
The system consisted of one Central Unit (CU) and several Peripheral Units (PUs)
for data collecting, which were located at the patients’ homes: this domiciliary equip-
ment was very useful and did not require too much skill or training for patients and
their caregivers [2-3]. All patients connected to the CU several times a day, and vital
signs and functional indicators were easily recorded according to the particular pro-
tocol scheduled by the specialist staff for each patient, depending on the original dis-
ease and severity. In other words, each patient had a specific scheduled timing (e.g.,
for the frequency and duration of contacts) for connection during the 24-hour period.
Moreover, in particular conditions (i.e. in the case of unstable patients and rapidly
changing clinical conditions), operators had the opportunity to activate further con-
nections in order to check patients more strictly. When needed, patients also had the
opportunity to connect directly for further spontaneous, non-scheduled use of the CU.
Finally, patients at home had the opportunity to transmit a priority message to the Lung
Centre and telephone for an immediate intervention (SOS) by pushing a red button that
was easily visible on the top of the domiciliary equipment. Once received, the prior-
15 Tele-Control at Home 173
Fig. 15.1 The first domiciliary/Central Unit connection for the daily telemetric monitoring of
LTOT patients at home
ity message was transformed into both visual and acoustic signals that remained ac-
tive until released by the CU operator(s) (Fig. 15.1).
The original system release enabled the following parameters to be recorded: heart
rate (HR); O2 saturation; O2 consumption. O2 reserve in the container for liquid oxy-
gen (Freelox) was purposefully modified, as was the patient’s adherence to the daily
oxygen prescription, in order to detect possible under-use or over-use easily and
quickly.
Both patients and caregivers (mainly family members) were carefully trained by
doctors and nurses of the Lung Centre to manage the technical devices located in their
homes, promoting the self-management of routine procedures and events. Their co-
operation proved to be very high, and both their skill and motivation was completely
unrelated to their educational or social level: data concerning how their perspective
changed during the last 10-15 years of telemetric LTOT are reported in other chap-
ters of this book.
Data from the 3-year survey that assessed for the first time long-term outcomes of
the telemetric approach to LTOT at home became available in 1994 [4]. This pivotal
study was originally carried out in 61 patients suffering from severe CRF included in
the telemetric LTOT protocol for two years (i.e., providing the centralized recording
of oximetry, HR, O2 consumption, O2 reserve, patient compliance, SOS calls): hos-
174 R.W. Dal Negro
2.5 Fig. 15.2 Changes in hospitalization

rates/year during the 3-year survey concerning
tele-LTOT (n = 61) [4]
2
1.5
0.5
0
1 year before +1 + 2 years
tele-LTOT of tele-LTOT
pital admissions (No./year) and their duration (days/year) were calculated and com-
pared annually to those of a corresponding pre-telemetric period lasting twelve
months. Corresponding direct and indirect costs were calculated in USD, whereas in-
direct costs were calculated only in employed subjects.
Dramatic improvements of both clinical and economic outcomes were docu-
mented. Firstly, mean PaO2 showed a significant and gradual increase from 53.2
mmHg ± 0.7 SD to 68.0 mmHg ± 0.9 SD, anova p < 0.02), while mean PaCO2 changed
from 48.2 mmHg ± 1.2 SD to 46.1 mmHg ± 1.0 SD, anova p < 0.8, respectively (Fig.
15.2). During the survey a corresponding substantial drop in home visits to LTOT sub-
jects was recorded. In fact, most of these visits were previously carried out periodi-
cally only to check all patients at home regardless of their stable or unstable clinical
condition, as a sort of a social need. However, tele-home monitoring led operators to
concentrate their attention and prompt action on cases truly requiring their interven-
tion due to the patient’s unstable or suddenly changing conditions.
Secondly, the economic outcomes were also dramatically optimized during two
years of tele-LTOT. Hospital admissions and duration decreased significantly from
1.8 to 0.5/year, and from 36.9 to 7.4 days/year, respectively. Correspondingly, direct
costs dropped from 769,000 USD to 25,300 USD, while indirect costs (such as those
mainly due to days off calculated using only the seven employed subjects) dropped
from 51,800 USD to 11,700 USD in the same period (Fig. 15.3) [4]. The annual cost
managing the same number of subjects only with stationary home oxygen concen-
trators in the United States was equal to 148,900 USD in the same period [5].
The reliability, effectiveness and economic convenience of the model was clearly
assessed by these studies albeit in a small cohort of subjects with CRF, the main pro-
portion of savings being mainly related to the substantial drop in admissions and the
optimization of medical and nursing activities [6]. From a general point of view, these
data were confirmed in another similar experience carried out a few years later [7].
Savings in direct and indirect costs (n = 61)

750 anova p < 0.001 60
500 40
€ x 1000
€ x 1000
250 20
0 0
Previoius yr 1° yr 2° yr
Fig. 15.3 Savings in direct and indirect costs during tele-LTOT [4]
Using data from these pivotal protocols, the interventional model for tele-LTOT at
home was implemented year by year, and a wide variety of technologies, together with
several transmission channels (such as PSDN, GSM, ISDN, ADSL, HDSL and
UMTS), were progressively implemented for management systems with self-moni-
toring devices, thus suggesting that there is an enormous potential for tele-monitor-
ing to assist subjects with long-term lung diseases [8].
Meanwhile, the cost-effectiveness of tele-medicine in chronic respiratory diseases
has become a true hot topic in recent times.
In view of limited resources available to health systems, tele-medicine has been re-
garded as an interesting tool for managing severe COPD patients because it offers pos-
sibilities to implement the usual forms of care and provides supervision of these pa-
tients. Even if it was regarded episodically as not able to fully replace traditional home
visits to patients, tele-medicine has nevertheless been described as a reproducible tech-
nology for improving communication between patients and doctors, for exchanging
data, and for defining the right time to see the patient personally, once the right pa-
tient has carefully been chosen the most suitable delivery systems adopted [9, 10].
A cost-minimization analysis was carried out by comparing a small group (n = 19)
of COPD patients in a home-care program with a comparable group of patients (n =
10) receiving usual care. Results clearly indicated that there were fewer home visits
and hospitalizations in the experimental group. Over a 6-month period, tele-moni-
toring generated 356 USD in savings per patient, or a net gain of 15% compared to
the usual care program. Finally, tele-monitoring was described as easily accepted by
all patients at home [11].
As mentioned before, all subjects (and caregivers) using telemetric LTOT at
home are invited to take a specific educational course of variable duration provided
by the staff of nurses and doctors of the Lung Centre in order to maximize both their
awareness and adherence to the program. In particular, the patient’s social conditions
and family setting are firstly investigated; then the LTOT protocol is illustrated and
176 R.W. Dal Negro
explained, and the patient’s views on telemetric LTOT are checked and recorded. Fol-
lowing this investigational phase, patients and caregivers enter a sort of health
school where the main problems related to chronic respiratory failure are discussed.
Usual educational tools are: open discussions, slides, videos and practice with domi-
ciliary devices that simulate the occurrence of emergency events (such as which clin-
ical signs to assess before sending the SOS message, quick use of the SOS red but-
ton, how to contact the CU operator, etc.). All actions intended to increase patient
self-management. In general, this educational approach greatly stimulates better ac-
ceptance of all protocol activities and related procedures, and contributes to minimis-
ing the initial scepticism of new entries (such as naive patients) and their caregivers.
Moreover, patients’ and caregivers’ suggestions and fulfilments are periodically
checked at fixed intervals using dedicated questionnaires: this action is quite valued
in the context of the whole program because the corresponding reports are regularly
used with patients for discussion during educational sessions of self help groups, and
for the continuous improvement of the LTOT program [12].
The positive role of a greater awareness of the disease and of active self-manage-
ment has been highly emphasized because it has been demonstrated that this can sig-
nificantly reduce healthcare services and improve patients’ health status [13].
Some years later, the same aspects were investigated in a population of 851 eld-
erly subjects managed at home with tele-medicine for two months after discharge.
In this study, which was centred on patients’ perceptions, the main results also rep-
resented an improvement in the quality of health, better understanding of the disease
and higher satisfaction rates [14].
As the skills and costs of human resources are the major component of care for
chronic respiratory patients in tele-assistance, a survey over a 5-year period was car-
ried out in 395 tele-assisted subjects for CRF, and the amount of time spent by staff
members was the primary outcome. The number of patients followed annually in-
creased over time; the amount of time spent by doctors on tele-assistance decreased
over time, while nurses’ time increased, thus allowing a cost saving of 39% [15].
Concerning the problem of frequent hospital admissions of patients suffering from
CRF in LTOT, a study carried out in severe COPD patients compared tele-assisted
individuals with usual care controls, with the number of patient re-admissions as the
primary endpoint over a 12-month period. The care team shared a single electronic
record accessible through the web. Also in this case, and in agreement with our piv-
otal results, findings indicated that the number of patients who were not re-admitted
was higher in the tele-monitored group (51% vs 33%, respectively) [16].
A systematic review (10 references and 858 subjects) compared the results ob-
tained with home tele-health (four studies) and tele-phone support (six studies) in
chronic respiratory patients with those receiving usual care. Even if the rate of clin-
ical heterogeneity was not negligible in different studies, the mortality rate was greater
in the tele-phone support group (risk ratio = 1.21), while the home tele-monitoring
Fig. 15.4 The current modular architecture for tele-LTOT
group added to telephone support was found to reduce rates of hospitalization and
emergency department visits, and quality of life and patient satisfaction outcomes
were much better [17].
Derived from the first version in 1990, our telemetric system for managing LTOT
at home was technically updated several times in the last twenty years. The last avail-
able release has been implemented with different technological functions (such as
spirometry, ECG, measurement of temperature and arterial blood pressure, ventila-
tor management) (Fig. 15.4 and Fig. 15.5) and daily use (such as the opportunity for
patients and doctors to communicate via written messages immediately available on
the screen, the management of quality of life questionnaires, the extension of the
graphic package, and implementation with the statistical package). This new release
was also created with the aim of connecting several CUs in order to create a national
unified database for patients receiving home LTOT. Moreover, despite the older ver-
sions, the most recent release of the telemetric system was created to match multi-
ple pathologies managed at home, and comprises a modular system that provides sev-
eral parameters for control in real time [18].
The reliability of the tele-home system is periodically checked in terms of com-
pliance and adherence to the LTOT protocol, and in terms of categorical outcomes,
such as stability of PaO2 and PaCO2 values over time, the incidence of lower airway
infections, and mortality.
178 R.W. Dal Negro
Fig. 15.5 The current organization for communication and multiple controls
Table 15.1 Changes in the rate of non-com-

pliance to tele-LTOT Concerning general patient compli-
ance, the number of non-compliant pa-
1990 9/64 14.1%
tients and families fell gradually from
1991 11/97 11.3% 10-14% two decades ago to 1.0 -1.7%
1991 8/101 7.9% now (Table 15.1). In particular, 78.9% of
... patients and 97.9% of caregivers manage
1998 8/124 6.4%
home equipment for liquid O2 properly,
and 98.2 % patients use the red alarm
1999 6/136 3.7%
button for emergency calls properly [7].
2000 4/148 2.7% Furthermore, significant improvements
... in patients’ quality of life were obtained,
2004 3/181 1.6% and data were in agreement with those
2005 2/177 1.1%
from other studies that focused on both
the social convenience and utility of tele-
2006 3/193 1.5%
metric domiciliary monitoring in this
2007 2/186 1.1% kind of patient [19-20].
2008 2/178 1.1% In order to check the reliability over
2009 4/236 1.7% time of the system, mean trends of both
PaO2 and PaCO2 are assessed monthly
2010 3/241 1.2%
in different clusters of patients at entry
2011 3/228 1.3%
into the protocol and for an average of
Table 15.2 Mean arterial PaO2 and PaCO2 before and 6 months after entering the tele-LTOT pro-
gram (mean ± SD). Each mean corresponds to the mean of several measurements per year
2005 2006 2011
N. patients 177 193 228
before after before after before after
PaO2 (mmHg) 51.7 ± 5.3 63.0 ± 10.2 52.6 ± 6.1 63.2 ± 7.8 52.4 ± 5.9 62.9 ± 8.1
PaO2 (mmHg) 50.5 ± 7.8 49.0 ± 9.0 49.1 ± 7.4 48.5 ± 7.7 50.3 ± 6.6 47.9 ± 8.1
Table 15.3 Different causes for hospitalization: incidence of LRTI vs other main causes
2005 2009 2011
N. patients 31 27 32
N. admissions 46 39 48
COPD exac. 33 (71.7%) 25 (64.1%) 30 (62.5%)
AHF 10 (21.7%) 12 (30.8%) 13 (27.1%)
LRTI 2 (4.4%) 2 (5.1%) 3 (6.2%)
Cancer 1 (2.2%) 5 (12.8%) 2/4.2%)
six months afterwards: data stability is still fairly acceptable and confirms the relia-
bility of the remote monitoring protocol (Table 15.2).
Since the beginning of the tele-LTOT protocol, aspects related to the changing in-
cidence of lower airway infections during LTOT at home were a challenge. Surprisingly,
in the first cohort of patients monitored, the incidence of lower airway infections
dropped significantly and dramatically over time in the great majority of subjects ad-
mitted to the program. In these subjects, the number of lower airway infections were
22 during the pre-LTOT year; but only 8 during the first, and 7 during the second year
of tele-home LTOT, with no fatal event occurring independently of the transient impair-
ment of basal hypoxemia (PaO2 = 52.1 mmHg ± 5.5 SD) and hypercapnia (PaCO2 =
53.3 mmHg ± 4.6 SD) recorded during pneumonia. Hospitalizations reduced signifi-
cantly (from an average of 0.3/patient/year ± 0.5 SD before LTOT to 0.1 ± 0.3 SD and
0.0 ± 0.3 SD in the following two years (anova p < 0.005), and the duration hospital
stays reduced substantially (from an average of 4.9 ± 10.3 SD before LTOT to 1.5 ±
5.2 SD and 1.1 ± 3.7) in the two following years (anova p < 0.005). Direct related costs
dropped from 12,600 to 2,100 USD/patient/year, and indirect related costs from 7,400
to 1,730 USD/patient/year, representing the major cause of savings [21].
This particular long-term outcome has been further investigated in recent times and
a 63.4% drop in the incidence of lower airways infections was confirmed, thus high-
lighting that these are no longer the main cause of hospitalization in patients with CRF
who are monitored via tele-LTOT at home (Table 15.3). These data were further con-
firmed by anatomical evidence that pneumonia currently represents the least common
180 R.W. Dal Negro
Fig. 15.6 Mean survival in subjects

