ERS monograph

Pulmonary Emergencies
ERS monograph

This Monograph, written by well recognised experts in the

Pulmonary
field, provides a comprehensive overview of pulmonary
emergencies. A broad range of different respiratory
emergencies is covered, from pneumothorax, pulmonary
Emergencies
embolism, right heart failure and haematothorax to acute
exacerbations of diseases such as asthma and chronic
obstructive pulmonary disease. Recent developments in
treatment strategies for acute pulmonary problems are also
Edited by Leo Heunks,
discussed in detail, with chapters on topics such as high-flow Alexandre Demoule
nasal cannula oxygen therapy, extracorporeal carbon dioxide
removal and noninvasive ventilation. and Wolfram Windisch

ERS monograph 74

Print ISSN: 2312-508X ISBN 978- 1- 84984- 073- 6

Online ISSN: 2312-5098
Print ISBN: 978-1-84984-073-6
Online ISBN: 978-1-84984-074-3

December 2016

9 781849 840736
FB:Cardiologia Siglo XXI
€60.00
 Pulmonary
Emergencies
Edited by
Leo Heunks, Alexandre Demoule
and Wolfram Windisch

Editor in Chief
Robert Bals

This book is one in a series of ERS Monographs. Each individual issue

provides a comprehensive overview of one specific clinical area of
respiratory health, communicating information about the most advanced
techniques and systems required for its investigation. It provides factual and
useful scientific detail, drawing on specific case studies and looking into
the diagnosis and management of individual patients. Previously published
titles in this series are listed at the back of this Monograph.

ERS Monographs are available online at www.erspublications.com and print

copies are available from www.ersbookshop.com

FB:Cardiologia Siglo XXI

 Continuing medical education (CME) credits are available through many issues of the ERS
Monograph. Following evaluation, successful Monographs are accredited by the European
Board for Accreditation in Pneumology (EBAP) for 5 CME credits. To earn CME credits, read
the book of your choice (it is clearly indicated on the online table of contents whether CME
credits are available) then complete the CME question form that is available at www.ers-
education.org/e-learning/cme-tests.aspx

Editorial Board: Antonio Anzueto (San Antonio, TX, USA), Leif Bjermer (Lund, Sweden), John R. Hurst (London,
UK) and Carlos Robalo Cordeiro (Coimbra, Portugal).

Managing Editors: Rachel White and Catherine Pumphrey

European Respiratory Society, 442 Glossop Road, Sheffield, S10 2PX, UK
Tel: 44 114 2672860 | E-mail: Monograph@ersj.org.uk

Published by European Respiratory Society ©2016

December 2016
Print ISBN: 978-1-84984-073-6
Online ISBN: 978-1-84984-074-3
Print ISSN: 2312-508X
Online ISSN: 2312-5098
Typesetting by Nova Techset Private Limited
Printed by Page Bros Ltd, Norwich, UK

All material is copyright to European Respiratory Society. It may not be reproduced in any way including
electronic means without the express permission of the company.

Statements in the volume reflect the views of the authors, and not necessarily those of the European Respiratory
Society, editors or publishers.

This journal is a member of and

subscribes to the principles of the
Committee on Publication Ethics

FB:Cardiologia Siglo XXI

 ERS monograph

Contents
Pulmonary Emergencies Number 74
December 2016

Preface v

Guest Editors vii

Introduction x

List of abbreviations xi

Clinical entities

1. Pneumothorax 1
Steve Walker and Nick Maskell

2. Pulmonary embolism 15
Stefano Barco and Stavros V. Konstantinides

3. Right heart failure 32

Benjamin Sztrymf, Constance Vuillard, Athénaïs Boucly, Elise Artaud-Macari,
Caroline Sattler, David Amar, Xavier Jaïs, Olivier Sitbon, Marc Humbert and
Laurent Savale

4. Acute exacerbations of COPD 48

Alison Patricia Butler, Laura-Jane E. Smith and Alexander John Mackay

5. Acute exacerbations of asthma 66

Nirav R. Bhakta and Stephen C. Lazarus

6. Hypercapnic respiratory failure in non-COPD 86

Neeraj M. Shah and Patrick B. Murphy

7. Severe community-acquired pneumonia 101

Adamantia Liapikou, Catia Cilloniz, Adrian Ceccato and Antoni Torres

8. Acute exacerbations of interstitial lung disease 117

Marcel Veltkamp and Jan C. Grutters

9. Severe haemoptysis 132

Muriel Fartoukh, Guillaume Voiriot, Samuel Hadad, Hicham Masmoudi, Jalal Assouad,
Marie-France Carette, Antoine Khalil and Antoine Parrot

FB:Cardiologia Siglo XXI

10. Foreign body aspiration and inhalation injury 151
Erik H.F.M. van der Heijden, Paul C. Fuchs and Jan-Philipp Stromps

11. Haematothorax 161

Erich Stoelben, Axel Gossmann and Servet Bölükbas

Acute pulmonary interventions

12. High-flow nasal cannula oxygen therapy 171

Rémi Coudroy, Jean-Pierre Frat and Arnaud W. Thille

13. Acute noninvasive ventilation 186

Rosanna Vaschetto, Federico Longhini and Paolo Navalesi

14. Extracorporeal carbon dioxide removal 200

Christian Karagiannidis, Stefan Kluge, Stephan Strassmann and Wolfram Windisch

15. Acute bronchoscopy 209

Raffaele Scala

16. Chest tube insertion 229

Sanjay Adlakha, Mark Roberts and Nabeel Ali

FB:Cardiologia Siglo XXI

 ERS | monograph

Preface
Robert Bals

Emergency situations in pulmonary medicine are critical for the

patient and often stressful for the care providers. The most
important factor in the successful management of such
situations is to be prepared. Interruption of the function of the
lung immediately results in an emergency situation. In the case
of severe impairment of gas exchange, a catastrophic outcome
will occur within a few minutes if adequate measures are not
started. The management of respiratory acute situations is a core
capability of respiratory and emergency medicine. Physicians in
all areas of pulmonary medicine face critical situations daily.
Maintaining the ability to manage emergencies adequately
requires keeping knowledge up to date and training in critical
procedures. In addition to the basic principles in this area, a
number of new techniques and procedures have been developed
in recent years. In contrast to the importance of this subject,
there are only a few comprehensive textbooks available.

This ERS Monograph aims to provide the reader with a detailed

overview of emergencies in pulmonary care, from a viewpoint
close to the bedside. The book is split into two sections. The
first section, on clinical entities, covers the most important
emergency situations, while the second section, on acute
pulmonary interventions, focuses on key techniques. This
structure allows readers to learn systematically or to refresh their
knowledge of the theory of pulmonary emergency management,
including bedside interventions. Together with practical training
and structural developments, this ERS Monograph will enable
physicians and other healthcare providers to treat their patients
safely in critical situations.

I would like to thank the Guest Editors, Leo Heunks, Alexandre

Demoule and Wolfram Windisch, who have worked very
successfully to select these topics and integrate them into a
comprehensive book. I would also like to thank all the authors
for their work. I am sure that this excellent ERS Monograph will

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: v–vi. DOI: 10.1183/2312508X.10018416 v

FB:Cardiologia Siglo XXI

be useful in clinical practice for a broad range of respiratory
physicians and will help to improve the care of our patients.

Disclosures: R. Bals has received grants from the German Research

Ministerium and the Deutsche Forschungsgemeinschaft. He has also received
personal fees from GSK, AstraZeneca, Boehringer Ingelheim and CSL Behring.

vi

FB:Cardiologia Siglo XXI

 ERS | monograph

Guest Editors

Leo Heunks

Leo Heunks is professor of intensive care medicine at the VU

University Medical Center Amsterdam (Amsterdam, the
Netherlands). He received his undergraduate training and MD at
the Radboud University (Nijmegen, the Netherlands). From
1996 to 2000, he was a PhD student in respiratory physiology.
During the PhD programme he visited the Mayo Clinic
(Rochester, MN, USA) for 7 months to study skeletal muscle
single fibre mechanics and intracellular calcium imaging (with
mentor Gary Sieck). He trained as a pulmonologist at the
Radboud University Medical Center from 2000 to 2006, followed
by a 2-year fellowship in intensive care medicine, and became
consultant in intensive care at the same hospital. He was
co-founder of the first specialised ventilator-weaning unit in the
Netherlands and chair of the Dutch guideline for difficult
weaning. In 2016, he moved to the VU University Medical
Center Amsterdam, Dept of Intensive Care.

His research interests include effects of critical illness on

respiratory muscle function, mechanical ventilation, weaning
from the ventilator and ARDS. He has spent research fellowships
at Loyola University Medical Center (Chicago, IL, USA) and St
Michael’s Hospital, Toronto (ON, Canada). In both clinical
work and research, he promotes the understanding of
physiological principles. Only when we are willing to understand
the underlying physiology can we conduct meaningful research
and optimal patient care.

Currently, Leo Heunks is secretary of European Respiratory

Society assembly 2 (respiratory intensive care).

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: vii–ix. DOI: 10.1183/2312508X.10018216 vii

FB:Cardiologia Siglo XXI

 Alexandre Demoule

Alexandre Demoule is professor of intensive care medicine at the

Pierre and Marie Curie University Medical Centre in Paris
(France). He is the director of the medical ICU, the step-down
unit and the weaning centre within the Dept of Pneumology and
Intensive Care Medicine, La Pitié-Salpêtrière hospital in Paris.
He was trained in pneumology and physiology at the Pierre and
Marie Curie University under the supervision of Thomas
Similowski and in intensive care medicine at Paris-Est University
in Créteil, where he was also a research fellow (2001–2002) in
mechanical ventilation with Laurent Brochard. From 2003 to
2006, he was a PhD student in respiratory physiology at the
Pierre and Marie Curie University. During the PhD programme
he spent 1.5 years at the Meakins-Christie Laboratories, McGill
University (Montreal, QC, Canada), under the supervision of
Basil Petrof.

His main research field is patient–ventilator interactions. It

involves specific research topics such as brain–ventilator
interactions, the impact of mechanical ventilation on respiratory
sensations and comfort, and respiratory muscle dysfunction in
mechanically ventilated patients. He also conducts clinical studies
on noninvasive mechanical ventilation in acute respiratory failure
and on new modes of mechanical ventilation. His research
projects are conducted within UMR_S 1158, a joint research unit
between Pierre and Marie Curie University and the French
National Institute of Health and Medical Research (Inserm).

Alexandre Demoule is the chair of the annual meeting of the

French Intensive Care Society. He has organised several
conferences on mechanical ventilation, is co-author of guidelines
in the field of intensive care medicine and serves as an invited
speaker at international conferences.

Wolfram Windisch

Wolfram Windisch is the medical director of the Dept of

Pneumology and Critical Care Medicine, Clinic of Cologne
(Cologne, Germany), and holds the professorial chair for
Pneumology at the University of Witten/Herdecke (Cologne).
His department is specifically dedicated to the acute and chronic
treatment of respiratory failure, invasive and noninvasive
mechanical ventilation, extracorporeal lung assist, weaning from
mechanical ventilation and sleep medicine. In addition, his other
main focuses are COPD/asthma, thoracic oncology, interstitial
lung diseases, infectious diseases and cystic fibrosis. His research
interests include respiratory physiology, all aspects of mechanical
ventilation, monitoring of respiratory function in the acute and

viii

FB:Cardiologia Siglo XXI

chronic setting, and health-related quality of life in patients with
severe chronic respiratory failure.

In addition, Wolfram Windisch has chaired the German

Interdisciplinary Society of Home Mechanical Ventilation, the
group for noninvasive ventilatory support within assembly 2 of
the European Respiratory Society, and the section for intensive
care medicine of the German Society of Pneumology and
Ventilation. He has organised several symposia and conferences
on mechanical ventilation and serves as an invited speaker at
national and international conferences. He also serves as the
responsible author for the German guidelines for noninvasive
and invasive mechanical ventilation for treatment of chronic
respiratory failure, and has served as a co-author for the German
guidelines on acute NIV and for the German guidelines on
prolonged weaning.

ix

FB:Cardiologia Siglo XXI

 ERS | monograph

Introduction
Leo Heunks1, Alexandre Demoule2,3 and Wolfram Windisch4

Pulmonary emergencies are potentially life-threatening conditions that require immediate

attention to avoid delay in treatment. These patients most often present with severe
dyspnoea, but other symptoms and signs may include collapse, chest pain and haemoptysis.
A variety of healthcare professionals, such as pulmonologists, emergency room (ER)
physicians, intensivists, general internists, anaesthesiologists, respiratory therapists, residents
and ER nurses, may be involved in the acute care of these patients. The differential
diagnosis of a pulmonary emergency, e.g. presenting with dyspnoea, may be very broad and
could result from dysfunction of the airways, lung parenchyma or pulmonary vasculature.
In every patient presenting to the ER, this differential diagnosis should be considered.

In this ERS Monograph, the most common and also rather less common causes for
pulmonary emergencies are described. Each chapter discusses pathophysiology, differential
diagnosis and treatment strategies. In addition, the last five chapters describe common
pulmonary interventions in detail. The chapters are written by recognised experts in their
field and all chapters have been peer reviewed. Thanks to the effort of so many
professionals, this has become a very impressive ERS Monograph that will definitely be of
value to all colleagues involved in the care of patients with pulmonary emergencies.

We would like to thank all the authors, reviewers and ERS staff for their time and effort to
make this ERS Monograph a success.

Disclosures: L. Heunks has received research grants from Orion Pharma and Bayer, and personal fees from
Biomarin, Maquet and Orion Pharma. A. Demoule has received grants from Maquet, Covidien and Philips,
personal fees from Maquet, Covidien and Merck Sharp & Dohme, and nonfinancial support from Philips and
Dräger, and also has financial relationships with ResMed and Fisher & Paykel. W. Windisch has received fees
for advisory board meetings and lectures, and an open research grant for Cologne-Merheim Hospital from
Maquet Cardiopulmonary.

1
Dept of Intensive Care Medicine, VU University Medical Center Amsterdam, Amsterdam, The Netherlands. 2Sorbonne Universités,
UPMC Univ Paris 06, INSERM, UMRS1158 Neurophysiologie respiratoire expérimentale et clinique, Paris, France. 3AP-HP, Groupe
Hospitalier Pitié-Salpêtrière Charles Foix, Service de Pneumologie et Réanimation Médicale (Département “R3S”), Paris, France. 4Dept of
Pneumology and Critical Care Medicine, Cologne-Merheim Hospital, ARDS and ECMO Centre, Kliniken der Stadt Köln gGmbH,
Witten/Herdecke University Hospital, Cologne, Germany.

Correspondence: Leo Heunks, VU University Medical Center Amsterdam, Dept of Intensive Care Medicine, P.O. Box 7057, 1007 MB,
Amsterdam, The Netherlands. E-mail: L.Heunks@VUmc.nl

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

x ERS Monogr 2016; 74: x. DOI: 10.1183/2312508X.10018316

FB:Cardiologia Siglo XXI

List of abbreviations

ARDS acute respiratory distress syndrome

BAL bronchoalveolar lavage
BMI body mass index
COPD chronic obstructive pulmonary disease
CPAP continuous positive airway pressure
CT computed tomography
ECMO extracorporeal membrane oxygenation
FEV1 forced expiratory volume in first second
FIO2 inspiratory oxygen fraction
ICU intensive care unit
NIV noninvasive ventilation
PaCO2 arterial carbon dioxide tension
PaO2 arterial oxygen tension
PEEP positive end-expiratory pressure
RCT randomised controlled trial
SpO2 arterial oxygen saturation measured by pulse oximetry

FB:Cardiologia Siglo XXI

 | Chapter 1
Pneumothorax
Steve Walker and Nick Maskell

Pneumothorax is a heterogeneous condition whose presentation and disease course are

influenced by individual phenotypes, risk factors and underlying pathophysiology. The
management of pneumothoraces should be personalised, taking into account the presenting
patient with their symptoms and accompanying chest imaging, as well as their risk of
developing a subsequent pneumothorax. Further understanding of risk stratification, newer
treatment options such as ambulatory devices and further research into the role of
conservative management are likely to influence future management pathways.

P neumothorax is a relatively common clinical problem. Despite its prevalence, there are
many areas of recognised uncertainty in the natural history and management of the
condition. This chapter provides an overview of the epidemiology and pathogenesis of
pneumothoraces, and how these influence current management strategies, as well as the
rationale behind newer individualised treatment strategies and the future treatment of
pneumothoraces.

Pneumothorax is defined as air in the pleural space [1] and is classically categorised into
spontaneous or traumatic. Spontaneous pneumothoraces occur without preceding trauma
and are further categorised into primary or secondary, depending on the absence or
presence of underlying lung disease, respectively. Traumatic pneumothoraces arise as a
result of direct or indirect trauma to the chest. When these occur as a result of a procedure,
they are termed iatrogenic. The focus of this chapter will be spontaneous pneumothoraces.

The American College of Chest Physicians (ACCP) Delphi consensus 2001 [2] and the
British Thoracic Society (BTS) guidelines 2010 [3] have guided recent management of
pneumothoraces. While there is disparity between the two guidelines, the underlying
premise of removing air from the pleural space in a symptomatic or large pneumothorax is
the same. A recent task force statement from the European Respiratory Society in 2015
reviewed the current evidence and highlighted areas of uncertainty, particularly how to
identify patients at risk of reoccurrence and those suitable for early definitive treatment [4].

Epidemiology

Primary spontaneous pneumothorax (PSP) has an annual incidence of 7.4 per 100 000
population in males and 1.2 per 100 000 in females [5]. The annual incidence of secondary

Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, UK

Correspondence: Nick Maskell, Academic Respiratory Unit, School of Clinical Sciences, University of Bristol, Bristol, BS10 5ND, UK.
E-mail: nick.maskell@bristol.ac.uk

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 1–14. DOI: 10.1183/2312508X.10001116 1

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

spontaneous pneumothorax (SSP) is 6.3 per 100 000 population in males and 2.0 per
100 000 in females [5]. There is bimodal distribution, with a peak incidence in young
people aged 15–34 years and another in those aged >55 years [6]. These peaks are often
associated with PSP and SSP, respectively [6].

Smoking is the most important risk factor in PSP. The relative risk of a first PSP was
increased 22-fold in men who smoked, and ninefold in women, compared with nonsmokers,
with a lifetime risk of developing pneumothorax of 12% in smoking males compared with
0.1% in nonsmoking males [7]. There is a strong dose–response relationship between the
risk of pneumothorax and the number of cigarettes smoked per day [7].

Cannabis smoking, causing bullous disease, is another risk factor for pneumothorax [8].
Male sex [9], height [9] and a low BMI [10] are also associated with increased risk of PSP.
There are also a range of inherited disorders that predispose to pneumothorax, including
Marfan syndrome [11] and cystic lung disorders such as Birt–Hogg–Dubé syndrome [12]
and pulmonary lymphangioleiomyomatosis (LAM). LAM is a rare disease that
characteristically affects women of reproductive age. It causes smooth muscle infiltration
and cystic destruction of the lung. It is thought that the prevalence of LAM in nonsmoking
women aged between 25 and 54 years with a spontaneous pneumothorax is 5%, with 70% of
patients with LAM having a pneumothorax at some point in their disease course [13]. A
temporal relationship between pneumothorax and menses has been identified. Catamenial
pneumothorax, which can occur 72 h either side of the start of menses, has been shown to
be responsible in >30% of pre-menopausal women who were treated surgically for PSP [14].

Pathophysiology

Historically, PSP and SSP have been divided into two separate pathophysiological groups.
SSP, a pneumothorax that occurs in patient with known lung disease, occurs across a
spectrum of diseases and the pathogenesis is multifactorial. Airways diseases (e.g. COPD,
asthma, cystic fibrosis) are the most common underlying diseases, although infectious lung
disease (e.g. Pneumocystis jiroveci infection, tuberculosis, necrotising pneumonia), interstitial
lung disease, connective tissue disease and cancer can also be underlying causes [15].

PSP is categorised by the absence of apparent lung disease. It has, however, become clearer
that the majority of patients with PSP have evidence of lung abnormalities, such as
emphysema-like changes, subpleural blebs and bullae. These emphysema-like changes were
identified by CT in a case–control series in 81% of nonsmokers with PSP compared with
0% of healthy volunteers [16].

These lung abnormalities, identified on CT and thoracoscopy, are thought by many to be

responsible for pneumothorax and are often the target for surgical management. It has
been hypothesised that there is progression from normal pleura to blebs to the larger
bullae, which can then rupture [17]. This view, however, is not universal, with many
patients not having detectable blebs [18]. Furthermore, studies comparing the appearance
of blebs and bullae after the first episode of PSP and those in recurrent PSP by medical
thoracoscopy did not find any significant difference in size, number or location of the blebs
and bullae, suggesting that they may not be a major risk factor [19]. The concept of pleural
porosity is another mechanism that has been proposed in the formation of a
pneumothorax, in additional to macroscopic changes. This hypothesis was investigated by

FB:Cardiologia Siglo XXI

 PNEUMOTHORAX | S. WALKER AND N. MASKELL

NOPPEN et al. [20] using fluorescein during thoracoscopy to visualise parenchymal

abnormalities of the visceral pleural and to determine whether this was localised to blebs.
Extensive subpleural fluorescein accumulation and fluorescein leakage, which they
described as high-grade lesions, were present exclusively in PSP and were not necessarily
associated with blebs or bullae or with other abnormalities visible on white-light inspection.
They described this as pleural porosity, postulating that loss of surface mesothelial cells,
thinning and rupture of the basement membrane, and/or downregulation of junctional
proteins may play a role. The concept of diffuse pleural porosity may explain the reported
significantly higher recurrence rates if pleurodesis of some form had been omitted during
video-assisted thoracoscopic surgery (VATS) [21].

The hypothesis that air trapping from peripheral airway obstruction could result in a
pressure increase, resulting in pneumothorax, was investigated in a study examining lung
density values in CT in patients with PSP and in normal volunteers [22]. It showed lower
lung densities, suggestive of air trapping, in patients with PSP. This was independent of
smoking and bullous disease [22]. The authors concluded that air trapping may be a
contributing factor in the pathogenesis of PSP. A study by BINTCLIFFE et al. [23] used CT to
investigate the lung structure and extent of emphysema in patients with PSP or SSP and in
a control group. They found that the majority of patients with PSP had quantifiable
evidence of parenchymal destruction and emphysema. Patients with PSP who smoked had
significantly greater low-attenuation areas than patients with PSP who were nonsmokers
[23]. The presence of these abnormalities in patients with PSP, combined with the
demonstrated relationship with smoking, belies the idea that PSP occurs in normal lungs.

Diagnosis

Patients with PSP often have minimal or absent symptoms. PSP can present with chest
pain (81%) and less commonly dyspnoea (39%) [24]. It is not provoked by exercise and
typically occurs at rest (80%) [24]. SSP usually presents with dyspnoea and can be
accompanied by chest pain, hypoxaemia, hypotension and hypercapnia. The patient may be
very unwell with their underlying lung disease.

Characteristic physical findings are ipsilateral diminished breath sounds, reduced lung
expansion and hyperresonance.

Diagnosis is confirmed by a posterior–anterior chest radiograph with displacement of the

pleural line, with absent lung markings distally (figure 1). An air–fluid level is visible in
50% of cases [25]. There is no benefit in an expiratory film [26].

Thoracic ultrasound is being used more frequently in the diagnosis of pneumothorax,

particularly in the emergency trauma and critical care setting. In this setting, it has been
shown to be more sensitive and specific than a chest radiograph, with one study
demonstrating a sensitivity for ultrasound of 98% and a specificity of 99% [27]. However,
there is limited evidence behind its use in spontaneous pneumothorax.

Chest CT is regarded as the “gold standard” [3] in the detection of pneumothorax and can
be helpful to further investigate complex pneumothoraces, identify small pneumothoraces
and distinguish pneumothorax from bullae in patients with SSP. The latter can be
particularly challenging with a plain chest radiograph. A visceral pleural line running

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Figure 1. Chest radiograph of a left-sided pneumothorax (indicated by white arrows).

parallel to the chest wall is more suggestive of a pneumothorax, while bullae have a concave
appearance (figure 2).

Management

As outlined above, pneumothorax is a heterogeneous condition, influenced by individual

modifiable and nonmodifiable risk factors and pathophysiology, and accordingly should be
managed in a personalised way. The management of spontaneous pneumothorax can be

a) b)

Figure 2. a) Chest radiograph of a left-sided secondary spontaneous pneumothorax and bullous emphysema
with b) corresponding chest CT.

FB:Cardiologia Siglo XXI

 PNEUMOTHORAX | S. WALKER AND N. MASKELL

divided into three areas: 1) immediate management of the pneumothorax; 2) how and
when to deal with failure of initial management; and 3) how to prevent reoccurrence.

Immediate management

The immediate management of spontaneous pneumothorax is determined by several

factors. If the patient is haemodynamically unstable or has bilateral pneumothoraces, then a
chest drain should be inserted as a first line [3]. If the patient is thought to be in tension,
they should be managed as detailed below, with needle decompression and a chest drain
(figure 3). For all other pneumothoraces, the management pathway, outlined by the ACCP
Delphi consensus 2001 [2] and the BTS guidelines 2010 [3] is determined by: 1) whether
the pneumothorax is deemed primary or secondary; 2) the presence of symptoms; and
3) the size of the pneumothorax on chest radiograph.

If a patient has a PSP, is asymptomatic and has a small pneumothorax, then a conservative
management plan of monitoring is advocated by the BTS [3]. The rate of resolution of an
untreated PSP has been calculated by CT volumetry at 2.2% per day [28]. The use of
high-flow oxygen in treatment of pneumothorax was shown to speed up the resolution of
PSP fourfold when patients were admitted for observation [29].

If the patient is symptomatic or has a large pneumothorax, an intervention to remove the

air from the pleural space is advised. The ACCP and BTS differ on the definition of a large

Spontaneous pneumothorax
confirmed on
chest radiograph

Age >50 years

No with significant Yes
smoking history or
known lung
disease
Primary pneumothorax Secondary pneumothorax

Size >2 cm and/or Size >2 cm or Size Size

symptomatic breathless 1–2 cm <1 cm

No Yes

Failure
Consider Aspirate with Aspirate with Admit for
discharge with cannula cannula observation
early review
Failure (still >1 cm)
Some patients with large Chest drain
primary pneumothorax Admit
but minimal symptoms
may be appropriate
for conservative
management

Figure 3. Pneumothorax management flow diagram. Reproduced and modified from [3] with permission.

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

pneumothorax. The ACCP suggests >3 cm from the apex of the hemidiaphragm to the
cupula [2]. The BTS definition is >2 cm from the lung margin to the chest at the level of
the hilum (figure 3) [3].

The BTS suggests that if the pneumothorax is large or the patient is symptomatic, simple
aspiration should be attempted. If this does not succeed, the clinician should proceed to
chest tube insertion, with a recommendation that a small-bore (<14-French) Seldinger chest
drain should be used (figure 3) [3]. The ACCP advocates proceeding directly to chest tube
insertion [2]. The rationale behind the BTS guidance comes from studies [30, 31] and
meta-analyses [32–34] that suggested that simple aspiration was as successful as a chest
drain in treating pneumothorax, and led to fewer bed days. It is recommended that if
>2.5 L of air is removed via simple aspiration, then the physician should proceed to a chest
tube, as there is likely to be a persistent air leak [3].

The guidance for SSP is similarly based on the size of the pneumothorax and symptoms.
Symptomatic patients or patients with large pneumothoraces should have a chest tube
inserted. The BTS suggests that if a patient is asymptomatic and the pneumothorax is
between 1 and 2 cm, simple aspiration can be attempted. If the pneumothorax is smaller
than 1 cm, admission with observation is recommended (figure 3) [3].

Managing a persistent air leak and failure to re-expand

Suction
The routine use of early suction is not recommended by the BTS guidelines [3]. A small
RCT found no significant difference in the rate of lung re-expansion or duration of hospital
stay with suction compared with no suction [35].

There may be a role for the use of high-volume, low-pressure suction in a persistent air
leak (arbitrarily defined as continuous bubbling for >48 h after chest drain insertion) or
incomplete re-expansion of the lung, with the theory that the air may be removed from the
pleural cavity at a greater rate than it enters via the visceral membrane. The use of suction
too early can precipitate re-expansion pulmonary oedema, particularly if the pneumothorax
has been present for more than a few days. High-pressure, high-volume suction may lead
to perpetuation and/or worsening of the air leak [3]. The typical pressure used is between
−10 cmH2O and −20 cmH2O.

Surgery
In cases of a persistent air leak or failure of the lung to re-expand after 3–5 days, the BTS
recommends that a thoracic surgical opinion should be sought.

The timing of surgical intervention is debated. A study by CHEE et al. [36] showed that
100% of PSPs and 79% of SSPs with a persistent air leak of >7 days treated with an
intercostal drain resolved by day 15 and day 14, respectively, with no mortality. However,
surgery carries a low morbidity risk and has good success rates.

There are two main types of surgery, thoracotomy and VATS, with both performed under
general anaesthetic. There are several approaches to thoracotomy: the standard posterolateral
thoracotomy or methods using a smaller incision, such as axillary thoracotomy, anterior
thoracotomy or various mini-thoracotomies [15]. The procedure consists of excision of blebs

FB:Cardiologia Siglo XXI

 PNEUMOTHORAX | S. WALKER AND N. MASKELL

and bullae, usually via stapling and treatment of smaller bullae with an electrocoagulant or
laser [15]. Usually, the surgeon will perform pleurodesis, either by a parietal pleurectomy or
by mechanical abrasion of the parietal pleura with gauze. Some surgeons perform chemical
pleurodesis. VATS is performed under general anaesthetic with single-lung ventilation.
Generally, three ports, a thoracoscope and two lung graspers, are inserted, with the patient
in the lateral decubitus position. The same intrathoracic procedure can be performed by
VATS as via an open thoracotomy [15].

Analysis of RCTs has demonstrated an equivalent success rate between VATS and thoracotomy,
with a reduction in analgesia and shorter hospital stays in the VATS cohort [37]. An RCT
comparing mini-thoracotomy with VATS showed equivalent reoccurrence rates (2.7% and 3%,
respectively) and postoperative pain, with VATS associated with greater patient satisfaction [38].
A recent large prospective cohort study of 1415 patients undergoing VATS with talc poudrage
found a recurrence rate of 1.9% and a complication rate of 2% [39]. Interestingly, the
recurrence rate was much higher in smokers (4.2%) compared with nonsmokers (0.2%) [39].

Accepted indications for surgical advice are shown in table 1.

Pleurodesis
Pleurodesis by chemical irritant, mechanical abrasion or parietal pleurectomy aims to achieve
adherence of the pleural membranes by promoting inflammation. Chemical pleurodesis by a
sclerosing agent can be delivered by chest tube, medical thoracoscopy or VATS.

Chemical pleurodesis with intrapleural administration via a chest tube has been investigated
with several agents, including antibiotics (minocycline, tetracycline and doxycycline) and talc
preparations. It is a suitable option for patients who would be ineligible or unwilling to have
surgery, after assessment by a respiratory specialist. It has been suggested that chemical
pleurodesis is an easy, safe and cost-effective method for the treatment of spontaneous
pneumothorax and could be considered as an initial treatment of PSP [40]. It has the
advantage of being able to be administered by the bedside; however, there are potential
drawbacks of uneven distribution of talc and the potential for only localised pleurodesis at the
site of administration [4]. An RCT investigating the use of minocycline pleurodesis via chest
drain versus chest drain with no pleurodesis in patients with PSP showed lower recurrence rates
of 29.2% in the minocycline pleurodesis arm versus 49.1% in the control group [41]. However,
it has been noted by others that this trial had a high recurrence rate in the control group
compared with other studies and compared unfavourably with surgical options [42].

Talc delivered by medical thoracoscopy under direct vision has good long-term success
rates. In an RCT in patients with PSP, talc poudrage medical thoracoscopy had a lower

Table 1. Indications for surgical opinion in the management of pneumothorax [3]

Second ipsilateral pneumothorax

First contralateral pneumothorax
Synchronous bilateral spontaneous pneumothorax
Persisting air leak (despite 5–7 days of chest tube drainage) or failure of lung re-expansion
Spontaneous haemothorax
Professions at risk (aircraft personnel, divers)
Pregnancy

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

recurrence rate when compared with chest tube alone (5% versus 27%, respectively) and
was more cost-effective [43].

Prevention of recurrence and risk stratification

As mentioned in the previous section, surgery and talc poudrage have both been shown to
dramatically reduce recurrence. The decision to perform a definitive invasive procedure is
based on the risk of recurrence, and the potential consequences if one occurs. Currently,
most centres wait until the second presentation of PSP before considering definitive
management, although it is often considered earlier in patients with SSP, due to the
potentially life-threatening risk of a recurrence. However, the decision is made difficult
because of a wide range in the quoted recurrence rates from 13.5% to 54% [41, 44, 45] and
limited data on how individual risk factors affects this. The studies examining recurrence
have used differing methodologies and include epidemiological and prospective randomised
studies with various inclusion criteria, timescales and definitions of recurrence. In a recent
prospective cohort study of 234 consecutive patients with their first episode of PSP who
were admitted and treated conservatively with a chest tube, recurrence was observed in 54%
of patients, with 30% of these patients experiencing a pneumothorax in the contralateral
lung [46]. Conversely, a recent epidemiological study of 246 534 episodes of spontaneous
pneumothorax (PSP and SSP) in the UK found a 13.5% risk of recurrence requiring
readmission to hospital within 1 year [45]. Studies looking at SSP have found that 40–50%
of patients will have a second pneumothorax if pleurodesis or definitive thoracic surgery is
not performed [47]. The rate of pneumothorax is also thought to increase with every
subsequent recurrence. A study from 1963 found that the risk of recurrence was 57% after
the first pneumothorax, 62% after the second and 83% after the third [48]. However, this
was only statistically significantly different between the first and third recurrence [49].

One of the aims in the management of pneumothorax should centre on the identification
of patients likely to have a recurrence and hence who may benefit from early surgery.
Height in men, female sex and low bodyweight are associated with an increased rate of
recurrence [44, 46]. Smoking is associated with a high risk of recurrence, with smoking
cessation after an initial PSP associated with a relative risk reduction of >40% [44]. As the
rupture of blebs or bullae is thought to be the main cause of PSP, studies have looked into
whether radiology can help in predicting the risk of reoccurrence, providing conflicting
answers. A prospective study by MARTÍNEZ-RAMOS et al. [50] of 55 patients could not
demonstrate that the presence, size or number of bullae on CT scans had any influence on
recurrence rate. A subsequent study using high-resolution CT on 176 patients with PSP
found that the risk of reoccurrence was significantly related to the presence of blebs or
bullae, or both [51]. Another study looked at the role of the chest radiography in
determining the reoccurrence risk. They looked for radiological abnormalities on the chest
radiograph including pleural thickening, blebs/bullae, pleural irregularities and pleural
adhesions. They found that the presence of an abnormality (irrespective of type) increased
the likelihood of recurrence, and the risk of recurrence increased with each additional
abnormality. They recommended surgical pleurodesis for the first episode of PSP when
multiple chest radiograph abnormalities are identified at the time of diagnosis [52].

Follow-up

The BTS guidelines recommend that all patients discharged after admission for pneumothorax
should be given verbal and written advice about re-presentation if they develop further

FB:Cardiologia Siglo XXI

 PNEUMOTHORAX | S. WALKER AND N. MASKELL

symptoms [3]. They should be followed up by a respiratory physician to ensure resolution,

institute optimal care of underlying lung disease, explain the risk of recurrence and discuss the
possible future need for surgical interventions, as well as re-emphasising lifestyle advice, such
as smoking cessation and air travel. Air travel is advised against until 1 week after full
resolution of the pneumothorax [3].

Tension pneumothorax

Tension pneumothorax is an uncommon, life-threatening emergency. It can be defined in

various ways [53]: 1) clinically, in terms of haemodynamic compromise improved by
decompression; 2) in terms of pleural pressures, with ipsilateral pleural pressures exceeding
atmospheric pressure; or 3) radiographically, with signs of mediastinal shift (although this
can also present in nontension pneumothorax).

Tension pneumothorax occurs from a pleural defect forming a one-way valve system in the
pleural membrane, with air entering the pleural cavity on inspiration but unable to exit on
expiration. It can arise in a wide range of clinical situations, including ventilated patients,
trauma, cardiopulmonary resuscitation, patients with acute exacerbation of lung disease,
blocked chest drains and patients receiving NIV. It rarely occurs in PSP [3].

The patient is often very symptomatic and in haemodynamic compromise, with decreased
air entry the most common sign (in 50–75% of patients). Trachea deviation away from the
affected lung, hyperresonance, hypomobility and hyperexpansion occur less frequently [3].
It is important to recognise the potential differences in clinical presentation in ventilated
and nonventilated patients [3]. Diagnosis of tension pneumothorax in ventilated patients
requires a high index of suspicion. Its presentation, however, is more consistent than in
awake patients, usually presenting with a sudden fall in SpO2, followed by hypotension over a
few minutes [53], with tachycardia, decreasing cardiac output, increased inflation pressures
and ultimately cardiac arrest [3].

Awake patients show a greater variability of presentation. They manifest compensatory

mechanisms and generally have progressive respiratory deterioration with final respiratory
arrest. The time lag from initial symptoms or thoracic insult to diagnosis ranges from a few
minutes to >16 h [53].

A chest radiograph is not usually useful and can be misleading, with the size of the
pneumothorax and mediastinal displacement not correlating with the degree of tension [3].

The management is high-flow oxygen and prompt emergency needle decompression in the
mid-clavicular line, second intercostal space, which is recommended prior to a chest
radiograph. A large study found that the mean chest wall thickness of 2574 healthy
volunteers, as determined by magnetic resonance imaging, was 5.7 cm on the right and
5.5 cm on the left side in the mid-clavicular line, second intercostal space [54], suggesting
that a 7-cm needle may be required [54]. A review article on tension pneumothorax
recognised that the standard 14-gauge (4.5 cm) cannula may not be long enough to penetrate
the parietal pleura in up to one-third of trauma patients, leading to treatment failure and
diagnostic confusion [53]. The use of a trocar instead (7 cm) may negate this problem and
prevent kinking. The BTS recommends that if needle decompression is not possible in the
second intercostal space, the chest wall may be less deep in the fourth and fifth interspace

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

and may provide an alternative [3]. This should be followed by a chest tube, with the cannula
left in place until bubbling is confirmed with an underwater seal system [3].

Novel management strategies

Ambulatory conservative management

Conservative management is recommended for patients with a small asymptomatic PSP by the
BTS [3]. The guidelines do suggest that selected asymptomatic patients with a large PSP may be
managed by observation alone. It has been hypothesised that the collapsed lung is more likely
to heal, allowing apposition of the visceral leak sites [55]. This is currently under investigation
by a multicentre RCT in Australasia, which has been set up to compare ambulatory
conservative management with standard management in asymptomatic patients with large
pneumothoraces (Australian New Zealand Clinical Trials Registry (www.anzctr.org.au), trial
number ACTRN12611000184976).

Use of a Heimlich valve and pleural vents

A Heimlich valve is a one-way valve system that can be attached to a chest tube to enable
ambulatory drainage for a patient. Their use has been evaluated in small RCTs and case
series, and was subject to a recent literature review (1235 cases in total), which concluded
that a Heimlich valve may have benefits for patients’ comfort, mobility and avoidance of
hospital admission, with comparable outcomes to other current practices, with serious
complications being rare [56].

A recent study evaluated their use in patients with iatrogenic pneumothorax following lung
biopsy [57]. In patients with a large or symptomatic pneumothorax at 30 min post-biopsy,
an enlarging pneumothorax at 60 min, or a persisting or symptomatic pneumothorax, an
8-French drain was inserted and connected to a Heimlich valve chest drain (HVCD). There
were no major complications, but eight of the 52 patients developed HVCD-related
pleuritic pain, which was successfully managed with 10 mL of intrapleural 0.5%
bupivacaine. All patients had their HVCD removed within 48 h. These results are
encouraging but may not translate to primary pneumothoraces.

The use of ambulatory pleural vents (figure 4) for the treatment of PSP is currently under
evaluation in a randomised multicentre trial for PSP (ISRCTN Registry (www.isrctn.com),
trial number ISRCTN79151659). An RCT on their use in SSP is about to commence
shortly (Hi-SPEC trial).

Endobronchial valves

Endobronchial valves, more commonly used as an alternative to lung reduction surgery in

emphysema, have been used in patients with pneumothorax and a persistent air leak who
were deemed not fit for surgical management. These one-way valves are inserted via
bronchoscopy and aim to obstruct the bronchial airway, resulting in atelectasis of the distal
lung, while still allowing drainage of secretions. The largest study into this was a
retrospective, nonrandomised study in 40 patients with pneumothoraces (iatrogenic, PSP and
SSP), and demonstrated that 19 patients (47.5%) had complete resolution of an acute air leak,

10

FB:Cardiologia Siglo XXI

 PNEUMOTHORAX | S. WALKER AND N. MASKELL

a) b)

Figure 4. a) Pleural vent in a patient with secondary spontaneous pneumothorax. b) Pleural vent with safety
insertion needle in situ.

18 patients (45.0%) had a reduction and two patients (5.0%) had no change in air leak status
[58]. The remaining patient had no reported outcome.

Air leak monitoring system

Digital drainage systems have been used to allow real-time, continuous quantification of air
leaks (figure 5). They have been studied in post-lobectomy chest drains, with several studies
showing a reduction in chest drain duration in patients with digital monitoring of air leaks
compared with a traditional protocol of using visual and subjective assessment of air leaks

Figure 5. Digital air leak monitoring system (Thopaz Digital Chest Drainage System; Medela Inc. Healthcare,
McHenry, IL, USA).

11

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

(bubbles) [59–61]. This was contradicted by a more recent study, which showed no change in
chest drain duration [62]. However, there are no published studies to date looking at the digital
assessment of air leaks in medical patients with PSP or SSP, and caution must be used in
applying post-surgical data, whose outcome was chest drain duration. It has been reasonably
suggested that digital assessment is a more accurate way of quantifying the air leak than visual
inspection of air bubbles in the chest drain bottle. It may allow earlier identification of patients
whose leak is not settling and would benefit from early thoracic surgery [4].

Conclusion

Pneumothoraces are a relatively common medical condition that can present as a medical
emergency. Any physician managing acute medical patients should be aware of the current
treatment algorithms and the factors that influence them, as well as how to identify a
life-threatening tension pneumothorax. A greater understanding of the underlying
pathophysiology and risk factors involved in the development and formation of pneumothoraces
will hopefully enable a more personalised management plan. Newer therapeutic options may
enable alternative management pathways for low-risk and ambulatory patients.

References
1. Miller A. Spontaneous pneumothorax. In: Light RW, Lee Y, eds. Textbook of Pleural Disease. 2nd Edn. London,
Hodder Arnold, 2008; pp. 515–532.
2. Baumann MH, Strange C, Heffner JE, et al. Management of spontaneous pneumothorax: an American College of
Chest Physicians Delphi consensus statement. Chest J 2001; 119: 590–602.
3. MacDuff A, Arnold A, Harvey J. Management of spontaneous pneumothorax: British Thoracic Society Pleural
Disease Guideline 2010. Thorax 2010; 65: Suppl. 2, ii18–ii31.
4. Tschopp JM, Bintcliffe O, Astoul P, et al. ERS task force statement: diagnosis and treatment of primary
spontaneous pneumothorax. Eur Respir J 2015; 46: 321–335.
5. Melton LJ III, Hepper NG, Offord KP. Incidence of spontaneous pneumothorax in Olmsted County, Minnesota:
1950 to 1974. Am Rev Respir Dis 1979; 120: 1379–1382.
6. Gupta D, Hansell A, Nichols T, et al. Epidemiology of pneumothorax in England. Thorax 2000; 55: 666–671.
7. Bense L, Eklund G, Wiman LG. Smoking and the increased risk of contracting spontaneous pneumothorax. Chest J
1987; 92: 1009–1012.
8. Gill A. Bong lung: regular smokers of cannabis show relatively distinctive histologic changes that predispose to
pneumothorax. Am J Surg Pathol 2005; 29: 980–982.
9. Melton L III, Hepper N, Offord K. Influence of height on the risk of spontaneous pneumothorax. Mayo Clin Proc
1981; 56: 678–682.
10. Biffl WL, Narayanan V, Gaudiani JL, et al. The management of pneumothorax in patients with anorexia nervosa:
a case report and review of the literature. Patient Saf Surg 2010; 4: 1.
11. Dyhdalo K, Farver C. Pulmonary histologic changes in Marfan syndrome: a case series and literature review. Am J
Clin Pathol 2011; 136: 857–863.
12. Toro JR, Pautler SE, Stewart L, et al. Lung cysts, spontaneous pneumothorax, and genetic associations in 89
families with Birt-Hogg-Dubé syndrome. Am J Respir Crit Care Med 2007; 175: 1044–1053.
13. Hagaman JT, Schauer DP, McCormack FX, et al. Screening for lymphangioleiomyomatosis by high-resolution
computed tomography in young, nonsmoking women presenting with spontaneous pneumothorax is cost-effective.
Am J Respir Crit Care Med 2010; 181: 1376–1382.
14. Rousset-Jablonski C, Alifano M, Plu-Bureau G, et al. Catamenial pneumothorax and endometriosis-related
pneumothorax: clinical features and risk factors. Hum Reprod 2011; 26: 2322–2329.
15. Tschopp J, Rami-Porta R, Noppen M, et al. Management of spontaneous pneumothorax: state of the art.
Eur Respir J 2006; 28: 637–650.
16. Bense L, Lewander R, Eklund G, et al. Nonsmoking, non-alpha1-antitrypsin deficiency-induced emphysema in
nonsmokers with healed spontaneous pneumothorax, identified by computed tomography of the lungs. Chest 1993;
103: 433–438.

12

FB:Cardiologia Siglo XXI

 PNEUMOTHORAX | S. WALKER AND N. MASKELL

17. Vanderschueren R. Le talcage pleural dans le pneumothorax spontané [Pleural talcage in patients with spontaneous
pneumothorax (author’s translation)]. Poumon Coeur 1981; 37: 273–276.
18. Cardillo G, Carleo F, Giunti R, et al. Videothoracoscopic talc poudrage in primary spontaneous pneumothorax: a
single-institution experience in 861 cases. J Thorac Cardiovasc Surg 2006; 131: 322–328.
19. Janssen JP, Schramel FM, Sutedja TG, et al. Videothoracoscopic appearance of first and recurrent pneumothorax.
Chest J 1995; 108: 330–334.
20. Noppen M, Dekeukeleire T, Hanon S, et al. Fluorescein-enhanced autofluorescence thoracoscopy in patients with
primary spontaneous pneumothorax and normal subjects. Am J Respir Crit Care Med 2006; 174: 26–30.
21. Hatz RA, Kaps MF, Meimarakis G, et al. Long-term results after video-assisted thoracoscopic surgery for first-time
and recurrent spontaneous pneumothorax. Ann Thorac Surg 2000; 70: 253–257.
22. Smit HJ, Golding RP, Schramel FM, et al. Lung density measurements in spontaneous pneumothorax demonstrate
airtrapping. Chest 2004; 125: 2083–2090.
23. Bintcliffe OJ, Edey AJ, Armstrong L, et al. Lung parenchymal assessment in primary and secondary pneumothorax.
Ann Am Thorac Soc 2015; 13: 350–355.
24. Bense L, Wiman L, Hedenstierna G. Onset of symptoms in spontaneous pneumothorax: correlations to physical
activity. Eur J Respir Dis 1987; 71: 181–186.
25. Glazer H, Anderson D, Wilson B, et al. Pneumothorax: appearance on lateral chest radiographs. Radiology 1989;
173: 707–711.
26. Bradley M, Williams C, Walshaw MJ. The value of routine expiratory chest films in the diagnosis of
pneumothorax. Arch Emerg Med 1991; 8: 115–116.
27. Blaivas M, Lyon M, Duggal S. A prospective comparison of supine chest radiography and bedside ultrasound for
the diagnosis of traumatic pneumothorax. Acad Emerg Med 2005; 12: 844–849.
28. Kelly A, Loy J, Tsang A, et al. Estimating the rate of re-expansion of spontaneous pneumothorax by a formula
derived from computed tomography volumetry studies. Emerg Med J 2006; 23: 780–782.
29. Chadha T, Cohn M. Noninvasive treatment of pneumothorax with oxygen inhalation. Respiration 1983; 44: 147–152.
30. Noppen M, Alexander P, Driesen P, et al. Manual aspiration versus chest tube drainage in first episodes of primary
spontaneous pneumothorax: a multicenter, prospective, randomized pilot study. Am J Respir Crit Care Med 2002;
165: 1240–1244.
31. Harvey J, Prescott RJ. Simple aspiration versus intercostal tube drainage for spontaneous pneumothorax in patients
with normal lungs. BMJ 1994; 309: 1338–1339.
32. Devanand A, Koh M, Ong T, et al. Simple aspiration versus chest-tube insertion in the management of primary
spontaneous pneumothorax: a systematic review. Respir Med 2004; 98: 579–590.
33. Zehtabchi S, Rios CL. Management of emergency department patients with primary spontaneous pneumothorax:
needle aspiration or tube thoracostomy? Ann Emerg Med 2008; 51: 91–100.
34. Wakai A, O’Sullivan RG, McCabe G. Simple aspiration versus intercostal tube drainage for primary spontaneous
pneumothorax in adults. Cochrane Database Syst Rev 2007; 1: CD004479.
35. So S, Yu D. Catheter drainage of spontaneous pneumothorax: suction or no suction, early or late removal? Thorax
1982; 37: 46–48.
36. Chee CBE, Abisheganaden J, Yeo JKS, et al. Persistent air-leak in spontaneous pneumothorax – clinical course and
outcome. Respir Med 1998; 92: 757–761.
37. Vohra HA, Adamson L, Weeden DF. Does video-assisted thoracoscopic pleurectomy result in better outcomes than
open pleurectomy for primary spontaneous pneumothorax? Interact Cardiovasc Thorac Surg 2008; 7: 673–677.
38. Foroulis CN, Anastasiadis K, Charokopos N, et al. A modified two-port thoracoscopic technique versus axillary
minithoracotomy for the treatment of recurrent spontaneous pneumothorax: a prospective randomized study. Surg
Endosc 2012; 26: 607–614.
39. Cardillo G, Bintcliffe OJ, Carleo F, et al. Primary spontaneous pneumothorax: a cohort study of VATS with talc
poudrage. Thorax 2016; 71: 847–853.
40. How CH, Hsu HH, Chen JS. Chemical pleurodesis for spontaneous pneumothorax. J Formos Med Assoc 2013; 112:
749–755.
41. Chen JS, Chan WK, Tsai KT, et al. Simple aspiration and drainage and intrapleural minocycline pleurodesis versus
simple aspiration and drainage for the initial treatment of primary spontaneous pneumothorax: an open-label,
parallel-group, prospective, randomised, controlled trial. Lancet 2013; 381: 1277–1282.
42. Bintcliffe O, Maskell N. Spontaneous pneumothorax. BMJ 2014; 348: g2928.
43. Tschopp J, Boutin C, Astoul P, et al. Talcage by medical thoracoscopy for primary spontaneous pneumothorax is
more cost-effective than drainage: a randomised study. Eur Respir J 2002; 20: 1003–1009.
44. Sadikot R, Greene T, Meadows K, et al. Recurrence of primary spontaneous pneumothorax. Thorax 1997; 52: 805–809.
45. Hallifax R, Goldacre R, Goldacre M, et al. The epidemiology of pneumothorax in England (1968–2011). Am J
Respir Crit Care Med 2016; 193: A3254.
46. Olesen WH, Lindahl-Jacobsen R, Katballe N, et al. Recurrent primary spontaneous pneumothorax is common
following chest tube and conservative treatment. World J Surg 2016: 1–8.

13

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

47. Lippert H, Lund O, Blegvad S, et al. Independent risk factors for cumulative recurrence rate after first spontaneous
pneumothorax. Eur Respir J 1991; 4: 324–331.
48. Gobbel WG, Rhea WG, Daniel RA, et al. Spontaneous pneumothorax. J Thorac Cardiov Sur 1963; 46: 331–345.
49. Schramel FM, Postmus PE, Vanderschueren RG. Current aspects of spontaneous pneumothorax. Eur Respir J 1997;
10: 1372–1379.
50. Martínez-Ramos D, Ángel-Yepes V, Escrig-Sos J, et al. Utilidad de la tomografía computarizada para determinar
el riesgo de recidiva tras un primer episodio de neumotórax espontáneo primario. Implicaciones terapéuticas
[Usefulness of computed tomography in determining risk of recurrence after a first episode of primary
spontaneous pneumothorax: therapeutic implications]. Arch Bronconeumol 2007; 43: 304–308.
51. Casali C, Stefani A, Ligabue G, et al. Role of blebs and bullae detected by high-resolution computed tomography
and recurrent spontaneous pneumothorax. Ann Thorac Surg 2013; 95: 249–255.
52. Ganesalingam R, O’Neil RA, Shadbolt B, et al. Radiological predictors of recurrent primary spontaneous
pneumothorax following non-surgical management. Heart Lung Circ 2010; 19: 606–610.
53. Leigh-Smith S, Harris T. Tension pneumothorax – time for a re-think? Emerg Med J 2005; 22: 8–16.
54. Hecker M, Hegenscheid K, Völzke H, et al. Needle decompression of tension pneumothorax: population-based
epidemiologic approach to adequate needle length in healthy volunteers in Northeast Germany. J Trauma Acute
Care Surg 2016; 80: 119–124.
55. Stradling P, Poole G. Conservative management of spontaneous pneumothorax. Thorax 1966; 21: 145–149.
56. Brims FJ, Maskell NA. Ambulatory treatment in the management of pneumothorax: a systematic review of the
literature. Thorax 2013; 68: 664–669.
57. Tavare A, Creer D, Khan S, et al. Ambulatory percutaneous lung biopsy with early discharge and Heimlich valve
management of iatrogenic pneumothorax: more for less. Thorax 2016; 71: 190–192.
58. Travaline JM, McKenna RJ, De Giacomo T, et al. Treatment of persistent pulmonary air leaks using endobronchial
valves. Chest J 2009; 136: 355–360.
59. Brunelli A, Salati M, Refai M, et al. Evaluation of a new chest tube removal protocol using digital air leak
monitoring after lobectomy: a prospective randomised trial. Eur J Cardiothorac Surg 2010; 37: 56–60.
60. Mier JM, Molins L, Fibla JJ. Beneficios del uso de dispositivos digitales para medir la fuga aérea después de una
resección pulmonar: estudio prospectivo y comparative [The benefits of digital air leak assessment after pulmonary
resection: prospective and comparative study]. Cir Esp 2010; 87: 385–389.
61. Pompili C, Brunelli A, Salati M, et al. Impact of the learning curve in the use of a novel electronic chest drainage
system after pulmonary lobectomy: a case-matched analysis on the duration of chest tube usage. Interact
Cardiovasc Thorac Surg 2011; 13: 490–493.
62. Lijkendijk M, Licht PB, Neckelmann K. Electronic versus traditional chest tube drainage following lobectomy:
a randomized trial. Eur J Cardiothorac Surg 2015; 48: 893–898.

Disclosures: N. Maskell has received grants and personal fees from Carefusion.

14

FB:Cardiologia Siglo XXI

 | Chapter 2
Pulmonary embolism
Stefano Barco1 and Stavros V. Konstantinides1,2

Pulmonary embolism (PE) is a significant contributor to global disease burden. The presence
and severity of right ventricle (RV) dysfunction is a key determinant of the patient’s prognosis
in the acute phase. Accordingly, risk-adapted treatment strategies have been developed and
continue to evolve, tailoring initial management to the clinical presentation and the functional
status of the RV. Beyond pharmacological and, if necessary, mechanical circulatory support,
systemic thrombolysis remains the mainstay of treatment for haemodynamically unstable
patients; in contrast, it is not routinely recommended for intermediate-risk PE.
Catheter-directed pharmacomechanical reperfusion treatment represents a promising option
for minimising bleeding risk; for reduced-dose intravenous thrombolysis, the data are still
preliminary. New, non-vitamin-K-dependent oral anticoagulants, directly inhibiting factor Xa
(rivaroxaban, apixaban, edoxaban) or thrombin (dabigatran), have simplified initial and
long-term anticoagulation for PE, while reducing major bleeding risk. Use of vena cava filters
should be restricted to selected patients with absolute contraindications to anticoagulation, or
with PE recurrence despite adequately dosed anticoagulants.

A cute pulmonary embolism (PE) (figure 1), in the majority of cases a consequence and
a threatening clinical manifestation of venous thromboembolism (VTE), is the third
most frequent acute cardiovascular syndrome behind acute myocardial infarction and
stroke, and is a major cause of both acute and long-term morbidity and mortality
worldwide. In Europe, for example, the annual number of PE-related deaths may exceed
500 000 in the population according to a frequently cited epidemiological model [1].
Depending on clinical severity and the presence of haemodynamic instability at
presentation, >30% of the patients suffering acute PE may die within the first 30 days [2],
and as many as 30% of survivors may present with VTE recurrence or some sort of chronic
disabling symptoms within months or years after the index event [3]. Finally, an unclear
proportion of PE patients (between 1% and 9%) will develop, over the long term, a
progressive and potentially lethal pulmonary vascular disease termed chronic
thromboembolic pulmonary hypertension [3, 4]. Unavoidably, the medical relevance of PE
and its continuously growing impact on the health of an ageing, increasingly
thrombosis-prone population are also accompanied by the substantial economic burden
that the disease imposes on healthcare systems [5]. These facts highlight the priority of
developing effective, and more efficient, management strategies for acute PE and its chronic
sequelae.

1
Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany. 2Dept of
Cardiology, Democritus University of Thrace, Alexandroupolis, Greece.

Correspondence: Stavros V. Konstantinides, Center for Thrombosis and Hemostasis, University Medical Center Mainz, Langenbeckstrasse
1, Building 403, 55131 Mainz, Germany. E-mail: stavros.konstantinides@unimedizin-mainz.de

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 15–31. DOI: 10.1183/2312508X.10001216 15

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

a) b)

c) d)

Figure 1. a–c) CT pulmonary angiogram demonstrating bilateral filling defects in the branches of the
pulmonary arteries, which are diagnostic of acute pulmonary embolism. a) Coronary plane and b)
transverse plane. c) A “four-chamber view” in the transverse plane, which allows a first assessment of right
ventricle size, more specifically of the right-to-left ventricle diameter ratio at the tricuspid/mitral annulus
level. d) Transthoracic echocardiogram (parasternal short axis view, mitral valve level) demonstrating right
ventricular enlargement and a D-shaped left ventricle.

The present chapter focuses on the acute-phase management of PE, viewing it from the
angle of medical emergency management. We start by reviewing the progress made
recently in risk assessment, which is based on combining clinical findings and the
functional status of the right ventricle (RV). Along with general measures for treating overt
or impending RV failure, we discuss the evolving, risk-adjusted reperfusion regimens and
strategies, focusing on “safer” thrombolysis and other emerging options of catheter-directed
treatment. Finally, we elaborate on the current status of, and remaining challenges in,

16

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

anticoagulation therapy in the era of non-vitamin-K-dependent, direct oral anticoagulants

(NOACs), and describe the use of vena cava filters when anticoagulants are contraindicated.

Risk stratification of patients with acute PE

The optimal management of patients following the diagnosis of acute PE requires the
stratification of patients into classes of disease severity in order to adjust the initial treatment to
the individual’s early death risk [6]. The key determinants of prognosis in the acute phase of
PE can be summarised as follows: 1) characteristics of the patient’s clinical presentation,
including the presence of comorbidities; and, 2) the presence and severity of RV dysfunction,
as assessed clinically by echocardiography or CT pulmonary angiography (figure 1), or with
the help of laboratory markers, such as cardiac troponins and natriuretic peptides [6]. At the
“high” end of the risk spectrum are patients with overt, noncompensated RV failure resulting
in reduced cardiac output and manifesting clinically as persistent arterial hypotension
accompanied by signs of end-organ hypoperfusion. The patients with high-risk (or “massive”,
as defined in [7]) PE are those expected to benefit most from immediate reperfusion
treatment, combined, if necessary, with circulatory and respiratory support; these measures
aim to reduce the RV pressure overload and restore adequate tissue perfusion and oxygenation.

Although high-risk PE patients are undoubtedly the most challenging subgroup, exhibiting
30-day fatality rates of 20–40% or even higher, they represent only ⩽5% of all PE patients
[2, 8]. The large remaining group of (apparently) stable, non-high-risk PE patients can be
further stratified by employing two categories of clinical tools: 1) the Pulmonary Embolism
Severity Index (PESI), or its simplified form (sPESI); and 2) imaging as well as laboratory
tests detecting manifest or subclinical RV dysfunction [6]. An updated overview of the
imaging and laboratory findings for prediction of intermediate-high risk or intermediate-
low risk PE, with the corresponding cut-off values, is provided in table 1.

While PESI and sPESI serve primarily to identify “low-risk” patients who may not require
further testing and who may be eligible for early discharge and home treatment,
echocardiographic (or CT) or biochemical markers of RV dysfunction represent the key tool
for defining the groups of “intermediate-low risk” (with either evidence of RV dysfunction
or elevated biochemical markers) or “intermediate-high risk” (with RV dysfunction
combined with elevated biochemical markers) (table 2). This advanced classification on the
basis of the functional status of the RV helps to determine the duration of haemodynamic
monitoring, the need for reperfusion treatment, and the choice of the anticoagulant drug
and regimen [6].

Current guidelines do not routinely recommend further risk assessment in patients

belonging to PESI class I or II, or with an sPESI of 0, who are considered to be at “low
risk” based on large cohort studies. Nevertheless, it is possible that some of these patients
will exhibit RV dysfunction on imaging tests and/or elevated biomarker (cardiac troponin
or natriuretic peptide) levels in the blood [22]. If any doubts persist regarding the severity
and haemodynamic impact of PE on the RV following clinical evaluation of the patient,
even in the presence of a formally low PESI or a sPESI of 0, the functional status of the RV
should be assessed by imaging and laboratory testing. This does not need to be a
complicated or time-consuming procedure: the first important piece of information can be
obtained by looking at the size of the RV on CT pulmonary angiography, which is already
the current gold standard for confirming acute PE (figure 1). If RV enlargement is then

17

FB:Cardiologia Siglo XXI

18

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 1. Update on imaging and laboratory tests for prediction of intermediate-high risk or intermediate-low risk pulmonary embolism

Test or biomarker Cut-off value Sensitivity Specificity NPV % (95% PPV % (95% OR or HR (95% Patients Study design [ref.]
% (95% CI) % (95% CI) CI) CI) CI) n

Echocardiography Various criteria 74 (61–84) 54 (51–56) 98 (96–99) 8 (6–10) 2.4 (1.3–4.3) 1249 Meta-analysis [9]
of RV
dysfunction
CT angiography RV/LV ⩾1.0 46 (27–66) 59 (54–64) 93 (89–96) 8 (5–14) 1.5 (0.7–3.4) 383 Meta-analysis [9]
RV/LV ⩾0.9 84 (65–94) 35 (30–39) 97 (94–99) 7 (5–10) 2.8 (0.9–8.2) 457 Prospective cohort [10]
LA volume NR NR NR NR 2.4 (1.5–3.9) 636 Retrospective cohort [11]
⩽62 mL
RA/LA >1.2 NR NR NR NR 2.1 (1.3–3.4)
LV ⩽67 mL NR NR NR NR 1.8 (1.1–3.0)
BNP 75–100 pg·mL−1 85 (64–95) 56 (50–62) 98 (94–99) 14 (9–21) 6.5 (2.0–21) 261 Meta-analysis [12]
NT-proBNP 600 pg·mL−1 86 (69–95) 50 (46–54) 99 (97–100) 7 (5–19) 6.3 (2.2–18.3) 688 Prospective cohort [13]#
Various assays/ NR NR NR NR 8.6 (4.1–18.0) 1664 Meta-analysis [14]
cut-off values
Troponin I Various assays/ NR NR NR NR 4.0 (2.2–7.2) 1303 Meta-analysis [15]
cut-off values
Troponin T Various assays/ NR NR NR NR 8.0 (3.8–16.7) 682 Meta-analysis [15]
cut-off values¶
14 pg·mL−1+ 87 (71–95) 42 (38–47) 98 (95–99) 9 (6–12) 5.0 (1.7–14.4) 526 Prospective cohort [16]#
Age adjusted 88 (70–96) 54 (50–58) 99 (98–100) 7 (5–10) 8.7 (2.6–29.3) 682 Prospective cohort [17]
H-FABP 6 ng·mL−1 89 (52–99) 82 (74–89) 99 (94–99) 28 (13–47) 36.6 (4.3–304) 126 Prospective cohort [18]#
95 (76–99) 59 (52–64) 99 (96–100) 15 (10–23) 26.9 (3.5–203.8) 271 Prospective cohort [19]
Various assays/ 88 (75–95) 70 (65–70) NR NR 26.0 (6.6–101.7) 749 Meta-analysis [14]
cut-off values
Copeptin+hsTnT 24 pmol·L−1, 73 (48–89) 83 (77–87) 98 (95–99) 20 (12–32) 13.0 (3.9–42.7) 268 Prospective cohort [20]
+NT-proBNP 14 pg·mL−1,
600 pg·mL−1

This table shows the results of meta-analyses or, in the absence thereof, of the largest or relevant prospective cohort studies. In most studies,
“early” refers to the in-hospital period or the first 30 days after the index event. NPV: negative predictive value; PPV: positive predictive value; OR:
odds ratio; HR: hazard ratio; BNP: brain natriuretic peptide; NT-proBNP: N-terminal proBNP; H-FABP: heart-type fatty acid-binding protein; hsTnT:
high-sensitivity troponin T; RV: right ventricle; LV: left ventricle; LA: left atrium; RA: right atrium; NR: not reported in the reference cited. #: these
studies included only normotensive patients, and used a combined outcome (all-cause death or major cardiovascular complications); ¶: in the studies
included in this meta-analysis, cut-off values for the cardiac troponin tests used corresponded to the 99th percentile of healthy subjects with a
coefficient variation of <10%; +: high-sensitivity assay. Reproduced and modified from [6] with permission.

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

detected, the RV status and patient’s risk should further be classified based on biochemical
tests (circulating cardiac troponins or natriuretic peptides) or, possibly, echocardiographic
imaging (table 2).

General management of acute respiratory and right heart failure

The principles of acute right heart failure management were recently reviewed in a
statement from the Heart Failure Association and the Working Group on Pulmonary
Circulation and Right Ventricular Function of the European Society of Cardiology [23]; an
overview of the current treatment options for acute RV failure is provided in table 3.

Hypoxia and hypercapnia caused by acute PE can cause or worsen pulmonary

vasoconstriction. Therefore, general supportive care should always be considered. This
includes the administration of oxygen therapy to maintain oxygen saturation at >90%,
including the use of NIV if standard measures fail in reaching this target. Caution is advised
regarding the use of positive-pressure ventilation and intubation with sedation due to their
negative effects on cardiac output [23, 24].

Acute RV failure responds principally to changes in pre-load; conversely, excessive volume

loading bears the risk of overdistending the RV and consequently increasing wall tension,
decreasing contractility, impairing left ventricle filling, and ultimately further reducing

Table 2. Evolving (2014–2016) risk stratification of patients with acute pulmonary embolism

Early Risk parameters and scores

mortality risk Shock or PESI class Signs of RV Cardiac
hypotension # III–V or dysfunction on an laboratory
sPESI ⩾1 imaging test biomarkers

High + (+) + (+)

Intermediate
Intermediate-high − (+)¶ + +
Intermediate-low − (+)¶ Either one (or none) positive
Low − − Assessment optional;
if assessed, both negative

+: positive; −: negative; (+): Neither calculation of the PESI (or sPESI) nor laboratory testing are
considered necessary in patients with hypotension or shock. #: based on at least one of the
following criteria [21]: 1) need for cardiopulmonary resuscitation; 2) systolic blood pressure
<90 mmHg for ⩾15 min; 3) drop in systolic blood pressure by ⩾40 mmHg for ⩾15 min with signs of
end-organ hypoperfusion (cold extremities or low urinary output <30 mL·h−1 or mental confusion);
4) need for catecholamine administration to maintain adequate organ perfusion and a systolic
blood pressure of >90 mmHg (including dopamine at the rate of >5 µg·kg−1·min−1). ¶: Note that
current guidelines do not routinely recommend further risk assessment in patients belonging to
Pulmonary Embolism Severity Index (PESI) class I or II, or with a simplified PESI (sPESI) of 0, who
are considered to be at “low risk” based on large cohort studies. Nevertheless, some of these
patients have been reported to exhibit right ventricle (RV) dysfunction on imaging tests and/or
elevated biomarker (cardiac troponin or natriuretic peptide) levels in the blood. If any doubts
persist regarding the severity of pulmonary embolism upon clinical evaluation of the patient, even
in the presence of a formally low PESI or an sPESI of 0, the functional status of the RV should be
assessed. If RV dysfunction is then detected, the patient’s risk should be classified based on the
results of imaging and biochemical tests. Reproduced and modified from [6] with permission.

19

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

systemic cardiac output and tissue perfusion. Cautious volume loading guided by central
venous pressure monitoring and aimed at maintaining normal central venous pressure
values is the appropriate approach.

Beyond volume management, vasopressors and/or inotropes are indicated in acute high-risk
PE with haemodynamic instability. Vasopressors, particularly noradrenaline, restore blood
pressure and improve cerebral, coronary and other organ perfusion; contrary to widespread
belief, pulmonary vascular resistance may not be seriously affected [23, 25]. Dobutamine
alone may reduce blood pressure and is therefore usually combined with a vasopressor, such
as noradrenaline. Levosimendan combines RV inotropy and pulmonary vasodilation; it is
typically preferred over dobutamine in patients with decompensated pulmonary
hypertension resulting from left-heart disease, but its place in acute PE is less clear [23].
Phosphodiesterase III inhibitors offer the theoretical advantage of exerting a positive
inotrope effect on the RV without deleterious effects on pulmonary vascular resistance.
Similar to dobutamine, these drugs may aggravate arterial hypotension and should be
combined with noradrenaline if needed. The role of vasopressin in addition to (or instead
of ) noradrenaline in hypotensive patients is uncertain in the setting of acute RV failure since
no data are available; theoretically, its use at a low dosage might be beneficial, since
vasopressin promotes pulmonary vasodilation along with being a systemic vasopressor.

Acute mechanical circulatory support of the RV may be required in certain clinical

situations including acute PE. Timely implantation is critical in order to avoid potentially
irreversible end-organ injury; therefore, early transfer of the patient to an appropriate
centre is essential for success. Device selection depends on the anticipated duration of
mechanical support. ECMO or extracorporeal life support may find increasing use as
short-term mechanical support in the future (table 3) [22].

Reperfusion techniques and regimens for acute PE

Thrombolytic agents have been used for the treatment of acute PE for almost five decades [26].
International guidelines and consensus statements agree that an immediate systemic
reperfusion treatment with intravenous thrombolysis represents the mainstay of therapy for
high-risk (or “massive”) PE [6, 7, 27]. This recommendation is partly supported by
meta-analyses of randomised trials, which enrolled >2000 patients with acute PE and indicated
that thrombolysis may reduce early mortality or the need for rescue treatment upon
decompensation (OR 0.34, 95% CI 0.22–0.52); these beneficial effects appeared to be most
prominent in high-risk PE (OR 0.18, 95% CI 0.04–0.79) [28]. However, the main (and difficult
to predict) adverse effect of systemic thrombolysis is major bleeding, which occurs much more
frequently than under anticoagulation alone (OR 2.91, 95% CI 1.95–4.36), particularly when
fatal or intracranial haemorrhage is considered (OR 3.18, 95% CI 1.25–8.11) [29]. In light of
this delicate balance, the patient subgroups with the most favourable benefit-to-risk ratio and
thus the best candidates for thrombolytic treatment remain rather poorly defined.

An overview of the recommendations for thrombolytic treatment of PE in current

evidence-based guidelines is provided in table 4. At present, systemic thrombolysis is indicated
only for haemodynamically unstable patients due to the high risk of early death [6, 30], while
intermediate-risk patients probably do not benefit from its routine use, and thrombolysis
should only be used as a rescue treatment in the case of haemodynamic decompensation
under anticoagulation alone [6]. This proposed strategy is based on the results of the

20

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

Table 3. Overview of the treatment of acute right heart failure in patients with high-risk
pulmonary embolism

Strategy Properties and use Caveats

Volume optimisation
Volume loading, saline Consider in patients with Volume loading can overdistend
or Ringer’s lactate, decompensated RV failure, the ventricles, worsen
>200 mL per 15–30 min normal central venous pressure, ventricular interdependence and
low arterial pressure reduce cardiac output
Vasopressors and
inotropes
Norepinephrine Increases RV inotropy and Excessive vasoconstriction may
0.2–1.0 µg·kg−1·min−1 systemic blood pressure, worsen tissue perfusion
promotes positive ventricular
interactions, restores coronary
perfusion gradient
Dobutamine 2– Increases RV inotropy, lowers May aggravate arterial
20 µg·kg−1·min−1 filling pressures hypotension if used alone,
without a vasopressor,
especially if left-heart failure
present
Levosimendan Combines RV inotropy and May aggravate arterial
0.1–0.2 µg·kg−1·min−1# pulmonary vasodilation; hypotension
favourably affects right
ventricular–arterial uncoupling
Mechanical circulatory
support
ECMO/ECLS Short-term support, Complications with use over
cost-effective and rapid; an longer periods (>5–10 days)
oxygenator can be added
Percutaneous Limited pump capacity; ECLS
catheter-mounted preferred in severe cardiogenic
micro-axial pumps shock or where high pump flow
required
Paracorporeal RVADs Appropriate for longer-term use
(e.g., weeks or months); can be
combined with oxygenators
when pulmonary support also
needed

ECLS: extracorporeal life support; RVAD: right ventricular assist device; RV: right ventricle. #: a bolus
of 6–12 µg·kg−1 over 10 min is optional and not recommended if systolic blood pressure is
<90 mmHg; infusion can be decreased to 0.05 µg·kg−1·min−1 or increased to 0.2 µg·kg−1·min−1.
Reproduced and modified from [23] with permission.

Pulmonary Embolism Thrombolysis (PEITHO) trial, which compared a single bolus of

tenecteplase (plus heparin) with placebo (plus heparin) in 1006 patients with acute PE and
RV dysfunction plus myocardial injury, detected by imaging and a positive cardiac troponin
test; even in this intermediate-high risk group, the clinical benefits of thrombolysis were offset
by the intracranial and other major bleeding risks [32].

The question of whether alternative approaches to reperfusion treatment of PE could achieve

comparable efficacy while minimising the bleeding risk associated with systemic thrombolysis
remains to be answered. The use of reduced-dose systemic thrombolysis might represent an

21

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

option for improving safety while maintaining the efficacy of this treatment. In a preliminary,
prematurely terminated trial of 118 patients, who roughly corresponded to the European
Society of Cardiology definition of high-risk or intermediate-high risk PE, half-dose
recombinant tissue plasminogen activator (rtPA; alteplase) appeared comparable to the full
dose in terms of efficacy, and improved safety was suggested [33]. In another study of 121
patients with rather arbitrarily defined “moderate PE”, reduced-dose rtPA seemed adequately
safe and effective over the long term [34]. These data are hypothesis-generating and are
insufficient, at the present stage, to support the use of “low-dose” thrombolytic regimens as
an alternative to the dosage approved for systemic (intravenous) use.

Catheter-directed pharmacomechanical reperfusion with low-dose local thrombolysis

represents a promising option for clearing pulmonary thrombi from the larger arteries [35];
this procedure is an alternative to operative embolectomy if systemic thrombolysis is
contraindicated (table 5) [6]. The phase II Ultrasound Accelerated Thrombolysis of
Pulmonary Embolism (ULTIMA) trial enrolled 59 acute PE patients with acute main- or
lower-lobe involvement and a right-to-left ventricle dimension ratio of ⩾1.0. The primary
objective was to compare unfractionated heparin plus a 15-h catheter-directed,
ultrasound-assisted regimen of 10–20 mg rtPA versus anticoagulant alone [36]. The
intervention led to significant recovery of RV function, indicated by a reduction of the
subannular right-to-left ventricle dimension ratio, at 24 h, with no increased risk of major
haemorrhage [36]. Supportive of the efficacy and safety of this approach are the results of a
prospective, single-arm multicentre trial on 150 patients with submassive or massive PE [37],
and those of a registry on catheter-directed, either purely mechanical or pharmacomechanical,
thrombus removal including 28 patients with massive PE and 73 with submassive PE [38].

Like any interventional procedure, catheter-directed pharmacomechanical reperfusion

requires adequate operator expertise and institutional volume. Furthermore, it remains to
be determined whether the speed of thrombus removal, and consequently of the relief of
the RV from pressure overload, is adequately high in patients with overt or imminent
haemodynamic decompensation, and whether the use of ultrasound is really necessary for
obtaining maximum efficacy [36].

Anticoagulant drugs and regimens

In patients with acute PE, early anticoagulant treatment should be initiated to reduce the
risk of recurrence and fatal thromboembolic events. In patients undergoing the diagnostic
workup for acute PE and classified as having an intermediate or high clinical probability
for PE (before imaging tests are performed), anticoagulant treatment with a parenteral
agent, preferably subcutaneous low-molecular-weight heparin or fondaparinux, is
recommended [6]. Subjects who are candidates for thrombolytic treatment should receive
agents with shorter half-lives (unfractionated heparin) and the possibility of laboratory
monitoring of their anticoagulant levels.

The standard length of anticoagulation covers a minimum duration of 3 months. For many
years, parenteral anticoagulant agents (heparins or the synthetic pentasaccharide
fondaparinux) followed by vitamin K antagonists (VKAs) represented the gold standard for
the anticoagulant treatment of VTE [39]. The standard regimen consisted of parenteral
anticoagulation and VKA co-administration for the first 5–10 days, until the international
normalised ratio (INR) values reached the target therapeutic range (INR between 2.0 and

22

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

Table 4. Recommendations for systemic thrombolysis in evidence-based guidelines and

consensus statements

Guidelines Population Recommendations Strength/ Level of

class evidence

ESC 2014 [6] High-risk PE Intravenous anticoagulation I C

with UFH to be initiated
without delay
Thrombolytic therapy I B
Surgical embolectomy for I C
patients in whom
thrombolysis is
contraindicated or has
failed
Percutaneous CDT as an IIa C
alternative to surgical
pulmonary embolectomy
for patients in whom
full-dose systemic
thrombolysis is
contraindicated or has
failed
Intermediate-high Routine primary systemic III B
risk PE thrombolysis not
recommended
Close monitoring to permit I B
early detection of
haemodynamic
decompensation
Thrombolytic therapy in IIa B
presence of clinical signs
of haemodynamic
decompensation
Surgical embolectomy or IIb C
percutaneous CDT may be
considered if the
anticipated risk of bleeding
under thrombolytic
treatment is high
ACCP 2016 [30] With hypotension In absence of high bleeding 2 B
risk: systemic thrombolysis
In presence of high bleeding 2 C
risk or if systemic
thrombolysis failed:
surgical embolectomy
Without Recommendation against 1 B
hypotension systemically administered
thrombolysis
Acutely Systemic thrombolysis 2 C
deteriorating
during
anticoagulation
Candidate for Systemic thrombolysis via a 2 C
thrombolysis peripheral vein over CDT
NICE 2015 [31] Haemodynamic Offer UFH and consider
instability systemic thrombolytic
therapy
Continued

23

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 4. Continued

Guidelines Population Recommendations Strength/ Level of

class evidence

Haemodynamic No systemic thrombolytic

stability therapy
USAT versus CDT The evidence on USAT raises
no major safety concerns
over those of CDT alone;
with regard to efficacy,
evidence of any
enhancement of
thrombolysis over CDT
alone is inadequate
AHA 2011 [7] Massive PE# Thrombolysis reasonable for IIa B
patients with acceptable
risk of bleeding
Submassive PE¶ Thrombolysis considered if IIb C
clinical evidence of adverse
prognosis (new
haemodynamic instability,
worsening respiratory
insufficiency, severe right
ventricle dysfunction, or
major myocardial necrosis)
and low risk of bleeding
Candidates for Catheter embolectomy and IIa C
thrombolysis fragmentation or surgical
embolectomy for patients
with contraindications to
fibrinolysis
Catheter embolectomy and IIa C
fragmentation or surgical
embolectomy for patients
who remain unstable after
receiving fibrinolysis

ESC: European Society of Cardiology; ACCP: American College of Chest Physicians; NICE: National
Institute for Health and Care Excellence; AHA: American Heart Association; PE: pulmonary
embolism; UFH: unfractionated heparin; CDT: catheter-directed thrombolysis; USAT: ultrasound-
accelerated thrombolysis. #: acute PE with sustained hypotension (systolic blood pressure
<90 mmHg for ⩾15 min or requiring inotropic support, not due to a cause other than PE, such as
arrhythmia, hypovolaemia, sepsis, or left ventricle (LV) dysfunction), pulselessness, or persistent
profound bradycardia (heart rate <40 beats·min−1 with signs or symptoms of shock) [7]; ¶: acute
PE without systemic hypotension (systolic blood pressure ⩾90 mmHg) but with either RV
dysfunction or myocardial necrosis [7].

3.0) for at least two consecutive days; then heparin was discontinued. This strategy is still
valid and is included in the guideline recommendations [6, 30]; however, in the past
decade, two classes of NOACs were approved for the treatment and secondary prophylaxis
of acute PE: three direct factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) and one
direct thrombin inhibitor (dabigatran etexilate). These drugs exhibit similarly short
half-lives (7–13 h) and a predictable anticoagulant effect, allowing fixed-dose
administration with no need for routine monitoring. Large phase III trials showed that
these drugs were non-inferior to standard treatment (heparin followed by VKAs) with

24

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

Table 5. Absolute and relative contraindications to thrombolytic therapy

Absolute contraindications Relative contraindications

Haemorrhagic stroke or stroke of unknown Transient ischaemic attack in the preceding

origin at any time 6 months
Ischaemic stroke in the preceding 6 months ral anticoagulant therapy
Central nervous system damage or neoplasms Pregnancy, or within 1 week post-partum
Recent major trauma/surgery/head injury in the Noncompressible puncture site
preceding 3 weeks
Gastrointestinal bleeding within the last month Traumatic resuscitation
Known bleeding risk Refractory hypertension (systolic blood
pressure >180 mmHg)
Advanced liver disease

Reproduced and modified from [6] with permission.

respect to the efficacy outcomes, while their safety profile was superior to that of the
comparator in terms of both total bleeding rates [40] and, possibly, bleeding severity [41,
42]. Table 6 summarises the approved regimens of the NOACs for the initial, long-term
and extended management of acute PE.

For specific “vulnerable” patient subgroups, or in specific situations during anticoagulation

treatment, adapted regimens or monitoring strategies may be necessary. Table 7 provides
an overview of these special conditions with the preferred anticoagulation strategies based
on the available evidence and/or expert opinion.

Vena cava filters

Vena cava filters may be considered in selected patients with acute VTE to prevent PE or
further PE events and reduce PE-associated mortality. The principal indications for
placement of filters in the infrarenal portion of the inferior vena cava are typically
considered to be the presence of absolute contraindications to anticoagulant treatment in a
patient with acute VTE, and with PE recurrence despite documented adequate
anticoagulation [6, 30]. Nevertheless, in some countries, an increasing use of filters has
been observed over the past decade [66–68], even in individuals who had no
contraindications to anticoagulation (9.6% of all placements according to a recent study
[69]). In the USA, the annual rate of vena cava filter placement increased from 19 to 32.5
per 100 000 hospitalisations between 1999 and 2010 ( p<0.001); among patients hospitalised
for (or with) acute PE, the proportion of those who received a vena cava filter increased
from 15.8% to 16.4% ( p=0.11) [67].