in tele-LTOT and those in standard care
(n = 886) (see text).
From [26] with permission
Days
LTOT Standard care tele-LTOT
cause of death (2.9%) in severe respiratory patients, while pulmonary embolism and
acute heart failure still represent the most frequent causes (58.8% and 14.8%, respec-
tively) (personal data). Nevertheless, in our clinical practice, only 6% of LTOT pa-
tients who are still admitted 2-3 times/year account for more than 55% of the total
economic burden due to hospitalizations.
In all these experiences the most crucial outcome is still represented by patient sur-
vival. It should be remembered that a couple of decades ago the mean survival for
LTOT patients whose PaO2 level was persistently <60mmHg was 20-40% at the third
year of LTOT [22-23].
In 2004 the mean survival calculated in 631 patients managed via tele-LTOT at
home was 71.4% of patients with CRF due to severe COPD at the third year of the
protocol, and 60.8% after 6 years. Unfortunately, mean survival was much shorter in
patients with CRF due to end-stage lung fibrosis, accounting for only 11.8% of those
still alive at the third year of LTOT: these outcomes are in complete agreement with
those obtained by other authors in the same kind of patients [16, 24-25].
These trends were confirmed in other studies [8]; however, an Australian study on
LTOT showed conflicting results in term of patient survival, even though the causes
of such poor results were not explained by the authors [26]. In the same year the joint
ATS/ERS document published the protocol for the management of LTOT patients,
which was quite similar to our program in terms of timing for arterial blood gas con-
trols and the frequency of specialist visits [27].
In 2009 the survival of a cohort of 886 patients suffering from very severe COPD
and receiving LTOT at home was revized over the last ten years. Subjects were divided
in two groups that were matched for age, sex, lung function and daily oxygen use:
group A included patients managed according to the usual protocol for home assis-
tance, and group B contained patients admitted to telemetric daily monitoring. Mean
survival was significantly longer (2.5 times longer) in subjects telemetrically controlled
at home (1239.6 days ± 382.1 SD versus 482.6 days ± 273.9 SD, p<0.01) (Fig. 15.6).
Fig. 15.7 Mean survival in patients managed with standard care and standard care + tele-LTOT
(n = 1192)
Table 15.4 Difference in survival by class of age in the standard care and standard care + tele-LTOT
groups
Age of start (y) SC SC + Tele-LTOT p
40-49 387.2 ± 343.6 2022.5 ± 2365.1 < 0.05
50-59 470.1 ± 500.4 2565.7 ± 1664.2 < 0.001
60-69 912.4 ± 1223.2 1878.5 ± 1361.6 < 0.001
70-79 374.9 ± 500.5 1601.5 ± 1159.9 < 0.001
≥ 80 366.2 ± 463.4 844.5 ± 387.3 < 0.001
Moreover, episodes of heart failure and lower airway infections were less common in
these subjects (17.3 vs 33.0% and 11.3 vs 21.1%, respectively, both p < 0.01), and these
possibly help to explain their longer survival [28]. Gender-related differences in
long-term survival will be considered and discussed in another chapter of this book.
Measured and expected rates of hospitalization were further calculated and com-
pared in two cohorts of subjects managed at home with standard care (n = 612) and
standard care plus tele-LTOT (n = 580). The demographic and clinical characteris-
tics of the two populations are reported in Fig. 15.7, where their similarity is clear.
Mean survival was 435.9 days ± 633.2 SD in those receiving usual care management,
and 1577.9 days ± 1293.8 SD in those also managed via tele-LTOT (p < 0.001). Fur-
thermore, the longer survival for tele-LTOT proved systematic and significant in all
ages, including the elderly, even if it was particularly relevant in younger age brack-
ets (40-49 and 50-59 years) (Table 15.4). Finally, when the rate of hospitalization in
182 R.W. Dal Negro
SC measured Tele-LTOT expected Tele-LTOT measured
1.5
n. admissions/year
-62.3% expected
1.0
0.5
500 1000 1500 2000 2500

Duration (days)
Fig. 15.8 Measured and expected rates of hospitalization per year in the standard care and tele-
LTOT groups: data were normalized by the different duration of groups’ survival
the two groups of patients was normalized by their different duration of survival, a
drop in hospital admission of 62.3% of the expected percentage was calculated in the
tele-LTOT subjects compared with those receiving usual care (Fig. 15.8).
Again, the strict program for tele-LTOT management at home was highly effec-
tive and convenient in terms of major long-term outcomes, such as the hospitaliza-
tion rate, the occurrence of severe infectious comorbidities, and consequently in terms
of cost optimisation.
For these reasons recent results led to the definition of tele-medicine as the future
of outpatient therapy due to the significant cost savings, and because patients at home
may feel more comfortable and actively involved in their own management than hos-
pitalized patients.
In conclusion, scientific interest in tele-medicine for the management of chronic
respiratory diseases at home, and of LTOT in particular, is still on the rise and will
develop further over the next few years.
References
1. Paramelle B, Brambilla C, Geraads A, Rigaud D (1984) Indications et critères de decision de
l’oxygénothérapie de suppléance pour l’hypoxémie chronique. Rev Fran Mal Respir 22-37
2. Dal Negro R, Turco P, Pomari C (1991) Progetto di telemetria per l’home care respiratoria. Ri-
sultati preliminari. Rass Pat App Resp 6:111
3. Refice G, Dal Negro R (1997) Assistenza sanitaria di qualità. Management e Telecomunicazioni

12:37-40
4. Micheletto C, Pomari C, Righetti P, Dal Negro R (1994) A 2-yr health economics survey on 61
subjects in telemetric LTOT: preliminary results. Eur Respir J 7;suppl.18:266
5. O’Donohue WJ Jr, Plummer AL (1995) Magnitude of usage and cost of home oxygen therapy
in the United States. Chest 107:301-2
6. Dal Negro RW et al (2005) Farmacoeconomia 6:349-52
7. Ringbaek TJ, Viskum K, Lange P (2002) Does long-term oxygen therapy reduce hospitaliza-
tion in hypoxemic chronic obstructive pulmonary disease? Eur Respir J 20:38-42
8. Eron K (2010) Telemedicine: the future of outpatient therapy. Clin Infect Dis 15;suppl.2:S224-30
9. Pfeifer M, Wemer B, Magnussen H (2004) Telecare of patients with chronic obstructive airway
diseases. Med Klin 99:106-10
10. Duck A (2006) Cost-effectiveness and efficacy in long-term oxygen therapy. Nurs Times
20:46-50
11. Paré G, Sicotte C, St.-Jules D, Gauthier R (2006) Cost-minimization analysis of a telehome-
care program for patients with chronic obstructive pulmonary disease. Telemed J E Health
12:114-21
12. Gibbons D, Conneelly J, Smith J (2002) An audit of provision of long-term oxygen therapy for
COPD patients. Prof Nurse 18:107-110
13. Bourbeau J, Julien M, Maltais F et al (2003) Reduction of hospital utilization in patients with
chronic obstructive pulmonary disease: a disease-specific self-management intervention. Arch
Intern Med 163:585-91
14. Cardozo L, Steinberg J (2010) Telemedicine for recently discharged older patients. Telemed J
E Health 16:49-55
15. Vitacca M, Bazza A, Bianchi L et al (2010) Tele-assistance in chronic respiratory failure: pa-
tients’ characterization and staff workload of 5-year activity. Telemed J E Health 16:299-305
16. de Toledo P, Jimenez S, del Pozo F et al (2006) IEEE Trans Inf Technol Biomed 10:567-73
17. Polisena J, Tran K, Cimon K et al (2010) Home telehealth for chronic obstructive pulmonary
disease: a systematic review and meta-analysis. J Telemed Telecare 16:120-7
18. Dal Negro RW, Turco P (2005) Telemedicine and LTOT in Italy: a 20-year experience. In: Dal
Negro RW, Goldberg AI (eds) Home long-term oxygen treatment in Italy. Springer, Milan, pp
69-83
19. Eaton T, Lewis C, Young P et al (2004) Long term oxygen therapy improves health-related qua-
lity of life. Respir Med 98:285-93
20. Maiolo C, Mohamed EI, Fiorani CM, De Lorenzo A (2003) Home telemonitoring for patients
with severe respiratory illness: the Italian experience. J Telemed Telecare 9:67-71
21. Dal Negro R, Pomari C, Micheletto C (1995) Ossigenoterapia domiciliare a lungo termine
(OTLT) sotto controllo telematico: aspetti farmacoeconomici. Farmacoeconomia 2:43-6
22. Stuart-Harris C, Flenley DC, Bishop M, Medical Research Council Working Party (1981) Long
term domiciliary oxygen therapy and emphysema. Lancet i:681-6
23. Nocturnal Oxygen Therapy Trial Group (1980) Continuous and nocturnal oxygen therapy in
hypoxemic chronic obstructive lung disease: A clinical trial. Ann Intern Med 93:391-8
24. Strom K, Boman G (1993) Long-term oxygen therapy in parenchymal lung diseases: an ana-
lysis of survival: The Swedish Society of Chest Medicine. Eur Respir J 6:1264-70
25. Chailleux E, Fauroux B, Binet F et al (1996) Predictor of survival in patients receiving domi-
ciliary oxygen therapy or mechanical ventilation. Chest 108:741-9
26. Cranston JM, Nguyen AM, Crockett A (2004) The relative survival of COPD patients on long-
term oxygen therapy in Australia: a comparative study. Respirology 9:237-42
27. Celli BR, MacNee W (2004) Standards for the diagnosis and treatment of patients with COPD:
a summary of the ATS/ERS positivo paper. Eur Respir J 23:932-46
28. Dal Negro RW, Bonadiman L, Tognella S et al (2009) Survival in severe COPD patients on home
LTOT with or without telemonitoring: a 10-year experience. Multidisciplinary Respiratory Me-
dicine 4:107-11
The Value of a Systemic Accreditation Path
16
Massimo Dutto and Nicoletta Palese
Undertaking a path for accreditation or certification has an important value based on the
presence of a third party who supervises the commitments and indicators of the model
and assures stakeholders, especially patients, by adopting a system that embraces all the
national and international security standards. It uses best practices and international
guidelines to create the most appropriate patient route such as standardising the struc-
ture and the way of working in hospitals, in order to ensure that institutions, according
to the highest ideals, carry out their work properly before the professional community,
and that institutions with lower standards are encouraged to improve the quality of their
work. In this way, patients receive the best treatment and tools are available for people
to recognize those institutions that are inspired by the highest ideals in medicine.
Over the years two procedures have been developed: accreditation and certification.
In recent years the concept of quality has become increasingly important in the
market performance/competitiveness of companies and economic and health systems.
Therefore, thanks to medical advances and increased life expectancy, we are facing
an aging general population and an increase in chronic diseases in general, especially
Chronic Obstructive Pulmonary Disease (COPD) and chronic respiratory failure
(CRF). Respiratory diseases are a major cause of death and morbidity in the world and
future expectations envisage an increase in the frequency of deaths from COPD and lung
cancer. The increase in respiratory diseases, especially of chronic and chronic respira-
tory insufficiency (CRI), leads to greater use of both human and financial resources for
the care of patients. The adoption of a quality management model (as per ISO 9001)
for pulmonology ensures that the needs of patients and other stakeholders are trans-
formed into coherent services, designed to maximize their need for care and satisfac-
tion. According to the classical model, the system is based on a statement of objectives
M. Dutto ()
Bureau Veritas Health Department
Milan, Italy
e-mail: massimo.dutto@it.bureauveritas.com
186 M. Dutto, N. Palese
that is consistent with requirements by directing the structure of these objectives, as well
as monitoring control systems to verify the progress and conformity status of the sys-
tem in order to improve it. Everything is supported by a documented and objective sys-
tem of reporting and by a shared organizational model approved by auditing tools.
16.1 Introduction
The value in taking the path to accreditation or certification is based on a third party
who supervises the commitments and indicators of the model and assures stakehold-
ers, mainly patients, by adopting a system that meets all standards on national and
international security. It uses best practices and international guidelines to define the
most appropriate patient route, as well as standardizing the structure and way of work-
ing in hospitals, to ensure that institutions, with the highest ideals, are properly rec-
ognized before the professional community and that institutions with lower standards
are encouraged to improve the quality of their work. In this way, patients receive the
best treatment and people will be able to use tools to recognize those institutions that
are inspired by the highest ideals of medicine. These words were spoken at the Third
Congress of Surgeons of North America in 1912, but are still valid in the light of mod-
ern concepts about acquiring quality standards and continuous improvement, which
always accompanies a change in health issues.
Over the years two procedures have been developed: accreditation and certification.
Accreditation is a professional evaluation conducted by an autonomous and inde-
pendent agency of the health facilities that request it, at regular intervals. This eval-
uation is intended to establish high acceptability standards for health services.
Two situations may lead to this procedure:
• the availability of a healthcare facility to obtain an objective assessment of the qual-
ity levels of its activities;
• the request by the health institution to comply with certain quality requirements,
for admission to the convention with the same institution, in order to ensure qual-
ity standards in the various structures.
The accreditation procedures are characterized as objectively as possible and are
reflected in the definition of a set of criteria that define the expected quality of care,
since they are measurable, repeatable, acceptable, specific and scientifically based.
The certification is a procedure that healthcare companies have borrowed from pri-
vate production companies and it verifies compliance of the organization, structures
and bodily procedures to predetermined quality standards. The certificate depends on
the outcome of the inspection visit and any comparisons stemming from it. To date,
certification in the healthcare sector has been able to better interpret the assessment
of conformity in relation to the safety of patients and, in fact, a health facility that
has not been able to map and measure its risk can not be certified. This new approach,
16 The Value of a Systemic Accreditation Path 187
especially from international certification bodies, ensures specularity with specific

international healthcare accreditation models and reinforces them because the per-
ception of patient satisfaction has become objectified [1].
16.2 Accreditation Throughout the World
In the various countries of the industrialized world several accreditation programs have
been developed over the last century as a means of regulation and control to meet the
increasing expectations of quality provided on the one hand and increased spending on
health on the other hand. The oldest system of accreditation is found in the United States.
It was sponsored by the American College of Surgeons (surgeons from North Amer-
ica) in 1918, in order to standardize the structure and way of working in hospitals, to
ensure that institutions with higher ideals are properly recognized before the profes-
sional community and that institutions with lower standards are encouraged to improve
the quality of their work. In this way, patients receive the best treatment and people will
be able to use tools to recognize those institutions that are inspired by the highest ideals
of medicine. Later, in 1951, the Joint Commission on Accreditation of Hospitals (JC-
AHO, latterly JCAHCO - Joint Commission on Accreditation of Health Care Organi-
zation) was founded to define, through an accreditation manual, good quality standards
for adequate service. At first only the hospital had access to accreditation programs,
which were later extended to all healthcare facilities (clinics, nursing homes, etc.).
In Canada, the Canadian Council of Health Care Facilities Accreditation (formed
in 1958) coordinates programs for the accreditation of health facilities. The program
is voluntary and does not depend on government facilities. The accreditation proce-
dures are similar to those in the U.S., although there is less bureaucracy and greater
involvement of the nursing component. Each year the list of accredited facilities is pub-
lished and those not accredited are not mentioned. Even in Australia the system of ac-
creditation is voluntary and is managed by the Australian Council on Healthcare Stan-
dards (ACHS) since 1974. Among the main features are intensive training, especially
in hospital management, the ability to make general requirements that meet rigorous
standards, and the use of clinical indicators. The main benefits for an accredited fa-
cility are prestige and economic aspects for private bodies. The accreditation visit is
carried out by sector professionals and culminates in a confidential report that is sent
to the hospital management and cannot be used to apply sanctions or incentives.
Based on the Australian model, a hospital services accreditation program was
started in the United Kingdom in 1998, coordinated by scientific societies and pro-
fessional associations, which, starting with a pilot project at some hospitals, was sub-
sequently extended to numerous healthcare facilities. The activity is voluntary.
In recent years, accreditation experiences have been undertaken in many other coun-
tries in Europe, South Asia and America [2].
16.3 Certification and Accreditation in Italy
The quality of health service management shifts the approach from patient to orga-
nizational management, with a view to improving the final result. In the health sec-
tor, in fact, the patient/client is central to the quality of the clinical care pathway: the
demonstrable goal is to fully meet the needs of those who most need the service, with
the lowest cost for the organization, within the limits and guidelines imposed by the
authorities and the buyers.
• The accreditation can be applied in the same way to public and private health fa-
cilities;
• functional requirements for the implementation of institutional accreditation are
different and more than the minimum requirements of authorisation defined by
DPR 14/1/1997 (Table 16.1);
• individual regions and autonomous provinces have the competence to define the
criteria for accreditation and to confer the status of accredited medical facility.
Table 16.1 Conditions of the accreditation model according to DPR 14.1.1997 (Cinotti R. Emilia-
Romagna Regional Healthcare Agency)
Quality management system (quality system)
1. Politics, objectives and activities
2. Organizational structure
3. Human resources management
4. Technological resources management
5. Quality management, assessment, improvement, guidelines and internal regulations
6. Information system
Infrastructure/Technological requirements
1. Seismic protection
2. Fire protection
3. Hearing protection
4. Safety and electrical continuity
5. Accident prevention safety
Specific Requirements (general)
Outpatient care Hospital assistance Residential or semi-residential
assistance
Clinics Hospital areas Day care centres for physical,
Laboratories Surgical department mental and sensorial
Diagnostic imaging Cildbirth area disabilities
Rehabilitation clinics Reanimation and intensive therapy Mental health centres
Day hospital Senior centres
Pharmacy and medical device
management
Pharmacy service
Disinfection and sterilization service
Mortuary service
The purposes of accreditation provide a dynamic nature to quality requirements,

as they must be constantly updated as a result of changes in technology and health
practices. Requirements should be determined according to the effectiveness of care
processes and patient safety; they must include action planning and staff training,
aimed at developing, maintaining and improving standards of quality and the proper
use of the services, treatments and technologies.
Developing a culture of evaluation and improvement between health profession-
als is the fundamental purpose of accreditation and certification programs. It is nec-
essary that the establishment and operation of the authorization, accreditation and con-
tractual agreement, are, in practice, an articulated, closely related and consistent
sequence of gradual levels of quality assurance of health services [3].
Another aspect that has to be considered is the recognition/credibility of accred-
itation systems at national and European level. The evolution of the mobility of cit-
izens, both within the national territory and in the European area, leads to the in-
evitable development of systems capable of guaranteeing the content of the
procedures, their level of safety and appropriateness, and scientific and environmen-
tal protection of the rights of citizens.
16.4 Certification of the Quality of Government

Health Services
In recent years the concept of quality has become increasingly important in the mar-
ket performance/competitiveness of companies and economic systems and health.
Quality must be understood in a global sense, starting with service and production
systems, until integrated structural quality is achieved with all the infrastructure that
interacts with it. The quality of a facility is defined as the ability to meet user needs,
which are different in relation to a product or service’s use.
In Europe the decisive impulse for the adoption of quality systems by healthcare
facilities was due to the single market, which broke down the barriers between dif-
ferent countries, and imposed the assurance of quality standards that would guaran-
tee target companies within the same context.
The quality standard is objective as validated and guaranteed by certificates that
are issued by certification bodies, through a transparent process of compliance with
internationally agreed standards.
ISO 8402 defines quality as the overall performance and characteristics of a prod-
uct or service that denotes its ability to satisfy stated or implied needs, which results
in the compliance of a product or service to specific customer requirements and char-
acteristics of perception of the company in the eyes of customers.
Through the quality assurance system certification, compliance to the organiza-
tional or service model is guaranteed to provide quality requirements.
The literature says that factors that lead a healthcare organization to be certified
differ:
• improvement in quality and effectiveness;
• improvement in internal controls and efficiency;
• patients and, in a wider sense, the interested parties;
• expansion into new contexts and national and international comparisons;
• keeping up with best practices;
• demonstrations of professionalism.
From a regulatory standpoint the quality world has internationally recognized in-
dicators and precise references. The ISO (International Standardization Organization)
is a worldwide standard organization. Through its technical committees, regulations
are developed for different production areas by representatives of several member
countries.
The certification process usually follows a path common to all international
health organizations: there is an initial stage of certification, followed by annual main-
tenance. The term quality certification is a definite assurance to the user of the serv-
ice, which means that the set of characteristics, procedures and stages of production
meet the requirements that users expect from that service [2].
16.5 Certification and Verification of the Model Applied

to ISO 9001 in Pulmonology
As a result, thanks to medical advances and increased life expectancy, we are fac-
ing an aging general population and an increase in chronic diseases in general and
especially COPD and CRF. Respiratory diseases are a major cause of death and mor-
bidity in the world and future expectations envisage an increase in the frequency
of deaths from COPD and lung cancer. Causes of death for these groups represent
more than 14% of annual deaths in Italy, and the impact of respiratory diseases on
Italian hospitals each year exceeds 6.5% of inpatient admissions. The increase in
respiratory diseases, especially CRI, leads to the increased use of human and finan-
cial resources for the care of patients. Therefore it is important not to overlook the
prevention, diagnosis and development of an adequate organizational model offer-
ing to the patient a continuous therapeutic diagnosis between the hospital and lo-
cal structures.
Actually in Italy both hospital services and outpatient services have assumed a par-
ticular importance in the prevention, diagnosis and treatment of respiratory diseases.
Once these structures were in fact appointed to the widespread control of tuberculo-
sis, but now, in addition to continuing to play the old tasks, they have become very
important in the prevention, diagnosis and treatment of respiratory diseases and serve
as a filter for admissions work.
In this perspective, the Support Service Respiratory Homecare Service is per-

formed at a patient’s home in order to guarantee a significant improvement in the qual-
ity of life and survival of patients, through specific skills and adequate technologies.
This also allows costs to be reduced.
Consistent with its approach, as explained in the preceding paragraphs, the adop-
tion of a quality management model (as per ISO 9001) for pulmonology ensures that
the needs of patients and other stakeholders are transformed into coherent services,
designed to maximize their need for care and satisfaction [4].
According to the classical model, the system is based on the statement of ob-
jectives that is consistent with requirements for the structure of these objectives,
and there is a monitoring control system to verify the progress and conformity sta-
tus of the system in order to improve it. Everything is supported by a documented
and objective system of reporting and a shared organizational model, approved by
auditing tools. The development of pulmonology services, according to the prin-
ciples of ISO 9001, and according to the methodology of “plan, do, check and act”
through data, indicators, and objective elements, helps in promoting an organiza-
tion model for diagnosis and care of patients. This also makes it possible to help
patients’ families.
A certified quality system ensures consistent and measurable objectives, through
appropriate indicators, for example in the pulmonary area:
• uniform performance throughout the local healthcare facility;
• reduction in waiting lists;
• increase in the supply of performance;
• regional reference points for patients;
• reduction in hospital admissions;
• containment and control of healthcare costs;
• improvement in patients’ quality and life expectancy through:
- educational and support intervention for the patient’s family;
- optimized therapy;
- interventions to maintain or improve the level of autonomy of the individual and
the family;
- reduced hospital admissions and bed days;
- % of internal consulting paid on time;
- % of medical records delivered within 15 days;
- number of complaints by users;
- % of patients with respiratory failure transferred to intensive care;
- % of patients with COPD undergoing spirometry;
- % of biopsies insufficient or non-diagnostic for bronchoscopy;
- number of hours of internal training;
- handling of complaints, number of non-conformities;
- prevention and treatment of pressure ulcers [5].
References
1. Barbarino F (2003) Capire i processi. Come organizzarli, gestirli e migliorarli, UNI, Trento
2. Palese A (2010) Implementazione e certificazione dei sistemi di gestione per la qualità nei ser-
vizi sanitari. Università di Trieste, Trieste
3. Bosset LJ (1991) Quality function deployment, ASQC Quality Press, Milwaukee
4. Dal Negro R, Farina M (2005) L’approccio e la gestione per processi in pneumologia, Sprin-
ger, Milan
5. Dal Negro R, Farina M (2001) La gestione per la qualità in pneumologia. Aspetti applicativi se-
condo il modello ISO 9001:2000, Springer, Milan
Section IV
The Outcomes
Clinical Outcomes
17
Claudio Micheletto
Since the introduction of oxygen as a therapeutic agent many years ago, much has
been learned regarding the detrimental effects of hypoxemia and the beneficial im-
pact of oxygen therapy on reversing hypoxemic complications in patients with ad-
vanced lung disease. Hypoxemia contributes to reduced quality of life, diminished
exercise tolerance, reduced skeletal muscle function, and ultimately an increased risk
of death [1].
Nowadays oxygen is regarded as an effective prescription drug for hypoxemic pa-
tients and long-term oxygen therapy (LTOT) has emerged as one treatment that clearly
increases the length and quality of life in patients with advanced stable chronic ob-
structive pulmonary disease (COPD) and chronic hypoxemia.
On the other hand, treatment of severe hypoxemia with LTOT is one of the few
interventions shown to prolong life in hypoxemic COPD patients [1]. This statement
is based upon a large body of science that began in the mid-1960s and became firmly
established by two major controlled clinical trials in COPD patients: the Nocturnal
Oxygen Therapy Trial (NOTT) and the British Medical Research Council (MRC) [2-
3]. Successively, LTOT has been used also for respiratory failure caused by other pul-
monary diseases, such as kyphoscoliosis, lung fibrosis and pulmonary embolism.
Nevertheless, also in our experience (Fig. 17.1) COPD remains the major cause of
chronic hypoxia requiring LTOT.
Nowadays, the large numbers of patients receiving supplemental oxygen as treat-
ment and the high costs incurred in providing oxygen therapy necessitate the prac-
titioner to be knowledgeable of the real effects of LTOT.
C. Micheletto ()
Department of Medicine – Respiratory Unit
Mater Salutis Hospital
Legnago (VR), Italy
e-mail: claudio.micheletto@aulsslegnago.it
196 C. Micheletto
Fig. 17.1 Condition justifying LTOT

in the last ten years (1995-2004, n = 309)
COPD Tuberculous sequelae

Fibrosis Neoplasm
Kyphoscoliosis Pneumoconisis
Pulmonary embolism
17.1 Effect of Long-Term Oxygen Therapy on Mortality
Supplemental oxygen is a well-established therapy with clear evidence of its benefits