The recent Prévention du Risque d’Embolie Pulmonaire par Interruption Cave (PREPIC 2)
trial enrolled hospitalised patients with acute, symptomatic PE associated with lower-limb
vein thrombosis and at least one severity criterion. The placement of a retrievable inferior
vena cava filter was compared with anticoagulation alone (n=399; randomisation ratio 1:1)
[28]. By 3 months, the frequency of recurrent PE was not reduced in the filter compared
with the control group (3.0% versus 2.0%, respectively; risk ratio with filter 2.0, 95% CI
0.51–7.89); similar results were observed at 6 months [28]. The case against the
“liberalisation” of the indications for vena cava filter placement beyond those explicitly

25

FB:Cardiologia Siglo XXI

26

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 6. Overview of non-vitamin-K-dependent, direct oral anticoagulants in the acute-phase treatment and secondary prevention of venous
thromboembolism (VTE)

Anticoagulant Dosage and interval Not recommended or contraindicated #

Initial phase Long-term Extended phase
phase

Rivaroxaban ¶ 15 mg twice daily for 21 days 20 mg once daily with food (15 mg CrCl <30 mL·min−1 (FDA), or CrCl <15 mL·min−1 (EMA);
once daily in VTE patients at higher moderate or severe hepatic impairment (Child-Pugh class
risk of bleeding (EMA)) B and C), or hepatic disease associated with
coagulopathy; concomitant use of combined P-gp and
strong CYP3A4 inhibitors or inducers
Dabigatran etexilate + Initial therapy with 150 mg twice daily (110 mg twice daily CrCl <30 mL·min−1; concomitant treatment with
parenteral anticoagulation in VTE patients at higher risk of P-gp inhibitors in patients with CrCl <50 mL·min−1;
for 5–10 days bleeding due to interfering concomitant treatment with P-gp inducers (i.e. rifampin)
co-medications (EMA))
Apixaban 10 mg twice daily for 7 days 5 mg twice 2.5 mg twice daily CrCl <15 mL·min−1; severe hepatic impairment (Child-Pugh
daily after ⩾6 months of class C), or hepatic disease associated with coagulopathy;
treatment strong dual inhibitors or inducers of CYP3A4 and P-gp
Edoxaban § Initial therapy with 60 mg once daily; 30 mg once daily CrCl <15 mL·min−1; moderate or severe hepatic impairment
parenteral anticoagulation can be considered in patients with one (Child-Pugh B and C), or hepatic disease associated with
for 5–10 days or more of the following factors: CrCl coagulopathy; concomitant treatment with rifampin
15–50 mL·min−1; body weight ⩽60 kg;
concomitant use of P-gp inhibitors,
cyclosporin, dronedarone,
erythromycin or ketoconazole

This table displays drugs and regimens on the basis of US Food and Drug Administration (FDA) approval for the treatment of acute VTE. EMA:
European Medicines Agency; CrCl: creatinine clearance; P-gp: P-glycoprotein; CYP3A4: cytochrome P450-3A4. #: all mentioned anticoagulant agents
should also be avoided in patients: 1) for whom thrombolysis or pulmonary embolectomy may be required; 2) requiring dialysis; 3) at significant risk of
bleeding; 4) receiving a concomitant anticoagulant; 5) with known hypersensitivity to the agent; and 6) during pregnancy or breastfeeding. ¶: according
to the EMA product information, rivaroxaban 15 mg should be considered for the long-term phase if the patient’s assessed risk for bleeding outweighs
the risk for recurrent VTE; in the European Union, rivaroxaban is contraindicated in patients with CrCl <15 mL·min−1 and should be used with caution
in patients with CrCl 15–30 mL·min−1; +: according to the EMA product information, dabigatran etexilate is not recommended in patients with elevated
liver enzymes more than twice the upper limit of normal or with liver disease expected to have any impact on survival, while dabigatran etexilate
110 mg twice daily can be considered in selected patients at higher risk of bleeding; §: although a separate extension trial was not conducted for
edoxaban, >40% of patients included in the Hokusai-VTE (Edoxaban versus Warfarin for the Treatment of Symptomatic Venous Thromboembolism) trial
received an extended treatment with edoxaban for up to 12 months. Reproduced and modified from [39] with permission.

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

Table 7. Preferred anticoagulation regimens in specific subgroups of patients with pulmonary

embolism

Group/condition Chronic oral anticoagulation # References ¶

Demographic challenge
Elderly (>75 years; see below for NOAC; VKA [43, 44]
comorbidity, particularly renal
dysfunction)
Children+ Heparin, VKA [45, 46]
Patients living in geographically NOAC [47]
remote or barely accessible areas,
with inflexible work schedule, or with
poor INR control
Acute or chronic comorbidity
Extreme obesity (BMI >40 kg·m−2) Heparin (adjusted dose, laboratory [48–51]
monitoring), VKA
Stage IV chronic kidney disease (eGFR VKA; in Europe, reduced dose of factor [49, 51, 52]
15–29 mL·min−1·1.73 m−2) Xa inhibitors may be considered
Stage V chronic kidney disease (eGFR Heparin (adjusted dose, laboratory [49, 52]
<15 mL·min−1·1.73 m−2), dialysis monitoring), VKA
treatment
Severe liver impairment (Child-Pugh Heparin (laboratory monitoring with [30]
class C) anti-factor Xa activity assay); VKA
Active cancer+ Low-molecular-weight heparin for the [6, 30]
first 3–6 months; NOAC
Heparin-induced thrombocytopenia Acute treatment: argatroban or [53–56]
danaparoid followed by VKA;
rivaroxaban; fondaparinux
followed by VKA
History of heparin-induced [54–56]
thrombocytopenia: NOAC;
fondaparinux followed by VKA
Antiphospholipid syndrome+ Aspirin plus VKA (or heparin) [57–59]
Concomitant non-valvular atrial NOAC; VKA [30, 60]
fibrillation
Concomitant valvular atrial fibrillation VKA [60, 61]
or mechanical cardiac valve
Concomitant stable coronary artery NOAC; VKA [30, 60]
disease
Concomitant treatment with aspirin [30, 60]
generally not indicated, and
increases bleeding risk
Temporary or reversible situations
Pregnancy Low-molecular-weight heparin [6, 57]
(adjusted dose, consider laboratory
monitoring)
Breastfeeding Low-molecular-weight heparin; VKA [6, 47, 57]
During and up to 48 h after Unfractionated heparin infusion [6, 30]
thrombolytic therapy
Time of thrombophilia workup with Heparin; if given, VKA must be [58, 62]
functional tests interrupted for ⩾3 weeks, and
NOAC for ⩾48 h

INR: international normalised ratio; eGFR: estimated glomerular filtration rate; NOAC:
non-vitamin K-dependent, direct oral anticoagulant; VKA: vitamin K antagonist. #: a semi-colon
separates the order of preference; ¶: also consult product monographs of the individual drugs;
+
: dedicated NOAC trials in these populations are currently ongoing [63–65].

27

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

mentioned in current guidelines is further supported by recent large epidemiological

studies, which did not observe a reduction in mortality or PE recurrence after filter
placement in most of the evaluated subgroups [67, 69]. In this context, it should also not
be forgotten that the procedure may be complicated by penetration of the filter into the
vena caval wall or its embolisation to the right heart cavities [70]; it is, in fact, to be
expected that the rate of filter-related complications will be much higher under real-world
conditions compared with the setting of large prospective trials such as PREPIC 2 [28].

Summary and conclusions

PE is the third most frequent acute cardiovascular syndrome and, as such, is a common
medical emergency and a significant contributor to early mortality. Based on the fact that
the presence and severity of RV dysfunction is a key determinant of the patient’s prognosis
in the acute phase, the risk-adapted treatment strategies that are recommended in current
guidelines have been developed to tailor initial management to the clinical presentation and
the functional status of the RV. Importantly, impending RV failure is not always evident
clinically, and very recent observational data suggest that assessment of the RV by imaging
modalities or biochemical markers may be necessary, even in some cases in which
standardised clinical risk scores such as the PESI suggest a “low” risk. Beyond
pharmacological and, if necessary, mechanical circulatory support, systemic thrombolysis
remains the mainstay of treatment for haemodynamically unstable patients with “high-risk”
PE. However, it has become clear that the (intracranial) bleeding risks of full-dose
thrombolysis outweigh its potential clinical benefits in intermediate-risk PE.
Catheter-directed and possibly ultrasound-facilitated pharmacomechanical reperfusion
treatment represents a promising option for minimising bleeding risk; experience with this
method, which continues to accumulate, will contribute to a better understanding of its
efficacy and future indications, particularly with regard to patients at intermediate risk. In
addition, preliminary data suggest a possible role for reduced-dose intravenous thrombolysis,
but this option cannot be recommended before robust evidence has been provided in its
favour. New NOACs directly inhibiting factor Xa (rivaroxaban, apixaban, edoxaban) or
thrombin (dabigatran) have simplified initial and long-term anticoagulation for PE, while
reducing major bleeding risk. Finally, the use of vena cava filters has increased in some
countries over the past decade, but recent trial data strongly support the notion that these
filters should be restricted to selected patients with absolute contraindications to
anticoagulation, or to cases of PE recurrence despite adequately dosed anticoagulants.

References
1. Cohen AT, Agnelli G, Anderson FA, et al. Venous thromboembolism (VTE) in Europe. The number of VTE
events and associated morbidity and mortality. Thromb Haemost 2007; 98: 756–764.
2. Becattini C, Agnelli G, Lankeit M, et al. Acute pulmonary embolism: mortality prediction by the 2014 European
Society of Cardiology risk stratification model. Eur Respir J 2016; 48: 780–786.
3. Klok FA, van der Hulle T, den Exter PL, et al. The post-PE syndrome: a new concept for chronic complications of
pulmonary embolism. Blood Rev 2014; 28: 221–226.
4. Lang IM, Pesavento R, Bonderman D, et al. Risk factors and basic mechanisms of chronic thromboembolic
pulmonary hypertension: a current understanding. Eur Respir J 2013; 41: 462–468.
5. Mahan CE, Barco S, Spyropoulos AC. Cost-of-illness model for venous thromboembolism. Thromb Res 2016; 145;
130–132.
6. Konstantinides SV, Torbicki A, Agnelli G, et al. 2014 ESC guidelines on the diagnosis and management of acute
pulmonary embolism. Eur Heart J 2014; 35: 3033–3069.

28

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

7. Jaff MR, McMurtry MS, Archer SL, et al. Management of massive and submassive pulmonary embolism,
iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement
from the American Heart Association. Circulation 2011; 123: 1788–1830.
8. Laporte S, Mismetti P, Decousus H, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with
venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa
(RIETE) Registry. Circulation 2008; 117: 1711–1716.
9. Coutance G, Cauderlier E, Ehtisham J, et al. The prognostic value of markers of right ventricular dysfunction in
pulmonary embolism: a meta-analysis. Crit Care 2011; 15: R103.
10. Becattini C, Agnelli G, Vedovati MC, et al. Multidetector computed tomography for acute pulmonary embolism:
diagnosis and risk stratification in a single test. Eur Heart J 2011; 32: 1657–1663.
11. Aviram G, Soikher E, Bendet A, et al. Prediction of mortality in pulmonary embolism based on left atrial volume
measured on CT pulmonary angiography. Chest 2016; 149: 667–675.
12. Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in
patients with pulmonary embolism: a systematic review and meta-analysis. Am J Respir Crit Care Med 2008; 178:
425–430.
13. Lankeit M, Jimenez D, Kostrubiec M, et al. Validation of N-terminal pro-brain natriuretic peptide cut-off values
for risk stratification of pulmonary embolism. Eur Respir J 2014; 43: 1669–1677.
14. Bajaj A, Rathor P, Sehgal V, et al. Prognostic value of biomarkers in acute non-massive pulmonary embolism:
a systematic review and meta-analysis. Lung 2015; 193: 639–651.
15. Becattini C, Vedovati MC, Agnelli G. Prognostic value of troponins in acute pulmonary embolism: a meta-analysis.
Circulation 2007; 116: 427–433.
16. Lankeit M, Jimenez D, Kostrubiec M, et al. Predictive value of the high-sensitivity troponin T assay and the
simplified pulmonary embolism severity index in hemodynamically stable patients with acute pulmonary
embolism: a prospective validation study. Circulation 2011; 124: 2716–2724.
17. Kaeberich A, Seeber V, Jimenez D, et al. Age-adjusted high-sensitivity troponin T cut-off value for risk
stratification of pulmonary embolism. Eur Respir J 2015; 45: 1323–1331.
18. Dellas C, Puls M, Lankeit M, et al. Elevated heart-type fatty acid-binding protein levels on admission predict an
adverse outcome in normotensive patients with acute pulmonary embolism. J Am Coll Cardiol 2010; 55: 2150–2157.
19. Dellas C, Tschepe M, Seeber V, et al. A novel H-FABP assay and a fast prognostic score for risk assessment of
normotensive pulmonary embolism. Thromb Haemost 2014; 111: 996–1003.
20. Hellenkamp K, Schwung J, Rossmann H, et al. Risk stratification of normotensive pulmonary embolism:
prognostic impact of copeptin. Eur Respir J 2015; 46: 1701–1710.
21. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J
Med 2014; 370: 1402–1411.
22. Hellenkamp K, Kaeberich A, Schwung J, et al. Risk stratification of normotensive pulmonary embolism based on
the sPESI – does it work for all patients? Int J Cardiol 2015; 197: 162–163.
23. Harjola VP, Mebazaa A, Celutkiene J, et al. Contemporary management of acute right ventricular failure:
a statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right
Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016; 18: 226–241.
24. Dalabih M, Rischard F, Mosier JM. What’s new: the management of acute right ventricular decompensation of
chronic pulmonary hypertension. Intensive Care Med 2014; 40: 1930–1933.
25. Ghignone M, Girling L, Prewitt RM. Volume expansion versus norepinephrine in treatment of a low cardiac
output complicating an acute increase in right ventricular afterload in dogs. Anesthesiology 1984; 60: 132–135.
26. Konstantinides S. Clinical practice. Acute pulmonary embolism. N Engl J Med 2008; 359: 2804–2813.
27. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel
Report. Chest 2016; 149: 315–352.
28. Mismetti P, Laporte S, Pellerin O, et al. Effect of a retrievable inferior vena cava filter plus anticoagulation vs
anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial. JAMA 2015; 313:
1627–1635.
29. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism:
a systematic review and meta-analysis. Eur Heart J 2015; 36: 605–614.
30. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel
Report. Chest 2016; 149: 315–352.
31. National Institute for Health and Care Excellence (NICE). Venous Thromboembolism. London, NICE, 2015.
http://pathways.nice.org.uk/pathways/venous-thromboembolism
32. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N Engl J
Med 2014; 370: 1402–1411.
33. Wang C, Zhai Z, Yang Y, et al. Efficacy and safety of low dose recombinant tissue-type plasminogen activator for
the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest 2010; 137:
254–262.

29

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

34. Sharifi M, Bay C, Skrocki L, et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT”
Trial). Am J Cardiol 2013; 111: 273–277.
35. Engelberger RP, Kucher N. Ultrasound-assisted thrombolysis for acute pulmonary embolism: a systematic review.
Eur Heart J 2014; 35: 758–764.
36. Kucher N, Boekstegers P, Muller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed
thrombolysis for acute intermediate-risk pulmonary embolism. Circulation 2014; 129: 479–486.
37. Piazza G, Hohlfelder B, Jaff MR, et al. A prospective, single-arm, multicenter trial of ultrasound-facilitated,
catheter-directed, low-dose fibrinolysis for acute massive and submassive pulmonary embolism: the SEATTLE II
study. JACC Cardiovasc Interv 2015; 8: 1382–1392.
38. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter
Thrombolysis (PERFECT): initial results from a prospective multicenter registry. Chest 2015; 148: 667–673.
39. Konstantinides SV, Barco S, Lankeit M, et al. Management of pulmonary embolism: an update. J Am Coll Cardiol
2016; 67: 976–990.
40. Becattini C, Agnelli G. Treatment of venous thromboembolism with new anticoagulant agents. J Am Coll Cardiol
2016; 67: 1941–1955.
41. Brekelmans MP, Bleker SM, Bauersachs R, et al. Clinical impact and course of major bleeding with edoxaban
versus vitamin K antagonists. Thromb Haemost 2016; 116: 155–161.
42. Eerenberg ES, Middeldorp S, Levi M, et al. Clinical impact and course of major bleeding with rivaroxaban and
vitamin K antagonists. J Thromb Haemost 2015; 13: 1590–1596.
43. Sharma M, Cornelius VR, Patel JP, et al. Efficacy and harms of direct oral anticoagulants in the elderly for stroke
prevention in atrial fibrillation and secondary prevention of venous thromboembolism: systematic review and
meta-analysis. Circulation 2015; 132: 194–204.
44. van Es N, Coppens M, Schulman S, et al. Direct oral anticoagulants compared with vitamin K antagonists for
acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124: 1968–1975.
45. Monagle P, Chan AK, Goldenberg NA, et al. Antithrombotic therapy in neonates and children: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012; 141: Suppl., e737S–e801S.
46. Schapkaitz E, Sherman GG, Jacobson BF, et al. Paediatric anticoagulation guidelines. S Afr Med J 2012; 102: 171–175.
47. Burnett AE, Mahan CE, Vazquez SR, et al. Guidance for the practical management of the direct oral
anticoagulants (DOACs) in VTE treatment. J Thromb Thrombolysis 2016; 41: 206–232.
48. Patel JP, Roberts LN, Arya R. Anticoagulating obese patients in the modern era. Br J Haematol 2011; 155: 137–149.
49. Garcia DA, Baglin TP, Weitz JI, et al. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of
Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
Chest 2012; 141 : Suppl., e24S–e43S.
50. Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance
from the SSC of the ISTH. J Thromb Haemost 2016; 14: 1308–1313.
51. Hillis C, Crowther MA. Acute phase treatment of VTE: anticoagulation, including non-vitamin K antagonist oral
anticoagulants. Thromb Haemost 2015; 113: 1193–1202.
52. Hughes S, Szeki I, Nash MJ, et al. Anticoagulation in chronic kidney disease patients – the practical aspects.
Clin Kidney J 2014; 7: 442–449.
53. Linkins LA, Warkentin TE, Pai M, et al. Rivaroxaban for treatment of suspected or confirmed heparin-induced
thrombocytopenia study. J Thromb Haemost 2016; 14: 1206–1210.
54. Linkins LA, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: Suppl., e495S–e530S.
55. Warkentin TE, Anderson JA. How I treat patients with a history of heparin-induced thrombocytopenia.
Blood 2016; 128: 348–359.
56. Greinacher A. Clinical practice. Heparin-induced thrombocytopenia. N Engl J Med 2015; 373: 252–261.
57. Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians
Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: Suppl., e691S–e736S.
58. Keeling D, Mackie I, Moore GW, et al. Guidelines on the investigation and management of antiphospholipid
syndrome. Br J Haematol 2012; 157: 47–58.
59. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic
Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical
Practice Guidelines. Chest 2012; 141: Suppl., e152S–e184S.
60. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial
fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the
special contribution of the European Heart Rhythm Association. Eur Heart J 2012; 33: 2719–2747.

30

FB:Cardiologia Siglo XXI

 PULMONARY EMBOLISM | S. BARCO AND S.V. KONSTANTINIDES

61. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart
valves. N Engl J Med 2013; 369: 1206–1214.
62. Favaloro EJ, Lippi G. Laboratory testing in the era of direct or non-vitamin K antagonist oral anticoagulants: a
practical guide to measuring their activity and avoiding diagnostic errors. Semin Thromb Hemost 2015; 41: 208–227.
63. van Es N, Di Nisio M, Bleker SM, et al. Edoxaban for treatment of venous thromboembolism in patients with
cancer. Rationale and design of the Hokusai VTE-cancer study. Thromb Haemost 2015; 114: 1268–1276.
64. Pengo V, Banzato A, Bison E, et al. Efficacy and safety of rivaroxaban vs warfarin in high-risk patients with
antiphospholipid syndrome: rationale and design of the Trial on Rivaroxaban in AntiPhospholipid Syndrome
(TRAPS) trial. Lupus 2016; 25: 301–306.
65. Woller SC, Stevens SM, Kaplan DA, et al. Apixaban for the secondary prevention of thrombosis among patients
with antiphospholipid syndrome: study rationale and design (ASTRO-APS). Clin Appl Thromb Hemost 2016; 22:
239–247.
66. Stein PD, Matta F, Hull RD. Increasing use of vena cava filters for prevention of pulmonary embolism. Am J Med
2011; 124: 655–661.
67. Bikdeli B, Wang Y, Minges KE, et al. Vena caval filter utilization and outcomes in pulmonary embolism: Medicare
hospitalizations from 1999 to 2010. J Am Coll Cardiol 2016; 67: 1027–1035.
68. Duszak RJr, Parker L, Levin DC, et al. Placement and removal of inferior vena cava filters: national trends in the
Medicare population. J Am Coll Radiol 2011; 8: 483–489.
69. White RH, Brunson A, Romano PS, et al. Outcomes after vena cava filter use in noncancer patients with acute
venous thromboembolism: a population-based study. Circulation 2016; 133: 2018–2029.
70. Jia Z, Wu A, Tam M, et al. Caval penetration by inferior vena cava filters: a systematic literature review of clinical
significance and management. Circulation 2015; 132: 944–952.

Support statement: The work of S.V. Konstantinides and S. Barco is supported by the German Federal
Ministry of Education and Research (BMBF 01EO1003 and 01EO1503).
Disclosures: S. Barco has received congress and travel payments from Daiichi-Sankyo and financial support
for the printing costs of his PhD thesis from Pfizer, CSL Behring, Sanquin Plasma Products, Boehringer
Ingelheim, Aspen Netherlands and Bayer. S.V. Konstantinides has received consultancy and lecture honoraria
from Boehringer Ingelheim and the Wyss Institute, and institutional grants from Boehringer Ingelheim.

31

FB:Cardiologia Siglo XXI

 | Chapter 3
Right heart failure
Benjamin Sztrymf1,2, Constance Vuillard1,3,4, Athénaïs Boucly1,3,4,
Elise Artaud-Macari1,3,4, Caroline Sattler1,3,4, David Amar1,3,4,
Xavier Jaïs1,3,4, Olivier Sitbon1,3,4, Marc Humbert1,3,4 and
Laurent Savale1,3,4

Pulmonary arterial hypertension (PAH) remains a progressive and fatal disease despite the
development of specific therapies over the past decades. Right ventricular function of these
patients is sustained by a delicate balance between progressively increasing pulmonary
vascular resistance and adaptation to right ventricular afterload. The development of acute
right heart failure (RHF), which can be precipitated by a trigger factor or the natural
worsening of the disease, is associated with a very poor prognosis. Management of RHF in
PAH suffers from a lack of clear recommendations and specific clinical trials. It is mainly
based on trigger factor identification, fluid volume optimisation and pharmacological
support to improve right ventricular function and perfusion pressure. At the same time,
specific management of PAH according to the aetiology must be considered to reduce right
ventricular afterload. The development of extracorporeal life support and the optimisation of
graft allocation rules contribute to improve the outcome of patients with refractory RHF
despite optimal medical management.

P re-capillary pulmonary hypertension (PH) is defined by an increase in mean

pulmonary artery pressure ⩾25 mmHg and a normal pulmonary artery wedge pressure
⩽15 mmHg. It can be classified in different subgroups, corresponding mainly to pulmonary
arterial hypertension (PAH, group 1 PH), pulmonary veno-occlusive disease (PVOD, group
1′ PH), PH due to chronic lung disease and/or hypoxia (group 3 PH) and chronic
thromboembolic PH (CTEPH, group 4 PH). Haemodynamically, PAH is characterised by
chronic elevation in pulmonary vascular resistance (PVR) >3 Wood units, which may lead
to right heart failure (RHF) and, eventually, to death [1, 2]. Over the past three decades,
improved understanding of the pathophysiology of PAH has led to the development of
several medications ( prostacyclin analogues, endothelin receptor antagonists,
phosphodiesterase (PDE)-5 inhibitors and soluble guanylate cyclase stimulators), thus
changing the therapeutic approach to the disease [3]. Despite these advances, PAH remains
a progressive and fatal disease [4, 5]. More dramatically, PVOD is a dismal condition,

1
Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Le Kremlin-Bicêtre, France. 2AP-HP, Service de Réanimation
Polyvalente, Hôpital Antoine Béclère, Clamart, France. 3AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.
4
INSERM UMR_S 999, Hôpital Marie Lannelongue, Le Plessis-Robinson, France.

Correspondence: Laurent Savale, Université Paris-Sud, Centre de Référence de l’Hypertension Pulmonaire Sévère, Service de
Pneumologie et Soins Intensifs Respiratoires, Hôpital Bicêtre, 78 Rue du Général Leclerc, 94270 Le Kremlin-Bicêtre, France.
E-mail: laurent.savale@aphp.fr

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

32 ERS Monogr 2016; 74: 32–47. DOI: 10.1183/2312508X.10013816

FB:Cardiologia Siglo XXI

 RIGHT HEART FAILURE | B. SZTRYMF ET AL.

which may deteriorate when treated with PAH-targeted therapies [1, 6]. Similarly, a large
number of CTEPH patients are still inoperable or present with persistent severe PH despite
pulmonary endarterectomy, medical therapy and/or balloon pulmonary angioplasty [1].

The ability of the right ventricle to adapt to the progressive increase in afterload plays a key
role in the prognosis of patients suffering from pre-capillary PH. The mechanisms of
adaptation are complex and multifactorial. Over the last few years, interest in the evaluation
of right ventricular function in PH has progressively evolved and expanded with the use of
echocardiography and cardiac magnetic resonance imaging [7]. The main objective is to
evaluate the severity of right ventricular dysfunction and to predict the risk of acute RHF,
which has been defined as a rapidly progressive syndrome with systemic congestion resulting
from impaired right ventricular filling and/or reduced right ventricular flow output [8]. Most
often, it is associated with increased right ventricular afterload or preload, and consequent
right ventricular chamber dilatation and tricuspid regurgitation [9, 10]. This clinical setting is
associated with a very poor short-term prognosis and requires urgent hospitalisation.

The pathophysiology of acute worsening of RHF in chronic pre-capillary PH remains poorly

understood, explaining why its optimal management is very challenging for specialised centres.
No specific recommendations regarding the medical care of these patients are currently
available. The present chapter will report epidemiological data, pathophysiological issues and
clinical experience of acute RHF in patients with chronic pre-capillary PH. In addition, current
treatment strategies are discussed and available monitoring methods are evaluated.

Epidemiology

No study has focused on the epidemiology of acute worsening of PH. Nevertheless, it is

possible to draw information from studies dealing with acute RHF management or recent
trials on PAH-targeted therapies.

In their studies on RHF in PAH patients, HADDAD et al. [11] retrospectively analysed 119
patients experiencing 207 episodes of RHF over a 12-year period. During the same period,
follow-up data of 218 PAH patients were registered in their clinic. HUYNH et al. [12] also
described the outcome of 99 PAH patients admitted to the ICU for acute RHF over a
5-year period. More than 900 patients with PH were seen in the outpatient setting during
the study period. In their retrospective analysis of PH patients admitted for RHF, KURZINA
et al. [13] described the evolution of 37 patients experiencing 60 episodes of RHF, while
172 patients were followed during the 3-year study period. According to these studies, the
incidence of RHF among PH patients ranges between 2.2% and 7.2%. It has to be
emphasised that these studies took place several years ago. Therefore, this may not provide
an accurate picture of current RHF in the whole PH population.

The incidence of RHF in PH patients can also be assessed from recent trials on PAH-targeted
therapies. These studies enrolled large cohorts of patients. Nevertheless, their investigational
nature implied baseline disease and treatment prerequisites, leading to specific patient profiles
that may not reflect the general PAH population. Furthermore, the existence of several
treatment arms may bias the interpretation of acute RHF rates. The GRIPHON investigators
[14] recently described the effect of selexipag in PAH patients. Over the 3 years of the study,
86 (15%) and 123 (21.1%) patients in the selexipag and placebo groups, respectively, were
admitted for RHF. In the AMBITION trial testing a combination of ambrisentan and

33

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

tadalafil, GALIE et al. [15] described 10 (4%) and 30 (12%) patients with RHF in the
combination and pooled monotherapy groups, respectively, over a 1.4-year study period.
Lastly, the SERAPHIN investigators testing macitentan also found between 8.8% and 17.7%
of patients according to the different groups (placebo, macitentan 3 mg or macitentan
10 mg) affected by RHF, syncope or haemodynamic impairment over 3 years [16]. Therefore,
although limited by the absence of dedicated studies and constraints pertaining to the design
of investigational trials, it can be estimated from the aforementioned data that the annual
incidence of RHF in PH patients probably ranges between 2% and 9%. It has to be kept in
mind that in most of those studies acute RHF was defined on a clinical and/or
echocardiographical basis with heterogeneous definitions of “abnormal” ranges of the
registered variables. This further limits the interpretation of acute RHF epidemiology.

Survival

To the best of our knowledge, only seven studies have reported the short-term survival
rates of PH patients affected by RHF (table 1) [11–13, 17–21]. It has to be noted that the
diagnosis of RHF was mostly based on clinical assessment (dyspnoea, lower limb oedema,
diuresis, systemic arterial pressure). Treatment protocols were different among these
studies, somewhat limiting the comparisons. The wide range of the reported mortality rates,
which varied from 14% to 100%, is likely to be explained by the gap in the severity of
illness among studies. The higher mortality rates were described among patients requiring
inotropes and vasoactive drugs, mechanical ventilation, and renal replacement therapy. It
has to be emphasised that availability and physician skills for both right ventricular assist
devices and/or emergency transplantation have considerably increased since the publication
of the aforementioned studies. Therefore, recent studies on the outcome of such patients in
the era of these new tools are warranted.

One study analysed the prognosis in survivors of a RHF episode. Six out of the 27 patients
discharged from the ICU were dead at 3 months. In this study, seven out of the 27 patients
discharged were subsequently referred for at least a second time to the ICU for similar
symptoms within the 18-month study period [21].

Pathophysiology and clinical features of RHF in pre-capillary PH

The right ventricle is characterised by a thin wall and a complex three-dimensional

conformation (unlike the left ventricle), which is appropriate for the low resistance and
high compliance found in the pulmonary circulation. The left and right ventricles interact
via the interventricular septum. Their synchronisation is also aided by the pericardium,
which maintains a consistent beat-by-beat intracardiac volume.

In pre-capillary PH, chronic elevation of PVR leads to chronic conformational adaptation

of the right ventricle. The objectives of the right ventricular wall changes are to increase
contractility and to maintain a preserved systolic and diastolic right ventricular function to
optimise ventriculo-arterial coupling despite high levels of PVR. In early stage of the
disease, adaptive mechanisms of the right ventricle are mainly characterised by progressive
concentric hypertrophy [10]. During this first stage, corresponding to a compensated state,
right ventricular function is generally relatively well preserved. With further disease
progression, inappropriate adjustment mechanisms develop. Progressive right ventricular

34

FB:Cardiologia Siglo XXI

 Table 1. Studies reporting short-term right heart failure outcome in pre-capillary pulmonary hypertension patients

HADDAD [11] HUYNH [12] KURZYNA [13] CAMPO [17] SZTRYMF [19] JIANG [20] SZTRYMF [21]

Design Single-centre, Single-centre, Single-centre, Single-centre, Single-centre, Single-centre, Single-centre,

retrospective retrospective retrospective retrospective prospective prospective prospective
Study period 1997–2009 2004–2009 2005–2007 2000–2009 2011–2012 2009–2010 2005–2007
Patients n 119 99 60 115 53 209 46
Age years ND 51.9±13.6 47±18 55±15 63.3 (47.8–71.9) ND 50 (16.2–77.4)
Admission in ICU n 28 99 ND 29 53 ND 46
Inotropic and/or vasoactive 32 44 33 35 7 209 46
drug intake n
Mechanical ventilation n 10 34 0 9 0 0 0
Renal replacement therapy n 4 20 0 3 0 0 ND
Length of stay days 9 (2–96) 10 (5–16) ND 7 (4–12) 5 (3–10) ND 9 (4–16)
Mortality %
Whole cohort 38 30.3 31.6 14 17 4.1–14.1# 41.3
Patients receiving ND 50 60 45.7 42.8 ND 41.3

RIGHT HEART FAILURE | B. SZTRYMF ET AL.

catecholamines
Patients undergoing renal ND 70 NA ND NA ND NA
replacement therapy
Patients undergoing ND 71 NA 100 NA ND NA
mechanical ventilation

Data are presented as mean±SD or median (range), unless otherwise stated. ND: not described; NA: not applicable. #: according to treatment arm
allocation (fasudil or placebo).
35

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

dilatation and conformational modifications lead to tricuspid regurgitation, gradual reversal

of the septal curvature and, finally, progressive deterioration of right ventricular function
[22, 23]. At a certain point, the compensatory mechanisms become insufficient, leading to
RHF characterised by the occurrence of symptoms or signs of heart failure. The right
ventricular enlargement and septal displacement leads to a reduction in left ventricular
preload by reducing venous return and impaired left ventricular diastolic compliance. All of
these modifications lead to a fall in cardiac output and subsequent decreased systemic
blood pressure, further reducing coronary perfusion of the right ventricle. These changes
also impair diastolic heart function, therefore increasing right atrial pressures and, in turn,
contributing to impaired liver and/or kidney function [22].

These modifications are the result of complex molecular mechanisms and cellular changes
that have been mainly studied in experimental models of RHF. The right ventricular
hypertrophy is the result of an increase in both protein synthesis (e.g. collagen fibres in the
extracellular matrix) and myocardial cell population. A change in contractile protein
isoforms has been observed with resultant alteration of cardiomyocyte function [23].
Progressive fibrosis of the extracellular matrix also contributes to maladaptative right
ventricular remodelling. The cellular damage leading to a decrease in right ventricular
performance is probably promoted by multiple molecular mechanisms, including changes
in the neurohormonal system [24], oxidative stress and increased apoptosis [25], and
inflammation and disorders of cellular energy metabolism [26].

The ability of the right ventricle to adapt to the modification of afterload varies widely
between individuals and according to the aetiology of PH. For example, specific myocardial
involvement in scleroderma probably participates in early impairment of right ventricular
function and, finally, a poorer prognosis compared with idiopathic PAH or other forms of
PH. In contrast, RHF occurs much later in Eisenmenger’s syndrome, leading to a better
long-term survival. In this setting, the better cardiac adaptation to the pressure overload is
promoted by the persistence of a fetal phenotype of the right ventricle that is characterised
by right ventricular wall hypertrophy. Moreover, the right–left shunt leads to ventricular
offloading [27].

There is currently no clear clinical definition that allows us to differentiate between right
ventricular dysfunction and RHF. RHF can present with a wide range of symptoms, which
are very heterogeneous in terms of severity. The insidious onset of exercise incapacity and
fatigue are already the result of decreased systolic reserve or low cardiac output. Diastolic
RHF leads to gradual fluid retention, which can be translated into peripheral oedema,
ascites or anasarca. Finally, impaired right ventricular function and dilatation of the
right-sided cavities promote the occurrence of supraventricular and ventricular arrhythmias
causing palpitations and some cases of sudden death. Some authors consider that the
appearance of any of these symptoms, whatever the severity, is already the manifestation of
deleterious adaptive phenomena and therefore of RHF [22].

All patients suffering from pre-capillary PH, and especially the patients suffering from
PAH, PVOD or CTEPH, may suffer from an acute exacerbation of RHF as the disease
progresses, characterised by the onset of clinical features of rapidly worsening right
ventricular insufficiency. This setting can be promoted by a triggering factor or can just be
a manifestation of disease progression. In some cases, RHF leads to the diagnosis of
pre-capillary PH. As acute worsening of RHF is associated with a very poor short-term
prognosis, it requires urgent care, most often in the ICU.

36

FB:Cardiologia Siglo XXI

 RIGHT HEART FAILURE | B. SZTRYMF ET AL.

Management of RHF in patients with chronic pre-capillary PH

Management of RHF in patients suffering from chronic pre-capillary PH is mainly based

on trigger factor identification, right ventricular afterload improvement, fluid volume
optimisation and pharmacological support to improve right ventricular function. In the
case of refractory RHF despite optimal medical management, the only option is lung or
heart–lung transplantation (HLT) with the use of extracorporeal circulatory support (ECLS)
as a bridge to transplantation (figure 1).

Identification and management of a possible RHF trigger factor

A trigger factor for RHF was identified in ∼40% of cases in French patients [21]. In chronic
pre-capillary PH, right ventricular function is sustained by a delicate balance between
progressively increasing PVR and adaptation to right ventricular afterload (e.g. myocardial
hypertrophy). All external factors leading to a destabilisation of this balance can precipitate
RHF. The identification and specific management of such a trigger factor is essential to increase
the chance of right ventricular function recovery and to improve the prognosis of patients.

Identification and management of a trigger factor

1) Fluid volume optimisation Right ventricular afterload reduction

Diuretic administration to decrease right
ventricular preload First PAH diagnosis:
Upfront combination therapy including
PGI2 analogues

2) Cardiac output optimisation Already known PAH:

β1-Agonists (dobutamine) Reinforcement of PAH-targeted therapies
Others (PDE-3 inhibitors, levosimendan) if possible

Specific aetiologies:
CTEPH: evaluation of endarterectomy
3) Systemic blood pressure optimisation possibility in emergency
α1- and β1-Adrenergic receptors SLE or MCTD: urgent immunosuppressive
(norepinephrine) therapies in combination with
Others (vasopressin?) PAH-targeted therapies

Consider the possibility of urgent DLT or HLT in case of nonreversible RHF

Consider the possibility of ECLS as a bridge to transplantation in

case of refractory RHF despite optimal medical therapies

Figure 1. Right heart failure (RHF) management in patients with chronic pulmonary hypertension. RHF in
pulmonary arterial hypertension (PAH) is mainly based on trigger factor identification, fluid volume
optimisation and pharmacological support to improve right ventricular function and perfusion pressure. At
the same time, specific management of PAH according to the aetiology must be considered to reduce right
ventricular afterload. Extracorporeal life support (ECLS) must be considered as a bridge to transplantation
in patients with refractory RHF despite optimal medical therapies. PDE-3: phosphodiesterase 3; PGI2:
prostaglandin I2; CTEPH: chronic thromboembolic pulmonary hypertension; SLE: systemic lupus
erythematosus; MCTD: mixed connective tissue disease; DLT: double-lung transplantation; HLT: heart–lung
transplantation.

37

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Various causes can be identified. Among them, supraventricular arrhythmias

(tachyarrhythmia, atrial fibrillation or atrial flutter) are frequently observed in pre-capillary
PH and identified as independent risk factors for death [28]. Impairment of atrial function
may cause or precipitate RHF in patients with severe haemodynamics at baseline. There is no
consensus on the management of supraventricular arrhythmias in PH. However, there are
some important points to note. Regarding the use of antiarrhythmic agents, β-blockers and
calcium channel blockers should be avoided in this setting because of their deleterious effects
on right ventricular inotropic function [29]. The use of digoxin is generally favoured initially
for its bradycardic effect [30]. Following this, the priority must be to reverse arrhythmias
under anticoagulant cover to improve overall cardiac function. In case of atrial fibrillation,
amiodarone is the preferred antiarrhythmic agent. This drug is generally well tolerated, but
its long-term safety has never been properly studied in PH [28, 31, 32]. Direct current
cardioversion is generally restricted to patients at imminent risk of death and avoided in
other conditions due to the high risk of sedation in patients with RHF. In the case of
persistent atrial flutter or atrial tachycardia, radiofrequency ablation must be considered [31].

The identification of an infectious aetiology on admission or during hospitalisation is

associated with a poor prognosis in comparison with other trigger factors [21]. The
gateway of infection is not always identified and may correspond in some patients to
bacterial translocation prompted by low cardiac output and increased venous pressure. In
patients treated with intravenous epoprostenol, indwelling catheter infection must be
systematically screened even if no fever is observed at admission. Insidious septicaemia can
be mainly manifested by RHF [33]. In all cases, management of an infectious trigger
should not be delayed because of its negative impact on outcomes in patients with RHF.

Rarely, RHF is associated with acute respiratory distress. Some patients may have profound
hypoxaemia during periods of RHF due to reopening of a foramen ovale, or in some
particular forms of PAH such as Eisenmenger’s syndrome or PVOD. Oxygen therapy is
recommended in PAH patients with decompensated RHF to maintain an oxygen saturation
>90%. Moreover, achieving adequate arterial oxygen saturation by supplemental oxygen
could also contribute to decreasing the PVR. Use of high-flow nasal oxygen therapy in this
indication could be an interesting option, but has not yet been evaluated in this setting. In
cases of acute respiratory distress related to other causes of PH, such as infectious lung
disease, the use of invasive ventilation must be avoided as far as possible because of the
high risk of RHF worsening and collapse after intubation [34].

A new thromboembolic event can be another potential treatable trigger of RHF, especially
in patients with CTEPH. This possibility must be suggested and investigated according to
the clinical probability and the current status of coagulation.

Right ventricular preload optimisation

In physiological terms, cardiac performance depends not only on afterload, contractility and
heart rate, but also on right ventricular preload. Recent reviews have highlighted the
importance of optimising blood volume and therefore the preload in patients with
pre-capillary PH, but also highlighted the small number of studies on this topic [35, 36]. The
optimisation of preload should help to decrease the right–left ventricular interdependence,
reduce the deleterious effect of the tricuspid insufficiency, and thus improve cardiac function
and the overall haemodynamics of these patients. Both hypervolaemia and hypovolaemia can

38

FB:Cardiologia Siglo XXI

 RIGHT HEART FAILURE | B. SZTRYMF ET AL.

be deleterious. Indeed, the aim is to find a delicate balance that is often difficult to assess.
The best method of monitoring right ventricular preload has not yet been identified. In most
cases, right heart decompensation is supported by hypervolaemia. Contrary to acute RHF of
a healthy heart, the key to the management is based on the use of diuretics to obtain a
negative fluid balance. In some patients with a cardiac output that is not too altered at
baseline, the use of diuretics as first-line therapy can be sufficient to improve global cardiac
function and reverse right ventricular decompensation. Renal replacement therapy has been
suggested as an alternative option in patients with severe metabolic abnormalities or in case
of insufficient preload reduction despite optimal medical management. We recently
performed a retrospective analysis of PH patients with acute heart failure requiring renal
replacement therapy in the ICU. Significant systemic hypotension requiring a therapeutic
intervention occurred in roughly half of the sessions. The ICU-related, 1- and 3-month
mortality of these patients was 46.7%, 66.7% and 73.3%, respectively [18]. In patients with
renal failure due to cardio-renal syndrome despite optimal medical management, the
best option is to consider ECLS and urgent lung transplantation or HLT (see below) [37].

Cardiac output optimisation and systemic arterial pressure support

In case of severely altered cardiac function, diuretic treatment can be insufficient to reverse
RHF. The diuretic treatment can lead in this case to insufficient diuresis, systemic
hypotension and impairment in renal function. In this setting, inotropic agents remain
important drugs in the management of severe systolic and diastolic RHF. The main goals of
such treatments are to improve cardiac output and then renal perfusion. β1-Adrenergic
agonists remain the inotropic agent of choice for managing RHF. Dobutamine is generally
initiated at doses of 2.5 µg·kg−1·min−1 and progressively uptitrated in case of persistent low
cardiac output signs. The proposed upper limit for the dose is 10 μg·kg−1·min−1. In this dose
range, dobutamine could improve right ventricle–pulmonary artery coupling by increasing
cardiac output and decreasing PVR [38]. The use of higher doses does not improve cardiac
function, but can precipitate decreased systemic vascular resistance, increase PVR and
tachycardia. We can observe a large heterogeneity of response to β1-adrenergic agonists
between patients. Recently, pre-clinical studies showed an impairment of inotropic response
to β1-adrenergic receptor agonists due to downregulation and desensitisation of β1-receptors
in right ventricular hypertrophy [39]. It has been suggested that PDE-3 inhibitors or the
inodilator levosimendan could be interesting alternative options to dobutamine. However,
very little data support this management strategy at present [36, 40, 41].

The combined use of dobutamine and diuretics can precipitate systemic hypotension in the
most severe patients. An essential goal in the management of RHF is to restore sufficient
systemic arterial pressure to preserve right coronary blood flow and organ perfusion.
Norepinephrine is the drug of choice in acute RHF and persistent hypotension despite
dobutamine therapy. In addition to its effect on systemic pressure, this drug could also
contribute to improve right ventricular function and the right ventricle–pulmonary artery
coupling [38]. In contrast, phenylephrine is not recommended due to its potential
paradoxical effects, leading to an increase in PVR and decrease in cardiac output [42, 43].
The use of vasopressin in RHF due to pre-capillary RHF is more controversial. At low doses,
experimental studies have reported a vasodilator effect of this drug on pulmonary vasculature
leading to a reduction in PVR. Some clinical cases of vasopressin use as rescue therapy in PH
have been published. At higher doses, vasopressin may in contrast increase PVR and cause
adverse myocardial effects [36].

39

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Reduction in right ventricular afterload

When managing such patients, the key is probably to determine the best option to decrease
the PVR that is the initial cause of the right ventricular insufficiency. After having
stabilised the systemic haemodynamics and restored cardiac function with symptomatic
treatment as described above, initiation or optimisation of specific PH treatment must be
considered to give these patients every possible way out of this unprecedented situation and
to decrease the risk of relapse in the long term.

The first step is to determine the mechanism of PH to consider the different treatment
options. In specific cases of CTEPH (group 4 PH), the possibility of a surgical treatment
by endarterectomy must be evaluated. The decision regarding surgery must take into
account the anatomical location of the pulmonary vascular obstruction, and the correlation
between the severity of the pulmonary haemodynamics and the degree of obstruction.
When lesions are too distal, the risk of surgery is elevated especially in patients with
RHF, and medical treatment and/or balloon pulmonary angioplasty must be considered
instead [44].

In all cases of PAH (group 1 PH), the best option to decrease the right ventricular afterload
is mainly based on PAH-targeted therapies. As mentioned above, the therapeutic approach
to PAH has changed over the past three decades with our improved understanding of the
pathophysiology of the disease, which has led to the development of several medications
( prostacyclin analogues, endothelin receptor antagonists, PDE-5 inhibitors and soluble
guanylate cyclase stimulators) [3]. In large randomised controlled clinical trials, these new
treatments produced short- and long-term improvements in various relevant clinical and
functional parameters, such as symptoms, exercise capacity, quality of life and time to
clinical worsening [3]. When PAH is diagnosed at the stage of RHF with New York Heart
Association Functional Class (NYHA-FC) IV dyspnoea, it is now clearly recommended to
initiate first-line combination therapy including a prostaglandin analogue by continuous
intravenous or subcutaneous perfusion [1]. Recently, initiation of upfront triple therapy in
patients with severe haemodynamics at baseline with NYHA-FC III or IV dyspnoea
demonstrated dramatically improved haemodynamic and functional status of patients in
the short and long term in idiopathic PAH [45]. For patients already treated for PAH, the
possibility of strengthening the specific PAH treatment should be considered on a
case-by-case basis. If the latter is already optimal, the only option is the possibility of a
pulmonary or cardiopulmonary transplant.

PVOD is a dismal condition, which may deteriorate dramatically when treated with PAH-
targeted therapies [1, 46]. In this setting, the possibility of double-lung transplantation
(DLT) must be considered promptly in the management [6].

We must also not ignore the benefits of immunosuppressive therapy in very specific cases
of PAH associated with systemic lupus erythematosus or mixed connective tissue disease.
Pulmonary vascular involvement in this setting of autoimmune disease can occur with a
subacute evolution and a sudden installation of RHF sometimes associated with pericardial
effusion. The immunological tests must be performed systematically in the aetiological
investigation of a first presentation with RHF due to PAH. The initiation of treatment with
steroids and a cyclophosphamide bolus in the initial phase, in combination with specific
PAH therapy, can lead to some spectacular results or even reversal of the pulmonary
vascular disease [47, 48].

40

FB:Cardiologia Siglo XXI

 RIGHT HEART FAILURE | B. SZTRYMF ET AL.

Lung or heart–lung transplantation and extracorporeal life support

DLT and HLT are well-established and valuable options for patients with end-stage pulmonary
PH whose NYHA-FC remains III or IV despite optimal medical treatment [1, 49, 50].
However, data from the International Society for Heart and Lung Transplantation registries
showed that the vast majority of PH patients received DLT in recent years [51]. Indeed, in
most cases we can observe a progressive reversibility of the myocardial remodelling, leading to
a recovery of a normal right and left ventricular function after DLT. RHF occurs frequently in
patients listed for DLT or HLT and is associated with a high risk of mortality in the absence of
transplantation. To decrease waiting list mortality, most countries have revised their transplant
allocation rules over the past decade or so. In the USA, implementation of a lung allocation
score algorithm in May 2005 [52] was followed by an increased incidence of transplantation, a
decrease in waiting list mortality and better post-transplantation survival in patients with
idiopathic PAH [53]. However, waiting list mortality remains higher for idiopathic PAH than
for other conditions [54]. In France, patients with RHF due to pre-capillary PH can have
national priority access to transplantation for a period of 8 days, renewable once. The initiation
of this high allocation programme led to a dramatic decrease in mortality of pre-capillary PH
patients on transplant lists [55].

In the case of refractory RHF with secondary organ failure despite optimal medical
management as previously described, ECLS must be considered as a bridge to urgent
transplantation. ECLS that is most often used in PAH patients with refractory RHF is
venoarterial ECMO, which can be set up by femoral insertion in awake patients under local
anaesthesia. This device leads to a sudden reduction in right ventricular afterload and a reversal
of the circulatory insufficiency. The disadvantages of this device are mainly due to the risk of
bleeding or infection and the impossibility of the patient to mobilise with venoarterial ECMO.

The Novalung interventional lung assist (Novalung, Heilbronn, Germany) is less often used
mainly because its implementation requires a sternotomy under general anaesthesia. This
device leads to an immediate reduction of right ventricular afterload and an increase in left
ventricular preload. Blood is pumped from the right ventricle through the Novalung and
returns to the left atrium. In our experience, we used the Novalung in patients who failed
pulmonary endarterectomy with severe persistent PH precluding weaning from the
cardiopulmonary bypass.

These devices have been used successfully as a bridge to transplantation in patients with
PH and refractory RHF despite optimal medical management in the ICU [56, 57]. In
France, 30% of patients transplanted under the high-priority allocation programme were on
ECLS before transplantation. The use of ECLS was, however, reserved for selected patients
at risk of imminent death despite inotropic support with dobutamine and norepinephrine.
ECLS was not deemed suitable in patients with uncontrolled infection or bleeding.

Balloon atrial septostomy (BAS) has been described as another option to decompress the
right heart cavities and increase left ventricular preload, leading to an improvement of
cardiac output [58, 59]. Only PH expert centres should perform this procedure, which
consists of creating an interatrial right-to-left shunt by graded balloon dilatation. A
beneficial effect of BAS in patients in World Health Organization functional class IV with
refractory RHF despite optimal medical therapy has been reported. Indeed, BAS can be a
possible option as a bridge to transplantation [1, 60]. However, the development of ECLS

41

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

combined with urgent transplantation and the inherent risks of the BAS procedure limit its
use in current practice.

Monitoring

The appropriate monitoring for this specific subset of patients remains a matter of
uncertainty. The ideal tool should be able to provide a reliable, repeatable, noninvasive
assessment of both haemodynamic treatment targets and peripheral organ failure. It has to
be emphasised that there is little data regarding the ability of the monitoring tools used in
the setting of PH worsening to translate into therapeutic modifications such as inotropic or
vasoactive agent rate modifications. Nevertheless, monitoring the consequences of cardiac
failure appears important in order to balance between metabolic demand and
haemodynamic impairment.

Haemodynamic monitoring

Echocardiography is an attractive option. Some variables evaluating right ventricular

function are recommended by the European Association of Cardiovascular Imaging [61].
Nevertheless, the precise assessment of right ventricular function remains a challenge and
very few data support its reliability in the setting of RHF [35]. This led some authors to
question the reliability of this tool in the day-to-day management of RHF in PH patients.
Recent work has shown good correlations between isovolumic contraction velocity
measured with tissue Doppler imaging and contractile reserve, directly influencing fluid
and inotropic management [62]. Right heart catheterisation is a safe investigation when
performed in stable patients [63], and remains the gold standard test for the diagnosis and
long-term follow-up of PH patients. However, concerns have been raised regarding the
efficacy of invasive haemodynamic testing in the setting of RHF in pre-capillary PH
patients, with no improvement on outcome or even worsening in specific circumstances
[12, 64]. Further data are clearly required to better understand the risk/benefit ratio of right
heart catheterisation in this setting. Mixed venous oxygen saturation reflects peripheral
oxygen consumption and may be a useful tool in that setting. Nevertheless, great caution
must be taken in the interpretation of such variables, as it may be affected by many other
factors such as anaemia or left ventricular afterload. Therefore, a low value does not
necessarily translate to an inotrope shortage.

Novel devices that use transpulmonary thermodilution-based methods to determine cardiac

output have generated considerable interest in the general ICU population. This technology
provides information regarding numerous physiological variables, including systemic
arterial pressure, cardiac output or stroke volume. This method has not been formally
validated in PH patients to date, and right ventricular dilation and tricuspid regurgitation
are thought to be major limitations in the reliability of the device. Nevertheless, preliminary
data support its reliability in cardiac output estimation [65].

Circulating biomarkers

Some circulating biomarkers have been linked to survival, such as brain natriuretic peptide
[17, 21] or troponin [13]. Elevated C-reactive protein (CRP) plasma levels may indicate an
infectious process in PAH patients with RHF. Nevertheless, moderately elevated CRP levels
are indeed predictors of poor prognosis in acute worsening of pre-capillary PH, even

42

FB:Cardiologia Siglo XXI

 RIGHT HEART FAILURE | B. SZTRYMF ET AL.

a) 80 p=0.003 b) 105 p<0.0001

75 100

70 95

65 90
MAP mmHg

SAP mmHg
60 85
55 80
50 75

45 70
Survivors
40 65
Nonsurvivors
35 60

c) 300 p<0.0001 d) 140.0 p<0.0001

137.5
250
135.0
200 132.5
Sodium mEq·L–1
CRP mg·L–1

150 130.0
127.5
100 125.0

50 122.5
120.0
0
117.5
–50 115.0

e) 600 p<0.0001 f) 4500 p<0.0001

4000
500
3500
Creatinine µmol·L–1

400 3000
BNP pg·mL–1

2500
300
2000
200 1500

1000
100
500
0 0
Admission Week 1 Week 2 Week 3 Admission Week 1 Week 2 Week 3

Figure 2. Clinical and biochemical data according to survival in the ICU: patients discharged from the ICU
(survivors) or patients who died in the ICU (nonsurvivors). There was a difference in the evolution of some
prognostic markers according to the outcome of pulmonary arterial hypertension patients experiencing
right heart failure: a) mean arterial systemic pressure (MAP), b) systolic arterial systemic pressure (SAP),
c) serum C-reactive protein (CRP) level, d) serum sodium level, e) serum creatinine level and f ) serum
brain natriuretic peptide (BNP) level. Reproduced and modified from [21] with permission.

43

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

without evidence of infection, raising the potential involvement of inflammation among

other pathophysiological pathways [21]. Although few studies have assessed the sodium and
water regulation imbalance in RHF, it has been documented that hyponatraemia is linked
to survival in stable PAH patients [66, 67]. A link between hyponatraemia and survival has
also been evidenced in RHF [21].

Although the prognostic value of a single measurement of the aforementioned biomarkers

has been found, changes in the values of some of these parameters may predict outcome in
the ICU (figure 2) [21]. This could be the basis for future clinical research aiming to better
adjust our day-to-day therapeutics on multiple, objective variables.

Peripheral organ status

Peripheral organ involvement is the result of both decreased cardiac output and venous
congestion, but may also be impaired by the triggering factor. Therefore, along with the
haemodynamic variables, organ function should be assessed regularly to reach a balance
between haemodynamic status and peripheral organ demand. Daily monitoring in this
setting has already been proposed. The main monitoring variables are summarised in table 2.

Conclusions

RHF is a common complication of pre-capillary PH and remains the most frequent cause of
death in this population. Improving prognosis of these patients will be a great challenge for

Table 2. Main monitored variables

System Tools End-points

Right heart failure

Cardiac output Echocardiography Maintain cardiac output
Right heart catheter
SvO2 monitoring
Systemic pressure Arterial pressure monitoring Mean arterial pressure >65–70 mmHg
Heart rate ECG Detect and treat arrhythmias
Biomarkers Serum BNP/pro-BNP dosage Decreasing level of BNP/pro-BNP
Serum troponin dosage Normalisation of troponin level
Serum lactate dosage Normalisation of lactate level
End organ failure
Renal function Estimated glomerular filtration rate Normalisation of renal function
Diuresis
Liver function Transaminases/bilirubin dosage Avoid venous congestion
and/or ischaemia
Gut Feeding tolerance Avoid food intolerance
Water balance Weight Reach the basic weight
Urine output Avoid fluid overload
Natraemia Avoid hyponatraemia
Others
Oxygenation Oxygen supply SaO2 >90%
Sepsis Temperature and inflammation Detect and treat associated sepsis
monitoring (CRP, PCT)

SvO2: mixed venous oxygen saturation; BNP: brain natriuretic peptide; CRP: C-reactive protein;
PCT: procalcitonin.

44

FB:Cardiologia Siglo XXI

 RIGHT HEART FAILURE | B. SZTRYMF ET AL.

the future. The development of PAH-targeted therapies and their use in combination has
probably contributed to delay the occurrence of this life-threatening condition in patients
with PAH. Active research is ongoing to improve assessment of right ventricular function
and to anticipate the risk of this potentially fatal complication in subjects suffering from
PAH. A better understanding of physiopathological mechanisms leading to RHF in chronic
pre-capillary PH is also necessary to improve its management. At present it remains based
on the experience of reference centres with few dedicated clinical trials. Management of
RHF in pre-capillary PH is actually based on trigger factor identification, right ventricular
afterload improvement, fluid volume optimisation and pharmacological support to improve
right ventricular function. At the same time, specific PH therapy according to the aetiology
must be considered to optimise the chances of recovery from RHF and to decrease the risk
of relapse in the long term. The development during the past decade of ECLS and the
optimisation of graft allocation rules in most countries were a first step contributing to
improve the outcome of patients with refractory RHF despite optimal medical management.

References
1. Galie N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary
hypertension. Eur Respir J 2015; 46: 903–975.
2. Simonneau G, Gatzoulis MA, Adatia I, et al. Updated clinical classification of pulmonary hypertension. J Am Coll
Cardiol 2013; 62: Suppl. 25, D34–D41.
3. Humbert M, Lau EM, Montani D, et al. Advances in therapeutic interventions for patients with pulmonary arterial
hypertension. Circulation 2014; 130: 2189–2208.
4. Humbert M, Sitbon O, Chaouat A, et al. Survival in patients with idiopathic, familial, and anorexigen-associated
pulmonary arterial hypertension in the modern management era. Circulation 2010; 122: 156–163.
5. Benza RL, Miller DP, Gomberg-Maitland M, et al. Predicting survival in pulmonary arterial hypertension: insights
from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management
(REVEAL). Circulation 2010; 122: 164–172.
6. Montani D, Lau EM, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2016; 47: 1518–1534.
7. Sanz J, Conroy J, Narula J. Imaging of the right ventricle. Cardiol Clin 2012; 30: 189–203.
8. Harjola VP, Mebazaa A, Celutkiene J, et al. Contemporary management of acute right ventricular failure: a
statement from the Heart Failure Association and the Working Group on Pulmonary Circulation and Right
Ventricular Function of the European Society of Cardiology. Eur J Heart Fail 2016; 18: 226–241.
9. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines
for the Diagnosis and Management of Heart Failure in Adults. A Report of the American College of Cardiology
Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the
International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009; 53: e1–e90.
10. Vonk-Noordegraaf A, Haddad F, Chin KM, et al. Right heart adaptation to pulmonary arterial hypertension:
physiology and pathobiology. J Am Coll Cardiol 2013; 62: Suppl. 25, D22–D33.
11. Haddad F, Peterson T, Fuh E, et al. Characteristics and outcome after hospitalization for acute right heart failure in
patients with pulmonary arterial hypertension. Circ Heart Fail 2011; 4: 692–699.
12. Huynh TN, Weigt SS, Sugar CA, et al. Prognostic factors and outcomes of patients with pulmonary hypertension
admitted to the intensive care unit. J Crit Care 2012; 27: 739.
13. Kurzyna M, Zylkowska J, Fijalkowska A, et al. Characteristics and prognosis of patients with decompensated right
ventricular failure during the course of pulmonary hypertension. Kardiol Pol 2008; 66: 1033–1039.
14. Sitbon O, Channick R, Chin KM, et al. Selexipag for the treatment of pulmonary arterial hypertension. N Engl J
Med 2015; 373: 2522–2533.
15. Galie N, Barbera JA, Frost AE, et al. Initial use of ambrisentan plus tadalafil in pulmonary arterial hypertension.
N Engl J Med 2015; 373: 834–844.
16. Pulido T, Rubin LJ, Simonneau G. Macitentan and pulmonary arterial hypertension. N Engl J Med 2014; 370: 82–83.
17. Campo A, Mathai SC, Le Pavec J, et al. Outcomes of hospitalisation for right heart failure in pulmonary arterial
hypertension. Eur Respir J 2011; 38: 359–367.
18. Sztrymf B, Prat D, Jacobs FM, et al. Renal replacement therapy in patients with severe precapillary pulmonary
hypertension with acute right heart failure. Respiration 2013; 85: 464–470.
19. Sztrymf B, Gunther S, Artaud-Macari E, et al. Left ventricular ejection time in acute heart failure complicating
precapillary pulmonary hypertension. Chest 2013; 144: 1512–1520.

45

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

20. Jiang R, Ai ZS, Jiang X, et al. Intravenous fasudil improves in-hospital mortality of patients with right heart failure
in severe pulmonary hypertension. Hypertens Res 2015; 38: 539–544.
21. Sztrymf B, Souza R, Bertoletti L, et al. Prognostic factors of acute heart failure in patients with pulmonary arterial
hypertension. Eur Respir J 2010; 35: 1286–1293.
22. Haddad F, Doyle R, Murphy DJ, et al. Right ventricular function in cardiovascular disease, part II: pathophysiology,
clinical importance, and management of right ventricular failure. Circulation 2008; 117: 1717–1731.
23. Bogaard HJ, Abe K, Vonk Noordegraaf A, et al. The right ventricle under pressure: cellular and molecular
mechanisms of right-heart failure in pulmonary hypertension. Chest 2009; 135: 794–804.
24. de Man FS, Handoko ML, Guignabert C, et al. Neurohormonal axis in patients with pulmonary arterial
hypertension: friend or foe? Am J Respir Crit Care Med 2013; 187: 14–19.
25. Giordano FJ. Oxygen, oxidative stress, hypoxia, and heart failure. J Clin Invest 2005; 115: 500–508.
26. Piao L, Marsboom G, Archer SL. Mitochondrial metabolic adaptation in right ventricular hypertrophy and failure.
J Mol Med (Berl) 2010; 88: 1011–1020.
27. Giusca S, Popa E, Amzulescu MS, et al. Is right ventricular remodeling in pulmonary hypertension dependent on
etiology? An echocardiographic study. Echocardiography 2016; 33: 546–554.
28. Tongers J, Schwerdtfeger B, Klein G, et al. Incidence and clinical relevance of supraventricular tachyarrhythmias in
pulmonary hypertension. Am Heart J 2007; 153: 127–132.
29. Provencher S, Herve P, Jais X, et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in
patients with portopulmonary hypertension. Gastroenterology 2006; 130: 120–126.
30. Rich S, Seidlitz M, Dodin E, et al. The short-term effects of digoxin in patients with right ventricular dysfunction
from pulmonary hypertension. Chest 1998; 114: 787–792.
31. Olsson KM, Nickel NP, Tongers J, et al. Atrial flutter and fibrillation in patients with pulmonary hypertension. Int
J Cardiol 2013; 167: 2300–2305.
32. Vardas PE, Kochiadakis GE, Igoumenidis NE, et al. Amiodarone as a first-choice drug for restoring sinus rhythm
in patients with atrial fibrillation: a randomized, controlled study. Chest 2000; 117: 1538–1545.
33. Boucly A, O’Connell C, Savale L, et al. Infections liees aux catheters veineux centraux tunnelises chez les patients
ayant une hypertension arterielle pulmonaire traitee par prostacycline intraveineuse. [Tunnelled central venous
line-associated infections in patients with pulmonary arterial hypertension treated with intravenous prostacyclin.]
Presse Med 2016; 45: 20–28.
34. Rush B, Biagioni BJ, Berger L, et al. Mechanical ventilation outcomes in patients with pulmonary hypertension in
the United States: a national retrospective cohort analysis. J Intensive Care Med 2016; in press [DOI: 10.1177/
0885066616653926].
35. Hoeper MM, Granton J. Intensive care unit management of patients with severe pulmonary hypertension and right
heart failure. Am J Respir Crit Care Med 2011; 184: 1114–1124.
36. Price LC, Wort SJ, Finney SJ, et al. Pulmonary vascular and right ventricular dysfunction in adult critical care:
current and emerging options for management: a systematic literature review. Crit Care 2010; 14: R169.
37. Ronco C, House AA, Haapio M. Cardiorenal syndrome: refining the definition of a complex symbiosis gone
wrong. Intensive Care Med 2008; 34: 957–962.
38. Kerbaul F, Rondelet B, Motte S, et al. Effects of norepinephrine and dobutamine on pressure load-induced right
ventricular failure. Crit Care Med 2004; 32: 1035–1040.
39. Piao L, Fang YH, Parikh KS, et al. GRK2-mediated inhibition of adrenergic and dopaminergic signaling in right
ventricular hypertrophy: therapeutic implications in pulmonary hypertension. Circulation 2012; 126: 2859–2869.
40. Vildbrad MD, Andersen A, Holmboe S, et al. Acute effects of levosimendan in experimental models of right
ventricular hypertrophy and failure. Pulm Circ 2014; 4: 511–519.
41. Kerbaul F, Rondelet B, Demester JP, et al. Effects of levosimendan versus dobutamine on pressure load-induced
right ventricular failure. Crit Care Med 2006; 34: 2814–2819.
42. Rich S, Gubin S, Hart K. The effects of phenylephrine on right ventricular performance in patients with
pulmonary hypertension. Chest 1990; 98: 1102–1106.
43. Leather HA, Segers P, Berends N, et al. Effects of vasopressin on right ventricular function in an experimental
model of acute pulmonary hypertension. Crit Care Med 2002; 30: 2548–2552.
44. Kim NH, Delcroix M, Jenkins DP, et al. Chronic thromboembolic pulmonary hypertension. J Am Coll Cardiol
2013; 62: Suppl. 25, D92–D99.
45. Sitbon O, Jais X, Savale L, et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot
study. Eur Respir J 2014; 43: 1691–1697.
46. Montani D, Price LC, Dorfmuller P, et al. Pulmonary veno-occlusive disease. Eur Respir J 2009; 33: 189–200.
47. Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue
disease-associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum
2008; 58: 521–531.
48. Chen Y, Guo L, Li Y, et al. Severe pulmonary arterial hypertension secondary to lupus in the emergency
department: proactive intense care associated with a better short-term survival. Int J Rheum Dis 2015; 18: 331–335.

46

FB:Cardiologia Siglo XXI

 RIGHT HEART FAILURE | B. SZTRYMF ET AL.

49. Weill D, Benden C, Corris PA, et al. A consensus document for the selection of lung transplant candidates: 2014 –
an update from the Pulmonary Transplantation Council of the International Society for Heart and Lung
Transplantation. J Heart Lung Transplant 2015; 34: 1–15.
50. Galie N, Corris PA, Frost A, et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll
Cardiol 2013; 62: Suppl. 25, D60–D72.
51. Christie JD, Edwards LB, Kucheryavaya AY, et al. The Registry of the International Society for Heart and Lung
Transplantation: 29th Adult Lung and Heart-Lung Transplant Report – 2012. J Heart Lung Transplant 2012;
31:1073–1086.
52. Davis SQ, Garrity ER Jr. Organ allocation in lung transplant. Chest 2007; 132: 1646–1651.
53. Schaffer JM, Singh SK, Joyce DL, et al. Transplantation for idiopathic pulmonary arterial hypertension:
improvement in the lung allocation score era. Circulation 2013; 127: 2503–2513.
54. Chen H, Shiboski SC, Golden JA, et al. Impact of the lung allocation score on lung transplantation for pulmonary
arterial hypertension. Am J Respir Crit Care Med 2009; 180: 468–474.
55. Savale L, Lador F, Jais X, et al. L’hypertension arterielle pulmonaire associee au VIH. [HIV-related pulmonary
arterial hypertension.] Rev Mal Respir 2012; 29: 491–500.
56. Struber M, Haverich A. Extracorporeal membrane oxygenation – new developments. Thorac Cardiovasc Surg 1999;
47: Suppl. 2, 304–306.
57. de Perrot M, Granton JT, McRae K, et al. Impact of extracorporeal life support on outcome in patients with idiopathic
pulmonary arterial hypertension awaiting lung transplantation. J Heart Lung Transplant 2011; 30: 997–1002.
58. Sandoval J, Gaspar J, Pulido T, et al. Graded balloon dilation atrial septostomy in severe primary pulmonary
hypertension. A therapeutic alternative for patients nonresponsive to vasodilator treatment. J Am Coll Cardiol
1998; 32: 297–304.
59. Kurzyna M, Dabrowski M, Bielecki D, et al. Atrial septostomy in treatment of end-stage right heart failure in
patients with pulmonary hypertension. Chest 2007; 131: 977–983.
60. Keogh AM, Mayer E, Benza RL, et al. Interventional and surgical modalities of treatment in pulmonary
hypertension. J Am Coll Cardiol 2009; 54: Suppl. 1, S67–S77.
61. Rudski LG, Lai WW, Afilalo J, et al. Guidelines for the echocardiographic assessment of the right heart in adults: a
report from the American Society of Echocardiography endorsed by the European Association of
Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of
Echocardiography. J Am Soc Echocardiogr 2010; 23: 685–713.
62. Dalabih M, Rischard F, Mosier JM. What’s new: the management of acute right ventricular decompensation of
chronic pulmonary hypertension. Intensive Care Med 2014; 40: 1930–1933.
63. Hoeper MM, Lee SH, Voswinckel R, et al. Complications of right heart catheterization procedures in patients with
pulmonary hypertension in experienced centers. J Am Coll Cardiol 2006; 48: 2546–2552.
64. Tsapenko MV, Herasevich V, Mour GK, et al. Severe sepsis and septic shock in patients with pre-existing non-cardiac
pulmonary hypertension: contemporary management and outcomes. Crit Care Resusc 2013; 15: 103–109.
65. Savale L, Maitre B, Bachir D, et al. Hypertension arterielle pulmonaire et drepanocytose. [Pulmonary arterial
hypertension and sickle cell disease.] Presse Med 2013; 42: 338–346.
66. Forfia PR, Mathai SC, Fisher MR, et al. Hyponatremia predicts right heart failure and poor survival in pulmonary
arterial hypertension. Am J Respir Crit Care Med 2008; 177: 1364–1369.
67. Shah SJ, Thenappan T, Rich S, et al. Association of serum creatinine with abnormal hemodynamics and mortality
in pulmonary arterial hypertension. Circulation 2008; 117: 2475–2483.

Disclosures: L. Savale and X. Jaïs have received personal fees and nonfinancial support from Actelion
Pharmaceuticals, Pfizer, GlaxoSmithKline and Bayer HealthCare. O. Sitbon and M. Humbert have received
grants, personal fees and nonfinancial support from Actelion Pharmaceuticals, Bayer HealthCare and
GlaxoSmithKline, personal fees and nonfinancial support from Pfizer, and personal fees from United
Therapeutics. M. Humbert has also received personal fees and nonfinancial support from Novartis.

47

FB:Cardiologia Siglo XXI

 | Chapter 4
Acute exacerbations of COPD
Alison Patricia Butler1, Laura-Jane E. Smith2 and
Alexander John Mackay3

Exacerbations of COPD cause considerable morbidity and mortality, and are among the
commonest causes of medical admissions to hospital. Exacerbations of COPD are triggered
predominantly by infection, resulting in increased airway inflammation in association with a
deterioration in symptoms and lung function. Current management remains dependent on
short-acting bronchodilators, oral corticosteroids and antibiotics, despite limited and often
contradictory results of clinical trials for these therapies. Careful oxygen administration is
appropriate in the context of hypoxia. Ventilatory support, both noninvasive and invasive, is
extremely effective during COPD exacerbations and should be considered and initiated early.
Where appropriate, palliative care is also an integral part of management, and rapid
initiation of supportive and end-of-life care in such circumstances is essential. Future
research is required to identify novel additional treatments in the acute setting, in particular
targeting the excess inflammation seen at exacerbation.

C OPD is a critically important disease as a leading cause of death worldwide [1]. The
World Health Organization estimates that 80 million people worldwide have COPD [2].
Approximately 15 million people in the USA [3] and >3 million people in the UK [4] are
estimated to have COPD. COPD is associated with episodic periods of symptom
deterioration, termed exacerbations. Exacerbations are among the commonest causes of
medical admissions to hospital [5] and are responsible for much of the morbidity [6] and
mortality [7] associated with this highly prevalent condition. This chapter discusses the
definition, diagnosis and aetiology of COPD exacerbations, and describes acute management,
including pharmacotherapy, ventilatory support and the treatment environment, with
reference to published studies, meta-analyses and guidelines.

Definition and diagnosis of exacerbations

COPD is a chronic inflammatory condition most commonly resulting from smoking-

related damage to the lungs [8]. Noxious agents in cigarette smoke damage the airway
epithelium, leading to inflammation and structural changes. The symptomatic hallmarks of
the condition are chronic dyspnoea, wheeze, cough and sputum production.

1
Dept of Respiratory Medicine, St Bartholomew’s Hospital, Barts Health NHS Trust, London, UK. 2Dept of Respiratory Epidemiology,
Occupational Medicine and Public Health, NHLI, Imperial College London, London, UK. 3Dept of Respiratory Medicine, The Royal
London Hospital, Barts Health NHS Trust, London, UK.

Correspondence: Alexander John Mackay, Dept of Respiratory Medicine, The Royal London Hospital, Whitechapel Road, Whitechapel,
London, E1 1BB, UK. E-mail: alexandermackay@nhs.net

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

48 ERS Monogr 2016; 74: 48–65. DOI: 10.1183/2312508X.10001416

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

An exacerbation of COPD is defined as an acute worsening of respiratory symptoms,

accompanied by a variable degree of physiological deterioration [9]. The critical study by
ANTHONISEN et al. [10] defined exacerbations symptomatically, with a particular focus on
the symptoms of increased dyspnoea, sputum volume and sputum purulence. However,
most pharmaceutical studies have used a healthcare utilisation definition, based on a
sustained worsening of the patient’s condition from the stable state that requires a change
in regular medication [11], which frequently takes the form of unscheduled physician visits,
the use of antibiotics or oral steroids at exacerbation, and hospital admission.

A healthcare utilisation definition of exacerbations has significant limitations. Healthcare

use in COPD varies depending on access, resulting in a lack of generalisability across
different healthcare systems. Most importantly, up to two-thirds of COPD exacerbations are
not reported to healthcare professionals and are either self-treated or untreated, and so may
not be captured by such definitions. Unreported exacerbations are important events to
recognise and quantify. Previous studies have shown that up to two-thirds of all
exacerbations are not reported to healthcare professionals for evaluation and treatment [6,
12]. These events impair health-related quality of life [13], and failure to report
exacerbations is also associated with an increased risk of emergency hospitalisation [14].

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy defines an
exacerbation as “an event in the natural course of the disease characterised by a change in
the patient’s baseline dyspnoea, cough, and/or sputum that is beyond normal day-to-day
variations, is acute in onset, and may warrant a change in regular medication in a patient
with underlying COPD” [15]. Regrettably, to date no single biomarker or panel of
biomarkers has been found that can reliably diagnose an exacerbation [16]. Furthermore,
patient-reported outcomes such as the EXAcerbations of Chronic pulmonary disease Tool
(EXACT) have not been capable of reliably detecting exacerbations [17, 18]. Thus, an
exacerbation is a clinical diagnosis based on history and examination, and does not rely
upon any single investigation, invasive or otherwise.

This definition can be problematic, since the symptoms of COPD exacerbations are
nonspecific, and a deterioration in breathlessness and/or sputum production may be caused
by alternative diagnoses in patients with COPD other than a COPD exacerbation [19]. Both
pneumothoraces and pulmonary embolism, for example, have a higher incidence in the
COPD population and can give rise to one or all of the previously described symptoms.
Therefore, the diagnosis of COPD requires that other pathologies must simultaneously be
ruled out using clinical acumen and appropriate investigations (such as chest radiograph,
electrocardiogram and, in some circumstances, CT pulmonary angiogram) if required.

Exacerbation aetiology

Exacerbations are associated with increased systemic and airway inflammation, and may be
precipitated by environmental factors. However, the majority of COPD exacerbations are
triggered by bacterial and/or respiratory viral infections (figure 1) [20].

Bacteria are isolated from sputum using standard culture techniques in 40–60% of
exacerbations [21]. The three most common species isolated in COPD exacerbations are
Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae. Less frequently,
Pseudomonas aeruginosa, Gram-negative Enterobacteriaceae, Staphylococcus aureus,

49

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

TRIGGERS

Bacteria Viruses Pollutants

Inflamed COPD
EFFECTS
airway

Greater airway
inflammation

Systemic Bronchoconstriction,
inflammation oedema, mucus

Expiratory flow
limitation

Cardiovascular Exacerbation Dynamic

comorbidity symptoms hyperinflation

Figure 1. Triggers of COPD exacerbations and associated pathophysiological changes leading to increased
exacerbation symptoms. Reproduced from [20] with permission.

Haemophilus parainfluenzae and Haemophilus haemolyticus are detected [22–24]. Bacteria are
present in the airways of patients with stable COPD when measured using quantitative PCR,
and airway bacterial prevalence and load increase during COPD exacerbations when measured
using quantitative PCR [25]. Therefore, bacteria are likely to be an important potential
aetiological factor in exacerbations.

Respiratory viral infections are detected in up to 60% of exacerbations using PCR

techniques, with rhinoviruses being the most common species identified [26, 27].
Experimental rhinovirus infection models also provide evidence of a direct causal
relationship between respiratory virus infection and acute exacerbations of COPD [28].
Furthermore, viral and bacterial infections demonstrate a synergistic effect at exacerbation,
with exacerbation symptoms, a decline in FEV1 and inflammation all being more severe in
the presence of bacteria and viruses [29].

50

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

Original studies of the respiratory tract made the presumption that the healthy human lung
was sterile, which we now know to be incorrect. The advent of next-generation sequencing
technologies has allowed the investigation of a previously unappreciated, complex microbial
community, referred to as the microbiome [30]. It has recently been proposed that
exacerbations of COPD may occur due to disorder and dysregulation of the dynamic
homoeostasis of the airway microbiome, known as respiratory dysbiosis. In this hypothesis,
an inflammatory trigger (such as a viral infection) initiates airway inflammation, which
alters the environmental growth conditions of airway microbiota. Altered growth conditions
result in a disordered microbiome, which provokes further airway inflammation, leading to a
self-amplifying cycle of airway inflammation and respiratory dysbiosis [31]. In such studies
conducted during stability, pathogenic Proteobacteria, particularly Haemophilus spp., are
more frequent in COPD patients than in controls [32], and recent work examining the
airway microbiome in small numbers of patients at baseline and at exacerbation has shown
that the microbiota members that increased at exacerbation were primarily members of the
phylum Proteobacteria, including nontypical COPD pathogens. Microbiome composition
varies depending upon the treatment given [33], and future treatment regimens may seek to
target the respiratory microbiome to improve clinical outcomes.

Exacerbation management

Currently, exacerbation therapy is typically administered in a stepwise model (figure 2)

[34]. The mainstay of exacerbation therapy is an increase in the dose and frequency of
short-acting bronchodilators and systemic corticosteroids. Antibiotics are reserved for
exacerbations associated with increasing sputum volume or purulence.

β2-agonists and anticholinergics

The pathophysiology underpinning COPD exacerbations involves an increase in airway

inflammation, leading to bronchoconstriction. Short-acting bronchodilators are therefore
one of the primary management options during an exacerbation.

Increase in dose/frequency of
inhaled bronchodilators

Systemic corticosteroids Oxygen ±

ventilatory
support
Antibiotics (if change in sputum)

Increasing Other interventions,

severity e.g. theophylline

And: consideration and management of comorbidities

Then: consider appropriate exacerbation prevention strategies

Figure 2. Stepwise management of COPD exacerbation. Reproduced from [34] with permission.

51

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Both GOLD and the National Institute for Health and Care Excellence (NICE) guidance
recommend short-acting inhaled β2-agonists as the first-line bronchodilator therapy, adding
in antimuscarinic agents should this prove insufficient [15, 35]. However, there are few
data that provide a comparison of either of these agents with one another, or with placebo.
A study has shown similar improvements in FEV1 at 90 min with both drugs, although it
did not use newer agents, such as salbutamol, which is in regular use today [36]. The same
meta-analysis also concluded that there was no improvement when an anticholinergic was
added to a short-acting inhaled β2-agonist [36]. Both nebulisers and hand-held inhalers
can be used to administer inhaled bronchodilators during exacerbations of COPD, and the
choice of delivery method should consider the ability of the patient to use the device, the
symptom burden and the dose of drug required [35].

An alternative strategy espoused in some centres for the inpatient management of acute
COPD exacerbations involves increasing the use of long-acting bronchodilators, in addition
to short-acting bronchodilators. Increasing the dose of a patient’s own long-acting
bronchodilator theoretically has the advantage that inhalation techniques may be checked
and optimised at the same time, so that after hospital discharge patients are more
experienced at using their own device. Using a long-acting inhaler may also prevent the
rapid relapse of symptoms that can occur when short-acting bronchodilators alone are
utilised. This approach has not specifically been validated externally, although a recent
Cochrane review found no difference between nebulisers versus pressurised metered dose
inhalers plus a spacer regarding the primary outcomes of FEV1 at 1 h and safety during
exacerbations of COPD, although the review was hampered by limited data [37].

In acute exacerbations of asthma, intravenous β2-agonists have been shown to have a

similar efficacy to nebulised ones but with a higher rate of side-effects [38]. No such
studies have been identified in COPD, and current guidelines for COPD do not
recommend the administration of these agents via an intravenous route.

Corticosteroids

COPD exacerbations are inflammatory in nature. The use of corticosteroids to dampen this
immune response therefore seems plausible, and multiple studies have found significant
short-term benefits of corticosteroids in the treatment of COPD exacerbations.
Corticosteroids lead to improvements in FEV1 in the first 3–5 days of treatment [39–41] and
in PaO2 in the first 72 h in comparison with placebo [42]. Corticosteroids have also been
shown to reduce the length of hospitalisation [41, 42], and a 2014 Cochrane review
comparing systemic corticosteroid use with placebo showed that steroids reduced the risk of
treatment failure in patients by over one-half compared with placebo [43]. Unfortunately,
improvements in lung function are not sustained at 30 days, and treatment of COPD
exacerbations with corticosteroids does not improve overall mortality [43]. Nevertheless,
guidelines recommend that all patients admitted to hospital with an exacerbation should
receive systemic corticosteroid therapy, as should patients in the community with significant
breathlessness that interferes with daily living [15, 35].