in patients with severe resting hypoxemia, which is defined as a room air PaO2 ≤ 55
mmHg or ≤ 59 mmHg with signs of right-sided heart strain or polycythemia [4].
Oxygen was the first treatment shown to prolong life in people with COPD [2-3].
Current recommendations for prescribing LTOT (Table 17.1) are based on results from
two randomized trials in patients with COPD published almost 30 years ago: the Noc-
turnal Oxygen Therapy Trial (NOTT) and the Medical Research Council (MRC) study
[2-3]. The MRC study was a randomized controlled oxygen therapy trial designed
to assess whether use of supplemental oxygen for 15h/d (including overnight) com-
pared with no supplemental oxygen yielded a survival advantage over ≥ 3 years. Re-
sults in 87 subjects showed that supplemental oxygen use improved survival (55%
vs 33% in controls; p < 0.05).
Further evidence of an enhanced survival benefit with supplemental oxygen is pro-
vided by the National Institute of Health NOTT study. The study assessed whether
continuous supplemental oxygen improved survival compared with nocturnal oxy-
gen. The study enrolled 203 subjects. Over a mean follow-up period of 19.3 months,
use of continuous oxygen provided a significant survival benefit (p = 0.01) with a rel-
ative risk of death of 1.94 (95% CI) with use of nocturnal oxygen compared with con-
tinuous oxygen. These studies showed that stable COPD patients, recruited accord-
ing to the pre-stablished inclusion criteria, live longer when they receive domiciliary
LTOT for more than 15 hours/day.
Nevertheless, more recent clinical studies have indicated a higher mortality rate
than that shown in earlier studies, especially in male subjects [5]. MacNee et al. found
that patients with more severe COPD may not derive a significant benefit from LTOT
17 Clinical Outcomes 197
Table 17.1 Measured and expected rates of hospitalization per year in the standard care and tele-
LTOT groups: data were normalized by the different duration of groups’ survival
Based on randomized controlled clinical trials Based on less evidence
Continuous oxygen use Intermittent oxygen use
Resting PaO2 ≤ 55 mmHg Desaturation (SpO2 ≤ 88%) with activity
Resting PaO2 of 56-59 mmHg with anyone Desaturation (SpO2 ≤ 88%) at night
of the following:
- Dependent edema
- P pulmonale on the electrocardiogram
(P wave exceeding 3 mm in standard lead II,
III or a VF)
- Polycythemia (hematocrit > 56%)
SpO2 = oxygen saturation by pulse oximetry.
[6] and Soler et al. stated that hypoxemic patients with COPD treated with LTOT seem
to have the same life expectancy as non-hypoxemic patients with COPD [7].
In a 10-year ANTADIR observatory analysis the mean survival for patients with
chronic bronchitis is 3 years, while it is slightly better for patients with bronchiec-
tasis and asthma and worse for those with emphysema [8]. Patients with kyphosco-
liosis and a neuromuscular disease have the longest survival, while patients with tu-
berculosis sequelae experience the same survival as COPD patients (3 years).
Prognosis is the worst in patients with pneumoconiosis or fibrosis: 50% of these pa-
tients die during the year following the beginning of home treatment. The associa-
tion of an obstructive lung disease worsens the prognosis of patients with kyphosco-
liosis or neuromuscular disease and tends to bring the survival rate of the patients with
pneumoconiosis or fibrosis closer to that of COPD patients. In COPD, male sex, older
age, lower body mass index (BMI), FEV1 percent predicted, PaO2, and PaCO2 are
independent negative prognostic factors. For tuberculous sequelae and kyphoscolio-
sis, female sex, younger age, a high BMI, PaO2, and PaCO2 (and for kyphoscoliosis
a higher FEV1/vital capacity [VC] ratio) are all independent favorable prognostic fac-
tors. In pulmonary fibrosis, lower PaO2 and PaCO2 values, lower VC percent pre-
dicted, and higher FEV/VC ratio are negative prognostic factors [8].
The experience of our group involves many LTOT patients followed for twenty
years; these patients have been managed with a special home care protocol includ-
ing continuous telemetric control of O2-saturation, heart frequency and oxygen con-
sumption. We have analysed the last ten years of work [9]: in 309 patients the over-
all mean age when the LTOT started was 70.7 years ± 13.7 SD and the corresponding
mean age when LTOT ended was 76.8 years ± 7.7 SD (Fig. 17.2).
Figure 17.3 shows that females (30.4% of subjects) usually start LTOT almost two
years later than males, and that the mean life duration of LTOT subjects is shorter than
expected for both males and females in Italy (ISTAT data). Unlike females, LTOT
males prove much closer to the ISTAT value in term of mean life duration.
198 C. Micheletto
78 Overall Female Male

77
76
75
74
Age (years)
73
72
71
70
69
68
67
At the beginning At the end
Fig. 17.2 Overall mean patient age upon admission to the telematic LTOT program and at the end
of LTOT; the latter value corresponds to the mean patient age at death in more than 98% of cases.
The corresponding mean ages for males and females are also reported
85 Mean expectancy for females
80 Mean expectancy for males
75
Age (years)
70
65
0 M F M F
When entering LTOT At the end of LTOT
Fig. 17.3 Comparison of mean male and female ages at the beginning and at the end of telemetric
LTOT compared with the corresponding mean life duration in Italy (ISTAT) (n = 309)
The overall male duration of telemetric LTOT is 3.6 years ± 2.8 SD, range 0.12-
13 years. A sample of 886 patients suffering from severe COPD and following al
LTOT program for the last ten years managed by our specialist center was evaluated
for survival (expressed in days from the start of the LTOT program) [10]. Subjects
were divided into two subgroups that were well matched in terms of sex, age, lung
function and daily oxygen consumption: group A, patients managed with conventional
protocol for home assistance, and group B, patients managed with telemetric daily
Fig. 17.4 Survival in patients managed

with a conventional protocol for home
assistance and patients managed
with telemetric daily monitoring
Days
LTOT Standard care tele-LTOT
p<0.01 p<0.01
600
p<0.01
400
Days
200
0
0 M F M F
Usual LTOT Tele-LTOT
Fig. 17.5 Survival (days) by sex in subjects admitted to usual or tele-LTOT (mean ± SD)
monitoring of clinical signs and exacerbation occurrence. Survival proved signifi-

cantly shorter (2.5 times) in group A (patients without telemetric management of
LTOT) compared to group B (patients with telemetric management of LTOT) (482.6
days ± 273.9 SD vs 1239.6 days ± 382.1 SD, p < 0.01, Fig. 17.4). In group B, both
the incidence of episodes of heart failure and of lower airway infections were signif-
icant lower (17.3 vs 33.0 % and 11.3 vs 21.1 %, respectively).
While males had a longer survival in the traditional protocol of management, fe-
males had a significantly longer survival when managed according to the telemetric
protocol of long-term LTOT (1166.4 days ± 556 SD vs 1433.7 days ± 656.3 SD, p
< 0.01, Fig. 17.5).
In contrast with the results of the MRC and NOTT studies, supplemental oxygen
has not been shown to improve survival in patients with COPD and moderate hypox-
emia [11-14]. However, these studies enrolled small numbers of subjects. Gòrecka
et al. [13] randomly assigned 135 patients with a resting room air PaO2 of 56 to 65
200 C. Micheletto
mmHg to receive supplemental oxygen for > 17h/d (to raise PaO2 to ≥ 65 mmHg) or
no supplemental oxygen. Over a mean observation of 40.9 months, cumulative sur-
vival in the treatment and controls groups did not differ significantly. Furthermore,
no survival difference was observed for patients using supplemental oxygen for more
than 15 h/day vs those using it for shorter periods.
Haidl et al. [14] randomly assigned 28 patients with COPD and moderate hypox-
emia (mean PaO2 66.5 ± 6.3 mmHg) to supplemental oxygen (2 L/min for > 15 h/d)
or no supplemental oxygen for 3 years. The mortality rate was similar in both groups.
17.2 Effect of Long-Term Oxygen Therapy on Pulmonary

Hemodynamics
Alveolar hypoxia is an important contributory factor to the development of pulmonary

hypertension (PH) in patients with severe COPD. Factors contributing to the devel-
opment of PH (Fig. 17.6) at an anatomic level include emphysematous obliteration
of the pulmonary capillary bed, thromboembolic disease, and pulmonary vascular
constriction and remodelling [15].
Pulmonary vasculature of COPD patients with PH is characterized by luminal nar-
rowing due to thickening of the intima, along with arteriolar muscularization. At a
functional level, a key factor contributing to the development of increased pul-
monary vascular resistance is hypoxic pulmonary vasoconstriction, driven by alve-
olar hypoxia [16]. PH, a common complication of severe COPD and chronic hypox-
emia, is associated with increased mortality, exacerbation rate and length of hospital
stay, independent of the degree of airflow limitation. LTOT is a proven therapy for
chronic hypoxemia with PH.
The first trials using LTOT for severe COPD patients assessed also its effects on
pulmonary arterial pressure (PAP) with very encouraging results. In the MRC study
The caregiver
Pulmonary
Polycythaemia Systemic inflammation
hypertension
Endothelial dysfunction
Fig. 17.6 Factors contributing to the development of pulmonary hypertension

[2] patients breathing with oxygen for 15 hours/day showed the stabilization of PAP
during almost two years of treatment, while in the control group without oxygen ther-
apy, PAP increased by 2.8 mmHg per year. In the NOTT trial [3], patients treated with
continuous oxygen (18 hours/day) demonstrated a fall in PAP by 3 mmHg, whereas
no change in PAP was observed in patients receiving oxygen for 12 hours.
Weitzenblum et al. [17] evaluated 16 patients with severe COPD (mean FEV1 =
0.89 L) and hypoxemia (mean PaO2 = 59.3 mmHg) over a period of 78 months. PAP
was measured by right-sided hearth catheterization before and twice after initiating
supplemental oxygen for > 15 h/d to achieve a PaO2 ≥ 65 mmHg. Supplemental oxy-
gen reversed a pre-treatment trend toward worsening pulmonary hypertension. Be-
tween the baseline measurement and the first post-oxygen catheterization, mean PAP
pressure rose by 1.47 mmHg, whereas over the ensuing 31 months, mean PA pres-
sure fell by 2.15 mmHg per year.
In the longest hemodynamic study of patients with COPD and hypoxemia (mean
PaO2 = 55 mmHg), receiving supplemental oxygen for a mean of 14.7 h/d, Zielin-
ski et al. [18] measured PAP serially for up to 6 years. Study conclusions were that
LTOT for 14 to 15 h/d resulted in a small reduction in pulmonary hypertension af-
ter the first 2 years followed by a return to initial values and subsequent stabilisation
of PAP over 6 years. The long-term stabilisation of pulmonary hypertension occurred
despite progression of the airflow limitation and of hypoxemia.
Cor pulmonale is defined as hypertrophy, dilation, or dysfunction of the right ven-
tricle (RV) due to pulmonary hypertension resulting from disorders and diseases of
the respiratory system. Cor pulmonale is common and accounts for approximately
80,000 deaths every year in the United States. It may result from one of numerous
heterogeneous processes, all of which lead to a common clinical picture: of these
processes, COPD accounts for the great majority of cases [19].
Oxygen therapy should be considered as a primary means of reducing RV after-
load in hypoxemic patients with cor pulmonale. In addition, oxygen therapy relieves
renal vasoconstriction and improves oxygen delivery to critical organs, including the
heart and brain [20]. One of the beneficial effects of oxygen therapy is the elimina-
tion of alveolar hypoxia, thus preventing the progression of PH and development of
clinical signs of cor pulmonale [21].
17.3 Effect of Long-Term Oxygen Therapy on Sleep
Sleep quality is poor in patients with COPD: nocturnal oxygen desaturation (NOD)
has been frequently reported with an awake PaO2 > 60 mmHg [4]. Subjective com-
plaints include difficulty falling and staying asleep, morning tiredness, early awak-
enings, and excessive daytime sleepiness. Recent American Thoracic Society guide-
lines [22] for the diagnosis and treatment of COPD recommended increasing oxygen
202 C. Micheletto
flow by 1 L/min during sleep in patients undergoing LTOT to prevent nocturnal oxy-
gen desaturation. This phenomenon was more frequent in the blue bloater type of
patients.
There are several mechanisms that may be responsible for nocturnal desaturations
in patients with COPD. The minute ventilation decreases during sleep similarly in
both normal subjects and COPD patients. The majority of desaturations appear dur-
ing rapid eye movement sleep. Irregular breathing, especially shallow rapid breath-
ing that increases physiological dead space ventilation, and hypoventilation are re-
sponsible for that phenomenon [23]. The decreased activity of intercostal muscles and
the increase of upper and lower airway resistance additionally decrease alveolar ven-
tilation. Resetting of respiratory control to higher PaCO2 and lower PaO2 during sleep
also reduces ventilatory response to blood gas disorders [24].
The absence of a cough reflex during sleep in patients with disturbed mucociliary
clearance increases the ventilation/perfusion imbalance due to mucus retention in the
small airways. Hypoventilation and the increase of the ventilation/perfusion ratio re-
sults in transient hypoxemic episodes, mainly during rapid eye movement sleep [25].
The clinical importance of nocturnal desaturation in COPD patients is still under
debate. In patients with isolated NOD, Fletcher et al. [26] showed a downward trend
in PAP pressure (-4 mmHg) with supplemental oxygen therapy compared with an in-
crease (+4 mmHg) in the control group. Desaturators had higher pulmonary artery
pressure (PAP) at rest and during exercise [27] During a 3-year follow-up period, de-
saturators treated with oxygen during sleep showed a decrease in PAP, contrary to de-
saturating control patients in whom PAP increased [28] and who also had a shorter
survival rate [29].
However, a paper by Chaouat et al. [30] did not confirm that nocturnal desatura-
tions in COPD patients with diurnal PaO2 > 55 mmHg resulted in a permanent in-
crease of PAP.
Generally, it was found that the level of PaO2 during the day correlates well with
nocturnal desaturations [31]. However, there are large individual variations in noc-
turnal hypoxemia in COPD patients. Plywaczewski’s data [32] confirm that it is rather
difficult to predict nocturnal desaturations from spirometric indexes and from the di-
urnal PaO2. The best predictor of nocturnal desaturation was diurnal PaCO2.
In summary, around half of COPD patients undergoing LTOT experience nocturnal
hypoxemia even though they are breathing oxygen at a flow that ensures satisfactory
oxygenation during the day. The desaturation during sleep may be expected in patients
with a PaCO2 of > 45 mmHg and a PaO2 of < 65 mmHg while breathing oxygen. Sleep-
related oxygen desaturation may also be present in patients not qualifying for conven-
tional LTOT, i.e. in patients with a diurnal PaO2 of > 55 ± 60 mmHg [33].
Nocturnal oxygen therapy (NOT) could be justified if isolated nocturnal hypox-
emia had deleterious effects on life expectancy, which has not been convincingly
demonstrated [28]; and on pulmonary hemodynamics, which is rather controversial.
The results of two initial studies [34-35], suggesting an increased risk of developing
pulmonary hypertension in nocturnal desaturators, without marked daytime hypox-
emia, have not been confirmed in a more recent study [36] including a larger group
of patients. This study has shown that NOT given to COPD patients not justifying con-
ventional LTOT, but exhibiting sleep-related oxygen desaturation, did not alter the
evolution of pulmonary hemodynamics. The most relevant result of this study was
the absence of significant changes in pulmonary hemodynamics in either group. Au-
thors concluded that the prescription of nocturnal oxygen therapy in isolation is prob-
ably not justified in chronic obstructive pulmonary disease patients.
17.4 Effect of Long-Term Oxygen Therapy on Exercise

Performance
In severe COPD, V/Q mismatching and peripheral oxygen extraction are increased,
and dynamic hyperinflation contributes to alveolar hypoventilation, with resultant ex-
ertional hypoxemia [19]. Desaturation with exercise appears to predict increased risk
of mortality, but the role of supplemental oxygen in this area is uncertain. It has been
demonstrated that supplemental oxygen during exercise results in acute improvements
in exercise tolerance and dyspnea in some patients with COPD with mild hypoxemia
at rest [37]. However, it has not been clarified in which type of patients with COPD
such acute improvement in exercise tolerance and dyspnea is more prominent. More-
over, it is difficult to predict in which patients’ oxygen inhalation will be effective
or more prominent than in others [38]. Important challenges in ascertaining the ef-
fectiveness of supplemental oxygen during activity in patients with COPD are the lack
of uniform criteria for defining exertional desaturation and standardized exercise pro-
tocols. Threshold values for oxygen desaturation range from 88% to 90%, and rela-
tive declines vary from 2% to 5% in published investigations.
It has been suggested that the mechanisms leading to improvement in exercise tol-
erance as a result of supplemental oxygen are multifactorial. These factors include
relief of dyspnoea, prevention of desaturation during exercise, improvement in pul-
monary hemodynamics, reduction of ventilation and associated dynamic hyperinfla-
tion, and improved oxygen delivery and oxidative metabolism in respiratory and pe-
ripheral muscles during exercise [38-40].
Fujimoto et al. confirmed that oxygen inhalation significantly increased the ex-
ercise performance of patients with COPD who showed mild hypoxemia at rest [41].
In the study the improvement in exercise performance with oxygen was more promi-
nent in the moderate-to-severe groups than in the mild group, and correlated nega-
tively with %FEV1, but was not associated with PaO2 at rest or the degree of desat-
uration during the walking test. The Fujimoto study findings suggest that oxygen
inhalation results in greater improvement in exercise performance by patients with
204 C. Micheletto
COPD showing severe airflow obstruction, even though these patients may show mild
hypoxemia at rest or during exercise.
It has been demonstrated that supplemental oxygen results in acute improvements
in exercise tolerance and breathlessness in patients with COPD who show exercise
hypoxemia [42], but this phenomenon has not been sufficiently examined in patients
without exercise hypoxemia.
Somfay et al. [43] recently demonstrated that supplemental oxygen significantly
reduces dyspnoea scores, dynamic hyperinflation assessed from inspiratory capac-
ity manoeuvre results, ventilation, and respiratory frequency during exercise also in
non-hypoxemic patients with severe COPD. This improvement in exercise capacity
was found to correlate with the reduction in dynamic hyperinflation. Dynamic hy-
perinflation, which readily develops in patients with COPD with severe airflow ob-
struction and hyperinflation, has a deleterious mechanical effect on the respiratory
muscles, contributes to a sensation of breathlessness, and limits exercise capacity [44].
It is therefore not surprising that the effect of oxygen was most prominent in patients
with severe airflow obstruction.
17.5 Effect of Long-Term Oxygen Therapy

on Cognitive-Neurological Dysfunction and QoL
Neurocognitive dysfunction appears to be relatively common in severe COPD pop-

ulations, and appears to increase in prevalence with impairment in gas exchange [45].
Patients with severe COPD suffer from cognitive impairment, anxiety and depression,
which is more common than in a control population.
Thus many factors, not only social and physical, but also patients’ expectations
and their hopes and fears may contribute to impaired health status in patients with
severe COPD. Exercise dyspnoea may increase anxiety and lead to loss of control over
their disease. It has been shown that although 50% of the variance in a disease-spe-
cific quality of life questionnaire can be explained by cough, wheeze, walking dis-
tance, and anxiety, which still left 50% of the variance in the health score attributa-
ble to other factors [46]. The reason for the psychological dysfunction in patients with
chronic hypoxemia is largely unknown. It is unlikely that direct effects of hypoxia
on brain metabolism are important, and some action on brain neurotransmitters, cou-
pled with the effects of aging in this population, are more probable [46].
It is very difficult to evaluate the possible relationship between neuropsychiatric
impairment and LTOT. In chronic hypoxemic COPD patients LTOT after six months
of treatment was found to improve general alertness, motor speed, and hand grip but
not emotional status or the quality of life [47]. Another study reported a slight pos-
itive influence of neuropshychological function, cerebral blood flow velocity and au-
tonomic function in COPD patients after 3 months of LTOT [48]. Thakur et al. found
supplemental oxygen to be protective against, or capable of ameliorating, neurocog-

nitive dysfunction [49].
Several studies have shown that quality of life (QoL) is impaired in patients with
COPD and hypoxemia [50]. Furthermore, in patients with moderate-to-severe hypox-
emia, the quality of life score is related to the degree of hypoxemia when measured
using a disease-specific questionnaire [51]. However, few studies have addressed the
impact of LTOT on QoL, this is mainly due, for ethical reasons, to the difficulty in
incorporating into the study a placebo control group. In an ancillary study to the
NOTT trial, in chronic hypoxemic COPD patients LTOT after six months of treat-
ment was found to improve general alertness, motor speed, and hand grip but not emo-
tional status or the quality of life [52]. Okubadejo [53] and other investigators have
reported similar results, detecting no change in the QoL of patients with COPD af-
ter 6 months of LTOT through oxygen concentrators. Conversely, there are some re-
ports of improved QoL after LTOT [54]. Anderson et al. [55] showed improved HRQL
in patients receiving liquid oxygen treatment and deterioration in those using con-
centrators in conjunction with small oxygen portable cylinders for mobility.
QoL can also be impaired by erectile impotence, which is commonly encountered
in male patients with respiratory failure and hypoxia. In the Aasebo study, 42% of
the patients experienced reversal of sexual impotence during LTOT: responders
showed a significant increase in arterial pO2 and serum testosterone, and a decline
in sex hormone binding globulin compared to non-responders [56]. The sparse data
on this topic warrants the use of oxygen for trying to improve COPD patient’s men-
tal function.
17.6 Effect of Long-Term Oxygen Therapy on Hospitalization
Since the cost of home oxygen therapy is high, demonstration of any economical ad-
vantage from a reduction in hospitalization related to use of LTOT is important. An
early study from the 1970s and two recent studies, all including a small number of
patients acting as their own control, have indicated that LTOT decreases hospitaliza-
tions [57-58]. However, MRC study, which had a randomized-control group, failed
to confirm this advantage of LTOT [2].
Today, it is considered unethical to undertake placebo-controlled studies in COPD
patients with chronic hypoxemia. Conversely, studies with patients acting as their own
control may be biased by the fact that frequent hospitalizations and the decision to
prescribe LTOT are interrelated; physicians may be more likely to initiate LTOT in
patients with frequent hospitalizations rather than in patients with a stable condition.
A reduction in hospitalizations after initiation of LTOT could therefore simply reflect
a regression to the mean phenomenon, a bias that has not been focused on in previ-
ous studies [57-58]. Taking this into account, the effect of LTOT on hospitalizations,
206 C. Micheletto
2.5 COPD Fibrosis
2.0
1.5
1.0
0.5
0
1 year before 1st year 2nd year 3rd year
40
35
30
25
20
15
10
5
0
1 year before 1st year 2nd year 3rd year
Fig. 17.7 Frequency and duration of hospitalization before and during three years of telemetric LTOT
in a larger study with patients acting as their own control, was investigated by Ring-
baek [59]. In addition, given that not all patients use oxygen for the recommended
number of hours (at least 15 hours daily), the authors investigated whether compli-
ance with hours spent on oxygen had an impact on hospitalization. Authors concluded
that in hypoxemic chronic obstructive pulmonary disease patients, LTOT is associ-
ated with a reduction in days spent in hospital and that the beneficial effect of long-
term oxygen therapy on hospitalization seems to reflect an effect of therapy per se
and not a regression to the mean phenomenon [59]. Similar data were found also by
our group [60]: by analysing the year before LTOT and the three following years of
active telemetric LTOT, a substantial drop of hospital admissions was seen, particu-
larly for COPD versus fibrotic patients (Fig. 17.7).
Nevertheless, in fibrotic patients the total number of in-days did not drop signif-
icantly. These peculiar trends seem to suggest that, even though some admission can
be avoided during LTOT also in fibrotic patients, when clinical condition precipitates
leading to an unavoidable hospitalization, the duration of their hospital stay cannot
be reduced because, unfortunately, they are proceeding towards the end stage con-
dition of their lungs.
17.7 Effect of Long-Term Oxygen Therapy on Polycythemia
COPD has long been recognized as an important cause of secondary polycythemia.

When present in COPD, polycythemia can contribute to the development of pul-
monary hypertension, and leads to pulmonary endothelial dysfunction, reduced
cerebral blood flow, hyperuricaemia and gout, and increased risk of venous throm-
boembolic disease [61-64]. Recent studies [65-66] have shown in severe COPD pa-
tients an high prevalence of normochromic normocytic anemia, which is character-
istic of chronic inflammatory diseases.
The low levels of hemoglobin appear to be due to resistance to the effects of ery-
thropoietin, the concentration of which is elevated in these patients [67]. In our re-
cent study [68] Hb tended to normalize during LTOT only in subgroups with basal
blood Hb > 15 g/dL (anova p < 0.001), while anemic subjects (Hb < 13 g/dL) showed
progressive but not significant changes in Hb in the same period (anova = 0.5). Mean
survival of patients was independent of the original Hb blood concentration. These
results are suggesting the presence of an Hb-dependent gradient in LTOT effect on
Hb itself and on PaCO2, which proves independent of the original impairment of
blood gases and of its effects on oxygenation.
In conclusion, LTOT is the only intervention known to increase life expectancy
in such patients. It also improves quality of life, especially when used in conjunction
with pulmonary rehabilitation. Specific benefits include amelioration of cor pul-
monale, enhanced cardiac function, increased body weight, reversal of polycythemia,
improved neuropsychiatric function and exercise performance, reduced pulmonary
hypertension, improved skeletal-muscle metabolism, and possible reversal of sexual
impotence. In addition, use of LTOT reduces the need for hospitalization.
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Humanistic Outcomes and Quality of Life
18
Mauro Carone and Sabina Antoniu
18.1 Introduction
The prevalence of chronic respiratory failure (CRF) is currently increasing. This is

due to the fact that CRF is the remote consequence of smoking exposure even in ex-
smokers, and also to the fact that there is a progressive increase in average life ex-
pectancy in western countries. CRF impacts negatively on the functioning of the lungs
as well as on other organs, and such negative influences can be measured objectively
with various diagnostic tests or subjectively, from the patient’s overall point of view,
by quality of life assessment.
The most common cause of CRF is chronic obstructive pulmonary disease (COPD):
such patients develop chronic hypoxia and have a severely impaired lung function, their
forced expiratory volume in 1 second (FEV1) being generally not more than one litre
[1-3]. It was demonstrated that under such circumstances, their life expectancy is ap-
proximately 4 years and decreases to about 2 years when FEV1 is about 0.5 litres [4].
Long-term oxygen therapy (LTOT) is the only therapeutic intervention demon-
strated to improve survival in patients with severe hypoxemia, adding about 3-5 years
of life [1-2, 5].
Severe lung function impairment and the presence of severe hypoxemia are
demonstrated to impact negatively on patients’ daily activities and well-being as far
as making them feeling severely disabled [6]. In fact, CRF was demonstrated to im-
pair severely daily activities such as washing, dressing and cooking. From the pa-
tients’ perspective, interference with their health, as reflected in their symptoms and
S. Antoniu ()
University of Medicine and Pharmacy
Pulmonary Disease University Hospital
Iasi, Romania
e-mail: sabinaantoniu@yahoo.com
212 M. Carone, S. Antoniu
the disturbance to daily life, is more important than variables such as spirometry or
arterial blood gas analysis [6]. Furthermore, in very severe patients the patient-re-
ported disability and its dynamics under various therapeutic methods may be one of
the main methods of determining disease severity and prognosis [4].
As a consequence, improvement in the well-being and daily functioning of patients
with CRF should be one of the main therapeutic goals. Such outcomes can be best
estimated based on the feedback provided by patients themselves, in a standardized
manner by applying them to validated quality of life questionnaires [7].
Quality of life (QoL), health-related quality of life (HRQoL) and health status (HS)
are terms that are used interchangeably to describe the impact of the disease on daily
functioning [7].
Outcomes such as QoL are currently widely used in various chronic diseases, in-
cluding COPD, to evaluate the impact of the therapies applied. LTOT was one of the
methods in which QoL measurement was applied.
Few studies evaluated the HS in patients undergoing LTOT, and yielded hetero-
geneous results due to the differences in the duration of assessment, the sample size
and the questionnaire(s) used. Other humanistic outcomes considered in clinical stud-
ies involving LTOT were patient adherence, neuropsychological functioning, patient
perceptions and the caregiver’s impact.
This chapter discusses these outcomes and the pending related issues.
18.2 Long-Term Oxygen Therapy and Quality of Life
In CRF, QoL can be measured with generic questionnaires that evaluate the impact
of the disease without taking into account its symptoms; with disease-specific ques-
tionnaires that do so; with both or, more recently, hybrid questionnaires that have
generic and symptom-specific components [7-8].
The generic questionnaire most commonly used in CRF was the SF-36, whereas
as disease specific questionnaires the SGRQ, CRQ and MRF-26 were those found
to be appropriate in this setting [7].
The Medical Outcome Study Questionnaire - Short Form 36 (SF-36) is a generic
questionnaire with 36 items, generating eight domain scores and two component
scores, physical (PCS) or mental (MCS): higher scores indicate a better QoL [9].
The SF-36 was evaluated in patients with LTOT in various settings and it was
found to be an appropriate measure of disease severity and subsequent outcome in
patients with exacerbations or in low income patients [10-11]. In another study, in-
cluding also patients without LTOT, the SF-36 PCS score was independently asso-
ciated with total and respiratory mortality [12].
The Saint George’s Respiratory Questionnaire (SGRQ) is the disease-specific
questionnaire most widely used for various respiratory diseases including asthma,
18 Humanistic Outcomes and Quality of Life 213
Deteriorated versus run-in, ^p=0.01; ^^p=0.03