Controversy exists regarding the optimal dose and duration of treatment for acute
exacerbations, often due to the heterogeneity of treatment regimens in different clinical trials.
Higher doses (>80 mg) are no more effective than lower doses (30–80 mg) [44], and there is
no clear benefit of intravenous therapy over oral preparations. Therefore, most guidelines

52

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

recommend 30–40 mg oral prednisolone where an enteral route is available [15, 45]. Short
courses (⩽7 days) are equally efficacious with respect to rates of treatment failure, risk of
relapse, time to next exacerbation, length of hospitalisation and lung function at the end of
treatment, compared with extended courses (>7 days) [45]. Shorter courses of therapy reduce
the risk of adverse effects, with tapering of dose not required for most patients. The
commonest reported adverse effect of corticosteroid therapy is hyperglycaemia, particularly
in patients with pre-existing diabetes mellitus [42]. Therefore, the GOLD strategy advises
5 days of treatment, whereas NICE recommends 7–14 days, without specific guidance on
which patients should receive longer or shorter treatment courses. There is little evidence to
support the use of inhaled corticosteroids in the management of acute exacerbations of
COPD, although nebulised budesonide alone may be an alternative [42].

As discussed in a previous section, exacerbations are triggered mainly by bacteria and

respiratory viruses, and result in increased airway and systemic inflammation [16, 46].
Typically, the rise in inflammation seen at exacerbation has been considered predominantly
neutrophilic [47–49]. However, more recently there has been considerable interest in
eosinophilic inflammation, which had previously been thought to be confined more to
asthmatic patients. BAFADHEL et al. [50] used cluster analysis to identify four distinct biological
clusters at exacerbation: bacteria-predominant, virus-predominant, eosinophil-predominant,
and one associated with limited changes in the inflammatory profile termed
“pauci-inflammatory” (figure 3). In their study, 28% of events were associated with sputum
eosinophilia, which can be identified using a peripheral blood eosinophil count of 2%. This
threshold had a sensitivity of 90% and a specificity of 60% for identifying a sputum
eosinophilia of >3% at exacerbation. Subsequently, it has been proposed that the use of
corticosteroids, in the stable state, in the form of inhaled corticosteroid-containing combination
therapy [51, 52] and in terms of systemic therapy at exacerbation, might have the greatest
benefit in patients with peripheral blood eosinophil levels above this threshold, and that in fact
use of corticosteroids in non-eosinophilic exacerbations may impair recovery [53]. However, to
date, prospective studies using blood eosinophil profiling are limited, and more research is
needed prior to the introduction of biomarker-guided corticosteroid therapy at exacerbation.

Antibiotics

As discussed previously, bacteria are thought to play a significant role in the aetiology of
COPD exacerbations, and purulent sputum is a reasonable surrogate of bacterial infection
[54]. Most guidelines therefore recommend the administration of antibiotics in events
associated with sputum purulence [15, 35].

The seminal study by ANTHONISEN et al. [10] is the foundation for these recommendations.
This pivotal study investigated antibiotic use in 173 patients over a period of 3.5 years. It
was a randomised, double-blind, crossover study comparing antibiotics with placebo at
acute exacerbation, which was defined as increased breathlessness, sputum volume and
purulence. The study concluded that antibiotics were associated with better success rates
and more rapid peak flow improvement, without being associated with more side-effects
[10]. However, the benefits were dependent upon the clinical phenotype of the event. Type
1 exacerbations (those associated with increased sputum volume, sputum purulence and
dyspnoea) benefited the most, with resolution of symptoms in 63% of the antibiotic-treated
exacerbations and 43% of the placebo group. Patients with type 3 exacerbations (who met
just one of the three cardinal symptoms) did not show significant benefit.

53

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Th2
Bacteria-predominant

Eosinophil-predominant

Virus-predominant

Pauci-inflammatory

Pro-inflammatory
Th1

Figure 3. Proportional representation of biological COPD exacerbation clusters in three-dimensional ellipsoids.

Cluster 1, shown in blue, is termed “bacteria-predominant”, cluster 2 in green is termed “eosinophil-
predominant”, cluster 3 in red is termed “virus-predominant” and cluster 4 in grey is termed “pauci-
inflammatory”. Th1: T-helper type 1; Th2: T-helper type 2. Reproduced and modified from [50] with permission.

More recently, antibiotics have been shown to increase the clinical cure rate and prolong
the time to next exacerbation in mild to moderate exacerbations (those requiring increased
use of bronchodilators, oral antibiotics and/or steroids) [55]. Results for hospitalised
patients, however, have been contradictory, and comparisons between studies have been
limited by differences in patient selection and antibiotic choice, and by lack of control for
interventions that influence outcome, such as the use of systemic corticosteroids and
ventilatory support. A recent Cochrane review found that antibiotics had no statistically
significant effect on mortality and length of hospital stay in inpatients [56]. However, a
prospective, randomised, double-blind, placebo-controlled trial of 93 COPD patients at
acute exacerbation who required mechanical ventilation found that mortality, duration of
mechanical ventilation, length of inpatient stay and treatment failure rates were reduced by
the use of oral ofloxacin [57]. This supports the recommendation that antibiotics should be
administered in severe exacerbations requiring ventilatory assistance [15].

The addition of antibiotics to oral steroids as part of exacerbation treatment may produce
synergistic benefits. Epidemiological research using data from historical cohorts has shown
that adding antibiotics to oral corticosteroids as part of the index exacerbation treatment
may increase the time to the next exacerbation [58], reduce the risk of future exacerbations
[59] and decrease all-cause mortality. However, new data presented to the American
Thoracic Society in 2016 from the TEXACOLD trial found that the addition of 7 days of
doxycycline treatment to exacerbations treated with 30 mg prednisolone for 10 days did not
prolong the time to next exacerbation [60]. Full publication of this study is currently
pending, but the efficacy may have been limited by antibiotic choice, with doxycycline
having reduced lung penetration compared with other antibiotics, such as amoxicillin and
clavulanic acid, and the inclusion of some patients without purulent sputum.

54

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

Due to the heterogeneity of results of previous antibiotic trials, potential complications

associated with their use and concerns about resistance, biomarkers have been studied in an
attempt to target antibiotics to those who would derive most benefit. Procalcitonin (PCT) is a
peptide produced in response to endotoxin and other mediators released in bacterial
infections. It has been evaluated as a marker of severe bacterial infection, including lower
respiratory tract infections and acute exacerbations of COPD [61, 62]. Use of PCT in severe
lower respiratory tract infections and COPD exacerbations has been shown to reduce the
duration of antibiotic use, with similar rates of adverse outcomes to standard guidelines,
suggesting that PCT may have a role in reducing inappropriate antibiotic use during COPD
exacerbation [63]. However, PCT is not readily available in most hospitals or community
settings. An alternative biomarker, which is readily available, including in point-of-care form,
is C-reactive protein. In general practice, C-reactive protein rapid testing has been shown to
reduce overprescription of antibiotics without additional adverse outcomes, although this
may have been due to sample size limitations [64]. Further research is required in this area.

Oxygen therapy

Hypoxaemia in any circumstance can be life-threatening and should be addressed as a

matter of urgency in the acutely unwell patient. However, although this is true for COPD
exacerbations, care must be taken over the delivery of oxygen in order to avoid suppression
of the patient’s respiratory drive and hypercapnia. Oxygen is a prescribed drug, and it is
imperative that it is used as a treatment for hypoxia, rather than for breathlessness. As with
any intervention in the acutely unwell patient, the patient should be reviewed promptly
following initiation to assess the treatment response.

A prevalence study in the UK concluded that 20% of admissions with an acute COPD
exacerbation had respiratory acidosis on arterial blood gas (ABG) analysis [65]. This
highlights the importance of careful oxygen delivery and early reassessment after initiating
therapy. Controlled oxygen delivery, generally achieved via a Venturi mask, allows accurate
assessment of FIO2, although it may be poorly tolerated. GOLD guidelines recommend
aiming for oxygen saturation of 88–92%, with ABG monitoring 30–60 min after oxygen
therapy has been initiated. If the patient remains hypoxaemic and acidotic despite controlled
oxygen and best medical therapy, ventilatory assistance should be considered. Figure 4,
adapted from the British Thoracic Society (BTS) guidance [66], shows the approach to
oxygen delivery in the acutely unwell COPD patient.

Noninvasive ventilation

The mechanics of NIV are discussed in another chapter in this Monograph [67], but NIV plays
a crucial role in the management of acute COPD exacerbations with hypercapnic respiratory
failure. The indications for NIV are shown in table 1; essentially, if a patient remains hypoxic,
hypercapnic and acidotic despite best medical therapy, then NIV should rapidly be considered.
NIV is an extremely effective treatment for hypercapnic respiratory failure in the context of
COPD exacerbations, reducing endotracheal intubation rate, treatment failure and short-term
mortality, as well as improving acidosis in the first few hours of treatment [69].

Despite this, NIV is not an appropriate option for all patients, and the contraindications
shown in table 1 should be considered. Severe respiratory acidosis (pH <7.25) is often
considered a relative contraindication, as these patients have poorer outcomes on NIV [70].

55

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

O2 saturation <94% on room air

Yes No

Start fixed rate 24% or 28% O2, No need for O2 or

target saturations 88–92%, ABG acutely
obtain ABG

pH <7.35, PCO2 >6.0 kPa pH ≥7.35, PCO2 >6.0 kPa PCO2 ≤6.0 kPa

Seek senior medical Repeat ABG after Target saturations 94–98%

help, consider NIV 30–60 min If patient has had previous
Aim saturations 88–92% via If pH <7.35, PCO2 >6.0 kPa, NIV or T2RF target 88–92%
Venturi mask pending seek senior medical help, Repeat ABG after 30–60 min
senior review/NIV consider NIV to look for hypercapnia
If PO2 >8.0 kPa, consider
reducing FIO2

Figure 4. Oxygenation in the acutely unwell COPD patient. ABG: arterial blood gas; PCO2: partial pressure of
carbon dioxide; PO2: partial pressure of oxygen; T2RF: type 2 respiratory failure. From the British Thoracic
Society guidelines for emergency oxygen use in adult patients [66].

Prompt invasive ventilation is more successful in these patients where appropriate.

Importantly, a ceiling of care should be established prior to initiation of NIV. By definition,
respiratory acidosis at the time of presentation makes an exacerbation “severe”, and many
of these patients have significant underlying COPD, as well as multiple comorbidities.
Should NIV fail, there is a cohort of patients for whom endotracheal intubation and
admission to the ICU may not be appropriate. This should be confirmed prior to
commencement of NIV, preferably in discussion with the patient.

Once NIV is initiated, ABG monitoring is required to ensure resolution of acidosis and
improvement of gas exchange. BTS guidelines advise that the time on NIV should be

Table 1. Indications and contraindications for NIV

Indications for NIV

pH <7.35, PCO2 >6.5 kPa, respiratory rate >23 breaths·min−1
If persisting after bronchodilators and controlled oxygen therapy
Relative contraindications#
pH <7.15 (or pH <7.25 and additional adverse features)
Glasgow Coma Score <8
Confusion/agitation
Cognitive impairment (warrants enhanced observation)
Absolute contraindications
Severe facial deformity
Facial burns
Fixed upper airway obstruction

PCO2: partial pressure of carbon dioxide. #: for patients with the relative contraindications listed,
treatment with NIV should be carried out in an appropriate area with ready access to staff who
can perform safe endotracheal intubation if needed. From the British Thoracic Society/Intensive
Care Society guidelines for ventilatory management of acute hypercapnic respiratory failure [68].

56

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

maximised in the first 24 h, depending on patient tolerance and/or complications. Thereafter,

NIV use during the day can be tapered over the following 2–3 days, depending on the partial
pressure of carbon dioxide (PCO2) levels measured while self-ventilating, before being
discontinued overnight. NIV can be discontinued when there has been normalisation of pH
and PCO2 and a general improvement in the patient’s condition [68].

Invasive ventilation

The indications for mechanical ventilation include failure of NIV and imminent respiratory
arrest (table 2). In practice, not all patients are candidates for invasive ventilation, and, as
with NIV, an early conversation about treatment escalation is imperative. In end-stage
COPD, factors such as comorbidities, frailty and the patient’s wishes should all be taken into
account prior to making a decision. The main complications associated with mechanical
ventilation are ventilator-associated pneumonia, barotrauma and failure to wean [15]. If
mechanical ventilation is not appropriate and NIV has failed or the patient is not suitable,
early involvement of palliative care should be considered. However, there is evidence to
suggest that acute mortality among COPD patients with respiratory failure is lower than
mortality among patients ventilated for non-COPD causes [71]. If the patient fits the criteria
shown in table 2 and would be a candidate for mechanical ventilation, referral should be
made early, particularly if NIV is unlikely to be successful or is not improving gas exchange.

Palliative care

Many hospitalised patients have palliative care needs, and such needs may extend for years
in chronic diseases such as COPD [72]. It is unclear how best to identify these patients
[73–76], and it is challenging to address the social and psychological needs of patients and
carers and create a holistic and calm environment in the acute setting [77]. In addition, an
acute exacerbation of COPD may be a terminal event, and breathlessness and respiratory
failure may be the end stage of a slow decline, mislabelled as an acute exacerbation on
initial assessment. A particular challenge for those at the front door is to identify those
patients who will benefit from and who wish to receive NIV and intubation, and to initiate
such treatments rapidly, but also to identify those for whom such treatments are likely to
be unsuccessful and may prolong death. For these patients, rapid initiation of supportive
and end-of-life care is essential. Risk scores may facilitate such decision making [78], but at
the core must be exploration of patient preferences and advance care planning [79].

Patients with advanced COPD have similar treatment preferences to patients with lung
cancer [80] but are more likely to undergo invasive interventions at the end of life [81]. This

Table 2. Indications for invasive ventilation

Imminent respiratory arrest

Severe respiratory distress
Failure of or contraindications to NIV
Persisting pH <7.15 or deterioration in pH despite NIV
Depressed consciousness (Glasgow Coma Score <8)

From the British Thoracic Society/Intensive Care Society guidelines for ventilatory management
of acute hypercapnic respiratory failure [68].

57

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

is partly due to the fact that they are less likely to complete advanced care planning [79].
Physicians find it challenging to know when is the right time to discuss intubation,
ventilation and ceilings of care with patients, and these conversations therefore often occur at
a time of crisis [82, 83]. Patients may be “invisible” until they have an exacerbation, as
traditional models of care for COPD are reactive and fragmented. Models of care that bridge
primary and secondary care and that integrate palliative care alongside disease-focused care
are needed since, in such models, advance care planning is improved [84, 85].

Hospital may be the preferred place of care for a greater number of patients with respiratory
disease than other conditions, since breathlessness is frightening. It is essential, therefore, to
ensure that hospice principles and practices are implemented in hospitals. A good death is
absolutely possible in the acute setting but is too often hindered by delays in diagnosis of
dying, delays in decision making, lack of confidence in the use of palliative medications, and
a default of systems and teams towards investigation and intervention [86–89].

Other interventions

Mucolytics
The role of mucolytics such as carbocisteine is unclear in COPD management. A 2010
Cochrane review suggested that long-term use reduces the frequency of exacerbations and
the number of disability days per year [90]. However, their use does not appear to result in
an improvement in lung function or quality of life. There is some suggestion that patients
not taking inhaled corticosteroids may receive a bigger benefit than those who are, and that
patients with very viscous sputum may benefit the most [90]. However, GOLD guidelines
do not recommend the use of mucolytics for long-term management at present, and their
role in the acute setting has not been established [15].

Methylxanthines
The use of theophylline in the management of COPD has been contentious, with conflicting
evidence. It is not currently recommended as a first-line therapy in either acute or chronic
management. A prospective double-blind RCT of 80 patients with non-acidotic COPD
exacerbations showed a small but statistically significant improvement in PaO2 with
intravenous theophylline compared with placebo [91]. However, this did not affect clinical
outcome, and patients were found to complain of nausea more commonly. The rate of
palpitations and headaches was equal in the placebo versus the treatment group. GOLD
guidelines recommend that intravenous methylxanthines be used if nebulised β2-agonists and
anticholinergics have failed [15].

Novel anti-inflammatory agents

Treatment failure with the standard of care is 27% at 30 days and rises to 37% at 90 days
[43, 92]. Persistently elevated inflammation during exacerbations is associated with clinical
nonrecovery and recurrence [93]. Thus, new therapies for the management of acute
exacerbations are urgently needed, in particular specifically targeting the increased
inflammation seen at exacerbation. Unfortunately, to date attempts to use alternative agents to
treat exacerbations have been unsuccessful. As described in previous sections, exacerbations are
inflammatory events, and are associated with increased sputum concentrations of tumour
necrosis factor (TNF)-α. TNF-α upregulates adhesion molecules, facilitates migration of

58

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

leukocytes into the bronchial mucosa during an acute exacerbation of COPD, and stimulates
neutrophil degranulation and superoxide production [94].

Etanercept binds to soluble TNF and blocks the interaction of TNF with cell-surface TNF
receptors. Therefore, the drug competitively inhibits TNF binding to cell-surface TNF2
receptors, rendering TNF biologically inactive [95]. Observational data suggested that the
use of etanercept in patients with both rheumatoid arthritis and COPD reduced
hospitalisation risk [96]. Subsequently, AARON et al. [97] conducted an RCT to establish
whether etanercept improved lung function and decreased treatment failure rates compared
with corticosteroids. Both groups received oral antibiotics and bronchodilators as part of
standard therapy. Unfortunately, etanercept failed to demonstrate any improved clinical
efficacy compared with standard treatment with prednisone with respect to a change in
FEV1 from baseline. Furthermore, the nonsignificant differences observed in the trial
tended to favour the prednisolone-treated group, with the relative risk of 90-day treatment
failure being greater (by 25%) in those randomised to etanercept.

Alternative anti-inflammatory agents include roflumilast, a phosphodiesterase 4 inhibitor

designed to target both the systemic and pulmonary inflammation associated with COPD.
COPD exacerbations are associated with increased neutrophilic inflammation [48], and
roflumilast demonstrates broad anti-inflammatory activities and has been shown to reduce
neutrophilic airway inflammation in COPD patients [98], improve lung function and
reduce exacerbations in stable COPD patients [99–101]. Results from a trial assessing the
efficacy of roflumilast as an additional therapy at acute exacerbation will report shortly
(ClinicalTrials.gov, trial number NCT01473758).

Early inpatient respiratory rehabilitation during an exacerbation

Historically, small-scale trials of exercise-based therapy during acute exacerbation of COPD

suggested that such approaches are feasible and may be effective [102–104]. More recently,
however, a large prospective RCT tested the efficacy of a 6-week intervention, started within 48 h
of admission for an exacerbation of chronic respiratory disease (>80% of patients had a primary
diagnosis of COPD). The intervention comprised prescribed, progressive aerobic, resistance and
neuromuscular electrical stimulation training. Patients also received a self-management and
education package. The results showed no significant effect of early pulmonary rehabilitation on
readmission rates in the year after initial admission compared with usual care. An increase in
mortality was seen in the intervention group at 1 year but not during the intervention period or
at 6 months. Physical performance and health status recovered after discharge in both groups,
with no significant difference between the groups at 1 year. Consequently, the authors concluded
that, beyond current standard physiotherapy practice, progressive exercise rehabilitation should
not be started during the early stages of the acute illness [105].

Self-management

Patient education is vital to improve the management of COPD exacerbations. Rapid

recognition of exacerbation symptoms and earlier treatment improves recovery and reduces
the risk of hospitalisation [14]. Self-management plans and programmes enable patients to
respond appropriately to the first signs of an exacerbation. Patients at high risk of
exacerbations are frequently provided with a course of “rescue” antibiotics and
corticosteroids, and are instructed to commence oral corticosteroid therapy if their increased

59

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

dyspnoea interferes with activities of daily living. Antibiotics should be started in response to
increased sputum volume and/or purulence, and bronchodilator therapy should be increased
to control symptoms [38]. Depending on patient confidence and support networks,
treatment can be initiated either independently or after seeking advice from a healthcare
professional. Such interventions reduce admission rates [106, 107]; however, not all patients
are suitable for these strategies. Anxiety and depression is common in COPD, and patients
are frequently elderly and may have cognitive impairment, limiting their ability to
self-manage, particularly when acutely unwell. Further research is required in this area, with a
focus on identification and management of patients at high risk of hospital admission.
Admission to hospital

Mild COPD exacerbations can be managed safely in the community. However, deciding
who fulfils the criteria of a “mild” exacerbation can be difficult in practice. The NICE
COPD guidelines from 2010 specifically address the issue of admission to hospital [35].
Table 3 is adapted from these guidelines, and indicates that hypoxic, acidotic or confused
patients warrant automatic admission, and that careful consideration should be given to
patients with severe underlying disease, such as those receiving long-term oxygen therapy
[35]. Patients with a good baseline level of function who are only mildly breathless can be
managed at home. Particular care must be taken over discharging vulnerable, frail patients.
In such circumstances, even if symptoms appear mild, admission may be warranted if
patients are unable to cope at home and/or live alone without assistance.

Prognosis

Due the heterogeneity of symptoms that can worsen during an exacerbation of COPD,
standardised instruments have been developed to evaluate the severity of exacerbations.

Table 3. Factors to consider when deciding where to treat patients

Factor Home Hospital

Able to cope at home Yes No

Breathlessness Mild Severe
General condition Good Poor/deteriorating
Level of activity Good Poor/confined to bed
Cyanosis No Yes
Worsening peripheral oedema No Yes
Level of consciousness Normal Impaired
Already receiving LTOT No Yes
Social circumstances Good Living alone/not coping
Acute confusion No Yes
Rapid rate of onset No Yes
Significant comorbidity No Yes
SaO2 <90% No Yes
Changes on chest radiograph No Yes
Arterial pH level ⩾7.35 <7.35
PO2 ⩾7 kPa <7 kPa

LTOT: long-term oxygen therapy; SaO2: arterial oxygen saturation; PO2: partial pressure of oxygen.
From the National Institute for Health and Care Excellence guidelines for the management of
COPD exacerbations [35].

60

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

Two such patient-reported outcome tools, the COPD Assessment Test (CAT) and EXACT,
have recently been shown to be effective instruments to monitor COPD exacerbation
severity and recovery in outpatients [17, 108]. Furthermore, in hospitalised patients,
exacerbation CAT scores relate to length of stay [109], and patients with higher CAT score
increases during the initial days of hospitalisation and with higher area-under-the-curve
CAT scores for the first 5 days of exacerbation may be more likely to require hospitalisation
for a recurrent exacerbation [110].

More-objective measures may also be utilised to determine exacerbation prognosis. The

Dyspnoea, Eosinopenia, Consolidation, Acidaemia and atrial Fibrillation (DECAF) scoring
system uses the following parameters, which are routinely available when patients attend
hospital: extended Medical Research Council dyspnoea score, eosinopenia
(<0.05×109 eosinophils·L−1), consolidation on chest radiograph, acidaemia (arterial pH
<7.30) and atrial fibrillation. The scoring system predicts mortality and may identify both
low-risk patients (DECAF score 0–1) who may be suitable for Hospital at Home or early
supported discharge schemes, as well as high-risk patients (DECAF score 3–6) for
escalation planning or appropriate early palliation [77]. More recently, smaller quadriceps
muscle size, as measured by ultrasound in the acute care setting, has been shown to be an
independent risk factor for unscheduled readmission or death in patients hospitalised with
an exacerbation of chronic respiratory disease [111], although at the present time this
remains predominantly a research tool and is not commonly available in clinical practice.

Conclusion

Exacerbations are critical events in COPD. Current management remains dependent on

short-acting bronchodilators, oral corticosteroids and antibiotics, despite limited and often
contradictory results of clinical trials for these therapies. Careful oxygen administration is
appropriate in the context of hypoxia. Ventilatory support, both noninvasive and invasive,
is extremely effective during COPD exacerbations, and should be considered and initiated
early. Where appropriate, palliative care is also an integral part of management, and rapid
initiation of supportive and end-of-life care in such circumstances is essential. Future
research is required to identify novel additional treatments in the acute setting, in particular
targeting the excess inflammation seen at exacerbation.

References
1. Lozano R, Naghavi M, Foreman, K, et al. Global and regional mortality from 235 causes of death for 20 age groups
in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012; 380: 2095–2128.
2. Bousquet J, Dahl R, Khaltaev N. Global alliance against chronic respiratory diseases. Allergy 2007; 62: 216–223.
3. Ward MM, Javitz HS, Smith WM, et al. Direct medical cost of chronic obstructive pulmonary disease in the U.S.A.
Respir Med 2000; 94: 1123–1129.
4. Shahab L, Jarvis MJ, Britton J, et al. Prevalence, diagnosis and relation to tobacco dependence of chronic
obstructive pulmonary disease in a nationally representative population sample. Thorax 2006; 61: 1043–1047.
5. British Thoracic Society (BTS). The Burden of Lung Disease. 2nd Edn. London, BTS, 2006. www.brit-thoracic.org.
uk/document-library/delivery-of-respiratory-care/burden-of-lung-disease/burden-of-lung-disease-2006/
6. Seemungal TA, Donaldson GC, Paul EA, et al. Effect of exacerbation on quality of life in patients with chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 1998; 157: 1418–1422.
7. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in
patients with chronic obstructive pulmonary disease. Thorax 2005; 60: 925–931.
8. Bourdin A, Burgel PR, Chanez P, et al. Recent advances in COPD: pathophysiology, respiratory physiology and
clinical aspects, including comorbidities. Eur Respir Rev 2009; 18: 198–212.

61

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

9. Seemungal TA, Donaldson GC, Bhowmik A, et al. Time course and recovery of exacerbations in patients with
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2000; 161: 1608–1613.
10. Anthonisen NR, Manfreda J, Warren CP, et al. Antibiotic therapy in exacerbations of chronic obstructive
pulmonary disease. Ann Intern Med 1987; 106: 196–204.
11. Rodriguez-Roisin R. Toward a consensus definition for COPD exacerbations. Chest 2000; 117: Suppl. 2, 398S–401S.
12. Langsetmo L, Platt RW, Ernst P, et al. Underreporting exacerbation of chronic obstructive pulmonary disease in a
longitudinal cohort. Am J Respir Crit Care Med 2008; 177: 396–401.
13. Xu W, Collet JP, Shapiro S, et al. Negative impacts of unreported COPD exacerbations on health-related quality
of life at 1 year. Eur Respir J 2010; 35: 1022–1030.
14. Wilkinson TM, Donaldson GC, Hurst JR, et al. Early therapy improves outcomes of exacerbations of chronic
obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 169: 1298–1303.
15. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management
and Prevention of COPD. 2016. Available from: http://goldcopd.org/
16. Hurst JR, Donaldson GC, Perera WR, et al. Use of plasma biomarkers at exacerbation of chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2006; 174: 867–874.
17. Mackay AJ, Donaldson GC, Patel AR, et al. Detection and severity grading of COPD exacerbations using the
exacerbations of chronic pulmonary disease tool (EXACT). Eur Respir J 2014; 43: 735–744.
18. Jones PW, Lamarca R, Chuecos F, et al. Characterisation and impact of reported and unreported exacerbations:
results from ATTAIN. Eur Respir J 2014; 44: 1156–1165.
19. Hurst JR, Wedzicha JA. What is (and what is not) a COPD exacerbation: thoughts from the new GOLD
guidelines. Thorax 2007; 62: 198–199.
20. Wedzicha JA, Seemungal TA. COPD exacerbations: defining their cause and prevention. Lancet 2007; 370: 786–796.
21. Sethi S. Infectious etiology of acute exacerbations of chronic bronchitis. Chest 2000; 117: Suppl. 2, 380S–385S.
22. Sethi S, Murphy TF. Bacterial infection in chronic obstructive pulmonary disease in 2000: a state-of-the-art
review. Clin Microbiol Rev 2001; 14: 336–363.
23. Sethi S, Evans N, Grant BJ, et al. New strains of bacteria and exacerbations of chronic obstructive pulmonary
disease. N Engl J Med 2002; 347: 465–471.
24. Murphy TF, Brauer AL, Sethi S, et al. Haemophilus haemolyticus: a human respiratory tract commensal to be
distinguished from Haemophilus influenzae. J Infect Dis 2007; 195: 81–89.
25. Garcha DS, Thurston SJ, Patel AR, et al. Changes in prevalence and load of airway bacteria using quantitative
PCR in stable and exacerbated COPD. Thorax 2012; 67: 1075–1080.
26. Seemungal T, Harper-Owen R, Bhowmik A, et al. Respiratory viruses, symptoms, and inflammatory markers in
acute exacerbations and stable chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 164:
1618–1623.
27. Rohde G, Wiethege A, Borg I, et al. Respiratory viruses in exacerbations of chronic obstructive pulmonary disease
requiring hospitalisation: a case–control study. Thorax 2003; 58: 37–42.
28. Mallia P, Message SD, Gielen V, et al. Experimental rhinovirus infection as a human model of chronic obstructive
pulmonary disease exacerbation. Am J Respir Crit Care Med 2011; 183: 734–742.
29. Wilkinson TM, Hurst JR, Perera WR, et al. Effect of interactions between lower airway bacterial and rhinoviral
infection in exacerbations of COPD. Chest 2006; 129: 317–324.
30. Charlson ES, Chen J, Custers-Allen R, et al. Disordered microbial communities in the upper respiratory tract of
cigarette smokers. PLoS One 2010; 5: e15216.
31. Dickson RP, Martinez FJ, Huffnagle GB. The role of the microbiome in exacerbations of chronic lung diseases.
Lancet 2014; 384: 691–702.
32. Hilty M, Burke C, Pedro H, et al. Disordered microbial communities in asthmatic airways. PLoS One 2010; 5: e8578.
33. Huang YJ, Sethi S, Murphy T, et al. Airway microbiome dynamics in exacerbations of chronic obstructive
pulmonary disease. J Clin Microbiol 2014; 52: 2813–2823.
34. Hurst JR, Wedzicha JA. Management and prevention of chronic obstructive pulmonary disease exacerbations:
a state of the art review. BMC Med 2009; 7: 40.
35. National Institute for Health and Care Excellence (NICE). Chronic Obstructive Pulmonary Disease in Over 16s:
Diagnosis and Management. NICE Guidelines CG101. London, NICE, 2010. Available from: www.nice.org.uk/
guidance/CG101
36. McCrory DC, Brown CD. Anti-cholinergic bronchodilators versus β2-sympathomimetic agents for acute
exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2002; 4: CD003900.
37. van Geffen WH, Douma WR, Slebos DJ, et al. Bronchodilators delivered by nebuliser versus pMDI with spacer or
DPI for exacerbations of COPD. Cochrane Database Syst Rev 2016; 8: CD011826.
38. Travers A, Jones AP, Kelly K, et al. Intravenous β2-agonists for acute asthma in the emergency department.
Cochrane Database Syst Rev 2001; 2: CD002988.
39. Davies L, Angus RM, Calverley PM. Oral corticosteroids in patients admitted to hospital with exacerbations of
chronic obstructive pulmonary disease: a prospective randomised controlled trial. Lancet 1999; 354: 456–460.

62

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

40. Niewoehner DE, Erbland ML, Deupree RH, et al. Effect of systemic glucocorticoids on exacerbations of chronic
obstructive pulmonary disease. N Engl J Med 1999; 340: 1941–1947.
41. Thompson WH, Nielson CP, Carvalho P, et al. Controlled trial of oral prednisone in outpatients with acute
COPD exacerbation. Am J Respir Crit Care Med 1996; 154: 407–412.
42. Maltais F, Ostinelli J, Bourbeau J, et al. Comparison of nebulized budesonide and oral prednisolone with placebo
in the treatment of acute exacerbations of chronic obstructive pulmonary disease: a randomized controlled trial.
Am J Respir Crit Care Med 2002; 165: 698–703.
43. Walters JA, Tan DJ, White CJ, et al. Systemic corticosteroids for acute exacerbations of chronic obstructive
pulmonary disease. Cochrane Database Syst Rev 2014; 9: CD001288.
44. Cheng T, Gong Y, Guo Y, et al. Systemic corticosteroid for COPD exacerbations, whether the higher dose is
better? A meta-analysis of randomized controlled trials. Clin Respir J 2013; 7: 305–318.
45. Walters JA, Tan DJ, White CJ, et al. Different durations of corticosteroid therapy for exacerbations of chronic
obstructive pulmonary disease. Cochrane Database Syst Rev 2014; 12: CD006897.
46. Bhowmik A, Seemungal TA, Sapsford RJ, et al. Relation of sputum inflammatory markers to symptoms and lung
function changes in COPD exacerbations. Thorax 2000; 55: 114–120.
47. Aaron SD, Angel JB, Lunau M, et al. Granulocyte inflammatory markers and airway infection during acute
exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 349–355.
48. Gompertz S, O’Brien C, Bayley DL, et al. Changes in bronchial inflammation during acute exacerbations of
chronic bronchitis. Eur Respir J 2001; 17: 1112–1119.
49. Tsoumakidou M, Tzanakis N, Chrysofakis G, et al. Nitrosative stress, heme oxygenase-1 expression and airway
inflammation during severe exacerbations of COPD. Chest 2005; 127: 1911–1918.
50. Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease:
identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med 2011; 184: 662–671.
51. Siddiqui SH, Guasconi A, Vestbo J, et al. Blood eosinophils: a biomarker of response to extrafine beclomethasone/
formoterol in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2015; 192: 523–525.
52. Pascoe S, Locantore N, Dransfield MT, et al. Blood eosinophil counts, exacerbations, and response to the addition
of inhaled fluticasone furoate to vilanterol in patients with chronic obstructive pulmonary disease: a secondary
analysis of data from two parallel randomised controlled trials. Lancet Respir Med 2015; 3: 435–442.
53. Bafadhel M, McKenna S, Terry S, et al. Blood eosinophils to direct corticosteroid treatment of exacerbations of
chronic obstructive pulmonary disease: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2012;
186: 48–55.
54. Stockley RA, O’Brien C, Pye A, et al. Relationship of sputum color to nature and outpatient management of acute
exacerbations of COPD. Chest 2000; 117: 1638–1645.
55. Llor C, Moragas A, Hernández S, et al. Efficacy of antibiotic therapy for acute exacerbations of mild to moderate
chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 716–723.
56. Vollenweider DJ, Jarrett H, Steurer-Stey CA, et al. Antibiotics for exacerbations of chronic obstructive pulmonary
disease. Cochrane Database Syst Rev 2012; 12: CD010257.
57. Nouira S, Marghli S, Belghith M, et al. Once daily oral ofloxacin in chronic obstructive pulmonary disease
exacerbation requiring mechanical ventilation: a randomised placebo-controlled trial. Lancet 2001; 358: 2020–2025.
58. Roede BM, Bresser P, Bindels PJ, et al. Antibiotic treatment is associated with reduced risk of a subsequent
exacerbation in obstructive lung disease: an historical population based cohort study. Thorax 2008; 63: 968–973.
59. Roede BM, Bresser P, Prins JM, et al. Reduced risk of next exacerbation and mortality associated with antibiotic
use in COPD. Eur Respir J 2009; 33: 282–288.
60. Van Velzen P, Ter Riet G, Bresser P, et al. Long-term effects of antibiotics in COPD exacerbations: a randomized
clinical trial. Am J Respir Crit Care Med 2016; 193: A1021.
61. Christ-Crain M, Jaccard-Stolz D, Bingisser R, et al. Effect of procalcitonin-guided treatment on antibiotic use and
outcome in lower respiratory tract infections: cluster-randomised, single-blinded intervention trial. Lancet 2004;
363: 600–607.
62. Bafadhel M, Clark TW, Reid C, et al. Procalcitonin and C-reactive protein in hospitalised adult patients with
community-acquired pneumonia or exacerbation of asthma or COPD. Chest 2010; 139: 1410–1418.
63. Schuetz P, Christ-Crain M, Thomann R, et al. Effect of procalcitonin-based guidelines vs standard guidelines on
antibiotic use in lower respiratory tract infections: the ProHOSP randomized controlled trial. JAMA 2009; 302:
1059–1066.
64. Strykowski DF, Nielsen AB, Llor C, et al. An intervention with access to C-reactive protein rapid test reduces
antibiotic overprescribing in acute exacerbations of chronic bronchitis and COPD. Fam Pract 2015; 32: 395–400.
65. Plant PK, Owen JL, Elliott MW. One year period prevalence study of respiratory acidosis in acute exacerbations of
COPD: implications for the provision of non-invasive ventilation and oxygen administration. Thorax 2000; 55:
550–554.
66. O’Driscoll BR, Howard LS, Davison AG. Guideline for emergency oxygen use in adult patients. Thorax 2008; 63:
Suppl. 6, vi1–vi68.

63

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

67. Vaschetto R, Longhini F, Navalesi P. Acute noninvasive ventilation. In: Heunks L, Demoule A, Windisch W, eds.
Pulmonary Emergencies (ERS Monograph). Sheffield, European Respiratory Society, 2016; pp. 186–199.
68. Davidson AC, Banham S, Elliott M, et al. BTS/ICS guidelines for the ventilatory management of acute
hypercapnic respiratory failure in adults. Thorax 2016; 71: Suppl. 2, ii1–ii35.
69. Ram FS, Picot J, Lightowler J, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure
due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2004; 1: CD004104.
70. Conti G, Antonelli M, Navalesi P, et al. Noninvasive vs. conventional mechanical ventilation in patients with
chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial. Intensive
Care Med 2002; 28: 1701–1707.
71. Esteban A, Anzueto A, Frutos F, et al. Characteristics and outcomes in adult patients receiving mechanical
ventilation: a 28-day international study. JAMA 2002; 287: 345–355.
72. Diaz-Lobato S, Smyth D, Curtis JR. Improving palliative care for patients with COPD. Eur Respir J 2015; 46: 596–598.
73. Highet G, Crawford D, Murray SA, et al. Development and evaluation of the Supportive and Palliative Care
Indicators Tool (SPICT): a mixed-methods study. BMJ Support Palliat Care 2014; 4: 285–290.
74. Gardiner C, Gott M, Ingleton C, et al. Extent of palliative care need in the acute hospital setting: a survey of two
acute hospitals in the UK. Palliat Med 2013; 27: 76–83.
75. Dalgaard KM, Bergenholtz H, Nielsen ME, et al. Early integration of palliative care in hospitals: a systematic
review on methods, barriers, and outcome. Palliat Support Care 2014; 12: 495–513.
76. Duenk RG, Heijdra Y, Verhagen SC, et al. PROLONG: a cluster controlled trial to examine identification of patients
with COPD with poor prognosis and implementation of proactive palliative care. BMC Pulm Med 2014; 14: 54.
77. Robinson J, Gott M, Ingleton C. Patient and family experiences of palliative care in hospital: what do we know?
An integrative review. Palliat Med 2014; 28: 18–33.
78. Echevarria C, Steer J, Heslop-Marshall K, et al. Validation of the DECAF score to predict hospital mortality in
acute exacerbations of COPD. Thorax 2016; 71: 133–140.
79. Janssen DJ, Engelberg RA, Wouters EF, et al. Advance care planning for patients with COPD: past, present and
future. Patient Educ Couns 2012; 86: 19–24.
80. Claessens MT, Lynn J, Zhong Z, et al. Dying with lung cancer or chronic obstructive pulmonary disease: insights
from SUPPORT. J Am Geriatr Soc 2000; 48: Suppl., S146–S153.
81. Gore JM, Brophy CJ, Greenstone MA. How well do we care for patients with end stage chronic obstructive
pulmonary disease (COPD)? A comparison of palliative care and quality of life in COPD and lung cancer. Thorax
2000; 55: 1000–1006.
82. Knauft E, Nielsen EL, Engelberg RA, et al. Barriers and facilitators to end-of-life care communication for patients
with COPD. Chest 2005; 127: 2188–2196.
83. Curtis JR, Wenrich MD, Carline JD, et al. Understanding physicians’ skills at providing end-of-life care
perspectives of patients, families, and health care workers. J Gen Intern Med 2001; 16: 41–49.
84. Rocker GM, Simpson AC, Horton R. Palliative care in advanced lung disease: the challenge of integrating
palliation into everyday care. Chest 2015; 148: 801–809.
85. Simpson AC, Rocker GM. Advanced chronic obstructive pulmonary disease: rethinking models of care. QJM
2008; 101: 697–704.
86. Ellershaw J, Ward C. Care of the dying patient: the last hours or days of life. BMJ 2003; 326: 30–34.
87. Smith R. A good death. An important aim for health services and for us all. BMJ 2000; 320: 129–130.
88. Witkamp FE, van Zuylen L, Borsboom G, et al. Dying in the hospital: what happens and what matters, according
to bereaved relatives. J Pain Symptom Manage 2015; 49: 203–213.
89. Virdun C, Luckett T, Davidson PM, et al. Dying in the hospital setting: a systematic review of quantitative studies
identifying the elements of end-of-life care that patients and their families rank as being most important.
Palliat Med 2015; 29: 774–796.
90. Poole P, Black PN, Cates CJ. Mucolytic agents for chronic bronchitis or chronic obstructive pulmonary disease.
Cochrane Database Syst Rev 2010; 8: CD001287.
91. Duffy N, Walker P, Diamantea F, et al. Intravenous aminophylline in patients admitted to hospital with
non-acidotic exacerbations of chronic obstructive pulmonary disease: a prospective randomised controlled trial.
Thorax 2005; 60: 713–717.
92. Aaron SD, Vandemheen KL, Hebert P, et al. Outpatient oral prednisone after emergency treatment of chronic
obstructive pulmonary disease. N Engl J Med 2003; 348: 2618–2625.
93. Perera WR, Hurst JR, Wilkinson TM, et al. Inflammatory changes, recovery and recurrence at COPD
exacerbation. Eur Respir J 2007; 29: 527–534.
94. Berkow RL, Wang D, Larrick JW, et al. Enhancement of neutrophil superoxide production by preincubation with
recombinant human tumor necrosis factor. J Immunol 1987; 139: 3783–3791.
95. Kawai S, Sekino H, Yamashita N, et al. The comparability of etanercept pharmacokinetics in healthy Japanese
and American subjects. J Clin Pharmacol 2006; 46: 418–423.

64

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF COPD | A.P. BUTLER ET AL.

96. Suissa S, Ernst P, Hudson M. TNF-α antagonists and the prevention of hospitalisation for chronic obstructive
pulmonary disease. Pulm Pharmacol Ther 2008; 21: 234–238.
97. Aaron SD, Vandemheen KL, Maltais F, et al. TNFα antagonists for acute exacerbations of COPD: a randomised
double-blind controlled trial. Thorax 2013; 68: 142–148.
98. Grootendorst DC, Gauw SA, Verhoosel RM, et al. Reduction in sputum neutrophil and eosinophil numbers by
the PDE4 inhibitor roflumilast in patients with COPD. Thorax 2007; 62: 1081–1087.
99. Calverley PM, Rabe KF, Goehring UM, et al. Roflumilast in symptomatic chronic obstructive pulmonary disease:
two randomised clinical trials. Lancet 2009; 374: 685–694.
100. Fabbri LM, Calverley PM, Izquierdo-Alonso JL, et al. Roflumilast in moderate-to-severe chronic obstructive pulmonary
disease treated with longacting bronchodilators: two randomised clinical trials. Lancet 2009; 374: 695–703.
101. Martinez FJ, Calverley PM, Goehring UM, et al. Effect of roflumilast on exacerbations in patients with severe
chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised
controlled trial. Lancet 2015; 385: 857–866.
102. Troosters T, Probst VS, Crul T, et al. Resistance training prevents deterioration in quadriceps muscle function during
acute exacerbations of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2010; 181: 1072–1077.
103. Giavedoni S, Deans A, McCaughey P, et al. Neuromuscular electrical stimulation prevents muscle function
deterioration in exacerbated COPD: a pilot study. Respir Med 2012; 106: 1429–1434.
104. Eaton T, Young P, Fergusson W, et al. Does early pulmonary rehabilitation reduce acute health-care utilization in
COPD patients admitted with an exacerbation? A randomized controlled study. Respirology 2009; 14: 230–238.
105. Greening NJ, Williams JE, Hussain SF, et al. An early rehabilitation intervention to enhance recovery during hospital
admission for an exacerbation of chronic respiratory disease: randomised controlled trial. BMJ 2014; 349: g4315.
106. Casas A, Troosters T, Garcia-Aymerich J, et al. Integrated care prevents hospitalisations for exacerbations in
COPD patients. Eur Respir J 2006; 28: 123–130.
107. Bourbeau J, Julien M, Maltais F, et al. Reduction of hospital utilization in patients with chronic obstructive
pulmonary disease: a disease-specific self-management intervention. Arch Intern Med 2003; 163: 585–591.
108. Mackay AJ, Donaldson GC, Patel AR, et al. Usefulness of the Chronic Obstructive Pulmonary Disease
Assessment Test to evaluate severity of COPD exacerbations. Am J Respir Crit Care Med 2012; 185: 1218–1224.
109. Hoyles KH, Sheehan AS, Forrester DLF, et al. The chronic obstructive pulmonary disease assessment tool (CAT)
in patients admitted to hospital for exacerbation. Thorax 2013; 68: Suppl. 3, A204.
110. Feliz-Rodriguez D, Zudaire S, Carpio C, et al. Evolution of the COPD assessment test score during chronic
obstructive pulmonary disease exacerbations: determinants and prognostic value. Can Respir J 2013; 20: e92–e97.
111. Greening NJ, Harvey-Dunstan TC, Chaplin EJ, et al. Bedside assessment of quadriceps muscle by ultrasound after
admission for acute exacerbations of chronic respiratory disease. Am J Respir Crit Care Med 2015; 192: 810–816.

Disclosures: A.J. Mackay has received personal fees and nonfinancial support from GSK and Takeda.

65

FB:Cardiologia Siglo XXI

 | Chapter 5
Acute exacerbations of asthma
Nirav R. Bhakta1 and Stephen C. Lazarus1,2

Acute severe asthma exacerbations are a significant cause of morbidity and mortality. A high
proportion of severe exacerbations and deaths result from undertreatment. Risk factors for
fatal asthma have been identified and should guide treatment. The time course for recovery
from an exacerbation mirrors that for onset of signs and symptoms. Thus, early intervention
is critical. Patients must be taught to adjust maintenance treatment to prevent an
exacerbation, as well as how and when to initiate treatment. Home treatment consists of
aerosolised short-acting β2-agonists, and systemic corticosteroids. If symptoms persist after
∼1 h, the patient should seek urgent medical attention, where the emphasis should be on
briefly confirming the diagnosis and severity, while initiating therapy with inhaled
bronchodilators and systemic corticosteroids and oxygen, titrated to SpO2 93–95%. The
decision to admit or discharge should be made within 1–3 h. For patients who progress to
respiratory failure, there are unique management issues related to noninvasive
positive-pressure ventilation, intubation, ventilator settings and medications.

A sthma is a common disease, and acute severe exacerbations are a significant cause of
morbidity and mortality throughout the world. A high proportion of severe
exacerbations and deaths result from undertreatment. Risk factors for fatal asthma include
previous severe exacerbations, hospitalisation in the past year, three or more emergency
department (ED) visits in the past year, recent use of oral corticosteroids, use of one or
more canisters of short-acting β2-agonist (SABA) per month, a history of poor adherence,
medical comorbidities and illicit drug use. In addition, up to 50% of fatal asthma occurs in
patients thought to have had mild or moderate asthma [1–3].

The time course for recovery from an exacerbation mirrors that for onset of signs and
symptoms. Thus, early intervention is critical. Education to teach patients how to adjust
maintenance treatment to prevent exacerbations, how to recognise an exacerbation, and
how and when to initiate treatment has been shown to improve outcomes [4, 5]. Objective
measurement of lung function (e.g. peak expiratory flow (PEF) or FEV1) can be helpful.

Treatment at home consists of aerosolised SABAs with assessment of response at ∼1 h. At

this point, a decision should be made to continue home treatment or to seek urgent
medical attention. In the urgent care setting, the emphasis should be on briefly confirming
the diagnosis and severity, while initiating therapy with inhaled bronchodilators and

1
Dept of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, University of California San Francisco,
San Francisco, CA, USA. 2Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, USA.

Correspondence: Stephen C. Lazarus, University of California San Francisco, 505 Parnassus Ave, San Francisco, CA 94143-0111, USA.
E-mail: lazma@ucsf.edu

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

66 ERS Monogr 2016; 74: 66–85. DOI: 10.1183/2312508X.10001516

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

systemic corticosteroids and oxygen, titrated to SpO2 93–95%. Patients should be reassessed
after ∼1–3 h of treatment, and the decision to admit or discharge should be made then.
Patients who are admitted to hospital generally have not only bronchoconstriction but also
significant airway inflammation, and often mucus hypersecretion. These resolve slowly and
require continued aggressive treatment. These patients can relapse rapidly if treatment is
stepped down too early, and can progress to respiratory failure as well. The approach to
respiratory failure in the asthmatic patient requires specialised knowledge of the
pathophysiology of asthma.

Epidemiology

Asthma is a common diagnosis throughout the world, especially in developed countries,

with a global prevalence of 7–10% [6]. Prevalence is increasing in many countries, especially
among children. In the USA, the prevalence of asthma increased from 3.1% in 1980 to 5.5%
in 1996, 7.3% in 2001 and 8.4% in 2010 [7]. The rate of increase was greater in black
persons compared with white, and in Hispanic persons compared with non-Hispanic. In
Europe, approximately 30 million children and adults <45 years of age have asthma, and the
prevalence increased significantly in the latter half of the 20th century before levelling off
[8]. Because of its high prevalence, asthma accounts for a high proportion of urgent care
and ED and hospital visits (figure 1). In 2009 in the USA, asthma accounted for
approximately 2 million ED visits, 500 000 hospitalisations and 3388 deaths [7]. In the
European Union, asthma accounts for only a small percentage of deaths [8], but a recent UK
study identified major preventable factors in two-thirds of asthma deaths [10]. Most factors
related to insufficient prescribing of corticosteroid preventer medications, failure to monitor
asthma control and failure to refer patients to an asthma specialist. In many instances,
patients with fatal asthma were thought to have mild asthma and thus were not prepared to
recognise danger signals and the need for help. Easily obtainable information on Asthma
Control Questionnaire scores, current smoking, chronic sinusitis, previous hospitalisations
for asthma and one or more severe exacerbations in the previous year identifies patients who
are prone to asthma exacerbations [11]. Adding spirometry improves the accuracy of this
predictive model. In several countries, targeted asthma programmes have been shown to
reduce asthma costs, as well as morbidity and mortality [12, 13].

a) Asthma in children b) Asthma in young adults

Deaths Deaths
40 380
Hospital Hospital
admissions admissions
167 000 per year 82 000 per year

Prevalence Prevalence
5 million ever had asthma 16 million ever had asthma

Children aged 0–14 years Adults aged 15–44 years

78 million 204 million

Figure 1. The burden of asthma in a) children and b) young adults, around 2010, in the 28 countries of the
European Union. Reproduced from [9] with permission.

67

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Prevention of asthma exacerbations

Early adjustment of maintenance regimens can “rescue” patients with worsening asthma
control before they develop an exacerbation. The Global Initiative for Asthma (GINA)
suggests that action plans recommend an early increase in inhaled corticosteroid (ICS) dose
[4], or that patients follow a single maintenance and reliever therapy (“SMART”) regimen,
using a single inhaler that contains both an ICS and a rapid-onset long-acting β2-agonist
[5]. More important than the specific regimen is that patients are educated to recognise
and treat poor asthma control before it exacerbates.

Home management

Early recognition of an impending exacerbation and early institution of treatment are key to
improving outcomes (figure 2). In contrast, delayed intervention is associated with worse
prognosis. A review of fatal asthma in the UK found that 45% of patients had not sought
help, and that 70% and 83% of children and adolescents, respectively, died before they
reached hospital [10]. Only 23% of patients who died had received a personalised asthma
action plan. Education that provides patients with the information necessary to assess their
asthma control, and guidelines for when to seek help, can reduce morbidity and mortality.
Similarly, providers should ensure that patients, especially those with prior exacerbations, are

Home Increase ICSs early to prevent asthma exacerbation

management SABA every 20 min for 1 h
Review symptoms and PEF after 1 h

Improved Continued symptoms

PEF >80% PEF ≤50–80%

SABA every 3–4 h SABA every 3–4 h

Increase ICSs ? Oral corticosteroids
Contact PCP or
Seek urgent care

Emergency Brief history and physical Oxygen, target SpO2 93–95% Reassess every 30 min
department PEF or spirometry SABA (MDI or nebuliser, Admit or discharge within 1–3 h
ABG if suspect respiratory continuous if available)
failure SABA + SAMA
Systemic corticosteroids
Consider magnesium

Oxygen; target SpO2 93–95%

SABA ± SAMA
In-hospital
Systemic corticosteroids
management
Assess for fatigue and
increased PaCO2

ICU SABA ± SAMA

management Systemic corticosteroids
NPPV with frequent monitoring
Intubation and mechanical ventilation:
Rapid-sequence intubation
VT ≤8 mL·kg–1, to avoid lung injury
Permissive hypercapnia
Early liberation to minimise harm

Figure 2. Management of asthma exacerbations. ICS: inhaled corticosteroid; SABA: short-acting β2-agonist;
PEF: peak expiratory flow; PCP: primary care provider; ABG: arterial blood gas; MDI: metered-dose inhaler;
SAMA: short-acting muscarinic antagonist; NPPV: noninvasive positive-pressure ventilation; VT: tidal volume.

68

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

prescribed and are taking the appropriate asthma medications. In the previously mentioned
UK study, 39% of patients who died used SABAs excessively (⩾12 canisters·year−1) and 4%
had used >50 canisters·year−1 [10]. In addition, a significant proportion of patients who died
were not taking ICSs regularly.

Initial treatment at home

Most patients with asthma, and certainly those with prior severe or life-threatening asthma,
should be taught self-management of exacerbations [14, 15]. A written personalised action
plan can facilitate intervention.

Treatment is usually initiated with inhaled SABAs, with two to four puffs via a
metered-dose inhaler (MDI) with a spacer, repeated every 20 min for 1 h. If the
exacerbation was triggered by an environmental exposure, every effort should be made to
separate the patient from the offending stimulus. If, after 1 h, symptoms have resolved and
PEF has improved significantly (to >80% of personal best), then the patient may continue
self-management with an inhaled SABA every 3–4 h for 24–48 h. The patient should
contact his/her healthcare provider, who may choose to add or increase the dose of ICSs,
or to initiate oral corticosteroids.

If, after 1 h of treatment, symptoms continue and/or the PEF is at 50–80% of the personal
best range, the patient should start oral corticosteroids (if included in their personal asthma
action plan) and contact his/her provider for further instructions. Use of SABAs should be
continued every 3–4 h.

Patients with a PEF of <50–60% of predicted, with very severe or increasing symptoms, or
with patient risk factors for fatal asthma should seek urgent medical attention.

Management in urgent care or the ED

Patients should be evaluated rapidly to confirm the diagnosis of asthma exacerbation, assess
the severity of the event and determine the need for urgent intervention [14, 15]. A brief
history and physical examination should focus on conditions such as pneumothorax,
altered mental status or a quiet chest that would necessitate different treatment. Risk factors
for fatal asthma should be reviewed (table 1). This assessment should be performed
simultaneously with initiation of treatment. Few laboratory tests should be routine, and
none should delay the initiation of therapy. If respiratory failure seems imminent, PaCO2
should be monitored; suspicion of pneumonia may warrant a chest radiograph or complete
blood count; concern for myocardial infarction, arrhythmia or heart failure may lead to an
electrocardiogram or echocardiogram.

Every patient should be treated simultaneously with oxygen, an inhaled SABA and systemic
corticosteroids. Oxygen should be titrated to SpO2 93–95%, as higher levels have been
associated with worse physiological outcomes [16–18].

β2-Adrenergic agonists

Inhaled SABAs are the most effective bronchodilators and should be administered as soon
as possible after presentation to the ED. In patients who are able to master the technique,

69

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 1. Risk factors for fatal asthma

Prior near-fatal exacerbation

Hospitalisation or emergency department visit in past year
Recent use of systemic corticosteroids
SABA use >12 canisters·year−1
Psychiatric disorder
Use of illicit drugs
Comorbid medical conditions
History of poor adherence to medications or action plan
“Poor perceiver”
Food allergy
Not currently using inhaled corticosteroids

SABA: short-acting β2-agonist. Information from [15].

the use of an MDI combined with a valved holding chamber or spacer is as effective as the
use of a pressurised nebuliser [19–21]. Unfortunately, many patients with severe
exacerbations are too dyspnoeic to use an MDI effectively. The choice between continuous
versus intermittent nebulisation is somewhat controversial, as individual trials as well as
systematic reviews have produced conflicting results. Although early meta-analyses
suggested either no difference between intermittent and continuous nebulisation in the ED
[22] or an advantage with as-needed versus scheduled intermittent therapy in patients who
were already hospitalised [23], the latest Cochrane review of eight acceptable trials
suggested that lung function improved more and there were fewer hospital admissions in
patients treated in the ED with continuous nebulisation, especially those patients with
severe asthma [24]. Based on these reports, the latest GINA guidelines suggest the use of
continuous nebulised salbutamol (albuterol) initially in the ED, followed by intermittent
therapy for patients who are hospitalised [15].

Salbutamol is the most widely used bronchodilator in the world, and is listed by the World
Health Organization as one of the essential medications needed in a basic healthcare
system [25]. It is available as a racemic mixture of the R- and S-enantiomers. The latter are
thought to be responsible for adverse effects (e.g. tachycardia, palpitations), which led to
the development of levosalbutamol (levalbuterol), the R-enantiomer. Although effective at
approximately half the dose of racemic salbutamol, it has not been convincingly
demonstrated to offer a clinical advantage over the racemic preparation in the ED [26, 27].
Oral administration of β2-agonists is not recommended, as the onset of action is slower and
systemic side-effects are greater, compared with inhalation. Similarly, a Cochrane analysis
found insufficient evidence to recommend the use of intravenous β2-agonists in acute
asthma [28]. Some authors suggest the use of the nonselective adrenergic agonist
epinephrine in patients with severe asthma that is refractory to standard therapy [29].
Although possibly acting to decrease airway mucosal oedema, there is not sufficient
evidence to support this approach. Finally, the long-acting β2-agonist formoterol has a
relatively rapid onset of action, and a systematic review and meta-analysis of nine RCTs
found no significant difference compared with SABAs for lung function, adverse effects
and hospitalisations [30]. However, the authors identified the quality of the studies
analysed as low, and as a result, most experts think further studies are needed before
formoterol can be recommended as treatment for asthma exacerbations.

70

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

Muscarinic antagonists

Antimuscarinic (anticholinergic) drugs can be effective bronchodilators, although their

onset of action is less rapid than that of salbutamol. For this reason, aerosolised
ipratropium should not be used as a monotherapy in the ED. Results of studies of the
combination of a SABA and ipratropium have not been consistent but suggest that the
combination results in greater improvement in lung function and approximately 25% fewer
hospitalisations than SABA use alone [31, 32]. This benefit may not carry over once
patients are hospitalised [33]. Long-acting muscarinic antagonists are not appropriate for
use in the ED or ICU.

Inhaled corticosteroids

In patients with mild-to-moderate exacerbations or loss of asthma control, increasing the

dose of ICSs may be useful, although this is best implemented when signs and symptoms
increase, before an exacerbation occurs. Doubling the dose of ICSs may not be sufficient
[34], but quadrupling the dose of ICSs has been reported to reduce the need for oral
corticosteroids [35, 36]. A recent Cochrane review concluded that, in patients who were not
already taking ICSs, high-dose ICSs given early in the ED reduced hospital admissions [37].
Despite this, guidelines recommend that nearly all patients treated in the ED receive
systemic corticosteroids [14, 15].

Systemic corticosteroids

Unless symptoms and lung function reverse rapidly and almost completely in response to
initial treatment with an inhaled β2-agonist, systemic corticosteroids are warranted, and
guidelines recommend administration within the first hour in the ED [14, 15]. Such
treatment results in a more rapid improvement in FEV1 and PEF, fewer hospitalisations
and a lower rate of relapse after discharge [38–42]. In patients who are unable to swallow
because of altered mental status or respiratory status, or who have nausea, vomiting or
suspected malabsorption, corticosteroids may be given intravenously; in most patients, oral
administration is preferred. Numerous studies have shown that oral administration is as
effective at improving lung function and reducing hospital length of stay as intravenous
administration.

Although the optimal dose of systemic corticosteroids is not known, most studies have
suggested that high doses are not necessary [15]. When administered orally, prednisone or
prednisolone is absorbed rapidly and has high bioavailability. GINA guidelines recommend
the equivalent of 50 mg prednisolone given as a single morning dose [15]; the Expert Panel
Report 3 (EPR-3) suggests 40–80 mg·day−1 in one or two divided doses [14]. Treatment for
5–7 days is as effective as 10–14-day regimens [43, 44], and tapering is not necessary if the
treatment course is 7–10 days, especially if patients are taking ICSs concomitantly.

Magnesium

Case reports and uncontrolled studies going back more than 75 years have described the
beneficial effects of intravenous magnesium in asthmatic patients refractory to standard
treatment [45, 46]. In 1989, SKOBELOFF et al. [47] conducted a double-blind placebo-controlled
trial of intravenous magnesium versus placebo in 38 patients with acute exacerbations of

71

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

asthma who failed to respond to ED treatment with a β2-agonist. They found greater
increases in PEF and fewer hospitalisations in the group who received a single infusion of
1.2 g of magnesium sulphate. Since that time, use of magnesium in the ED has become
common for patients with severe exacerbations refractory to initial treatment. A 2009 survey
of EDs in the UK found that 93% used magnesium in this situation [48]. Clinical trials,
however, have provided conflicting results and do not support this widespread usage. Several
have shown benefit in patients who presented with very low FEV1 and in those with
persistent hypoxaemia [49–51], but a more recent large RCT found no additional benefit
when magnesium was administered intravenously or by nebulisation [52]. However, this
latter trial excluded participants with severe asthma, which is the group shown previously to
be most responsive. Because it is generally thought to be safe, use of magnesium can be
considered in severe exacerbations that have not responded to initial interventions.

Leukotriene modifiers

Data from early in the development of leukotriene modifier drugs suggested that they
might be useful for treatment of acute asthma exacerbations [53, 54]. Subsequent studies of
intravenous or oral montelukast found a transiently higher FEV1 but no reduction in rate
of hospitalisation or length of stay after admission [55, 56]. Finally, a Cochrane review of
eight trials that included 1470 adults and 470 children found no significant difference in
hospital admission rates and found inconsistent effects on lung function [57]. Thus,
leukotriene modifiers should not be used routinely for treatment of acute exacerbations of
asthma, and additional studies are needed to determine if they have any role in this setting.

Aminophylline

Prior to the development of effective, inhaled forms of selective β2-agonists, methylxanthines

were used routinely for the emergency treatment of asthma. Although they are effective
bronchodilators, their narrow therapeutic margin makes them far less attractive than
β2-agonists as a monotherapy. Several Cochrane reviews have concluded that intravenous
aminophylline combined with standard care adds adverse effects but no benefit [e.g. 58].

Treatments that are not recommended

Treatments that are not recommended or that have no evidence to support their use in
routine asthma exacerbations are listed in table 2. Although exacerbations are often
triggered by respiratory infections, these are usually viral, and the routine use of antibiotics
to treat exacerbations is not supported by evidence. Antibiotics may be warranted if fever,
purulent sputum, or sinusitis or pneumonia is present. Similarly, sedative hypnotics should
not be used because of the potential for respiratory depression and increased morbidity and
mortality [59, 60]. Heliox, a mixture of helium and oxygen that is less dense than air, has
been shown to increase airflow in some studies, but a systematic analysis did not
demonstrate an impact on hospitalisation or other clinical outcomes [61].

Assessment of response in the ED

Treatment for acute asthma should not be open-ended, and most experts recommend that
a decision to discharge to home or admit to hospital should be made within 1–3 h [14, 15].
Specific criteria and guidelines are provided in the GINA and EPR-3 documents [14, 15].

72

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

Table 2. Treatments without evidence to support their routine use in asthma exacerbations

Treatments without evidence

Magnesium (inhaled or intravenous) or leukotriene modifiers
Ketamine or inhaled anaesthetics for bronchodilation
Bronchoscopy to remove mucus
Mucolytics (N-acetylcysteine, DNase)
Treatments that are not recommended
Intravenous salbutamol (albuterol)
Subcutaneous or intravenous terbutaline, epinephrine and aminophylline
Heliox
Antibiotics in the absence of suspected infection

Of note, assessment of asthma severity after 1 h of treatment in the ED is a better predictor

of the need for hospitalisation than assessment at initial presentation [62].

Treatment in the hospital

Patients whose symptoms and lung function have not improved after initial treatment in
the ED should be admitted to hospital for further aggressive treatment and close
monitoring. These patients have bronchoconstriction and significant airway inflammation,
often have mucus hypersecretion and can rapidly develop respiratory failure. Most
treatments initiated in the ED are continued during hospitalisation. Patients with
impending respiratory failure should be transferred to the ICU.

Respiratory failure

Definition and presentation

The majority of patients hospitalised for asthma respond to medical therapy within the first
few hours. In a minority, fatigue and unrelieved airway obstruction lead to respiratory failure.

On examination, patients may have difficulty speaking and, in the early stages before
complete exhaustion, may demonstrate use of accessory muscles of respiration. Fatigue and
airflow obstruction commonly present with decreased air movement, and wheezing may be
difficult to auscultate. Exhaustion and gas exchange abnormalities may lead to altered
consciousness, which should prompt the measurement of arterial blood gases. When
respiratory effort is preserved, pulsus paradoxus may be evident. Tachycardia is common in
the setting of respiratory distress and β-agonist treatment.

Hypoxaemia is uncommon and responds to minimal supplemental oxygen. Estimates of

hypercarbia vary widely in the literature from 10% to 63%, and its presence signifies a
significant obstructive ventilatory defect [63]. While hypercarbia is one manifestation of
fatigue, it is not an absolute indication for mechanical ventilation [64].

Lactic acidosis in acute asthma is common and appears to reflect a direct effect of β-agonists
on cellular metabolism rather than tissue hypoxia; its incidence and magnitude are correlated
with serum albuterol levels [65]. The presence of lactic acidosis is not associated with worse

73

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

outcomes, but the acidaemia itself may contribute to dyspnoea, even when airway obstruction
has improved. Arterial blood gas analysis along with serial lung function testing (bedside PEF
or FEV1) or measurement of airway resistance on a ventilator can help the clinician decide
whether the ratio of acidaemia to obstruction warrants a reduction in β-agonist dose. β-agonist
treatment may also lead to hypokalaemia, which should be monitored to prevent arrhythmias.

Mechanisms of respiratory failure

In the majority of fatal asthma cases, extensive mucus plugs fully occlude the airways [66].
These plugs increase airway resistance, thereby increasing the work of breathing and
interfering with effective ventilation and gas exchange. Bronchoconstriction and airway
oedema, along with changes in the airway walls from long-standing asthma, also contribute
to airflow limitation. Together, these processes can result in an inability to fully empty the
lungs during exhalation. This air trapping progressively increases functional residual
capacity (hyperinflation), increases the work of breathing by placing tidal breaths into a low
compliance region of the total lung capacity, and eventually decreases ventilation further.
The increased intrathoracic pressure with hyperinflation can contribute to cardiovascular
collapse and death. The proportion of cases of asthma with respiratory failure that have
extensive mucus plugging or hyperinflation is unknown.

Management of respiratory failure

Patients who fail to improve after a few hours of medical therapy need close monitoring to
detect worsening of respiratory, cardiac or neurological status, and require the availability of
nurses, respiratory therapists and physicians to make rapid changes in therapy. This is best
accomplished in the ICU, where there is also expertise with advanced interventions including
noninvasive positive-pressure ventilation (NPPV) and invasive mechanical ventilation.

Role of NPPV

The availability and use of NPPV has increased dramatically over the past 15 years. NPPV
is used to avoid intubation and to accelerate the response to medical therapy. Beyond these
short-term responses, the goal is to reduce ICU or hospital length of stay and to increase
survival. The most compelling data that NPPV can achieve these goals come from studies
of COPD exacerbations with hypercapnic acidosis, which have consistently shown a
significant reduction in the rate of intubation and in mortality, with purported mechanisms
including offloading of respiratory muscles and prevention of dynamic airway collapse
through PEEP [67].

A number of RCTs have examined whether NPPV can improve outcomes, including
intubation rate and mortality, in severe acute asthma [68, 69]. Although none has
definitively answered these questions due to low-power, supoptimal medical therapy and
the use of rescue NPPV in the control group, studies have shown significantly greater and
faster improvements in PEF and FEV1 [68, 69], and one study demonstrated shorter ICU
and hospital stays and smaller total doses of bronchodilator [70]. Bronchodilators can be
delivered by placing the nebuliser between the leak port and the patient in order to
maximise the delivered dose effectively [71, 72]. Bronchodilators can also be delivered
during short breaks in NPPV [73].

74

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

In a retrospective analysis of 13 930 patients treated for acute asthma exacerbation across 97
hospitals, 9% of patients required some form of mechanical ventilation, 40% of whom
received NPPV [74]. Older patients and those with a lower severe acute physiology score
were more likely to receive NPPV than endotracheal intubation. The low rate of NPPV
failure (4.7%) suggested that it was used primarily in a nonsevere population who would
have improved regardless of this therapy. Although NPPV was associated with a lower risk
of death in this propensity-matched analysis, the increased risk of death in the setting of
NPPV failure underscores the need for careful monitoring.

The possibility of shorter hospital stays and reduced doses of bronchodilator may be desirable
to payers and patients, but there are a number of issues to consider in the application of
NPPV. Some patients with severe acute asthma, respiratory distress and the associated anxiety
are intolerant of a tight-fitting mask, and patients whose exacerbations are characterised by
sputum production may have difficultly clearing secretions while wearing a mask delivering
positive pressure. Further studies are needed to address optimal inspiratory and expiratory
pressures and how early in the course of an exacerbation NPPV should be applied. An
important variable in deciding when to apply NPPV is the increased nursing and respiratory
therapist time involved in set-up, adjustment and monitoring; this lost time can be an
opportunity cost in other aspects of patient care if NPPV is applied too early or for
inappropriately mild exacerbations. While it may seem that early NPPV use, even in mild
cases, may at best lead to no harm, there is reason to be concerned about such an approach.
Positive pressure may accelerate hyperinflation and contribute to large tidal volumes, which
may increase the risk of developing lung injury. Finally, the usual contraindications to
positive-pressure mask therapy apply in the setting of asthma as well: these are difficulty in
managing secretions, nausea and vomiting, altered consciousness and cardiovascular instability.

In summary, without evidence from trials for a benefit in patient outcomes, NPPV can be
given to patients with an inadequate response to early medical therapy, who can cooperate
with positive pressure through a mask and who do not have contraindications including a
need for immediate endotracheal intubation. In the absence of further data, the settings
used in one RCT provide a reasonable place to start (table 3) [73]. There is a theoretical
concern for worsened hyperinflation with the resistance to emptying from positive airway
pressure and, although none of the trials to date has reported this as a complication, it is
reasonable to be cautious of high expiratory pressures. NPPV should be used only in an
environment with experienced nurses and respiratory therapists, and where patients are
constantly monitored and can be intubated immediately if required.

Endotracheal intubation and invasive mechanical ventilation

Rates of intubation for severe acute asthma vary widely, probably reflecting variations in
the populations studied (e.g. in pre-hospitalisation care and social/genetic determinants of
disease) and the variable thresholds of individual centers and practitioners as well as their
resources to intubate. In a recent study of ∼750 000 admissions across the USA, 7.4%
required intubation, and rates were higher during the autumn and winter months [75].
Two prior analyses of US databases of 30 000 and 65 000 admissions for asthma
exacerbations reported lower rates of intubation of 2.1% and 4.2%, respectively [76, 77].

The decision to intubate is made by the same criteria used in other cases of respiratory
failure: exhaustion, significantly abnormal gas exchange including progressive hypercapnia

75

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 3. Summary and recommendations for noninvasive positive-pressure ventilation (NPPV)

Evidence-based benefits of NPPV

Faster improvement in PEF and FEV1; decreased dose of bronchodilators and reduced hospital
stay in one study only [70]
Recommended settings [73]
Start with IPAP 8 cmH2O, EPAP 3 cmH2O
Small increases (2 cmH2O IPAP, 1 cmH2O EPAP) every 15 min targeting a reduction in
respiratory rate and improvement in gas exchange
Limit EPAP to 5 cmH2O, given a theoretical concern for worsening hyperinflation
Contraindications
Difficulty managing secretions, nausea and vomiting, altered consciousness and cardiovascular
instability

PEF: peak expiratory flow; IPAP: inspiratory positive airway pressure; EPAP: expiratory positive
airway pressure.

despite current therapy, cardiovascular instability and airway protection for depressed
consciousness. An addition to this list specific to asthma is the presence of a silent chest,
which is a consequence of severe airway obstruction, hyperinflation and exhaustion.
Importantly, while a progressively increasing PaCO2 with mental status changes is an
indication for intubation, hypercarbia by itself does not mandate intubation [64].

Recommendations for the intubation procedure

We recommend following the widely accepted core principles of safe intubation. Adequate
pre-oxygenation, laryngoscopy equipment familiar to the proceduralist and backup plans
for an unanticipated difficult airway are essential. Consensus opinion favours the induction
of general anaesthesia and paralysis with rapid-sequence intubation [78]. This opinion
stems in part from the wide familiarity with this approach, the high rates of success in
emergency situations and the minimisation of aspiration risk. Although awake fibreoptic
intubation is attractive, given the preservation of ventilation and lack of paralysis, it can be
difficult in the setting of respiratory distress due to patient discomfort and inadequate
topical anaesthesia, and should be performed only by those highly experienced in this
technique. Oral intubation is preferred over the nasopharyngeal route given the coexistence
of rhinosinusitis and nasal polyps with asthma and the desire to use the largest tube
possible to facilitate removal of airway secretions.

Given that increased intrathoracic pressure due to hyperinflation may be present, the
sympatholytic, vasodilatory and myocardial suppressant effects of induction agents warrant
anticipation of and readiness to address hypotension. Prior to induction, dehydration
should be corrected with judicious use of intravenous fluids, and a vasopressor such as
norepinephrine or phenylephrine should be ready to administer.

There are many valid choices for drugs to induce anaesthesia at the time of intubation.
Ketamine has a theoretical advantage of promoting bronchodilation by releasing
catecholamines and directly relaxing airway smooth muscle; it is also not expected to cause
hypotension. It is unclear whether the potential risks of hypersecretion necessitate
pre-treatment with an anti-sialogogue. The use of ketamine is relatively contraindicated in
the setting of significant hypertension and ischaemic heart disease, and controversy

76

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

remains regarding its contribution to increased intracranial pressure in the setting of brain
injury. Propofol has the advantage of very fast on and off kinetics, along with a few reports
of bronchodilatory effects [78]; however, hypotension may limit the dose. Etomidate has
the fewest haemodynamic effects and is an acceptable alternative in the setting of
hypotension; despite its association with adrenal suppression, a single dose does not appear
to cause harm [79]. While benzodiazepines are also successful in achieving rapid induction
of anaesthesia, the high doses required are frequently associated with hypotension. Opiates,
especially morphine, are generally avoided during induction, due to concern over histamine
release and the associated increase in bronchoconstriction, although they may be warranted
in cases of advanced myocardial dysfunction or elevated intracranial pressure where
sympathetic responses from pain during intubation need to be blunted.

Neuromuscular paralysis simultaneous with the induction of anaesthesia is a key feature of

rapid-sequence intubation, and improves the ability to visualise and intubate the glottis.
Succinylcholine has the advantages of a rapid onset and short duration of paralysis, but
concerns about its ability to raise potassium levels, which contribute to arrhythmias, and to
release histamine, which worsens bronchospasm, have led to greater use of nondepolarising
agents. The nondepolarising agents (e.g. vecuronium and rocuronium) are longer acting
and therefore substantially increase the risk of hypoxia if there is difficulty intubating.
Regardless of the agent chosen, the risks associated with paralysis warrant an assessment of
the ability to intubate and ventilate before the procedure begins.

Ventilator settings

Two major concepts in ventilator management guide the choice of settings in an asthma
exacerbation. The first is that expiratory times too short to allow for complete exhalation lead
to progressive hyperinflation (figure 3a). Short expiratory times occur when the ventilator is
set to have high minute ventilation through an increased respiratory rate or tidal volume, or
both. Seminal studies in the 1980s raised awareness of the increased risk of hypotension,
barotrauma (e.g. pneumothorax) and death from dynamic hyperinflation when the ventilator
was adjusted in this way to normalise arterial carbon dioxide [81, 82]. It was found that
correcting hypoxaemia with supplemental oxygen without attempting to normalise alveolar
ventilation led to decreased hyperinflation and an improvement in all of these outcomes.
Hypercarbia is usually tolerated and, except in cases with elevated intracranial pressure or
myocardial dysfunction, ventilator settings should aim to reduce hyperinflation rather than
correct arterial carbon dioxide. As airflow obstruction improves, hypercarbia will naturally
improve. Volume-targeted modes are preferred in asthma exacerbations due to the variable
tidal volumes delivered in pressure-targeted modes as the degree of airflow obstruction
changes. A constant inspiratory flow (rather than decelerating ramp) is recommended in
order to decrease inspiratory time, leaving more time for exhalation.

Hyperinflation is recognised through inspection of flow and pressure waveforms, which

may show an inhalation that starts before expiratory flow returns to zero, elevated plateau
pressure (Pplat, measured during an inspiratory pause) or high auto-PEEP (measured
during an expiratory pause) (figure 3b and c). If hyperinflation is present, the ventilator
should be adjusted to prolong the expiratory time by decreasing the respiratory rate or
lowering the inspiratory time; in volume-targeted modes, a lower inspiratory time is
achieved by increasing the inspiratory flow rate and decreasing the tidal volume. Targeting
a respiratory rate of 10–14 breaths·min−1 with minute ventilation of <10 L·min−1 reduces

77

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

a)
Airway obstruction
Progressive dynamic hyperinflation
Lung volume
VT

VEI
Normal
lungs VDHI

FRC
tI tE

b) Ppeak
Pres
PA
Pplat
Pressure

Auto-PEEP
PEEP

c)
Flow

Inspiratory Expiratory
pause pause

Figure 3. a) Graphical representation of the development of dynamic hyperinflation, indicated by a rise in

end-expiratory lung volume above functional residual capacity (FRC) due to inadequate time for complete
exhalation of tidal volume (VT). b and c) Schematic representation of b) airway pressure and c) flow during
controlled mechanical ventilation. Note that flow persists at end-expiration, indicating that end-expiratory
alveolar pressure (PA) exceeds circuit pressure (i.e. auto-PEEP is present). The dashed line represents PA. tI:
inspiratory time; tE: expiratory time; VDHI: volume (above FRC) caused by dynamic hyperinflation; VEI: volume
(above FRC) at end inspiration; Ppeak: peak airway pressure; Pres: inspiratory flow-resistive pressure; Pplat:
plateau airway pressure. Reproduced from [80] with permission.

the risk of hypotension and barotrauma [82]. There are few data to dictate threshold
pressures below which the risk of negative outcomes is minimised. In line with
recommendations from the field of ventilator-induced lung injury, there is a low incidence
of hypotension and barotrauma when Pplat is <30 cmH2O [78]. Interpretation of Pplat
should take into account factors such as reduced chest wall compliance (e.g. in obesity),
which will lead to overestimation of transpulmonary pressure through Pplat, and
heterogeneity in lung compliance, which will lead to some areas experiencing much higher
stress than indicated by Pplat. A goal of keeping auto-PEEP at <10 cmH2O is reasonable,
with the recognition that forced exhalation can cause overestimation of auto-PEEP and
airway closure can cause underestimation. There are no data available to suggest that

78

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

increasing the set PEEP offers benefits in terms of reduced work to trigger the ventilator or
to keep airways open, as it might in COPD; in the absence of significant hypoxaemia, set
PEEP should be ⩽5 cmH2O to minimise resistance to exhalation.

The second, evidence-based principle to follow is avoidance of large tidal volumes to

reduce the risk of ventilator-induced lung injury. Numerous studies have demonstrated a
reduction in lung injury and mortality when low tidal volumes (⩽6 mL·kg−1 of predicted
body weight) are used in ARDS [83]. In asthma and other obstructive diseases, the goal to
reduce tidal volume to prevent lung injury, which sometimes necessitates higher respiratory
rates to ensure adequate minute ventilation, needs to be balanced by the need to allow
adequate time for exhalation to prevent air trapping. On balance, it is reasonable to target a
tidal volume of ⩽8 mL·kg−1 of predicted body weight in the setting of an asthma
exacerbation. Table 4 provides recommended ventilator settings.

Pharmacological treatment during mechanical ventilation

Discomfort from the endotracheal tube or dyssynchrony between patient and the ventilator
requires sedation. Ventilator dyssynchrony contributes to breath stacking and
hyperinflation if there is inadequate time for exhalation, and must be addressed to prevent
barotrauma and hypotension. If sedation is required once pain is adequately treated, we
recommend a continuous infusion of propofol, given its short duration of action and
associated decreased risk of delirium and prolonged intubation compared with
benzodiazepines [84]. Boluses or an infusion of benzodiazepines may be required when
propofol is not tolerated due to hypotension, hypertriglyceridaemia or concern about
propofol infusion syndrome. In cases where agitation or anxiety is driving a mild degree of
dyssynchrony, a dexmedetomidine infusion may be all that is needed; similar to propofol,
dexmedetomidine has a short duration of action and also induces hypotension (but, unlike
propofol, induces bradycardia as well). Regardless of the sedation agent chosen, opiates are
useful adjuncts to suppress respiratory effort. Fentanyl is preferred over morphine, which
has the potential for histamine release. Sedation with ketamine is appealing, given the
potential for additional bronchodilation and lack of associated hypotension. However, there
is a substantial risk of dysphoric reactions with ketamine when it is used at sedating doses.
Furthermore, at subdissociative continuous infusion doses, one RCT showed no benefit in
symptoms, lung function, respiratory rate or the rate of hospital admission when ketamine
was given in the ED to spontaneously breathing patients [85], and only case reports suggest
a benefit in the setting of mechanical ventilation [86, 87]. Finally, one must consider

Table 4. Recommendations to prevent hyperinflation on mechanical ventilation

Ventilator settings
Respiratory rate 10–14 breaths·min−1, VT 8 mL·kg−1 of PBW, adequate time to exhale,
PEEP ⩽5 cmH2O
Sedation
Deep sedation may be required in some cases to prevent dyssynchrony and hyperinflation
Paralysis
Use only if hyperinflation cannot be managed with the above, given the risk of myopathy and
neuromuscular weakness

VT: tidal volume; PBW: predicted body weight.

79

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

whether the patient’s obstruction has improved enough such that, rather than increased
sedation, the best change to counter dyssynchrony is to convert to a spontaneous mode of
breathing (see section on Liberation from mechanical ventilation).

Ongoing neuromuscular paralysis should only be used if there is difficulty in achieving

stability with adjustment of the ventilator and increases in sedation. Based on retrospective
data, concern remains about an increased risk of myopathy with the addition of
neuromuscular blockade to corticosteroid therapy. In one study, with each additional day of
muscle relaxation, there was an OR of 2.1 (95% CI 1.4–3.2) for the development of myopathy
[88]. We recommend limiting the duration of paralysis by weaning from it early and
continuing deep sedation if needed.

Bronchodilators are effective in mechanically ventilated patients. Although the tubing and
humidification in the ventilator circuit contribute to loss of drug, the few data available
have found that, as long as the dose is adjusted accordingly, MDIs and nebulisers are
effective and equivalent. Guidelines for optimising bronchodilator delivery in mechanically
ventilated patients are available [78].