Improved versus run-in, +p=0.007
Improved versus oxygen alone, *p=0.03; **p=0.002; ***p=0.001
100
90
80
+* ^^
70
***
SGRQ scores %
^
60
**
50
40
30
20
10
0
Symptoms Activity Impact Total
Fig. 18.1 St. George’s Respiratory Questionnaire (SGRQ) scores in patients with hypercapnic
Chronic Obstructive Pulmonary Disease at baseline, after 3 months of oxygen therapy alone, and
after 3 months of oxygen therapy plus nasal pressure support ventilation (NPSV) [14]
COPD and CRF [6]. It is a 50-item questionnaire generating three domain scores for
symptoms, activity and impact, as well as a total score: the higher the score the lower
(i.e. more impaired) the QoL. The fact that there is a minimal clinical important dif-
ference (MCID) of 4 units in the score allows the detections of improvements which
can be reported by the patients [7].
The impact of LTOT initiation was evaluated in a study using SGRQ and in a small
sample of 41 hypoxemic COPD patients (23 patients in LTOT and 18 less severe pa-
tients in the control group) in whom the QoL was evaluated at baseline, 2 weeks, 3
and 6 months. QoL in patients with LTOT was found to be more impaired compared
to that in the control group at all evaluations, and LTOT was not demonstrated to im-
prove it significantly [13].
In another study performed on patients with hypercapnic CRF (Fig. 18.1), QoL
as assessed by SGRQ, the combination of nasal pressure support ventilation and
LTOT was associated with a better QoL as compared to LTOT alone, and this differ-
ence was more than 2 fold the MCID; conversely, LTOT alone was associated with
a significant worsening in the SGRQ impact and total scores [14].
The Chronic Respiratory Questionnaire (CRQ) was the first disease-specific
questionnaire developed for chronic respiratory diseases and has 20 items generat-
ing four domain scores for dyspnoea, fatigue and emotional function, and a total score
[15]. Its MCID is 0.5 units of score.
5 Fig. 18.2 Change in MRF-28 score following

two years of non-invasive positive pressure
ventilation. Negative values indicate improved
health. Adapted from [21]
Change in MRF-28 score
-5
-10
LTOT NIPPV+LTOT
In a study performed on patients who were to start LTOT, QoL was evaluated at
baseline with a battery of questionnaires including CRQ. Those questionnaires were
also applied subsequently at 3 and 6 months. QoL scores were not found to corre-
late with physiological variables such as lung function or blood gas analysis, but were
found to be slightly improved in female patients upon LTOT initiation [16]. In an-
other study CRQ and SF-36 were applied in 114 patients at baseline and 3, 6 and 12
months after starting LTOT. Results found again that females exhibited significant
improvements in fatigue, emotional function and mastery in the CRQ and in some
domains of the SF-36 (role-physical, role-emotional, vitality and mental health),
whereas males improved just in the fatigue domain of the CRQ and in the vitality di-
mension of the SF-36 [17].
A subsequent study on patients with very severe COPD with or without LTOT cri-
teria, demonstrated that this therapy was associated with a significant QoL improve-
ment at 2 and 6 months, whereas in patients not receiving LTOT a progressive de-
cline in HRQL was reported. MCID was detected in 67% of patients receiving
LTOT at 2 months and in 68% of those receiving it at 6 months [18].
The Maugeri Respiratory Failure 28-item Questionnaire (MRF-28) [19] and its 26-
item reduced form (MRF-26) [20] is a more recently developed questionnaire to be
used specifically in the CRF setting. It has three domain scores: activity, invalidity
and cognitive function and a total score. It demonstrated to be a good instrument to
measure QoL impairment in CRF patients irrespective of the underlying disease [19].
Its responsiveness and sensibility were tested versus the SGRQ in COPD patients with
CRF [21]. The SGRQ failed to distinguish between the patients undergoing noctur-
nal intermittent positive pressure ventilation (NIPPV) plus LTOT and those on LTOT
alone. Conversely, the MRF showed this ability: at 2 years of follow-up it showed that
patients in the latter group exhibited a worsening of the QoL (Fig. 18.2), whereas
those also receiving ventilation had an improved quality of life [21].
18.3 Long-Term Oxygen Therapy and Activities of Daily Living
Activities of daily living (ADL) have been evolving in the last two decades as a rel-
evant patient-reported outcome (PRO), and in COPD in particular they have become
useful in rehabilitation programs [22]. ADL in COPD patients can be measured with
various scales but their choice should be guided by the presence of the conceptual
framework for physical activities in the development procedure [23]. In a study per-
formed in patients with moderate-to very severe COPD it was demonstrated that ADL
assessed with the London Chest Activity of Daily Living scale correlated well with
other prognostic indexes such as BODE, and that its limitation was a good measure
of the disease severity [24].
ADL was only sporadically considered in patients with CRF and LTOT and
would be an excellent complementary measure to QoL in this setting.
18.4 Long-Term Oxygen Therapy and Adherence
In order to ensure the therapeutic effectiveness of oxygen therapy in patients who need
it, appropriate adherence should be maintained by the patients: in this particular case
it means that oxygen therapy should be given for at least 15 hours a day. However,
quite often oxygen-dependent patients are not able to comply with this regimen due
to various factors such as family functioning, illness severity, psychological deficit,
limited access to healthcare or lower socioeconomic status [25-26].
All these aspects should be taken into account when following up the patients on
LTOT in order to maximize the efficacy of this therapy and to avoid the waste of med-
ical resources.
18.5 Long-Term Oxygen Therapy and Neuropsychological

Functioning
In COPD the neuropsychological functioning is impaired even in the absence of

chronic sustained hypoxemia: thus symptoms such as anxiety and depression, are
commonly diagnosed in such patients and represent one of the systemic components
of the disease [27]. This is an important issue to be addressed with both non-phar-
macological and pharmacological therapies as the association of COPD with anxi-
ety and depression may determine an increased risk of subsequent morbidity or mor-
tality [28-29]. Anxiety and depression are commonly reported in chronic bronchitis,
especially in females and patients with associated comorbidities [30].
In patients with very severe COPD, hypoxemia is associated with more complex
and profound neuropsychological impairment: apart from depression and anxiety
other disorders similar to those encountered in persons living at high altitude, such
as concentration impairment, loss of motor abilities or disorientation, were also re-
ported [31].
Besides, a correlation between the degree of hypoxemia and neuropsychological
impairment was demonstrated, mild hypoxemia being associated with a 27% deficit,
whereas severe hypoxemia was 61% [32].
One of the initial studies evaluated this in small samples of COPD patients with
hypoxemia before and one month after oxygen therapy and it found that this was able
to improve significantly most of the domains previously found to be severely affected,
whereas in patients without oxygen therapy these variables changed just a little un-
der constant therapy [33].
The Nocturnal Oxygen Therapy Trial (NOTT) was the first large-scale study
evaluating over a longer duration the effects of a nocturnal vs. continuous regimen
of oxygen on neuropsychological functioning in COPD patients: prior to oxygen
therapy initiation this functioning was found to be significantly altered in these pa-
tients when compared to age-matched normal subjects [1, 34]. Oxygen therapy im-
proved the neuropsychological functioning in both groups (n = 150 patients) after
6 months, although this therapeutic effect was modest when assessed individually
or generally [1, 34]. However, subset analyses performed in 37 patients who, af-
ter 12 months of follow-up, were under the continuous oxygen therapy regimen
demonstrated more significant improvements when compared to the other oxygen
therapy group [1, 34].
18.6 Long-Term Oxygen Therapy: Patient’s Perceptions
Although at the initiation of LTOT patients are informed that this therapeutic method
is able to prolong their lives and improve disease outcomes overall, an oxygen ther-
apy-related burden may subsequently develop.
In a study performed in Sweden, COPD patients’ perceptions of self-management
of the disease, including oxygen therapy, were assessed. It was found that oxygen ther-
apy was associated with a significant limitation of social interactions, mobility and
an increased dependency from other members of the family or friends [35].
Domiciliary oxygen therapy can also be perceived as a less friendly therapy, which
impacts negatively on its acceptance and on the perceived benefits: in a study com-
paring patients’ perceptions of four therapeutic interventions delivered at home,
namely antibiotic intravenous therapy, parenteral nutrition, peritoneal dialysis and
oxygen therapy, it was demonstrated that, compared to the other interventions eval-
uated, the technical tasks related to manipulation and maintenance of the oxygen de-
livery systems were relatively simple, but sometimes required the intervention of the
caregiver [36].
18.7 Long-Term Oxygen Therapy and Caregivers
The care of an oxygen-dependent patient represents a challenge not only for the pa-
tient him/herself but also for the caregivers: this was demonstrated in a study inter-
viewing both patients with COPD and their spouses in which it was shown that this
can be addressed by adequate partner-coping and by establishing appropriate rela-
tionships with the healthcare team [37]. Generally, in families with adequate func-
tioning prior to oxygen therapy it was demonstrated that the initiation of this method
further strengthened the supportive relationships of caregivers, especially if the oxy-
gen therapy was delivered at home.
When family dynamics and coping were compared in patients with home oxygen
therapy and patients residing in nursing facilities, it was found that the degree of mu-
tuality was significantly better in the former category, who also experienced better
adaptability to various situations and better overall functioning [38].
The burden of LTOT on the caregivers of COPD patients and the effectiveness of
various interventions to improve their coping and the outcome of the cared disease has
not yet been evaluated in detail: however, a study protocol was recently established
to evaluate these issues. Caregivers will be randomized to receive repeated education
sessions at home or no such intervention, and will be followed up for a period of 12
months. The primary outcome is represented by the percentage of patients with no dis-
ease-related exacerbation requiring therapy outside the home, whereas secondary out-
comes are caregiver burden, social support received/expected, level of mastery, self
esteem, health-related quality of life in patient/caregiver, ability to perform various
domiciliary activities, degree of social insertion and respiratory disease status [39].
Results of such a study may help to shape targeted interventions to be performed
concomitantly in both the patient and caregivers, to reduce the incidence of moder-
ate to severe disease exacerbations, thus leading to an overall improvement in patients’
and caregivers’ quality of life.
18.8 Conclusions
CRF is associated with significant impairment not only in the lungs but also in var-
ious extra pulmonary organs and this leads to the worsening of respiratory symptoms
as well as the development of other non-respiratory symptoms such as depression,
anxiety or fatigue. These have a remarkable impact on daily functioning and con-
tribute to the increased perception of the disability found in such patients.
Moreover, in certain cases LTOT further limits the performance of routine activ-
ities and paradoxically may accentuate this feeling. Unfortunately, such handicaps
cannot always be detected with physiological measures such lung function or exer-
cise capacity, so that other, more patient-centred outcome measures should be used
instead, e.g. quality of life, activities of daily living, adherence or neuropsycholog-

ical functioning.
In studies in LTOT patients such measures were not always used, instruments were
not always the most reliable, and the study design and sample size differed consid-
erably; therefore an overall conclusion that LTOT may have a defined beneficial ef-
fect on humanistic outcomes, is hazardous.
Furthermore, there is a need for larger, multicentre long-term studies, which
should assess such outcomes in a detailed manner, and which should provide the real
relevant picture of the benefits of LTOT as perceived by the patient.
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The Economic Impact of Long-Term
Oxygen Therapy 19
Lorenzo G. Mantovani, Marco Cristiani and Gianluca Furneri
19.1 Use of Long-Term Oxygen Therapy
19.1.1 Demography and Incidence
Unfortunately, an exact figure for the actual number of individuals currently receiv-
ing home oxygen therapy remains elusive. In the United States, previous estimates
ranged from an upper limit of 800,000 individuals to a lower limit of 540,000 with
additional uncertainty from the fact that each estimate was for a different calendar
year [1]. In this study, the authors used reported Medicare expenditure in 1998 for a
different approach to evaluate the prevalence of usage of long-term oxygen therapy
(LTOT) and test the reliability of previous findings. Medicare reported total expen-
ditures for all stationary home oxygen equipment (concentrators and liquid systems)
in 1997 to be 1.7 billion USD. Assuming the average monthly Medicare payment in
1997 for home oxygen is 260 USD (80% of the 1997 monthly allowable of 328 USD),
an annual cost per beneficiary of 3,120 USD was calculated. Dividing the annual es-
timated cost per Medicare beneficiary by the total Medicare expenditures for home
oxygen therapy equipment, the total number of Medicare patients was 570,206. Us-
ing the 80% rule (e.g. Medicare covers up to 80% of all patients in the United States
using home oxygen therapy), the total number of users of home oxygen therapy in
1997 amounted to 712,758. In 1998, total annual Medicare expenditure for all sta-
tionary home oxygen equipment was 1.3 billion USD and reflected the 25% cut man-
dated by the Balanced Budget Act of 1997. The average monthly Medicare payment
in 1998 was 196 USD (2,352 USD annually). Using the same formula, the total num-
ber of Medicare patients receiving LTOT in 1998 amounted to 593,034 (with an over-
L.G. Mantovani ()

Faculty of Pharmacy, Federico II University of Naples, Naples, Italy
e-mail: mantovani@unina.it
222 L.G. Mantovani et al.
all population of 741,292). The authors highlight that the estimation could be biased
by the fact that during each year a certain percentage of LTOT users stopped were
home oxygen therapy, primarily as a result of death.
At more than 1.6 billion USD per year, annual expenditure for home oxygen ther-
apy in the United States far exceeds what is spent in other countries. Furthermore,
the incidence of usage in the United States (241 per 100,000 inhabitants) is likewise
far beyond what is found in other countries.
For example, the reported incidence [2] is:
• 26 per 100,000 in France;
• 20 per 100,000 in England;
• 19 per 100,000 in Japan;
• 60 per 100,000 in Canada.
According to this estimation, more patients are receiving LTOT in the United States
than in all the other countries together [3]. This gives rise to speculation about the
cause for such a high degree of use.
Some studies evaluated the usage of oxygen therapy among patients with COPD,
but they clearly did not distinguish between short-term and long-term usage. Dalal
et al. [4] reported that percentage of oxygen therapy users was 18.8% among COPD
patients. The number of users rapidly increased in acute settings (e.g. emergency de-
partments and intensive care units, Fig. 19.1).
A Spanish study [5] published in 2008 on COPD patients in primary care (with
70
60 57.3%
48.0%
Percentage of patients (%)
50
40
33.1%
30
20 18.8% 18.2%
14.4%
10
0
Total patients Outpatient cohort Urgent Ed cohort Standard ICU cohort
(n=37,089) (n=19,641) outpatient cohort (n=1,231) admission cohort (n=837)
(n=13,833) (n=1,547)
ED = emergency department; ICU = intensive care unit
Fig. 19.1 Prevalence of oxygen therapy usage in different COPD cohorts [4]
19 The Economic Impact of Long-Term Oxygen Therapy 223
stable chronic disease) found a 13.5% prevalence of oxygen usage (1,351 of 10,711
enrolled subjects). This prevalence of usage is somehow comparable with that of the
outpatient subgroup evaluated by Dalal (14.4%).
Oxygen therapy is more common in high-severity COPD patients, who are at high
risk of developing acute episodes. In a US study, Tsai et al. [6] found that 25% of pa-
tients admitted in emergency departments for COPD exacerbations used domiciliary
oxygen therapy. Finally, in a study evaluating healthcare costs of COPD exacerba-
tions [7], 28% of admitted patients were using long-term domiciliary oxygen.
19.1.2 Compliance (Treatment Adherence)
Although many scientifically validated studies demonstrate the positive impact of

LTOT on survival and quality of life for chronically hypoxemic COPD patients, there
is a growing concern about the overall degree of sustained adherence to the treating
physician’s prescription. Several evaluations have been carried out in different coun-
tries. In the United Kingdom, Walshaw et al. studied 67 patients receiving LTOT via
oxygen concentrators, and found that only 55% were using oxygen therapy appro-
priately [8]. Also in the United Kingdom, Howard et al. evaluated 531 LTOT patients
who were prescribed oxygen concentrators, and reported that 50% of the patients were
not using the equipment at the level at which a clinical benefit could be expected [9].
Pepin et al. studied 930 LTOT users in France, and observed that only 45% achieved
therapy for 15 hours or more per day [10]. In a Spanish study of 62 LTOT users,
Granados et al. reported an astounding 69% non-compliance rate, although these re-
searchers also reported that only 36 of the 62 users (58%) had what was identified
as an appropriate prescription [11]. Shiner et al. evaluated 63 LTOT users in Israel,
and found that only 33% used LTOT in the 12-24 hours per day range [12]. Finally,
Farrero et al. studied 128 LTOT patients in Spain, and found that LTOT use was ap-
propriate in only 26% [13]. Several reasons for such poor compliance have been put
forward. Pepin et al. suggest that a primary contributing factor is the failure of the
prescribing physician to adequately inform the patient beforehand of the expected us-
age [14]. Kampelmacher et al. evaluated surveys received from 528 LTOT users in
the Netherlands, and reported that the most common complaint contributing to non-
compliance was restricted autonomy [15]. Along the same lines, Ring and Daniel-
son expressed concern over the social isolation they witnessed during their study of
a relatively small number of LTOT users in Sweden [16]. Weitzenblum, comment-
ing on the work of Pepin, believes that LTOT is often poorly prescribed and there-
fore provided inappropriately [17]. On the other hand, Farrero et al. argue that a lack
of follow-up through structured home visits and outpatient care is the contributing
factor [18]. The issue of LTOT non-compliance is a very serious challenge in order
to reduce the reimbursement for LTOT equipment.
19.2 Costs of LTOT in COPD
The estimation of the economic burden of COPD is increasingly attracting the atten-
tion of professionals and policy makers, as COPD prevalence and incidence are likely
to rise as a result of increasing air pollution, the burden of tobacco/cigarette smoking
in developing countries and population ageing. In the United States, COPD is the fourth
leading cause of death and accounts for 15.4 million physician visits, 1.5 million emer-
gency department (ED) visits, and 636,000 hospitalizations each year [19, 20]. Based
on national survey data, the total economic burden of COPD in the United States in 2007
was calculated to be 42.6 billion USD, including 26.7 billion USD in direct healthcare
expenditure, of which 11.3 billion USD was for hospital care [21]. The burden of COPD
is expected to increase considerably as the US population ages [22]. Several economic
evaluations have been carried out, even recently [23-24].
Overall costs of LTOT are relevant. The first attempts to estimate the economic
burden of LTOT go back to late 1990s, from the US Healthcare Financing Adminis-
tration, which estimated an annual economic impact for Medicare of 1.8 billion USD
over the period 1997-1998. LTOT expenditure accounted for 41% and 35% of total
expenditure for durable medical devices, in 1997 and 1998, respectively. The over-
all economic impact of LTOT has been increasing over the last 15 years, but it is rea-
sonable to believe that its relative impact on total costs for medical devices has been
falling, due to the introduction of new high-cost medical devices in many therapeu-
tic areas (e.g. defibrillators, stents, insulin infusion pumps, etc.). Another US study
published in 2000 [25], evaluated COPD costs from Medicare administrative records
in 1993. At that time, COPD direct costs were found to amount to 6.6 billion USD,
with one-third of the costs (2.3 billion USD) being attributable to domiciliary oxy-
gen therapy. The high economic burden of LTOT is an unquestionable proof that dis-
ease severity is the main cost driver in COPD. Table 19.1 illustrates the distribution
of COPD costs in the mentioned study.
Other studies confirmed that domiciliary LTOT is a cost driver for COPD man-
agement. According to Hilleman et al. [26], who retrospectively analysed a cohort
of patients with a history of COPD, confirmed by hospitalization for exacerbations,
oxygen therapy significantly contributes to increase costs. In the analysis the authors
highlighted that (Fig. 19.2):
• Oxygen therapy, as well as other types of costs, grow exponentially with increas-
ing severity;
• The costs of oxygen therapy are the second highest in both stage II COPD patients
(14% of total costs, similarly to drug costs, vs. 53% of hospital costs) and stage
III COPD patients (19% of total costs, vs. 63% of hospital costs).
A large observational study carried out in Spain [27] evaluated the direct costs of
a COPD cohort, with or without the concomitant diagnosis of diabetes. In this study,
the mean annual costs of oxygen therapy amounted to 157 EUR in the subgroup of
Table 19.1 Distribution of COPD annual healthcare costs in the US. From [25] with permission
Type of cost Annual U.S. Cost ($) Percent (%)
Hospitalizations 1 609,640,720 24
Inpatient physician services 256,198,146 4
Emergency department visits 147,909,508 2
Outpatient physician visits 480,471,525 7
Outpatient diagnostic procedures 54,963,720 1
Nursing home stays 942,086,534 14
Hospice care 27,983,469 <1
Home health care 309,418,057 5
Prescription medication 461,907,519 7
Long-term oxygen therapy 2 284,128,000 35
Grand total 6 574,707,198 100
12,000 Total annual costs

10,812
LTOT annual costs
10,000
8,000
Costs (US $)
6,000
5,037
4,000
2,012
2,000 1,681
699
0
0
Stage I Stage II Stage III
COPD Stage
Fig. 19.2 Total and LTOT annual costs, according to COPD severity [26]
diabetes patients (6% of total costs: 2,580 EUR) and 87 in the subgroup of non-di-
abetes patients (5% of total costs: 1,854 EUR). As previously mentioned, usage of
LTOT is a significant predictor of high costs in COPD patients, even in the acute phase
(i.e. disease exacerbations). In a recent study carried out in Australia by Hutchinson
et al. [7], usage of domiciliary oxygen was statistically associated to both number of
days spent at hospital (p = 0.016) and annual incidence of hospitalization (p =
0.008). Clearly, the economic burden of oxygen therapy depends on the character-
istics of the enrolled population (age, disease severity, hospital vs. primary care set-
ting etc.). In another Spanish study [5], for which a cohort COPD subjects in primary
care was enrolled, the economic impact of oxygen therapy was about 5% of annual
overall costs (1,923 EUR).
19.3 Economic Assessment of LTOT
19.3.1 Cost-Effectiveness Comparison of LTOT Disposables
During the last decade, there has been intense debate among healthcare payers about
the economic sustainability of modern, more comfortable, but high-cost technologies
for oxygen delivery. Generally speaking, the acquisition costs of portable devices are
higher than fixed systems, although the cost gap between the two has been reduced
over the years. Therefore, initially, higher costs represented an important barrier to
the adoption of this technology [28]. On the other hand, the impossibility of receiv-
ing oxygen therapy outside home negatively affects appropriate usage of LTOT, as
it reduces COPD patients’ compliance and quality of life [29].
An evaluation of the cost-opportunity of different devices should rely on the
medium-long term timeframe, and take into account the negative implications of in-
appropriateness on clinical and economic outcomes [30].
Moreover, a scenario of costs in this area is in continuous evolution: therefore
health-economic analyses must be updated in light of the price change of such de-
vices. Currently the costs of portable devices in the US are around 1,000 USD, while
a portable concentrator costs about 3,000 USD.
Unfortunately, the number of health economics evaluations on this topic seems
quite limited. A recent study conducted in the US [30] evaluated resource consump-
tion in COPD subjects, detected through Medicare administrative databases during
the period from 1 January 1999 to 30 December 2004, and receiving LTOT for at least
12 months, with one of the following alternatives: i) portable devices; ii) fixed de-
vices (E-cylinders); fixed devices initially, then portable devices (switchers). The date
of the first prescription of oxygen therapy was the index date, coinciding with the be-
ginning of observation. The analysis included 2,725 patients. Only 203 patients
(7.5%) used a portable device, 254 (9.3%) received standard oxygen therapy, then
were switched to portable devices, and the remaining 2,268 (83.2%) used fixed sys-
tems. Baseline characteristics (age, level of comorbidities measured with Charlson
index at baseline, spirometry outcomes: FEV1, FVC) were similar in the three
groups. Interestingly, the subgroup of patients using portable devices at the beginning
of observation had a numerically lower hospitalization admission rate (but not sta-
tistically significant), compared to other two groups during the 12 months following
the index date (29.1%, vs. 37.3% of subjects using e-cylinders and 37.4% of switch-
ers). The median annual costs of portable devices were 9,503 USD per year (interquar-
tile range, IR: 4,392–20,447 USD), vs. 6,515 USD per year (IR: 3,076–12,840
USD) of patients in LTOT therapy with standard systems. However the numerical cost
difference between the two groups, about 3,000 USD, was not statistically signifi-
cant. In the subgroups of switchers, monthly cost during treatment with standard sys-
tems and with portable devices was similar (1,396 USD [IR: 879–1,914 USD] vs.
1,428 USD [1,201–1,655 USD]). This study provides interesting insights, and sug-
gests further elaborations for future research. In this context, new studies should
analyse the cost-benefit profile (rather than costs only) of portable vs. standard de-
vices, adopting a medium-to-long term time horizon. Using this approach, it would
be possible to capture the effects of using different devices on patients’ quality of life
and, overall, on compliance, which is perhaps the main therapeutic objective to re-
duce the burden of exacerbations.
19.3.2 Economic Assessment of Telemetric Home Monitoring

Management
Telemedicine has been used in the past decade in several countries for domiciliary man-
agement of chronic respiratory patients. Even though some aspects are still debated
(such as regulatory aspects and responsibilities), the clinical effectiveness of this model
of assistance and the optimization of outcomes (both clinical and economic) were
proven in more severe stages of COPD [31-33]. In an economic evaluation carried out
in Italy, Ravasio et al. [34] compared the costs of two samples of severe chronic res-
piratory patients (COPD patients in 89% of cases) managed at home either with (n =
61) or without (n = 20) home telemetric monitoring, over a 24-month period. In the
analysis the authors found that telemetric management reduced frequency of hospi-
talizations (-56.3% in the first year and -66.7% in the second year), compared to stan-
dard management. In both groups the main driver of LTOT was cost for O2, account-
ing for 60% of the total mean cost, followed by medical-nursing staff costs, (13% of
LTOT costs). The difference between the mean daily cost in the two groups was 0.41
EUR (+3.3%), attributable to the mean daily cost of the telemetric service needed to
carry out the telemetry. Table 19.2 shows main results of the economic assessment.
Table 19.2 Total mean annual costs. From [34] with permission
Telemetric management
Description First year Second year
Yes No Yes No
OTLT cost (€) 4,668.35 4,518.70 4,668.35 4,518.70
Hospitalizations cost (€) 2,252.60 5,148.80 1,609.00 4,827.00
Total mean treatment cost (€) 6,920.95 9,667.50 6,277.35 9,345.70
Total mean treatment costs were calculated for both patients groups. In the first
year the group with telemetric home monitoring had lower mean annual costs than
the group without telemetric home monitoring (-28%). The difference increased in
the second year (-33%). These savings (2,746.55 EUR and 3,068.35 EUR in first and
second year respectively) were mainly due to the lower mean cost of hospitalizations
in the telemetric home monitoring group, despite of the higher mean LTOT costs
(4,668.35 EUR vs. 4,518.70 EUR).
19.3.3 Evaluations of LTOT and non-LTOT Technologies
As described in chapter 1.2, LTOT is indicated and recommended under specific in-
dications. As an example, the National Institute of Clinical Excellence (NICE) has
recently issued (June 2010) recommendations for COPD management in adults in pri-
mary and secondary care [35]. Therefore, no alternatives currently exist to LTOT. In
the guideline, other interventions (nocturnal oxygen therapy, non-invasive mechan-
ical ventilation) are also evaluated for certain indications and subsets of COPD pa-
tients. Sometimes, respiratory therapies can be used for the same purpose and/or as-
sociated to each other to assure better clinical outcomes. In this context, some
scientific articles have evaluated, from an economic view point, LTOT and non-LTOT
strategies, and combination of LTOT and non- LTOT strategies vs. LTOT only.
An example of parallel evaluation is provided by a cost-utility analysis con-
ducted by Oba et al. [36], who studied two different oxygen therapy programs, long-
term and nocturnal, vs. no-oxygen therapy, in COPD patients. Specifically, long-term
therapy was evaluated in a cohort of patients with severe resting hypoxemia, while
nocturnal therapy was evaluated for a cohort of patients with nocturnal desaturation.
In order to carry out the analysis, a three-state Markov model was elaborated, adopt-
ing two different time horizons, either three or five years. The analysis adopted a third-
party payer perspective (Medicare costs and tariffs). Clinical and quality of life data
for the different alternatives were retrieved from scientific literature. As usual, one-
way and probabilistic sensitivity analyses were conducted to test the robustness of
the estimations.
Figure 19.3 shows the results of cost-utility evaluations for the different treatments.
In COPD patients with severe resting hypoxemia, LTOT was cost-effective vs. no
treatment (16,124 USD, below the willingness-to-pay per QALY threshold of 50,000
USD). In the other cohort of COPD patients with nocturnal desaturation, the cost-util-
ity ratio was not favourable (306,356 USD/QALY), due to a similar effectiveness
(QALYs gained) of nocturnal therapy and no-oxygen therapy. The author concluded
that, by adopting a US third-party perspective, continuous oxygen therapy was cost-
effective, while nocturnal oxygen therapy was not.
An Italian analysis by Clini et al. [37] assessed the economic opportunity of adding
Additionals costs Additionals QALYs