Nonstandard therapies

Some nonstandard therapies are given in table 2. The pathology of fatal asthma suggests that
efforts to mechanically and pharmacologically remove and break down mucus can improve
outcomes, at least if the mucus is proximal enough to be affected. Bronchoscopy with or
without simultaneous instillation of a mucolytic such as N-acetylcysteine or recombinant
human DNase has been reported anecdotally to improve obstruction [80]. However, no
RCTs exist to evaluate the benefits of these interventions and, given the possibility of airway
irritation with these procedures, we recommend against routine use. They can be considered
in the setting of refractory respiratory failure or if there is concern for an airway lesion, such
as when focal wheezing or lobar collapse is present. Similarly, there are no data to suggest a
benefit from heliox during mechanical ventilation. Case reports suggest that ECMO, and the
less invasive modality of extracorporeal carbon dioxide removal, can be considered in severe
hypoxaemia or hypercarbia refractory to standard management, especially if barotrauma is
already present. Rarely, volatile anaesthetics with bronchodilatory properties are used for
cases of refractory bronchoconstriction if trained personnel and specialised gas-conserving
systems are available in the ICU. Case reports and small, uncontrolled studies suggest a
benefit to using inhaled anaesthetics, but the treatment remains experimental [78, 80].

Outcomes of mechanical ventilation

Patients requiring endotracheal intubation and mechanical ventilation have a higher

mortality rate (5–20%) compared with non-intubated cases (<1%) of inpatient asthma
exacerbations [75–78]. It is unknown how much of this is due to increased severity of the
disease and associated consequences (e.g. pre-hospital cardiac arrest and cerebral anoxia)
versus the adverse effects of critical care (e.g. barotrauma, hypotension, nosocomial
pneumonia, sepsis, gastrointestinal bleeding, deep venous thrombosis and neuromuscular
weakness) mediated by mechanical ventilation, sedation, immobility and indwelling
catheters. Preventative measures such as ventilator bundles, minimisation of sedation, early
mobilisation, and attention to catheter care and removal may reduce the harm associated
with mechanical ventilation. Fortunately, the data suggest that a ventilator strategy that

80

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

minimises hyperinflation and lung injury reduces the complications and mortality
associated with mechanical ventilation [89].

Liberation from mechanical ventilation

The duration of mechanical ventilation and determinants thereof are understudied. In one
report, patients were intubated for 3.4±3.8 days on average [89]. Many patients require ⩽48 h
of mechanical ventilation, consistent with the reversible nature of airway obstruction and the
responsiveness to medications in asthma. The aetiology of asthma exacerbation and the
pre-hospital course have an impact on the duration to improvement once intubated. In cases
where the duration of symptoms preceding hospital admission is short, such as with inhalation
of irritants, including cocaine, the duration of intubation is significantly shorter than in
patients with other aetiologies of exacerbation [89]. Patients with more significant mucus
impaction, as might be expected to occur with infection or high levels of allergic, type-2
inflammation, may have both a longer prodrome and a longer duration of intubation. A
spontaneous breathing trial should be done in awake patients and extubation considered when
there is no evidence of hyperinflation, airway resistance has improved (<20 cmH2O·L−1·s−1),
PaCO2 has normalised and patients can handle secretions with an effective cough. Difficulty
weaning or post-extubation failure should lead to expansion of the differential diagnosis to
include neuromuscular weakness (from corticosteroids, neuromuscular blockade, critical
illness or hypophosphataemia), vocal cord dysfunction, laryngospasm, tracheobronchomalacia,
airway lesions, and parenchymal, vascular or pleural lung disease.

Discharge from the hospital

Careful discharge planning has the potential to reduce the high risk of relapse after an
exacerbation. Patients should use SABAs as needed and continue oral corticosteroids for
5–7 days [14, 15, 43, 44]. The risk of relapse is reduced when patients are discharged with
ICSs [90, 91]. Although the data do not provide guidance on whether there is any benefit
to adding ICSs during the hospital stay, earlier initiation does give patients time to practise
administration. Exacerbations of asthma often indicate inadequate therapy, improper use of
medications, poor adherence or lack of an action plan to respond to early changes in
asthma control. Therefore, during hospitalisation and discharge, providers and patients
should review inhaler technique, and develop plans to minimise exposure to environmental
triggers and to self-adjust medications in response to changes in symptoms or PEF.
Samples of action plans and other educational materials are available in expert guidelines
[14]. In addition to an action plan, expert guidelines also recommend that patients follow
up with their primary care provider or an asthma specialist within 1–4 weeks of discharge
from the ED or hospital, and they are encouraged to call a provider if there are problems
with asthma control in the first 3–5 days after discharge.

Future directions

Phenotypes of asthma delineated by dysregulation in immune responses and molecular

pathways in lung-resident cells have refined the care of asthma in the outpatient setting.
Recognition of the variable presence of type-2 airway inflammation has led to targeted
therapies that reduce the number of exacerbations and improve lung function [92]. Studies
on how these molecular phenotypes and associated biomarkers can inform the

81

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

management of asthma exacerbations in the hospital are lacking. The growing recognition
of an overlap in features of asthma and COPD, the unique characteristics of asthma in the
setting of obesity, and the presence of severe, fixed airflow obstruction are additional
phenotypes that warrant study of their impact on care of the hospitalised patient. The
observation of marked mucus impaction in fatal asthma suggests a potential for high
impact from the development of more effective mucolytic strategies.

Conclusion

Worldwide, acute asthma exacerbations account for a high proportion of urgent healthcare
visits. Although self-management at home may avert some of these visits, patients who
present for evaluation require immediate attention. Medical treatment is directed towards
rapid reversal of airflow obstruction with β2-agonists to relax airway smooth muscle,
corticosteroids to decrease inflammation and supplemental oxygen to correct hypoxaemia.
Beyond these medications, muscarinic antagonists may provide some benefit prior to
hospital admission, but other therapies, including magnesium, leukotriene modifiers,
methylxanthines, heliox and antibiotics, are not supported by published evidence. Lack of
significant early improvement should prompt hospital admission. It is important to
recognise impending respiratory failure and admit these patients to the ICU, where
mechanical assistance with ventilation can be provided. NPPV may accelerate recovery in
some patients but does not appear to prevent intubation; the ideal candidate for NPPV and
the best timing need to be better defined. With the use of modern strategies to intubate
and mechanically ventilate the asthmatic patient, and the increased attention to minimising
nosocomial harm, hospital morbidity and mortality are low. Nonetheless, exacerbations
often signal the need for more intensive disease management in the outpatient setting. In
order to prevent relapse, every attempt should be made to provide education and optimise
access to medications and providers prior to discharge.

References
1. Campbell S, Hood I, Ryan D, et al. Death as a result of asthma in Wayne County Medical Examiner cases,
1975–1987. J Forensic Sci 1990; 35: 356–364.
2. Robertson CF, Rubinfeld AR, Bowes G. Pediatric asthma deaths in Victoria: the mild are at risk. Pediatr Pulmonol
1992; 13: 95–100.
3. Strunk RC. Death due to asthma. New insights into sudden unexpected deaths, but the focus remains on
prevention. Am Rev Respir Dis 1993; 148: 550–552.
4. Reddel HK, Bateman ED, Becker A, et al. A summary of the new GINA strategy: a roadmap to asthma control.
Eur Respir J 2015; 46: 622–639.
5. Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current
best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane
Database Syst Rev 2013; 4: CD007313.
6. Pearce N, Sunyer J, Cheng S, et al. Comparison of asthma prevalence in the ISAAC and ECRHS. ISAAC Steering
Committee and the European Community Respiratory Health Survey. International Study of Asthma and Allergies
in Childhood. Eur Respir J 2000; 16: 420–426.
7. Moorman JE, Akinbami LJ, Bailey CM, et al. National surveillance of asthma: United States, 2001–2010.
Vital Health Stat 2012; 3: 1–58.
8. Gibson GJ, Loddenkemper R, Lundback B, et al. Respiratory health and disease in Europe: the new European Lung
White Book. Eur Respir J 2013; 42: 559–563.
9. The burden of lung disease. In: Gibson GJ Loddenkemper R Sibille Y, et al., eds. European Lung White Book. 2nd
Edn. Sheffield, European Respiratory Society, 2013; p. 10.
10. Royal College of Physicians, National Review of Asthma Deaths. Why Asthma Still Kills. www.rcplondon.ac.uk/
projects/outputs/why-asthma-still-kills Date last updated: August 11, 2015.

82

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

11. Loymans RJ, Honkoop PJ, Termeer EH, et al. Identifying patients at risk for severe exacerbations of asthma:
development and external validation of a multivariable prediction model. Thorax 2016; 71: 838–846.
12. Haahtela T, Tuomisto LE, Pietinalho A, et al. A 10 year asthma programme in Finland: major change for the
better. Thorax 2006; 61: 663–670.
13. Kupczyk M, Haahtela T, Cruz AA, et al. Reduction of asthma burden is possible through National Asthma Plans.
Allergy 2010; 65: 415–419.
14. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): guidelines for the Diagnosis
and Management of Asthma – Summary Report 2007. J Allergy Clin Immunol 2007; 120: Suppl., S94–S138.
15. Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention. 2016. Available
from: www.ginasthma.org
16. Chien JW, Ciufo R, Novak R, et al. Uncontrolled oxygen administration and respiratory failure in acute asthma.
Chest 2000; 117: 728–733.
17. Rodrigo GJ, Rodriquez Verde M, Peregalli V, et al. Effects of short-term 28% and 100% oxygen on PaCO2 and peak
expiratory flow rate in acute asthma: a randomized trial. Chest 2003; 124: 1312–1317.
18. Perrin K, Wijesinghe M, Healy B, et al. Randomised controlled trial of high concentration versus titrated oxygen
therapy in severe exacerbations of asthma. Thorax 2011; 66: 937–941.
19. Newman KB, Milne S, Hamilton C, et al. A comparison of albuterol administered by metered-dose inhaler and
spacer with albuterol by nebulizer in adults presenting to an urban emergency department with acute asthma.
Chest 2002; 121: 1036–1041.
20. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulisers for β-agonist treatment of acute
asthma. Cochrane Database Syst Rev 2006; 2: CD000052.
21. Dhuper S, Chandra A, Ahmed A, et al. Efficacy and cost comparisons of bronchodilatator administration
between metered dose inhalers with disposable spacers and nebulizers for acute asthma treatment. J Emerg Med 2011;
40: 247–255.
22. Rodrigo GJ, Rodrigo C. Continuous vs intermittent β-agonists in the treatment of acute adult asthma: a systematic
review with meta-analysis. Chest 2002; 122: 160–165.
23. Bradding P, Rushby I, Scullion J, et al. As-required versus regular nebulized salbutamol for the treatment of acute
severe asthma. Eur Respir J 1999; 13: 290–294.
24. Camargo CA Jr, Spooner CH, Rowe BH. Continuous versus intermittent β-agonists in the treatment of acute
asthma. Cochrane Database Syst Rev 2003; 4: CD001115.
25. World Health Organization. 19th WHO Model List of Essential Medicines. Geneva, World Health Organization,
2015. www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf
26. Carl JC, Myers TR, Kirchner HL, et al. Comparison of racemic albuterol and levalbuterol for treatment of acute
asthma. J Pediatr 2003; 143: 731–736.
27. Qureshi F, Zaritsky A, Welch C, et al. Clinical efficacy of racemic albuterol versus levalbuterol for the treatment of
acute pediatric asthma. Ann Emerg Med 2005; 46: 29–36.
28. Travers AH, Milan SJ, Jones AP, et al. Addition of intravenous β2-agonists to inhaled β2-agonists for acute asthma.
Cochrane Database Syst Rev 2012; 12: CD010179.
29. Papiris S, Kotanidou A, Malagari K, et al. Clinical review: severe asthma. Crit Care 2002; 6: 30–44.
30. Rodrigo GJ, Neffen H, Colodenco FD, et al. Formoterol for acute asthma in the emergency department:
a systematic review with meta-analysis. Ann Allergy Asthma Immunol 2010; 104: 247–252.
31. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma:
a systematic review with meta-analysis. Thorax 2005; 60: 740–746.
32. Griffiths B, Ducharme FM. Combined inhaled anticholinergics and short-acting β2-agonists for initial treatment of
acute asthma in children. Cochrane Database Syst Rev 2013; 8: CD000060.
33. Vézina K, Chauhan BF, Ducharme FM. Inhaled anticholinergics and short-acting β2-agonists versus short-acting
β2-agonists alone for children with acute asthma in hospital. Cochrane Database Syst Rev 2014; 7: CD010283.
34. Quon BS, Fitzgerald JM, Lemiere C, et al. Increased versus stable doses of inhaled corticosteroids for exacerbations
of chronic asthma in adults and children. Cochrane Database Syst Rev 2010; 12: CD007524.
35. Foresi A, Morelli MC, Catena E. Low-dose budesonide with the addition of an increased dose during exacerbations
is effective in long-term asthma control. Chest 2000; 117: 440–446.
36. Oborne J, Mortimer K, Hubbard RB, et al. Quadrupling the dose of inhaled corticosteroid to prevent asthma
exacerbations: a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Am J Respir Crit Care
Med 2009; 180: 598–602.
37. Edmonds ML, Milan SJ, Camargo CA Jr, et al. Early use of inhaled corticosteroids in the emergency department
treatment of acute asthma. Cochrane Database Syst Rev 2012; 12: CD002308.
38. Fanta CH, Rossing TH, McFadden ER Jr. Glucocorticoids in acute asthma. A critical controlled trial. Am J Med
1983; 74: 845–851.
39. Littenberg B, Gluck EH. A controlled trial of methylprednisolone in the emergency treatment of acute asthma.
N Engl J Med 1986; 314: 150–152.

83

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

40. Rodrigo G, Rodrigo C. Corticosteroids in the emergency department therapy of acute adult asthma: an
evidence-based evaluation. Chest 1999; 116: 285–295.
41. Rowe BH, Edmonds ML, Spooner CH, et al. Corticosteroid therapy for acute asthma. Respir Med 2004; 98: 275–284.
42. Krishnan JA, Davis SQ, Naureckas ET, et al. An umbrella review: corticosteroid therapy for adults with acute
asthma. Am J Med 2009; 122: 977–991.
43. Hasegawa T, Ishihara K, Takakura S, et al. Duration of systemic corticosteroids in the treatment of asthma
exacerbation; a randomized study. Intern Med 2000; 39: 794–797.
44. Jones AM, Munavvar M, Vail A, et al. Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in
acute adult asthma. Respir Med 2002; 96: 950–954.
45. Haury VG. Blood serum magnesium in bronchial asthma and its treatment by the administration of magnesium
sulphate. J Lab Clin Med 1940; 26: 340–341.
46. Okayama H, Aikawa T, Okayama M, et al. Bronchodilating effect of intravenous magnesium sulfate in bronchial
asthma. JAMA 1987; 257: 1076–1078.
47. Skobeloff EM, Spivey WH, McNamara RM, et al. Intravenous magnesium sulfate for the treatment of acute asthma
in the emergency department. JAMA 1989; 262: 1210–1213.
48. Jones LA, Goodacre S. Magnesium sulphate in the treatment of acute asthma: evaluation of current practice in
adult emergency departments. Emerg Med J 2009; 26: 783–785.
49. Rowe BH, Bretzlaff JA, Courdon C, et al. Intravenous magnesium sulfate treatment for acute asthma in the
emergency department: a systematic review of the literature. Ann Emerg Med 2000; 36: 234–236.
50. FitzGerald JM. Magnesium sulfate is effective for severe acute asthma treated in the emergency department. West J
Med 2000; 172: 96.
51. Gallegos-Solorzano MC, Perez-Padilla R, Hernandez-Zenteno RJ. Usefulness of inhaled magnesium sulfate in the
coadjuvant management of severe asthma crisis in an emergency department. Pulm Pharmacol Ther 2010; 23: 432–437.
52. Goodacre S, Cohen J, Bradburn M, et al. Intravenous or nebulised magnesium sulphate versus standard therapy for
severe acute asthma (3Mg trial): a double-blind, randomised controlled trial. Lancet Respir Med 2013; 1: 293–300.
53. Liu MC, Dube LM, Lancaster J. Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month
randomized multicenter trial. J Allergy Clin Immunol 1996; 98: 859–871.
54. Dockhorn RJ, Baumgartner RA, Leff JA, et al. Comparison of the effects of intravenous and oral montelukast on
airway function: a double blind, placebo controlled, three period, crossover study in asthmatic patients. Thorax 2000;
55: 260–265.
55. Camargo CA Jr, Gurner DM, Smithline HA, et al. A randomized placebo-controlled study of intravenous
montelukast for the treatment of acute asthma. J Allergy Clin Immunol 2010; 125: 374–380.
56. Ramsay CF, Pearson D, Mildenhall S, et al. Oral montelukast in acute asthma exacerbations: a randomised,
double-blind, placebo-controlled trial. Thorax 2011; 66: 7–11.
57. Watts K, Chavasse RJ. Leukotriene receptor antagonists in addition to usual care for acute asthma in adults and
children. Cochrane Database Syst Rev 2012; 5: CD006100.
58. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled β2-agonists in adults with acute
asthma. Cochrane Database Syst Rev 2012; 12: CD002742.
59. Joseph KS, Blais L, Ernst P, et al. Increased morbidity and mortality related to asthma among asthmatic patients
who use major tranquillisers. BMJ 1996; 312: 79–82.
60. FitzGerald JM, Macklem P. Fatal asthma. Annu Rev Med 1996; 47: 161–168.
61. Colebourn CL, Barber V, Young JD. Use of helium–oxygen mixture in adult patients presenting with exacerbations
of asthma and chronic obstructive pulmonary disease: a systematic review. Anaesthesia 2007; 62: 34–42.
62. Kelly AM, Kerr D, Powell C. Is severity assessment after one hour of treatment better for predicting the need for
admission in acute asthma? Respir Med 2004; 98: 777–781.
63. McFadden ER Jr. Acute severe asthma. Am J Respir Crit Care Med 2003; 168: 740–759.
64. Leatherman J. Life-threatening asthma. Clin Chest Med 1994; 15: 453–479.
65. Lewis L, Ferguson I, House SL, et al. Albuterol administration is commonly associated with increases in serum
lactate in patients with asthma treated for acute exacerbation of asthma. Chest 2014; 145: 53–59.
66. Kuyper LM, Pare PD, Hogg JC, et al. Characterization of airway plugging in fatal asthma. Am J Med 2003; 115: 6–11.
67. Ram FS, Picot J, Lightowler J, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure
due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2004; 1: CD004104.
68. Scala R. Noninvasive ventilation in severe acute asthma? Still far from the truth. Respir Care 2010; 55: 630–637.
69. Lim WJ, Mohammed Akram R, Carson KV, et al. Non-invasive positive pressure ventilation for treatment of
respiratory failure due to severe acute exacerbations of asthma. Cochrane Database Syst Rev 2012; 12: CD004360.
70. Gupta D, Nath A, Agarwal R, et al. A prospective randomized controlled trial on the efficacy of noninvasive
ventilation in severe acute asthma. Respir Care 2010; 55: 536–543.
71. Galindo-Filho VC, Brandao DC, Ferreira RdCS, et al. Noninvasive ventilation coupled with nebulization during
asthma crises: a randomized controlled trial. Respir Care 2013; 58: 241–249.

84

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ASTHMA | N.R. BHAKTA AND S.C. LAZARUS

72. Op’t Holt TB. Additional evidence to support the use of noninvasive ventilation in asthma exacerbation.
Respir Care 2013; 58: 380–382.
73. Soroksky A, Stav D, Shpirer I. A pilot prospective, randomized, placebo-controlled trial of bilevel positive airway
pressure in acute asthmatic attack. Chest 2003; 123: 1018–1025.
74. Stefan MS, Nathanson BH, Lagu T, et al. Outcomes of noninvasive and invasive ventilation in patients hospitalized
with asthma exacerbation. Ann Am Thorac Soc 2016; 13: 1096–1104.
75. Kaur BP, Lahewala S, Arora S, et al. Asthma: hospitalization trends and predictors of in-hospital mortality and
hospitalization costs in the USA (2001–2010). Int Arch Allergy Immunol 2015; 168: 71–78.
76. Pendergraft TB, Stanford RH, Beasley R, et al. Rates and characteristics of intensive care unit admissions and
intubations among asthma-related hospitalizations. Ann Allergy Asthma Immunol 2004; 93: 29–35.
77. Krishnan V, Diette GB, Rand CS, et al. Mortality in patients hospitalized for asthma exacerbations in the United
States. Am J Respir Crit Care Med 2006; 174: 633–638.
78. Brenner B, Corbridge T, Kazzi A. Intubation and mechanical ventilation of the asthmatic patient in respiratory
failure. Proc Am Thorac Soc 2009; 6: 371–379.
79. Gu WJ, Wang F, Tang L, et al. Single-dose etomidate does not increase mortality in patients with sepsis: a systematic
review and meta-analysis of randomized controlled trials and observational studies. Chest 2015; 147: 335–346.
80. Leatherman J. Mechanical ventilation for severe asthma. Chest 2015; 147: 1671–1680.
81. Darioli R, Perret C. Mechanical controlled hypoventilation in status asthmaticus. Am Rev Respir Dis 1984; 129:
385–387.
82. Tuxen DV, Lane S. The effects of ventilatory pattern on hyperinflation, airway pressures, and circulation in
mechanical ventilation of patients with severe air-flow obstruction. Am Rev Respir Dis 1987; 136: 872–879.
83. Wilson JG, Matthay MA. Mechanical ventilation in acute hypoxemic respiratory failure: a review of new strategies
for the practicing hospitalist. J Hosp Med 2014; 9: 469–475.
84. Lonardo NW, Mone MC, Nirula R, et al. Propofol is associated with favorable outcomes compared with
benzodiazepines in ventilated intensive care unit patients. Am J Respir Crit Care Med 2014; 189: 1383–1394.
85. Howton JC, Rose J, Duffy S, et al. Randomized, double-blind, placebo-controlled trial of intravenous ketamine in
acute asthma. Ann Emerg Med 1996; 27: 170–175.
86. Hemming A, MacKenzie I, Finfer S. Response to ketamine in status asthmaticus resistant to maximal medical
treatment. Thorax 1994; 49: 90–91.
87. Garg D, Kaistha S, Sood D. Subanaesthetic dose of ketamine in intractable asthma. J Indian Med Assoc 2011; 109:
430–434.
88. Behbehani NA, Al-Mane F, D’Yachkova Y, et al. Myopathy following mechanical ventilation for acute severe
asthma: the role of muscle relaxants and corticosteroids. Chest 1999; 115: 1627–1631.
89. Kao CC, Jain S, Guntupalli KK, et al. Mechanical ventilation for asthma: a 10-year experience. J Asthma 2008; 45:
552–556.
90. Edmonds ML, Camargo CA, Saunders LD, et al. Inhaled steroids in acute asthma following emergency department
discharge. Cochrane Database Syst Rev 2000; 12: CD002316.
91. Rowe BH, Bota GW, Fabris L, et al. Inhaled budesonide in addition to oral corticosteroids to prevent asthma relapse
following discharge from the emergency department: a randomized controlled trial. JAMA 1999; 281: 2119–2126.
92. Fahy JV. Type 2 inflammation in asthma – present in most, absent in many. Nat Rev Immunol 2015; 15: 57–65.

Disclosures: N.R. Bhakta has received a K23 Mentored Career Development Award from the National
Institutes of Health National Heart, Lung, and Blood Institute (NIH-NHLBI). S.C. Lazarus has received grants
from the NIH-NHLBI through the NHLBI-funded AsthmaNet network, of which the University of California,
San Francisco, is part. He has also received personal fees from the 2015 Respiratory Disease Young
Investigators’ Forum for chairing a meeting of pulmonary and allergy research.

85

FB:Cardiologia Siglo XXI

 | Chapter 6
Hypercapnic respiratory failure
in non-COPD
Neeraj M. Shah1,2 and Patrick B. Murphy1,2

This chapter discusses the pathophysiology of hypercapnic respiratory failure in conditions

other than COPD. First, the development of alveolar hypoventilation is explained, and the
load–capacity–drive model of hypercapnic respiratory failure is described. An increase in
respiratory load or a decrease in respiratory muscle capacity or neural drive will lead to
alveolar hypoventilation. This model is used to explain the pathophysiology of hypercapnic
failure in acute and chronic neuromuscular diseases and obesity hypoventilation syndrome.
It is outside the scope of this chapter to comprehensively discuss the management of these
conditions; however, key concepts related to the management of acute deteriorations and
hypoventilation are outlined. Other causes of alveolar hypoventilation, such as cystic fibrosis
and chest wall disorders, are discussed briefly.

R espiratory failure occurs when there is inadequate exchange of oxygen and carbon
dioxide to meet the requirements of metabolism. Hypoxaemic (type I) respiratory
failure occurs when disease processes impair oxygen transfer, leading to insufficient oxygen
levels in the blood. Hypercapnic (type II) respiratory failure occurs when inadequate
alveolar ventilation (V′A) leads to the failure to clear carbon dioxide.

The most common cause of hypercapnic respiratory failure is COPD, which is discussed in
another chapter in this Monograph [1]. This chapter will focus on the pathophysiology of
hypercapnic failure in other important conditions leading to respiratory morbidity,
including neuromuscular disorders (NMDs) and obesity hypoventilation syndrome (OHS).
First, it is important to understand the fundamental pathophysiology of hypercapnic
respiratory failure, before applying these fundamentals to each condition.

Pathophysiology of hypercapnic failure

As already mentioned, V′A is crucial for the removal of carbon dioxide from the blood.
V′A, carbon dioxide production (V′CO2) and PaCO2 are linked via the following equation:

V 0A ¼ V 0CO2 =PaCO2  K

1
Lane Fox Respiratory Unit, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. 2Division of Asthma, Allergy and Lung
Biology, King’s College London, London, UK.

Correspondence: Patrick B. Murphy, Lane Fox Respiratory Unit, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH, UK.
E-mail: patrick.murphy@gstt.nhs.uk

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

86 ERS Monogr 2016; 74: 86–100. DOI: 10.1183/2312508X.10001616

FB:Cardiologia Siglo XXI

 HYPERCAPNIC FAILURE IN NON-COPD | N.M. SHAH AND P.B. MURPHY

where K is a constant that takes into account the different units of V′A, V′CO2 and PaCO2.

This can be rearranged as:

PaCO2 ¼ V 0CO2 =V 0A  K

In other words, as V′A decreases, PaCO2 will increase, i.e. PaCO2 is inversely proportional to
V′A. Factors that contribute to inadequate V′A are reduced minute ventilation (V′E) and
increased dead space. V′E is the sum of dead space ventilation (V′D) and V′A:

V 0E ¼ V 0D þ V 0A

Alternatively:

V 0A ¼ V 0E  V 0D

Under normal conditions, V′E is controlled by ventilatory drive, which adjusts respiratory
muscle pump function to match metabolic activity, to maintain adequate carbon dioxide
clearance. Thus, adequate V′E requires integrity of the neural pathway from the central
respiratory centre to the respiratory musculature, and satisfactory force generation, as well
as coordination of the respiratory muscles. The numerous causes of alveolar
hypoventilation can be considered according to this anatomical framework.

Central respiratory depression is caused by any higher-level lesion such as stroke, a

space-occupying mass or haemorrhage, as well as drugs (e.g. anaesthetics, benzodiazepines,
opiates) and spinal cord lesions.

Many conditions can interrupt the pathway from the central drive in the medulla to the
respiratory musculature. Upper motor neurons can be affected by a cervical cord lesion (e.g.
trauma, tumour, demyelination or syringomyelia). Complete spinal cord lesions above C4
produce phrenic nerve dysfunction whereas a fracture-dislocation of the lower cervical spine
will lead to interrupted function of the intercostal and expiratory muscles (but will spare the
diaphragm). Conditions affecting the anterior horn cell (e.g. poliomyelitis, amyotrophic
lateral sclerosis, spinal muscular atrophies), lower motor neuron (e.g. trauma, motor neuron
disease, Guillain–Barré syndrome) and the neuromuscular junction (e.g. myasthenia gravis,
botulism toxin, drugs such as anaesthetics or organophosphates) can all lead to impaired
ventilation and hypercapnia. Figure 1 displays this anatomical pathway.

Conditions directly affecting the respiratory musculature will result in unsatisfactory force
generation. These include muscular dystrophies, critical care myopathy and the
hyperinflation of COPD, which results in poor contractility due to a mechanically
disadvantaged diaphragm. Finally, conditions that result in reduced compliance of the chest
wall (e.g. kyphosis, scoliosis, obesity, contracted burn scars) or the lungs (e.g. fibrosis, acute
lung injury, empyema) can also result in impaired ventilation.

A useful framework to use when considering the contribution of disease processes to

hypercapnic respiratory failure is the load–capacity–drive model (figure 2) [2]. Respiratory

87

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Drive

Cortex Cortical and brainstem lesions Muscular dystrophies

(including trauma) Inflammatory myopathies
Encephalitis, ischaemia, Malnutrition myopathy
haemorrhage, Cheyne– Acid maltase deficiency
Brainstem Stokes respiration (CHF) Thyroid myopathy
Drugs Biochemical anomalies
Sedatives, opioids Hypokalaemia
Metabolic alkalosis Hypophosphataemia
Loop diuretics

Extradiaphragmatic muscles

Transmission
Spinal motor neurons
Phrenic nerves
Spinal cord lesion
Polio Diaphragm
MND
Phrenic nerve injury
GBS
Abdominal muscles
CINMA
NMB agents
Aminoglycosides Action
Myasthenia gravis

Figure 1. Schematic diagram representing the anatomical distribution of possible pathological lesions
disrupting the respiratory muscle load–capacity–drive system. CHF: congestive heart failure; MND: motor
neuron disease; GBS: Guillain–Barré syndrome; CINMA: critical illness neuromuscular abnormality; NMB:
neuromuscular blocking.

load refers to the combination of resistive load (airways resistance to airflow), elastic load
(inversely proportional to compliance) and threshold load (intrinsic PEEP). Load can be
quantified using invasive pulmonary mechanics to measure oesophageal pressure, as a
surrogate for pleural pressure, and air flow during the respiratory cycle. Load is increased in
airway obstruction and hyperinflation (e.g. COPD, asthma, cystic fibrosis), stiff lungs (e.g.

Increased load

Reduced drive
Reduced capacity

Hypoventilation

Figure 2. The respiratory muscle load–capacity–drive model. Alveolar ventilation is determined by the
balance between respiratory load, muscle capacity and neural drive. An increase in load, or a decrease in
muscle capacity or neural drive, will result in hypoventilation and respiratory failure.

88

FB:Cardiologia Siglo XXI

 HYPERCAPNIC FAILURE IN NON-COPD | N.M. SHAH AND P.B. MURPHY

fibrosis, pulmonary oedema) and chest wall disease (e.g. obesity, kyphoscoliosis, pleural
disease). Excessive respiratory load can be overcome by driving the respiratory muscle pump
harder; however, at sufficient loads the system moves to prevent fatigue by reducing tidal
volume, with the subsequent development of hypoventilation and hypercapnia. Respiratory
muscle capacity is a measure of inspiratory respiratory muscle strength and endurance.
Global respiratory muscle strength can be assessed by measuring the maximum inspiratory
mouth pressure or the sniff nasal inspiratory pressure. Diaphragm-specific function can be
assessed using the transdiaphragmatic pressure (Pdi) produced during these manoeuvres
(figure 3). Capacity is reduced by direct respiratory muscle weakness or indirectly by adverse
pulmonary mechanics, such as hyperinflation in COPD. If there is insufficient respiratory
muscle capacity, V′A decreases and hypercapnic failure will ensue. Finally, respiratory drive is
the process by which the respiratory centre in the medulla controls the rate and work of
breathing in response to pH and PaCO2. The spinal cord is the conduit of this response to the
muscles of respiration. Without adequate respiratory drive and passage of neural information
to the muscles of respiration, there will be no stimulus to respond to increased PaCO2,
resulting in hypercapnic failure. Acute acidosis has been demonstrated to be deleterious to
pulmonary function, leading to diminished diaphragm contractility [3–5], reducing
respiratory muscle capacity and thereby further exacerbating ventilatory failure. Table 1
displays conditions causing hypercapnic respiratory failure with the anatomical source of
failure and their impact on the load–capacity–drive model.

When discussing NMDs and OHS, this framework will be used to demonstrate how they
each lead to hypercapnic failure in both the chronic and acute settings.

Pdi
Pdimax Pdi
cmH2O
Pmo
cmH2O

Poes
cmH2O

Pgas
cmH2O tI

Flow
L·min–1

ttot
EMGpara
mV

EMGdi
mV

PImax PImax Tidal breathing

Figure 3. Invasive pulmonary mechanics. This figure is an example of invasive pulmonary mechanics
recorded in a healthy individual. Pressure recordings, followed by flow measurement and finally
electromyogram traces are displayed, initially during a maximal inspiratory pressure (PImax) manoeuvre, and
then during tidal breathing. Pdi: transdiaphragmatic pressure (the pressure the diaphragm produces during
tidal breathing); Pdimax: maximal pressure the diaphragm can generate, displayed here during a PImax
manoeuvre; Pmo: mouth pressure; Poes: oesophageal pressure; Pgas: gastric pressure; tI: inspiratory time
(the time the diaphragm is contracted); ttot: length of the total respiratory cycle; EMGpara: parasternal
electromyogram; EMGdi: diaphragmatic electromyogram.

89

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 1. Conditions causing hypercapnic respiratory failure

Anatomical region affected Condition Effect on load–capacity–drive

Central nervous system Brainstem lesion Reduced drive

Opiates/benzodiazepines Reduced drive
Cervical cord lesion Reduced drive
Peripheral nervous system Poliomyelitis Reduced capacity
Motor neuron disease Reduced capacity
Guillain–Barré syndrome Reduced capacity
Neuromuscular junction Myasthenia gravis Reduced capacity
Botulism Reduced capacity
Organophosphates Reduced capacity
Muscle Muscular dystrophies Reduced capacity
Chest wall Obesity hypoventilation syndrome Increased load
Kyphoscoliosis Increased load
Pulmonary fibrosis Increased load
Airway Cystic fibrosis Increased load

Conditions are categorised according to the anatomical region they affect, and the load–capacity–
drive model is used to illustrate how each condition leads to hypercapnic failure.

Neuromuscular disorders

Chronic NMDs

The term “neuromuscular disorder” encompasses a wide range of progressive neurological

diseases that can affect the respiratory system. While these conditions are rare, with a
prevalence of one to 10 per 100 000 population [6], they can develop significant respiratory
morbidity, which is often the cause of death [7, 8]. The likelihood of respiratory failure in
NMDs is dependent on the pattern of muscle involvement; conditions most commonly
associated with respiratory failure include motor neuron disease, spinal muscular atrophy,
myasthenia gravis and the muscular dystrophies. These disorders cause respiratory
dysfunction via respiratory pump failure, impaired cough function by affecting the
inspiratory, expiratory and glottic muscles, and upper-airway dysfunction by affecting glottic
muscles. This chapter focuses on their effect on ventilatory function; however, it is
important to have an appreciation of their effect on cough and upper-airway function to
understand the cause of acute deterioration.

NMDs cause hypercapnic respiratory failure by four routes: 1) respiratory muscle weakness;
2) altered respiratory mechanics; 3) abnormal central control of breathing; and
4) non-respiratory means [9]. Respiratory muscle weakness in NMDs is associated with
increased susceptibility to muscle fatigue. In order to counter this risk, patients adopt a rapid,
shallow breathing pattern, which reduces tidal volume by minimising inspiratory time (tI) and
Pdi. While this will reduce the risk of muscle fatigue, it is at the expense of hypercapnia [10].

NMDs tend to result in increased elastic recoil and therefore reduced respiratory
compliance. The rapid shallow breathing pattern adopted by patients with NMDs has been
demonstrated to reduce chest wall compliance [11]. Fibrosis of the rib cage muscles in
muscular dystrophies [12] will further reduce compliance and limit inspiratory capacity.
Similarly, spinal deformities found in many NMDs will also reduce compliance [13]. Poor

90

FB:Cardiologia Siglo XXI

 HYPERCAPNIC FAILURE IN NON-COPD | N.M. SHAH AND P.B. MURPHY

pharyngeal dilator muscle function, seen in many NMDs, will result in reduced
upper-airway calibre and so will increase upper-airway resistance in inspiration. This
produces a higher load on the diaphragm in inspiration and so increases the work of
breathing. Combined with the decreased upper-airway tone in sleep, this leads to the
development of sleep-disordered hypoventilation [14–16].

Sleep-disordered breathing is prevalent in NMDs and has been reported as having an incidence
of between 10.3% and 61.2%, depending on the definition [17]. Sleep-disordered breathing
leads to impaired central respiratory drive in NMDs [18, 19], which may be caused by loss of
sensitivity to PaCO2 [7]. This reduced drive leads to a gradual build-up of carbon dioxide,
resulting in hypercapnic respiratory failure. As many NMDs affect the central nervous system,
they may have a direct effect on the central respiratory centre, independent of sleep-disordered
breathing. It is difficult to elucidate this, as usual measures of central drive, such as airway
occlusion pressure (P0.1), are affected not only by central drive but also by respiratory muscle
weakness and deranged respiratory mechanics, all of which are seen in NMDs [20].

Many NMDs are associated with cardiomyopathies [21], leading to left ventricular failure
[22]. Resultant pulmonary venous congestion reduces pulmonary compliance and therefore
increases the work of breathing. Recent evidence suggests that heart failure impairs
pulmonary muscle blood flow [23], suggesting that pulmonary muscle blood flow will also be
impaired in patients with neuromuscular cardiomyopathy, exacerbating respiratory muscle
dysfunction. Some patients with NMDs are overweight due to poor dietary habits, sedentary
status and steroid use [24]. Increased abdominal adiposity places a significantly increased
load on the respiratory system, and favours the development of hypoventilation in sleep. The
implications of obesity and hypoventilation on the respiratory system are discussed in more
detail in a later section of this chapter. Patients with NMDs may also be poorly nourished
due to disorders of the gastrointestinal tract and musculature [25]. Poor nutrition is
associated with diaphragmatic atrophy [26], and this may independently contribute to poor
respiratory pump function, with increased risk of adverse respiratory morbidity [27].

Patients with NMDs frequently present with acute respiratory deterioration. This is usually
due to a combination of aspiration secondary to oropharyngeal muscle weakness, cough
weakness causing impaired secretion clearance and respiratory muscle fatigue leading to
hypoventilation. Oropharyngeal muscle weakness caused by the direct effect of the NMD
on the musculature [28] weakens the ability to swallow and to protect the airway,
increasing the risk of aspiration and recurrent infections.

Individuals need an effective cough to clear secretions. The production of an effective cough
involves several respiratory muscles. Upon stimulation of the cough reflex, the diaphragm and
external intercostal muscles contract to create a negative pressure around the lung. This allows
air to enter the lungs to equalise the pressure, which stimulates closure of the glottis. The
abdominal muscles then contract to accentuate the action of the relaxing diaphragm, while
other expiratory muscles contract. This action combines to increase the pressure inside the
lungs, which stimulates the glottis to relax, allowing air to be projected through the upper
respiratory tract and expelled into the atmosphere. Therefore, patients with weakening of any of
these muscles due to neuromuscular pathology will have reduced cough strength, causing
difficulties with clearing respiratory secretions adequately. This impaired secretion clearance can
lead to respiratory infections, and acutely can cause small-airway occlusion with subsequent
ventilation–perfusion mismatch adversely affecting pulmonary mechanics. Worsening of the
ventilation–perfusion mismatch will eventually lead to hypercapnic respiratory failure [29].

91

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

As well as presenting with infections, patients with NMDs can present acutely with
hypercapnic failure. This is usually due to respiratory muscle fatigue. As the diaphragm
performs the majority of inspiratory work at rest [30], diaphragmatic fatigue also has the
most significant role in ventilatory failure in NMD patients. Diaphragmatic fatigue occurs
within 60 min if: 1) the ratio of the time the diaphragm must contract (tI) to the total
respiratory cycle (ttot) is 0.5, or 2) the pressure the diaphragm needs to produce for tidal
breathing (Pdi) is >40% of the maximum pressure it can generate (Pdimax) [31]. Figure 3
shows a representation of invasive pulmonary mechanics to illustrate these points.
Decreased respiratory compliance increases tidal Pdi, with Pdimax being reduced by muscle
weakness, both favouring the development of respiratory muscle fatigue. An increase in
respiratory rate due to pyrexia, or compensation against hypercapnia will increase the tI/ttot
ratio, again predisposing to fatigue [32]. The normal response to hypercapnia is to increase
V′E; patients with NMDs also increase V′E, but they do so by increasing the respiratory
rate rather than the tidal volume, unlike normal controls [33]. In addition to muscle
fatigue, central respiratory drive has been demonstrated to be reduced in acute hypercapnic
failure in NMD patients [34, 35]. Without an adequate compensatory response to the
hypercapnia, these patients will develop worsening respiratory failure, leading to acute
presentation.

It is outside the scope of this chapter to discuss the respiratory management of chronic
NMDs in detail; however, some important management concepts will be highlighted. In
chronic NMDs, the slow progressive reduction in respiratory muscle function will cause
nocturnal hypoventilation and recurrent infections. The advent of sleep-disordered
breathing predates the onset of diurnal hypercapnia [36], and its onset can be used to
consider initiation of long-term NIV [37], an important step in chronic management [38,
39], which is discussed in detail in a later chapter in this Monograph [40]. Other key
management tools include nutritional assistance to maintain healthy respiratory muscle
and airway clearance techniques, such as manually assisted coughing or mechanical
insufflation–exsufflation, to reduce the risk of infections.

Acute NMDs

While motor neuron disease and the muscular dystrophies tend to present with chronic
respiratory failure and are invariably progressive with superimposed acute deteriorations,
other neuromuscular diseases can present de novo with acute respiratory failure (ARF). Those
most commonly encountered include Guillain–Barré syndrome and myasthenia gravis.

Guillain–Barré syndrome is an inflammatory polyradiculoneuropathy that causes acutely

progressive diffuse weakness and areflexia, by damaging neurons in the peripheral nervous
system. It is most commonly precipitated by a respiratory or gastrointestinal illness, which
stimulates the production of antibodies that cross-react with specific gangliosides. There are
various clinical entities, and the specific target of the antibodies on the neuron will lead to
the various entities [41]. Acute inflammatory demyelinating polyneuropathy presents with
both sensory and motor weakness, often with cranial nerve involvement, most commonly
in Europe and North America. Acute motor axonal neuropathy presents with isolated
muscle weakness, more commonly in Asia and in Central and South America. Acute motor
and sensory axonal neuropathy presents with severe muscle weakness and sensory loss.
Miller Fisher syndrome presents with ataxia, eye muscle weakness and areflexia but no limb
weakness [42–44].

92

FB:Cardiologia Siglo XXI

 HYPERCAPNIC FAILURE IN NON-COPD | N.M. SHAH AND P.B. MURPHY

Up to 30% of Guillain–Barré syndrome patients will develop respiratory failure [45]. This is
primarily due to diaphragmatic failure. Loss of motor nerve output (neural respiratory
drive) to the diaphragm and other respiratory muscles causes respiratory pump failure;
ventilatory failure ensues, resulting in hypercapnia. Furthermore, the loss of motor nerve
stimulus to the respiratory muscles can cause a decline in respiratory muscle capacity,
further compromising respiratory function. Significant morbidity and mortality in
Guillain–Barré syndrome is associated with respiratory failure and invasive mechanical
ventilation [46]. It is important to identify at-risk patients to ensure appropriate monitoring
and to prevent delayed intubation and ventilation. Patients with rapid-onset presentation
(<7 days), the inability to lift their head from the bed, an ineffective cough or evidence of
significant respiratory muscle weakness (vital capacity <60% predicted) are more likely to
require ventilatory support and should be closely monitored within critical care [47].
Invasive mechanical ventilation may be required to support patients while
disease-modifying treatments (e.g. plasma exchange, intravenous immunoglobulin) are
given and recovery occurs [48, 49]. Once intubated, significant numbers of patients will
require prolonged mechanical ventilation and tracheostomy formation, and frequently need
input from specialist weaning centres [50, 51].

Myasthenia gravis is an autoimmune condition causing dysfunction of the neuromuscular

junction by generating antibodies against the post-synaptic terminal. Up to 20% of
myasthenia patients will suffer from a myasthenia crisis, usually within 12–18 months of
diagnosis [52]. Patients suffer from respiratory failure due to muscle weakness, causing
respiratory pump failure. Crises tend to involve all respiratory muscles [53], affecting the
intercostals first and then sequentially the accessory muscles of respiration and then the
diaphragm [54]. Respiratory muscle weakness decreases the respiratory capacity, making
adequate ventilation difficult. Crises can also affect upper-airway and bulbar muscles, causing
upper-airway collapse [55]. Upper-airway collapse will increase the work of breathing and so
increase the load on the system, thereby causing hypercapnic failure. Signs of impending
ventilatory failure include the inability to raise the head and paradoxical breathing [55].
Traditional management of a myasthenic crisis involved invasive mechanical ventilation,
which often resulted in prolonged ventilation, weaning and tracheostomy formation [56, 57].
Early NIV may have a role in reducing the need for invasive mechanical ventilation and
prolonged weaning [58, 59], although no prospective trials have been performed to compare
the efficacy of NIV with invasive mechanical ventilation.

Obesity hypoventilation syndrome

OHS is defined as the triad of obesity, daytime hypercapnia and sleep-disordered breathing
in the absence of another cause of respiratory failure. The prevalence is unclear but has been
reported as 0.15–0.6% in the general population [60]. Among patients referred to a sleep
clinic, the prevalence of OHS was considerably higher in women (16%) than in men (5%),
and higher in post-menopausal women (21%) than in pre-menopausal women (5%) [61].
OHS is a distinct condition from obstructive sleep apnoea (OSA), although they often
coexist, and is associated with higher morbidity [62] and healthcare costs [63]. The
prevalence of OSA is between 2% and 7% of the population [64, 65]. In patients with OSA,
the prevalence of OHS is reported as 10–38% [66–69], and, conversely, 90% of OHS patients
will have OSA [70]. The narrow definition of OHS may be underestimating the prevalence
of OHS due to the unreliable nature of daytime hypercapnia as a marker of nocturnal
hypoventilation [71]. There are now calls to include a raised serum bicarbonate level as an

93

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

alternative to hypercapnia, as a measure of nocturnal hypoventilation, in the diagnostic

definition of OHS, which may increase its overall prevalence [72, 73]. OHS is already the
most common indication for domiciliary NIV in some countries [74], and given that, by
2025, one in five adults is expected to be obese [75], this suggests that the prevalence of
OHS will substantially increase in the coming years. It is thus important to understand the
pathophysiology of OHS and to improve ventilation in these patients.

Obesity increases the work of breathing by causing an increase in the resistance of the airway
and a decrease in pulmonary compliance. Obese individuals tend to breathe at lower volumes
[76]; for every 1 unit increase in BMI, functional residual capacity and expiratory reserve
volume fall by 1% [77]. The lower volumes are probably caused by increased load,
demonstrated by significantly increased oesophageal and gastric pressure when compared with
normal-weight individuals [78]. This results in limited expiratory flow and gas trapping,
generating intrinsic PEEP [79], which increases airway resistance. Pulmonary compliance will
fall, due to mass loading on the chest wall [80], breathing at lower lung volumes [81] and
reduced lung compliance due to increased pulmonary blood volume [82]. The increased work
of breathing requires a higher respiratory drive and increased respiratory muscle recruitment.
In OHS patients, the respiratory system is unable to match the demand of the work of
breathing. This occurs particularly during sleep due to the exaggeration of the normal
physiological changes that occur during sleep stage changes [83]. In the supine position, the
diaphragm is projected towards the head by central adiposity, increasing the mass loading
effect on compliance [76]. In addition, accessory muscles of breathing are atonic in
rapid-eye-movement sleep [84, 85], so cannot be used to help the system adapt to the
increased requirement. In addition, there is increased oxygen consumption in OHS, which
contributes to respiratory muscle fatigue [86].

Obesity also affects respiratory drive, with increased drive to accommodate the increased load
on the respiratory system [76]. Obese patients have a higher oxygen consumption and high
V′CO2 than non-obese individuals, due to the metabolic activity of the excess fat and the
increased work of the supportive tissues [87, 88]. These patients therefore need an increase in
V′E to match the increased ventilatory demand. In OHS patients, there is a failure to increase
the central respiratory drive to compensate for the added load, demonstrated by an inadequate
increase in tidal volume [69, 89] and the ability to voluntarily hyperventilate to eucapnia [90].

OHS patients can be categorised into two groups: those with associated OSA (90%) and
those with sleep hypoventilation only (10%) [73, 91, 92]. OSA causes an increase in PaCO2
through a combination of reduced clearance by cessation of ventilation, and increased V′CO2
by continued metabolic production and the increased work of breathing against an occluded
airway. In patients without OHS, this increase in PaCO2 is compensated for by an increase in
V′A post-apnoea, which aids the clearance of carbon dioxide [93]. This requires an intact
ventilatory control system and normal respiratory mechanics [94]. In patients with OHS, the
time period between apnoeas tends to be shorter than in OSA patients without OHS [91],
which results in inadequate clearance of carbon dioxide and therefore accumulation. This is
exacerbated by the altered pulmonary mechanics already described. This hypercapnia during
sleep leads to a renal response to increase serum bicarbonate to buffer the carbon dioxide.
As this is a slower compensatory mechanism, the build-up of bicarbonate stimulated by
nocturnal hypoventilation therefore persists during wakefulness. This metabolic alkalosis
blunts the ventilatory response to carbon dioxide in subsequent sleep [95, 96], further
exacerbating hypoventilation and worsening carbon dioxide clearance. This leads initially to
nocturnal but eventually to daytime hypercapnia [71, 97].

94

FB:Cardiologia Siglo XXI

 HYPERCAPNIC FAILURE IN NON-COPD | N.M. SHAH AND P.B. MURPHY

An important complication of OHS is pulmonary hypertension, with a reported prevalence

of 43% [98]. Up to 50% of OHS patients present with symptoms of right heart failure,
whereas very few patients with OSA only present similarly [99]. In patients presenting with
acutely decompensated OHS, pulmonary hypertension contributes significantly to the
severity of hypoxia, with the majority of such patients requiring supplementary oxygen
[100]. Failure to reverse this supplemental oxygen requirement is a negative prognostic
factor, whereas successful correction of nocturnal hypoventilation with NIV results in
improved pulmonary hypertension and fewer patients requiring ongoing oxygen
supplementation [100, 101].

All of these changes in the respiratory system leave the OHS patient more vulnerable to
acute deterioration when the system undergoes further insult, such as with infection or
worsening cardiac function. This increases the risk of ARF. The most common cause of
ARF in OHS is idiopathic, followed by pneumonia, acute cardiac failure and sepsis [102,
103]. It is always important to seek and treat any underlying cause of decompensation
while providing respiratory support in acute obesity-related respiratory failure.

A detailed discussion about the management of OHS is outside the scope of this chapter;
however it is important to highlight some key management strategies [104]. While the
management of chronic obesity-related respiratory failure remains debated, with evidence
supporting both CPAP and NIV, the cornerstone of management during acute
decompensation is unequivocally NIV [105]. Treatment of OHS with NIV has been proved
to be physiologically effective in improving sleep architecture and sleep-disordered
breathing [92, 106], reversing respiratory failure [107, 108] and improving pulmonary
function [101, 107, 109], with more limited data suggesting clinical efficacy to reduce
healthcare utilisation [63, 108] and mortality [101, 110]. The successful management of
patients with chronic respiratory failure plays an important role during acute episodes. A
significant number of patients presenting acutely have no identifiable cause for
deterioration [103]; these patients are likely to have suboptimal control of their
sleep-disordered breathing. Patients presenting with acute de novo obesity-related
respiratory failure have a lower perceived symptom burden than those who present via
sleep services, and therefore a high index of suspicion should be maintained and PaCO2
measured in high-risk patients [111]. Furthermore, if patients poorly tolerate NIV at home,
they are more likely to fail NIV acutely [103, 112], so it is important to identify these
patients and make early decisions on escalation of therapy and then manage them in an
appropriate clinical setting with access to rapid endotracheal intubation if needed. The
effect of pharmacotherapy in OHS is unclear. Limited studies have been conducted on
medroxyprogesterone and acetazolamide, and these should be preserved for uses in
specialist centres for treatment-resistant cases [113].

Other causes of hypoventilation

Cystic fibrosis

Although cystic fibrosis is usually associated with type I respiratory failure, in its advanced
stages, hypercapnia can develop and is associated with poor outcomes [114, 115].
Management tends to be with invasive mechanical ventilation [115]; however, some
evidence reports the value of NIV in these patients [116, 117]. There are increasing reports
of its use as a bridge to support the patient until transplantation [117–119]. As with

95

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

COPD, respiratory failure is the result of a significant load on the respiratory system,
which, even with a compensatory elevated drive, cannot maintain eucapnia.

Chest wall disorders

Isolated chest wall disorders, such as kyphoscoliosis, ankylosing spondylitis and pectus
excavatum, can all cause hypercapnia due to hypoventilation. They cause a decrease in
respiratory system compliance by increasing stiffness of the system [120], causing a
decrease in lung volumes and worsening pulmonary mechanics by moving the respiratory
system to an inefficient portion of the pressure–volume curve [121]. This leads to alveolar
hypoventilation and hypercapnia. The increased work of breathing that this causes will
increase oxygen consumption in the inspiratory muscles, causing muscle fatigue and
further exacerbating the respiratory pump failure.

Conclusion

A number of pathological entities produce hypercapnic respiratory failure. These disorders

produce ventilatory failure via disruption of the respiratory muscle load–capacity–drive
relationship. While COPD is the commonest cause encountered in clinical practice, a
number of other important conditions will frequently present to critical care or pulmonary
physicians. The two largest groups are obesity-related respiratory failure and
neuromuscular-related respiratory failure. Both of these clinical groups can complicate
respiratory failure acutely or present as acute decompensation of chronic respiratory failure.
In both circumstances, it is important to evaluate the patient comprehensively for an
underlying precipitant, for example pneumonia or heart failure, and treat this
appropriately. An understanding of the mechanism of respiratory failure allows appropriate
ventilatory support to be instigated. In the majority of cases, this will be via NIV, but a
cohort of patients will require transition to invasive mechanical ventilation, and appropriate
physiological monitoring of patients and the use of clinical predictors of failure of NIV are
important in the acute management.

References
1. Butler AP, Smith LJE, Mackay AJ. Acute exacerbations of COPD. In: Heunks L, Demoule A, Windisch W, eds.
Pulmonary Emergencies (ERS Monograph). Sheffield, European Respiratory Society, 2016; pp. 48–65.
2. Moxham J, Jolley C. Breathlessness, fatigue and the respiratory muscles. Clin Med 2009; 9: 448–452.
3. Juan G, Calverley P, Talamo C, et al. Effect of carbon dioxide on diaphragmatic function in human beings.
N Engl J Med 1984; 310: 874–879.
4. Rafferty GF, Harris ML, Polkey MI, et al. Effect of hypercapnia on maximal voluntary ventilation and diaphragm
fatigue in normal humans. Am J Respir Crit Care Med 1999; 160: 1567–1571.
5. Michelet P, Carreira S, Demoule A, et al. Effects of acute respiratory and metabolic acidosis on diaphragm muscle
obtained from rats. Anesthesiology 2015; 122: 876–883.
6. Deenen JCW, Horlingsa CGC, Verschuurenb JJGM, et al. The epidemiology of neuromuscular disorders:
a comprehensive overview of the literature. J Neuromusc Dis 2015; 2: 73–85.
7. Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J 2002; 19: 1194–1201.
8. Seddon PC, Khan Y. Respiratory problems in children with neurological impairment. Arch Dis Child 2003; 88:
75–78.
9. Ambrosino N, Carpenè N, Gherardi M. Chronic respiratory care for neuromuscular diseases in adults. Eur Respir J
2009; 34: 444–451.
10. Misuri G, Lanini B, Gigliotti F, et al. Mechanism of CO2 retention in patients with neuromuscular disease.
Chest 2000; 117: 447–453.

96

FB:Cardiologia Siglo XXI

 HYPERCAPNIC FAILURE IN NON-COPD | N.M. SHAH AND P.B. MURPHY

11. Vitacca M, Clini E, Facchetti D, et al. Breathing pattern and respiratory mechanics in patients with amyotrophic
lateral sclerosis. Eur Respir J 1997; 10: 1614–1621.
12. Laghi F, Tobin TB. Disorders of the respiratory muscles. Am J Respir Crit Care Med 2003; 168: 10–48.
13. Tsiligiannis T, Grivas T. Pulmonary function in children with idiopathic scoliosis. Scoliosis 2012; 7: 7.
14. Culebras A. Sleep and neuromuscular disorders. Neural Clin 2005; 23: 1209–1223.
15. Boentert M, Karabul N, Wenninger S, et al. Sleep-related symptoms and sleep-disordered breathing in adult
Pompe disease. Eur J Neurol 2015; 22: 369–376.
16. Aboussouan LS. Sleep-disordered breathing in neuromuscular disease. Am J Respir Crit Care Med 2015; 191: 979–989.
17. Ogna A, Quera Salva MA, Prigent H, et al. Nocturnal hypoventilation in neuromuscular disease: prevalence
according to different definitions issued from the literature. Sleep Breath 2016; 20: 575–581.
18. Corfield DR, Roberts CA, Griffiths MJ, et al. Sleep-related changes in the human ‘neuromuscular’ ventilatory
response to hypoxia. Respir Physiol 1999; 117: 109–120.
19. De Vito EL, Monteiro SG, Aruj PK. Blunted hypercapnic respiratory drive response in subjects with late-onset
Pompe disease. Respir Care 2016; 61: 930–935.
20. Polkey MI, Kyroussis D, Hamnegard CH, et al. Diaphragm strength in chronic obstructive pulmonary disease.
Am J Respir Crit Care Med 1996; 154: 1310–1317.
21. Dellefave LM, McNally EM. Cardiomyopathy in neuromuscular disorders. Prog Pediatr Card 2007; 24: 35–46.
22. Sachdev B, Elliott PM, McKenna WJ. Cardiovascular complications of neuromuscular disorders. Curr Treat
Options Cardiovasc Med 2002; 4: 171–179.
23. Oliveira MF, Arbex F, Alencar MC, et al. Heart failure impairs muscle blood flow and endurance exercise
tolerance in COPD. COPD 2016: 13: 407–415.
24. Aitkens S, Kilmer DD, Wright NC, et al. Metabolic syndrome in neuromuscular disease. Arch Phys Med Rehabil
2005; 86: 1030–1036.
25. Pessolano FA, Súarez AA, Monteiro SG, et al. Nutritional assessment of patients with neuromuscular diseases.
Am J Phys Med Rehabil 2003; 82: 182–185.
26. Doorduin J, van Hees HWH, van der Hoeven JG, et al. Monitoring of the respiratory muscles in the critically ill.
Am J Respir Crit Care Med 2013; 187: 20–27.
27. Reddy A, Weekes CE, Ahmed H, et al. Nutritional status and admission risk in Duchenne muscular dystrophy
(DMD). Eur Respir J 2013; 42: Suppl. 57, P422.
28. Pilz W, Baijens LW, Passos VL, et al. Swallowing assessment in myotonic dystrophy type 1 using fiberoptic
endoscopic evaluation of swallowing (FEES). Neuromuscul Disord 2014; 24: 1054–1062.
29. Polverino M, Polverino F, Fasolino M, et al. Anatomy and neuro-pathophysiology of the cough reflex arc.
Multidiscip Respir Med 2012; 7: 5.
30. Hutchinson D, Whyte K. Neuromuscular disease and respiratory failure. Pract Neurol 2008; 8: 229–237.
31. Roussos CS, Macklem PT. Diaphragmatic fatigue in man. J Appl Physiol Respir Environ Exerc Physiol 1977; 43:
189–197.
32. Bodkin CL Pascuzzi RM. Acute respiratory failure in neuromuscular disorders. In: Roos KL ed. Emergency
Neurology. New York, Springer Science+Business Media; pp. 295–297.
33. Panitch HB. The pathophysiology of respiratory impairment in paediatric neuromuscular diseases. Pediatrics
2009; 123: Suppl. 4, S215–S218.
34. Rialp G, Raurich JM, Llompart-Pou JA, et al. Central respiratory drive in patients with neuromuscular diseases.
Respir Care 2013; 58: 450–457.
35. Poussel M, Thil C, Kaminsky P, et al. Lack of correlation between the ventilatory response to CO2 and lung
function impairment in myotonic dystrophy patients: evidence for a dysregulation at central level. Neuromuscul
Disord 2015; 25: 403–408.
36. Panitch HB. Diurnal hypercapnia in patients with neuromuscular disease. Paediatr Respir Rev 2010; 11: 3–8.
37. Ward S, Chatwin M, Heather S, et al. Randomised controlled trial of non-invasive ventilation (NIV) for nocturnal
hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax 2005; 60:
1019–1024.
38. Boentert M, Brenscheidt I, Glatz C, et al. Effects of non-invasive ventilation on objective sleep and nocturnal
respiration in patients with amyotrophic lateral sclerosis. J Neurol 2015; 262: 2073–2082.
39. Vrijsen B, Buyse B, Belge C, et al. Noninvasive ventilation improves sleep in amyotrophic lateral sclerosis:
a prospective polysomnographic study. J Clin Sleep Med 2015; 11: 559–566.
40. Vaschetto R, Longhini F, Navalesi P. Acute noninvasive ventilation. In: Heunks L, Demoule A, Windisch W, eds.
Pulmonary Emergencies (ERS Monograph). Sheffield, European Respiratory Society, 2016; pp. 186–199.
41. van den Berg B, Walgaard C, Drenthen J, et al. Guillain–Barré syndrome: pathogenesis, diagnosis, treatment and
prognosis. Nat Rev Neurol 2014; 10: 469–482.
42. Vucic S, Kiernan MC, Cornblath DR. Guillain–Barré syndrome: an update. J Clin Neurosci 2009; 16: 733–741.
43. Fujimura H. The Guillain–Barré syndrome. Handb Clin Neurol 2013; 115: 383–402.
44. Willison HJ, Jacobs BC, van Doorn PA. Guillain–Barré syndrome. Lancet 2016; 388: 717–727.

97

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

45. Orlikowski D, Prigent H, Sharshar T, et al. Respiratory dysfunction in Guillain–Barré Syndrome. Neurocrit Care
2004; 1: 415–422.
46. Fletcher DD, Lawn ND, Wolter TD, et al. Long-term outcome in patients with Guillain–Barré syndrome
requiring mechanical ventilation. Neurology 2000; 54: 2311–2315.
47. Sharshar T, Chevret S, Bourdain F, et al. Early predictors of mechanical ventilation in Guillain–Barré syndrome.
Crit Care Med 2003; 31: 278–283.
48. Raphaël JC, Chevret S, Hughes RA, et al. Plasma exchange for Guillain–Barré syndrome. Cochrane Database Syst
Rev 2012; 7: CD001798.
49. Hughes RA, Swan AV, van Doorn PA. Intravenous immunoglobulin for Guillain–Barré syndrome. Cochrane
Database Syst Rev 2014; 9: CD002063.
50. Ng KK, Howard RS, Fish DR, et al. Management and outcome of severe Guillain–Barré syndrome. QJM 1995; 88:
243–250.
51. Mifsud Bonnici D, Sanctuary T, Warren A, et al. Prospective observational cohort study of patients with weaning
failure admitted to a specialist weaning, rehabilitation and home mechanical ventilation centre. BMJ Open 2016;
6: e010025.
52. Alshekhlee A, Miles JD, Katirji B, et al. Incidence and mortality rates of myasthenia gravis and myasthenic crisis
in US hospitals. Neurology 2009; 72: 1548–1554.
53. Juel VC. Myasthenia gravis: management of myasthenic crisis and perioperative care. Semin Neurol 2004; 24: 75–81.
54. Putman MT, Wise RA. Myasthenia gravis and upper airway obstruction. Chest 1996; 109: 400–404.
55. Chaudhuri A, Behan PO. Myasthenic crisis. QJM 2009; 102: 97–107.
56. Thomas CE, Mayer SA, Gungor Y, et al. Myasthenic crisis: clinical features, mortality, complications, and risk
factors for prolonged intubation. Neurology 1997; 48: 1253–1260.
57. O’Riordan JI, Miller DH, Mottershead JP, et al. The management and outcome of patients with myasthenia gravis
treated acutely in a neurological intensive care unit. Eur J Neurol 1998; 5: 137–142.
58. Seneviratne J, Mandrekar J, Wijdicks EF, et al. Noninvasive ventilation in myasthenic crisis. Arch Neurol 2008; 65:
54–58.
59. Wu JY, Kuo PH, Fan PC, et al. The role of non-invasive ventilation and factors predicting extubation outcome in
myasthenic crisis. Neurocrit Care 2009; 10: 35–42.
60. Balachandran JS, Masa JF, Mokhleso B. Obesity hypoventilation syndrome epidemiology and diagnosis. Sleep Med
Clin 2014; 9: 341–347.
61. Bahammam AS, Pandi-Perumal SR, Piper A, et al. Gender differences in patients with obesity hypoventilation
syndrome. J Sleep Res 2016; 25: 445–453.
62. Castro-Añón O, Pérez de Llano LA, et al. Obesity-hypoventilation syndrome: increased risk of death over sleep
apnea syndrome. PLoS One 2015; 10: e0117808.
63. Berg G, Delaive K, Manfreda J, et al. The use of health-care resources in obesity–hypoventilation syndrome.
Chest 2001; 1202: 377–383.
64. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults.
N Engl J Med 1993; 328: 1230–1235.
65. Punjabi NM. The epidemiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008; 5: 136–143.
66. Verin E, Tardif C, Pasquis P. Prevalence of daytime hypercapnia or hypoxia in patients with OSAS and normal
lung function. Respir Med 2001; 95: 693–696.
67. Akashiba T, Kawahara S, Kosaka N, et al. Determinants of chronic hypercapnia in Japanese men with obstructive
sleep apnea syndrome. Chest 2002; 121: 415–421.
68. Nowbar S, Burkart KM, Gonzales R, et al. Obesity-associated hypoventilation in hospitalized patients: prevalence,
effects, and outcome. Am J Med 2004; 116: 1–7.
69. Macavei VM, Spurling KJ, Loft J, et al. Diagnostic predictors of obesity-hypoventilation syndrome in patients
suspected of having sleep disordered breathing. J Clin Sleep Med 2013; 9: 879–884.
70. Mokhlesi B. Obesity hypoventilation syndrome: a state-of-the-art review. Respir Care 2010; 55: 1347–1362.
71. Norman RG, Goldring RM, Clain JM, et al. Transition from acute to chronic hypercapnia in patients with
periodic breathing: predictions from a computer model. J Appl Physiol 2006; 100: 1733–1741.
72. Hart N, Mandal S, Manuel A, et al. Obesity hypoventilation syndrome: does the current definition need
revisiting? Thorax 2014; 69: 83–84.
73. Murphy PB, Janssens JP. NIV for OHS without severe OSAS: is it worth it? Thorax 2016; 71: 877–878.
74. Mandal S, Suh E, Davies M, et al. Provision of home mechanical ventilation and sleep services for England
survey. Thorax 2013; 68: 880–881.
75. NCD Risk Factor Collaboration (NCD-RisC). Trends in adult body-mass index in 200 countries from 1975 to
2014: a pooled analysis of 1698 population-based measurement studies with 19.2 million participants.
Lancet 2016; 387: 1377–1396.
76. Steier J, Jolley CJ, Seymour J, et al. Neural respiratory drive in obesity. Thorax 2009; 64: 719–725.
77. Jones RL, Nzekwu MM. The effects of body mass index on lung volumes. Chest 2006; 130: 827–833.

98

FB:Cardiologia Siglo XXI

 HYPERCAPNIC FAILURE IN NON-COPD | N.M. SHAH AND P.B. MURPHY

78. Steier J, Lunt A, Hart N, et al. Observational study of the effect of obesity on lung volumes. Thorax 2014; 69:
752–759.
79. Pankow W, Podszus T, Gutheil T, et al. Expiratory flow limitation and intrinsic positive end-expiratory pressure
in obesity. J Appl Physiol 1998; 85: 1236–1243.
80. O’Donnell DE, O’Donnell CDJ, Webb KA, et al. Respiratory consequences of mild-to-moderate obesity: impact
on exercise performance in health and in chronic obstructive pulmonary disease. Pulm Med 2012; 2012: 818925.
81. Behazin N, Jones SB, Cohen RI, et al. Respiratory restriction and elevated pleural and esophageal pressures in
morbid obesity. J Appl Physiol 2010; 108: 212–218.
82. Oppenheimer BW, Berger KI, Ali S, et al. Pulmonary vascular congestion: a mechanism for distal lung unit
dysfunction in obesity. PLoS One 2016; 11: e0152769.
83. Becker HF, Piper AJ, Flynn WE, et al. Breathing during sleep in patients with nocturnal desaturation. Am J Respir
Crit Care Med 1999; 159: 112–118.
84. Tabachnik E, Muller NL, Bryan AC, et al. Changes in ventilation and chest wall mechanics during sleep in
normal adolescents. J Appl Physiol Respir Environ Exerc Physiol 1981; 51: 557–564.
85. Eckert DJ, Malhotra A, Yo YL, et al. The influence of obstructive sleep apnea and gender on genioglossus activity
during rapid eye movement sleep. Chest 2009; 135: 957–964.
86. Kress JP, Pohlman AS, Alverdy J, et al. The impact of morbid obesity on oxygen cost of breathing (VO2RESP) at
rest. Am J Respir Crit Care Med 1999; 160: 883–886.
87. Adams JP, Murphy PG. Obesity in anaesthesia and intensive care. Br J Anaesth 2000; 85: 91–108.
88. Pierce AM, Brown LK. Obesity hypoventilation syndrome: current theories of pathogenesis. Curr Opin Pulm Med
2015; 21: 557–562.
89. Sampson MG, Grassino AE. Load compensation in obese patients during quiet tidal breathing. J Appl Physiol
Respir Environ Exerc Physiol 1983; 55: 1269–1276.
90. Leech J, Onal E, Aronson R, et al. Voluntary hyperventilation in obesity hypoventilation. Chest 1991; 100: 1334–1338.
91. Egea-Santaolalla C, Javaheri S. Obesity hypoventilation syndrome. Curr Sleep Medicine Rep 2016; 2: 12–19.
92. Masa JF, Corral J, Caballero C, et al. Non-invasive ventilation in obesity hypoventilation syndrome without severe
obstructive sleep apnoea. Thorax 2016; 71: 899–906.
93. Javaheri S, Colangelo G, Lacey W, et al. Chronic hypercapnia in obstructive sleep apnea–hypopnea syndrome.
Sleep 1994; 17: 416–423.
94. Fogel RB, Malhotra A, White DP. Sleep. 2: pathophysiology of obstructive sleep apnoea/hypopnoea syndrome.
Thorax 2004; 59: 159–163.
95. Javaheri S, Shore NS, Rose B, et al. Compensatory hypoventilation in metabolic alkalosis. Chest 1982; 81: 296–301.
96. Edwards BA, Sands SA, Eckert DJ, et al. Acetazolamide improves loop gain but not the other physiological traits
causing obstructive sleep apnoea. J Physiol 2012; 590: 1199–1211.
97. Berger KI, Goldring RM, Rapoport DM. Obesity hypoventilation syndrome. Semin Respir Crit Care Med 2009; 30:
253–261.
98. Kauppert CA, Dvorak I, Kollert F, et al. Pulmonary hypertension in obesity–hypoventilation syndrome.
Respir Med 2013; 107: 2061–2070.
99. Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest 2007; 132: 1322–1336.
100. Held M, Walthelm J, Baron S, et al. Functional impact of pulmonary hypertension due to hypoventilation and
changes under noninvasive ventilation. Eur Respir J 2014; 43: 156–165.
101. Budweiser S, Riedl SG, Jörres RA, et al. Mortality and prognostic factors in patients with obesity–hypoventilation
syndrome undergoing noninvasive ventilation. J Intern Med 2007; 261: 375–383.
102. BaHammam A. Acute ventilatory failure complicating obesity hypoventilation: update on a ‘critical care
syndrome’. Curr Opin Pulm Med 2010; 16: 543–551.
103. Lemyze M, Taufour P, Duhamel A, et al. Determinants of noninvasive ventilation success or failure in morbidly
obese patients in acute respiratory failure. PLoS One 2014; 9: e97563.
104. Murphy PB, Hart N. Chronic NIV in OHS. In: Simonds AK (ed.) ERS Practical Handbook of Noninvasive
Ventilation. Sheffield, European Respiratory Society, 2015; pp. 197–203.
105. Carrillo A, Ferrer M, Gonzalez-Diaz G, et al. Noninvasive ventilation in acute hypercapnic respiratory failure
caused by obesity hypoventilation syndrome and chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 2012; 186: 1279–1285.
106. Borel JC, Tamisier R, Gonzalez-Bermejo J, et al. Noninvasive ventilation in mild obesity hypoventilation
syndrome: a randomized controlled trial. Chest 2012; 141: 692–702.
107. Masa JF, Corral J, Alonso ML, et al. Efficacy of different treatment alternatives for obesity hypoventilation
syndrome. Pickwick Study. Am J Respir Crit Care Med 2015; 192: 86–95.
108. Masa JF, Corral J, Romero A, et al. Protective cardiovascular effect of sleep apnea severity in obesity
hypoventilation syndrome. Chest 2016; 150: 68–79.
109. Heinemann F, Budweiser S, Dobroschke J, et al. Non-invasive positive pressure ventilation improves lung volumes
in the obesity hypoventilation syndrome. Respir Med 2007; 101: 1229–1235.

99

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

110. Priou P, Hamel JF, Person C, et al. Long-term outcome of noninvasive positive pressure ventilation for obesity
hypoventilation syndrome. Chest 2010; 138: 84–90.
111. Murphy PB, Davidson C, Hind MD, et al. Volume targeted versus pressure support non-invasive ventilation in
patients with super obesity and chronic respiratory failure: a randomised controlled trial. Thorax 2012; 67: 727–734.
112. Duarte AG, Justino E, Bigler T, et al. Outcomes of morbidly obese patients requiring mechanical ventilation for
acute respiratory failure. Crit Care Med 2007; 35: 732–737.
113. Chau EH, Lam D, Wong J, et al. Obesity hypoventilation syndrome: a review of epidemiology, pathophysiology,
and perioperative considerations. Anesthesiology 2012; 117: 188–205.
114. Slieker MG, van Gestel JPJ, Heijermans HGM, et al. Outcome of assisted ventilation for acute respiratory failure
in cystic fibrosis. Intensive Care Med 2006; 32: 754–758.
115. Sheikh HS, Tiangco ND, Harrell C, et al. Severe hypercapnia in critically ill adult cystic fibrosis patients. J Clin
Med Res 2011; 3: 209–212.
116. Young AC, Wilson JW, Kotsimbos TC, et al. Randomised placebo controlled trial of non-invasive ventilation for
hypercapnia in cystic fibrosis. Thorax 2008; 63: 72–77.
117. Flight WG, Shaw J, Johnson S, et al. Long-term non-invasive ventilation in cystic fibrosis – experience over two
decades. J Cyst Fibrosis 2012; 11: 187–192.
118. Madden BP, Kariyawasam H, Siddiqi AJ, et al. Noninvasive ventilation in cystic fibrosis patients with acute or
chronic respiratory failure. Eur Respir J 2002; 19: 310–313.
119. Vedam H, Moriarty C, Torzillo PJ, et al. Improved outcomes of patients with cystic fibrosis admitted to the
intensive care unit. J Cyst Fibros 2004; 3: 8–14.
120. Conti G, Rocco M, Antonelli M, et al. Respiratory system mechanics in the early phase of acute respiratory failure
due to severe kyphoscoliosis. Intensive Care Med 1997; 23: 539–544.
121. Lisboa C, Moreno R, Fava M, et al. Inspiratory muscle function in patients with severe kyphoscoliosis. Am Rev
Respir Dis 1985; 132: 48–52.

Disclosures: None declared.

100

FB:Cardiologia Siglo XXI

 | Chapter 7
Severe community-acquired
pneumonia
Adamantia Liapikou1, Catia Cilloniz2, Adrian Ceccato3 and Antoni Torres2

Severe community-acquired pneumonia (sCAP) is the most frequent infectious cause of

admission to the ICU and is associated with a high mortality rate that can reach 30–50%.
Severity assessment is a main point of sCAP management to ensure the appropriate site of
care and antibiotic therapy. The microbial aetiology of sCAP has changed over time;
Streptococcus pneumoniae ( pneumococcus) is the most frequent pathogen, and the
proportion of sCAP caused by respiratory viruses and with a polymicrobial aetiology has
increased, mainly due to better detection with new molecular techniques. Antibiotic therapy
is a key factor in the management of sCAP, and several studies have shown that early
empirical antibiotic administration improves patient outcomes. In general, the management
of sCAP includes microbiological diagnosis, severity assessment and early empirical
antibiotic treatment. The main challenge is the high prevalence of multidrug-resistant
pathogens worldwide. This chapter focuses on the current state of knowledge on the
management of sCAP.

C ommunity-acquired pneumonia (CAP) represents a public health problem of

substantial magnitude, with an annual incidence ranging from 1.6 to 10.6 per 1000
adult population in Europe [1]. The incidence of CAP increases considerably with age and
has a wide spectrum of clinical severity, from self-limiting disease to septic shock and
ARDS [2]. The term severe CAP (sCAP) identifies patients who require ICU admission and
higher levels of care, such as mechanical ventilation and vasopressor support [3, 4].
Transfer to the ICU for delayed respiratory failure or delayed onset of septic shock is
associated with a 2- to 2.6-fold increase in the risk of hospital mortality [3, 5]. Despite
advances in antimicrobial therapy and supportive measures, mortality in patients with
sCAP remains high, ranging from 31% to 58% [6–9]. However, there are conflicting data
regarding whether these rates are increasing over time [10, 11].

This chapter provides an overview of the current data on sCAP in immunocompetent

patients, including its epidemiology, microbial aetiology, antimicrobial therapy and
management. We discuss the major studies on sCAP.

1
Sotiria Chest Diseases Hospital, Athens, Greece. 2Dept of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona – Institut
d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, SGR 911, Ciber de Enfermedades Respiratorias
(Ciberes), Barcelona, Spain. 3Seccion Neumología, Hospital Nacional Alejandro Posadas, Palomar, Argentina.

Correspondence: Adamantia Liapikou, Sotiria Chest Diseases Hospital, Mesogion 152, 11527, Athens, Greece. E-mail: mliapikou@yahoo.com

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 101–116. DOI: 10.1183/2312508X.10001716 101

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Epidemiology

The Genetic and Inflammatory Markers of Sepsis (GenIMS) study group examined a
population of 1895 CAP patients, of which 302 patients were admitted to the ICU, with
17.3% hospital mortality [6]. It is well recognised that there is also an increased rate of
death in CAP patients in the months following discharge [12], and in patients with sepsis,
there is significant excess mortality for at least 5 years [13]. The Genetics of Sepsis in
Europe (GenOSept) study, which analysed 1166 patients with sCAP admitted to the ICU,
reported the following mortality rates: 17% at 28 days, 19% at intensive care discharge, 24%
at hospital discharge and 27% at 6 months [14].

However, there is reason to believe that outcomes for sCAP are improving with
implementation of the Surviving Sepsis Campaign (SSC) guidelines [15] and CAP guidelines
[3], a greater awareness of the importance of therapy timing and the use of new diagnostic
microbiology tests [16]. GATTARELLO et al. [17], in a case–control study of the outcomes of
160 patients with non-Streptococcus pneumoniae (nonpneumococcal) CAP in the ICU over
two time periods (2000–2002 and 2008–2013), reported that the latter group had improved
ICU survival (34.7% versus 16.7%; p=0.002) and had more patients receiving combined and
early antimicrobial therapy within 3 h (76.4 versus 90.3% and 37.5 versus 63.9%,
respectively; p<0.05). In the case of pneumococcal sCAP, the study by MONGARDON et al.
[18] analysed 222 cases and found that, although antibiotic therapy was adequate in 92.3%
of cases, hospital mortality reached 28.8%. The study concluded that, in the ICU, mortality
for pneumococcal CAP remains high, despite adequate antimicrobial treatment.

Pathophysiology of pneumonia

Pneumonia is an infectious process resulting from the invasion and overgrowth of

pathogenic micro-organisms in lung parenchyma, the breakdown of respiratory tract
defence mechanisms and the production of intra-alveolar exudates [19]. The development
of pneumonia and its severity are influenced by the balance between pathogen factors (e.g.
virulence and inoculum size) and host factors (e.g. loss of protective upper airway reflexes
allowing aspiration of contents from the upper airways into the lung). The inflammatory
cascade triggers an exuberant immune response in the lungs in response to infection and
the leakage of plasma into the alveoli and loss of surfactant, resulting in air loss and
consolidation. The patient breathes faster and faster in an effort to inhale more oxygen and
remove more carbon dioxide. sCAP cases with hypoxia or hypercapnia generally require
intubation and mechanical ventilation.

Clinical presentation and primary investigations

Diagnosis of sCAP includes clinical criteria, radiographic examination and diagnostic

testing for microbial aetiology. The most frequent symptoms in sCAP include cough, fever,
dyspnoea, pleuritic chest pain and sputum production. Mental confusion and
gastrointestinal symptoms will also be present in some cases [3].

Clinicians should take into consideration risk factors such as age, which is an important
risk factor for the development of sCAP, and comorbidities (e.g. COPD, diabetes mellitus,
chronic renal failure) that may affect the severity of pneumonia.

102

FB:Cardiologia Siglo XXI

 SEVERE COMMUNITY-ACQUIRED PNEUMONIA | A. LIAPIKOU ET AL.

Primary investigations include blood tests that provide information about the inflammatory
state (e.g. C-reactive protein (CRP), leukocyte cell count), associated organ failure (i.e. acute
renal failure) and the severity of the disease. Biomarkers are another important test that
can help clinicians distinguish bacterial pneumonia from other disorders such as congestive
heart failure in elderly patients presenting with respiratory symptoms and suspicion of
pneumonia (frequent entities such as chronic cardiovascular disease are a common
comorbidity in this population) [20].

According to CAP management guidelines [3, 4, 21], blood cultures, sputum Gram stains
and cultures, urinary antigen tests for pneumococcus and Legionella pneumophila, and
invasive respiratory tract sample cultures should be carried out in sCAP cases.

If the patient is intubated, bronchoscopy using BAL or a protected specimen brush are
alternative invasive methods for aetiological diagnosis (e.g. resistant micro-organisms,
polymicrobial infections, unusual pathogens). For quantitative cultures of endotracheal aspirate
samples, a threshold of >105 CFU·mL−1 is used to distinguish colonisation from infection [22].

Risk factors and genetics

Some individuals are more prone to pneumonia than others due to both intrinsic and
extrinsic factors, and recent data have revealed a role of individual genetic variability in
predisposition to the development of pneumonia and its clinical presentation [2]. For
example, specific variants of the FER gene are associated with a reduced risk of death in
patients with sepsis due to pneumonia [23]. Therefore, the FER gene may be a potential
target for new therapies. MISCH et al. [24] showed that a single-nucleotide polymorphism in
a Toll-like receptor, specifically the Toll-like receptor 6 polymorphism T359C, is associated
with increased risk of Legionnaires’ disease.

Assessment of severity

Many studies of the epidemiology of patients with CAP have demonstrated the importance
of assessing the severity of illness and stratifying patients on the basis of their risk of
mortality The most firmly established prediction scores, as determined by the Pneumonia
Severity Index (PSI) [25] and CURB-65 (Confusion, Urea, Respiratory rate, Blood pressure,
age ⩾65 years) test [26], do not have sufficient operating characteristics to be useful for
making ICU triage decisions in sCAP. Unfortunately, the use of mortality as the definition
of CAP severity is often clouded by questions of limitations of care in patients of advanced
age and the influence of comorbidities.

In 2007, the Infectious Diseases Society of America (IDSA)/American Thoracic Society

(ATS) issued guidelines [3] on the management of CAP, including specific criteria to
identify patients for ICU admission. These guidelines recommended that the presence of
one of the major or three or more of the nine minor criteria should indicate ICU
admission (table 1). The major criteria represent the stronger indicators for sCAP and
comprise the need for mechanical ventilation or vasopressors (or both). The IDSA/ATS
criteria have now been validated for prediction of 30-day mortality and ICU admission in
several countries [27–29]. However, individual studies have argued that the minor criteria
are of unequal weight; for example, in our study published in 2009 [29], we found that

103

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 1. Criteria for ICU admission in severe community-acquired pneumonia

Major criteria
Invasive mechanical ventilation
Septic shock with need for vasopressors
Minor criteria
Blood urea nitrogen level ⩾20 mg·dL−1 (7.14 mmol·L−1)
Confusion/disorientation
Hypotension requiring aggressive fluid resuscitation
Hypothermia: core temperature <96.8°F (36°C)
Leukopenia: WBCs <4000 cells·mm−3 (4×109 cells·L−1)
Multilobar infiltrates
PaO2/FIO2 ratio ⩽250 mmHg
Respiratory rate ⩾30 breaths·min−1
Thrombocytopenia: <100×103 PLTs·mm−3 (100×109 PLTs·L−1)

WBC: white blood cell; PLT: platelet. Reproduced and modified from [3] with permission.

mental confusion and leukopenia had the strongest association with mortality. Thus, the
need for ICU admission derived from minor severity criteria alone is uncertain.

Other new models specific to sCAP, which focus on the early detection of respiratory and
circulatory failure rather than on age and underlying illnesses, have been developed,
including an Australian model called SMART-COP (low systolic blood pressure, multilobar
chest radiography involvement, low albumin level, high respiratory rate, tachycardia,
confusion, poor oxygenation and low arterial pH) [30] and a Spanish model called
CURXO-80 (altered mental status, blood urea nitrogen >30 mg·dL−1, respiratory rate
>30 breaths·min−1, systolic blood pressure <90 mmHg, arterial pH <7.30, multilobar/
bilateral lung affectation, oxygen arterial pressure <54 mmHg or ratio of arterial oxygen
tension to fraction of inspired oxygen <250 mmHg and age >80 years) [31]. These scores
incorporate variations of the ATS minor criteria and/or additional factors such as low
arterial pH, albumin, tachycardia and hyponatraemia. SpO2 and arterial blood gas analysis
can give important information about severity (e.g. SpO2 <92% can be considered a safer
cut-off than SpO2 <90% for hospital admission); SpO2 is therefore a criterion in these scores.

Clinical high-risk identification should focus on acute respiratory or extrapulmonary sepsis,

or comorbidity-associated organ dysfunction, and careful clinical evaluation should be
complemented by regular assessment of abnormal vital signs and the minor criteria during
the first days of hospitalisation. This strategy must be supplemented by the continuous
evaluation of individual treatment goals.

Biomarkers

The role of biomarkers in the inflammatory response and their association with diagnosis,
severity of the infection and treatment management continue to be subjects of growing interest.
Procalcitonin (PCT) has high sensitivity but moderate specificity in differentiating between
bacterial and viral infections [32, 33]. In the most comprehensive study on the prognostic
properties of CAP, including new biomarkers (e.g. mid-regional pro-adrenomedullin
(MR-proADM), mid-regional pro-atrial natriuretic peptide, pro-arginine-vasopressin (copeptin),
C-terminal proendothelin-1) and biomarkers already in use (e.g. PCT, CRP, white blood cell

104

FB:Cardiologia Siglo XXI

 SEVERE COMMUNITY-ACQUIRED PNEUMONIA | A. LIAPIKOU ET AL.

count and CRB-65 score (CURB-65 without urea)), MR-proADM showed the best individual
performance, and a combination of CRB-65 with MR-proADM showed the best overall
prognostic performance [34, 35].

The main advantage of PCT over CRP in CAP diagnosis lies in its faster kinetics. Studies
suggest that PCT levels on admission can identify the severe outcomes of CAP and add to
the prognostic properties of clinical risk scores [34].

SCHUETZ et al. [34], in a two-centre, retrospective derivation–validation study of septic

patients, found that a 72-h PCT decrease of >80% had a negative predictive value of
around 90%; this may help to identify individuals with a reduced risk of mortality, who are
therefore good candidates for early discharge from the ICU. However, false-negative levels
of PCT in patients with severe sepsis or even septic shock have been reported [36]. Despite
this, the presence of CRP and the speed with which it decreases during the first week of
therapy have been found to correlate with prognosis in ICU patients with severe
pneumonia [37].

In the field of therapy, evolving data on PCT suggest its potential utility in deciding the
duration of antibiotic therapy. Thus, low PCT levels in the course of pneumonia have been
shown to shorten the duration of antibiotic treatment without compromising patient safety
in a variety of interventional trials and even in an ICU setting [38, 39].

Currently, all these markers are limited by absent rapid or even on-site availability and high
costs. Furthermore, the cut-off points for all biomarkers for different clinical settings still
have to be confirmed by large interventional trials [40].

Microbial aetiology

The spectrum of causal pathogens in sCAP is broader than that in nonsevere cases [41].
The gold standard diagnostic techniques used to identify bacteria causing respiratory tract
infections remain the Gram stain and semi-quantitative conventional culture from direct
respiratory samples, followed by bacterial identification, currently using matrix-assisted
laser desorption/ionisation time-of-flight mass spectrometry, and susceptibility testing of
the potential pathogen [42–44]. In addition to the difficulty of differentiating between
colonisation and infection, this process requires a minimum of 2 days and has low
sensitivity, especially if the sample is taken after the start of antibiotic treatment [45]. As a
consequence, many patients receive inappropriate antibiotic treatment, which may increase
morbidity and mortality [46–48]. Development of molecular techniques, especially
real-time PCR, has contributed to the recognition of the real incidence of respiratory
viruses and polymicrobial infection in sCAP. One of the advantages of molecular
diagnostics is the ability to identify pathogens in patients already receiving antibiotic
treatment. Thus, these techniques can increase the rate of microbiological findings of
respiratory pathogens in pneumonia from 39% using culture-based methods to 87% of
cases using these new techniques, as shown in a recent study [49].

The pathogens that cause sCAP can vary according to geographical area and underlying risk
factors. Streptococcus pneumoniae is still the leading pathogen, followed by Haemophilus
influenzae, Staphylococcus aureus, Legionella pneumophila, Enterobacteriaceae (especially
Escherichia coli and Klebsiella spp.) and Pseudomonas aeruginosa (figure 1) [50–52].

105

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Respiratory virus
8.2%

Atypical bacteria
5.2%

Legionella pneumophila
5.2%

Staphylococcus aureus
4.6%

Streptococcus pneumoniae Gram-negative enteric bacilli

48.5% 3.1%
Pseudomonas aeruginosa
3.1%
Haemophilus influenzae
2.1%
Streptococcus pneumoniae
plus respiratory viruses
5.7%
Streptococcus pneumoniae
plus Pseudomonas aeruginosa
1.5%
Other combinations
12.9%

Figure 1. Microbial aetiology distribution of pathogens in severe community-acquired pneumonia. Data from [50].

The most common blood isolate in patients with CAP is S. pneumoniae, which is also
reported to be common in patients with severe sepsis. It has been found to trigger
bacteraemia and sepsis in mouse lung infection models [53].

In a study by CILLONIZ et al. [41] in patients with CAP admitted to the ICU, the most
common aetiologies were S. pneumoniae (42%), polymicrobial aetiology (22%) and atypical
pathogens (18%). S. pneumoniae infection resulted in the highest number of deaths,
although the relative mortality rates were higher for S. aureus, Gram-negative
enterobacteria, P. aeruginosa and polymicrobial aetiologies.

Regarding respiratory viruses, a study from the USA investigating the aetiology in patients
with sCAP admitted to ICU found that the most frequently reported viruses were influenza
virus (9.7%), rhinovirus (8.4%) and metapneumovirus (3.3%) [54].

Bacteraemia is more common than respiratory virus infections in sCAP, and up to 20% of
sCAP episodes are caused by polymicrobial infection [55]. An interesting study carried out
in Japan on 1032 patients with CAP found that polymicrobial infection was confirmed in
9.2% of all cases, 18% in sCAP and 12.5% in the group of nonsurvivors, and that
polymicrobial infection was a risk factor for the severity of CAP [56]. A study by CILLONIZ
et al. [50] found that 11% of 362 ICU patients with CAP had a polymicrobial infection,
and the predictors of polymicrobial aetiology were chronic respiratory disease and ARDS
criteria on admission.

Respiratory viruses are the micro-organisms most frequently associated with a

polymicrobial aetiology. Polymicrobial infection involving influenza virus A and S. aureus
is one of the main causes of sCAP [57]. Aspiration pneumonia is a common cause of sCAP
and is generally polymicrobial, with both Gram-positive and Gram-negative anaerobes [58].

106

FB:Cardiologia Siglo XXI

 SEVERE COMMUNITY-ACQUIRED PNEUMONIA | A. LIAPIKOU ET AL.

Multidrug-resistant organisms in sCAP

Multidrug-resistant (MDR) organisms that cause CAP represent an emerging problem

because of the increasing number of residents living in healthcare facilities and others
receiving immunosuppressant therapy because of cancer or transplantation. The most
common MDRs in sCAP are P. aeruginosa, Enterobacteriaceae positive for
extended-spectrum β-lactamase and methicillin-resistant S. aureus (MRSA) (collectively
referred to as PES) [59]. Although the prevalence of MDR pneumonia is still low in Europe
(7.6% in Spain and 3% in UK, with the most common organism found being MRSA), this
represents patients requiring ICU admission, with unfavourable outcomes [60].

In an attempt to evaluate risk factors for acquiring MDR bacteria in CAP, ALIBERTI et al.
[61] found that hospitalisation in the preceding 90 days (OR 4.87, 95% CI 1.90–12.4;
p<0.001) and residency in a nursing home (OR 3.55, 95% CI 1.12–11.24; p<0.031) were
independent predictors for an actual infection with a resistant pathogen.

SHORR et al. [62] developed a simple risk score that appears valid for assessing the probability
of an MRD organism in patients hospitalised initially with CAP. The criteria are as follows:
recent hospitalisation, living in a long-term care facility, chronic haemodialysis and ICU
admission within 24 h of evaluation in the emergency department, with an area under the
receiver operating characteristic curve (AUROC) for the risk score of 0.71; the AUROC for
healthcare-associated CAP was 0.62. After validating the score in a later study by ALIBERTI
et al. [63], the authors concluded that the application of risk scores in clinical practice makes
it possible predict the presence of MDR pneumonia. A study by PRINA et al. [59], which
analysed 1519 patients with CAP who presented aetiological diagnosis, found that PES
pathogens were identified in 6% of the CAP cases; the study also found that PES pathogens
are associated with increased risk of 30-day mortality (OR 2.51, 95% CI 1.20–5.25; p=0.015).

Further studies are needed to evaluate these scores and to identify patients with MDR
sCAP as early as possible.

Therapy

The initial treatment of sCAP requires complex management involving multiple tasks:
respiratory support, monitoring, haemodynamic assessment and antimicrobial therapy (figure 2).

Antimicrobial therapy

Antibiotic treatment for sCAP remains largely empirical; it should be started as soon as
cultures have been taken, with a broad-spectrum regimen, without waiting for the results to
be reported.

The importance of guideline-concordant therapy remains a main factor to improve clinical

outcomes in sCAP, as indicated by subanalysis of the Community-Acquired Pneumonia in
Intensive Care Study (CAPUCI) study [64].

The goal of appropriate antimicrobial treatment therefore is to maximally reduce or eradicate

the bacterial load in order to achieve clinical success and minimise the potential for

107

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Severe community-acquired pneumonia

Early fluid resuscitation; haemodynamic

stabilisation and respiratory support

Evaluate MDR risk and start antibiotic

treatment (adequate to local environment)#

High MDR risk: Antimicrobial treatment

Low MDR risk:
broad-spectrum de-escalation according to
β-lactam plus macrolide
antibiotic treatment aetiological diagnosis

Consider glucocorticosteroid therapy in the

case of high inflammatory response¶

Figure 2. Initial management of severe community-acquired pneumonia. MDR: multidrug-resistant. #: consider

antimicrobial treatment according to the recommendations in table 2; ¶: a high inflammatory response is
defined as a level of C-reactive protein >150 mg·mL−1.

development of resistance. Specific risk factors, such as comorbidities (e.g. COPD,

bronchiectasis) or previous hospitalisation, should be taken into account on an individual basis.

Patients with septic shock

In patients with septic shock, treatment must not be delayed for >1 h after diagnosis [3, 65].
A multicentre study by KUMAR et al. [47] of 2154 septic shock patients showed that effective
antimicrobial administration within the first hour of documented hypotension was
associated with increased survival to hospital discharge.

In patients with septic shock, resuscitation requires the use of intravenous fluids and
vasopressors, oxygen therapy and mechanical ventilation provided as necessary. The
European Society of Intensive Care Medicine also advocates the measurement of lactate
concentrations after adequate fluid resuscitation until they return to a normal level
(<2 mmol·L−1) [66]. There is evidence, however, that a mean arterial pressure (MAP) of
around 65 mmHg is sufficient in most patients with septic shock, although in patients with
a history of hypertension, a higher MAP is associated with a lower risk of acute kidney
injury [66]. Vasopressors may have to be used if fluid resuscitation is not sufficient, or may
be indicated to maintain the desired value of MAP. A major concern in patients with sepsis
due to pneumonia is the risk associated with cumulative fluid balance and blood transfusion
because of worsening respiratory function [67].

sCAP

The most consistent data come from studies of sCAP, where guideline adherence is
associated with reduced mortality [68, 69]. In a study by BODI et al. [68], which included
529 patients with sCAP, significantly higher mortality was documented among patients
with nonadherence to treatment guidelines (33.2% versus 24.2%).

108

FB:Cardiologia Siglo XXI

 SEVERE COMMUNITY-ACQUIRED PNEUMONIA | A. LIAPIKOU ET AL.

According to the guidelines for management of CAP in Europe and the USA [3, 4],
therapy for sCAP depends on the presence of risk factors for P. aeruginosa infection. These
are chronic or prolonged use of broad-spectrum antibiotic therapy, structural lung disease
(bronchiectasis), repeated exacerbations of COPD, corticosteroid therapy, malnutrition, and
HIV infection and other forms of immunosuppression [3, 4]. In a recent study by CILLONIZ
et al. [52] on CAP due to P. aeruginosa, the authors reported that male sex, chronic
respiratory disease, CRP <12.35 mg·dL−1 and PSI risk class IV–V were independently
associated with P. aeruginosa CAP, whereas prior antibiotic treatment was the only risk
factor for MDR P. aeruginosa CAP. In the analysis of 30-day mortality for this CAP
population, CAP due to P. aeruginosa was one of the risk factors [52].

For treatment of sCAP in patients without pseudomonal risk, an intravenous β-lactam (usually
cephalosporin III) plus either a macrolide or respiratory fluoroquinolone is recommended. In
patients with risk factors for pseudomonal infection, an antipseudomonal β-lactam should be
combined with either levofloxacin or ciprofloxacin, or the antipseudomonal β-lactam can be
combined with an aminoglycoside and azithromycin (table 2) [4].

In cases of suspected community-acquired MRSA infection (e.g. prior influenza-like illness,

necrotising severe pneumonia), the guidelines recommend adding vancomycin or linezolid
to the other recommended agents [3].

Anaerobic coverage with a combination of a cephalosporin and clindamycin is indicated

only in patients with a risk of aspiration, such as those suffering from alcoholism, loss of
consciousness, neurological disease or dysphagia due to mechanical or neurological upper
digestive tract dysfunction.

The implementation of early (<2 days) antiviral therapy was found to be associated with
lower mortality in ventilated patients with pneumonia caused by the 2009 H1N1 strain of
influenza virus [3, 70]. The neuraminidase inhibitors oseltamivir and zanamivir can be
used for pneumonia caused by influenza viruses and reduce the duration of symptoms, risk
of hospitalisation and complications [70]. In addition to antiviral agents, antibacterial
agents targeting S. pneumoniae and S. aureus are also necessary [50].

Table 2. Therapy for severe community-acquired pneumonia following clinical assessment

No risk factors for Pseudomonas aeruginosa

Nonantipseudomonal cephalosporin III+macrolide
or
Moxifloxacin or levofloxacin±nonantipseudomonal cephalosporin III
Risk factors for Pseudomonas aeruginosa #
Antipseudomonal cephalosporin¶ or acyl ureidopenicillin/β-lactamase inhibitor or carbapenem
(meropenem preferred, up to 6 g possible, 3 g twice a day in 3 h infusion)
Plus ciprofloxacin+
or
Plus macrolide+aminoglycoside (gentamycin, tobramycin, amikacin)
#
: risk factors include: 1) recent hospitalisation (in last 3 months), 2) frequent (>4 courses·year−1)
or recent administration of antibiotics (in last 3 months), 3) severe disease (FEV1 <30% in last 3
months) and 4) oral steroid use (>10 mg prednisolone daily in the last 2 weeks); ¶: ceftazidime
plus penicillin G for coverage of Streptococcus pneumoniae; +: levofloxacin 750 mg over 24 h or
500 mg twice a day is an alternative. Reproduced and modified from [4] with permission.

109

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

As soon as the causative pathogen has been identified, de-escalation should be performed
by selecting the most appropriate antimicrobial agent that covers the pathogen.
De-escalation of initial broad-spectrum therapy to a narrow-spectrum agent may prevent
the emergence of resistant organisms, minimise the risk of drug toxicity and reduce costs.

Combination antibiotic therapy

Data regarding the use of combination therapy are limited to a few RCTs, and most of the
data come from observational studies that have evaluated the benefit of using combination
antibiotic therapy versus monotherapy in patients with sCAP who were admitted to the
ICU. The most thoroughly investigated combination is macrolide combination therapy,
which is associated with lower mortality compared with a quinolone combination, a
consistent finding in almost all large databases of patients with sCAP [71–73]. A study by
WATERER et al. [74] showed that mortality associated with pneumococcal pneumonia was
reduced when patients were treated empirically with combined antibiotic therapy including
a macrolide. RODRIGUEZ et al. [71], in the CAPUCI study, found that, in the subset of ICU
patients who had CAP and septic shock, combination antibiotic therapy improved survival
rates (OR 1.69, 95% CI 1.09–2.60; p=0.01). Similarly, only patients with sCAP and septic
shock who were treated with combination antibiotic therapy (58% with a third-generation
cephalosporin plus a macrolide), compared with those treated with monotherapy (42%
fluoroquinolone), had a higher 28-day in-ICU survival rate (hazard ratio (HR) 2.69, 95%
CI 1.09–2.60) [73]. Conclusively, in a meta-analysis including 28 observational studies of
almost 10 000 critically ill patients with CAP, macrolide use was associated with a
significant 18% relative (3% absolute) reduction in mortality compared with nonmacrolide
therapies [75]. However, in a study by GARIN et al. [76], in Switzerland, patients infected
with atypical pathogens (HR 0.33, 95% CI 0.13–0.85) or with PSI category IV pneumonia
(HR 0.81, 95% CI 0.59–1.10) were less likely to reach clinical stability with monotherapy
compared with combination therapy (β-lactam plus a macrolide).

From the above-mentioned data, it has become increasingly clear that the benefit of
combination therapy in sCAP is seen only when a macrolide is part of the regimen,
especially in pneumococcal bacteraemia [77, 78]. The benefit of a macrolide may also
explain the finding of greater clinical relapse in patients randomised to a β-lactam alone if
their streptococcal urinary antigen was positive [79]. The benefit also extends to patients
infected with macrolide-resistant pathogens (e.g. macrolide-resistant pneumococcal
infections, and even cases of Gram-negative infections) [72]. Clearly, the
immunomodulatory effects of macrolides may have an important effect on mortality in
CAP, but these drugs also have direct effects on bacteria by inhibiting quorum sensing [80].
Thus, for intubated patients, macrolides have been shown to inhibit biofilm formation and
decrease mucus hypersecretion, leading to improved mucociliary clearance. However, the
cardiotoxicity of macrolides has been linked recently to a slight increase in mortality. The
study by SCHEMBRI et al. [81] is currently the only study that has looked specifically at
protocol-defined CAP and showed an increased risk of long-term cardiac events. However,
MORTENSEN et al. [82] showed that the benefit of azithromycin in reducing CAP mortality
outweighed the risk of cardiotoxicity.

The SSC guidelines recommend antibiotic therapy for 7–10 days [65]. Longer treatments
are suggested for slow responses, nondrainable foci, S. aureus bacteraemia, some fungal or
viral infections, and immunological deficiencies such as neutropenia [65]. These guidelines

110

FB:Cardiologia Siglo XXI

 SEVERE COMMUNITY-ACQUIRED PNEUMONIA | A. LIAPIKOU ET AL.

now also include the use of biomarkers, especially PCT, which can be used to assist in
decisions regarding the discontinuation of empirical antibiotics (grade 2C) and when
considering the diagnosis of candidiasis [65]. The largest RCT published to date reported
that a PCT-guided strategy to treat suspected bacterial infections in nonsurgical patients
may reduce antibiotic exposure [38].

Recently, a multicentre observational study by MILLER et al. [83] reported that, after
implementing a resuscitation bundle, hospital mortality for severe sepsis and septic shock
declined from 21.2% to 8.7% over 7 years. Better compliance with resuscitation bundles
reduced the subsequent need for support for another organ.

Adjunctive therapies

Corticosteroids

The relationship between low-dose corticosteroid use and mortality in patients with sCAP
remains unclear. Corticosteroids may be used in patients with sCAP because they are the
most powerful inhibitors of inflammation and can potentially decrease the development of
ARDS, sepsis and mortality. In a recent study from Japan of 6925 patients with sCAP in
the ICU, the authors concluded that low-dose corticosteroid use may be associated with
reduced 28-day mortality in patients with CAP complicated by septic shock [84].

Recently, TORRES et al. [85] performed an RCT comparing methylprednisolone (0.5 mg·kg−1
twice daily for 5 days) versus placebo in patients with sCAP according to ATS or PSI risk
class V and with a high systemic inflammatory response (CRP >15 mg·dL−1). They found
that corticosteroids reduced the risk of treatment failure, with an OR of 0.34 (95% CI
0.14–0.87). This reduction in treatment failure was more evident in late treatment failure
(3% versus 25%; p=0.001), and especially in radiographic progression (2% versus 15%;
p=0.007). In another RCT by BLUM et al. [86], a total of 785 patients with CAP were
randomised to receive oral corticosteroids (50 mg prednisone for 7 days) or placebo as
adjunctive treatment. The corticosteroid group reported a shorter time to reach clinical
stability in comparison with the placebo group (3 days versus 4.4 days; p<0.001), with no
increase in complications. Additionally, NIE et al. [87], in a meta-analysis, concluded that
corticosteroids produced a benefit in terms of reduction of ARDS, length of hospital and
ICU stay, duration of intravenous antibiotics and time to clinical stability, without a
significant increase in side-effects.

The potential side-effects from corticosteroids in CAP should be mentioned. Theoretically,

corticosteroids may favour the onset of metabolic disorders, such as hyperglycaemia,
gastroduodenal bleeding, osteonecrosis, muscle weakness, psychotic reactions and
superinfection [88]. In most of the studies, hyperglycaemia occurred frequently in patients
treated with corticosteroids. However, for influenza sCAP, the results of a Cochrane
meta-analysis suggested that corticosteroids should not be used as an adjunctive treatment,
as they were associated with increased mortality [89].

High-flow oxygen therapy

High-flow oxygen therapy is the first approach for the management of hypoxaemic
respiratory failure and may also decrease the need for tracheal intubation in patients with

111

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 3. Advisory Committee on Immunization Practices (ACIP) 2015 recommendations for

PCV13 and PPV23

Pneumococcal vaccine in naïve persons ⩾65 years of age

Naïve persons should receive a single dose of PCV13 first, followed by a dose of PPV23
⩾1 year later.
Prior vaccination with PPV23 at ⩾65 years of age
Adults ⩾65 years of age who have previously received one or more doses of PPV23 should also
receive a dose of PCV13 if they have not yet received it. A dose of PCV13 should be given
⩾1 year after receipt of the most recent PPV23 dose. In the case of patients who need
repeated PPV23, the period between received PCV13 and the new dose of PPV23 should be
⩾1 year, and 5 years after the most recent dose of PPV23.
Immunocompromised patients
The ACIP recommendations for immunocompromised patients remain unchanged [92].
Routine PCV13 use among adults ⩾65 years of age
The recommendations for routine PCV13 use among adults ⩾65 years of age will be
re-evaluated in 2018 and revised as needed.

PCV13: pneumococcal conjugate vaccine protecting against 13 types of pneumococcal bacteria;

PPV23: pneumococcal polysaccharide vaccine protecting against 23 types of pneumococcal
bacteria. Data from [93, 94].

sCAP. Several studies have indicated that NIV may also work in patients with sCAP,
particularly in patients with COPD [1]. A meta-analysis suggested that the appropriate use
of NIV in pneumonia can reduce the need for endotracheal intubation (OR 0.28, 95% CI
0.09–0.88), ICU mortality (OR 0.26, 95% CI 0.11–0.61) and the length of stay in ICUs
(mean OR −1.00, 95% CI −2.05 to −0.05) [90]. NIV has been shown to reduce intubation
in patients with ARDS in 54% of treated cases [91]. However, use of high-flow nasal
cannulae and NIV must not delay endotracheal intubation when needed. Among patients
in a French study who were intubated after failure of NIV for severe CAP, those with a
longer delay in intubation were more likely to die [91]. For mechanically ventilated
patients, protective ventilation is strongly recommended on diagnosis of ARDS.

Prevention

The most important specific measure to prevent pneumonia is the use of pneumococcal
vaccines ( polysaccharide and conjugated) and influenza vaccines in all adults >65 years of
age and for younger people with medical conditions that place them at a high risk of
pneumonia morbidity and mortality. The Advisory Committee on Immunization Practices
2015 recommendations for vaccination are given in table 3.

Conclusions

Despite the improvement in microbial diagnosis, antibiotic therapy and clinical

management, overall mortality remains high in patients who present with sCAP. Clinicians
in emergency departments should pay attention to early diagnosis of sCAP cases in order
to decide on early ICU admission, microbial diagnosis and appropriate antibiotic therapy
selection to prevent patient deterioration.

112

FB:Cardiologia Siglo XXI

 SEVERE COMMUNITY-ACQUIRED PNEUMONIA | A. LIAPIKOU ET AL.

References
1. Torres A, Peetermans WE, Viegi G, et al. Risk factors for community-acquired pneumonia in adults in Europe:
a literature review. Thorax 2013; 68: 1057–1065.
2. Prina E, Ranzani OT, Torres A. Community-acquired pneumonia. Lancet 2015; 386: 1097–1108.
3. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society
consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis 2007; 44:
Suppl. 2, S27–S72.
4. Woodhead M, Blasi F, Ewig S, et al. Guidelines for the management of adult lower respiratory tract infections –
full version. Clin Microbiol Infect 2011; 17: Suppl. 6, E1–E59.
5. Restrepo MI, Mortensen EM, Rello J, et al. Late admission to the ICU in patients with community-acquired
pneumonia is associated with higher mortality. Chest 2010; 137: 552–557.
6. Kellum JA, Kong L, Fink MP, et al. Understanding the inflammatory cytokine response in pneumonia and sepsis:
results of the Genetic and Inflammatory Markers of Sepsis (GenIMS) Study. Arch Intern Med 2007; 167: 1655–1663.
7. Angus DC, Marrie TJ, Obrosky DS, et al. Severe community-acquired pneumonia: use of intensive care services and
evaluation of American and British Thoracic Society Diagnostic criteria. Am J Respir Crit Care Med 2002; 166: 717–723.
8. Sligl WI, Marrie TJ. Severe community-acquired pneumonia. Crit Care Clin 2013; 29: 563–601.
9. Woodhead M, Welch CA, Harrison DA, et al. Community-acquired pneumonia on the intensive care unit:
secondary analysis of 17,869 cases in the ICNARC Case Mix Programme Database. Crit Care 2006; 10: Suppl. 2, S1.
10. Gattarello S, Borgatta B, Sole-Violan J, et al. Decrease in mortality in severe community-acquired pneumococcal
pneumonia: impact of improving antibiotic strategies (2000–2013). Chest 2014; 146: 22–31.
11. Cavallazzi R, Wiemken T, Arnold FW, et al. Outcomes in patients with community-acquired pneumonia admitted
to the intensive care unit. Respir Med 2015; 109: 743–750.
12. Yende S, D’Angelo G, Kellum JA, et al. Inflammatory markers at hospital discharge predict subsequent mortality
after pneumonia and sepsis. Am J Respir Crit Care Med 2008; 177: 1242–1247.
13. Winters BD, Eberlein M, Leung J, et al. Long-term mortality and quality of life in sepsis: a systematic review.
Crit Care Med 2010; 38: 1276–1283.
14. Walden AP, Clarke GM, McKechnie S, et al. Patients with community acquired pneumonia admitted to European
intensive care units: an epidemiological survey of the GenOSept cohort. Crit Care 2014; 18: R58.
15. Daniels R, Nutbeam T, McNamara G, et al. The sepsis six and the severe sepsis resuscitation bundle: a prospective
observational cohort study. Emerg Med J 2011; 28: 507–512.
16. Mahony J, Chong S, Merante F, et al. Development of a respiratory virus panel test for detection of twenty human
respiratory viruses by use of multiplex PCR and a fluid microbead-based assay. J Clin Microbiol 2007; 45: 2965–2970.
17. Gattarello S, Lagunes L, Vidaur L, et al. Improvement of antibiotic therapy and ICU survival in severe
non-pneumococcal community-acquired pneumonia: a matched case–control study. Crit Care 2015; 19: 335.
18. Mongardon N, Max A, Bougle A, et al. Epidemiology and outcome of severe pneumococcal pneumonia admitted
to intensive care unit: a multicenter study. Crit Care 2012; 16: R155.
19. Alcon A, Fabregas N, Torres A. Pathophysiology of pneumonia. Clin Chest Med 2005; 26: 39–46.
20. Cilloniz C, Polverino E, Ewig S, et al. Impact of age and comorbidity on cause and outcome in community-
acquired pneumonia. Chest 2013; 144: 999–1007.
21. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia
in adults: update 2009. Thorax 2009; 64: Suppl. 3, iii1–iii55.
22. Rello J, Bodi M, Mariscal D, et al. Microbiological testing and outcome of patients with severe community-
acquired pneumonia. Chest 2003; 123: 174–180.
23. Rautanen A, Mills TC, Gordon AC, et al. Genome-wide association study of survival from sepsis due to
pneumonia: an observational cohort study. Lancet Respir Med 2015; 3: 53–60.
24. Misch EA, Verbon A, Prins JM, et al. A TLR6 polymorphism is associated with increased risk of Legionnaires’
disease. Genes Immun 2013; 14: 420–426.
25. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired
pneumonia. N Engl J Med 1997; 336: 243–250.
26. Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to
hospital: an international derivation and validation study. Thorax 2003; 58: 377–382.
27. Phua J, See KC, Chan YH, et al. Validation and clinical implications of the IDSA/ATS minor criteria for severe
community-acquired pneumonia. Thorax 2009; 64: 598–603.
28. Brown SM, Jones BE, Jephson AR, et al. Validation of the Infectious Disease Society of America/American
Thoracic Society 2007 guidelines for severe community-acquired pneumonia. Crit Care Med 2009; 37: 3010–3016.
29. Liapikou A, Ferrer M, Polverino E, et al. Severe community-acquired pneumonia: validation of the Infectious
Diseases Society of America/American Thoracic Society guidelines to predict an intensive care unit admission.
Clin Infect Dis 2009; 48: 377–385.

113

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

30. Charles PG, Wolfe R, Whitby M, et al. SMART-COP: a tool for predicting the need for intensive respiratory or
vasopressor support in community-acquired pneumonia. Clin Infect Dis 2008; 47: 375–384.
31. Espana PP, Capelastegui A, Gorordo I, et al. Development and validation of a clinical prediction rule for severe
community-acquired pneumonia. Am J Respir Crit Care Med 2006; 174: 1249–1256.
32. Hedlund J, Hansson LO. Procalcitonin and C-reactive protein levels in community-acquired pneumonia:
correlation with etiology and prognosis. Infection 2000; 28: 68–73.
33. Christ-Crain M, Stolz D, Bingisser R, et al. Procalcitonin guidance of antibiotic therapy in community-acquired
pneumonia: a randomized trial. Am J Respir Crit Care Med 2006; 174: 84–93.
34. Schuetz P, Suter-Widmer I, Chaudri A, et al. Prognostic value of procalcitonin in community-acquired pneumonia.
Eur Respir J 2011; 37: 384–392.
35. Kruger S, Ewig S, Giersdorf S, et al. Cardiovascular and inflammatory biomarkers to predict short- and long-term
survival in community-acquired pneumonia: results from the German Competence Network, CAPNETZ. Am J
Respir Crit Care Med 2010; 182: 1426–1434.
36. Koeze J, Hendrix MG, van den Bergh FA, et al. In critically ill patients the procalcitonin level can be misleading.
Crit Care 2011; 15: 422.
37. Coelho LM, Salluh JI, Soares M, et al. Patterns of c-reactive protein ratio response in severe community-acquired
pneumonia: a cohort study. Crit Care 2012; 16: R53.
38. Bouadma L, Luyt CE, Tubach F, et al. Use of procalcitonin to reduce patients’ exposure to antibiotics in intensive
care units (PRORATA trial): a multicentre randomised controlled trial. Lancet 2010; 375: 463–474.
39. Schuetz P, Chiappa V, Briel M, et al. Procalcitonin algorithms for antibiotic therapy decisions: a systematic review of
randomized controlled trials and recommendations for clinical algorithms. Arch Intern Med 2011; 171: 1322–1331.
40. Kolditz M, Ewig S, Hoffken G. Management-based risk prediction in community-acquired pneumonia by scores
and biomarkers. Eur Respir J 2012.
41. Cilloniz C, Ewig S, Polverino E, et al. Microbial aetiology of community-acquired pneumonia and its relation to
severity. Thorax 2011; 66: 340–346.
42. Mok JH, Eom JS, Jo EJ, et al. Clinical utility of rapid pathogen identification using matrix-assisted laser
desorption/ionization time-of-flight mass spectrometry in ventilated patients with pneumonia: a pilot study.
Respirology 2016; 21: 321–328.
43. Carbonnelle E, Mesquita C, Bille E, et al. MALDI-TOF mass spectrometry tools for bacterial identification in
clinical microbiology laboratory. Clin Biochem 2011; 44: 104–109.
44. Sparbier K, Schubert S, Weller U, et al. Matrix-assisted laser desorption ionization-time of flight mass
spectrometry-based functional assay for rapid detection of resistance against β-lactam antibiotics. J Clin Microbiol
2012; 50: 927–937.
45. Song JY, Eun BW, Nahm MH. Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward.
Infect Chemother 2013; 45: 351–366.
46. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of
survival in human septic shock. Chest 2009; 136: 1237–1248.
47. Houck PM, Bratzler DW, Nsa W, et al. Timing of antibiotic administration and outcomes for Medicare patients
hospitalized with community-acquired pneumonia. Arch Intern Med 2004; 164: 637–644.
48. Falcone M, Russo A, Giannella M, et al. Individualizing risk of multidrug-resistant pathogens in community-onset
pneumonia. PLoS One 2015; 10: e0119528.
49. Gadsby NJ, Russell CD, McHugh MP, et al. Comprehensive molecular testing for respiratory pathogens in
community-acquired pneumonia. Clin Infect Dis 2016; 62: 817–823.
50. Cilloniz C, Ewig S, Ferrer M, et al. Community-acquired polymicrobial pneumonia in the intensive care unit:
aetiology and prognosis. Crit Care 2011; 15: R209.
51. Falguera M, Carratala J, Ruiz-Gonzalez A, et al. Risk factors and outcome of community-acquired pneumonia due
to Gram-negative bacilli. Respirology 2009; 14: 105–111.
52. Cilloniz C, Gabarrus A, Ferrer M, et al. Community-acquired pneumonia due to multidrug and non-multidrug
resistant Pseudomonas aeruginosa. Chest 2016; 150: 415–425.
53. Chiavolini D, Pozzi G, Ricci S. Animal models of Streptococcus pneumoniae disease. Clin Microbiol Rev 2008; 21:
666–685.
54. Wiemken T, Peyrani P, Bryant K, et al. Incidence of respiratory viruses in patients with community-acquired
pneumonia admitted to the intensive care unit: results from the Severe Influenza Pneumonia Surveillance (SIPS)
project. Eur J Clin Microbiol Infect Dis 2013; 32: 705–710.
55. Amaro R, Liapikou A, Cilloniz C, et al. Predictive and prognostic factors in patients with blood-culture-positive
community-acquired pneumococcal pneumonia. Eur Respir J 2016; 48: 797–807.
56. Ishiguro T, Takayanagi N, Yamaguchi S, et al. Etiology and factors contributing to the severity and mortality of
community-acquired pneumonia. Intern Med 2013; 52: 317–324.
57. Palacios G, Hornig M, Cisterna D, et al. Streptococcus pneumoniae coinfection is correlated with the severity of
H1N1 pandemic influenza. PLoS One 2009; 4: e8540.

114

FB:Cardiologia Siglo XXI

 SEVERE COMMUNITY-ACQUIRED PNEUMONIA | A. LIAPIKOU ET AL.

58. Marik PE. Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 2001; 344: 665–671.
59. Prina E, Ranzani OT, Polverino E, et al. Risk factors associated with potentially antibiotic-resistant pathogens in
community-acquired pneumonia. Ann Am Thorac Soc 2015; 12: 153–160.
60. Aliberti S, Cilloniz C, Chalmers JD, et al. Multidrug-resistant pathogens in hospitalised patients coming from the
community with pneumonia: a European perspective. Thorax 2013; 68: 997–999.
61. Aliberti S, Zanaboni AM, Blasi F. Pneumonia in the community caused by multidrug-resistant organisms: keep
working on probabilistic scores. Clin Infect Dis 2012; 54: 1519–1520.
62. Shorr AF, Zilberberg MD, Reichley R, et al. Validation of a clinical score for assessing the risk of resistant
pathogens in patients with pneumonia presenting to the emergency department. Clin Infect Dis 2012; 54: 193–198.
63. Aliberti S, Di Pasquale M, Zanaboni AM, et al. Stratifying risk factors for multidrug-resistant pathogens in
hospitalized patients coming from the community with pneumonia. Clin Infect Dis 2012; 54: 470–478.
64. Rello J, Diaz E, Manez R, et al. Improved survival among ICU-hospitalized patients with community-acquired
pneumonia by unidentified organisms: a multicenter case–control study. Eur J Clin Microbiol Infect Dis 2016; in
press [DOI: 10.1007/s10096-016-2779-5].
65. Dellinger RP, Levy MM, Rhodes A, et al. Surviving Sepsis Campaign: international guidelines for management of
severe sepsis and septic shock, 2012. Intensive Care Med 2013; 39: 165–228.
66. Cecconi M, De Backer D, Antonelli M, et al. Consensus on circulatory shock and hemodymnamic monitoring.
Task Force of the European Society of Intensive Care Medicine. Intensive Care Med 2014; 40: 1795–1815.
67. Gajic O, Rana R, Winters JL, et al. Transfusion-related acute lung injury in the critically ill: prospective nested
case–control study. Am J Respir Crit Care Med 2007; 176: 886–891.
68. Bodi M, Rodriguez A, Sole-Violan J, et al. Antibiotic prescription for community-acquired pneumonia in the
intensive care unit: impact of adherence to Infectious Diseases Society of America guidelines on survival. Clin
Infect Dis 2005; 41: 1709–1716.
69. Frei CR, Attridge RT, Mortensen EM, et al. Guideline-concordant antibiotic use and survival among patients with
community-acquired pneumonia admitted to the intensive care unit. Clin Ther 2010; 32: 293–299.
70. Muthuri SG, Venkatesan S, Myles PR, et al. Effectiveness of neuraminidase inhibitors in reducing mortality in
patients admitted to hospital with influenza A H1N1pdm09 virus infection: a meta-analysis of individual
participant data. Lancet Respir Med 2014; 2: 395–404.
71. Rodriguez A, Mendia A, Sirvent JM, et al. Combination antibiotic therapy improves survival in patients with
community-acquired pneumonia and shock. Crit Care Med 2007; 35: 1493–1498.
72. Restrepo MI, Mortensen EM, Waterer GW, et al. Impact of macrolide therapy on mortality for patients with severe
sepsis due to pneumonia. Eur Respir J 2009; 33: 153–159.
73. Martin-Loeches I, Lisboa T, Rodriguez A, et al. Combination antibiotic therapy with macrolides improves survival
in intubated patients with community-acquired pneumonia. Intensive Care Med 2010; 36: 612–620.
74. Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal
pneumonia. Arch Intern Med 2001; 161: 1837–1842.
75. Sligl WI, Asadi L, Eurich DT, et al. Macrolides and mortality in critically ill patients with community-acquired
pneumonia: a systematic review and meta-analysis. Crit Care Med 2014; 42: 420–432.
76. Garin N, Genne D, Carballo S, et al. β-lactam monotherapy vs β-lactam–macrolide combination treatment in moderately
severe community-acquired pneumonia: a randomized noninferiority trial. JAMA Intern Med 2014; 174: 1894–1901.
77. Baddour LM, Yu VL, Klugman KP, et al. Combination antibiotic therapy lowers mortality among severely ill
patients with pneumococcal bacteremia. Am J Respir Crit Care Med 2004; 170: 440–444.
78. Martinez JA, Horcajada JP, Almela M, et al. Addition of a macrolide to a β-lactam-based empirical antibiotic
regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia.
Clin Infect Dis 2003; 36: 389–395.
79. Falguera M, Ruiz-Gonzalez A, Schoenenberger JA, et al. Prospective, randomised study to compare empirical
treatment versus targeted treatment on the basis of the urine antigen results in hospitalised patients with
community-acquired pneumonia. Thorax 2010; 65: 101–106.
80. Wise MP, Williams DW, Lewis MA, et al. Macrolides and community-acquired pneumonia: is quorum sensing the
key? Crit Care 2010; 14: 181.
81. Schembri S, Williamson PA, Short PM, et al. Cardiovascular events after clarithromycin use in lower respiratory
tract infections: analysis of two prospective cohort studies. BMJ 2013; 346: f1235.
82. Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events
among older patients hospitalized with pneumonia. JAMA 2014; 311: 2199–2208.
83. Miller RR III, Dong L, Nelson NC, et al. Multicenter implementation of a severe sepsis and septic shock treatment
bundle. Am J Respir Crit Care Med 2013; 188: 77–82.
84. Tagami T, Matsui H, Fushimi K, et al. Low-dose corticosteroid treatment and mortality in refractory abdominal
septic shock after emergency laparotomy. Ann Intensive Care 2015; 5: 32.
85. Torres A, Sibila O, Ferrer M, et al. Effect of corticosteroids on treatment failure among hospitalized patients with
severe community-acquired pneumonia and high inflammatory response: a randomized clinical trial. JAMA 2015;
313: 677–686.

115

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

86. Blum CA, Nigro N, Briel M, et al. Adjunct prednisone therapy for patients with community-acquired pneumonia:
a multicentre, double-blind, randomised, placebo-controlled trial. Lancet 2015; 385: 1511–1518.
87. Nie W, Zhang Y, Cheng J, et al. Corticosteroids in the treatment of community-acquired pneumonia in adults:
a meta-analysis. PLoS One 2012; 7: e47926.
88. Feldman C, Anderson R. Corticosteroids in the adjunctive therapy of community-acquired pneumonia: an
appraisal of recent meta-analyses of clinical trials. J Thorac Dis 2016; 8: E162–E171.
89. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam J, et al. Corticosteroids as adjunctive therapy in the treatment of
influenza. Cochrane Database Syst Rev 2016; 3: CD010406.
90. Wan YD, Sun TW, Liu ZQ, et al. Efficacy and safety of corticosteroids for community-acquired pneumonia:
a systematic review and meta-analysis. Chest 2016; 149: 209–219.
91. Rodrigo C, Leonardi-Bee J, Nguyen-Van-Tam JS, et al. Effect of corticosteroid therapy on influenza-related
mortality: a systematic review and meta-analysis. J Infect Dis 2015; 212: 183–194.
92. Centers for Disease Control and Prevention (CDC). Use of 13-valent pneumococcal conjugate vaccine and
23-valent pneumococcal polysaccharide vaccine for adults with immunocompromising conditions:
recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep
2012; 61: 816–819.
93. Kobayashi M, Bennett NM, Gierke R, et al. Intervals between PCV13 and PPSV23 vaccines: recommendations of
the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2015; 64: 944–947.
94. Kim DK, Bridges CB, Harriman KH. Advisory Committee on Immunization Practices recommended
immunization schedule for adults aged 19 years or older – United States, 2015. MMWR Morb Mortal Wkly Rep
2015; 64: 91–92.

Disclosures: None declared.

116

FB:Cardiologia Siglo XXI

 | Chapter 8
Acute exacerbations of interstitial
lung disease
Marcel Veltkamp1 and Jan C. Grutters1,2

Interstitial lung diseases (ILDs), or diffuse parenchymal lung disorders, constitute a group of
more than 150 different disorders characterised by inflammation of the lung parenchyma or
interstitium, sometimes followed by the occurrence of pulmonary fibrosis. In the most
frequently occurring interstitial disorders, such as sarcoidosis, idiopathic pulmonary fibrosis
(IPF), idiopathic nonspecific interstitial pneumonia, hypersensitivity pneumonitis and
collagen vascular disease-related interstitial pneumonias, acute worsening of pulmonary
symptoms can occur that can be defined as an acute exacerbation. There are important
differences in presentation, aetiology and prognosis of acute exacerbations between these
different ILDs. In sarcoidosis, an acute exacerbation is defined as an increase of pulmonary
symptoms caused by new or worsening granulomatous inflammation. In acute exacerbations
of IPF, for example, an acute worsening has to be present with new ground-glass
abnormalities on CT and can be provoked by multiple triggers, such as infection, mechanical
ventilation, drug toxicity and aspiration. When an acute exacerbation occurs in sarcoidosis,
starting or increasing the dose of prednisolone is often successful. Steroids are also often
used in treating an acute exacerbation of IPF, although unfortunately with a much lower
chance of success. In acute exacerbations of non-IPF pulmonary fibrosis there might be an
even more logical rationale for increasing the amount of immune suppression. However, in
line with IPF, strong evidence is also lacking, indicating the need for future studies
addressing this issue. Best supportive care during acute exacerbations, such as mechanical
ventilation, is challenging and should be discussed case by case.

I nterstitial lung diseases (ILDs), or diffuse parenchymal lung disorders, constitute a group
of more than 150 different disorders characterised by inflammation of the lung
parenchyma or interstitium, sometimes followed by the occurrence of pulmonary fibrosis.
Clinical outcomes differ greatly, varying from a benign mediastinal lymphadenopathy in
Lofgren’s syndrome to a devastating deterioration of pulmonary function in idiopathic
pulmonary fibrosis (IPF). This heterogeneous group of diseases can be divided in four
major subgroups [1]: 1) ILD with a known cause or association (e.g. medication, metals or
connective tissue disease), 2) idiopathic interstitial pneumonias (IIPs), 3) granulomatous
ILD (e.g. sarcoidosis or hypersensitivity pneumonitis) and 4) other forms of ultra-rare ILD
(e.g. lymphangioleiomyomatosis or pulmonary alveolar proteinosis). The group of IIPs
consists of nine different entities as summarised in table 1.

1
ILD Center of Excellence, St Antonius Hospital, Nieuwegein, The Netherlands. 2Division Heart and Lungs, University Medical Center,
Utrecht, The Netherlands.

Correspondence: Jan C. Grutters, ILD Center of Excellence, St Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The
Netherlands. E-mail: j.grutters@antoniusziekenhuis.nl

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 117–131. DOI: 10.1183/2312508X.10001816 117

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 1. Revised American Thoracic Society/European Respiratory Society classification of

idiopathic interstitial pneumonias (IIPs): multidisciplinary diagnoses

Major IIPs
Idiopathic pulmonary fibrosis
Idiopathic nonspecific interstitial pneumonia
Respiratory bronchiolitis–interstitial lung disease
Desquamative interstitial pneumonia
Cryptogenic organising pneumonia
Acute interstitial pneumonia (formerly known as Hamman–Rich syndrome)
Rare IIPs
Idiopathic lymphoid interstitial pneumonia
Pleuroparenchymal fibroelastosis
Unclassifiable IIPs #
#
: causes of unclassifiable IIPs include 1) inadequate clinical, radiological or pathological data,
and 2) major discordance between clinical, radiological and pathological findings that may occur
in the following situations: a) previous therapy resulting in substantial alteration of radiological or
histological findings (e.g. biopsy of desquamative interstitial pneumonia after steroid therapy,
which shows only residual nonspecific interstitial pneumonia), b) new entity, or unusual variant of
recognised entity, not adequately characterised by the current American Thoracic Society/
European Respiratory Society classification (e.g. variant of organising pneumonia with supervening
fibrosis), and c) multiple high-resolution CT and/or pathological patterns that may be encountered
in patients with IIP. Reproduced and modified from [1] with permission.

ILDs can present as acute entities, such as the acute interstitial pneumonia formerly known
as Hamman–Rich syndrome, or as a more chronic disease with or without pulmonary
fibrosis. Unfortunately, a rapid deterioration can also occur during the course of chronic
ILDs, presenting as an acute exacerbation. In clinical practice, most exacerbations occur in
five different ILDs: sarcoidosis, IPF, idiopathic nonspecific interstitial pneumonia (iNSIP),
hypersensitivity pneumonitis and collagen vascular disease (CVD)-related ILD. In this
chapter, we will focus on the current insights into the pathogenesis, definitions and treatment
options for these specific acute exacerbations. There are important differences in
presentation, aetiology and prognosis of acute exacerbations between these different ILDs
which we will outline in more detail in the following sections.

Sarcoidosis

Sarcoidosis is a multisystemic disease characterised by the formation of nonnecrotising

granulomas in different organs, mostly affecting intrathoracic lymph nodes, lungs and skin [2].

The aetiology of sarcoidosis remains unknown and no curative treatment exists. Fortunately,
however, not all sarcoidosis patients require treatment. It has been reported that the need for
systemic treatment varies between 20% and 70% [2–4]. Main treatment indications are risk
of organ failure and substantial impact on quality of life. Drugs often used are
glucocorticoids, methotrexate, azathioprine or leflunomide [5]. Targeted tumour necrosis
factor (TNF)-α inhibition can be used in refractory sarcoidosis patients [5].

Acute exacerbation of pulmonary sarcoidosis

Worsening of respiratory symptoms occurs frequently in patients with pulmonary sarcoidosis

[6, 7]. The estimated frequency of pulmonary worsening is between 13% and 75%, based on

118

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ILD | M. VELTKAMP AND J.C. GRUTTERS

the definition used [8–11]. In 2012, PANSELINAS and JUDSON [12] made an excellent effort to
accurately define such acute episodes of pulmonary worsening as an acute pulmonary
exacerbation of sarcoidosis (APES). APES was defined as an increase of pulmonary
symptoms caused by new or worsening granulomatous inflammation, combined with a
decline of forced vital capacity (FVC) or FEV1 >10% compared with baseline. The term
“acute” can be somewhat misleading, however, due to the fact that the symptoms should be
present for at least 1 month [12]. The latter is important because airway hyperreactivity has
been demonstrated in up to 58% of sarcoidosis patients [13–15]. When pulmonary
complaints and decline in pulmonary function resolve in just several days, it is unlikely that
an increase in granulomatous inflammation was responsible for the initial complaints. When
dealing with APES it is also challenging to differentiate worsening of symptoms based on
increased pulmonary granulomatous inflammation from symptoms caused by
extrapulmonary sarcoidosis (cardiac localisation or pulmonary hypertension), complications
of immunosuppressive treatment (e.g. infections, toxicity or steroid myopathy) or other
conditions related to sarcoidosis (e.g. embolism [16, 17], depression [18], fatigue [19] or
small fibre neuropathy [20]). Symptoms of APES are not specific. However, in their cohort of
sarcoidosis patients presenting with APES, MCKINZIE et al. [21] demonstrated that >90% of
patients experienced cough, whereas fever or night sweats seldom occurred. In clinical
practice, a chest radiograph is performed routinely in patients with increased pulmonary
symptoms to rule out causes other than sarcoidosis. It is important to note, however, that
chest radiographs in APES are often unchained so they cannot be used to exclude APES [22].
In these patients, a CT scan should be performed in order to evaluate the lung parenchyma.

Treatment of APES

Treatment with corticosteroids is advised when a diagnosis of APES is made. In a study of

36 patients with APES treated with prednisolone the median time for normalisation of
pulmonary function was only 21 days with a marked improvement of pulmonary
symptoms [21]. If after 4–6 weeks no improvement on steroids is seen, an alternative
diagnosis other than APES should be considered. A proposed algorithm for the treatment
of APES is shown figure 1. Interestingly, sarcoidosis patients receiving steroids are also
prone to develop APES. One theory is that the granulomatous inflammation in sarcoidosis
is necessary for the host to clear the causative agent. If such an antigen can be cleared, the
inflammatory response will terminate [23]. This granulomatous inflammation is inhibited
when patients receive corticosteroids, possibly resulting in persistence of the antigen. If
corticosteroids are tapered then the granulomatous inflammation will flare when the
causative antigen is still present. Other risk factors for APES are listed in table 2.

Summary

Acute exacerbations of pulmonary sarcoidosis occur regularly and respond well to

corticosteroids. In clinical practice it is important to rule out other causes for worsening of
symptoms or pulmonary dysfunction before an accurate diagnosis of APES can be made.

Idiopathic pulmonary fibrosis

Definition of acute exacerbation in IPF

IPF is a devastating, progressive lung disease characterised by the formation of parenchymal

fibrosis. It is the most common disease entity within the group of IIPs [40] and median

119

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

APES

Prednisolone equivalent of 20–40 mg·day–1 or consider raising

corticosteroid dose to the minimum dose at which APES did not occur

Cumulative corticosteroid therapy of >1 year

and/or history of corticosteroid toxicity and/or
high risk of corticosteroid toxicity

No Yes

Consider withholding addition of Add corticosteroid-sparing agent.

corticosteroid-sparing agent. If patient was already receiving
APES Taper in 2–6 weeks to previous a corticosteroid-sparing agent,
minimum dose of corticosteroids add a new one and consider
at which APES did not develop. discontinuing the previous one if it
was not corticosteroid sparing.

No Corticosteroid No corticosteroid
APES toxicity toxicity

APES Attempt to taper Individualise tapering of Taper to no less

No
off corticosteroids corticosteroids and than 10 mg of
APES APES
in 3–9 months corticosteroid-sparing daily prednisolone
agents based on: equivalent for
Development/risk of ≥3 months
No corticosteroid toxicity
APES Development/risk of toxicity
from corticosteroid-sparing APES
agents
Moniter off
Pulmonary symptoms
therapy

Figure 1. Proposed treatment algorithm for acute pulmonary exacerbation of sarcoidosis (APES).
Reproduced and modified from [12] with permission.

survival is ∼3–4 years in patients without antifibrotic treatment [41–43]. Most patients with
IPF die from respiratory failure due to progression of the disease, concomitant infections or
pulmonary hypertension. Respiratory failure in patients with IPF can also be precipitated by
acute deterioration of the disease without an attributable cause, which has been called acute
exacerbation of IPF (AE-IPF). Many different definitions of AE-IPF have been published
throughout the years, eventually resulting in the first consensus definition in 2007 [44]. At
that time, the following criteria had to be met for the diagnosis of AE-IPF: 1) previous
diagnosis of IPF, 2) unexplained or worsening of dyspnoea within the past 30 days, 3) new
bilateral areas of ground-glass attenuation or consolidations on high-resolution CT
(figure 2) and 4) exclusion of other causes, such as infection, cardiac decompensation or
pulmonary embolism. It was important to define consensus criteria for AE-IPF in order to
obtain insights into the pathophysiology and prevalence of such exacerbations in IPF

120

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ILD | M. VELTKAMP AND J.C. GRUTTERS

Table 2. Risk factors for acute pulmonary exacerbation of sarcoidosis

African-American versus Caucasian [8, 24]

Longer disease duration (median 33 months versus median 10 months) [25]
Female versus male [8]
Older age [9]
Musculoskeletal sarcoidosis at presentation [8]
Extrapulmonary sarcoidosis [10]
Fibrocystic pulmonary sarcoidosis [9, 11]
Presence of worsening of pulmonary symptoms [8, 25, 26]
Treatment with corticosteroids or other immunosuppressive therapy
(e.g. etanercept) [8, 10, 25–32]
Antiretroviral therapy [33–35]
Post lung transplant [36–39]

Reproduced and modified from [12] with permission.

patients. Recently, an international working group report on AE-IPF was published with a
revision of the 2007 criteria for AE-IPF (table 3) [45]. An important difference is that an
acute exacerbation is no longer seen as an idiopathic event but, in concordance with
exacerbations in asthma or COPD, for example, can have multiple different triggers, such as
infection, aspiration, drug toxicity and surgery/mechanical ventilation [45]. Furthermore,
the previous 30-day time period was found arbitrary and has been changed to a more
flexible time window. The authors state that the proposed revised criteria are more inclusive
and practical for clinicians and researchers involved in clinical trials relating to IPF.

Based on placebo group analysis of multiple RCTs addressing new therapies in IPF, the
annual incidence of AE-IPF is estimated to be between 1% and 20% [46–50]. AE-IPF has a
3-month survival rate of ∼50% and is estimated to account for up to 40% of all deaths in
patients with IPF [43]. Risk factors for developing AE-IPF are low FVC, use of
immunosuppressive therapy, increased BMI, absence of a smoking history [51, 52],
mechanical ventilation, thoracic surgery and aspiration [53, 54].

Aetiology of AE-IPF

The aetiology of AE-IPF is unknown. It is thought that AE-IPF consists of a sudden

acceleration of the underlying fibrosis in IPF [55]. The histopathology of AE-IPF most
often reveals a pattern of diffuse alveolar damage (DAD) superimposed on the underlying
usual interstitial pneumonia (UIP) pattern [44, 56]. The histopathological pattern of DAD
is not specific for AE-IPF. It has been demonstrated that pulmonary infections, connective
tissue diseases, complications of lung transplantation or exposure to radiation can also
cause DAD [57, 58].

Corticosteroids and immunosuppressive drugs in AE-IPF

Treatment with corticosteroids can be beneficial in some stages of ARDS [59–61]. It is

therefore not surprising that high-dose corticosteroids are often prescribed in the
management of AE-IPF. Treatment of AE-IPF with high-dose corticosteroids is
recommended in the international consensus statement on the diagnosis and management of
IPF [62]. However, it is important to note that it is described as a weak recommendation
with very low quality of evidence. In Europe, differences can be found between national

121

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

a) d)

b) e)

c) f)

Figure 2. High-resolution CT in acute exacerbation of idiopathic pulmonary fibrosis (IPF). Patient with IPF
a–c) 2 years before an acute exacerbation and d–f) at the time of an acute exacerbation. During this
exacerbation, bilateral ground-glass opacities can be seen superimposed on the already existing usual
interstitial pneumonia pattern. The patient survived, but became oxygen dependent.

guidelines for the treatment of AE-IPF. The French practical guideline for the treatment of
AE-IPF, for example, recommends the use of high-dose steroids, but also mentions that
intravenous cyclophosphamide can be given [63]. The Dutch guideline for the treatment of
IPF recommends not using high-dose steroids during AE-IPF in the majority of patients [64].

122

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ILD | M. VELTKAMP AND J.C. GRUTTERS

Table 3. Proposed revised definition and criteria for acute exacerbation of idiopathic pulmonary
fibrosis (AE-IPF)

Revised definition
An acute, clinically significant respiratory deterioration characterised by evidence of new
widespread alveolar abnormality
Revised diagnostic criteria
Previous or concurrent diagnosis of IPF#
Acute worsening or development of dyspnoea, typically <1 month duration
CT with new bilateral ground-glass opacity and/or consolidation superimposed on a
background pattern consistent with usual interstitial pneumonia¶
Deterioration not fully explained by cardiac failure or fluid overload

Events that are clinically considered to meet the definition of AE-IPF but fail to meet all four
diagnostic criteria owing to missing CT data should be termed “suspected acute exacerbations”.
#
: if the diagnosis of IPF is not previously established, this criterion can be met by the presence
of radiological and/or histopathological changes consistent with the usual interstitial pneumonia
pattern on the current evaluation; ¶: if no previous CT is available, the qualifier “new” in the
definition can be dropped. Reproduced and modified from [45] with permission.

Both guidelines are based on expert opinions and no RCTs regarding the use of
corticosteroids in AE-IPF exist.

A rationale for using steroids is the possibility of a superimposed histological pattern of

organising pneumonia during AE-IPF. Unfortunately, retrospective studies of different patient
cohorts with AE-IPF treated with high-dose steroids persist in demonstrating high mortality
rates [52, 53, 65]. Furthermore, elevated C-reactive protein levels, leukocytosis, and increased
levels of interleukin-8, α-defensin and ST2 protein in AE-IPF suggest a triggered immune
response [44, 65, 66]. Multiple studies, often retrospectively in a small cohort, evaluated the
combination of steroids and immunosuppressive therapy, such as tacrolimus, cyclosporine,
azathioprine or cyclophosphamide [67–72], with positive outcomes. However, RCTs are still
needed to prove the efficacy of immunosuppressive treatment in AE-IPF. With regard to the use
of azathioprine, it is has become clear that use in patients in a stable phase of their IPF does not
prevent the occurrence of AE-IPF and, more strikingly, may even increase its incidence [73].

Interestingly, in the field of ARDS research, two new clinical ARDS phenotypes have been
described recently [74]: phenotype I demonstrates low inflammatory markers and shock,
phenotype II demonstrates high plasma levels of inflammatory markers, severe shock and
metabolic acidosis. This could be in line with the observation made by LORENTE et al. [75]
that a histological pattern of DAD was found in only 33% of patients with ARDS on autopsy,
and may be the first step in predicting which patients with ARDS would benefit from
immunosuppressive therapy. Hopefully, similar research in AE-IPF will be performed that
helps determine criteria for the identification of a subgroup that benefits from corticosteroids.

Antibiotics in AE-IPF

Due to the fact that most patients presenting with AE-IPF are not eligible for invasive
diagnostic procedures such as bronchoscopy, the majority will receive empiric treatment
with antibiotics [76]. The use of haemoperfusion with polymyxin B, a cationic polypeptide
antibiotic, has been studied in patients with AE-IPF [77]. Haemoperfusion with a
polymyxin B-immobilised fibre column can absorb endotoxins, such as lipopolysaccharide,

123

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

reactive oxygen species and neutrophils, and benefits patients with septic shock [78]. Its use
has also been studied in patients with ARDS with improvement of oxygenation [79]. In a
retrospective small cohort study, ENOMOTO et al. [77] reported an improved survival of
patients with AE-IPF treated with polymyxin B haemoperfusion. Further prospective RCTs
are needed to definitely determine its value in the treatment of patients with AE-IPF.

Antifibrotic drugs in AE-IPF

Since the adjusted guideline on diagnosis and treatment of IPF [80], the antifibrotic drugs
pirfenidone and nintedanib have become the standard of care in patients with mild to
moderate IPF. In the first prospective trial using pirfenidone in IPF patients, a lower incidence
of AE-IPF was observed in the treatment group [81]. In the following three worldwide RCTs
(CAPACITY-1, CAPACITY-2 and ASCEND), the incidence of AE-IPF was not a specified
end-point [82, 83]. When patients using pirfenidone develop AE-IPF the clinician has to
decide whether to stop or continue the drug. In a post hoc analysis of the above-mentioned
trials it has been shown that patients with a clinically meaningful decline in pulmonary
function during treatment with pirfenidone can benefit from continuation of therapy. In
particular, continued use of pirfenidone reduced the risk of a second decline of >10% FVC or
death compared with placebo [84]. These analyses suggest a benefit for patients when
continuing pirfenidone; however, this has not been studied specifically in any trial. A decrease
in the frequency of AE-IPF was seen in the phase 2 trial addressing dose finding and safety of
nintedanib in patients with IPF [46]. In the following RCTs (INPULSIS-1 and INPULSIS-2) a
reduction of AE-IPF was only demonstrated in the latter trial [85]. It was found that
nintedanib had a significant benefit compared with placebo in a pre-specified sensitivity
analysis on the pooled data on the time to the first adjudicated acute exacerbation [85].

However, in concordance with pirfenidone, studies specifically addressing continuation of

nintedanib in patients with AE-IPF are also lacking. A post hoc analysis of the INPULSIS
trials could suggest a benefit of continuation of nintedanib in patients after AE-IPF. This is
based on the observation that the effect of nintedanib seemed to be present only in the
most severe patients (FVC <70%) [86].

N-acetylcysteine (NAC) is a precursor of the antioxidant glutathione. Based on its

antioxidative effect, low costs and the promising results of the IFIGENIA trial in 2005 [87],
it has been used widely in the treatment of IPF. In 2014, it was demonstrated that treatment
with NAC did not favour disease outcome in patients with stable IPF [50]. Pragmatically, in
some clinics NAC is still used in patients presenting with AE-IPF. Most patients with IPF
are currently being treated with either pirfenidone or nintedanib. As mentioned above, there
is no indication to stop these drugs in IPF patients presenting with an acute exacerbation.
Interestingly, in a recent phase 2 study comparing pirfenidone with pirfenidone and NAC
combination treatment, data suggested that addition of NAC to pirfenidone could even be
harmful in patients with IPF [88]. This indicates that currently there is no rationale left for
the use of NAC in IPF patients with either stable disease or acute exacerbations.

Anticoagulants in AE-IPF

An important aspect in the pathogenesis of IPF is alveolar epithelial cell injury resulting in an
abnormal wound-healing response leading to fibrotic remodelling. The coagulation cascade is
thought to be involved in normal wound healing [89]. In a small prospective cohort study
where patients were assigned to receive prednisolone alone or prednisolone plus

124

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ILD | M. VELTKAMP AND J.C. GRUTTERS

anticoagulant therapy it was suggested that adding anticoagulant therapy had a beneficial
effect on survival in patients with IPF [90]. Unfortunately, in the following ACE-IPF
(Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) trial, a double-blind RCT of
warfarin in IPF patients, it was demonstrated that the use of anticoagulants in patients with
stable disease or AE-IPF was potentially harmful [91]. In line with this result, KREUTER et al.
[92] recently described the negative effect of medically initiated anticoagulation on mortality
and other clinical outcomes in patients with IPF.

Mechanical ventilation during AE-IPF

As mentioned above, AE-IPF has a 3-month survival rate of ∼50% and is estimated to account
for up to 40% of all deaths in patients with IPF [43]. Multiple small case series reported very
high in-hospital mortality rates of IPF patients treated with mechanical ventilation, even up to
90% [93–96]. In the 2011 guidelines for the diagnosis and management of IPF [62], a
recommendation was made to consider mechanical ventilation in only a small minority of IPF
patients. Once again, published data on a large cohort of IPF patients undergoing mechanical
ventilation was not available at that time. Recently, in a nationwide retrospective cohort
analysis, RUSH et al. [97] described 17 770 hospitalisations of IPF patients, of whom 1703
patients received mechanical ventilation and 778 received noninvasive mechanical ventilation.
The mortality of IPF patients receiving mechanical ventilation in this cohort was ∼50%, a
much better outcome than thought previously. Obviously, not all patients in this cohort were
ventilated during AE-IPF and there was no stratification for disease severity. It could be that the
most severe IPF patients did not receive mechanical ventilation, based on previous indications
of very high mortality rates. At most, these data suggest that the outcome in IPF patients
receiving mechanical ventilation could be better than expected previously.

Therefore, the decision about whether to intubate a patient with AE-IPF should be
discussed case by case, preferably in a multidisciplinary setting, taking into account issues
such as the presence of a potentially reversible cause of the exacerbation, opportunity for
lung transplantation, availability and/or response to antifibrotic drugs, and expectations and
values of the patient and their family.

Summary

In IPF patients presenting with symptoms suggesting AE-IPF, acute worsening from
extraparenchymal causes (e.g. pulmonary embolism or congestive heart failure) should first be
ruled out. If there is AE-IPF then the clinician should try to identify triggers, such as infection,
medication capable of inducing ILD or aspiration, and treat accordingly (figure 3). International
evidence-based guidelines addressing the management of IPF make a weak recommendation
for the use of corticosteroids during AE-IPF based on anecdotal reports and the high mortality
rate. The use of mechanical ventilation should be discussed case by case, addressing issues such
as lung transplantation, change of reversibility and expectations of patients.

Pulmonary fibrosis other than IPF

Frequency of acute exacerbations in non-IPF fibrotic pulmonary disease

Acute exacerbations are not seen solely in patients with IPF. Acute exacerbations have been
also described in patients with fibrotic interstitial pneumonias, such as iNSIP, interstitial

125

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Acute respiratory deterioration in IPF

(typically <1 month duration)

Not acute exacerbation

Yes
Extraparenchymal cause identified? Alternative diagnosis (e.g. pneumothorax,
pleural effusion, pulmonary embolism)

No

New, bilateral GGO/consolidation on CT? Acute exacerbation of IPF

Yes
(Not fully explained by cardiac failure or
fluid overload) Triggered acute exacerbation
(e.g. infection, post-procedural/post-operative,
No drug toxicity, aspiration)

Not acute exacerbation

Alternative diagnosis (e.g. infection, Idiopathic acute exacerbation
aspiration, drug toxicity, congestive No trigger identified
heart failure)

Figure 3. Proposed conceptual framework for evaluation of acute respiratory deterioration in idiopathic
pulmonary fibrosis (IPF). Acute respiratory deterioration of IPF (defined as “typically <1 month in duration”)
can be categorised as extraparenchymal (e.g. pulmonary embolism, pneumothorax or pleural effusion) or
parenchymal. Parenchymal causes that demonstrate new bilateral ground-glass opacification (GGO)/
consolidation on CT that is not fully explained by cardiac failure or fluid overload are categorised as acute
exacerbations of IPF, regardless of the presence or absence of a known trigger (e.g. infection). Acute
exacerbations are further categorised as triggered acute exacerbations or idiopathic acute exacerbations,
depending on whether an underlying trigger for acute exacerbation is found. Reproduced and modified from
[45] with permission.

pneumonia associated with CVD and chronic hypersensitivity pneumonitis [52, 95–105]. In a
retrospective cohort study, PARK et al. [106] described the estimated 1-year frequency of an
acute exacerbation in iNSIP of 4.2%. It is important to note that all patients in this study
underwent a surgical lung biopsy to confirm the diagnosis and in two of the 74 iNSIP patients
an acute exacerbation developed immediately after surgery. The clinical features of patients
with exacerbations of iNSIP were similar to those of AE-IPF, except that patients with an
acute exacerbation of iNSIP were younger and predominantly female [106]. As mentioned
above, acute exacerbations can also occur in CVDs, such as systemic sclerosis, Sjögren’s
disease, rheumatoid arthritis, polymyositis/dermatomyositis, mixed connective tissue disease
and systemic lupus erythematosus. SUDA et al. [98] described a cohort of 83 patients with ILD
based on CVD. The overall incidence of acute exacerbation was 7.2% with an annual
incidence of 1.3%. Acute exacerbation was most commonly found in patients with rheumatoid
arthritis, perhaps based on the fact that in rheumatoid arthritis, in comparison with other
CVDs, a UIP pattern is the most common underlying ILD. This observation was also found
in a study of TACHIKWA et al. [107] where 40% of CVD patients with an acute exacerbation
had rheumatoid arthritis, 40% had dermatomyositis and 20% has systemic sclerosis. The
overall 3-month mortality in this study of patients with underlying CVD presenting with an
acute exacerbation was significantly lower compared with patients with AE-IPF (33% versus
69%). According to underlying CVD, 3-month mortality was 17% in rheumatoid arthritis,
50% in dermatomyositis and 33% in patients with systemic sclerosis [107]. Tapering of
corticosteroids within 1 month preceded the development of an acute exacerbation in 27% of
patients with CVD. In chronic hypersensitivity pneumonitis, MIYAZAKI et al. [108] described

126

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ILD | M. VELTKAMP AND J.C. GRUTTERS

an overall incidence of acute exacerbation of 14%. Not surprisingly, the frequency of an acute
exacerbation was significantly higher in hypersensitivity pneumonitis patients with a UIP
pattern compared with hypersensitivity pneumonitis patients with a fibrotic NSIP pattern
[108]. The mortality is very high (86–100%).

Treatment

Obviously, the rationale for using steroids or immunosuppressive drugs in acute

exacerbations of non-IPF pulmonary fibrosis such as CVD-related interstitial pneumonia is
much stronger compared with that for treating AE-IPF. This is based on the underlying
immunological mechanisms of this disease group. As in AE-IPF, in patients presenting
with symptoms suggesting an acute exacerbation, acute worsening from extraparenchymal
causes such as pulmonary embolism or congestive heart failure should first be ruled out. If
there is an acute exacerbation then the clinician should try to identify triggers, such as
infection, medication capable of inducing ILD and aspiration, and treat accordingly. Most
patients with pulmonary fibrosis based on CVD, iNSIP or hypersensitivity pneumonitis are
treated with steroids with or without immunosuppressive drugs. Therefore, the treating
clinician should be extra aware of underlying opportunistic infections, such as Pneumocystis
jiroveci [109, 110]. Furthermore, immunosuppressive drugs themselves, such as
methotrexate, TNF-α inhibitors, tocilizumab and rituximab, can cause ILD [111].
High-dose corticosteroids, cyclophosphamide or rituximab can be used when treating acute
exacerbations in non-IPF pulmonary fibrosis [112, 113].

Summary

Acute exacerbations can occur in patients with non-IPF pulmonary fibrosis, such as iNSIP,
CVD-related ILD or fibrotic hypersensitivity pneumonitis. During the management, a
similar approach as for the evaluation of acute respiratory worsening in AE-IPF can be
followed. However, based on the fact that many patients will have used immunosuppressive
drugs, an extra focus should be on excluding opportunistic infections and drug toxicity.
Using high-dose corticosteroids, cyclophosphamide or rituximab is advised when treating
these acute exacerbations.

Conclusions

Acute exacerbations occur over a broad spectrum of ILDs, such as sarcoidosis, IPF, iNSIP,
hypersensitivity pneumonitis and CVD-related ILDs. There are important differences in the
presentation, aetiology and prognosis of acute exacerbations between these different ILDs.
In sarcoidosis, acute exacerbations in general respond very well to corticosteroids and have
a good prognosis based on reversibility. On the contrary, in more fibrotic diseases such as
IPF, an effective response to corticosteroids during an acute exacerbation is less likely,
making such events often fatal. It is becoming increasingly recognised that an acute
exacerbation in fibrotic ILD does not necessarily have to be idiopathic, but can be provoked
by various triggers, such as infection, mechanical ventilation, drug toxicity and aspiration.
Decisions regarding mechanical ventilation in patients with acute exacerbations of ILD are
challenging and should be discussed case by case, preferably in a multidisciplinary setting.
Future trials studying new treatment options for patients with acute exacerbation in ILDs
are eagerly awaited.

127

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

References
1. Travis WD, Costabel U, Hansell DM, et al. An official American Thoracic Society/European Respiratory Society
statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias.
Am J Respir Crit Care Med 2013; 188: 733–748.
2. Baughman RP, Teirstein AS, Judson MA, et al. Clinical characteristics of patients in a case control study of
sarcoidosis. Am J Respir Crit Care Med 2001; 164: 1885–1889.
3. Gibson GJ, Prescott RJ, Muers MF, et al. British Thoracic Society Sarcoidosis study: effects of long term
corticosteroid treatment. Thorax 1996; 51: 238–247.
4. Judson MA, Boan AD, Lackland DT. The clinical course of sarcoidosis: presentation, diagnosis, and treatment in
a large white and black cohort in the United States. Sarcoidosis Vasc Diffuse Lung Dis 2012; 29: 119–127.
5. Baughman RP, Grutters JC. New treatment strategies for pulmonary sarcoidosis: antimetabolites, biological drugs,
and other treatment approaches. Lancet Respir Med 2015; 3: 813–822.
6. Mana J, Montero A, Vidal M, et al. Recurrent sarcoidosis: a study of 17 patients with 24 episodes of recurrence.
Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 212–221.
7. Baughman RP, Lower EE. Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients. Respir
Med 2013; 107: 2009–2013.
8. Gottlieb JE, Israel HL, Steiner RM, et al. Outcome in sarcoidosis. The relationship of relapse to corticosteroid
therapy. Chest 1997; 111: 623–631.
9. Hunninghake GW, Gilbert S, Pueringer R, et al. Outcome of the treatment for sarcoidosis. Am J Respir Crit Care
Med 1994; 149: 893–898.
10. Rizzato G, Montemurro L, Colombo P. The late follow-up of chronic sarcoid patients previously treated with
corticosteroids. Sarcoidosis Vasc Diffuse Lung Dis 1998; 15: 52–58.
11. Johns CJ, Schonfeld SA, Scott PP, et al. Longitudinal study of chronic sarcoidosis with low-dose maintenance
corticosteroid therapy. Outcome and complications. Ann NY Acad Sci 1986; 465: 702–712.
12. Panselinas E, Judson MA. Acute pulmonary exacerbations of sarcoidosis. Chest 2012; 142: 827–836.
13. Bechtel JJ, Starr T 3rd, Dantzker DR, et al. Airway hyperreactivity in patients with sarcoidosis. Am Rev Respir
Dis 1981; 124: 759–761.
14. Marcias S, Ledda MA, Perra R, et al. Aspecific bronchial hyperreactivity in pulmonary sarcoidosis. Sarcoidosis
1994; 11: 118–122.
15. Mihailovic-Vucinic V, Zugic V, Videnovic-Ivanov J. New observations on pulmonary function changes in
sarcoidosis. Curr Opin Pulm Med 2003; 9: 436–441.
16. Swigris JJ, Olson AL, Huie TJ, et al. Increased risk of pulmonary embolism among US decedents with sarcoidosis
from 1988 to 2007. Chest 2011; 140: 1261–1266.
17. Vorselaars AD, Snijder RJ, Grutters JC. Increased number of pulmonary embolisms in sarcoidosis patients. Chest
2012; 141: 826–827.
18. Chang B, Steimel J, Moller DR, et al. Depression in sarcoidosis. Am J Respir Crit Care Med 2001; 163: 329–334.
19. Drent M, Lower EE, De Vries J. Sarcoidosis-associated fatigue. Eur Respir J 2012; 40: 255–263.
20. Hoitsma E, De Vries J, Drent M. The small fiber neuropathy screening list: construction and cross-validation in
sarcoidosis. Respir Med 2011; 105: 95–100.
21. McKinzie BP, Bullington WM, Mazur JE, et al. Efficacy of short-course, low-dose corticosteroid therapy for acute
pulmonary sarcoidosis exacerbations. Am J Med Sci 2010; 339: 1–4.
22. Judson MA, Gilbert GE, Rodgers JK, et al. The utility of the chest radiograph in diagnosing exacerbations of
pulmonary sarcoidosis. Respirology 2008; 13: 97–102.
23. Celada LJ, Hawkins C, Drake WP. The etiologic role of infectious antigens in sarcoidosis pathogenesis. Clin Chest
Med 2015; 36: 561–568.
24. Israel HL, Karlin P, Menduke H, et al. Factors affecting outcome of sarcoidosis. Influence of race, extrathoracic
involvement, and initial radiologic lung lesions. Ann NY Acad Sci 1986; 465: 609–618.
25. Rodrigues SC, Rocha NA, Lima MS, et al. Factor analysis of sarcoidosis phenotypes at two referral centers in
Brazil. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28: 34–43.
26. Alazemi S, Campos MA. Interferon-induced sarcoidosis. Int J Clin Pract 2006; 60: 201–211.
27. Eule H, Weinecke A, Roth I, et al. The possible influence of corticosteroid therapy on the natural course of
pulmonary sarcoidosis. Late results of a continuing clinical study. Ann NY Acad Sci 1986; 465: 695–701.
28. Li SD, Yong S, Srinivas D, et al. Reactivation of sarcoidosis during interferon therapy. J Gastroenterol 2002; 37: 50–54.
29. Hurst EA, Mauro T. Sarcoidosis associated with pegylated interferon alfa and ribavirin treatment for chronic
hepatitis C: a case report and review of the literature. Arch Dermatol 2005; 141: 865–868.
30. Burns AM, Green PJ, Pasternak S. Etanercept-induced cutaneous and pulmonary sarcoid-like granulomas
resolving with adalimumab. J Cutan Pathol 2012; 39: 289–293.
31. Louie GH, Chitkara P, Ward MM. Relapse of sarcoidosis upon treatment with etanercept. Ann Rheum Dis 2008;
67: 896–898.