10,000 9,517 0,7
8,615
0,6
8,000
0,5
6,000
Costs (US $)
0,4
QALYs
4,000 0,3
0,2
2,000
0,1
0 0
LTOT vs. no treatment Nocturnal oxygen therapy
vs. no treatment
Fig. 19.3 Results of economic analysis of LTOT and nocturnal oxygen therapy vs. no treatment [36]
Table 19.3 Distribution of per patient daily costs in the two arms [38]
Type of cost NNV+LTOT (n=35) LTOT alone (n=42)
Cost (€ per pt/day) Cost (€ per pt/day)
Drugs 2.36 2.41
Hospitalizations 8.25 *12.50
Oxygen 6.18 6.56
Subtotal 17.17 **21.42
Total (including NNV) 23.73 21.42
* p< 0.05; ** p < 0.03.
nocturnal non-invasive ventilation (NNV) to LTOT in patients with stable hypercap-

nic COPD. The economic analysis used data from a clinical study [38], demonstrat-
ing superiority of association NNV+LTOT vs. LTOT only. The analysis. Seventy-
seven of the 90 enrolled patients had a follow-up longer than 180 days (n = 35 in the
NNV+LTOT group and n = 42 in the LTOT group), and were considered eligible for
the economic analysis.
Table 19.3 illustrates the distribution of costs in the two treatment groups. The au-
thors found that the association between NNV and LTOT did not lead to an increase
of direct costs, compared to LTOT alone (23.73 EUR/day in the NNV+LTOT com-
pared to 21.42 EUR/day in the LTOT group; p>0.05). The authors concluded that the
cost of associating a second technology to LTOT was offset by the reduction of hos-
pital admissions for exacerbations (and consequentially of hospital costs).
19.4 Conclusions
Long-term oxygen therapy (LTOT) is one of the leading cost factors in COPD pa-
tients with moderate or severe disease, thus representing an area of serious concern
for health policy makers. Costs for LTOT are destined to increase in the next few years
due to the expected growth of COPD prevalence and the improvement of technolo-
gies for oxygen delivery. Health economics research should address the cost benefit
profile of alternative technologies within this indication, taking into account the im-
portance of conducting country-specific evaluations and frequently performing up-
dates in order to capture the quick price evolution of oxygen therapy disposables.
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Index
A Cognitive function 67-72, 118, 214

Accreditation path 185 Communication 8, 11, 13-14, 98, 103, 121,
Adherence 4-5, 11-14, 16, 19, 22, 83, 125-131, 133, 137, 142, 163, 175, 178
90-93, 95, 105, 110, 112-113, 121, Comorbidities 3, 22, 41, 45, 70, 82, 182,
163-164, 173, 175, 177, 212, 215, 218, 215, 226
223 Complex system 167
ADL (Activities of Daily Living) 10, 17, Compliance 93, 105, 112, 136, 161,
20, 21, 40, 215 163-165, 173, 177-178, 186, 189, 206,
Agnosia 67-68 223, 226-227
Ambulatory oxygen 4, 11-12, 16, 19-21 Complications 4, 13-14, 36, 82, 85, 101,
Amino acid content 75-76 103, 195
Anemia 3-4, 51-52, 111, 207 Continuity of care 90, 161, 163, 166
Antioxidant levels 75-76 Cor pulmonale 5-6, 8, 82, 102, 201, 207
Anxiety 70-71, 92, 204, 215, 217 Costs 15, 97, 103, 105, 108, 110, 121, 123,
Aphasia 67-68 133, 163, 172, 174-176, 179, 191, 195,
Atherosclerosis 46, 48 223-229
ATP 45, 50, 77 C-reactive protein 51
Axonal degeneration 59, 61
D
B Dementia 67-69
Brain ageing 68 Depression 48, 69-71, 204, 215, 217
Desaturation 2, 8, 18-19, 40-41, 92, 109,
C 197, 201-203, 228
Cardiovascular disease 36, 47, 70 Diabetes mellitus 50, 58
Care-giver 90, 93, 95 Disability 11, 13, 37, 90, 92, 94, 118-119,
Chronic obstructive pulmonary disease 2, 125, 171, 212, 217
17, 35, 57, 67, 75, 81, 97, 106, 122, Dynamic hyperinflation 16, 21, 40,
156-157, 161, 185, 195, 203, 206, 211, 203-204
213 Dyspnoea 8, 20-21, 35, 52, 70-71, 76, 92,
Cigarette smoking 9, 61-63, 224 107-108, 131, 203-204, 213
233
234 Index
E M
Economic impact 221, 224, 226 Management 8, 12, 85, 89-93, 95, 99, 103,
Educational programs 89, 95 106, 123, 161, 169, 176, 177, 182, 188,
Electrolyte content 75 191, 199, 216, 227-228
Essential amino acids (EAAs) 78 Metabolic disease 22, 51, 82
Exercise performance 40, 203, 207 6 minute walking test 18, 38, 40, 48, 50,
52, 78, 109
G MMSE 70-72
Gender differences 36, 70-71, 81-82, Mortality in COPD 17, 22
84-85, 181 Multidisciplinary team 164
General practitioner 97, 117, 123, 163 Myopathy 62-63
Glomerular filtration rate 48-49, 52
Glutamine 76 N
Neuropathy 57-63
H Neuropsychological functioning 212,
Health communication 129, 131 215-216, 218
Health Institutions 117, 186 Nocturnal desaturation 8, 18-19, 202, 228
Heart failure 8-9, 16-18, 22, 36-37, 39-40, NT-proBNP 47-49, 52
52, 109, 180-181, 199 Nutritional deficiencies 75
Hematocrit 3, 6, 8-9, 39, 197
Hemoglobin 3, 5, 47, 207 O
Hospital-Territory Integration 166 OSA 16, 18, 47
Hospitalizations 15, 20, 38, 92, 122, 166, Oxidative stress 14, 16, 18, 46, 50, 62-64,
175, 179-180, 205, 224-225, 227-229 76-77, 82
Humanistic outcomes 211-212, 218 Oxygen
Hyperoxia 47 delivery 3, 105-106, 108-109, 111,
Hypoxemia 2-9, 15-21, 35, 39-41, 45-52, 113, 135, 167-168, 172, 201, 203,
58, 60-62, 64, 67, 71, 75, 102, 107-109, 216, 226
131, 156, 179, 195-196, 199-205, 211, desaturation 2, 18-19, 40, 109, 201-203
215-216, 228 distribution 100
flow 19, 94, 108-111, 138, 140, 143,
I 145, 164-165
IADL (Instrumental Activities of Daily prescription 9, 11, 19, 93, 107, 109, 135,
Living) 10 173
Inflammation 3, 51-52, 62-64, 75-77 remote control 85, 111, 172
Inflammatory indices 50-51 Oxygen therapy
clinical outcomes of 5, 22,114, 195
L cost-effectiveness of 172, 175, 226
Long-term outcomes 20, 173, 182 survival 3, 6, 12, 15, 20, 38-41, 81-85,
Long-term oxygen therapy 1-21, 45, 64, 106, 108, 121, 122, 180-182, 196-200
75, 81, 97, 121-122, 131, 135, 195-196,
200, 201, 203-205, 207, 212, 215-217, P
221 Phosphocreatine 47, 77
Lower airway infections 177, 179, 181, 199 Pneumological examinations 164, 165
Index 235
Polycythemia 2-3, 5, 8, 15, 39-40, 109, Respiratory Home Care Service 164-165,
196-197, 207 169
Primary care 97, 117, 222, 225 Right ventricular dysfunction 50
ProANP 49 Risks of oxygen 150
ProAVP 49
Progressive levels of intensity of care 166 S
Pulmonary Sarcopenia 48-49, 78, 82
function tests 35 Short burst oxygen therapy 21
hemodynamics 122, 200, 202-203 Sleep quality 4, 18, 201
hypertension 2-4, 8, 16, 18, 39, 50, 200, Standard care 84, 161, 180-182, 197, 199
201, 207 Subclinical cognitive impairment 68
vasoconstriction 2, 46, 200 Systems for oxygen delivery 135
Q T
Quality of life 3, 37, 70-71, 89, 103, 107, Telemedicine 103, 172, 227
119, 121, 133, 177, 195, 205, 207, 211-218 The economic impact 221, 226
TMT-A 72-73
R TMT-B 72
Reference model 161, 164 Training on Oxygen equipment 123, 137,
Respiratory failure 36, 37, 39, 70, 106-109, 163-165, 167, 169, 221
111-113, 121, 171, 172, 176, 185, 191, Travelling with oxygen 153
195, 205, 211, 214

(Roberto W. Dal Negro, Richard Hodder (Auth.), Rob

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Long-Term Oxygen Therapy

Roberto Walter Dal Negro • Richard Hodder

New Insights and Perspectives

Forewords by Marc Miravitlles and Dario Olivieri

ISBN 978-88-470-2579-0 ISBN 978-88-470-2580-6 H%RRN

Springer Milan Dordrecht Heidelberg London New York

© Springer-Verlag Italia 2012

987654321 2012 2013 2014 2015

Cover design: Ikona S.r.l., Milan, Italy

Typesetting: Ikona S.r.l., Milan, Italy

Springer-Verlag Italia S.r.l., Via Decembrio 28, I-20137 Milan

1 The Patient Candidate for Long-Term Oxygen Therapy . . . . . . . . . . 1

Section I The Multidimensional Evaluation of Patients

2 Lung Function Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35

3 Cardiovascular and Metabolic Indices . . . . . . . . . . . . . . . . . . . . . . . . . 45

4 Chronic Obstructive Pulmonary Disease (COPD):

5 The Psychological and Cognitive Profile . . . . . . . . . . . . . . . . . . . . . . . 67

Section II The Cooperating Roles

8 Home LTOT: The Role of the Caregiver . . . . . . . . . . . . . . . . . . . . . . . 89

9 The General Practitioner (GP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97

10 The Cooperating Roles: The Lung Physician . . . . . . . . . . . . . . . . . . . 105

11 The Health Institutions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117

12 The Role of Media . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125

13 Systems for Oxygen Delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

Section III Models for LTOT Management

14 Standard Care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161

15 Tele-Control at Home . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171

16 The Value of a Systemic Accreditation Path . . . . . . . . . . . . . . . . . . . . 185

Section IV The Outcomes

17 Clinical Outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195

18 Humanistic Outcomes and Quality of Life . . . . . . . . . . . . . . . . . . . . . 211

19 The Economic Impact of Long-Term Oxygen Therapy . . . . . . . . . . . 221

Raffaele Antonelli Incalzi Chair of Geriatrics, University Campus Bio Medico,

Sabina Antoniu Pulmonary Disease University Hospital, University of Medicine and

Roberto Aquilani Service of Metabolic-Nutritional Pathophysiology and of Clin-

Roberta Barian ULSS22 Bussolengo, Lung Disease Department, Orlandi Hospital,

Stefano Bertacco ULSS22 Bussolengo, Lung Disease Department, Orlandi Hospi-

Germano Bettoncelli General practitioner, Ospitaletto, Italy

Federica Boschi Department of Drug Sciences, University of Pavia, Pavia, Italy

Fernanda Bricolo Psychologist and Psychotherapist, Verona, Italy

Ebba Buffone Neurology Unit, Department of Internal Medicine, Orlandi Hospital,

Carlo Castiglioni Medical Director VitalAire, Milan, Italy

Andrea Corsonello Unit of Geriatric Pharmacoepidemiology, Italian National Re-

Marco Cristiani Charta Foundation, Milan, Italy

Sonia Dal Ben Psychologist and Psychotherapist, Verona, Italy

Daniel Della Seta Journalist, Rome, Italy

Cristina Deluca Neurology Unit, Department of Internal Medicine, Orlandi Hospi-

Massimo Dutto Bureau Veritas Health Department, Milan, Italy

Gianluca Furneri Charta Foundation, Milan, Italy

Richard Hodder† Divisions of Pulmonary and Critical Care, University of Ottawa,

Carlo G. Leo Health Technology Assessment Unit, National Council of Research –

Lorenzo G. Mantovani Faculty of Pharmacy, Federico II University of Naples,

Claudio Micheletto Respiratory Unit, Department of Medicine, Mater Salutis Hos-

Elena Minguzzi Neurology Unit, Department of Internal Medicine, Orlandi Hospi-

Nicoletta Palese Bureau Veritas Health Department, Milan, Italy

Evasio Pasini Scientific Institute of Lumezzane, “S. Maugeri Foundation”, Brescia,

Maria Grazia Passarin Neurology Unit, Department of Internal Medicine, Orlandi

Eugenio Sabato Pulmonary Unit, ASL BR, Brindisi, Italy

Saverio Sabina Health Technology Assessment Unit, National Council of Research

Cleante Scarduelli Cardio-pulmonary Rehabilitation Unit, Cardio-thoracic-vascu-

Paola Turco Research & Clinical Governance, Verona, Italy

1.1 A Brief History of Oxygen Therapy

R.W. Dal Negro ()