128

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ILD | M. VELTKAMP AND J.C. GRUTTERS

32. Verschueren K, Van Essche E, Verschueren P, et al. Development of sarcoidosis in etanercept-treated rheumatoid
arthritis patients. Clin Rheumatol 2007; 26: 1969–1971.
33. Lenner R, Bregman Z, Teirstein AS, et al. Recurrent pulmonary sarcoidosis in HIV-infected patients receiving
highly active antiretroviral therapy. Chest 2001; 119: 978–981.
34. Mirmirani P, Maurer TA, Herndier B, et al. Sarcoidosis in a patient with AIDS: a manifestation of immune
restoration syndrome. J Am Acad Dermatol 1999; 41: 285–286.
35. Morris DG, Jasmer RM, Huang L, et al. Sarcoidosis following HIV infection: evidence for CD4+ lymphocyte
dependence. Chest 2003; 124: 929–935.
36. Martinez FJ, Orens JB, Deeb M, et al. Recurrence of sarcoidosis following bilateral allogeneic lung transplantation.
Chest 1994; 106: 1597–1599.
37. Barbers RG. Role of transplantation (lung, liver, and heart) in sarcoidosis. Clin Chest Med 1997; 18: 865–874.
38. Walker S, Mikhail G, Banner N, et al. Medium term results of lung transplantation for end stage pulmonary
sarcoidosis. Thorax 1998; 53: 281–284.
39. Nunley DR, Hattler B, Keenan RJ, et al. Lung transplantation for end-stage pulmonary sarcoidosis. Sarcoidosis
Vasc Diffuse Lung Dis 1999; 16: 93–100.
40. Coultas DB, Zumwalt RE, Black WC, et al. The epidemiology of interstitial lung diseases. Am J Respir Crit Care
Med 1994; 150: 967–972.
41. Barlo NP, van Moorsel CH, van den Bosch JM, et al. Idiopathic pulmonary fibrosis; description of a Dutch
cohort. Ned Tijdschr Geneeskd 2009; 153: B425.
42. Jeon K, Chung MP, Lee KS, et al. Prognostic factors and causes of death in Korean patients with idiopathic
pulmonary fibrosis. Respir Med 2006; 100: 451–457.
43. Natsuizaka M, Chiba H, Kuronuma K, et al. Epidemiologic survey of Japanese patients with idiopathic pulmonary
fibrosis and investigation of ethnic differences. Am J Respir Crit Care Med 2014; 190: 773–779.
44. Collard HR, Moore BB, Flaherty KR, et al. Acute exacerbations of idiopathic pulmonary fibrosis. Am J Respir Crit
Care Med 2007; 176: 636–643.
45. Collard HR, Ryerson CJ, Corte TJ, et al. Acute exacerbation of idiopathic pulmonary fibrosis. An international
working group report. Am J Respir Crit Care Med 2016; 194: 265–275.
46. Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis.
N Engl J Med 2011; 365: 1079–1087.
47. King TE Jr, Brown KK, Raghu G, et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic
pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184: 92–99.
48. King TE Jr, Albera C, Bradford WZ, et al. Effect of interferon gamma-1b on survival in patients with idiopathic
pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 2009; 374: 222–228.
49. Raghu G, Behr J, Brown KK, et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel,
randomized trial. Ann Intern Med 2013; 158: 641–649.
50. Idiopathic Pulmonary Fibrosis Clinical Research Network. Randomized trial of acetylcysteine in idiopathic
pulmonary fibrosis. N Engl J Med 2014; 370: 2093–2101.
51. Kondoh Y, Taniguchi H, Katsuta T, et al. Risk factors of acute exacerbation of idiopathic pulmonary fibrosis.
Sarcoidosis Vasc Diffuse Lung Dis 2010; 27: 103–110.
52. Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors
and outcome. Eur Respir J 2011; 37: 356–363.
53. Kim DS. Acute exacerbations in patients with idiopathic pulmonary fibrosis. Respir Res 2013; 14: 86.
54. Knipscheer BJ, van Moorsel CH, Grutters JC. Non-specific and usual interstitial pneumonia, short-term survival
after surgical biopsy. Lung 2015; 193: 449–450.
55. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol 2014; 9: 157–179.
56. Kim DS, Park JH, Park BK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: frequency and clinical
features. Eur Respir J 2006; 27: 143–150.
57. Parambil JG, Myers JL, Aubry MC, et al. Causes and prognosis of diffuse alveolar damage diagnosed on surgical
lung biopsy. Chest 2007; 132: 50–57.
58. Ryerson CJ, Cottin V, Brown KK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the
paradigm. Eur Respir J 2015; 46: 512–520.
59. Meduri GU, Headley AS, Golden E, et al. Effect of prolonged methylprednisolone therapy in unresolving acute
respiratory distress syndrome: a randomized controlled trial. JAMA 1998; 280: 159–165.
60. Steinberg KP, Hudson LD, Goodman RB, et al. Efficacy and safety of corticosteroids for persistent acute
respiratory distress syndrome. N Engl J Med 2006; 354: 1671–1684.
61. Boyle AJ, Mac Sweeney R, McAuley DF. Pharmacological treatments in ARDS; a state-of-the-art update. BMC
Med 2013; 11: 166.
62. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis:
evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788–824.
63. Cottin V, Crestani B, Valeyre D, et al. Diagnosis and management of idiopathic pulmonary fibrosis: French
practical guidelines. Eur Respir Rev 2014; 23: 193–214.

129

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

64. Nederlandse Vereniging van Artsen voor Longziekten en Tuberculose. Position paper diagnostiek en behandeling
Idiopathische Pulmonale Fibrose. [Position paper diagnostics and treatment of idiopathic pulmonary fibrosis.]
2014. www.nvalt.nl/uploads/63/Un/63UnZRbFCx42ZiOatvasyQ/Position-paper-Idiopathische-Pulmonale-Fibrose-
FINAL.pdf Date last accessed: October 5, 2016.
65. Tajima S, Oshikawa K, Tominaga S, et al. The increase in serum soluble ST2 protein upon acute exacerbation of
idiopathic pulmonary fibrosis. Chest 2003; 124: 1206–1214.
66. Sakamoto S, Homma S, Miyamoto A, et al. Cyclosporin A in the treatment of acute exacerbation of idiopathic
pulmonary fibrosis. Intern Med 2010; 49: 109–115.
67. Horita N, Akahane M, Okada Y, et al. Tacrolimus and steroid treatment for acute exacerbation of idiopathic
pulmonary fibrosis. Intern Med 2011; 50: 189–195.
68. Inase N, Sawada M, Ohtani Y, et al. Cyclosporin A followed by the treatment of acute exacerbation of idiopathic
pulmonary fibrosis with corticosteroid. Intern Med 2003; 42: 565–570.
69. Ambrosini V, Cancellieri A, Chilosi M, et al. Acute exacerbation of idiopathic pulmonary fibrosis: report of a
series. Eur Respir J 2003; 22: 821–826.
70. Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of patients with acute exacerbation of
idiopathic pulmonary fibrosis undergoing surgical lung biopsy. Chest 2005; 128: 3310–3315.
71. Okamoto T, Ichiyasu H, Ichikado K, et al. Clinical analysis of the acute exacerbation in patients with idiopathic
pulmonary fibrosis. Nihon Kokyuki Gakkai Zasshi 2006; 44: 359–367.
72. Shishido M, Ichiki H, Yano M, et al. A case of idiopathic pulmonary fibrosis with histology of usual interstitial
pneumonia that responded to pulse therapy followed by combined immunosuppression with prednisolone and
azathioprine. Nihon Kyobu Shikkan Gakkai Zasshi 1992; 30: 2139–2145.
73. Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for
pulmonary fibrosis. N Engl J Med 2012; 366: 1968–1977.
74. Calfee CS, Delucchi K, Parsons PE, et al. Subphenotypes in acute respiratory distress syndrome: latent class
analysis of data from two randomised controlled trials. Lancet Respir Med 2014; 2: 611–620.
75. Lorente JA, Cardinal-Fernandez P, Munoz D, et al. Acute respiratory distress syndrome in patients with and
without diffuse alveolar damage: an autopsy study. Intensive Care Med 2015; 41: 1921–1930.
76. Antoniou KM, Cottin V. The challenge of acute exacerbation of pulmonary fibrosis. Respiration 2012; 83: 13–16.
77. Enomoto N, Mikamo M, Oyama Y, et al. Treatment of acute exacerbation of idiopathic pulmonary fibrosis with direct
hemoperfusion using a polymyxin B-immobilized fiber column improves survival. BMC Pulm Med 2015; 15: 15.
78. Kase Y, Obata T, Okamoto Y, et al. Removal of 2-arachidonylglycerol by direct hemoperfusion therapy with
polymyxin B immobilized fibers benefits patients with septic shock. Ther Apher Dial 2008; 12: 374–380.
79. Tsushima K, Kubo K, Koizumi T, et al. Direct hemoperfusion using a polymyxin B immobilized column
improves acute respiratory distress syndrome. J Clin Apher 2002; 17: 97–102.
80. Raghu G, Rochwerg B, Zhang Y, et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of
Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med
2015; 192: e3–e19.
81. Azuma A, Nukiwa T, Tsuboi E, et al. Double-blind, placebo-controlled trial of pirfenidone in patients with
idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171: 1040–1047.
82. Noble PW, Albera C, Bradford WZ, et al. Pirfenidone in patients with idiopathic pulmonary fibrosis
(CAPACITY): two randomised trials. Lancet 2011; 377: 1760–1769.
83. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic
pulmonary fibrosis. N Engl J Med 2014; 370: 2083–2092.
84. Nathan SD, Albera C, Bradford WZ, et al. Effect of continued treatment with pirfenidone following clinically
meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic
pulmonary fibrosis. Thorax 2016; 71: 429–435.
85. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl
J Med 2014; 370: 2071–2082.
86. Costabel U, Inoue Y, Richeldi L, et al. Efficacy of nintedanib in idiopathic pulmonary fibrosis across prespecified
subgroups in INPULSIS. Am J Respir Crit Care Med 2016; 193: 178–185.
87. Demedts M, Behr J, Buhl R, et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;
353: 2229–2242.
88. Behr J, Bendstrup E, Crestani B, et al. Safety and tolerability of acetylcysteine and pirfenidone combination
therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial.
Lancet Respir Med 2016; 4: 445–453.
89. Mercer PF, Chambers RC. Coagulation and coagulation signalling in fibrosis. Biochim Biophys Acta 2013; 1832:
1018–1027.
90. Kubo H, Nakayama K, Yanai M, et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 2005; 128:
1475–1482.
91. Noth I, Anstrom KJ, Calvert SB, et al. A placebo-controlled randomized trial of warfarin in idiopathic pulmonary
fibrosis. Am J Respir Crit Care Med 2012; 186: 88–95.

130

FB:Cardiologia Siglo XXI

 ACUTE EXACERBATIONS OF ILD | M. VELTKAMP AND J.C. GRUTTERS

92. Kreuter M, Wijsenbeek MS, Vasakova M, et al. Unfavourable effects of medically indicated oral anticoagulants on
survival in idiopathic pulmonary fibrosis. Eur Respir J 2016; 47: 1776–1784.
93. Vial-Dupuy A, Sanchez O, Douvry B, et al. Outcome of patients with interstitial lung disease admitted to the
intensive care unit. Sarcoidosis Vasc Diffuse Lung Dis 2013; 30: 134–142.
94. Zafrani L, Lemiale V, Lapidus N, et al. Acute respiratory failure in critically ill patients with interstitial lung
disease. PLoS One 2014; 9: e104897.
95. Mollica C, Paone G, Conti V, et al. Mechanical ventilation in patients with end-stage idiopathic pulmonary
fibrosis. Respiration 2010; 79: 209–215.
96. Mallick S. Outcome of patients with idiopathic pulmonary fibrosis (IPF) ventilated in intensive care unit.
Respir Med 2008; 102: 1355–1359.
97. Rush B, Wiskar K, Berger L, et al. The use of mechanical ventilation in patients with idiopathic pulmonary
fibrosis in the United States: a nationwide retrospective cohort analysis. Respir Med 2016; 111: 72–76.
98. Suda T, Kaida Y, Nakamura Y, et al. Acute exacerbation of interstitial pneumonia associated with collagen
vascular diseases. Respir Med 2009; 103: 846–853.
99. Lee HK, Kim DS, Yoo B, et al. Histopathologic pattern and clinical features of rheumatoid arthritis-associated
interstitial lung disease. Chest 2005; 127: 2019–2027.
100. Olson AL, Huie TJ, Groshong SD, et al. Acute exacerbations of fibrotic hypersensitivity pneumonitis: a case
series. Chest 2008; 134: 844–850.
101. Churg A, Muller NL, Silva CI, et al. Acute exacerbation (acute lung injury of unknown cause) in UIP and other
forms of fibrotic interstitial pneumonias. Am J Surg Pathol 2007; 31: 277–284.
102. Park JH, Kim DS, Park IN, et al. Prognosis of fibrotic interstitial pneumonia: idiopathic versus collagen vascular
disease-related subtypes. Am J Respir Crit Care Med 2007; 175: 705–711.
103. Rice AJ, Wells AU, Bouros D, et al. Terminal diffuse alveolar damage in relation to interstitial pneumonias.
An autopsy study. Am J Clin Pathol 2003; 119: 709–714.
104. Parambil JG, Myers JL, Lindell RM, et al. Interstitial lung disease in primary Sjögren syndrome. Chest 2006; 130:
1489–1495.
105. Parambil JG, Myers JL, Ryu JH. Diffuse alveolar damage: uncommon manifestation of pulmonary involvement in
patients with connective tissue diseases. Chest 2006; 130: 553–558.
106. Park IN, Kim DS, Shim TS, et al. Acute exacerbation of interstitial pneumonia other than idiopathic pulmonary
fibrosis. Chest 2007; 132: 214–220.
107. Tachikawa R, Tomii K, Ueda H, et al. Clinical features and outcome of acute exacerbation of interstitial
pneumonia: collagen vascular diseases-related versus idiopathic. Respiration 2012; 83: 20–27.
108. Miyazaki Y, Tateishi T, Akashi T, et al. Clinical predictors and histologic appearance of acute exacerbations in
chronic hypersensitivity pneumonitis. Chest 2008; 134: 1265–1270.
109. Yoshida Y, Takahashi Y, Minemura N, et al. Prognosis of pneumocystis pneumonia complicated in patients with
rheumatoid arthritis (RA) and non-RA rheumatic diseases. Mod Rheumatol 2012; 22: 509–514.
110. Arita Y, Taguchi H, Kobayashi M, et al. Pneumocystis jirovecii pneumonia developed in a patient with rheumatoid
arthritis after 14 weeks of iguratimod add-on to treatment with methotrexate and etanercept. Mod Rheumatol
2016; in press [DOI: 10.1080/14397595.2016.1181026].
111. Roubille C, Haraoui B. Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in
rheumatoid arthritis: a systematic literature review. Semin Arthritis Rheum 2014; 43: 613–626.
112. Wallace B, Vummidi D, Khanna D. Management of connective tissue diseases associated interstitial lung disease:
a review of the published literature. Curr Opin Rheumatol 2016; 28: 236–245.
113. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in
collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax
2008; 63: Suppl. 5, v1–v58.

Disclosures: None declared.

131

FB:Cardiologia Siglo XXI

 | Chapter 9
Severe haemoptysis
Muriel Fartoukh1, Guillaume Voiriot1, Samuel Hadad2,
Hicham Masmoudi3, Jalal Assouad3, Marie-France Carette2,
Antoine Khalil4 and Antoine Parrot1

Haemoptysis may be life threatening, with a mortality rate >50% in the absence of early and
adequate management. Evaluation of the severity of haemoptysis is crucial to determine the
most appropriate treatment in a timely fashion. The therapeutic management of severe
haemoptysis has improved considerably with the advances in vascular interventional
radiology, with thoracic surgery being reserved for failure of endovascular treatment or focal
lesions at high risk of bleeding recurrence in selected patients. Evaluation of therapeutic
strategies targeted on the risk of adverse outcomes and mortality is necessary to refine the
management of severe haemoptysis and improve its prognosis.

H aemoptysis is a common symptom accounting for 15% of recruitment in pneumology

or thoracic surgery wards [1–3]. In a few cases (5–10%), haemoptysis may be life
threatening, with a mortality rate >50% in the absence of early and adequate management
[4–7]. A methodical reasoning and a rigorous algorithm of management may improve the
prognosis of severe haemoptysis [1, 8, 9].

Here, we will focus on haemoptysis related to systemic bronchial and nonbronchial arteries
or pulmonary artery involvement. More rarely, haemoptysis may be related to injury of the
alveolar/capillary barrier. Alveolar haemorrhage should be suspected in case of haemoptysis,
anaemia and diffuse bilateral infiltrates with a peri-bronchovascular disposition. Alveolar
haemorrhage is mainly related to immune disorders and cardiac dysfunction, although
infectious diseases may account for a few cases [10].

Definition, pathogenesis, mechanism(s) and aetiologies

Severe haemoptysis is a life-threatening expectoration of blood originating from the

lower respiratory tract, by virtue of airway obstruction and/or alveolar inundation or blood
loss [11].

1
AP-HP, Hôpital Tenon, Unité de Réanimation Médico-chirurgicale, Hôpitaux Universitaires de l’Est Parisien, Hôpital Tenon, Sorbonne
Universités, UPMC Université Paris 06, Collégium Galilée, GRC CARMAS, Paris, France. 2AP-HP, Hôpital Tenon, Service de Radiologie,
Hôpitaux Universitaires de l’Est Parisien, Hôpital Tenon, Sorbonne Universités, UPMC Université Paris 06, Paris, France. 3AP-HP,
Hôpital Tenon, Service de Chirurgie Thoracique et Vasculaire, Hôpitaux Universitaires de l’Est Parisien, Hôpital Tenon, Sorbonne
Universités, UPMC Université Paris 06, UMRS1158, Institut Thoracique de Tenon, Paris, France. 4Service de Radiologie, Hôpital Bichat
Claude Bernard, HUPNVS, Paris, France.

Correspondence: Muriel Fartoukh, AP-HP, Hôpital Tenon, 4 rue de la Chine, 75020 Paris, France. E-mail: muriel.fartoukh@aphp.fr

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

132 ERS Monogr 2016; 74: 132–150. DOI: 10.1183/2312508X.10001916

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

The lungs are supplied by a dual vasculature involving the systemic bronchial arteries
(nutritional role) and the pulmonary arteries (functional role) [12]. Physiological
connections exist between both systems, at different anatomical levels (bronchopulmonary,
pre-capillary, capillary and post-capillary) (figure 1).

In most cases (90%), blood may enter into the bronchi from the systemic arteries
(bronchial and nonbronchial) [1, 13–16]. The pulmonary system, mainly arterial, is
implicated in 5–10% of cases [1, 9, 17–19], while post-capillary anastomosis is involved in a
minority of cases (e.g. pulmonary vein stenosis, fibrosing mediastinitis and mitral stenosis)
[20, 21]. Exceptionally, large intrathoracic vessels may be involved (e.g. aortobronchial
fistula, bronchopulmonary sequestration or tumoural invasion of a large vessel) [22–25].

The bronchial arteries arise from the descending thoracic aorta, at the level of the T5/T6
vertebrae, and may originate directly from the aorta or from a right broncho-intercostal
trunk. Several anatomic variants have been described. The anterior spinal artery usually
arises from a left intercostal artery, but may arise from a right intercostal artery originating
from the right broncho-intercostal trunk in 3% of cases. For direct collaterals of bronchial
arteries, the inferior oesophageal artery (arising directly from the aorta or from the left
inferior bronchial artery) may be injured during bronchial artery embolisation [25–30].

Distal bronchial arterial capillary network

Distal bronchial venous capillary network

Pulmonary
Pre-capillary functional
anastomosis unit

Bronchial Bronchopulmonary
artery anastomosis

Pulmonary
vein

Pulmonary
artery

Figure 1. The dual vasculature of the lungs. The bronchial veins are not represented in the figure.

133

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Regional vascular remodelling and neoangiogenesis may develop within the systemic
bronchial and nonbronchial vessels, conversely to the pulmonary vessels [31, 32], under the
following pathological conditions: 1) reduction in the proximal pulmonary blood flow (e.g.
congenital pulmonary stenosis, pulmonary embolism and pulmonary vasculitis such as
Takayasu arteritis or Behçet disease [33–36]), 2) destruction of the cartilage support of the
bronchial wall induced by a chronic inflammatory process (e.g. bronchiectasis and cystic
fibrosis) [37–39] and 3) lung cancer [1, 12, 40, 41].

A wide range of aetiologies of severe haemoptysis have been reported, among which
chronic inflammatory conditions and infectious diseases, including bronchiectasis, cystic
fibrosis, tuberculosis, mycetoma and lung cancer, are the most common and account for
80% of all cases [37, 38, 42, 43] (table 1). Despite a thorough aetiological investigation, 15%
of severe haemoptysis cases remain with no identified cause. Cryptogenic haemoptysis may
be massive; active smoking and airway inflammation could be contributing factors [44–46].
In abundant cryptogenic haemoptysis, ectopic bronchial arteries have been identified in
very superficial positions, contiguous to the bronchial mucosa, with disruption of the
arterial wall in the bronchial lumen (bronchial Dieulafoy syndrome). The exact prevalence
of these vascular abnormalities is not known [45, 46].

Table 1. Main aetiologies of severe haemoptysis

Tumour
Lung cancer
Carcinoid tumour
Infectious diseases
Tuberculosis: active and sequelae
Aspergillus disease: mycetoma; invasive pulmonary aspergillosis
Necrotising pneumonia; lung abscess
Parasitic infection
Bronchopulmonary diseases
Bronchiectasis
Cystic fibrosis
Acute and chronic bronchitis
Miscellaneous
Sarcoidoisis
Endometriosis
Coagulation disorders
Vascular pulmonary diseases
Acute pulmonary embolism and chronic thromboembolic pulmonary hypertension
Pulmonary aneurysm and pulmonary artery pseudo-aneurysm
Pulmonary arteriovenous malformations
Pulmonary arterial hypertension
Pulmonary malformations
Cardiovascular diseases
Congenital heart diseases
Pulmonary venous hypertension
Aortobronchial fistula
Trauma/foreign body
Aspirated foreign body
Tracheovascular fistula
Pulmonary arterial catheter induced pulmonary pseudo-aneurysm
Cryptogenic
Bronchial Dieulafoy disease

134

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

Severity assessment of haemoptysis

Evaluation of the severity of haemoptysis is crucial to target the most appropriate

management in a timely fashion, but remains without consensus [11]. First, the
terminologies used (e.g. “life-threatening”, “massive” or “exsanguinating” haemoptysis) may
refer to heterogeneous populations of patients and different clinical situations [11, 15, 16, 47,
48]. Second, the severity criteria vary, including those related to the patient (i.e. comorbid
conditions or bleeding diathesis [2, 15]) and those associated with the bleeding event or its
consequences (i.e. abundance [11, 15, 16, 47], mechanism (pulmonary arterial involvement),
cause (e.g. lung cancer [40], mycetoma [1, 8, 49] or necrotising pneumonia [49–51]) and
respiratory or haemodynamic consequences [9, 11, 16, 47]). When taken together, the most
commonly reported severity criteria are the abundance of haemoptysis [9, 11, 47], the need
for hospitalisation [47], the administration of systemic vasoconstrictors [15], the need for
mechanical ventilation, vasoactive drugs or blood products [9, 11, 47] and, ultimately, the
occurrence of death [9, 47].

Expectorated blood volume or flow

It is commonly accepted that the quantitative criterion “expectorated blood volume or

flow” is associated with in-hospital mortality [2, 4, 7]. The abundance of haemoptysis is
not easy to assess before admission in clinical practice and may be misestimated. However,
after admission, the estimation of the abundance of haemoptysis may be helpful, using
samples with a known volume (such as a glass, spoon, etc.). The reported thresholds of
volume/flow vary greatly across the literature, ranging from 100 mL per 24 h to 1000 mL
per 48 h [11, 47]. The volume of conductive airways is ∼250 mL and some authors
therefore evaluate the risk of asphyxiation as volumes >400 mL [52].

Magnitude of bleeding effects

The respiratory and haemodynamic consequences of haemoptysis may also contribute to the
characterisation of the severity of haemoptysis [9, 11, 16, 47]. However, the administration of
mechanical ventilation for acute respiratory failure (ARF) only applies to 15–20% of the
patients admitted to the ICU [9, 53]. In addition, the haemodynamic consequences of
haemoptysis (shock) are unusual, and delayed, except when mechanical ventilation is
required [9]. Lastly, the radiological extent of the alveolar flooding may be indicative of the
amount of bleeding, use of mechanical ventilation and in-hospital mortality [54].

Comorbid conditions

Comorbidities, especially chronic lung diseases, cardiovascular diseases and bleeding

diathesis, are also deemed to be severity criteria [1, 2, 9, 15, 38, 40].

Analysis of the mechanism and cause of haemoptysis

Most episodes of severe haemoptysis are related to the regional development of a

bronchosystemic hypervascularisation. There has been a gradual change in the aetiologies of
haemoptysis over the past decades, with chronic infectious processes or inflammatory lung
diseases, including lung cancer, bronchiectasis, tuberculosis (active and sequelae) and
mycetoma, being the most prevalent [1, 6, 15, 40, 55, 56]. Severe haemoptysis related to

135

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

bronchiectasis may involve almost exclusively the bronchial and nonbronchial systemic
vasculature. Conversely, haemoptysis related to lung cancer or infectious and inflammatory
diseases (Rasmussen aneurysm, necrotising pneumonia, aspergillosis and Hughes–Stovin
syndrome) may be related to the involvement of the pulmonary arterial vasculature, the
latter being either concomitant to a systemic hypervascularisation or occurring secondarily
over time [18, 57–59].

The different steps of the therapeutic decision-making process

The therapeutic decision should be based on the following thorough step-by-step reasoning:
1) positive diagnosis of haemoptysis, 2) severity assessment and site of haemoptysis,
3) diagnosis of the mechanism of haemoptysis, and 4) diagnosis of the cause of haemoptysis
(figure 2).

Positive diagnosis

The diagnosis of haemoptysis is easy in most cases [43, 60]. However, pseudo-haemoptysis
(gastrointestinal or ear, nose and throat (ENT) bleeding) may mimic haemoptysis in
3–10% of cases [61, 62] and should always be considered.

Once the diagnosis of haemoptysis has been established, it should be determined if the
bleeding arises from the bronchi or the alveoli. Alveolar haemorrhage should be suspected in
the case of combined haemoptysis, anaemia and chest radiograph diffuse bilateral infiltrates.
A CT scan shows a diffuse alveolar and interstitial syndrome, with a subpleural location, and

No: rule out severe haemoptysis

Does blood originate from the Pseudo-haemoptysis
lower respiratory tract?
Yes Alveoli

Bronchi

Bleeding volume/rate
What is the severity and Respiratory consequences (respiratory rate, SpO2, PaO2,
the site of haemoptysis? mechanical ventilation)
Comorbid condition: chronic respiratory disease (FEV1 <30%)
Use of systemic vasoconstrictive agents
Pulmonary arterial mechanism
Aetiology (lung cancer, Aspergillus disease)

Systemic bronchial and nonbronchial hypervascularisation

What is the mechanism of Pulmonary arterial involvement
haemoptysis? Large intrathoracic vessels
Dieulafoy bronchial disease

Lung cancer
Account for 80%
What is the cause of Bronchiectasis; cystic fibrosis
of the causes of
haemoptysis? Tuberculosis, active and sequellae
severe haemoptysis
Aspergillus disease

Figure 2. The different steps of the therapeutic decision-making process.

136

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

no signs of pulmonary oedema (no cardiomegaly, no pleural effusion). BAL revealing an

increasingly bloody lavage fluid and/or a siderophagic alveolitis is the cornerstone of the
diagnosis [10]. Of note, diffuse infiltrates may also result from inhalation of massive
haemoptysis. Extrathoracic clues such as renal involvement may be helpful to differentiate
alveolar haemorrhage from inhalation related to massive haemoptysis.

Severity assessment

The assessment of the severity of haemoptysis [11] is based on the abundance of

haemoptysis [9, 11, 47], administration of a systemic vasoconstrictor [15], use of
mechanical ventilation, vasoactive drugs or blood products [9, 11, 47] and, ultimately, death
[9, 47]. It is noteworthy that most of these severity criteria are based on management
practices, which may vary widely across centres, countries, technical facilities, etc. We
recently attempted to identify early factors for in-hospital mortality, aiming at developing a
simple prognostic rule available in the early hours of ICU admission as an aid to
therapeutic decision making [9]. Among 1087 patients, 71 (6.5%) died during
hospitalisation. In patients mechanically ventilated (n=80), hospital mortality reached
32.5%. Factors independently associated with in-hospital mortality were chronic alcoholism,
cause of haemoptysis (especially lung cancer and aspergillosis), radiological extent of
bleeding and administration of mechanical ventilation or vasoactive drugs. A pulmonary
arterial mechanism was marginally significant. A score system including chronic alcoholism
(1 point), cancer (2 points) or aspergillosis (2 points), pulmonary arterial mechanism
(1 point), radiological extent (1 point) and mechanical ventilation (2 points) was used to
classify the patients; accordingly, the probability of in-hospital mortality was 1% for score
0, 2% for score 1, 6% for score 2, 16% for score 3, 34% for score 4, 58% for score 5, 79%
for score 6 and 91% for score 7 (area under the receiver operating characteristics curve
0.87). An external validation of this score is required before applying a therapeutic
algorithm based on its use in patients with haemoptysis referred to the ICU [9].

Location

Haemoptysis may be located by physical exam and chest radiograph in 50–80% of cases [16,
63, 64], and by fibreoptic bronchoscopy in 90% of cases (when performed during active
bleeding) [1, 65]. Multidetector CT angiography (MDCTA) provides a topographic diagnosis
in 80–100% of cases [57, 66], by showing abnormalities reflecting the filling of the airways or
the alveolar lumen with blood (i.e. ground-glass opacities), alveolar consolidation, atelectasis
or unilateral aetiological lesion (e.g. tumour or aspergilloma). Exceptionally, MDCTA may
show extravasation of the contrast medium into the bronchial lumen [26, 57]. If fibreoptic
bronchoscopy remains essential for the aetiological diagnostic evaluation of all episodes of
haemoptysis, it may be performed as a secondary technique. Indeed, there is no indication to
perform it in an emergency for the topographic diagnosis of severe haemoptysis, except in
cases of bilateral lung diseases for which MDCTA might not locate the bleeding (e.g. bilateral
bronchiectasis). Thus, in our experience, the residual indications for performing fibreoptic
bronchoscopy are therapeutic, at the initial phase of severe haemoptysis [65].

Mechanism and cause

The diagnostic approach to the mechanism of haemoptysis should be inseparable from that
of its cause. These steps are crucial for deciding the most appropriate treatment to
administer in a given clinical situation [1].

137

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Therapeutic management of severe haemoptysis

The therapeutic decision is mainly guided by the amount of bleeding and its respiratory
repercussions, the presumed mechanism and cause, and also the patient’s operability and
the potential resectability of the causal lesion. The therapeutic management of severe
haemoptysis is based on medical measures, interventional vascular radiology and thoracic
surgery. The goals are 1) symptomatic (aiming at avoiding suffocation by alveolar flooding
or bronchial obstruction and controlling the bleeding) and 2) therapeutic. Respiratory rate
and pulse oximetry should be monitored closely.

Medical measures

General treatment
The first part of the medical treatment is based on general measures, including bed rest,
free airways, oxygenation and control of bleeding disorders.

The administration of supplemental oxygen is essential to prevent respiratory distress. The

patient may be positioned on the bleeding side, if this is known. When mechanical
ventilation is required (active bleeding or airways compromise), the use of a conventional
large endotracheal tube (8–8.5 French) is recommended in order to perform bronchial
suction and cleaning, and administer topical treatments [67–69]. A selective intubation
should be preferred and is easier to place to the right, despite the exclusion of the right
upper lobe bronchus. A double-lumen tube may be used [70]. Endoscopic control of the
correct positioning is imperative [71, 72]. Ventilatory settings rely on the usual modalities
for improving gas exchanges (FIO2, PEEP, positioning). High levels of PEEP are
recommended in the case of pulmonary arterial involvement, by reducing pulmonary blood
flow and therefore pulmonary artery pressure [73]. Antimicrobial treatments are highly
recommended in haemoptysis related to bronchiectasis, cystic fibrosis and lung abscess or
necrotising pneumonia [38, 49–51], but are still debated in other cases. Cough suppression
remains controversial [1, 47, 71].

Topical treatment (bronchoscopy techniques)

The second part of the medical treatment is based on topical measures, including chemical
and mechanical measures that may be administered by flexible or rigid bronchoscopy [74].

In the case of persistent and abundant bleeding despite the administration of general
measures, bronchoscopic techniques may be useful to control the bleeding, and to perform
blood suction and clear the clots that may obstruct the airways. Rigid bronchoscopy may
provide a more efficient suction, as compared with flexible fibreoptic bronchoscopy, but is
usually performed under general anaesthesia and may require a skilled operative and a
secure environment [56, 71, 74].

Different bronchoscopic techniques may be attempted. Cold saline solution lavage or

epinephrine instillation may be successful [75–77]. Other vasoconstrictive agents (terlipressin,
ornipressin) may also be used [78, 79]. Three studies have suggested the efficacy and safety of
topical administration of ornipressin and terlipressin in the treatment of haemoptysis related to
lung cancer (aerosolised ornipressin) [80] and in iatrogenic haemoptysis [78, 79]. A study
comparing the two methods of administration of terlipressin in humans (i.e. intravenous and
topical) showed that the plasma level of terlipressin was 251 times lower when it was

138

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

administered locally, as compared with a general administration, with a local effect on bronchial
mucosa (pallor) and no significant circulatory side-effects [78]. Other topical haemostatic
tamponades have been reported using either rigid or flexible bronchoscopy [77, 81, 82].

Mechanical tamponade using bronchial blockers or Fogarty catheters at the segment or

subsegment bronchial level may be helpful temporary control measures [67–69, 83]. Lastly,
bronchial cleaning may improve gas exchange [84]. Note, however, that bronchial cleaning
should not remove the clots obstructing the alleged bronchial bleed territory. Bronchial
biopsies should not be performed during active haemoptysis.

Systemic vasoconstrictors
The administration of a systemic vasoconstrictor (vasopressin, terlipressin) may be indicated if
the measures mentioned above are unavailable or insufficient, or in the case of uncontrolled
and massive bleeding [1, 15, 56, 71, 85, 86]. Terlipressin was first used in the treatment of
gastrointestinal bleeding [87, 88]. It has also demonstrated its usefulness in gynaecological [89]
and ENT [90] bleeding. The role of intravenous terlipressin in the treatment of severe
haemoptysis has been suggested by some experimental and clinical observations [91, 92], and
only one open clinical study [85]. These pharmacological agents should be used with caution
in patients with coronary disease and systemic hypertension, and may compromise the success
of bronchial arteriography owing to the vasoconstriction of the bronchial arteries.

Other systemic treatments may be used to control severe haemoptysis, such as tranexamic
acid [28] and recombinant factor VII [93–97].

Interventional vascular radiology

Following the first reports of REMY et al. [30], bronchial artery embolisation (BAE) has
progressively emerged as the first-line treatment of severe haemoptysis [66, 98]. The
procedure has evolved and the use of microcatheters may allow very distal embolisation to
be performed beyond the origin of the critical branches (middle anterior spinal artery,
oesophageal branch) with safety and efficacy [99, 100]. A recent series of reports shows that
severe haemoptysis may be controlled with BAE in 65–100% and 51–90% of cases in the
short and medium term, respectively (table 2).

Endovascular treatment should always be performed after MDCTA (figure 3), which may
help to: 1) identify the site of haemoptysis (ground-glass opacity or localised lung
consolidation), although it is noteworthy that the direct radiological sign of haemoptysis,
i.e. the extravasation of the contrast medium into the bronchial lumen, occurs in <10% of
cases [46, 64, 107, 109] (figure 4); 2) haemoptysis: involvement of the pulmonary arterial
vasculature (e.g. necrosis, pseudo-aneurysm, irregular pulmonary artery in the wall of a cavity
or necrosis) (figure 4), and/or involvement of the systemic bronchial and nonbronchial
arterial vasculature (e.g. hypertrophic and tortuous arteries, neovascularisation, or
hypervascularisation shunting into the pulmonary artery or vein) (figure 5); 3) establish a
comprehensive mapping of the bronchial and nonbronchial systemic arteries before
performing arteriography [25, 29] (figure 6); 4) diagnose the cause of haemoptysis
(tuberculosis, bronchiectasis and lung tumour account for 80% of cases) [25, 66] (figure 7);
and 5) assess the abundance of haemoptysis (e.g. involvement of more than three lobes) [54].
When taken together, the use of MDCTA prior to endovascular treatment may improve the
prognosis of severe haemoptysis [58, 110].

139

FB:Cardiologia Siglo XXI

140

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 2. Performance of endovascular treatment to control haemoptysis in the short and medium/long term

First author [ref.] Study period Patients Haemoptysis characteristics Bleeding control
n Immediate 1 month >1 month

REMY [30] 1977 49 Various amounts 41/49 (84%) NA 35/49 (71%)

(100–500 mL per 24 h)
CREMASHI [101] 1976–1990 209 Various amounts 205/209 (98%) NA 172/209 (82%)
(100 to >300 mL per 24 h)
UFLACKER [102] 1983 33 Various amounts 26/26 (100%) 22/26 (85%) 22/26 (85%)
(26 patients >150 mL per 24 h)
UFLACKER [103] 1985 75 Various amounts (>150 mL per 24 h) 49/75 (65%) NA 39/75 (52%)
MAL [15] 1985–1997 56 Various amounts 43/56 (77%) 32/56 (57%) 25/56 (45%)
RABKIN [104] 1987 306 Various amounts 278/306 (91%) 239/306 (78%) 242/306 (79%)
(120 patients >500 mL per 24 h)
HAYAKAWA [105] 1992 63 Various amounts 50/63 (79%) NA 36/63 (57%)
SWANSON [106] 1981–2000 54 Various amounts; acute and 51/54 (94%) 46/54 (85%) 43/54 (80%)
chronic haemoptysis
RAMAKANTAN [107] 1996 140 Bleeding flow >300 mL per 24 h 102/140 (73%) 72/140 (51%) 94/140 (67%)
WONG [108] 1996–1998 16 Bleeding flow >250 mL 16/16 (100%) 9/10 (90%) 7/10 (70%)
ONG [16] 1997–2001 23 Bleeding flow >300 mL per 24 h or 20/23 (86%) NA 15/23 (65%)
mechanical ventilation
CHUN [13] 2002–2008 50 Various amounts 43/50 (86%) 41/50 (82%) 66% (1 year)
56% (3 years)
CHAN [53] 2000–2006 167 Bleeding flow >300 mL 155/167 (97%) NA 74.5% (1 year)
per 24 h (n=156) or mechanical 55% (5 years)
ventilation (n=56)

NA: not available.

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

MDCTA
The primary diagnostic tool in
severe haemoptysis

1. Bleeding location 2. Bleeding mechanism 3. Systemic arteries 4. Bleeding aetiology

Identify the bleeding Search for pulmonary network analysis
side and site artery involvment#

No Yes Yes No Bronchial artery normotopic

Fibreoptic Pulmonary artery Systemic arteries Bronchial artery atypical

bronchoscopy embolisation embolisation

Bronchial artery ectopic

Nonbronchial systemic artery

Figure 3. The role of multidetector CT angiography (MDCTA) in severe haemoptysis. #: the visualisation of
contrast medium in a necrotic or excavated lesion adjoining the pulmonary artery should suggest a
pulmonary arterial mechanism, especially in the case of acute or necrotic aspergillosis, acute tuberculosis
(Rasmussen aneurysm), Hughes–Stovin syndrome, cancer or necrotising pneumonia. Reproduced and
modified from [25] with permission.

Contraindications of BAE
In the era of MDCTA and the widespread use of microcatheters, the contraindications of
BAE are very limited and the risk/benefit ratio should be assessed for each situation.

Failure of BAE
Failure of BAE may occur in 10–15% of cases, under the following situations: absence of
systemic hypervascularisation, failure of vascular catheterisation, unstable catheter, vasospasm
(especially when systemic vasoconstrictors have been recently administered), arterial
dissection or haematoma [15, 25, 30, 49, 103, 107] and presence of a forgotten or unseen
eutopic or ectopic systemic or bronchial artery involved in the haemorrhage.

a) b)

Figure 4. Pulmonary artery false aneurysm. Medical history: a 29-year-old man with a history of Behçet
disease was admitted to the ICU with severe haemoptysis (300 mL per 24 h). a) Axial CT scan (lung window)
shows an upper left lobe consolidation. b) Axial CT scan (maximal intensity projection, 8 mm thick;
mediastinal window) shows a pulmonary artery false aneurysm (arrow) as the mechanism of haemoptysis.

141

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

a) b)

c) d)

Figure 5. Systemic hypervascularisation. Medical history: a 45-year-old man with chronic aspergillosis
complicating diffuse emphysema was admitted to the ICU with chronic haemoptysis (50 mL per day for
2 weeks). a) Axial and b) sagittal CT scans (parenchymal window) show a fungal ball (#) within the lung
consolidation, bullous emphysema and intercostal artery enlargement (arrow). c) A right broncho-intercostal
trunk angiogram shows a large bronchial artery (arrow) with systemic-to-pulmonary artery shunting
(arrowhead). d) An angiogram of the eighth right intercostal artery shows an enlargement of this artery
(arrow), with the same systemic-to-pulmonary artery shunting (arrowhead) as the bronchial artery in c).

Bleeding recurrences
Bleeding recurrence has been reported in 15–45% of cases [8, 47, 49].

In the short term (1 month), bleeding recurrences may be related to 1) the absence of
identification of nonbronchial systemic arteries such as the internal mammary artery [13, 14,
111]; 2) a procedure performed with ongoing vasoconstrictor treatment or administered <6 h
before the procedure, or with a too proximal occlusion; or 3) a pulmonary arterial mechanism,
initially unknown, or an active lesion in contact with the pulmonary vasculature, such as in
lung cancer, aspergillosis, cystic fibrosis, active tuberculosis and necrotising pneumonia [18, 39,
40, 102, 112, 113].

In the long term (⩾3 months), bleeding recurrences may be favoured by the persistence of
the aetiology or the development of hypervascularisation [1, 53, 107, 114]. Some causes are
particularly at risk of recurrence, such as aspergillosis, lung cancer and tuberculosis [13, 15,
58, 103, 115–117].

142

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

a) b)

c) d) e)

Figure 6. Bronchial artery aneurysm. Medical history: a 30-year-old man was admitted to the ICU with
severe haemoptysis (300 mL per 24 h). a) A coronal maximum intensity projection CT scan (6 mm thick;
parenchymal window) shows a left apical cavitation with disseminated centrolobular micronodules (“tree in
bud”) leading to the diagnosis of active tuberculosis and locates the bleeding in the left upper lobe. b) An
axial maximum intensity projection CT scan (6 mm thick; mediastinal window) shows an enlargement of left
bronchial artery (arrow). c) A coronal maximum intensity projection CT scan (15 mm thick; mediastinal
window) shows a false aneurysm (arrowhead) arising from the left bronchial artery (arrow). d) A left
bronchial artery angiogram confirms the presence of the false aneurysm (arrowhead) and the presence of
pulmonary hypervascularisation. e) A control angiogram after embolisation of the left bronchial artery
shows the complete occlusion of this artery.

Complications of BAE
Complications of BAE are rare (<5%) and dominated by vascular complications, primarily
neurological [9, 43, 60–63]. Several minor complications (e.g. chest pain, dysphagia and
subintimal dissection of the aorta) have been commonly reported [102, 111]. Serious
adverse events requiring discontinuation of the procedure have been very exceptional; the
frequency of these accidents is largely influenced by the operator’s experience and the use
of a microcatheter that allows supraselective catheterisation of the bronchial arteries [1, 15].
A recent study from our centre suggested that the systematic implementation of MDCTA
before interventional radiology was associated with a reduction of the rate of failure of
interventional radiology (especially in elderly patients), an increase in the indications of
pulmonary angiography for pulmonary arterial occlusion and a decrease in the indications
of emergency thoracic surgery [58].

143

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

a) b)

c)

Figure 7. Bronchial artery aneurysm. Medical history: a 30-year-old man was admitted to the ICU with
severe haemoptysis (300 mL per 24 h). a) Tumour obstructing the middle lobar bronchus. b) Ground-glass
opacity around the tumour. c) Tumoural hypervascularisation without shunt, from a right bronchial artery
from a common right/left bronchial trunk.

Pulmonary arterial involvement

In the case of pulmonary arterial involvement, pulmonary angiography with vascular
occlusion using mainly coils may control the bleeding and avoid traditional surgical
treatment. A transcatheter occlusion of the pulmonary arterial circulation might allow
definitive and nonsurgical treatment of these vascular lesions in selected patients [1, 9, 17, 36,
40, 117]. In cancer patients, covered stents grafts have recently been successfully used to stop
the bleeding [118].

Surgery

Until the late 1970s, thoracic surgery was the only treatment likely to change the immediate
prognosis of severe haemoptysis, as compared with medical measures that were limited to
the administration of local cold saline lavage using rigid bronchoscopy. A systematised
pulmonary resection is the rule, ranging from segmentectomy to pneumonectomy, in the
absence of contraindications [118]. Apical thoracoplasty may be associated, especially in the

144

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

case of tuberculous sequelae. Thoracic surgery may radically treat the cause of haemoptysis
and prevent bleeding recurrence when the localised lesion has been resected [6]. The
“surgical” aetiologies of severe haemoptysis have gradually changed over the past 20 years,
and are dominated by bronchiectasis, tuberculosis and its complications (including
mycetoma), and lung cancer [8, 86].

Thoracic surgery may be associated with a high morbidity (bronchopleural fistula, empyema,
haemothorax and prolonged mechanical ventilation) and significant in-hospital mortality when
performed during uncontrolled active bleeding (mortality up to 35%) and in the case of
pneumonectomy [8, 84, 86]. Except for those situations during which bleeding is not
controlled, the decision to perform a lung resection with the aim of preventing bleeding
recurrence remains difficult and should be based on the risk/benefit ratio in each case [86].
Some situations deemed at risk of recurrence (e.g. cavitary lesions associated with nonbronchial
systemic arteries hypervascularisation or secondary atrophic lung segments combined with a
chronic infection) appear to be good surgical indications [115, 119, 120]. Conversely, bilateral
lesions such as in bronchiectasis are poor candidates for surgery [86, 121–123].

The residual role of thoracic surgery has been recently investigated in the initial
management of 111 patients with severe haemoptysis in the era of interventional vascular
radiology [8]. 80% of the patients were operated on after a first procedure of interventional
vascular radiology that controlled the bleeding in only one-third of the cases. More than
half of the patients in whom the interventional vascular radiology did not control the
bleeding were operated on in an emergency setting. The main indications were mycetoma,
lung cancer, bronchiectasis and active tuberculosis. Altogether, surgery was performed in
an emergency setting for uncontrolled active bleeding in 48 patients (43%), during the
same hospital stay after bleeding control in 48 patients (43%) or planned after hospital
discharge in 15 patients (14%). Three patients died during surgery and 49 (46%) developed
post-operative complications. Emergency thoracic surgery, mycetoma and pneumonectomy
were strongly associated with post-operative complications. 15 patients (13.5%) died in the
ICU, 14 of whom had been operated on in an emergency setting. Chronic alcoholism, use
of mechanical ventilation or vasoactive drugs on ICU admission and the administration of
blood products prior to surgery were independent factors for ICU mortality. The majority
of ICU deaths were related to haemoptysis or its complications, whereas deaths after
hospital discharge (n=9) were mainly related to the causal disease [8].

Recommended strategy

The therapeutic management of severe haemoptysis should be multidisciplinary and

implemented in an emergency setting. It is based on a proper assessment of the initial
severity, combining the amount of bleeding and its respiratory consequences, the
mechanism and cause of haemoptysis, as well as comorbid conditions.

The following algorithm may be proposed based on first-line MDCTA to guide the
endovascular treatment in the case of abundant haemoptysis (>200 mL) or ARF.

In the case of successful endovascular treatment, elective thoracic surgery may be proposed to
prevent recurrence, according to the patient’s operability and the resectability of the causal
lesion: localised lesions complicated by abundant haemoptysis or by repeated episodes of
haemoptysis in the same territory (e.g. focal bronchiectasis and sequestration), aetiological

145

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Yes
Acute respiratory failure MDCTA

No Endovascular treatment

MDCTA
Treatment of the cause

Bleeding amount# Thoracic surgery

Failure of endovascular
treatment
Pulmonary arterial
mechanism
Low Moderate High
Focal lesion at high risk of
bleeding recurrence
ARTEMHYS trial¶

Comorbid conditions
Mechanism and cause

Observation Endovascular
Medical measures treatment

Treatment of the Treatment of the

cause cause

Figure 8. Recommended strategy for the management of severe haemoptysis. MDCTA: multidetector CT
angiography. #: low amounts of bleeding usually refer to <100 mL; moderate amounts of bleeding usually refer
to 100–200 mL; high amounts of bleeding usually refer to >200 mL. ¶: ARTEMHYS (ClinicalTrials.gov, trial
number NCT01278199) is a randomised study, involving two parallel groups of patients with haemoptysis of
moderate abundance (100–200 mL) related to a systemic bronchial/nonbronchial hypervascularisation, and
comparing the efficacy and safety of two therapeutic strategies: bronchial artery embolisation combined with
medical measures and medical measures alone. The primary outcome measure is the bleeding recurrence
rate, after the initial strategy. The secondary outcome measure is the evaluation of the rate of serious adverse
events, according to the therapeutic strategy during hospitalisation and the follow-up period.

lesions at risk of high amounts of bleeding or recurrence (e.g. focal aspergillosis and localised
lung cancer), or lesions associated with proximal pulmonary arterial involvement.

If embolisation is technically impossible, and if haemoptysis persists or recurs despite one

or multiple endovascular treatments, surgery should be performed in an emergency, despite
its risks (figure 8).

Conclusions

Severe haemoptysis is related to chronic inflammatory and infectious diseases, of which

lung cancer, bronchiectasis, tuberculosis and aspergillosis are the most common. A
thorough and multidisciplinary approach to the severity of haemoptysis is essential to guide
any therapeutic decision and its implementation. Vascular interventional radiology has
become the first-line treatment of severe haemoptysis, with emergency surgical lung

146

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

resection being reserved for failure of endovascular treatment or focal lesions at high risk of
recurrence. Therapeutic strategies based on knowledge of early prognostic factors should be
developed to improve the prognosis of severe haemoptysis.

References
1. Fartoukh M, Khalil A, Louis L, et al. An integrated approach to diagnosis and management of severe haemoptysis
in patients admitted to the intensive care unit: a case series from a referral centre. Respir Res 2007; 8: 11.
2. Hirshberg B, Biran I, Glazer M, et al. Hemoptysis: etiology, evaluation, and outcome in a tertiary referral hospital.
Chest 1997; 112: 440–444.
3. O’Neil KM, Lazarus AA. Hemoptysis. Indications for bronchoscopy. Arch Intern Med 1991; 151: 171–174.
4. Crocco JA, Rooney JJ, Fankushen DS, et al. Massive hemoptysis. Arch Intern Med 1968; 121: 495–498.
5. Garzon AA, Gourin A. Surgical management of massive hemoptysis. A ten-year experience. Ann Surg 1978; 187:
267–271.
6. Knott-Craig CJ, Oostuizen JG, Rossouw G, et al. Management and prognosis of massive hemoptysis. Recent
experience with 120 patients. J Thorac Cardiovasc Surg 1993; 105: 394–397.
7. Sehhat S, Oreizie M, Moinedine K. Massive pulmonary hemorrhage: surgical approach as choice of treatment.
Ann Thorac Surg 1978; 25: 12–15.
8. Andrejak C, Parrot A, Bazelly B, et al. Surgical lung resection for severe hemoptysis. Ann Thorac Surg 2009; 88:
1556–1565.
9. Fartoukh M, Khoshnood B, Parrot A, et al. Early prediction of in-hospital mortality of patients with hemoptysis:
an approach to defining severe hemoptysis. Respiration 2012; 83: 106–114.
10. de Prost N, Parrot A, Cuquemelle E, et al. Diffuse alveolar hemorrhage in immunocompetent patients: etiologies
and prognosis revisited. Respir Med 2012; 106: 1021–1032.
11. Ibrahim WH. Massive haemoptysis: the definition should be revised. Eur Respir J 2008; 32: 1131–1132.
12. Deffebach ME, Charan NB, Lakshminarayan S, et al. The bronchial circulation. Small, but a vital attribute of the
lung. Am Rev Respir Dis 1987; 135: 463–481.
13. Chun JY, Belli AM. Immediate and long-term outcomes of bronchial and non-bronchial systemic artery
embolisation for the management of haemoptysis. Eur Radiol 2010; 20: 558–565.
14. Chung MJ, Lee JH, Lee KS, et al. Bronchial and nonbronchial systemic arteries in patients with hemoptysis:
depiction on MDCT angiography. AJR Am J Roentgenol 2006; 186: 649–655.
15. Mal H, Rullon I, Mellot F, et al. Immediate and long-term results of bronchial artery embolization for
life-threatening hemoptysis. Chest 1999; 115: 996–1001.
16. Ong TH, Eng P. Massive hemoptysis requiring intensive care. Intensive Care Med 2003; 29: 317–320.
17. Khalil A, Parrot A, Fartoukh M, et al. Pulmonary artery occlusion with ethylene vinyl alcohol copolymer in
patients with hemoptysis: initial experience in 12 cases. AJR Am J Roentgenol 2012; 198: 207–212.
18. Picard C, Parrot A, Boussaud V, et al. Massive hemoptysis due to Rasmussen aneurysm: detection with helicoidal
CT angiography and successful steel coil embolization. Intensive Care Med 2003; 29: 1837–1839.
19. Sbano H, Mitchell AW, Ind PW, et al. Peripheral pulmonary artery pseudoaneurysms and massive hemoptysis.
AJR Am J Roentgenol 2005; 184: 1253–1259.
20. Braun S, Platzek I, Zöphel K, et al. Haemoptysis due to pulmonary venous stenosis. Eur Respir Rev 2014; 23: 170–179.
21. Williamson WA, Tronic BS, Levitan N, et al. Pulmonary venous infarction. Chest 1992; 102: 937–940.
22. Liu SF, Chen YC, Lin MC, et al. Thoracic aortic aneurysm with aortobronchial fistula: a thirteen-year experience.
Heart Lung 2004; 33: 119–123.
23. Pirrelli S, Bozzani A, Arici V, et al. Endovascular treatment of acute haemoptysis secondary to aortobronchial
fistula. Eur J Vasc Endovasc Surg 2006; 32: 366–368.
24. Wheatley GH III, Nunez A, Preventza O, et al. Have we gone too far? Endovascular stent-graft repair of
aortobronchial fistulas. J Thorac Cardiovasc Surg 2007; 133: 1277–1285.
25. Khalil A, Fedida B, Parrot A, et al. Severe hemoptysis: from diagnosis to embolization. Diagn Interv Imaging
2015; 96: 775–788.
26. Bruzzi JF, Remy-Jardin M, Delhaye D, et al. Multi-detector row CT of hemoptysis. Radiographics 2006; 26: 3–22.
27. Cowling MG, Belli AM. A potential pitfall in bronchial artery embolization. Clin Radiol 1995; 50: 105–107.
28. Moen CA, Burrell A, Dunning J. Does tranexamic acid stop haemoptysis? Interact Cardiovasc Thorac Surg 2013;
17: 991–994.
29. Remy-Jardin M, Bouaziz N, Dumont P, et al. Bronchial and nonbronchial systemic arteries at multi-detect row
CT angiography: comparison with conventional angiography. Radiology 2004; 233: 741–749.
30. Remy J, Arnaud A, Fardou H, et al. Treatment of hemoptysis by embolization of bronchial arteries. Radiology
1977; 122: 33–37.

147

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

31. Mitzner W, Wagner EM. Vascular remodeling in the circulations of the lung. J Appl Physiol 2004; 97: 1999–2004.
32. Muller KM, Meyer-Schwickerath M. Bronchial arteries in various stages of bronchogenic carcinoma. Pathol Res
Pract 1978; 163: 34–46.
33. Fadel E, Wijtenburg E, Michel R, et al. Regression of the systemic vasculature to the lung after removal of
pulmonary artery obstruction. Am J Respir Crit Care Med 2006; 173: 345–349.
34. Malik AB, Tracy SE. Bronchovascular adjustments after pulmonary embolism. J Appl Physiol Respir Environ Exerc
Physiol 1980; 49: 476–481.
35. Matsuda A. Bronchial arteriography in patients with pulmonary embolism. Chest 1984; 85: 767–773.
36. Pelage JP, El HM, Lagrange C, et al. Pulmonary artery interventions: an overview. Radiographics 2005; 25: 1653–1667.
37. Brinson GM, Noone PG, Mauro MA, et al. Bronchial artery embolization for the treatment of hemoptysis in
patients with cystic fibrosis. Am J Respir Crit Care Med 1998; 157: 1951–1958.
38. Flume PA, Yankaskas JR, Ebeling M, et al. Massive hemoptysis in cystic fibrosis. Chest 2005; 128: 729–738.
39. Barben J, Robertson D, Olinsky A, et al. Bronchial artery embolization for hemoptysis in young patients with
cystic fibrosis. Radiology 2002; 224: 124–130.
40. Razazi K, Parrot A, Khalil A, et al. Severe haemoptysis in patients with nonsmall cell lung carcinoma. Eur Respir J
2015; 45: 756–764.
41. Kvale PA, Selecky PA, Prakash UB. Palliative care in lung cancer: ACCP evidence-based clinical practice
guidelines (2nd edition). Chest 2007; 132: Suppl. 3, 368S–403S.
42. Revel MP, Fournier LS, Hennebicque AS, et al. Can CT replace bronchoscopy in the detection of the site and
cause of bleeding in patients with large or massive hemoptysis? AJR Am J Roentgenol 2002; 179: 1217–1224.
43. Lenner R, Schilero GJ, Lesser M. Hemoptysis: diagnosis and management. Compr Ther 2002; 28: 7–14.
44. Delage A, Tillie-Leblond I, Cavestri B, et al. Cryptogenic hemoptysis in chronic obstructive pulmonary disease:
characteristics and outcome. Respiration 2010; 80: 387–392.
45. Menchini L, Remy-Jardin M, Faivre JB, et al. Cryptogenic haemoptysis in smokers: angiography and results of
embolisation in 35 patients. Eur Respir J 2009; 34: 1031–1039.
46. Savale L, Parrot A, Khalil A, et al. Cryptogenic hemoptysis: from a benign to a life-threatening pathologic
vascular condition. Am J Respir Crit Care Med 2007; 175: 1181–1185.
47. Dweik RA, Stoller J. Role of bronchoscopy in massive hemoptysis. Clin Chest Med 1999; 20: 89–105.
48. Garzon AA, Cerruti MM, Golding ME. Exsanguinating hemoptysis. J Thorac Cardiovasc Surg 1982; 84: 829–833.
49. Fartoukh M, Parrot A, Khalil A. Aetiology, diagnosis and management of infective causes of severe haemoptysis
in intensive care units. Curr Opin Pulm Med 2008; 14: 195–202.
50. Gillet Y, Issartel B, Vanhems P, et al. Association between Staphylococcus aureus strains carrying gene for
Panton–Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients.
Lancet 2002; 359: 753–759.
51. Gillet Y, Vanhems P, Lina G, et al. Factors predicting mortality in necrotizing community-acquired pneumonia
caused by Staphylococcus aureus containing Panton–Valentine leukocidin. Clin Infect Dis 2007; 45: 315–321.
52. Holsclaw DS Jr. Recognition and management of patients with cystic fibrosis. Pediatr Ann 1978; 7: 9–6, 21.
53. Chan VL, So LK, Lam JY, et al. Major haemoptysis in Hong Kong: aetiologies, angiographic findings and
outcomes of bronchial artery embolisation. Int J Tuberc Lung Dis 2009; 13: 1167–1173.
54. Khalil A, Soussan M, Mangiapan G, et al. Utility of high-resolution chest CT scan in the emergency management
of haemoptysis in the intensive care unit: severity, localization and aetiology. Br J Radiol 2007; 80: 21–25.
55. De Gregorio MA, Medrano J, Mainar A et al. Tratamiento endovascular mediante embolizacion arterial bronquial
en la hemoptisis masiva. Seguimiento a corto y largo plazo durante 15 anos. [Endovascular treatment of massive
hemoptysis by bronchial artery embolization: short-term and long-term follow-up over a 15-year period.]
Arch Bronconeumol 2006; 42: 49–56.
56. Lordan JL, Gascoigne A, Corris PA. The pulmonary physician in critical care. Illustrative case 7: assessment and
management of massive haemoptysis. Thorax 2003; 58: 814–819.
57. Khalil A, Fartoukh M, Tassart M, et al. Role of MDCT in identification of the bleeding site and the vessels
causing hemoptysis. AJR Am J Roentgenol 2007; 188: W117–W125.
58. Khalil A, Fartoukh M, Parrot A, et al. Impact of MDCT angiography on the management of patients with
hemoptysis. AJR Am J Roentgenol 2010; 195: 772–778.
59. Sanyika C, Corr P, Royston D, et al. Pulmonary angiography and embolization for severe hemoptysis due to
cavitary pulmonary tuberculosis. Cardiovasc Intervent Radiol 1999; 22: 457–460.
60. Bidwell JL, Pachner RW. Hemoptysis: diagnosis and management. Am Fam Physician 2005; 72: 1253–1260.
61. DiLeo MD, Amedee RG, Butcher RB. Hemoptysis and pseudohemoptysis: the patient expectorating blood.
Ear Nose Throat J 1995; 74: 822–828.
62. Unsal E, Koksal D, Cimen F, et al. Analysis of patients with hemoptysis in a reference hospital for chest diseases.
Tuberk Toraks 2006; 54: 34–42.
63. Hsiao EI, Kirsch CM, Kagawa FT, et al. Utility of fiberoptic bronchoscopy before bronchial artery embolization
for massive hemoptysis. AJR Am J Roentgenol 2001; 177: 861–867.

148

FB:Cardiologia Siglo XXI

 SEVERE HAEMOPTYSIS | M. FARTOUKH ET AL.

64. Pursel SE, Lindskog GE. Hemoptysis. A clinical evaluation of 105 patients examined consecutively on a thoracic
surgical service. Am Rev Respir Dis 1961; 84: 329–336.
65. Chalumeau-Lemoine L, Khalil A, Prigent H, et al. Impact of multidetector CT-angiography on the emergency
management of severe hemoptysis. Eur J Radiol 2013; 82: e742–e747.
66. Haponik EF, Chin R. Hemoptysis: clinicians’ perspectives. Chest 1990; 97: 469–475.
67. Freitag L, Tekolf E, Stamatis G, et al. Three years experience with a new balloon catheter for the management of
haemoptysis. Eur Respir J 1994; 7: 2033–2037.
68. Gottlieb LS, Hillberg R. Endobronchial tamponade therapy for intractable hemoptysis. Chest 1975; 67: 482–483.
69. Hiebert CA. Balloon catheter control of life-threatening hemoptysis. Chest 1974; 66: 308–309.
70. Morell RC, Prielipp RC, Foreman AS, et al. Intentional occlusion of the right upper lobe bronchial orifice to
tamponade life-threatening hemoptysis. Anesthesiology 1995; 82: 1529–1531.
71. Jean-Baptiste E. Clinical assessment and management of massive hemoptysis. Crit Care Med 2000; 28: 1642–1647.
72. Klein U, Karzai W, Bloos F, et al. Role of fiberoptic bronchoscopy in conjunction with the use of double-lumen
tubes for thoracic anesthesia: a prospective study. Anesthesiology 1998; 88: 346–350.
73. Scuderi PE, Prough DS, Price JD, et al. Cessation of pulmonary artery catheter-induced endobronchial
hemorrhage associated with the use of PEEP. Anesth Analg 1983; 62: 236–238.
74. Sakr L, Dutau H. Massive hemoptysis: an update on the role of bronchoscopy in diagnosis and management.
Respiration 2010; 80: 38–58.
75. Conlan AA, Hurwitz SS. Management of massive haemoptysis with the rigid bronchoscope and cold saline
lavage. Thorax 1980; 35: 901–904.
76. Dupree HJ, Lewejohann JC, Gleiss J, et al. Fiberoptic bronchoscopy of intubated patients with life-threatening
hemoptysis. World J Surg 2001; 25: 104–107.
77. Valipour A, Kreuzer A, Koller H, et al. Bronchoscopy-guided topical hemostatic tamponade therapy for the
management of life-threatening hemoptysis. Chest 2005; 127: 2113–2118.
78. Breuer HW, Charchut S, Worth H, et al. Endobronchial versus intravenous application of the vasopressin
derivative glypressin during diagnostic bronchoscopy. Eur Respir J 1989; 2: 225–228.
79. Tuller C, Tuller D, Tamm M, et al. Hemodynamic effects of endobronchial application of ornipressin versus
terlipressin. Respiration 2004; 71: 397–401.
80. Anwar D, Schaad N, Mazzocato C. Aerosolized vasopressin is a safe and effective treatment for mild to moderate
recurrent hemoptysis in palliative care patients. J Pain Symptom Manage 2005; 29: 427–429.
81. Bhattacharyya P, Dutta A, Samanta AN, et al. New procedure: bronchoscopic endobronchial sealing; a new mode
of managing hemoptysis. Chest 2002; 121: 2066–2069.
82. Tsukamoto T, Sasaki H, Nakamura H. Treatment of hemoptysis patients by thrombin and fibrinogen-thrombin
infusion therapy using a fiberoptic bronchoscope. Chest 1989; 96: 473–476.
83. Jolliet P, Soccal P, Chevrolet JC. Control of massive hemoptysis by endobronchial tamponade with a pulmonary
artery balloon catheter. Crit Care Med 1992; 20: 1730–1732.
84. Shigemura N, Wan IY, Yu SC, et al. Multidisciplinary management of life-threatening massive hemoptysis:
a 10-year experience. Ann Thorac Surg 2009; 87: 849–853.
85. Ramon P, Wallaert B, Derollez M, et al. Traitement des hemoptysies graves par la terlipressine. Etude de
l’efficacite et de la tolerance du produit. [Treatment of severe hemoptysis with terlipressin. Study of the efficacy
and tolerance of this product.] Rev Mal Respir 1989; 6: 365–368.
86. Jougon J, Ballester M, Delcambre F, et al. Massive hemoptysis: what place for medical and surgical treatment.
Eur J Cardiothorac Surg 2002; 22: 345–351.
87. Freeman JG, Cobden I, Lishman AH, et al. Controlled trial of terlipressin (‘Glypressin’) versus vasopressin in the
early treatment of oesophageal varices. Lancet 1982; 2: 66–68.
88. Levacher S, Letoumelin P, Pateron D, et al. Early administration of terlipressin plus glyceryl trinitrate to control
active upper gastrointestinal bleeding in cirrhotic patients. Lancet 1995; 346: 865–868.
89. Rundqvist E, Allen D, Larsson G. Comparison between lysine vasopressin and a long-acting analogue
(N alpha-triglycyl-lysine vasopressin) used as local hemostatic agents for conization. Acta Obstet Gynecol Scand
1988; 67: 301–305.
90. Vinayak BC, Birchall MA, Donovan B, et al. A randomized double-blind trial of glypressin in the management of
acute epistaxis. Rhinology 1993; 31: 131–134.
91. Trimble HG, Wood JR. Pulmonary hemorrhage: its control by the use of intravenous pituitrin. Dis Chest 1950;
18: 345–351.
92. Magee G, Williams MH Jr. Treatment of massive hemoptysis with intravenous pitressin. Lung 1982; 160:
165–169.
93. Lau EM, Yozghatlian V, Kosky C, et al. Recombinant activated factor VII for massive hemoptysis in patients with
cystic fibrosis. Chest 2009; 136: 277–281.
94. Macdonald JA, Fraser JF, Foot CL, et al. Successful use of recombinant factor VII in massive hemoptysis due to
community-acquired pneumonia. Chest 2006; 130: 577–579.

149

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

95. Mitrovic M, Elezovic I, Suvajdzic-Vukovic N, et al. Successful non-standard approaches to massive hemoptysis in
invasive pulmonary aspergillosis. Srp Arh Celok Lek 2012; 140: 505–507.
96. Tien HC, Gough MR, Farrell R, et al. Successful use of recombinant activated coagulation factor VII in a patient
with massive hemoptysis from a penetrating thoracic injury. Ann Thorac Surg 2007; 84: 1373–1374.
97. Meijer K, de Graaff WE, Daenen SM, et al. Successful treatment of massive hemoptysis in acute leukemia with
recombinant factor VIIa. Arch Intern Med 2000; 160: 2216–2217.
98. Haponik EF, Fein A, Chin R. Managing life-threatening hemoptysis: has anything really changed? Chest 2000;
118: 1431–1435.
99. Tanaka N, Yamakado K, Murashima S, et al. Superselective bronchial artery embolization for hemoptysis with a
coaxial microcatheter system. J Vasc Interv Radiol 1997; 8: 65–70.
100. White RI Jr. Bronchial artery embolotherapy for control of acute hemoptysis: analysis of outcome. Chest 1999;
115: 912–915.
101. Cremaschi P, Nascimbene C, Vitulo P, et al. Therapeutic embolization of bronchial artery: a successful treatment
in 209 cases of relapse hemoptysis. Angiology 1993; 44: 295–299.
102. Uflacker R, Kaemmerer A, Neves C, et al. Management of massive hemoptysis by bronchial artery embolization.
Radiology 1983; 146: 627–634.
103. Uflacker R, Kaemmerer A, Picon PD, et al. Bronchial artery embolization in the management of hemoptysis:
technical aspects and long-term results. Radiology 1985; 157: 637–644.
104. Rabkin JE, Astafjev VI, Gothman LN, et al. Transcatheter embolization in the management of pulmonary
hemorrhage. Radiology 1987; 163: 361–365.
105. Hayakawa K, Tanaka F, Torizuka T, et al. Bronchial artery embolization for hemoptysis: immediate and long-term
results. Cardiovasc Intervent Radiol 1992; 15: 154–158.
106. Swanson KL, Johnson CM, Prakash UB, et al. Bronchial artery embolization: experience with 54 patients. Chest
2002; 121: 789–795.
107. Ramakantan R, Bandekar VG, Gandhi MS, et al. Massive hemoptysis due to pulmonary tuberculosis: control with
bronchial artery embolization. Radiology 1996; 200: 691–694.
108. Wong ML, Szkup P, Hopley MJ. Percutaneous embolotherapy for life-threatening hemoptysis. Chest 2002; 121: 95–102.
109. Parrot A, Antoine M, Khalil A, et al. Approach to diagnosis and pathological examination in bronchial Dieulafoy
disease: a case series. Respir Res 2008; 9: 58.
110. Hartmann IJ, Remy-Jardin M, Menchini L, et al. Ectopic origin of bronchial arteries: assessment with
multidetector helical CT angiography. Eur Radiol 2007; 17: 1943–1953.
111. Yoon W, Kim YH, Kim JK, et al. Massive hemoptysis: prediction of nonbronchial systemic arterial supply with
chest CT. Radiology 2003; 227: 232–238.
112. Khalil A, Parrot A, Nedelcu C, et al. Severe hemoptysis of pulmonary arterial origin: signs and role of
multidetector row CT angiography. Chest 2008; 133: 212–219.
113. Katoh O, Kishikawa T, Yamada H, et al. Recurrent bleeding after arterial embolization in patients with
hemoptysis. Chest 1990; 97: 541–546.
114. Jewkes J, Kay PH, Paneth M, et al. Pulmonary aspergilloma: analysis of prognosis in relation to haemoptysis and
survey of treatment. Thorax 1983; 38: 572–578.
115. van den Heuvel MM, Els Z, Koegelenberg CF, et al. Risk factors for recurrence of haemoptysis following
bronchial artery embolisation for life-threatening haemoptysis. Int J Tuberc Lung Dis 2007; 11: 909–914.
116. Nath H. When does bronchial arterial embolization fail to control hemoptysis? Chest 1990; 97: 515–516.
117. Remy J, Lemaitre L, Lafitte JJ, et al. Massive hemoptysis of pulmonary arterial origin: diagnosis and treatment.
AJR Am J Roentgenol 1984; 143: 963–969.
118. Park A, Cwikiel W. Endovascular treatment of a pulmonary artery pseudoaneurysm with a stent graft: report of
two cases. Acta Radiol 2007; 48: 45–47.
119. Endo S, Otani S, Saito N, et al. Management of massive hemoptysis in a thoracic surgical unit. Eur J Cardiothorac
Surg 2003; 23: 467–472.
120. Gross AM, Diacon AH, van den Heuvel MM, et al. Management of life-threatening haemoptysis in an area of
high tuberculosis incidence. Int J Tuberc Lung Dis 2009; 13: 875–880.
121. Ayed A. Pulmonary resection for massive hemoptysis of benign etiology. Eur J Cardiothorac Surg 2003; 24: 689–693.
122. Bobrowitz ID, Ramakrishna S, Shim YS. Comparison of medical v surgical treatment of major hemoptysis.
Arch Intern Med 1983; 143: 1343–1346.
123. Gourin A, Garzon AA. Operative treatment of massive hemoptysis. Ann Thorac Surg 1974; 18: 52–60.

Disclosures: A. Khalil has received personal fees from Medtronic for workshop animations and from BARD
for consulting, and nonfinancial support from COOK and GEMS for congress payments.

150

FB:Cardiologia Siglo XXI

 | Chapter 10
Foreign body aspiration and
inhalation injury
Erik H.F.M. van der Heijden1, Paul C. Fuchs2 and Jan-Philipp Stromps2

Foreign body aspiration is seen predominantly in children and elderly patients. Depending
on the size, type and location of the foreign object, occlusion of the central airway can occur,
resulting in life-threatening situations. Bronchoscopy is the cornerstone in the diagnosis and
treatment of foreign body aspiration. Rigid bronchoscopy is preferred due to its larger
lumen, allowing the use of more robust and larger tools and providing a secure airway
during the procedure. In extreme cases, ECMO can be life-saving in children. The sooner
the foreign body is removed, the less local inflammatory reaction occurs. The vast majority
of foreign bodies can be retrieved by bronchoscopy. When unsuccessful, a thoracotomy may
be needed. Inhalation injuries caused by smoke or chemical products of combustion are
often associated with long-standing pulmonary dysfunction and significant morbidity and
mortality. These traumas are often associated with skin burns, which increase the overall
morbidity. Factors such as systemic inflammation, sepsis, ventilator-induced lung injury and
post-traumatic development of pneumonia may also negatively affect the injured respiratory
system. There is still no common consensus about the diagnostic strategy, and relatively few
novel therapeutic options are available; therefore, treatments are for the most part
supportive.

F oreign body aspiration is a globally widespread pulmonary emergency that may result
in a life-threatening pulmonary emergency as result of an acute central airway
obstruction. In children, especially in the case of unwitnessed (small) foreign body
aspiration in the peripheral airways, a chronic clinical syndrome may develop, combining
signs and symptoms of recurrent pneumonia, cough and wheezing. However, in this
chapter, we will focus on the acute situation, discussing the clinical features of foreign body
aspiration, and the emergency and initial general treatment of foreign body aspiration in
children and adults.

Inhalation injuries are caused by smoke or chemical products of combustion. They are
associated with significant morbidity and mortality, and often lead to long-term pulmonary
dysfunction. It is recognised that a general consensus on treatment is needed. Here, we
discuss the types and diagnosis of inhalation injuries and the available treatment options.

1
Radboud University Medical Center, Interventional Pulmonology and Thoracic Oncology, Dept of Pulmonary Diseases, Nijmegen, The
Netherlands. 2Dept of Plastic Surgery, Hand Surgery, Burn Center, University of Witten/Herdecke, Cologne-Merheim Medical Center,
Cologne, Germany.

Correspondence: Jan-Philipp Stromps, Dept of Plastic Surgery, Hand Surgery, Burn Center, Cologne-Merheim Medical Center,
Ostmerheimer Str. 200, Cologne, 51109, Germany. E-mail: StrompsJ@kliniken-koeln.de

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 151–160. DOI: 10.1183/2312508X.10015416 151

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Foreign body aspiration

Foreign body aspiration may result in a life-threatening pulmonary emergency as result of

an acute central airway obstruction. It is essential that this clinical situation is recognised
and that prompt and suitable action is undertaken. The incidence of foreign body aspiration
is related to age, region and other factors, such as trends in clothing and games; it occurs
most frequently in children and the elderly. The most frequently aspirated foreign bodies are
peanuts, water melon seeds, hairpins and toy parts but also, in some regions, live organisms
[1–11]. In adults, aspiration of food parts, medical devices, tooth fragments (resulting from
trauma) and pills and other medication is more often reported (figure 1). Most of the
available literature, and especially larger studies, have focused on children [12–14].

Clinical features

The presentation of foreign body aspiration depends on the size and nature of the foreign
body. In general, the majority of patients with (suspected) foreign body aspiration present
within 24 h [15, 16]. The presentation and acute risk depend on the relative size of the
foreign body and the airway in which it is lodged (pharynx or central, upper or lower
airway). Choking occurs when the foreign body is wedged in the retropharynx or central
airway, and when witnessed it has a high predictive sensitivity for foreign body aspiration.
However, whether the foreign body is (completely) expectorated after the often rapid

a) b)

c) d)

Figure 1. a and b) Bone fragment wedged in the anterior segment of the right lower lobe of the lung, and c and
d) a surgical tool in the right lower lobe of the bronchus caught in a basket, before (a, c) and after (b, d) removal.

152

FB:Cardiologia Siglo XXI

 FOREIGN BODY ASPIRATION AND INHALATION INJURY | E.H.F.M. VAN DER HEIJDEN ET AL.

resolution of choking is uncertain. Often, after a period with few symptoms, a chronic
syndrome may recur. The most frequently reported symptoms are cough, dyspnoea,
tachypnoea, wheezing and stridor (table 1). Upon clinical examination, the combination of
cough with diminished breath sounds, a hyperinflated lung, atelectasis and pneumonia is
indicative of foreign body aspiration.

Most foreign bodies are aspirated in the right main and lower lobe bronchi due to their
anatomical position [5, 12]. When the foreign body aspiration was unwitnessed or
unnoticed, local inflammation may occur due to a chemical interaction, depending on the
nature of the foreign body (e.g. pills, peanut oil) [13]. Granulation tissue formation may
also mimic the symptoms of a pulmonary malignancy.

Imaging can be used in subacute situations in the diagnostic workup of foreign body
aspiration and consists of a standard chest radiograph to reveal radio-opaque foreign bodies
or to detect atelectasis or hyperinflation in radiolucent foreign bodies [2–5, 7, 12, 15, 16].
The sensitivity of CT scanning to detect foreign bodies is higher [17, 18].

Management of patients with foreign body aspiration

Prompt airway management is key in acute life-threatening foreign body aspiration. In these
situations, it is critical that the airway is secured, and no time must be lost on, for example,
imaging procedures. In children with asphyxia and complete airway obstruction (i.e. without
the ability to speak), back blows, chest compression or the Heimlich manoeuvre can be
attempted to dislodge the foreign body. In children who are able to speak or cough, these
manoeuvres should be avoided outside the hospital (in a setting where the airway can be
regained) to avoid complete blocking of the central airway [7, 15, 19]. Similarly, probing of
the hypopharynx with a finger must be done with caution, since this may push a loose
foreign body into the larynx, occluding the entire airway [15]. It is advised to retrieve
foreign bodies in the hypopharynx with direct laryngoscopy and using Magill forceps.

Rigid bronchoscopy under general anaesthesia is the mainstay of foreign body aspiration
treatment. The bronchoscope allows the passage of larger instruments and different types of
graspers, allows the passage of the foreign body through the glottis and, most importantly,
allows assisted or mechanical ventilation during the procedure. Furthermore, rigid
bronchoscopy can easily be combined with flexible bronchoscopy to allow easy and complete

Table 1. Reported incidence of symptoms of foreign body (FB) aspiration

First author [ref.] Subjects n Symptom incidence

Cough Stridor/wheezing Tachypnoea/dyspnoea Fever

BOUFERSAOUI [2] 2624 70% 63% 60% NR

SAHIN [5] 1660 75% 14% 29% 8%
HUANKANG [3]
Tracheal FB 146 96% 29% 12% 7%
Bronchial FB 843 98% 22% 7% 11%
LIANG [4] 2000 33% NR 55% 11%

NR: not reported.

153

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

examination of the peripheral airways. However, it is important that the referral centre has
access to the full range of clinical expertise, since foreign body aspiration may still result in
death, as occurs in approximately 0.3% of cases [2, 11], or in severe complications, with a rate
of up to 9% of cases consisting of laryngeal oedema or spasm, hypoxaemia and
pneumothorax [11]. Life-saving acute interventions other than rigid bronchoscopy include
acute cricotracheotomy and ECMO in severe life-threatening cases [20–22] and surgical
procedures such as bronchotomy carried out by a trained airway surgical team [2, 23].

In areas where rigid bronchoscopy is not available, or in the case of severe or unstable facial
or cervical trauma, flexible bronchoscopy in combination with endotracheal intubation or
laryngeal mask ventilation is an effective approach [12, 16]. Sometimes, tracheotomy may be
a valuable alternative [24]. In the case of a history of choking or of prolonged symptoms,
diagnostic flexible bronchoscopy can be used. It may be possible to remove the foreign body
immediately; however, care must be taken not to lose the captured foreign body upon
passing the glottis, and one should be prepared to maintain or regain a patent airway.

Foreign body retrieval is carried out under general anaesthesia. Different techniques are
used and are subject to local preference, and it should be noted that, in an acute situation,
the patient may have a full stomach [25]. Often, spontaneous breathing is preferred over
controlled ventilation [26] and isoflurane over the combination of intravenous propofol and
remifentanil [25, 27–29]. However, since rigid bronchoscopy is essentially an open airway
procedure, intravenous sedatives are preferred to avoid ambient fumes. In general, local
protocol preference seems the most important factor.

Several tools are available for the retrieval of foreign bodies using both rigid and flexible
bronchoscopy. A variety of accessories including specially designed forceps, snares, baskets,
balloons and magnets can be used during rigid and flexible bronchoscopy for foreign body
extraction. Cryoprobes can also be used to freeze organic material onto the tip of the
cryoprobe and retract the foreign body [12], similar to ablative therapy used for airway
recanalisation in malignant central airway obstruction. Cryotherapy as well as electrocautery
or laser therapy may be needed to remove granulation tissue around foreign bodies that have
been in situ for a longer period. When the foreign body is located in segmental bronchi, it
may be difficult to reach with a rigid bronchoscope. In such cases, flexible bronchoscopy can
be used through the rigid bronchoscope. An important limitation in the use of flexible
bronchoscopes in children is the size of the outer diameter of the bronchoscope and its
working channel diameter. Adult therapeutic videobronchoscopes are available with 2.8 mm
or 3.2 mm working channels and allow the use of a wide range of accessories. For narrower
bronchoscopes, the working channel is 2.0 mm, and for ultrathin bronchoscopes with an
outer diameter of <4 mm, the working channel is 1.2 mm. Such ultrathin bronchoscopes
with these small working channels allow the use of baskets and can also be used to position
guide wires past the foreign body over which a retraction balloon can be inserted to retract
the foreign body under vision into the rigid bronchoscope or a larger airway where it can be
retrieved using larger instruments or accessories. It is strongly advised that a wide variety of
these tools and accessories is available for immediate use in centres for interventional
pulmonology. Special expertise and dedicated experience is needed for the successful
removal of living foreign bodies, such as leeches or fish [6, 9].

In the rare case when the foreign body cannot be removed from the airways, surgeons
trained in airway surgery must be consulted. In a large retrospective study, surgery was
found to be needed in only 3% of cases where (rigid) bronchoscopy was unsuccessful [2].

154

FB:Cardiologia Siglo XXI

 FOREIGN BODY ASPIRATION AND INHALATION INJURY | E.H.F.M. VAN DER HEIJDEN ET AL.

Thoracotomy is often preferred over video-assisted techniques to allow bronchotomy or

lobectomy to remove the foreign body [23, 30, 31].

Inhalation injury

Injuries of the respiratory system caused by inhalation of smoke or chemical products of

combustion are often associated with long-standing pulmonary dysfunction and significant
morbidity and mortality [32, 33]. In combination with burns, inhalation injury leads to an
increased overall mortality from thermal injury [34]. In critically ill patients in particular,
other factors such as systemic inflammation, sepsis and ventilator-induced lung injury may
also negatively affect the injured respiratory system [35]. Another problem is the
post-traumatic development of pneumonia during hospitalisation. The need for a common
consensus on diagnostic strategy has been recognised in the burn literature over the last few
decades. Relatively few novel therapeutic options are available and treatment concepts are
for the most part supportive [36].

Anatomy and physiology

Inhalation injury is defined as trauma to the respiratory system caused by either thermal or
chemical irritants. These traumas can be divided into three categories: 1) heat injuries to
the upper airways; 2) chemical irritation to the lower airways; and 3) systemic toxicity.

Heat injuries to the upper airways

Injuries to the upper airways are commonly caused by heated air, which can reach >500°C
in a burning room. Due to the reflex closure of the larynx, these injuries are limited to the
structures above the carina. Inhalation can lead directly to massive swelling of the tongue
and epiglottitis, resulting in severe obstruction of the upper respiratory tract.

Chemical irritation to the lower airways

Toxic products of combustion (table 2) mainly affect the epithelial and capillary endothelial
cells of the lower respiratory tract. Damage to these cells leads to a lower surfactant level,
which further promotes alveolar collapse and atelectasis. An early inflammatory response
by excretion of mediators such as interleukins and tumour necrosis factor-α is initiated
mainly through the alveolar macrophages [37]. Mucociliary transport is constrained and
therefore bacterial clearance is reduced, leading to the development of additive pneumonia.
A summary of the complex relationships that occur following inhalation of toxic gases is
shown in figure 2.

Table 2. Examples of toxic products of combustion

Sulphur dioxide
Nitrogen dioxide
Ammonia
Chlorine
Cyanide
Various toxic aldehydes and acids

155

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Inhalation of toxic gases

Chemical damage Alveolar membrane

of the mucosa damage

Restriction of Oedema of the Venous mediator

ciliar function mucous membrane transport

Ineffective bacterial Separation of Fibrinous Oedema

clearance the mucosa sloughing

Peribronchitis Acute airway

Atelectasis obstruction Hypoxia
Pneumonia Hypercapnia

Figure 2. The complex relationships after inhalation of toxic gases.

Systemic toxicity
Apart from the systemic inflammatory reaction after inhalation injury, systemic toxicity is
tied mainly to high levels of carbon monoxide, which is a product of incomplete combustion
during fires. The main risk of this tasteless and odourless gas is that it competes with oxygen
for haemoglobin binding. The binding capacity of carbon monoxide is 200–250-fold greater
than that of oxygen, which leads to higher carboxyhaemoglobin levels, resulting in reduced
overall oxygen saturation of the patient. Long-term morbidity due to carbon monoxide
intoxication includes vascular and neurological consequences.

Diagnosis of inhalation injury

The diagnosis of inhalation injuries is often based on the patient’s history of smoke
exposure and on critical symptoms such as unconsciousness. The most common clinical
symptoms are listed in table 3. These symptoms may not be proportional to the degree of
smoke exposure or injury.

The clinical course of inhalation injury can be divided into three phases according to
HERNDON et al. [38]: 1) the early phase, which is determined by reduced oxygenation and
acute alveolar lung oedema; 2) the following intermediate phase (from 6 h up to 72 h

Table 3. Clinical symptoms of acute inhalation injury

Swelling of the tongue

Irritated throat and sinuses
Obstruction of the airways and coughing
Vomiting and nausea
Shortness of breath
Chest pain
Headaches
Stinging eyes

156

FB:Cardiologia Siglo XXI

 FOREIGN BODY ASPIRATION AND INHALATION INJURY | E.H.F.M. VAN DER HEIJDEN ET AL.

post-trauma), with increased excretion and decreased clearance within the injured lung
leading to atelectasis and an interstitial oedema; and 3) the late phase (beginning 7 days
after trauma), described by further obstruction and fibrin formation and the possible
development of pneumonia, which can result in the development of ARDS.

Diagnostic strategies include fibreoptic bronchoscopy, with the possibility of investigating

the bronchoalveolar lavage fluid [39, 40]. Various scoring systems have been proposed to
estimate the severity of the injury to the respiratory tract and estimate the further clinical
course; these are based on the bronchoscopic findings, which can range from mild erythema
and carbonaceous deposits up to mucosal necrosis [40, 41]. Various diagnostic tools have
been developed to determine carbon monoxide intoxication, but they are very unpredictable
since the level of initial carbon monoxide does not correlate with the outcome [42, 43].

In general, it is difficult to predict pulmonary dysfunction, the development of ARDS and

overall mortality, since these reactions are orchestrated and influenced by many different
factors. The clinical use of other diagnostic tools, such as lung scanning with xenon or
technetium-99, is limited due to logistical reasons [44].

Therefore, a diagnosis determined by clinical findings and bronchoscopy should be

considered in clinical practice [36].

Treatment of inhalation injury

Patients suffering an inhalation injury need special treatment concepts. The therapeutic
options include the following, depending on the individual severity of injury: fluid
resuscitation, bronchoscopy, hyperbaric oxygen treatment, mechanical ventilation and
specific agents for treating inhalation injury.

Fluid resuscitation
Patients with inhalation injuries usually require high volumes of fluid during immediate
resuscitation [40, 45]. When there is a concomitant burn injury, the Parkland formula
(4 mL·kg−1 bodyweight per % burned body surface area) is merely used to calculate the
basic fluid requirements within the first 24 h after trauma.

The individual fluid requirements should be adjusted according to the haemodynamic

stability and the hourly urine output, which should not be <1 mL·kg−1 bodyweight [46].

Bronchoscopy
As well as its diagnostic value, bronchoscopy also provides therapeutic options, such as
clearing the respiratory tract of obstructions caused by carbonaceous deposits, sloughed
epithelial cells, mucus and fibrin formations.

Hyperbaric oxygen treatment

To reduce the negative influence of carbon monoxide and accelerate its displacement from
haemoglobin, hyperbaric oxygen (HBO) can be used if logistically available. The half-life of
haemoglobin can be reduced to <60 min by inhalation of 100% oxygen, compared with 240
min under normal oxygen saturation. Although many studies and clinical trials suggest a
positive effect of HBO treatment, its use remains controversial [47]. Complications
associated with HBO treatment include barotrauma and air embolism.

157

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Mechanical ventilation
If necessary, ventilation and oxygenation can be enhanced by noninvasive and invasive
treatment modalities. Since it is difficult to evaluate the severity of obstruction and lung
damage directly after trauma, intubation for airway protection must always be considered.
The benefits of NIV are associated mainly with avoidance of the complications of
endotracheal intubation. These include the trauma during intubation, the need for higher
sedation levels, and impaired communication and swallowing after extubation. Unconscious
patients generally require intubation and invasive ventilation.

The use of PEEP has been proven to enhance arterial oxygenation by increasing functional
residual capacity, especially in patients with ARDS [48]. The use of ventilator strategies,
which induce hypercapnia by limitation of minute ventilation by using low tidal volumes,
has been controversially discussed [49].

Agents for treating inhalation injury

There are different specific antidotes available to combat the toxic products of combustion, but
most of these drugs, which can be additionally administered, reduce the inflammatory response
and address the physiological changes; they have been the focus of many animal models. The
use of antibiotics should be limited to cases of documented infection and pneumonia.

Some studies have shown reduced mortality in patients following inhalation injury by using
a combination of aerosolised heparin/N-acetylcysteine, but their widespread use remains
controversial [50, 51]. In this context, the use of nebulised inhaled β-agonists has been
proven to ameliorate bronchoconstriction and thus lead to enhanced gas exchange in
various animal studies [52, 53]. Another target of studies is changing the pulmonary blood
flow through vasodilatation by inhalation of nitric oxide [54, 55].

Conclusion

Foreign body aspiration and inhalation injuries can be life-threatening situations for which
immediate and prompt action is warranted. In case of central airway occlusion, Heimlich
manoeuvres or back blows should be avoided in choking patients with the ability to cough or
speak. Most often, the foreign body is aspirated in the main bronchi and predominantly in the
right main or lower lobe bronchus. Bronchoscopic retrieval of the foreign body is indicated,
preferably by means of rigid bronchoscopy. A wide variety of accessory tools is available for the
complete retrieval of different foreign bodies. In emergency cases, it is critical to secure the
airway, and in exceptional cases this may involve an emergency tracheostomy, ECMO or surgery.

The diagnosis of inhalation injuries is often based on the patient’s history of smoke
exposure and on critical symptoms such as unconsciousness. Bronchoscopy should be
performed not only for diagnostic reasons but also for therapeutic options, such as clearing
the respiratory system. Fluid resuscitation is also mandatory within the early phase
following these injuries. Intubation for airway protection should always be considered, since
it is difficult to evaluate the severity of obstruction and lung damage directly after
inhalation traumas. If necessary, ventilation and oxygenation can be enhanced by
noninvasive and invasive treatment modalities, or even HBO treatment. Additionally, drugs
can be administered to reduce the inflammatory response, but the use of antibiotics should
be limited to cases of documented infection and pneumonia.

158

FB:Cardiologia Siglo XXI

 FOREIGN BODY ASPIRATION AND INHALATION INJURY | E.H.F.M. VAN DER HEIJDEN ET AL.

References
1. Ludemann JP, Riding KH. Choking on pins, needles and a blowdart: aspiration of sharp, metallic foreign bodies
secondary to careless behavior in seven adolescents. Int J Pediatr Otorhinolaryngol 2007; 71: 307–310.
2. Boufersaoui A, Smati L, Benhalla KN, et al. Foreign body aspiration in children: experience from 2624 patients.
Int J Pediatr Otorhinolaryngol 2013; 77: 1683–1688.
3. Huankang Z, Kuanlin X, Xiaolin H, et al. Comparison between tracheal foreign body and bronchial foreign body:
a review of 1,007 cases. Int J Pediatr Otorhinolaryngol 2012; 76: 1719–1725.
4. Liang J, Hu J, Chang H, et al. Tracheobronchial foreign bodies in children – a retrospective study of 2,000 cases in
Northwestern China. Ther Clin Risk Manag 2015; 11: 1291–1295.
5. Sahin A, Meteroglu F, Eren S, et al. Inhalation of foreign bodies in children: experience of 22 years. J Trauma
Acute Care Surg 2013; 74: 658–663.
6. Gantwerker EA, Hamilton SS, Casper KA. A fish way out of water: case report of a unique airway foreign body.
Ann Otol Rhinol Laryngol 2014; 123: 232–234.
7. Rizk H, Rassi S. Foreign body inhalation in the pediatric population: lessons learned from 106 cases. Eur Ann
Otorhinolaryngol Head Neck Dis 2011; 128: 169–174.
8. Rizk N, Gwely NE, Biron VL, et al. Metallic hairpin inhalation: a healthcare problem facing young Muslim
females. J Otolaryngol Head Neck Surg 2014; 43: 21.
9. Saki N, Rahim F, Nikaghlagh S, et al. Meta analysis of the leech as a live foreign body: detection, precaution and
treatment. Pak J Biol Sci 2009; 12: 1556–1563.
10. Walz PC, Scholes MA, Merz MN, et al. The internet, adolescent males, and homemade blowgun darts: a recipe for
foreign body aspiration. Pediatrics 2013; 132: e519–e521.
11. Zhang X, Li WX, Cai YR. A time series observation of Chinese children undergoing rigid bronchoscopy for an
inhaled foreign body: 3,149 cases in 1991–2010. Chin Med J 2015; 128: 504–509.
12. Fang YF, Hsieh MH, Chung FT, et al. Flexible bronchoscopy with multiple modalities for foreign body removal in
adults. PLoS One 2015; 10: e0118993.
13. Kinsey CM, Folch E, Majid A, et al. Evaluation and management of pill aspiration: case discussion and review of
the literature. Chest 2013; 143: 1791–1795.
14. Lin L, Lv L, Wang Y, et al. The clinical features of foreign body aspiration into the lower airway in geriatric
patients. Clin Interv Aging 2014; 9: 1613–1618.
15. Tan HK, Brown K, McGill T, et al. Airway foreign bodies (FB): a 10-year review. Int J Pediatr Otorhinolaryngol
2000; 56: 91–99.
16. Tang LF, Xu YC, Wang YS, et al. Airway foreign body removal by flexible bronchoscopy: experience with 1027
children during 2000–2008. World J Pediatr 2009; 5: 191–195.
17. Bai W, Zhou X, Gao X, et al. Value of chest CT in the diagnosis and management of tracheobronchial foreign
bodies. Pediatr Int 2011; 53: 515–518.
18. Tong B, Zhang L, Fang R, et al. 3D images based on MDCT in evaluation of patients with suspected foreign body
aspiration. Eur Arch Otorhinolaryngol 2013; 270: 1001–1007.
19. Solanki SL, Bansal S, Khare A, et al. Heimlich’s maneuver-assisted bronchoscopic removal of airway foreign body.
Anesth Essays Res 2011; 5: 201–203.
20. Brown KL, Shefler A, Cohen G, et al. Near-fatal grape aspiration with complicating acute lung injury successfully
treated with extracorporeal membrane oxygenation. Pediatr Crit Care Med 2003; 4: 243–245.
21. Isherwood J, Firmin R. Late presentation of foreign body aspiration requiring extracorporeal membrane
oxygenation support for surgical management. Interact Cardiovasc Thorac Surg 2011; 12: 631–632.
22. Park AH, Tunkel DE, Park E, et al. Management of complicated airway foreign body aspiration using
extracorporeal membrane oxygenation (ECMO). Int J Pediatr Otorhinolaryngol 2014; 78: 2319–2321.
23. Duan L, Chen X, Wang H, et al. Surgical treatment of late-diagnosed bronchial foreign body aspiration: a report of
23 cases. Clin Respir J 2014; 8: 269–273.
24. Tamiru T, Gray PE, Pollock JD. An alternative method of management of pediatric airway foreign bodies in the
absence of rigid bronchoscopy. Int J Pediatr Otorhinolaryngol 2013; 77: 480–482.
25. Zur KB, Litman RS. Pediatric airway foreign body retrieval: surgical and anesthetic perspectives. Paediatr Anaesth
2009; 19: Suppl. 1, 109–117.
26. Liu Y, Chen L, Li S. Controlled ventilation or spontaneous respiration in anesthesia for tracheobronchial foreign
body removal: a meta-analysis. Paediatr Anaesth 2014; 24: 1023–1030.
27. Chai J, Wu XY, Han N, et al. A retrospective study of anesthesia during rigid bronchoscopy for airway foreign
body removal in children: propofol and sevoflurane with spontaneous ventilation. Paediatr Anaesth 2014; 24:
1031–1036.
28. Chen K, Shen X. Dexmedetomidine and propofol total intravenous anesthesia for airway foreign body removal. Ir J
Med Sci 2014; 183: 481–484.

159

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

29. Chen KZ, Ye M, Hu CB, et al. Dexmedetomidine vs remifentanil intravenous anaesthesia and spontaneous
ventilation for airway foreign body removal in children. Br J Anaesth 2014; 112: 892–897.
30. Fenane H, Bouchikh M, Bouti K, et al. Scarf pin inhalation: clinical characteristics and surgical treatment.
J Cardiothorac Surg 2015; 10: 61.
31. Hoff SR, Chang KW. The proximal bronchoplasty retrieval technique for removal of embedded distal airway
foreign bodies. Int J Pediatr Otorhinolaryngol 2014; 78: 148–151.
32. Clark WR Jr. Smoke inhalation: diagnosis and treatment. World J Surg 1992; 16: 24–29.
33. Park GY, Park JW, Jeong DH, et al. Prolonged airway and systemic inflammatory reactions after smoke inhalation.
Chest 2003; 123: 475–480.
34. Miller SF, Bessey P, Lentz CW, et al. National burn repository 2007 report: a synopsis of the 2007 call for data.
J Burn Care Res 2008; 29: 862–870.
35. Colohan SM. Predicting prognosis in thermal burns with associated inhalational injury: a systematic review of
prognostic factors in adult burn victims. J Burn Care Res 2010; 31: 529–539.
36. Ching JA, Ching YH, Shivers SC, et al. An analysis of inhalation injury diagnostic methods and patient outcomes.
J Burn Care Res 2016; 37: e27–e32.
37. Stromps JP, Fuchs P, Demir E, et al. Intraalveolar TNF-α in combined burn and inhalation injury compared with
intraalveolar interleukin-6. J Burn Care Res 2015; 36: e55–e61.
38. Herndon DN, Langner F, Thompson P, et al. Pulmonary injury in burned patients. Surg Clin North Am 1987; 67:
31–46.
39. Fuchs PC, Demir E, Reuber K, et al. Intra-alveolar IL-6 levels following burn and inhalation injury. Burns 2009; 35:
840–844.
40. Endorf FW, Gamelli RL. Inhalation injury, pulmonary perturbations, and fluid resuscitation. J Burn Care Res 2007;
28: 80–83.
41. Marek K, Piotr W, Stanislaw S, et al. Fibreoptic bronchoscopy in routine clinical practice in confirming the
diagnosis and treatment of inhalation burns. Burns 2007; 33: 554–560.
42. Grieb G, Groger A, Bozkurt A, et al. The diversity of carbon monoxide intoxication: medical courses can differ
extremely – a case report. Inhal Toxicol 2008; 20: 911–915.
43. Piatkowski A, Ulrich D, Grieb G, et al. A new tool for the early diagnosis of carbon monoxide intoxication.
Inhal Toxicol 2009; 21: 1144–1147.
44. Spyropoulou GA, Iconomou T, Tsagarakis M, et al. The value and prognostic role of the CT scan versus chest
radiography in the follow-up of intubated burn patients with possible inhalation injury. Ann Burns Fire Dis 2005;
18: 79–82.
45. Masaki F, Isao T, Hiroshi I, et al. A case of severe smoke inhalation injury without cutaneous burn required
massive fluid for resuscitation. Burns 2007; 33: 670–671.
46. Inoue T, Okabayashi K, Ohtani M, et al. Effect of smoke inhalation injury on fluid requirement in burn
resuscitation. Hiroshima J Med Sci 2002; 51: 1–5.
47. Thom SR, Mendiguren I, Fisher D. Smoke inhalation-induced alveolar lung injury is inhibited by hyperbaric
oxygen. Undersea Hyperb Med 2001; 28: 175–179.
48. Cox CS Jr, Zwischenberger JB, Traber DL, et al. Immediate positive pressure ventilation with positive end-
expiratory pressure (PEEP) improves survival in ovine smoke inhalation injury. J Trauma 1992; 33: 821–827.
49. Fuchs H, Mendler MR, Scharnbeck D, et al. Very low tidal volume ventilation with associated hypercapnia –
effects on lung injury in a model for acute respiratory distress syndrome. PLoS One 2011; 6: e23816.
50. Desai MH, Mlcak R, Richardson J, et al. Reduction in mortality in pediatric patients with inhalation injury with
aerosolized heparin/N-acetylcystine [correction of acetylcystine] therapy. J Burn Care Rehabil 1998; 19: 210–212.
51. Holt J, Saffle JR, Morris SE, et al. Use of inhaled heparin/N-acetylcystine in inhalation injury: does it help? J Burn
Care Res 2008; 29: 192–195.
52. Enkhbaatar P, Herndon DN, Traber DL. Use of nebulized heparin in the treatment of smoke inhalation injury.
J Burn Care Res 2009; 30: 159–162.
53. Lopez E, Fujiwara O, Lima-Lopez F, et al. Nebulized epinephrine limits pulmonary vascular hyperpermeability to
water and protein in ovine with burn and smoke inhalation injury. Crit Care Med 2016; 44: e89–e96.
54. Lundin S, Westfelt UN, Stenqvist O, et al. Response to nitric oxide inhalation in early acute lung injury. Intensive
Care Med 1996; 22: 728–734.
55. Soejima K, Schmalstieg FC, Traber LD, et al. Role of nitric oxide in myocardial dysfunction after combined burn
and smoke inhalation injury. Burns 2001; 27: 809–815.

Disclosures: E.H.F.M. van der Heijden has received grants from Pentax Medical and AstraZeneca Oncology,
personal fees from Medi-Globe Corporation and other financial support from Merck Sharp & Dohme Oncology
and Pfizer Oncology.

160

FB:Cardiologia Siglo XXI

 | Chapter 11
Haematothorax
Erich Stoelben1, Axel Gossmann2 and Servet Bölükbas3

Haematothorax (or haemothorax) is defined as an accumulation of blood in the pleural

cavity. Spontaneous haematothorax is a rare complication of various intrathoracic diseases,
especially pneumothorax or benign and malignant neoplasms. In contrast, haematothorax
has to be faced regularly after thoracic interventions due to the high number of
interventional procedures in the thorax, especially thoracentesis or thoracic drainage.
Diagnosis has to be made by means of the clinical picture, sonography and CT scan of the
chest. Spontaneous or post-interventional haematothorax might turn out to be an emergency
situation requiring immediate interdisciplinary treatment. Depending on the underlying
cause, conservative and surgical treatment might be appropriate. However, early
video-assisted thoracic surgery is an effective and safe treatment for the management of
haematothorax irrespective of the underlying disease.

H aematothorax (or haemothorax) is defined as an accumulation of blood in the pleural

cavity. This chapter focuses on patients with spontaneous haematothorax or
intrapleural bleeding after medical interventions. Post-interventional haematothorax is a
clinical emergency that requires rapid treatment and close cooperation of the primary
attending physician, the radiologist and the respiratory specialists in pneumological and
thoracic surgery.

The PubMed literature was searched for haemo- or haematothorax (and spelling variations
thereof ). Literature concerning post-operative, post-traumatic and in context with aortic
aneurysm-treated haematothorax was excluded. If appropriate, well-written reviews are cited
in this chapter in order to limit the number of case reports in the list of references. The
recommendations given here are mainly based on clinical case series, case reports and the
clinical experience of the authors. They are not supported by prospective randomised studies.

Definition criterion and clinical presentation

Pleural effusion is common and has to be distinguished from haemorrhagic exudate and
haematothorax. In a visual examination, a content of 5% haematocrit makes the effusion
indistinguishable from blood.

1
Lung Clinic/Thoracic Surgery, Cologne Hospital, Witten/Herdecke University, Cologne, Germany. 2Clinic for Diagnostic and
Interventional Radiology and Neuroradiology, Cologne Hospital, Witten/Herdecke University, Cologne, Germany. 3Dept of Thoracic
Surgery, Helios University Hospital Wuppertal, Witten/Herdecke University, Wuppertal, Germany.

Correspondence: Erich Stoelben, Lung Clinic/Thoracic Surgery, Cologne Hospital, Witten/Herdecke University, 51109 Cologne,
Germany. E-mail: StoelbenE@kliniken-koeln.de

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 161–170. DOI: 10.1183/2312508X.10002116 161

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

A haematocrit in the punctate of at least 50% of the haematocrit in the patient’s blood is
postulated for the definition of haematothorax [1, 2]. However, the haematocrit in the
punctate should be interpreted with caution. The process of coagulation binds the red cells,
leaving a fluid supernatant with a low content of erythrocytes. Therefore, the criterion for
the definition of haematothorax is not always really helpful.

The patient should be treated in the same way as an emergency for haematothorax and
haemorrhagic pleural effusion and whenever coagulated or solid masses with the pleural
effusion are detected by sonography and/or a CT scan of the chest. In cases of previous
intervention, the cause of the haematothorax is obvious. Otherwise, such as in rare
spontaneous haematothorax, the history of the patient may give some suggestions.
Nonetheless, diagnosis can be challenging.

The intrathoracic accumulation of blood leads to chest pain, dyspnoea and cough. Patients
might compensate for the loss of intravascular volume by vasoconstriction. In this case, the
clinical sign might be a cold white nose. If bleeding persists and compensation mechanisms
such as dilution of blood from the interstitial space are overstressed (i.e. leading to a fall in
haematocrit), the blood pressure decreases and the heart rate rises. This may result in a
positive shock index (heart rate (beats·min–1)/systolic blood pressure (mmHg)). Furthermore,
the accumulation of large amounts of fluid in the thoracic cavity can lead to respiratory stress
with elevated breathing frequency. Now the patient is in a life-threatening situation and needs
effective help by volume resuscitation and interventions to stop the bleeding. Intrathoracic
bleeding is regularly underestimated, as the bleeding is not visible and the pleural cavity on
one side comprises a volume of ∼3–6 L. Therefore, the primary task of the attending physician
is to prevent the patient reaching the life-threatening stage of intrapleural bleeding.

Causes and epidemiology

Haematothorax is a rare event except in traumatic and post-interventional situations. As we

do not have access to epidemiological data, we are forced to cite case series, which carry the
risk of selection bias. On this basis, we can quantify the risk of haematopneumothorax to
be 3–5% of all pneumothorax cases and the risk of haematothorax in patients with
hereditary haemorrhagic telangiectasia to be 3–5% of the patients with this disease. Only a
small number of case reports have been published for all other causes of spontaneous
haematothorax and this does not allow an estimation of the incidence (table 1).

Spontaneous haematothorax

Haematopneumothorax
In patients with pneumothorax, concomitant haematothorax can occur in 3–5% of the
patients because a solitary apical adhesion bearing a small interpleural artery ruptures due
to the lung collapsing (figure 1).

The artery has developed following inflammatory adhesions and does not contain normal
structures such as smooth muscle cells. Therefore, the bleeding can persist, requiring
emergency surgical intervention in about one-third of patients [3, 4, 23]. A current
epidemiological study on the incidence of pneumothorax in France [24] confirmed a rate of
22.7 spontaneous pneumothoraxes per 100 000 population per year with a female/male ratio
of 1:3.3. Therefore, haematopneumothorax may be a relevant clinical setting in young males.

162

FB:Cardiologia Siglo XXI

 HAEMATOTHORAX | E. STOELBEN ET AL.

Table 1. Causes and incidences of haematothorax

Cause Incidence Reference(s)

Spontaneous
Haematopneumothorax 3–5% of patients with pneumothorax [3, 4]
Hereditary haemorrhagic 3–5% of patients with hereditary [5, 6]
telangiectasia haemorrhagic telangiectasia
Malignant tumours of the lung Case reports [7]
or pleura
von Recklinghausen disease/ Case reports [1, 7–9]
schwannoma
Multiple exostosis Case reports [1, 7]
Anticoagulation and coagulation Case reports [7]
disorders
Endometriosis Case series [10–12]
Extramedullary haematopoiesis Case reports [1, 7, 13]
Vascular aneurysm (Ehlers–Danlos Case reports [14, 15]
syndrome)
Post-interventional
Central venous catheter <0.5% [16, 17]
CT-guided lung biopsy 1–3.5% [18, 19]
Thoracic drainage 0.2–1.4% (depending on size of drainage) [20]
Thoracentesis 0–1% [21, 22]

Hereditary haemorrhagic telangiectasia

The cause of haematothorax is not known. One explanation might be a superficial
pulmonary arteriovenous malformation rupturing and bleeding into the pleural space. In the
published case series, the diagnosis of hereditary haemorrhagic telangiectasia was made after
the third decade of life in most of the patients. The prevalence of hereditary haemorrhagic
telangiectasia is estimated to be between 1 per 5000 and 1 per 10 000 population [5, 6]. In
the case of spontaneous haematothorax, the CT scan should be checked for pulmonary
arteriovenous malformation and telangiectasia of the lips and the mucosa.

a) b)

Figure 1. a) Chest radiograph of spontaneous primary haematopneumothorax. b) Thoracoscopic view of a

solitary apical adhesion.

163

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Malignant tumours
Haematothorax can be generated by intrapulmonary tumours such as lung cancer or
pulmonary metastases penetrating the visceral pleura, or by tumour spread in the interpleural
space. Furthermore, tumours from the mediastinum, chest wall or subdiaphragmatic space
can lead to intrathoracic bleeding. Highly vascularised malignancies such as angiosarcoma
[25], renal cell carcinoma (experience of the authors) or hepatocellular cancer [1] as the
cause of haematothorax are published in small series. Overall, the risk of bleeding is low
considering the high number of intrathoracic primary and secondary tumours. In most cases,
haematothorax indicates an advanced tumour stage and a very limited prognosis (figure 2).

Von Recklinghausen disease/schwannoma

Small case series with haematothorax have been analysed in patients with von
Recklinghausen disease and/or schwannoma. In some patients, bleeding was associated
with the local growth and complication of a schwannoma. Indeed, resection of a
schwannoma (figure 3) can be bloody, this being caused by peritumoural hypertrophied
intercostal vessels. In other patients, rupture of a subclavian or intercostal artery showing
histopathological signs of dysplasia was the cause of bleeding [1, 8, 9, 26].

Coagulopathy
Bleeding in the thoracic cavity under anticoagulation or in patients with congenital or
acquired coagulopathy is extremely rare without an underlying intrathoracic disease [1].
However, in the case of pleural disease, which can cause haematothorax, coagulopathy may
aggravate bleeding and complications.

Endometriosis
Endometriosis is a relatively common disease in pre-menopausal women (5–15%). The
catamenial thoracic symptoms of thoracic endometriosis are a rare manifestation of the
disease, and comprise pneumothorax, haemoptysis and haematothorax. The right side of
the thorax is affected in 80% of cases. The symptoms are recurrent. Haematothorax occurs
in 8–15% of patients with thoracic endometriosis and is associated with the pleural implants

Figure 2. Thoracoscopic view of pleural carcinosis from a renal cell carcinoma.

164

FB:Cardiologia Siglo XXI

 HAEMATOTHORAX | E. STOELBEN ET AL.

Figure 3. CT scan of neoplasm of the posterior mediastinum: schwannoma.

of endometriosis [10–12]. Treatment requires the cooperation of gynaecological and thoracic

surgery with local and systemic interventions.

Others
Diseases such as extramedullary haematopoiesis [13], vascular-type Ehlers–Danlos syndrome
[14, 15], (multiple) exostosis of the ribs [1, 7] and rare vascular aneurysm [27] can also be
complicated by haematothorax. The number of published cases is below 20 for each entity.

Haematothorax after medical intervention

Central venous catheterisation

The procedure is routine in anaesthesia, intensive care medicine, oncology and other
medical specialities. Most papers focus on pneumothorax or infection after catheter
placement. The risk of haematothorax is low [16, 17]. The main cause of bleeding is
puncture of the accompanying artery (carotid or subclavian artery). A non-self-limiting
haematoma can disrupt the mediastinal pleura or the needle can perforate the artery and
the pleura with direct bleeding into the pleural space. In our experience, the risk of
clinically relevant haematothorax is elevated in patients with antiplatelet medication and
other coagulation disorders. Treatment can be demanding, as the exact localisation of the
injury of the artery in a sometimes extended haematoma in the upper sulcus of the thorax
or supraclavicular region can be difficult.

CT-guided biopsy
CT-guided biopsies are regularly used to confirm the histology or stage of lung tumours.
The main complications are pneumothorax and intraparenchymal bleeding with
haemoptysis. The overall rate of complications is ∼30%. Between 6% and 10% of patients
need therapy, mainly thoracic drainage. The risk of haematothorax is 1–3.5%; none of the
patients studied needed an intervention [18, 19].

Thoracic drainage
This procedure is used for the therapy of pneumothorax or pleural effusion, including
haematothorax and pleural empyema. The rate of adverse events depends on the

165

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

circumstances involved (emergency, experience of the physician), method of application,

diameter of drainage and underlying disease, including coagulation disorders [20, 28]. The
source of bleeding can be the intercostal artery (figure 4), the lungs and all other organs in or
around the thoracic cavity. The use of large-bore trocar drainage bears the highest risk of
bleeding. The safest way to treat the patient is the use of small-bore drainages (9–14 French)
in combination with sonography and the Seldinger technique. As in thoracentesis, impaired
coagulation is not an absolute contraindication for drainage.

Thoracentesis
The indication for thoracentesis is sometimes liberal. Although the rate of pneumothorax
(2–6%) and haematothorax (<1%) is low, the bleeding complications in patients with
cardiovascular disease and antiplatelet therapy can be life threatening. Injury to the
intercostal artery or a diaphragm vessel can remain undetected until a patient develops signs
of hypovolaemia. However, correction of coagulopathy does not decrease the risk of bleeding
[18, 20–22].

Diagnosis

Spontaneous haematothorax

In patients with spontaneous haematothorax, the clinical signs of chest pain, including pain
in the upper abdomen, cough and dyspnoea, initiate a routine check-up involving chest
radiography and/or sonography. In experienced hands, sonography might give the same or
even more information than a chest radiograph. The echo image of the fluid can provide
important suggestions for the differentiation between uncomplicated pleural effusion,
pleural empyema or haematothorax. Sonography is performed more quickly and is always
available [20, 29]. It should be kept in mind that the studies on the use of sonography in
haematothorax were mainly conducted on trauma patients. The patient’s history has to be
checked for the above-mentioned conditions, including coagulopathies.

Figure 4. CT of the chest demonstrating haematothorax after trocar chest tube placement.

166

FB:Cardiologia Siglo XXI

 HAEMATOTHORAX | E. STOELBEN ET AL.

If haematothorax is suspected, a CT scan is indicated to identify the cause, extent and

source of bleeding. This information is important to plan further treatment.
Simultaneously, laboratory tests, including blood group determination, should be initiated.

The diagnostic step has to be cancelled if the patient presents with signs of cardiorespiratory
and circulatory insufficiency. Therapy with volume resuscitation and thoracic drainage
(minimum 24 French) must start immediately and a blood transfusion has to be prepared. In
the case of massive haematothorax of >1500 mL or persistent bleeding of >200 mL·h–1, patients
have to be operated on immediately. This approach is recommended in nearly all studies for
patients with haematothorax of variable causes without any compelling evidence [2, 30].

Haematothorax after medical intervention

After the thoracic interventions detailed earlier, the attending physician has to organise
appropriate clinical and/or imaging follow-up. If pleural effusion occurs within 24 h,
haematothorax is likely. The bleeding source is predetermined by the intervention and
intervention site. Therefore, a CT scan is not always necessary. In stable patients, thoracic
drainage and correction of an underlying coagulopathy is the first step of diagnosis and
therapy. In unstable patients, or in the case of massive haematothorax or persistent bleeding,
the same procedure has to be used as in patients with spontaneous haematothorax (see the
later section on surgical treatment).

Treatment

Conservative treatment

In stable patients with spontaneous or post-interventional haematothorax, initial treatment

consists of a thoracic drainage of 24–36 French, which has to be placed following
standardised guidelines [20].

We do not know in which and in how many patients drainage and correction of
coagulopathy solve the problem by stopping the bleeding. Furthermore, there is a risk of
retained haematothorax. The coagulated blood cannot always be drained completely, and
this leads to the risk of pleural empyema, recurrent pleural effusion and fibrothorax. Once
again, these risks have been well studied in trauma patients with haematothorax, but
detailed evidence-based data for the patients discussed here are not available.

Importantly, about one-third of the patients with haematopneumothorax have to be operated

on for massive haematothorax or persistent bleeding. Most of the remaining patients need a
secondary surgical intervention for retained haematothorax or persistent pneumothorax
using a minimally invasive, video-assisted thoracoscopic surgery (VATS) procedure.
Therefore, a primary surgical procedure is recommended for most of the patients [4].
However, the application of fibrinolytic agents (urokinase, streptokinase and tissue
plasminogen activator) was performed with a success rate of ∼80% [31–33]. Unfortunately,
the number of studies is small and the quality low. The time point of application, dose, agent
and number of applications are not well defined.

Bleeding from injury to the intercostal or mammary artery or from a ruptured aneurysm
can be treated by interventional radiology and application of coils by means of bronchial
artery embolisation (figure 5) [27, 34].

167

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

a)

b) c)

Figure 5. Sarcoidosis of the mediastinal lymph nodes and aneurysm of a bronchial artery in the
mediastinum. a) CT of the chest with contrast enhancement, b) angiography and c) embolisation.

Immediate treatment is required in unstable patients. We discussed the emergency

procedure in the earlier section on diagnosis (figure 6).

Surgical treatment

Following medical intervention or persistent bleeding in spontaneous haematothorax, the

surgeon could plan the intervention depending on a CT scan, the anatomical situation and
the underlying disease. Thoracic surgery is turning more and more to minimally invasive
surgery, ranging from diagnostic procedures to complex anatomical resections and
interventions. Therefore, in experienced hands, minimally invasive, video-assisted access
could be used safely and effectively to control bleeding in most cases and to evacuate the
coagulated blood [2, 30].

In the case of retained haematothorax, the evacuation of the clotted blood should be
performed as early as possible before organisation starts, preferably within 1 week [7, 30,
35]. In patients who are not candidates for surgery, the local application of fibrinolytic
agents might be an alternative.

168

FB:Cardiologia Siglo XXI

 HAEMATOTHORAX | E. STOELBEN ET AL.

Spontaneous haematothorax Haematothorax after intervention

Radiography and sonography Radiography or sonography

Clinical signs,
blood pressure,
Stable Unstable Stable
pulse rate,
respiratory rate

CT scan Volume resuscitation/drainage Drainage

Drainage
VATS/thoracotomy >1500 mL <1500 mL >1500 mL
Intervention, angiography >200 mL·h–1 <200 mL·h–1 >200 mL·h–1
Systemic therapy

Thoracotomy CT scan/wait and see VATS

Retained
haematothorax VATS (or fibrinolysis)

Figure 6. Haematothorax treatment strategy algorithm. VATS: video-assisted thoracoscopic surgery.

The most challenging situation for the thoracic surgeon may be the unstable patient with
spontaneous haematothorax without a CT scan. The surgeon has to face a number of
causes and sources of bleeding. In this situation, emergency thoracotomy enables the
broadest spectrum of interventions. Otherwise, and in the case of massive bleeding,
thoracotomy is the access of choice anyway.

Conclusions

Haematothorax is a rare event except in traumatic and post-interventional situations.

Haematothorax has to be distinguished from haemorrhagic exudate and pleural effusion.
Spontaneous or post-interventional haematothorax might turn out to be an emergency
situation requiring immediate interdisciplinary treatment. Depending on the underlying cause,
conservative and surgical treatment might be appropriate. However, early VATS is an effective
and safe treatment for the management of haematothorax irrespective of the underlying
disease. Thoracotomy should be used in unstable patients with unknown cause of bleeding.

References
1. Ali HA, Lippmann M, Mundathaje U, et al. Spontaneous hemothorax: a comprehensive review. Chest 2008; 134:
1056–1065.
2. Boersma WG, Stigt JA, Smit HJ. Treatment of haemothorax. Respir Med 2010; 104: 1583–1587.
3. Ng CS, Wong RH, Wan IY, et al. Spontaneous haemopneumothorax: current management. Postgrad Med J 2011;
87: 630–635.
4. Tay CK, Yee YC, Asmat A. Spontaneous hemopneumothorax: our experience with surgical management.
Asian Cardiovasc Thorac Ann 2015; 23: 308–310.
5. Circo S, Gossage JR. Pulmonary vascular complications of hereditary haemorrhagic telangiectasia. Curr Opin Pulm
Med 2014; 20: 421–428.
6. Cottin V, Chinet T, Lavole A, et al. Pulmonary arteriovenous malformations in hereditary hemorrhagic
telangiectasia: a series of 126 patients. Medicine 2007; 86: 1–17.

169

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

7. Patrini D, Panagiotopoulos N, Pararajasingham J, et al. Etiology and management of spontaneous haemothorax.

J Thorac Dis 2015; 7: 520–526.
8. Baldo X, Ortiz MR, Sebastian F, et al. Fatal right spontaneous haemothorax in Von Recklinghausen’s disease.
Interact Cardiovasc Thorac Surg 2003; 2: 35–37.
9. Miura H, Taira O, Uchida O, et al. Spontaneous haemothorax associated with von Recklinghausen’s disease: review
of occurrence in Japan. Thorax 1997; 52: 577–578.
10. Alifano M, Trisolini R, Cancellieri A, et al. Thoracic endometriosis: current knowledge. Ann Thorac Surg 2006; 81:
761–769.
11. Rousset P, Rousset-Jablonski C, Alifano M, et al. Thoracic endometriosis syndrome: CT and MRI features.
Clin Radiol 2014; 69: 323–330.
12. Channabasavaiah AD, Joseph JV. Thoracic endometriosis: revisiting the association between clinical presentation
and thoracic pathology based on thoracoscopic findings in 110 patients. Medicine 2010; 89: 183–188.
13. Tassiopoulos S, Konstantopoulos K, Rombos Y, et al. Hemothorax due to extramedullary erythropoietic masses.
Ann Thorac Surg 2004; 77: 323–324.
14. Chu LC, Johnson PT, Dietz HC, et al. Vascular complications of Ehlers–Danlos syndrome: CT findings. AJR Am J
Roentgenol 2012; 198: 482–487.
15. Hasan RI, Krysiak P, Deiranyia AK, et al. Spontaneous rupture of the internal mammary artery in Ehlers–Danlos
syndrome. J Thorac Cardiovasc Surg 1993; 106: 184–185.
16. Ruesch S, Walder B, Tramer MR. Complications of central venous catheters: internal jugular versus subclavian
access – a systematic review. Crit Care Med 2002; 30: 454–460.
17. McGee DC, Gould MK. Preventing complications of central venous catheterization. N Engl J Med 2003; 348:
1123–1133.
18. Anzidei M, Sacconi B, Fraioli F, et al. Development of a prediction model and risk score for procedure-related
complications in patients undergoing percutaneous computed tomography-guided lung biopsy. Eur J Cardiothorac
Surg 2015; 48: e1–e6.
19. Schulze R, Seebacher G, Enderes B, et al. Complications in CT-guided, semi-automatic coaxial core biopsy of
potentially malignant pulmonary lesions. Rofo 2015; 187: 697–702.
20. Havelock T, Teoh R, Laws D, et al. Pleural procedures and thoracic ultrasound: British Thoracic Society Pleural
Disease Guideline 2010. Thorax 2010; 65: Suppl. 2, ii61–ii76.
21. Ault MJ, Rosen BT, Scher J, et al. Thoracentesis outcomes: a 12-year experience. Thorax 2015; 70: 127–132.
22. Cantey EP, Walter JM, Corbridge T, et al. Complications of thoracentesis: incidence, risk factors, and strategies for
prevention. Curr Opin Pulm Med 2016; 22: 378–385.
23. Hsu NY, Shih CS, Hsu CP, et al. Spontaneous hemopneumothorax revisited: clinical approach and systemic review
of the literature. Ann Thorac Surg 2005; 80: 1859–1863.
24. Bobbio A, Dechartres A, Bouam S, et al. Epidemiology of spontaneous pneumothorax: gender-related differences.
Thorax 2015; 70: 653–658.
25. Moriya Y, Sugawara T, Arai M, et al. Bilateral massive bloody pleurisy complicated by angiosarcoma. Intern Med
2007; 46: 125–128.
26. Teitelbaum GP, Hurvitz RJ, Esrig BC. Hemothorax in type I neurofibromatosis. Ann Thorac Surg 1998; 66: 569–571.
27. Rodriguez M, Gonzalez de la Huebra Labrador T, Aranda JL. Diagnosis and treatment of hemothorax caused by
intercostal artery pseudoaneurysm. Arch Bronconeumol 2016; 52: 219.
28. Harris A, O’Driscoll BR, Turkington PM. Survey of major complications of intercostal chest drain insertion in the
UK. Postgrad Med J 2010; 86: 68–72.
29. McEwan K, Thompson P. Ultrasound to detect haemothorax after chest injury. Emerg Med J 2007; 24: 581–582.
30. Broderick SR. Hemothorax: etiology, diagnosis, and management. Thorac Surg Clin 2013; 23: 89–96.
31. Inci I, Ozcelik C, Ulku R, et al. Intrapleural fibrinolytic treatment of traumatic clotted hemothorax. Chest 1998;
114: 160–165.
32. Kumar S, Rathi V, Rattan A, et al. VATS versus intrapleural streptokinase: a prospective, randomized, controlled
clinical trial for optimum treatment of post-traumatic residual hemothorax. Injury 2015; 46: 1749–1752.
33. Huang D, Zhao D, Zhou Y, et al. Intrapleural fibrinolytic therapy for residual coagulated hemothorax after lung
surgery. World J Surg 2016; 40: 1121–1128.
34. Motos-Mico JJ, Alves-Conciecao T, Lopez-Martinez L, et al. Embolization of intercostal arteries in iatrogenic
haemothorax. Cir Esp 2015; 93: 340–341.
35. Parry GW, Morgan WE, Salama FD. Management of haemothorax. Ann R Coll Surg Engl 1996; 78: 325–326.

Disclosures: None declared.

170

FB:Cardiologia Siglo XXI

 | Chapter 12
High-flow nasal cannula oxygen
therapy
Rémi Coudroy1,2, Jean-Pierre Frat1,2 and Arnaud W. Thille1,2

High-flow nasal cannula (HFNC) oxygen therapy is a recent technique enabling delivery of a
high flow rate of gas heated and humidified as under physiological conditions. The main
clinical effects include a significant decrease in respiratory rate, work of breathing, and patient
discomfort and breathlessness as compared with standard oxygen. These effects are mainly
due to the high flow rate of gas that effectively matches the high ventilatory demand in
patients, and provides high FIO2, PEEP and continuous washing of dead space, thereby
flushing carbon dioxide out of the upper airways. Several RCTs have compared HFNC oxygen
versus standard oxygen or NIV. In keeping with this literature, the use of HFNC oxygen could
be the first-line strategy of oxygenation in patients admitted to the ICU with acute
hypoxaemic respiratory failure, during the post-extubation period or after cardiac surgery.

T he use of standard oxygen through a reservoir mask has long been the first-line
therapy of choice in patients with acute respiratory failure (ARF). However, this
strategy is far from ideal. Indeed, it does not reduce the work of breathing and/or improve
alveolar ventilation, and FIO2 delivered to the patient does not exceed 70%, even with a flow
rate of 15 L·min−1. Moreover, the oxygen provided by a hospital outlet or by a tank is a
particularly dry gas that may irritate the airways, alter mucociliary clearance and cause
discomfort for the patient.

The use of NIV is the main alternative to standard oxygen in patients with ARF. The gas
delivered to the patient can be heated and humidified, with a FIO2 close to 100% in the
absence of leaks, and provide positive pressure which improves gas exchange and reduces
patient inspiratory effort. However, good tolerance to NIV is sometimes difficult to achieve
due to frequent leaks around the mask, often leading to patient–ventilator asynchronies.
Moreover, some deleterious effects may occur with NIV, such as delayed intubation by
masking signs of respiratory distress or potential barotrauma provoked by the high tidal
volumes that can occur with pressure support ventilation.

High-flow nasal cannula (HFNC) oxygen therapy is a more recent oxygenation technique
enabling delivery of high FIO2. Although there is no pressure support, the high flow

1
CHU de Poitiers, Réanimation Médicale, Poitiers, France. 2INSERM CIC 1402 (ALIVE Group), Université de Poitiers, Faculté de
Médecine, Poitiers, France.

Correspondence: Arnaud W. Thille, Service de Réanimation Médicale, CHU de Poitiers, 2 rue la Milétrie, 86021 Poitiers Cedex, France.
E-mail: aw.thille@gmail.com

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 171–185. DOI: 10.1183/2312508X.10002216 171

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

generates low levels of PEEP and provides continuous washout of dead space in the
airways. These physiological effects may help to improve gas exchange, and to reduce
respiratory rate and patient effort, without increased risk of barotrauma. This oxygenation
strategy seems particularly comfortable for the patient thanks to nasal cannulae (“prongs”)
delivering a warmed and humidified gas similar to physiological conditions, and allowing
the patient to continue drinking and eating. The use of HFNC oxygen therapy is growing,
and we focus our chapter first on physiological aspects to understand its clinical effects and
then on clinical evidence for its use in clinical practice.

Characteristics and physiological effects of HFNC oxygen therapy

Physiological effects of HFNC oxygen therapy are due to 1) the warming and
humidification of gas delivered through nasal cannulae, and 2) the high flow rate.

Warming and humidification of delivered gas

Under physiological conditions, and regardless of the external environment, the inspired
gas needs to be heated and humidified in the airways to reach the alveoli with a
temperature of 37 °C and containing 44 mg·L−1 of water, i.e. completely saturated with
water (relative humidity of 100%). Oxygen delivered from a hospital outlet or from a tank
is a particularly cold and dry gas with humidity <5 mg·L−1 of water [1], which could
irritate and increase the resistance of the airways [2]. HFNC oxygen is delivered via a
heated humidifier and it has been shown that it significantly decreases the sensation of
airway dryness as compared with standard oxygen [3–5]. Warming and humidification of
oxygen possibly help to decrease patient discomfort and a sensation of dyspnoea observed
when switching from standard oxygen to HFNC oxygen [5, 6]. Whether or not heating and
humidification of inspired gases may prevent thick secretions and subsequent atelectasis is
an unproven hypothesis.

Mismatch between the patient’s inspiratory flow rate and oxygen flow rate: impact
of high flow on FIO2

Although FIO2 delivered to the patient can reach up to 100% when using NIV in the
absence of leaks, maximal FIO2 does not exceed 70% with standard oxygen despite a
reservoir mask and a flow rate up to 15 L·min−1 [6, 7]. Indeed, the inspiratory flow rate
generated by a patient suffering from ARF reaches at least 30–40 L·min−1 on average, and
can even exceed 60 L·min−1 in more severe patients [8], which is markedly higher than the
flow rate delivered with standard oxygen. Oxygen is consequently mixed with room air,
reducing FIO2 delivered to the patient. In a physiological study, SIM et al. [7] measured FIO2
in healthy subjects ventilated using a standard mask, a non-rebreathing mask with a
reservoir and HFNC oxygen. Using a standard mask, FIO2 was <60% despite a flow rate of
12 L·min−1 and dropped to <50% when they simulated ARF by thoracic contention.
Although the non-rebreathing mask avoided such a drop of FIO2 during ARF, FIO2 was
<70% even with a flow rate of 15 L·min−1. By comparison, FIO2 reached 85% using HFNC
oxygen set with a flow rate of 40 L·min−1. This effect could directly contribute to
improvement in oxygenation and to the decrease in the respiratory rate observed when
switching from standard oxygen to HFNC oxygen.

172

FB:Cardiologia Siglo XXI

 HIGH-FLOW NASAL CANNULA OXYGEN THERAPY | R. COUDROY ET AL.

Positive pressure generated by high gas flow rate

The use of HFNC oxygen could generate PEEP directly proportional to the gas flow
delivered: the higher the flow, the higher the pressure. The large nasal cannulae could
create a certain degree of nasal obstruction while the continuously delivered high flow
causes resistance during expiration, thereby generating positive pressure. Consequently, this
PEEP effect is markedly reduced when the patient opens his/her mouth. PARKE et al. [9]
measured nasopharyngeal pressure in patients at different levels of flow using HFNC
delivery. The PEEP level exceeded 3 cmH2O with a gas flow rate of 50 L·min−1 and with a
closed mouth, whereas it dropped to <2 cmH2O with an open mouth. Although the PEEP
level seems only moderate, this PEEP effect could help to improve gas exchange and
decrease the work of breathing in patients, as with CPAP in patients with intrinsic PEEP
[10]. In a physiological study that measured pulmonary volumes after cardiac surgery using
inductance plethysmography, an increase in end-expiratory lung volume was found with
HFNC oxygen therapy, suggesting alveolar recruitment induced by this PEEP effect [11].

Washout of dead space in the airways induced by high gas flow rate

The high flow rate of gas continuously delivered in the airways may generate a washout of
dead space into the pharynx, flushing carbon dioxide out of the upper airways [12]. This
phenomenon may help to improve the efficiency of ventilation [13] and to reduce the work
of breathing [14]. HFNC oxygen is delivered through nasal cannulae, thereby reducing the
dead space and making rebreathing less likely. By contrast, a reservoir mask delivering
standard oxygen or a facial mask for NIV is a supplemental dead space that may promote
rebreathing of carbon dioxide [15–17].

Clinical effects of HFNC oxygen therapy

Taken together, all the above-mentioned physiological effects may enable an improvement
in oxygenation, a significant reduction in respiratory rate and patient effort, and better
comfort with less sensation of dyspnoea (figure 1).

Improvement in oxygenation

In patients with ARF, it has been observed that PaO2 is significantly increased by switching
from standard oxygen to HFNC oxygen [5, 18–20]. This improvement in oxygenation
could be due to a higher amount of oxygen delivered to the patient or due to the PEEP
effect and subsequent recruitment. The impact of the PEEP effect on oxygenation is
uncertain and its improvement seems mainly driven by higher FIO2. In a pilot study
assessing standard oxygen, HFNC oxygen and NIV successively in patients with ARF, PaO2
increased from standard oxygen to HFNC oxygen without changes in PaO2/FIO2, suggesting
that improvement in oxygenation was directly due to an increase in FIO2 [20]. By contrast,
PaO2 further increased with NIV with a significant increase in PaO2/FIO2, suggesting alveolar
recruitment induced by PEEP. The same group then compared standard oxygen, HFNC
oxygen and NIV in a large multicenter study [6]. At baseline, all patients received standard
oxygen and FIO2 was measured using an oxygen analyser. Again, FIO2 and PaO2 increased
from standard oxygen to HFNC oxygen without changes in PaO2/FIO2, whereas it was
markedly higher with NIV than with the other two oxygenation strategies.

173

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

High-flow oxygen Heated and humidified gas

Delivered via nasal

cannulae

Washout of PEEP Better

dead space effect comfort
Alveolar recruitment
Decreased
PaCO2

Decreased Decreased sensation

respiratory rate of dyspnoea
High FIO2
Improved
oxygenation

Decreased work of
breathing

Figure 1. Impact of physiological and clinical effects on the work of breathing with high-flow nasal cannula
oxygen therapy.

Decrease in respiratory rate and work of breathing

It has been found that the work of breathing in patients with ARF is lower with HFNC
oxygen than with standard oxygen [14]. In this physiological study, the work of breathing was
measured with a non-rebreathing mask, with HFNC oxygen or with CPAP at 5 cmH2O [14].
The decrease in the work of breathing observed with HFNC oxygen was the same as that
observed with CPAP at 5 cmH2O. However, the mechanism by which the work of breathing
decreased has not been fully elucidated. The decrease in the work of breathing could be due to
decreased airway resistance, improved pulmonary compliance or only to decreased respiratory
rate. Most studies have observed a rapid decrease in respiratory rate when switching from
standard oxygen to HFNC oxygen in healthy subjects [21] as well as in patients with ARF and
tachypnoea [5, 6, 18–20]. The respiratory rate in patients treated with HFNC oxygen was also
lower than that in patients treated with NIV [6]. A recent study evaluating HFNC oxygen in
post-extubation found a reduced incidence of upper airway obstruction as compared with
standard oxygen [22]. Although this finding may suggest a decrease in inspiratory resistance
of the upper airways, this hypothesis is unproven. The use of HFNC oxygen may also decrease
the elastic work of breathing by increasing the tidal volume [21]. Tidal volumes should
nonetheless remain lower than those observed with NIV. Indeed, as compared with standard
oxygen or CPAP alone, the pressure support applied during NIV significantly increases tidal
volumes in patients with ARF [23]. Recently, it has been suggested that the large tidal volumes
generated by the pressure support may generate high transpulmonary pressures and
barotrauma, worsening lung injury in patients with ARF [24, 25].

Improvement of patient comfort and breathlessness

Most studies assessing HFNC oxygen therapy have found that patients felt better comfort,
less sensation of dyspnoea and less dryness of the mouth compared with standard oxygen

174

FB:Cardiologia Siglo XXI

 HIGH-FLOW NASAL CANNULA OXYGEN THERAPY | R. COUDROY ET AL.

through a nonreservoir mask [3–5, 18]. Compared with NIV, patients treated with HFNC
oxygen also had less discomfort and less breathlessness [6, 20, 26]. This improvement in
comfort probably has a major impact on the clinical benefits of HFNC oxygen that we will
discuss in the following section.

Clinical evidence for the use of HFNC oxygen therapy

The use of HFNC oxygen therapy to treat patients with ARF as well as to prevent
hypoxaemia in various clinical settings is increasing. The results from RCTs comparing
HFNC oxygen versus standard oxygen or NIV are detailed in table 1.

To treat acute respiratory failure

Based on observational studies, the use of HFNC oxygen in patients with ARF improved
oxygenation and decreased the respiratory rate with less sensation of dyspnoea as compared
with standard oxygen [5, 18, 19]. As compared with NIV, the use of HFNC oxygen was less
effective in terms of oxygenation, but better tolerated with less discomfort and less
breathlessness [20, 26]. The use of NIV is controversial in hypoxaemic patients and, to
date, few RCTs have found a better outcome with NIV than with standard oxygen [43] and
they mostly included small samples of immunocompromised patients [44, 45]. Therefore, a
RCT was recently conducted by FRAT et al. [6] to compare these three strategies of
oxygenation (i.e. standard oxygen, HFNC oxygen and NIV). They included 310
nonhypercapnic patients with ARF defined by a respiratory rate >25 breaths·min–1,
PaO2/FIO2 <300 mmHg and PaCO2 ⩽45 mmHg. The mortality rate at day 90 was lower with
HFNC oxygen than using the other two strategies: 12% with HFNC oxygen versus 23%
with standard oxygen and 28% with NIV ( p=0.02). Although the rate of intubation was not
significantly different among the three groups in the overall population, it was significantly
lower among the more severe patients (PaO2/FIO2 ⩽200 mmHg) treated with HFNC oxygen
than in those treated with standard oxygen or NIV (35%, 53% and 58%, respectively;
p=0.009). One hour after initiation of HFNC oxygen, the dyspnoea score and discomfort
felt by patients were significantly lower as compared with standard oxygen or NIV.
Therefore, HFNC oxygen could be considered as the first-line strategy of oxygenation in
patients admitted to the ICU for ARF. Two points from this study must be highlighted.
First, patients treated with NIV received HFNC oxygen between NIV sessions and their
mortality was significantly higher than in patients treated with HFNC oxygen alone. This
finding suggests deleterious effects of NIV with the assumption that it might be due to
high tidal volumes (mean >9 mL·kg−1) and subsequent high transpulmonary pressures
generated with NIV. A recent study found that nearly half of hypoxaemic patients treated
with NIV had tidal volumes >10 mL·kg−1, with increased risk of intubation [25]. Second,
criteria for intubation were clearly defined to avoid delayed intubation that may in certain
circumstances increase mortality [46]. In a retrospective observational cohort of 175
patients, late intubation beyond the first 48 h after initiation of HFNC oxygen was
associated with increased mortality as compared with early intubation (67% versus 39%;
p=0.001) [47], raising concerns about the criteria to stop HFNC oxygen for intubation. In
the study by FRAT et al. [6], the time to intubation was not significantly different between
the three groups, suggesting that poor outcomes observed in this study could be due to the
oxygenation strategy applied and not to delayed intubation.

175

FB:Cardiologia Siglo XXI

176

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 1. Summary of recent (2011–2016) RCTs on high-flow nasal cannula (HFNC) oxygen therapy according to different clinical conditions

First author [ref.] Setting Patients n Inclusion criteria Main results (including primary end-points#)
comparing HFNC oxygen versus
standard oxygen or NIV

Acute respiratory failure

FRAT [6] ICU 310 Respiratory rate Intubation rate: 38% with HFNC oxygen versus
>25 breaths·min−1; 47% with standard oxygen and 50% with NIV (p=0.18)
PaO2/FIO2 ⩽300 mmHg; Intubation rate (PaO2/FIO2 ⩽200 mmHg): 35% with
PaCO2 <45 mmHg HFNC oxygen versus 53% with standard
oxygen and 58% with NIV (p=0.009)
Day 90 mortality: 12% with HFNC oxygen
versus 23% with standard oxygen and 28%
with NIV (p=0.02)
LEMIALE [27] ICU 100 Immunocompromised Need for NIV or intubation at 2 h: 15% with HFNC
patients: hypoxaemia or oxygen versus 8% with standard oxygen (p=0.36)
respiratory distress
FRAT [28] ICU (subgroup 82 Immunocompromised Intubation rate: 31% with HFNC oxygen versus
analysis) patients: respiratory 43% with standard oxygen and 65% with NIV (p=0.04)
rate >25 breaths·min−1; In-ICU mortality: 15% with HFNC oxygen versus 20%
PaO2/FIO2 ⩽300 mmHg; with standard oxygen and 42%
PaCO2 <45 mmHg with NIV (p=0.06)
Day 90 mortality: 15% with HFNC oxygen
versus 27% with standard oxygen and 46%
with NIV (p=0.046)
JONES [29] Emergency 322 Hypoxia and tachypnoea Intubation in the emergency room: 4% with HFNC
department oxygen versus 7% with standard oxygen (p=0.16)
Intubation at 24 h: 6% with HFNC oxygen versus 12%
with standard oxygen (p=0.05)
BELL [30] Emergency 100 Respiratory rate Need for escalation in ventilation therapy at
department ⩾25 breaths·min−1; 2 h: 4% with HFNC oxygen versus 19%
SpO2 ⩽93% with standard oxygen (p=0.02)
Reduction in respiratory rate >20% at
2 h: 39% with HFNC oxygen versus 67% with
standard oxygen (p=0.005)
Reduction in Borg score at 2 h: 75% with HFNC
oxygen versus 56% with standard oxygen (p=0.04)
Continued

FB:Cardiologia Siglo XXI

 Table 1. Continued

First author [ref.] Setting Patients n Inclusion criteria Main results (including primary end-points#)
comparing HFNC oxygen versus
standard oxygen or NIV

HUI [31] Palliative care 23 Palliative cancer patients; Reduction in dyspnoea score at 2 h: 2/10 with
unit dyspnoea score ⩾3/10 HFNC oxygen versus 3/10 with bilevel
under oxygen positive airway pressure (p=0.32)
Reduction in Borg score at 2 h: 2/10 with HFNC
oxygen versus 2/10 with bilevel positive airway

HIGH-FLOW NASAL CANNULA OXYGEN THERAPY | R. COUDROY ET AL.

pressure (p=0.29)
Pre-oxygenation
before intubation
SEMLER [32] ICU 150 All intubations (excluding Lowest SpO2: 92% with HFNC oxygen versus 90%
urgent intubation) with standard oxygen (p=0.16)
Proportion of patients with SpO2 <80%: 16% with
HFNC oxygen versus 25% with standard
oxygen (p=0.22)
SIMON [33] ICU 40 Intubation in hypoxaemic Lowest mean SpO2: 89% with HFNC oxygen versus 86%
respiratory failure with standard oxygen (p=0.56)
VOURC’H [34] ICU 119 Intubation in patients with Lowest SpO2: 92% with HFNC oxygen versus 90%
respiratory rate with standard oxygen (p=0.44)
>30 breaths·min−1 and Proportion of patients with SpO2 <80%: 26%
PaO2/FIO2 ⩽300 mmHg with HFNC oxygen versus 22% with standard
oxygen (p=0.70)
Oxygenation during
bronchoscopy
LUCANGELO [35] Bronchoscopy 45 SpO2 ⩾90% PaO2/FIO2 at the end of bronchoscopy: 245 mmHg
room with HFNC oxygen 60 L·min −1 versus 165 mmHg
with standard oxygen (p<0.05)
SIMON [36] Bronchoscopy in 40 PaO2/FIO2 <300 mmHg Lowest SpO2 during endoscopy: 92% with HFNC
the ICU oxygen versus 95% with NIV (p=0.07)

Continued
177

FB:Cardiologia Siglo XXI

178

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 1. Continued

First author [ref.] Setting Patients n Inclusion criteria Main results (including primary end-points#)
comparing HFNC oxygen versus
standard oxygen or NIV

After planned extubation

in the ICU
HERNANDEz [22] After planned 527 Patients intubated at least Re-intubation within the first 72 h: 5% with HFNC
extubation in 12 h considered at low oxygen versus 12% with standard oxygen (p=0.004)
the ICU risk of extubation failure Post-extubation respiratory failure: 8% with HFNC
oxygen versus 14% with standard oxygen (p=0.03)
MAGGIORE [4] After planned 105 Patients intubated at least PaO2/FIO2 at 24 h: 287 mmHg with HFNC oxygen versus
extubation in 24 h (excluding difficult 274 mmHg with standard oxygen (p=0.03)
the ICU weaning and Grade of discomfort at 24 h: 2/10 with HFNC oxygen
hypercapnic patients) versus 6/10 with standard oxygen (p<0.01)
Re-intubation at 48 h: 4% with HFNC oxygen versus
21% with standard oxygen (p<0.001)
RITTAYAMAI [37] After planned 17 Spontaneous breathing Dyspnoea score at 30 min: 1.6/10 with HFNC oxygen
extubation in trial success versus 2.9 with standard oxygen (p=0.04)
the ICU Respiratory rate at 30 min: 20 breaths·min−1 with
HFNC oxygen versus 23 breaths·min−1 with
standard oxygen (p=0.009)
In post-operative patients
STÉPHAN [38] After 830 Spontaneous breathing Treatment failure: 21% with HFNC oxygen versus
cardiothoracic trial failure or extubation 22% with NIV (p=0.83)
surgery failure or high risk of Re-intubation: 14% with HFNC oxygen
post-extubation versus 14% with NIV (p=0.99)
respiratory failure PaO2/FIO2 at 1 h: 184 mmHg with HFNC oxygen
versus 221 mmHg with NIV (p<0.01)
Respiratory rate at 1 h: 21 breaths·min−1 with HFNC
oxygen versus 23 breaths·min−1 with NIV (p<0.001)
Continued

FB:Cardiologia Siglo XXI

 Table 1. Continued

First author [ref.] Setting Patients n Inclusion criteria Main results (including primary end-points#)
comparing HFNC oxygen versus
standard oxygen or NIV

PARKE [39] After cardiac 338 Cardiac surgery requiring SpO2/FIO2 ⩾445 at day 3: 46% with HFNC oxygen
surgery sternotomy versus 42% with standard oxygen (p=0.45)
In-ICU treatment escalation: 38% with HFNC oxygen
versus 62% with standard oxygen (p=0.001)
Comfort score at day 1: 7/10 with HFNC oxygen versus

HIGH-FLOW NASAL CANNULA OXYGEN THERAPY | R. COUDROY ET AL.

8/10 with standard oxygen (p<0.001)
CORLEY [40] After cardiac 155 Direct extubation after Atelectasis score on chest radiograph at day 1: 2 with
surgery cardiopulmonary HFNC oxygen versus 2 with standard oxygen (p=0.70)
bypass; BMI ⩾30 kg·m−2 PaO2/FIO2 at 24 h: 228 mmHg with HFNC oxygen versus
253 mmHg with standard oxygen (p=0.08)
Respiratory rate at 24 h: 17 breaths·min−1 with
HFNC oxygen versus 17 breaths·min−1 with
standard oxygen (p=0.17)
Dyspnoea score at 8 h: 1/10 with HFNC oxygen versus
0/10 with standard oxygen (p=0.008)
PARKE [41] After cardiac 60 Respiratory rate ⩾25·min−1 Success at 24 h: 90% with HFNC oxygen versus 56%
surgery and need for oxygen with standard oxygen (p=0.006)
⩾4 L·min−1 for 4 h or Need for NIV: 10% with HFNC oxygen versus 30% with
⩾6 L·min−1 for 2 h standard oxygen (p=0.10)
ANSARI [42] After thoracic 59 Post lung resection Better 6-min walk distance with HFNC oxygen
surgery than with standard oxygen
Better patient satisfaction with HFNC oxygen
than with standard oxygen
Length of hospital stay: 3 days with HFNC oxygen
versus 2 days with standard oxygen (p=0.03)
#
: primary end-points are given in italic.
179

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

In the subset of immunocompromised patients admitted to the ICU for ARF, two small studies
have shown a reduction in intubation and mortality rate with NIV as compared with standard
oxygen [44, 45]. Recently, a large RCT found no difference in terms of intubation or mortality
between patients treated with NIV and those treated with oxygen alone [27]. In this last study,
nearly 40% of patients received HFNC, and the mortality rate did not differ between patients
treated with HFNC oxygen alone and those treated with NIV and HFNC oxygen between NIV
sessions (32% with HFNC oxygen alone versus 25% with NIV and HFNC oxygen). Conversely,
in a post hoc analysis including 82 immunocompromised patients, those treated with HFNC
oxygen alone had a lower intubation rate than the others (31% with HFNC oxygen versus 43%
with standard oxygen and 65% with NIV; p=0.04) [6]. Similarly, the mortality rate at day 90
was lower with HFNC oxygen than with standard oxygen or NIV (15% versus 27% and 46%,
respectively; p=0.046). Likewise, in a retrospective cohort including 115 immunocompromised
patients admitted to our ICU for ARF, patients treated with HFNC oxygen as first-line therapy
had lower intubation (35% versus 55%; p=0.04) and mortality rates at day 28 (20% versus 40%;
p=0.02) than those treated with NIV [48]. Thus, although its efficacy has not yet been proven,
HFNC oxygen could improve the outcome of immunocompromised patients admitted to
the ICU for ARF. A large-scale RCT is needed to compare HFNC oxygen with NIV in this
subset of patients.

Finally, as HFNC oxygen seems well tolerated and comfortable, this strategy of oxygenation
may be an alternative to NIV for end-of-life palliative care in patients suffering from ARF [31]
or those with a do-not-intubate order [49].

To avoid desaturation during intubation ( pre-oxygenation)

Desaturation is a common complication during intubation of hypoxaemic patients [50]. In

a prospective observational cohort, SpO2 <80% occurred in ∼25% of patients intubated in
the ICU [51]. As compared with standard oxygen, the theoretical advantage of HFNC oxygen
may be first to increase PaO2 and the end-expiratory lung volume before intubation, and then
to maintain oxygenation during the apnoeic phase of intubation and thereby avoid
desaturation [52]. In a prospective before–after study including 101 patients, the use of HFNC
oxygen at a flow rate of 60 L·min−1 resulted in higher SpO2 at the end of pre-oxygenation
(median 100% versus 94%, respectively; p=0.007) and lower incidence of severe desaturation
<80% during intubation than with standard oxygen through a non-rebreathing mask: only 2%
with HFNC oxygen versus 14% (p=0.03) [53]. However, these encouraging results have not
been confirmed in the different RCTs carried out to date [32–34]. In a recent RCT including
150 nonselected patients requiring intubation, oxygenation during the apnoeic phase did not
prevent severe desaturation <80%, with a rate of 16% versus 25% in the group with standard
pre-oxygenation without apnoeic oxygenation (p=0.22) [32]. However, oxygenation during the
apnoeic phase was performed using a flow rate of only 15 L·min−1 [32], which is very far from
that used with HFNC oxygen therapy and, thus, this study does not allow for conclusions to be
drawn. In another RCT, HFNC oxygen set with a flow rate of 60 L·min−1 did not prevent
desaturation [34]. In this study including 119 hypoxaemic patients, the lowest SpO2 during
intubation did not differ between the two strategies (92% with HFNC oxygen versus 90% with
standard oxygen; p=0.44) [34]. The proportion of patients who had desaturation <80% was
∼25% regardless of the strategy, a rate very close to that previously reported in the ICU [51],
reinforcing the external validity of this study and suggesting an absence of benefit of HFNC
oxygen for pre-oxygenation. However, a recent RCT including 40 ICU patients reported a
significant drop of SpO2 with standard oxygen during apnoea after the induction of

180

FB:Cardiologia Siglo XXI

 HIGH-FLOW NASAL CANNULA OXYGEN THERAPY | R. COUDROY ET AL.

anaesthesia, whereas there was no significant decrease with HFNC oxygen [33]. Again, the
lowest SpO2 during intubation did not differ between the two strategies. Although HFNC
oxygen therapy may have theoretical advantages for pre-oxygenation before intubation in the
ICU, no significant benefit has been reported in the different RCTs conducted to date. This
does not mean that HFNC oxygen is pointless for pre-oxygenation, but rather that we should
wait for findings from other ongoing studies to draw sound conclusions. In a patient already
treated with HFNC oxygen for ARF, it seems reasonable that pre-oxygenation should not be
performed with standard oxygen and would be better carried out with HFNC oxygen or NIV.

Pre-oxygenation using NIV with FIO2 100% may be the best strategy as PaO2 is markedly
higher using NIV than using HFNC oxygen or standard oxygen. However, only one RCT
performed in the ICU has shown a decrease in episodes of severe desaturation with NIV as
compared with standard oxygen [50], while a recent retrospective trial did not find any
differences between pre-oxygenation with NIV and HFNC oxygen [54]. However, the small
sample size of these two studies does not allow for conclusions to be drawn and, in order to
clearly identify the best strategy for pre-oxygenation in the ICU, we are currently conducting
a multicenter prospective trial comparing NIV versus HFNC oxygen in a population of 320
hypoxaemic patients requiring intubation (ClinicalTrials.gov, trial number NCT02668458).

To avoid desaturation during invasive procedures

Fibreoptic bronchoscopy is a high-risk procedure in the ICU. In a prospective observational

study including 169 hypoxaemic patients, 35% had desaturation requiring a significant
increase in oxygen flow or NIV and 15% required intubation [55]. As compared with
standard oxygen, the use of NIV during fibreoptic bronchoscopy could improve
oxygenation and reduce the need for intubation [56]. However, HFNC oxygen therapy
could be used as an alternative. A recent observational study of 30 hypoxaemic ICU
patients suggested that HFNC oxygen therapy could be effective, well tolerated and safe to
ensure oxygenation during nasal bronchoscopy with BAL [57].

In a RCT performed in the bronchoscopy room, 45 patients were randomised to receive

standard oxygen or HFNC oxygen set at 40 or 60 L·min−1 [35]. Oxygenation was better in
the group receiving HFNC oxygen at 60 L·min−1 as compared with the other two strategies
(PaO2/FIO2 at the end of the bronchoscopy 245 versus 141 mmHg with HFNC oxygen
40 L·min−1 and 165 mmHg with standard oxygen; p<0.05).

Another trial compared HFNC oxygen versus NIV in 40 hypoxaemic patients undergoing
BAL in the ICU and found better oxygenation with NIV than with HFNC oxygen 15 min
after BAL (PaO2/FIO2 220 mmHg with NIV versus 150 mmHg with HFNC oxygen;
p=0.002), while the lowest SpO2 during the procedure was not significantly different [36].
Again, a trial comparing HFNC oxygen versus NIV seems necessary to determine the best
oxygenation strategy during bronchoscopy.

To prevent post-extubation respiratory distress and re-intubation in the ICU

Extubation failure occurs in ∼15% of patients in the ICU and is associated with high mortality
rates reaching 25–50% [58, 59]. The use of HFNC oxygen may prevent post-extubation ARF
and re-intubation in this setting. In a bicentric randomised trial on 105 hypoxaemic patients
extubated after at least 24 h of mechanical ventilation (PaO2/FIO2 <300 mmHg after planned

181

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

extubation), oxygenation was significantly better with preventive HFNC oxygen than with
standard oxygen (PaO2/FIO2 at 24 h 287 versus 247 mmHg; p=0.03) [4]. Although it was not
the primary outcome, the need for re-intubation was significantly lower with HFNC oxygen
than with standard oxygen (4% versus 21%; p=0.005). Similar results were found in a
multicenter randomised trial including 527 patients considered at low risk of extubation failure
[22]. In this study, the re-intubation rate at 72 h was lower in patients treated with HFNC
oxygen than with standard oxygen (5% versus 12%; p=0.004) [22]. Most of these ICU patients
were easy to wean and nearly half of them were post-operative patients with a median duration
of mechanical ventilation prior to planned extubation of only 24–48 h. Although prophylactic
treatment with HFNC oxygen could reduce the extubation failure rate in low-risk patients,
HFNC oxygen has not yet been compared with NIV in high-risk patients, a condition where
NIV could be particularly effective. In patients at high risk of extubation failure, such as elderly
patients, those with underlying cardiac or respiratory disease, and especially in hypercapnic
patients, the use of prophylactic NIV immediately after planned extubation remains the best
strategy as it could reduce the rates of intubation [60–62] and even mortality [63, 64]. By
contrast, NIV should only be used with caution to treat ARF after extubation in the ICU.
Indeed, in this situation, the use of therapeutic NIV has been associated with increased
mortality, probably due to delayed re-intubation [46].

To prevent respiratory distress after cardiac surgery

Post-operative hypoxia is frequent after cardiac surgery and occurs in about one-third of
patients [65], and these patients may benefit from HFNC oxygen immediately after
extubation. CORLEY et al. [40] randomised 155 obese patients with BMI ⩾30 kg·m−2 to
prophylactic HFNC oxygen or standard oxygen immediately after cardiac surgery. The
radiological atelectasis score calculated on chest radiographs at days 1 and 5 (primary
outcome) did not differ between the two groups, nor did PaO2/FIO2 or respiratory rate at 24 h.

In a larger trial including 338 nonselected patients who underwent cardiopulmonary bypass,
the proportion of patients achieving SpO2/FIO2 ⩾445 mmHg (i.e. SpO2 ⩾93% on room air) at
day 3 was similar between the groups receiving HFNC oxygen and standard oxygen (46%
versus 42%, respectively; p=0.45) [39]. However, the need for NIV or intubation based on
predefined criteria was lower in the HFNC oxygen group than in the standard oxygen group
(38% versus 62%; p=0.001), suggesting a potential benefit of HFNC oxygen in this
population. The main limitation of this trial was the absence of a comparison with NIV that
could reduce re-intubation, especially after thoracic surgery [66]. For this reason, STÉPHAN
et al. [38] compared NIV to HFNC oxygen after cardiothoracic surgery in 830 patients at
high risk of extubation failure. Treatment failure was not inferior in the HFNC group
compared with the NIV group (21% versus 22%, respectively). However, NIV was more
likely to be discontinued prematurely than HFNC oxygen (4% versus 1%, respectively;
p=0.04), suggesting the use of HFNC oxygen as first-line therapy after cardiac surgery.

To treat acute-on-chronic lung disease?

The use of NIV is the cornerstone of first-line therapy in patients with ARF due to chronic
lung disease [67, 68]. However, in patients who did not tolerate any NIV, several case
reports have proposed HFNC oxygen as an alternative with better tolerance and good
results (i.e. a decrease in PaCO2 and a progressive correction of acidosis) [69, 70]. The high
flow could decrease PaCO2 by continuous washing of dead space and by flushing carbon

182

FB:Cardiologia Siglo XXI

 HIGH-FLOW NASAL CANNULA OXYGEN THERAPY | R. COUDROY ET AL.

dioxide out of the airways. In a recent randomised crossover study, FRASER et al. [13]
assessed short-term physiological responses to HFNC oxygen (30 L·min−1) in 30 COPD
patients chronically treated with long-term oxygen therapy (2–4 L·min−1). They observed a
rapid decrease in transcutaneous carbon dioxide, with a decreased respiratory rate and an
increased tidal volume. The use of HFNC oxygen in COPD deserves to be assessed in
stable patients in who inhalation of dry cold gas could be detrimental to mucociliary
clearance as well as in patients with acute exacerbation between NIV sessions.

Conclusions

HFNC oxygen therapy seems to be a real technological innovation. This technique is well
tolerated, easy to use and improves gas exchange without the potential deleterious effects of
mechanical ventilation. Physiological effects include high FIO2 delivery, PEEP effect and
washout of dead space of the airways. Several large RCTs suggest beneficial effects in patients
with ARF or in the post-extubation period. However, its use should not delay intubation if
respiratory criteria for re-intubation are met or in the case of other dysfunction, especially
shock or neurological failure.

References
1. Lellouche F, Maggiore SM, Lyazidi A, et al. Water content of delivered gases during non-invasive ventilation in
healthy subjects. Intensive Care Med 2009; 35: 987–995.
2. Fontanari P, Burnet H, Zattara-Hartmann MC, et al. Changes in airway resistance induced by nasal inhalation of
cold dry, dry, or moist air in normal individuals. J Appl Physiol 1996; 81: 1739–1743.
3. Cuquemelle E, Pham T, Papon JF, et al. Heated and humidified high-flow oxygen therapy reduces discomfort
during hypoxemic respiratory failure. Respir Care 2012; 57: 1571–1577.
4. Maggiore SM, Idone FA, Vaschetto R, et al. Nasal high-flow versus Venturi mask oxygen therapy after extubation.
Effects on oxygenation, comfort, and clinical outcome. Am J Respir Crit Care Med 2014; 190: 282–288.
5. Roca O, Riera J, Torres F, et al. High-flow oxygen therapy in acute respiratory failure. Respir Care 2010; 55: 408–413.
6. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory
failure. N Engl J Med 2015; 372: 2185–2196.
7. Sim MA, Dean P, Kinsella J, et al. Performance of oxygen delivery devices when the breathing pattern of
respiratory failure is simulated. Anaesthesia 2008; 63: 938–940.
8. Katz JA, Marks JD. Inspiratory work with and without continuous positive airway pressure in patients with acute
respiratory failure. Anesthesiology 1985; 63: 598–607.
9. Parke RL, Eccleston ML, McGuinness SP. The effects of flow on airway pressure during nasal high-flow oxygen
therapy. Respir Care 2011; 56: 1151–1155.
10. Petrof BJ, Legare M, Goldberg P, et al. Continuous positive airway pressure reduces work of breathing and dyspnea
during weaning from mechanical ventilation in severe chronic obstructive pulmonary disease. Am Rev Respir Dis
1990; 141: 281–289.
11. Corley A, Caruana LR, Barnett AG, et al. Oxygen delivery through high-flow nasal cannulae increase end-expiratory
lung volume and reduce respiratory rate in post-cardiac surgical patients. Br J Anaesth 2011; 107: 998–1004.
12. Möller W, Celik G, Feng S, et al. Nasal high flow clears anatomical dead space in upper airway models. J Appl
Physiol 2015; 118: 1525–1532.
13. Fraser JF, Spooner AJ, Dunster KR, et al. Nasal high flow oxygen therapy in patients with COPD reduces
respiratory rate and tissue carbon dioxide while increasing tidal and end-expiratory lung volumes: a randomised
crossover trial. Thorax 2016; 71: 759–761.
14. Vargas F, Saint-Leger M, Boyer A, et al. Physiologic effects of high-flow nasal cannula oxygen in critical care
subjects. Respir Care 2015; 60: 1369–1376.
15. Lee HY, Rhee CK, Lee JW. Feasibility of high-flow nasal cannula oxygen therapy for acute respiratory failure in
patients with hematologic malignancies: a retrospective single-center study. J Crit Care 2015; 30: 773–777.
16. Lellouche F, Maggiore SM, Deye N, et al. Effect of the humidification device on the work of breathing during
noninvasive ventilation. Intensive Care Med 2002; 28: 1582–1589.

183

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

17. Boyer A, Vargas F, Hilbert G, et al. Small dead space heat and moisture exchangers do not impede gas exchange
during noninvasive ventilation: a comparison with a heated humidifier. Intensive Care Med 2010; 36: 1348–1354.
18. Sztrymf B, Messika J, Bertrand F, et al. Beneficial effects of humidified high flow nasal oxygen in critical care
patients: a prospective pilot study. Intensive Care Med 2011; 37: 1780–1786.
19. Sztrymf B, Messika J, Mayot T, et al. Impact of high-flow nasal cannula oxygen therapy on intensive care unit
patients with acute respiratory failure: a prospective observational study. J Crit Care 2012; 27: 324.
20. Frat JP, Brugiere B, Ragot S, et al. Sequential application of oxygen therapy via high-flow nasal cannula and
noninvasive ventilation in acute respiratory failure: an observational pilot study. Respir Care 2015; 60: 170–178.
21. Mündel T, Feng S, Tatkov S, et al. Mechanisms of nasal high flow on ventilation during wakefulness and sleep.
J Appl Physiol 2013; 114: 1058–1065.
22. Hernandez G, Vaquero C, Gonzalez P, et al. Effect of postextubation high-flow nasal cannula vs conventional
oxygen therapy on reintubation in low-risk patients: a randomized clinical trial. JAMA 2016; 315: 1354–1361.
23. L’Her E, Deye N, Lellouche F, et al. Physiologic effects of noninvasive ventilation during acute lung injury. Am J
Respir Crit Care Med 2005; 172: 1112–1118.
24. Slutsky AS, Ranieri VM. Ventilator-induced lung injury. N Engl J Med 2014; 370: 980.
25. Carteaux G, Millán-Guilarte T, De Prost N, et al. Failure of noninvasive ventilation for de novo acute hypoxemic
respiratory failure: role of tidal volume. Crit Care Med 2016; 44: 282–290.
26. Schwabbauer N, Berg B, Blumenstock G, et al. Nasal high-flow oxygen therapy in patients with hypoxic respiratory
failure: effect on functional and subjective respiratory parameters compared to conventional oxygen therapy and
non-invasive ventilation (NIV). BMC Anesthesiol 2014; 14: 66.
27. Lemiale V, Mokart D, Resche-Rigon M, et al. Effect of noninvasive ventilation vs oxygen therapy on mortality
among immunocompromised patients with acute respiratory failure: a randomized clinical trial. JAMA 2015; 314:
1711–1719.
28. Frat J-P, Ragot S, Girault C, et al. Effect of non-invasive oxygenation strategies in immunocompromised patients
with severe acute respiratory failure: a post-hoc analysis of a randomised trial. Lancet Respir Med 2016; 4: 646–652.
29. Jones PG, Kamona S, Doran O, et al. Randomized controlled trial of humidified high-flow nasal oxygen for acute
respiratory distress in the emergency department: the HOT-ER Study. Respir Care 2016; 61: 291–299.
30. Bell N, Hutchinson CL, Green TC, et al. Randomised control trial of humidified high flow nasal cannulae versus
standard oxygen in the emergency department. Emerg Med Australas 2015; in press [DOI: 10.1111/1742-6723.12490].
31. Hui D, Morgado M, Chisholm G, et al. High-flow oxygen and bilevel positive airway pressure for persistent
dyspnea in patients with advanced cancer: a phase II randomized trial. J Pain Symptom Manage 2013; 46: 463–473.
32. Semler MW, Janz DR, Lentz RJ, et al. Randomized trial of apneic oxygenation during endotracheal intubation of
the critically ill. Am J Respir Crit Care Med 2016; 193: 273–280.
33. Simon M, Wachs C, Braune S, et al. High-flow nasal cannula versus bag-valve-mask for preoxygenation before
intubation in subjects with hypoxemic respiratory failure. Respir Care 2016; 61: 1160–1167.
34. Vourc’h M, Asfar P, Volteau C, et al. High-flow nasal cannula oxygen during endotracheal intubation in
hypoxemic patients: a randomized controlled clinical trial. Intensive Care Med 2015; 41: 1538–1548.
35. Lucangelo U, Vassallo FG, Marras E, et al. High-flow nasal interface improves oxygenation in patients undergoing
bronchoscopy. Crit Care Res Pract 2012; 2012: 506382.
36. Simon M, Braune S, Frings D, et al. High-flow nasal cannula oxygen versus non-invasive ventilation in patients
with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy – a prospective randomised trial.
Crit Care 2014; 18: 712.
37. Rittayamai N, Tscheikuna J, Praphruetkit N, et al. Use of high-flow nasal cannula for acute dyspnea and
hypoxemia in the emergency department. Respir Care 2015; 60: 1377–1382.
38. Stéphan F, Barrucand B, Petit P, et al. High-flow nasal oxygen vs noninvasive positive airway pressure in
hypoxemic patients after cardiothoracic surgery: a randomized clinical trial. JAMA 2015; 313: 2331–2339.
39. Parke R, McGuinness S, Dixon R, et al. Open-label, phase II study of routine high-flow nasal oxygen therapy in
cardiac surgical patients. Br J Anaesth 2013; 111: 925–931.
40. Corley A, Bull T, Spooner AJ, et al. Direct extubation onto high-flow nasal cannulae post-cardiac surgery versus standard
treatment in patients with a BMI ⩾30: a randomised controlled trial. Intensive Care Med 2015; 41: 887–894.
41. Parke RL, McGuinness SP, Eccleston ML. A preliminary randomized controlled trial to assess effectiveness of nasal
high-flow oxygen in intensive care patients. Respir Care 2011; 56: 265–270.
42. Ansari BM, Hogan MP, Collier TJ, et al. A randomized controlled trial of high-flow nasal oxygen (Optiflow) as
part of an enhanced recovery program after lung resection surgery. Ann Thorac Surg 2016; 101: 459–464.
43. Ferrer M, Esquinas A, Leon M, et al. Noninvasive ventilation in severe hypoxemic respiratory failure: a randomized
clinical trial. Am J Respir Crit Care Med 2003; 168: 1438–1444.
44. Antonelli M, Conti G, Bufi M, et al. Noninvasive ventilation for treatment of acute respiratory failure in patients
undergoing solid organ transplantation: a randomized trial. JAMA 2000; 283: 235–241.
45. Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary
infiltrates, fever, and acute respiratory failure. N Engl J Med 2001; 344: 481–487.

184

FB:Cardiologia Siglo XXI

 HIGH-FLOW NASAL CANNULA OXYGEN THERAPY | R. COUDROY ET AL.

46. Esteban A, Frutos-Vivar F, Ferguson ND, et al. Noninvasive positive-pressure ventilation for respiratory failure
after extubation. N Engl J Med 2004; 350: 2452–2460.
47. Kang BJ, Koh Y, Lim CM, et al. Failure of high-flow nasal cannula therapy may delay intubation and increase
mortality. Intensive Care Med 2015; 41: 623–632.
48. Coudroy R, Jamet A, Petua P, et al. High-flow nasal cannula oxygen therapy versus noninvasive ventilation in
immunocompromised patients with acute respiratory failure: an observational cohort study. Ann Intensive Care
2016; 6: 45.
49. Peters SG, Holets SR, Gay PC. High-flow nasal cannula therapy in do-not-intubate patients with hypoxemic
respiratory distress. Respir Care 2013; 58: 597–600.
50. Baillard C, Fosse JP, Sebbane M, et al. Noninvasive ventilation improves preoxygenation before intubation of
hypoxic patients. Am J Respir Crit Care Med 2006; 174: 171–177.
51. Jaber S, Amraoui J, Lefrant JY, et al. Clinical practice and risk factors for immediate complications of endotracheal
intubation in the intensive care unit: a prospective, multiple-center study. Crit Care Med 2006; 34: 2355–2361.
52. Ricard JD. Hazards of intubation in the ICU: role of nasal high flow oxygen therapy for preoxygenation and
apneic oxygenation to prevent desaturation. Minerva Anestesiol 2016; 82: 1098–1106.
53. Miguel-Montanes R, Hajage D, Messika J, et al. Use of high-flow nasal cannula oxygen therapy to prevent
desaturation during tracheal intubation of intensive care patients with mild-to-moderate hypoxemia. Crit Care Med
2005; 43: 574–583.
54. Besnier E, Guernon K, Bubenheim M, et al. Pre-oxygenation with high-flow nasal cannula oxygen therapy and
non-invasive ventilation for intubation in the intensive care unit. Intensive Care Med 2016; 42: 1291–1292.
55. Cracco C, Fartoukh M, Prodanovic H, et al. Safety of performing fiberoptic bronchoscopy in critically ill
hypoxemic patients with acute respiratory failure. Intensive Care Med 2013; 39: 45–52.
56. Maitre B, Jaber S, Maggiore SM, et al. Continuous positive airway pressure during fiberoptic bronchoscopy in hypoxemic
patients. A randomized double-blind study using a new device. Am J Respir Crit Care Med 2000; 162: 1063–1067.
57. La Combe B, Messika J, Labbé V, et al. High-flow nasal oxygen for bronchoalveolar lavage in acute respiratory
failure patients. Eur Respir J 2016; 47: 1283–1286.
58. Thille AW, Cortés-Puch I, Esteban A. Weaning from the ventilator and extubation in ICU. Curr Opin Crit Care
2013; 19: 57–64.
59. Thille AW, Richard J-CM, Brochard L. The decision to extubate in the intensive care unit. Am J Respir Crit Care
Med 2013; 187: 1294–1302.
60. Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent respiratory failure after extubation in
high-risk patients. Crit Care Med 2005; 33: 2465–2470.
61. Ornico SR, Lobo SM, Sanches HS, et al. Noninvasive ventilation immediately after extubation improves weaning
outcome after acute respiratory failure: a randomized controlled trial. Crit Care 2013; 17: R39.
62. Thille AW, Boissier F, Ben-Ghezala H, et al. Easily identified at-risk patients for extubation failure may benefit
from noninvasive ventilation: a prospective before-after study. Crit Care 2016; 20: 48.
63. Ferrer M, Sellarés J, Valencia M, et al. Non-invasive ventilation after extubation in hypercapnic patients with
chronic respiratory disorders: randomised controlled trial. Lancet 2009; 374: 1082–1088.
64. Ferrer M, Valencia M, Nicolas JM, et al. Early noninvasive ventilation averts extubation failure in patients at risk: a
randomized trial. Am J Respir Crit Care Med 2006; 173: 164–170.
65. Ranucci M, Ballotta A, La Rovere MT, et al. Postoperative hypoxia and length of intensive care unit stay after
cardiac surgery: the underweight paradox? PLoS One 2014; 9: e93992.
66. Auriant I, Jallot A, Hervé P, et al. Noninvasive ventilation reduces mortality in acute respiratory failure following
lung resection. Am J Respir Crit Care Med 2001; 164: 1231–1235.
67. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive
pulmonary disease. N Engl J Med 1995; 333: 817–822.
68. Keenan SP, Sinuff T, Cook DJ, et al. Which patients with acute exacerbation of chronic obstructive pulmonary
disease benefit from noninvasive positive-pressure ventilation? A systematic review of the literature. Ann Intern
Med 2003; 138: 861–870.
69. Horio Y, Takihara T, Niimi K, et al. High-flow nasal cannula oxygen therapy for acute exacerbation of interstitial
pneumonia: a case series. Respir Investig 2016; 54: 125–129.
70. Lepere V, Messika J, La Combe B, et al. High-flow nasal cannula oxygen supply as treatment in hypercapnic
respiratory failure. Am J Emerg Med 2016; 34: 1914.

Disclosures: J-P. Frat has received travel expenses and payments for consulting activity from Fisher &
Paykel. Fisher & Paykel have also provided the equipment for his clinical studies. He has also received travel
expenses from SOS Oxygène, LFB and AstraZeneca; payments for consulting activity from SOS Oxygène; and
payments for lectures from LFB and AstraZeneca.

185

FB:Cardiologia Siglo XXI

 | Chapter 13
Acute noninvasive ventilation
Rosanna Vaschetto1, Federico Longhini2 and Paolo Navalesi2,3,4

The use of NIV for acute respiratory failure (ARF) has progressively increased in the last two
decades. In patients with ARF secondary to exacerbation of COPD, NIV largely decreases
the need for intubation and invasive ventilation. Meta-analyses indicate that NIV reduces the
risk of death in these patients. While strong evidence supports the use of noninvasive CPAP
in patients with episodes of cardiogenic pulmonary oedema, fewer and less robust data are
available on NIV for other forms of hypoxaemia, both in immunosuppressed and
immunocompetent patients. NIV has been successfully applied to prevent re-intubation in
post-operative patients, as a weaning strategy after early extubation and as a means to
prevent post-extubation respiratory failure in at-risk patients.

T he use of NIV for acute respiratory failure (ARF) has progressively increased in the last
two decades. NIV provides effective ventilatory support, improving gas exchange while
reducing dyspnoea and inspiratory effort, and averts the risks secondary to endotracheal
intubation, both in hypercapnic and hypoxaemic patients [1]. NIV preserves airway defence
mechanisms, speech and swallowing, requires less sedation, and can be easily applied and
removed, as opposed to invasive ventilation [2].

In patients with ARF secondary to COPD exacerbation, NIV averts the need for intubation
and invasive ventilation [3–5]. Meta-analyses [6, 7] of RCTs indicate that NIV reduces the
risk of death by up to 55% [7], being the only hospital-based intervention shown able to
improve mortality [7]. While strong evidence supports the use of noninvasive CPAP
(n-CPAP) in addition to the standard medical treatment for acute cardiogenic pulmonary
oedema (ACPO), fewer and less robust data are available on NIV for other forms of
hypoxaemia, such as pneumonia and ARDS [8–11], both in immunosuppressed [9, 10, 12]
and immunocompetent patients [11, 13]. NIV has been successfully applied to prevent
re-intubation in post-operative patients [14, 15], as a weaning strategy after early extubation
[16] and as a means to prevent post-extubation respiratory failure in at-risk patients [17–19].

Although associated with decreased rates of intubation and mortality in several patient
populations, NIV requires knowledge of specific features that are crucial determinants of its
outcome, such as contraindications (table 1), patient selection, location of administration,
adequate monitoring and proper equipment [1].

1
SCDU Anestesia e Rianimazione, Azienda Ospedaliero Universitaria “Maggiore della Carità”, Novara, Italy. 2SC Anestesia e
Rianimazione, Ospedale Sant’Andrea, Vercelli, Italy. 3Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale
“Amedeo Avogadro”, Novara, Italy. 4CRRF Mons. L. Novarese, Moncrivello, Italy.

Correspondence: Paolo Navalesi, Dipartimento di Medicina Traslazionale, Università del Piemonte Orientale “Amedeo Avogadro”, Via
Solaroli 17, 28100 Novara, Italy. E-mail: paolo.navalesi@med.uniupo.it

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

186 ERS Monogr 2016; 74: 186–199. DOI: 10.1183/2312508X.10002316

FB:Cardiologia Siglo XXI

 ACUTE NONINVASIVE VENTILATION | R. VASCHETTO ET AL.

Table 1. Contraindications to NIV

Altered consciousness (severe agitation or encephalopathy#)

Respiratory or cardiac arrest
Inability to protect the airways
Unmanageable secretions
Haemodynamic instability or life-threatening arrhythmia
Multiple organ failure
Upper gastrointestinal bleeding or haemoptysis
Recent facial, oesophageal, gastric or laryngeal surgery
Facial burns or trauma
Uncontrolled vomiting, bowel obstruction or gastric stasis
Patient refusal
Lack of potential recovery to acceptable quality of life
Inadequate staff to closely monitoring the patient in case of deterioration

#
: NIV can be considered if encephalopathy secondary to hypercapnia.

Patient selection

COPD exacerbation

Exacerbations of COPD are common reasons for admission to hospital and are
characterised by an elevated mortality rate (up to 30%) [3, 20]. The increased use of NIV is
associated with a decreased rate of intubation and in-hospital mortality [21, 22]. NIV can
be applied at different stages of severity with different objectives [23]: 1) prevention of ARF
in patients who are hypercapnic but not acidotic (i.e. pH is normal), 2) avoidance of
endotracheal intubation in established mild-to-moderate ARF and 3) as an alternative to
invasive ventilation in the sickest patients without specific contraindications to NIV.

The use of NIV at a very early stage to prevent hypercapnic ARF has not proved clearly
beneficial and remains debated. Two studies [24, 25] in which NIV and standard medical
treatment alone were compared with mild COPD exacerbation showed no difference in any
clinical outcome considered, except for a reduction in dyspnoea with NIV, although mask
ventilation was found to be poorly tolerated [25]. Conversely, a large prospective
multicentre RCT, also comparing NIV with standard treatment, including 342 patients with
COPD exacerbation, showed that early application of NIV reduced the number of patients
meeting criteria for intubation (1.4% versus 4.6%, p=0.002), but had no difference in terms
of mortality [26]. A subgroup of patients with normal pH (n=151, pH 7.4 versus 7.396)
showed similar benefits. However, NIV was initiated at a later stage than in other studies
(24–48 h after admission) and the numbers of patients deteriorating to the point at which
intubation was necessary was very high when considering the mild acidosis [26].

The strongest evidence relates to the use of NIV to avoid intubation in patients with established
mild or moderate hypercapnic ARF (pH 7.20–7.35). A number of RCTs [3, 4, 5, 20, 27, 28]
have shown the beneficial effects of adding NIV to the medical therapy in this patient
population, producing an improvement in dyspnoea [5, 20], vital signs and gas exchange [3, 5,
20], and a reduction of endotracheal intubations [3–5], infectious (both respiratory and
nonrespiratory) complications [29, 30], length of hospital stay [3, 27] and mortality [3, 5].

187

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Although infrequent, because of the rapid onset of ARF, its progression and/or delays in
receiving medical evaluation and appropriate treatment, patients may worsen to a point at
which mechanical ventilation becomes mandatory. If the patient does not meet other
contraindications to NIV, this technique may still play a role in these more severe patients by
eliminating the additional resistive load [31] and the increased risk of superimposed pulmonary
infections [32] determined by the endotracheal tube. Two RCTs compared NIV with invasive
ventilation in patients with these characteristics [33, 34]. In both studies, the mean pH was
∼7.2. In the study by CONTI et al. [33], the rate of survival was similar; however, in patients
with successful NIV treatment, the lengths of ICU and hospital stay were shorter, and there
were less complications and fewer hospital readmissions in the following year. The study by
JURJEVIC et al. [34] found that NIV was associated with a shorter duration of ventilation and
ICU stay, less ventilator-associated pneumonia, and a reduced number of tracheotomies; the
rate of mortality, however, was similar in the two groups. These studies suggest that applying
NIV at a later stage is less likely beneficial, but some patients may still benefit. In severely
acidotic patients, SQUADRONE et al. [35] showed that a NIV attempt before proceeding to
intubation and invasive ventilation did not harm the patients and NIV may be attempted with
caution, closely monitoring the patients in an ICU and avoiding excessive delay in intubation.

As shown in figure 1, NIV can be profitably used at all stages of severity of hypercapnic
ARF due to COPD exacerbation. In addition, NIV also plays a role in facilitating weaning
and extubation of COPD patients requiring intubation. Following the seminal work of NAVA
et al. [36], several studies have subsequently confirmed the potential of NIV for this
purpose [37]. Furthermore, as COPD patients who are extubated after a successful

Admission for COPD exacerbation

Medical therapy
(SpO2 target 88–92%)

Arterial blood gases

Respiratory acidosis pH >7.35

Medical therapy+NIV Continue medical therapy

pH <7.20 pH 7.20–7.29 pH 7.30–7.35

Some patients High risk of Some patients
avoid intubation intubation if NIV at risk of
if NIV instituted. not instituted. intubation if NIV
High risk of High chance of not instituted.
NIV failure. NIV success. High chance of
NIV success.

Figure 1. Flow chart for treatment of COPD exacerbations.

188

FB:Cardiologia Siglo XXI

 ACUTE NONINVASIVE VENTILATION | R. VASCHETTO ET AL.

spontaneous breathing trial have an increased risk of post-extubation respiratory failure, the
preventive application of NIV soon after extubation has proven effective in reducing the
rate of re-intubation [17–19]. The overall role of NIV in the management of hypercapnic
ARF in patients with COPD is summarised in figure 2.

Episodes of acute-on-chronic respiratory failure sustained by causes other than COPD can
also be successfully treated by NIV [38]. Consequent to the increasing prevalence of
extreme obesity, obesity hypoventilation syndrome (OHS) has become a common cause of
hypercapnic ARF. In acute OHS, NIV appears to be as effective as in COPD [39].

Cardiogenic pulmonary oedema

Exacerbation of congestive heart failure leading to ACPO is the single most frequent cause
of hospitalisation for individuals aged ⩾65 years and the in-hospital mortality rate can be
as high as 12% [40]. Strong evidence supports the use of n-CPAP in addition to the
standard medical treatment for ACPO. A Cochrane systematic review and meta-analysis,
including 32 studies and 2916 participants, found that n-CPAP or bilevel positive airway
pressure (i.e. NIV) significantly reduced the need for endotracheal intubation (relative risk
0.52, 95% CI 0.36–0.75) and hospital mortality (relative risk 0.66, 95% CI 0.48–0.89) [41].
Nevertheless, when n-CPAP and bilevel positive airway pressure were compared
individually with standard therapy, only n-CPAP demonstrated a statistical improvement in
mortality [41]. According to the data, one death is avoided for every nine ACPO patients
treated with n-CPAP. It should be noted that this meta-analysis excludes any additional
risk of acute myocardial infarction with NIV, compared with standard medical care
(relative risk 1.24, 95% CI 0.79–1.95), a concern following the findings of earlier studies
[42–44]. Inexpensive and easy to implement, n-CPAP is widely recognised as the first-line
intervention in this patient population [45], while bilevel positive airway pressure does not
seem to add benefit, even in the more severe hypercapnic patients.

De novo (hypoxaemic) ARF

Whether or not patients with hypoxaemic ARF due to reasons other than ACPO may also
benefit from NIV is questionable. Different from COPD, these patients often need
near-continuous support, which is commonly required for a longer time than in ACPO. In
hypoxaemic patients, NIV failure was found to be associated with increased mortality
irrespective of ARF severity [46], which was attributed to erroneous patient selection,
higher risk of emergency intubation and additional lung injury caused by the increased
transpulmonary pressure [46–48]. Intermittent applications of NIV delivered with low
PEEP levels have been shown to be of no benefit and even detrimental in patients with
pneumonia [12, 48], but to be beneficial in post-operative patients [14, 15, 49]. In these
patients, n-CPAP without inspiratory support is also beneficial, as opposed to standard
oxygen therapy [49, 50]. Hypoxaemic patients with immunosuppression are, in
principle, those more likely to benefit from NIV, while those with ARDS are the least likely
to benefit [51].

Immunocompromised patients
The survival of immunocompromised patients has improved in recent years, likely due to
advances in diagnostic and therapeutic options [52]. Unfortunately, the number of
immunocompromised patients with severe complications requiring treatment in the ICU has

189

FB:Cardiologia Siglo XXI

190

ERS MONOGRAPH | PULMONARY EMERGENCIES

COPD exacerbations

pH ≥7.35 pH <7.35#

Medical treatment
If one of the following:
Respiratory arrest
Haemodynamic instability
If one of the following:
Lack of airway protection
Worsening of
At least 24 h of IMV with:
dyspnoea/tachypnoea Medical treatment+NIV
Normalisation of ABGs
Development of respiratory
Good neurological status
acidosis (pH <7.35) Medical treatment+IMV No fever
Evaluate after 2 h Haemodynamic stability
SpO2 >88% with FIO2 ≤40%

Spontaneous breathing trial

No improvement in
Improvement
ABGs or neurological
in ABGs
deterioration¶

Failure Success
Continue medical
treatment+NIV
Re-institute IMV → Extubation and
normalisation of ABGs protective NIV
→ extubation and
NIV for weaning+

Figure 2. Flow chart depicting the overall approach to hypercapnic acute respiratory failure. ABG: arterial blood gas; IMV: invasive mechanical ventilation. #: see figure
1 for more details; ¶: unless NIV ceiling of treatment; +: expertise required.

FB:Cardiologia Siglo XXI

 ACUTE NONINVASIVE VENTILATION | R. VASCHETTO ET AL.

also increased [53]. ICU admission is necessary in up to 15% of patients with acute leukaemia
[54] and 20% of bone marrow transplantation recipients [55], and the main reason for ICU
referral is ARF. Although mechanical ventilation is the main supportive therapy for those with
severe gas exchange impairment, the need for intubation has been consistently indicated as one
of the most adverse factors in these patients [56–58]. Early use of NIV was shown to positively
affect patient outcome in a few small single-centre RCTs. In a cohort of solid organ transplant
patients with ARF, ANTONELLI et al. [9] demonstrated decreased rates of intubation (20% versus
70%, p=0.002) and mortality (20% versus 50%, p=0.05) in patients randomised to NIV, as
opposed to those receiving only standard therapy. HILBERT et al. [10] compared intermittent
NIV with the sole medical therapy in 52 patients with immunosuppression of different causes,
presenting with pulmonary infiltrates, fever and hypoxaemic ARF, as defined by the presence of
dyspnoea at rest, respiratory rate >30 breaths·min–1 and a PaO2/FIO2 ratio <200 mmHg while
breathing oxygen. The patients who received NIV in addition to the medical treatment had
fewer intubations and lower mortality. Data from a multicentre database, which prospectively
included 1302 patients with haematological malignancies admitted for ARF to 158 Italian ICUs
between 2002 and 2006, demonstrated similar mortality rates between the patients initially
treated with NIV and those undergoing invasive ventilation ab initio [59]. One single-centre
RCT investigated the potential role of early n-CPAP in patients with haematological
malignancies [60]. The authors found that the delivery of n-CPAP in the medical ward reduced
the occurrence of ICU admission for mechanical ventilation [60]. Based on these data, NIV has
been considered in many centres as the first-line approach for ARF in patients with various
causes of immunosuppression [47].

More recently, however, the benefit of NIV for immunocompromised patients has been
questioned [12, 61, 62]. LEMIALE et al. [12] performed the largest randomised clinical trial to
date, with the aim of assessing whether NIV could improve patient outcome. For this
purpose, 374 immunocompromised patients with PaO2 <60 mmHg in room air, respiratory
rate >30 breaths·min–1 and/or signs of respiratory distress were randomised to receive NIV
or conventional oxygen therapy. No difference was found between the two groups in terms
of day-28 mortality and rate of intubation, ICU-acquired infections, duration of mechanical
ventilation and length of ICU stay. However, these results may have been affected by some
methodological limitations potentially reducing the ability to detect the possible benefit of
NIV [62, 63], such as a lower than expected mortality rate, making the study likely
underpowered, and the significantly higher proportion of patients receiving high-flow nasal
oxygen in the control group. In addition, NIV was applied with low levels of PEEP and for
relatively short periods.

Further studies are necessary to clarify the potential of NIV in immunocompromised

patients, which may be affected by several factors, such as underlying disease, ARF severity,
timing and modalities of NIV application.

ARDS
The Berlin Definition of ARDS proposes a possible role for NIV in the milder forms of
ARDS, i.e. PaO2/FIO2 ⩽300 and >200 mmHg with PEEP ⩾5 cmH2O [64]. The use of NIV
in patients with ARDS is, nonetheless, controversial and studies evaluating the role of NIV
in the ventilator treatment of ARDS are scarce. In a prospective cohort study, ANTONELLI
et al. [65] applied NIV in 147 ARDS patients admitted to the ICU who were not yet
intubated. NIV improved gas exchange and avoided intubation in 54% of patients.
Avoidance of intubation was associated with lower rates of ventilator-associated pneumonia
(2% versus 20%) and ICU mortality (6% versus 53%).

191

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Two RCTs evaluated NIV in nonhypercapnic immunocompetent patients with de novo

hypoxaemic ARF. DELCLAUX et al. [11] reported no beneficial effects and a higher number of
adverse events in patients receiving n-CPAP. FERRER et al. [13] randomised 105 subjects with
severe hypoxaemic ARF to receive either NIV or oxygen therapy with high FIO2. The
respiratory failure aetiologies were predominantly pneumonia and cardiogenic pulmonary
oedema, but there were also 15 individuals with ARDS. NIV prevented intubation, reduced
the incidence of septic shock and improved survival in a very select population of patients;
however, ARDS was associated with the highest risk of NIV failure [13]. A meta-analysis [66]
focusing on these two RCTs [11, 13] and another study conducted in solid organ transplant
recipients [9] concluded that the addition of NIV to standard care in patients with ARDS did
not reduce either intubation rate or ICU mortality. RANA et al. [67] assessed the outcome of
subjects with ARDS initially treated with NIV. All those with shock failed NIV. Metabolic
acidosis (odds ratio 1.27, 95% CI 1.03–0.07 per unit of base deficit) and severe hypoxaemia
(odds ratio 1.03, 95% CI 1.01–1.05 per unit decrease in PaO2/FIO2) predicted NIV failure.

Very recent data by PATEL et al. [68], however, open a new perspective on the use of NIV in
ARDS by means of a helmet. 83 ARDS patients undergoing NIV through a face mask for at
least 8 h were randomly assigned to continue NIV by the face mask or switch to a helmet
for NIV support. The study was interrupted early for efficacy. The intubation rate was
61.5% with the mask and 18.2% with the helmet ( p<0.001), with increased ventilator-free
days in the helmet group (28 versus 12.5 days, p<0.001). The mortality rates at 90 days were
34.1% in the helmet group and 56.4% in the face mask group. Although the results of this
single-centre study are interesting and promising, external validation is needed [68].

In patients with ARDS due to H1N1 influenza virus infection, KUMAR et al. [69] found that
33% of subjects initially received NIV, with a failure rate as high as 85%. The reported rate
of NIV failure averaged 52% (from 14% to 70%) [70]. The rate of failure was, however, lower
in mild ARDS (34%) than in moderate or severe ARDS (68%) [71]. Crucial predisposing
factors for NIV failure included altered level of consciousness and shock [71]. NICOLINI et al.
[72] found the early application of NIV to avoid invasive ventilation in H1N1 patients to be
associated with an overall success rate of 48%. Patients presenting at admission with a high
SAPS (Simplified Acute Physiological Score) II score and a low PaO2/FIO2 and/or unable to
promptly correct gas exchange were at higher risk of intubation and death.

A recent international observational study found 15% of all patients with ARDS received
NIV in routine care [73]. Nonetheless, the studies available at present suggest extreme
caution in the use of NIV in ARDS [46, 74, 75].

Technical aspects

Some logistical and technical aspects assume crucial importance for NIV outcome.
Location, ventilators, interfaces and use of sedatives are the most important, and deserve
particular attention.

Location

The location of NIV treatment is an important predictor of the outcome of NIV in patients
with ARF [75]. NIV is used in different settings, such as the emergency room, ICU,
respiratory ICU, step-down unit and general ward. Successful use of NIV has been shown

192

FB:Cardiologia Siglo XXI

 ACUTE NONINVASIVE VENTILATION | R. VASCHETTO ET AL.

in post-operative care units [14, 76]. Data from a recent North American study [77]
showed that NIV is most frequently initiated in ICUs and emergency departments, but the
rate of utilisation is also high in the general wards where a fifth of NIV is initiated. This
study also showed that the actual location depends on ARF aetiology: in patients with
acute-on-chronic lung disease and ACPO, NIV is started more often in emergency
departments, while for “de novo” hypoxaemic ARF it is started more often in the ICU.
Patients with hypercapnic ARF who respond promptly to NIV can also be effectively
treated in the medical ward [78, 79], while those with a poor response should be treated
wherever intubation can be promptly performed. In the pre-hospital setting, interesting
results in terms of reduction of mortality and intubation rates have been obtained by early
application of NIV, especially in the form of n-CPAP in patients with ACPO [80].

The decision on where to deliver NIV should be made considering the type of ARF,
severity of illness, need for monitoring, ICU bed availability, and capabilities of the location
to provide monitoring, staff skills and experience [70–72].

Ventilators

The ventilator is crucial in determining NIV success in the acute setting [81]. Dedicated
NIV platforms perform better than ICU ventilators using the NIV algorithm. In particular,
advances in software technology offer newer algorithms that enhance interactions (and
synchrony) between the patient and ventilator [81].

The ability to tolerate air leaks is important for the functioning of ventilators for NIV. Leaks
are either intentional leaks through the passive exhalation port or unintentional leaks,
frequently as a result of loose-fitting interfaces. Originally designed for home care purposes,
bilevel ventilators always compensate for leaks; more recently, enhanced monitoring and
graphics capabilities have allowed improved tuning of ventilator settings [75]. Whereas in
the past ICU ventilators were not designed to work in the presence of leaks, the vast
majority of these devices nowadays incorporate NIV-dedicated modules intended for
detecting, monitoring and compensating for air leaks. Some features, such as trigger type
and sensitivity, adjustable flow cycling-off threshold and maximal inspiratory time, allow
adjustments aimed at improving patient–ventilator interactions and synchrony [81, 82].

The performance of NIV ventilators has been predominantly evaluated on the bench, often
with varying criteria [83]. In a laboratory and clinical study by CARTEAUX et al. [81], bilevel
ventilators outperformed critical care ventilators for NIV use with respect to patient–ventilator
interaction and synchrony. New modes of mechanical ventilation, such as neurally adjusted
ventilatory assist (NAVA) [84, 85], have been shown to significantly add to interaction and
synchrony, but the clinical importance of these improvements remains to be determined.

Interfaces

The interface is an important determinant for NIV success, which holds particularly true
for prolonged NIV applications [23]. The availability and quality of NIV interfaces has
substantially increased over the past decade [2]. NAVALESI et al. [86] evaluated nasal prongs,
and oronasal and nasal masks for NIV application in 26 stable hypercapnic patients with
either COPD or restrictive thoracic disorders who had not received NIV. They found all
three interfaces effective in improving gas exchange; the nasal mask being better tolerated

193

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

than the two other interfaces, but less effective in decreasing PaCO2 [86]. As acute patients
with ARF are generally mouth breathers, nasal interfaces are infrequently used in acute
patients. In patients receiving NIV for COPD exacerbation, however, ANTON et al. [87]
found no differences between nasal and facial masks in terms of patient effort, gas
exchange and inspiratory effort. A subsequent study comparing oronasal and nasal masks
in ARF patients found the two interfaces to have similar effects regarding improvement in
vital signs and gas exchange, and rate of NIV failure and intubation, but the nasal mask
was less well tolerated in terms of comfort [88]. In patients with hypercapnic ARF, GIRAULT
et al. [89] assessed the influence of the mask used for initiating NIV (facial versus nasal)
on efficacy and tolerance. They found mask failures occurred significantly more often with
the nasal mask primarily due to air leaks and concluded that the facial mask should be
used in the initial management of hypercapnic ARF [89].

In a study evaluating four interfaces for NIV in ICU patients, FRATICELLI et al. [90] found
that despite differences in internal volume, i.e. very high (977 mL), high (163 mL), moderate
(84 mL) or virtually no internal volume, there were no major effects due to the internal dead
space on minute ventilation, work of breathing and gas exchange. NIV was successful in
reducing the patient’s inspiratory effort regardless of the interface. The only important
difference observed related to air leaks and asynchronies that were greater with the
mouthpiece, i.e. the interface with the smallest dead space, which also resulted in reduced
comfort [90]. These data indicate that NIV interfaces are largely interchangeable, supporting
a “rotating” strategy for reducing the risk of skin breakdown and intolerance [2].

Two new interfaces have been made available for clinical use more recently: the total full
face mask, incorporating the eyes within the perimeter of the mask in addition to the nose
and mouth, and the helmet, containing the whole head inside a transparent hood that, in
its standard configuration, is joined by a rigid plastic ring to a soft collar and secured by
two padded armpit braces at four hooks.

With the total full face mask the seal is around the perimeter of the face, thereby avoiding
contact on the nasal bridge, i.e. the area most commonly affected by bruises consequent to
skin friction [91]. OZSANCAK et al. [92] found the oronasal and total full face mask were
equally tolerated by patients with a similar time of application, while CHACUR et al. [93]
reported improved comfort with the total full face mask, which allowed longer NIV
application but did not improve NIV outcome. LEMYZE et al. [94] evaluated the effects of
changing the mask, from an oronasal mask to a total full face, in 74 do-not-intubate
patients after NIV failure to reverse ARF. After switching the mask, NIV reversed ARF and
led to hospital survival in 64% of the patients who had previously failed NIV.

The helmet has been shown to improve NIV comfort over time compared with the
oronasal mask, eliminating facial skin breakdown, gastric distension and eye irritation [91,
92]. Despite these advantages, the helmet has specific drawbacks primarily related to its
highly compliant soft collar [95]. Inspiratory pressure dissipation increases the time lag
between inspiratory effort and ventilator assistance, worsening patient–ventilator synchrony
and resulting in less efficient reduction of the patient’s inspiratory effort [81, 94, 95]. In
addition, the armpit braces that maintain the helmet in place may cause patient discomfort
and axillary skin lesions leading to NIV intolerance and failure [96]. To overcome these
limitations, a new helmet has been recently developed and introduced in clinical use, in
which an opening ring placed underneath an inflatable cushion secures the helmet without
the need for armpit braces and reduces the pressure dissipated because of the downward

194

FB:Cardiologia Siglo XXI

 ACUTE NONINVASIVE VENTILATION | R. VASCHETTO ET AL.

displacement of the soft collar during ventilator insufflation. Studies on the bench [83], in
healthy volunteers [97] and in ICU patients [98] indicate this new helmet is effective in
improving patient–ventilator interaction, as opposed to the standard version. A pilot
multicentre RCT found this new helmet equally effective as the face mask in delivering
NIV to patients with hypercapnic ARF [99].

Sedation

Despite the aforementioned strategies, some patients remain intolerant, in particular

following application for long periods and/or with elevated airway pressure, causing NIV
discontinuation and the subsequent requirement for endotracheal intubation. The
administration of analgesia and sedation in an attempt to reverse this situation is
controversial [100, 101]. While the “preventive” administration of sedation and analgesia, i.e.
at initiation of NIV, has so far not shown encouraging results [102], the “curative” infusion of
opioids [103, 104], propofol [105] or dexdemethomidine [106] was seen to be beneficial in
small uncontrolled studies for the treatment of discomfort and NIV intolerance, being able to
avoid intubation in a large fraction of intolerant patients [105, 106]. Whereas it is important
to note the different respiratory effects of these drugs [107–109], recent data suggest that
combining sedative and analgesic drugs during NIV worsens NIV outcome, while the
separate administration of single drugs does not [102]. Finally, it is worth remarking that
sedative infusion should not be considered for managing patients outside the ICU.

Conclusions

NIV is nowadays a valid tool for treating patients with ARF. NIV should be used for early
treatment of established episodes of hypercapnic ARF, in order to avoid further deterioration
and intubation, and to prevent post-extubation respiratory failure and re-intubation in
patients at increased risk of extubation failure because of predisposing conditions such as the
presence of underlying respiratory and cardiac diseases. Evidence also supports the use of
n-CPAP in addition to the standard medical treatment for patients with ACPO. A skilled
team may also advantageously use NIV to facilitate weaning and extubation. Uncertainty
remains about the possible role of NIV in the treatment of patients who are hypoxaemic
because of pneumonia or ARDS, in which NIV is not advisable at present. It should be noted
that, unless NIV is the ceiling of treatment, one should always be ready to intubate patients
who do not improve with NIV. Some specific technical aspects are crucial and deserve careful
attention to increase the chance of applying NIV to the right patient in the appropriate
setting with the appropriate equipment, and thus improve the overall rate of success.

References
1. Nava S, Navalesi P, Carlucci A. Non-invasive ventilation. Minerva Anestesiol 2009; 75: 31–36.
2. Nava S, Navalesi P, Gregoretti C. Interfaces and humidification for noninvasive mechanical ventilation.
Respir Care 2009; 54: 71–84.
3. Brochard L, Mancebo J, Wysocki M, et al. Noninvasive ventilation for acute exacerbations of chronic obstructive
pulmonary disease. N Engl J Med 1995; 333: 817–822.
4. Kramer N, Meyer TJ, Meharg J, et al. Randomized, prospective trial of noninvasive positive pressure ventilation
in acute respiratory failure. Am J Respir Crit Care Med 1995; 151: 1799–1806.
5. Plant PK, Owen JL, Elliott MW. Early use of non-invasive ventilation for acute exacerbations of chronic
obstructive pulmonary disease on general respiratory wards: a multicentre randomised controlled trial. Lancet
2000; 355: 1931–1935.

195

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

6. Lightowler JV, Wedzicha JA, Elliott MW, et al. Non-invasive positive pressure ventilation to treat respiratory
failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and
meta-analysis. BMJ 2003; 326: 185.
7. Quon BS, Gan WQ, Sin DD. Contemporary management of acute exacerbations of COPD: a systematic review
and metaanalysis. Chest 2008; 133: 756–766.
8. Antonelli M, Conti G, Rocco M, et al. A comparison of noninvasive positive-pressure ventilation and
conventional mechanical ventilation in patients with acute respiratory failure. N Engl J Med 1998; 339: 429–435.
9. Antonelli M, Conti G, Bufi M, et al. Noninvasive ventilation for treatment of acute respiratory failure in patients
undergoing solid organ transplantation: a randomized trial. JAMA 2000; 283: 235–241.
10. Hilbert G, Gruson D, Vargas F, et al. Noninvasive ventilation in immunosuppressed patients with pulmonary
infiltrates, fever, and acute respiratory failure. N Engl J Med 2001; 344: 481–487.
11. Delclaux C, L’Her E, Alberti C, et al. Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency
with continuous positive airway pressure delivered by a face mask: a randomized controlled trial. JAMA 2000;
284: 2352–2360.
12. Lemiale V, Mokart D, Resche-Rigon M, et al. Effect of noninvasive ventilation vs oxygen therapy on mortality
among immunocompromised patients with acute respiratory failure: a randomized clinical trial. JAMA 2015; 314:
1711–1719.
13. Ferrer M, Esquinas A, Leon M, et al. Noninvasive ventilation in severe hypoxemic respiratory failure:
a randomized clinical trial. Am J Respir Crit Care Med 2003; 168: 1438–1444.
14. Auriant I, Jallot A, Herve P, et al. Noninvasive ventilation reduces mortality in acute respiratory failure following
lung resection. Am J Respir Crit Care Med 2001; 164: 1231–1235.
15. Jaber S, Lescot T, Futier E, et al. Effect of noninvasive ventilation on tracheal reintubation among patients with
hypoxemic respiratory failure following abdominal surgery: a randomized clinical trial. JAMA 2016; 315: 1345–1353.
16. Vaschetto R, Turucz E, Dellapiazza F, et al. Noninvasive ventilation after early extubation in patients recovering
from hypoxemic acute respiratory failure: a single-centre feasibility study. Intensive Care Med 2012; 38: 1599–1606.
17. Ferrer M, Valencia M, Nicolas JM, et al. Early noninvasive ventilation averts extubation failure in patients at risk:
a randomized trial. Am J Respir Crit Care Med 2006; 173: 164–170.
18. Ferrer M, Sellares J, Valencia M, et al. Non-invasive ventilation after extubation in hypercapnic patients with
chronic respiratory disorders: randomised controlled trial. Lancet 2009; 374: 1082–1088.
19. Nava S, Gregoretti C, Fanfulla F, et al. Noninvasive ventilation to prevent respiratory failure after extubation in
high-risk patients. Crit Care Med 2005; 33: 2465–2470.
20. Bott J, Carroll MP, Conway JH, et al. Randomised controlled trial of nasal ventilation in acute ventilatory failure
due to chronic obstructive airways disease. Lancet 1993; 341: 1555–1557.
21. Chandra D, Stamm JA, Taylor B, et al. Outcomes of noninvasive ventilation for acute exacerbations of chronic
obstructive pulmonary disease in the United States, 1998–2008. Am J Respir Crit Care Med 2012; 185: 152–159.
22. Ram FS, Picot J, Lightowler J, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure
due to exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2004; CD004104.
23. Nava S, Navalesi P, Conti G. Time of non-invasive ventilation. Intensive Care Med 2006; 32: 361–370.
24. Bardi G, Pierotello R, Desideri M, et al. Nasal ventilation in COPD exacerbations: early and late results of a
prospective, controlled study. Eur Respir J 2000; 15: 98–104.
25. Keenan SP, Powers CE, McCormack DG. Noninvasive positive-pressure ventilation in patients with milder chronic
obstructive pulmonary disease exacerbations: a randomized controlled trial. Respir Care 2005; 50: 610–616.
26. Collaborative Research Group of Noninvasive Mechanical Ventilation for Chronic Obstructive Pulmonary
Disease. Early use of non-invasive positive pressure ventilation for acute exacerbations of chronic obstructive
pulmonary disease: a multicentre randomized controlled trial. Chin Med J 2005; 118: 2034–2040.
27. Celikel T, Sungur M, Ceyhan B, et al. Comparison of noninvasive positive pressure ventilation with standard
medical therapy in hypercapnic acute respiratory failure. Chest 1998; 114: 1636–1642.
28. Thys F, Roeseler J, Reynaert M, et al. Noninvasive ventilation for acute respiratory failure: a prospective
randomised placebo-controlled trial. Eur Respir J 2002; 20: 545–555.
29. Girou E, Schortgen F, Delclaux C, et al. Association of noninvasive ventilation with nosocomial infections and
survival in critically ill patients. JAMA 2000; 284: 2361–2367.
30. Girou E, Brun-Buisson C, Taille S, et al. Secular trends in nosocomial infections and mortality associated with
noninvasive ventilation in patients with exacerbation of COPD and pulmonary edema. JAMA 2003; 290: 2985–2991.
31. Navalesi P, Hernandez P, Laporta D, et al. Influence of site of tracheal pressure measurement on in situ
estimation of endotracheal tube resistance. J Appl Physiol 1994; 77: 2899–2906.
32. Cunnion KM, Weber DJ, Broadhead WE, et al. Risk factors for nosocomial pneumonia: comparing adult
critical-care populations. Am J Respir Crit Care Med 1996; 153: 158–162.
33. Conti G, Antonelli M, Navalesi P, et al. Noninvasive vs. conventional mechanical ventilation in patients with
chronic obstructive pulmonary disease after failure of medical treatment in the ward: a randomized trial. Intensive
Care Med 2002; 28: 1701–1707.

196

FB:Cardiologia Siglo XXI

 ACUTE NONINVASIVE VENTILATION | R. VASCHETTO ET AL.

34. Jurjevic M, Matic I, Sakic-Zdravcevic K, et al. Mechanical ventilation in chronic obstructive pulmonary disease
patients, noninvasive vs. invasive method (randomized prospective study). Coll Antropol 2009; 33: 791–797.
35. Squadrone E, Frigerio P, Fogliati C, et al. Noninvasive vs invasive ventilation in COPD patients with severe acute
respiratory failure deemed to require ventilatory assistance. Intensive Care Med 2004; 30: 1303–1310.
36. Nava S, Ambrosino N, Clini E, et al. Noninvasive mechanical ventilation in the weaning of patients with
respiratory failure due to chronic obstructive pulmonary disease. A randomized, controlled trial. Ann Intern Med
1998; 128: 721–728.
37. Burns KE, Meade MO, Premji A, et al. Noninvasive ventilation as a weaning strategy for mechanical ventilation
in adults with respiratory failure: a Cochrane systematic review. CMAJ 2014; 186: E112–E122.
38. Hess DR. Noninvasive ventilation for acute respiratory failure. Respir Care 2013; 58: 950–972.
39. Carrillo A, Ferrer M, Gonzalez-Diaz G, et al. Noninvasive ventilation in acute hypercapnic respiratory failure
caused by obesity hypoventilation syndrome and chronic obstructive pulmonary disease. Am J Respir Crit Care
Med 2012; 186: 1279–1285.
40. Roger VL. The changing landscape of heart failure hospitalizations. J Am Coll Cardiol 2013; 61: 1268–1270.
41. Vital FM, Ladeira MT, Atallah AN. Non-invasive positive pressure ventilation (CPAP or bilevel NPPV) for
cardiogenic pulmonary oedema. Cochrane Database Syst Rev 2013; 5: CD005351.
42. Mehta S, Jay GD, Woolard RH, et al. Randomized, prospective trial of bilevel versus continuous positive airway
pressure in acute pulmonary edema. Crit Care Med 1997; 25: 620–628.
43. Rusterholtz T, Bollaert PE, Feissel M, et al. Continuous positive airway pressure vs. proportional assist ventilation
for noninvasive ventilation in acute cardiogenic pulmonary edema. Intensive Care Med 2008; 34: 840–846.
44. Sharon A, Shpirer I, Kaluski E, et al. High-dose intravenous isosorbide-dinitrate is safer and better than Bi-PAP
ventilation combined with conventional treatment for severe pulmonary edema. J Am Coll Cardiol 2000; 36: 832–837.
45. Winck JC, Azevedo LF, Costa-Pereira A, et al. Efficacy and safety of non-invasive ventilation in the treatment of
acute cardiogenic pulmonary edema – a systematic review and meta-analysis. Crit Care 2006; 10: R69.
46. Demoule A, Girou E, Richard JC, et al. Benefits and risks of success or failure of noninvasive ventilation.
Intensive Care Med 2006; 32: 1756–1765.
47. Demoule A, Chevret S, Carlucci A, et al. Changing use of noninvasive ventilation in critically ill patients: trends
over 15 years in francophone countries. Intensive Care Med 2016; 42: 82–92.
48. Frat JP, Thille AW, Mercat A, et al. High-flow oxygen through nasal cannula in acute hypoxemic respiratory
failure. N Engl J Med 2015; 372: 2185–2196.
49. Chiumello D, Chevallard G, Gregoretti C. Non-invasive ventilation in postoperative patients: a systematic review.
Intensive Care Med 2011; 37: 918–929.
50. Squadrone V, Coha M, Cerutti E, et al. Continuous positive airway pressure for treatment of postoperative
hypoxemia: a randomized controlled trial. JAMA 2005; 293: 589–595.
51. Schnell D, Timsit JF, Darmon M, et al. Noninvasive mechanical ventilation in acute respiratory failure: trends in
use and outcomes. Intensive Care Med 2014; 40: 582–591.
52. Peigne V, Rusinova K, Karlin L, et al. Continued survival gains in recent years among critically ill myeloma
patients. Intensive Care Med 2009; 35: 512–518.
53. Del Sorbo L, Jerath A, Dres M, et al. Non-invasive ventilation in immunocompromised patients with acute
hypoxemic respiratory failure. J Thorac Dis 2016; 8: E208–E216.
54. Schellongowski P, Staudinger T, Kundi M, et al. Prognostic factors for intensive care unit admission, intensive
care outcome, and post-intensive care survival in patients with de novo acute myeloid leukemia: a single center
experience. Haematologica 2011; 96: 231–237.
55. Scales DC, Thiruchelvam D, Kiss A, et al. Intensive care outcomes in bone marrow transplant recipients:
a population-based cohort analysis. Crit Care 2008; 12: R77.
56. Molina R, Bernal T, Borges M, et al. Ventilatory support in critically ill hematology patients with respiratory
failure. Crit Care 2012; 16: R133.
57. Bello G, De Pascale G, Antonelli M. Noninvasive ventilation for the immunocompromised patient: always
appropriate? Curr Opin Crit Care 2012; 18: 54–60.
58. Rabbat A, Chaoui D, Montani D, et al. Prognosis of patients with acute myeloid leukaemia admitted to intensive
care. Br J Haematol 2005; 129: 350–357.
59. Gristina GR, Antonelli M, Conti G, et al. Noninvasive versus invasive ventilation for acute respiratory failure
in patients with hematologic malignancies: a 5-year multicenter observational survey. Crit Care Med 2011; 39:
2232–2239.
60. Squadrone V, Massaia M, Bruno B, et al. Early CPAP prevents evolution of acute lung injury in patients with
hematologic malignancy. Intensive Care Med 2010; 36: 1666–1674.
61. Azoulay E, Lemiale V. Non-invasive mechanical ventilation in hematology patients with hypoxemic acute
respiratory failure: a false belief? Bone Marrow Transplant 2012; 47: 469–472.
62. Frat JP, Coudroy R, Thille AW. Noninvasive ventilation and outcomes among immunocompromised patients.
JAMA 2016; 315: 1901–1902.

197

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

63. Navalesi P, Gregoretti C, Antonelli M. Noninvasive ventilation and outcomes among immunocompromised
patients. JAMA 2016; 315: 1902.
64. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respiratory distress syndrome: the Berlin Definition.
JAMA 2012; 307: 2526–2533.
65. Antonelli M, Conti G, Esquinas A, et al. A multiple-center survey on the use in clinical practice of noninvasive
ventilation as a first-line intervention for acute respiratory distress syndrome. Crit Care Med 2007; 35: 18–25.
66. Agarwal R, Reddy C, Aggarwal AN, et al. Is there a role for noninvasive ventilation in acute respiratory distress
syndrome? A meta-analysis. Respir Med 2006; 100: 2235–2238.
67. Rana S, Jenad H, Gay PC, et al. Failure of non-invasive ventilation in patients with acute lung injury:
observational cohort study. Crit Care 2006; 10: R79.
68. Patel BK, Wolfe KS, Pohlman AS, et al. Effect of noninvasive ventilation delivered by helmet vs face mask on the
rate of endotracheal intubation in patients with acute respiratory distress syndrome: a randomized clinical trial.
JAMA 2016; 315: 2435–2441.
69. Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with 2009 influenza A(H1N1) infection in Canada.
JAMA 2009; 302: 1872–1879.
70. Agarwal R, Aggarwal AN, Gupta D. Role of noninvasive ventilation in acute lung injury/acute respiratory distress
syndrome: a proportion meta-analysis. Respir Care 2010; 55: 1653–1660.
71. Thille AW, Contou D, Fragnoli C, et al. Non-invasive ventilation for acute hypoxemic respiratory failure:
intubation rate and risk factors. Crit Care 2013; 17: R269.
72. Nicolini A, Tonveronachi E, Navalesi P, et al. Effectiveness and predictors of success of noninvasive ventilation
during H1N1 pandemics: a multicenter study. Minerva Anestesiol 2012; 78: 1333–1340.
73. Bellani G, Laffey JG, Pham T, et al. Epidemiology, patterns of care, and mortality for patients with acute
respiratory distress syndrome in intensive care units in 50 countries. JAMA 2016; 315: 788–800.
74. Demoule A, Hill N, Navalesi P. Can we prevent intubation in patients with ARDS? Intensive Care Med 2016; 42:
768–771.
75. Hill NS. Where should noninvasive ventilation be delivered? Respir Care 2009; 54: 62–70.
76. Jhanji S, Pearse RM. The use of early intervention to prevent postoperative complications. Curr Opin Crit Care
2009; 15: 349–354.
77. Ozsancak UA, Sidhom SS, Khodabandeh A, et al. Where is noninvasive ventilation actually delivered for acute
respiratory failure? Lung 2015; 193: 779–788.
78. Fiorino S, Bacchi-Reggiani L, Detotto E, et al. Efficacy of non-invasive mechanical ventilation in the general ward
in patients with chronic obstructive pulmonary disease admitted for hypercapnic acute respiratory failure and pH
< 7.35: a feasibility pilot study. Intern Med J 2015; 45: 527–537.
79. Olivieri C, Carenzo L, Vignazia GL, et al. Does noninvasive ventilation delivery in the ward provide early effective
ventilation? Respir Care 2015; 60: 6–11.
80. Pandor A, Thokala P, Goodacre S, et al. Pre-hospital non-invasive ventilation for acute respiratory failure: a
systematic review and cost-effectiveness evaluation. Health Technol Assess 2015; 19 [DOI: 10.3310/hta19420].
81. Carteaux G, Lyazidi A, Cordoba-Izquierdo A, et al. Patient–ventilator asynchrony during noninvasive ventilation:
a bench and clinical study. Chest 2012; 142: 367–376.
82. Hess DR. Ventilator waveforms and the physiology of pressure support ventilation. Respir Care 2005; 50: 166–186.
83. Olivieri C, Costa R, Spinazzola G, et al. Bench comparative evaluation of a new generation and standard helmet
for delivering non-invasive ventilation. Intensive Care Med 2013; 39: 734–738.
84. Cammarota G, Olivieri C, Costa R, et al. Noninvasive ventilation through a helmet in postextubation hypoxemic
patients: physiologic comparison between neurally adjusted ventilatory assist and pressure support ventilation.
Intensive Care Med 2011; 37: 1943–1950.
85. Navalesi P, Longhini F. Neurally adjusted ventilatory assist. Curr Opin Crit Care 2015; 21: 58–64.
86. Navalesi P, Fanfulla F, Frigerio P, et al. Physiologic evaluation of noninvasive mechanical ventilation delivered
with three types of masks in patients with chronic hypercapnic respiratory failure. Crit Care Med 2000; 28:
1785–1790.
87. Anton A, Tarrega J, Giner J, et al. Acute physiologic effects of nasal and full-face masks during noninvasive
positive-pressure ventilation in patients with acute exacerbations of chronic obstructive pulmonary disease.
Respir Care 2003; 48: 922–925.
88. Kwok H, McCormack J, Cece R, et al. Controlled trial of oronasal versus nasal mask ventilation in the treatment
of acute respiratory failure. Crit Care Med 2003; 31: 468–473.
89. Girault C, Briel A, Benichou J, et al. Interface strategy during noninvasive positive pressure ventilation for
hypercapnic acute respiratory failure. Crit Care Med 2009; 37: 124–131.
90. Fraticelli AT, Lellouche F, L’Her E, et al. Physiological effects of different interfaces during noninvasive ventilation
for acute respiratory failure. Crit Care Med 2009; 37: 939–945.
91. Holanda MA, Reis RC, Winkeler GF, et al. Influence of total face, facial and nasal masks on short-term adverse
effects during noninvasive ventilation. J Bras Pneumol 2009; 35: 164–173.

198

FB:Cardiologia Siglo XXI

 ACUTE NONINVASIVE VENTILATION | R. VASCHETTO ET AL.

92. Ozsancak A, Sidhom SS, Liesching TN, et al. Evaluation of the total face mask for noninvasive ventilation to treat
acute respiratory failure. Chest 2011; 139: 1034–1041.
93. Chacur FH, Vilella Felipe LM, Fernandes CG, et al. The total face mask is more comfortable than the oronasal
mask in noninvasive ventilation but is not associated with improved outcome. Respiration 2011; 82: 426–430.
94. Lemyze M, Mallat J, Nigeon O, et al. Rescue therapy by switching to total face mask after failure of face
mask-delivered noninvasive ventilation in do-not-intubate patients in acute respiratory failure. Crit Care Med
2013; 41: 481–488.
95. Chiumello D, Pelosi P, Carlesso E, et al. Noninvasive positive pressure ventilation delivered by helmet vs.
standard face mask. Intensive Care Med 2003; 29: 1671–1679.
96. Lucchini A, Valsecchi D, Elli S, et al. The Helmet Bundle: il comfort del paziente ventilato con CPAP con
scafandro. [The comfort of patients ventilated with the Helmet Bundle.] Assist Inferm Ric 2010; 29: 174–183.
97. Vaschetto R, De Jong A, Conseil M, et al. Comparative evaluation of three interfaces for non-invasive ventilation:
a randomized cross-over design physiologic study on healthy volunteers. Crit Care 2014; 18: R2.
98. Olivieri C, Longhini F, Cena T, et al. New versus conventional helmet for delivering noninvasive ventilation:
a physiologic, crossover randomized study in critically ill patients. Anesthesiology 2016; 124: 101–108.
99. Pisani L, Mega C, Vaschetto R, et al. Oronasal mask versus helmet in acute hypercapnic respiratory failure.
Eur Respir J 2015; 45: 691–699.
100. Conti G, Hill NS, Nava S. Is sedation safe and beneficial in patients receiving NIV? No. Intensive Care Med 2015;
41: 1692–1695.
101. Hilbert G, Navalesi P, Girault C. Is sedation safe and beneficial in patients receiving NIV? Yes. Intensive Care
Med 2015; 41: 1688–1691.
102. Muriel A, Penuelas O, Frutos-Vivar F, et al. Impact of sedation and analgesia during noninvasive positive pressure
ventilation on outcome: a marginal structural model causal analysis. Intensive Care Med 2015; 41: 1586–1600.
103. Constantin JM, Schneider E, Cayot-Constantin S, et al. Remifentanil-based sedation to treat noninvasive
ventilation failure: a preliminary study. Intensive Care Med 2007; 33: 82–87.
104. Rocco M, Conti G, Alessandri E, et al. Rescue treatment for noninvasive ventilation failure due to interface
intolerance with remifentanil analgosedation: a pilot study. Intensive Care Med 2010; 36: 2060–2065.
105. Clouzeau B, Bui HN, Vargas F, et al. Target-controlled infusion of propofol for sedation in patients with
non-invasive ventilation failure due to low tolerance: a preliminary study. Intensive Care Med 2010; 36: 1675–1680.
106. Akada S, Takeda S, Yoshida Y, et al. The efficacy of dexmedetomidine in patients with noninvasive ventilation:
a preliminary study. Anesth Analg 2008; 107: 167–170.
107. Cavaliere F, Antonelli M, Arcangeli A, et al. A low-dose remifentanil infusion is well tolerated for sedation in
mechanically ventilated, critically-ill patients. Can J Anaesth 2002; 49: 1088–1094.
108. Conti G, Mantz J, Longrois D, et al. Sedation and weaning from mechanical ventilation: time for ‘best practice’ to
catch up with new realities? Multidiscip Respir Med 2014; 9: 45.
109. Vaschetto R, Cammarota G, Colombo D, et al. Effects of propofol on patient–ventilator synchrony and
interaction during pressure support ventilation and neurally adjusted ventilatory assist. Crit Care Med 2014; 42:
74–82.

Disclosures: R. Vaschetto has received a grant from Maquet Critical Care, and nonfinancial support from
Maquet Critical Care, Fisher & Paykel and Biotest. F. Longhini has received a grant from Maquet Critical Care,
and nonfinancial support from Maquet Critical Care, Fisher & Paykel, Draeger and Hill-Rom. P. Navalesi has
received a grant, personal fees and nonfinancial support from Maquet Critical Care, a grant from Biotest,
personal fees and nonfinancial support from Draeger and Hill-Rom, personal fees from Philips, Breas, Linde
and Resmed, as well as nonfinancial support from Fisher & Paykel and Intersurgical SpA; he also contributed
to the development of the helmet CaStar Next, whose licence for patent belongs to Intersurgical SpA, and
receives royalties for that invention.

199

FB:Cardiologia Siglo XXI

 | Chapter 14
Extracorporeal carbon dioxide
removal
Christian Karagiannidis1, Stefan Kluge2, Stephan Strassmann1 and
Wolfram Windisch1

Extracorporeal carbon dioxide removal (ECCO2R) is an emerging technology in ICU

medicine aimed at compensating for severe respiratory acidosis. Thereby, ECCO2R aims at
immediately saving lives or reducing complications related to intubation and subsequent
invasive mechanical ventilation by either avoiding intubation or allowing protective
ventilation or early extubation following initial intubation. ECCO2R can be applied by
pumpless arteriovenous (av-ECCO2R) and pump-driven venovenous (vv-ECCO2R) systems.
Both systems require the cannulation of large vessels and are associated with
technique-specific complications, most importantly bleeding, ischaemia and clotting.
Therefore, the potential benefits of ECCO2R must be balanced against the possible
complications in each individual. However, scientific evidence for ECCO2R is limited, and
restricted to only a few experimental and clinical trials. Despite this, ECCO2R has been
suggested to be live saving in selected patients when adequately considering the potential
complications. Furthermore, technical developments have allowed ECCO2R to become
widespread and larger RCTs are now in progress. Thus, ECCO2R is suggested to become an
established treatment option in the near future in ICU medicine.

E xtracorporeal carbon dioxide removal (ECCO2R) is a rapidly developing live-saving

technique in ICU medicine aimed at treating very severe respiratory acidosis, avoiding
intubation and subsequent long-term invasive mechanical ventilation or shortening the
time spent on invasive mechanical ventilation by allowing early extubation in patients with
acute hypercapnic respiratory failure following ventilatory insufficiency, most importantly
COPD [1–4]. In addition, ECCO2R is also capable of compensating for respiratory acidosis
occurring in patients with severe ARDS and lung protective ventilation [5–7].

This chapter will summarise our knowledge on ECCO2R in the context of the emergency
situation. The chapter starts with a description of the technical considerations of
ECCO2R. Next, possible complications but also the suggested benefits of ECCO2R are

1
Dept of Pneumology and Critical Care Medicine, Cologne-Merheim Hospital, ARDS and ECMO Centre, Kliniken der Stadt Köln
gGmbH, Witten/Herdecke University Hospital, Cologne, Germany. 2Dept of Intensive Care Medicine, University Medical Centre
Hamburg-Eppendorf, Hamburg, Germany.

Correspondence: Christian Karagiannidis, Dept of Pneumology and Critical Care Medicine, ARDS and ECMO Centre,
Cologne-Merheim Hospital, Kliniken der Stadt Köln gGmbH, Witten/Herdecke University Hospital, Ostmerheimer Strasse 200, 51109
Cologne, Germany. E-mail: KaragiannidisC@kliniken-koeln.de

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

200 ERS Monogr 2016; 74: 200–208. DOI: 10.1183/2312508X.10002516

FB:Cardiologia Siglo XXI

 EXTRACORPOREAL CARBON DIOXIDE REMOVAL | C. KARAGIANNIDIS ET AL.

discussed. This is followed by a summary of the current literature on the clinical

applications of ECCO2R. Finally, future directions and unmet needs are addressed.

Technical considerations of ECCO2R

In principle, ECCO2R can be applied in two different ways: pumpless arteriovenous

(av-ECCO2R) (figure 1) and pump-driven venovenous (vv-ECCO2R) (figure 2). The
pumpless arteriovenous system, also known as interventional lung assist (iLA; Novalung,
Heilbronn, Germany), utilises the natural pressure gradient between the arterial and venous
systems, i.e. femoral artery and vein (figure 1). Av-ECCO2R provides a substantial shunt
between the arterial and venous sides, and thus sufficient cardiac output is mandatory for
this approach. Accordingly, blood flow rates range between 1.0 and 2.0 L·min−1 depending
on cannula size and cardiac output [8]. As the oxygenator of the system has a low
resistance with a pressure drop of <10 mmHg under optimal circumstances, blood flow is
mainly dependent on the diameter and resistance of the draining arterial cannula. On
average, a 15-French draining cannula with a slightly larger venous backflow cannula
generates a blood flow of ∼1.6 L·min−1 and a 17-French cannula generates a blood flow of
2.0 L·min−1 [8]. Depending on blood flow, sweep gas flow (see below) and baseline PaCO2,
av-ECCO2R systems are capable of removing ∼50% of the total carbon dioxide production
of patients on mechanical ventilation, i.e. ∼150 mL·min−1 of carbon dioxide. In contrast,
oxygenation capability is low and reaches ∼40 mL·min−1 of oxygen, which is ∼10% of the
estimated oxygen consumption. One major problem with av-ECCO2R is that arterial
cannulation can lead to poor perfusion of the relevant limb and leg with subsequent
ischaemia depending on the anatomical circumstances of the artery. In addition, there are
only limited regulatory possibilities for av-ECCO2R. Therefore, this approach is restricted in
clinical application, particularly in emergencies, and thus its use has decreased during
recent years when considering the alternative approach of vv-ECCO2R systems [9].

Flow meter

Sweep gas

Oxygenator

Figure 1. Arteriovenous extracorporeal carbon dioxide removal system. Cannulation of the right femoral
artery and left femoral vein with pumpless gas exchange through a low-resistance oxygenator. Photograph
kindly provided by Alois Philip (University of Regensburg, Regensburg, Germany).

201

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

a)

Centrifugal pump

b)

Oxygenator

Sweep gas
line

Figure 2. a) Venovenous extracorporeal carbon dioxide removal system driven by a centrifugal pump through
an electromagnetic field. b) Oxygenator with a surface area of 0.98 m2 with green sweep gas line. For
primary carbon dioxide removal, 21% or 100% oxygen can be used as sweep gas.

Further advances in ECCO2R systems have been achieved with the developments in
vv-ECMO systems [9] over the last 5–10 years. Basically, heparin-coated vv-ECCO2R
systems consist of two venous cannulae (one draining and one backflow) or one
double-lumen cannula, a polymethylpentene membrane lung and a blood pump (figure 2).
Importantly, no clear recommendations on how to choose blood flow rates for vv-ECCO2R
have been established. Thus, blood flow rates range between 200 mL·min−1 and 2 L·min−1
according to different trials [1, 3], but are still lower than rates chosen for full vv-ECMO
used to treat severe hypoxaemia in ARDS patients [10]. Very low blood flow rates are
similar to the flow rates used for haemodialysis [11], whereas higher flow rates of up to
2 L·min−1 are derived from high-flow vv-ECMO systems. Correspondingly, some ECCO2R
systems are driven by roller pumps comparable to haemodialysis systems, whereas others are
driven by centrifugal pumps comparable to high-flow ECMO systems (table 1). Accordingly,
when considering the different systems available for vv-ECCO2R the crucial question is how
much blood flow is required for sufficient carbon dioxide removal, especially in the
emergency situation. Here, one should consider that the amount of carbon dioxide removal
achieved by vv-ECCO2R depends on four key factors: 1) blood flow, 2) sweep gas flow,
3) surface area of the oxygenator and 4) venous carbon dioxide tension (PvCO2) [12, 13].

202

FB:Cardiologia Siglo XXI

 Table 1. Currently available extracorporeal carbon dioxide removal systems

Device Manufacturer Blood flow Oxygenator Pump

surface area

EXTRACORPOREAL CARBON DIOXIDE REMOVAL | C. KARAGIANNIDIS ET AL.

CARDIOHELP 5.0 Maquet, Rastatt, Germany Maximum 5 L·min−1 1.2 m2 Centrifugal pump

iLA activve Novalung, Heilbronn, 0.25–4.5 L·min−1 depending 0.32–1.3 m2 Centrifugal pump
Germany on oxygenator

Hemolung Alung, Pittsburgh, PA, USA 350–550 mL·min−1 0.59 m2 Centrifugal pump

PrismaLung/PRISMAFLEX Baxter, Unterschleißheim, Maximum 450 mL·min−1 0.32 m2 Roller pump

Germany

ApherCap Aferetica, Mirandola, Italy 30–450 mL·min−1 Not published Roller pump

Abylcap Bellco, Mirandola, Italy Maximum 450 mL·min−1 0.67 m2 Roller pump

DECAP Hemodec, Salerno, Italy <500 mL·min−1 0.3–1.35 m2 Roller pump

Interventional lung assist (iLA) Novalung, Heilbronn, Depending on cardiac output and 1.3 m2 Pumpless,
Germany cannula size, usually <2.0 L·min−1 arteriovenous
203

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Again, the blood flow rate is suggested to be one of the most important determinants of the
amount of carbon dioxide removal. Interestingly, recent experimental research has
determined that even low blood flow rates of 200–400 mL·min−1 with a conventional
haemodialysis catheter are capable of removing significant amounts of carbon dioxide, but
are not sufficient to counterbalance severe respiratory acidosis. Although up to 80 mL·min−1
can be removed with a blood flow of 400 mL·min−1, the corresponding pH does not
increase to the normal range if a severe respiratory acidosis exists. For this purpose, blood
flow rates >750–1000 mL·min−1 have been shown to be required for normalising severely
acidotic pH values, i.e. removing up to 150 mL·min−1 of carbon dioxide, corresponding to
50–60% of the estimated carbon dioxide production [13].

However, even though low blood flow rates have less effects on real carbon dioxide
removal, clinical data in acidotic COPD patients indeed suggest significant improvements
in pH and reduction in PaCO2 even with the application of low blood flow rates of
∼250 mL·min−1, and this may be attributed to an improved breathing pattern in
dynamically hyperinflated patients [4]. In addition, increasing sweep gas flow rates help to
augment carbon dioxide removal, but this effect is limited [13].

Low-flow vv-ECCO2R systems require smaller draining and backflow cannulae in the range
of 13–19 French or a small double-lumen cannula (16.5–20 French). Therefore,
implantation is less risky and can be performed in the emergency situation even in awake
patients under local anaesthesia [14]. As an alternative, modern double-lumen cannulae can
be implanted in the jugular vein (figure 3) guided by ultrasound or even fluoroscopy, or, as
an alternative, into the femoral vein. Although the concept of a double-lumen cannula
seems to be attractive, only 150 out of nearly 2000 vv-ECMO patients treated in 2014 in
Germany had double-lumen cannulation [9]. However, especially with regard to cannula
size and positioning, implantation even in the emergency situation is less risky than in
high-flow ECMO.

As already noted, the primary physiological aim of ECCO2R is the improvement in blood
gases. However, another physiological consequence of ECCO2R with subsequent reduction
of PvCO2 is the decrease of pulmonary artery pressures, which are typically high in patients
with acute respiratory acidosis that is linked to hypercapnia, and this is true for patients
with both COPD [15] and ARDS [16].

Complications of ECCO2R

Complications of extracorporeal systems may be significant and must be balanced against the
established benefits. The main technical complication relates to the activation of the
coagulation system and, therefore, clotting and bleeding [3, 10, 17]. Unfortunately, low-flow
systems are more prone to clot than high-flow systems and, thus, require more aggressive
anticoagulation. Although there is currently insufficient data, an activated prothrombin time of
1.5–2.0 times the normal range may be recommended to avoiding excessive clotting. As
patients on extracorporeal systems are more prone to heparin-induced thrombocytopenia type
II, up to 10% of all patients develop this complication [18]. Furthermore, case–control studies
and case series [3, 4, 19] report major and minor bleeding complications, which can limit
treatment success and may even lower the benefits of ECCO2R. In this regard, it must be
acknowledged that cannulation, especially in the emergency situation, also represents a
substantial risk for perforation with concomitant major bleeding. Nevertheless, life-threatening

204

FB:Cardiologia Siglo XXI

 EXTRACORPOREAL CARBON DIOXIDE REMOVAL | C. KARAGIANNIDIS ET AL.

a)

b)

Figure 3. a) Extracorporeal carbon dioxide removal (ECCO2R) in acute exacerbation of COPD with a jugular
double-lumen cannula. Initial high-intensity NIV with early NIV failure was not successful on day 1. b) Note
that lid oedemas due to high PaCO2 before ECCO2R disappeared 1 day later.

complications are less often observed compared with high-flow ECMO and occur only in a
small percentage of all patients. However, at present ECCO2R should be restricted to
experienced centres with the possibility to adequately respond to major complications, such as
bleeding following vessel perforation or coagulation activation.

Potential applications and pathophysiological considerations of

ECCO2R in acute hypercapnic respiratory failure

Noninvasive and invasive mechanical ventilation are well-established treatment options for
acute hypercapnic respiratory failure. However, despite optimal treatment some patients
remain severely hypercapnic, resulting in respiratory acidosis with pH values <7.20, and
this is particularly true for severe airway obstruction as in COPD or asthma. Potentially,
these patients might be candidates for ECCO2R as long as the long-term prognosis is
suggested to be favourable. Life-threatening cases of asthma may be treated by ECCO2R as
long as no severe hypoxaemia occurs, since reversibility of airway obstruction is typical of

205

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

the disease. One potential application relates to the management of huge bronchopleural
fistulae, which may hinder carbon dioxide removal and are usually aggravated by
mechanical ventilation [20]. FUEHNER et al. [14] demonstrated that ECMO in awake
patients, also including primary ECCO2R, serves as a better bridge to transplant than
invasive mechanical ventilation. Although this group of patients is small, ECCO2R is also
an increasingly recognised emergency option for patients bridged to transplant as long as
oxygenation is possible without extracorporeal systems.

Another potential application of ECCO2R is in severe COPD patients with early or late
NIV failure. It is well accepted that invasive mechanical ventilation is associated with
several complications, most importantly infectious complication [21], that worsen the
prognosis of patients with an acute exacerbation [22]. Therefore, it has been suggested that
avoidance of mechanical ventilation by ECCO2R may improve outcomes. Interestingly, in
acute exacerbation of COPD, ECCO2R has more impact on the pathophysiology of the
disease than only reducing PaCO2. We could show that carbon dioxide removal leads to a
lowering of initially high pulmonary arterial pressure in acute exacerbation, since carbon
dioxide is a well-know vasoconstrictor of the pulmonary vessels [15]. Furthermore, lowered
carbon dioxide leads to a reduction of the respiratory drive and therefore breathing
frequency, which in turn further reduces dynamic hyperinflation and therefore carbon
dioxide [19]. The effect on lowering HCO–3 with ECCO2R during several days of treatment
to prevent re-exacerbation is under current investigation and may also be a secondary
beneficial effect.

Finally, uncompensated respiratory acidosis following protective or ultraprotective mechanical

ventilation in ARDS is a promising field for ECCO2R [6, 7], which will be further evaluated
in the future.

Current clinical data

The current clinical evidence is very limited. Nevertheless, there is no doubt that
life-threatening severe respiratory acidosis resistant to established treatment strategies can
be successfully addressed by ECCO2R. Therefore, ECCO2R has the potential to be life
saving. Recently, two case–control studies [4, 19] and a number of case series [2, 23] have
been published. DEL SORBO et al. [4] showed avoidance of intubation for patients at risk of
NIV failure following vv-ECCO2R establishment. Four major and nine minor complications
were reported in 25 patients, mainly major and minor bleeding and circuit clotting. In a
retrospective study, KLUGE et al. [19] demonstrated that intubation could be avoided in 19
out of 21 patients treated with av-ECCO2R. Further case series led to the impression that
avoidance of invasive mechanical ventilation is possible and technically feasible, but
associated with significant side-effects. In a recent review, SKLAR et al. [3] summarised the
evidence in ECCO2R in 87 patients with severe COPD. ECCO2R was shown to be capable
of preventing intubation in 65 out of 70 patients (success rate 93%) and allowing
extubation in nine out of 17 patients (success rate 53%). However, time of extubation,
cannulation in the emergency setting, weak coughing after extubation requiring frequent
bronchoscopy and bleeding complications have been suggested to be major limiting factors.

In a very recent study by BRAUNE et al. [24] these limitations led to an intubation rate of
44% in patients with COPD failing NIV for acute hypercapnic respiratory failure despite
ECCO2R being started successfully. In addition, a third of all cases had relevant side-effects.

206

FB:Cardiologia Siglo XXI

 EXTRACORPOREAL CARBON DIOXIDE REMOVAL | C. KARAGIANNIDIS ET AL.

Conclusion and future directions

ECCO2R has the potential to avoid complications related to invasive mechanical ventilation,
can be live saving and is, therefore, suggested to become an established treatment option in
the near future in ICU medicine. However, the current scientific evidence for ECCO2R is
sparse and complications related to ECCO2R, most importantly bleeding and clotting, may
counterbalance its benefits. Therefore, there is a need for further RCTs in acute airway
obstruction, most importantly exacerbation of COPD, in the emergency situation, when
respiratory acidosis cannot be sufficiently equalised by conventional treatment strategies
including NIV. Planned and ongoing trials (ClinicalTrials.gov, trial number NCT02086084;
further trials upcoming) are needed to address the following important issues: the impact
of the underlying disease, indication criteria, technical differences of the various approaches
and impact of complications on outcome. Furthermore, ECCO2R should not be regarded as
a standalone treatment option, but rather should be viewed in the context of preceding and
subsequent treatment modalities, and this is suggested to be particularly true for patients
with end-stage disease, such as with COPD.

References
1. Abrams D, Roncon-Albuquerque R Jr, Brodie D. What’s new in extracorporeal carbon dioxide removal for COPD?
Intensive Care Med 2015; 41: 906–908.
2. Abrams DC, Brenner K, Burkart KM, et al. Pilot study of extracorporeal carbon dioxide removal to facilitate
extubation and ambulation in exacerbations of chronic obstructive pulmonary disease. Ann Am Thorac Soc 2013;
10: 307–314.
3. Sklar MC, Beloncle F, Katsios CM, et al. Extracorporeal carbon dioxide removal in patients with chronic
obstructive pulmonary disease: a systematic review. Intensive Care Med 2015; 41: 1752–1762.
4. Del Sorbo L, Pisani L, Filippini C, et al. Extracorporeal CO2 removal in hypercapnic patients at risk of noninvasive
ventilation failure: a matched cohort study with historical control. Crit Care Med 2015; 43: 120–127.
5. Fanelli V, Ranieri MV, Mancebo J, et al. Feasibility and safety of low-flow extracorporeal carbon dioxide removal to
facilitate ultra-protective ventilation in patients with moderate acute respiratory distress sindrome. Crit Care 2016;
20: 36.
6. Bein T, Weber-Carstens S, Goldmann A, et al. Lower tidal volume strategy (approximately 3 ml/kg) combined with
extracorporeal CO2 removal versus ‘conventional’ protective ventilation (6 ml/kg) in severe ARDS: the prospective
randomized Xtravent-study. Intensive Care Med 2013; 39: 847–856.
7. Terragni PP, Del Sorbo L, Mascia L, et al. Tidal volume lower than 6 ml/kg enhances lung protection: role of
extracorporeal carbon dioxide removal. Anesthesiology 2009; 111: 826–835.
8. Muller T, Lubnow M, Philipp A, et al. Extracorporeal pumpless interventional lung assist in clinical practice:
determinants of efficacy. Eur Respir J 2009; 33: 551–558.
9. Karagiannidis C, Brodie D, Strassmann S, et al. Extracorporeal membrane oxygenation: evolving epidemiology and
mortality. Intensive Care Med 2016; 42: 889–896.
10. Brodie D, Bacchetta M. Extracorporeal membrane oxygenation for ARDS in adults. N Engl J Med 2011; 365: 1905–1914.
11. Romagnoli S, Ricci Z, Ronco C. Novel extracorporeal therapies for combined renal-pulmonary dysfunction. Semin
Nephrol 2016; 36: 71–77.
12. Lehle K, Philipp A, Hiller KA, et al. Efficiency of gas transfer in venovenous extracorporeal membrane
oxygenation: analysis of 317 cases with four different ECMO systems. Intensive Care Med 2014; 40: 1870–1877.
13. Karagiannidis C, Kampe KA, Sipmann FS, et al. Veno-venous extracorporeal CO2 removal for the treatment of
severe respiratory acidosis: pathophysiological and technical considerations. Crit Care 2014; 18: R124.
14. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung
transplantation. Am J Respir Crit Care Med 2012; 185: 763–768.
15. Karagiannidis C, Strassmann S, Philipp A, et al. Veno-venous extracorporeal CO2 removal improves pulmonary
hypertension in acute exacerbation of severe COPD. Intensive Care Med 2015; 41: 1509–1510.
16. Morimont P, Guiot J, Desaive T, et al. Veno-venous extracorporeal CO2 removal improves pulmonary
hemodynamics in a porcine ARDS model. Acta Anaesthesiol Scand 2015; 59: 448–456.
17. Fan E, Gattinoni L, Combes A, et al. Venovenous extracorporeal membrane oxygenation for acute respiratory
failure: a clinical review from an international group of experts. Intensive Care Med 2016; 42: 712–724.

207

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

18. Glick D, Dzierba AL, Abrams D, et al. Clinically suspected heparin-induced thrombocytopenia during
extracorporeal membrane oxygenation. J Crit Care 2015; 30: 1190–1194.
19. Kluge S, Braune SA, Engel M, et al. Avoiding invasive mechanical ventilation by extracorporeal carbon dioxide
removal in patients failing noninvasive ventilation. Intensive Care Med 2012; 38: 1632–1639.
20. Hommel M, Deja M, von Dossow V, et al. Bronchial fistulae in ARDS patients: management with an
extracorporeal lung assist device. Eur Respir J 2008; 32: 1652–1655.
21. Girou E, Schortgen F, Delclaux C, et al. Association of noninvasive ventilation with nosocomial infections and
survival in critically ill patients. JAMA 2000; 284: 2361–2367.
22. Chandra D, Stamm JA, Taylor B, et al. Outcomes of noninvasive ventilation for acute exacerbations of chronic
obstructive pulmonary disease in the United States, 1998–2008. Am J Respir Crit Care Med 2012; 185: 152–159.
23. Burki NK, Mani RK, Herth FJ, et al. A novel extracorporeal CO2 removal system: results of a pilot study of
hypercapnic respiratory failure in patients with COPD. Chest 2013; 143: 678–686.
24. Braune S, Sieweke A, Brettner F, et al. The feasibility and safety of extracorporeal carbon dioxide removal to avoid
intubation in patients with COPD unresponsive to noninvasive ventilation for acute hypercapnic respiratory failure
(ECLAIR study): multicentre case-control study. Intensive Care Med 2016; 42: 1437–1444.

Disclosures: C. Karagiannidis has received travel grants, lecture fees and performs consultant services for
Maquet Cardiopulmonary (Rastatt, Germany). S. Kluge has received fees for advisory board meetings and
lectures from Novalung GmbH (Heilbronn, Germany). S. Strassmann has received travel grants and lecture
fees from Maquet Cardiopulmonary. W. Windisch has received fees for advisory board meetings and lectures
from Maquet Cardiopulmonary. C. Karagiannidis and W. Windisch have received an open research grant for
Cologne-Merheim Hospital from Maquet Cardiopulmonary.

208

FB:Cardiologia Siglo XXI

 | Chapter 15
Acute bronchoscopy
Raffaele Scala

Acute bronchoscopy has a pivotal role in the bronchoscopy unit and intensive care settings.
In the bronchoscopy unit, flexible bronchoscopy (FBO) is helpful for the diagnosis of
intrathoracic tumours, interstitial lung diseases and suspected pneumonia, while rigid
bronchoscopy with/without FBO is useful to manage central airway obstruction, haemoptysis
and removal of inhaled foreign bodies. In intensive care settings, FBO is used to facilitate
intubation in difficult airways scenarios, guide percutaneous dilatational tracheostomy and
resolve lobar/lung atelectasis. “Bronchoscopic” sampling should be considered in suspected
ventilator-associated pneumonia only if “noninvasive” techniques are inconclusive, as well as
in nonventilated immunosuppressed patients. Despite the variable quality of evidence that
exists in favour of the combined use of NIV and bronchoscopy in different scenarios, the
best evidence supports prophylactic NIV to prevent intubation in nonventilated patients. The
role of high-flow nasal cannula oxygen in “assisting” FBO needs to be further investigated.
Benefits of acute bronchoscopy should be weighed against the risk of cardiopulmonary
complications, bleeding and pneumothorax.

B ronchoscopy represents a fundamental technique for the management of patients

admitted to respiratory high-dependency care units (RHDCUs) and ICUs [1, 2]. It is
not a coincidence that the first application of bronchoscopy in 1897 was for the emergency
removal of an inhaled foreign body [3, 4].

Bronchoscopy can be performed with flexible and rigid instruments. Flexible bronchoscopy
(FBO) is widely used thanks to its lower invasiveness, the ability to explore larger regions of
the bronchial tree and its shorter learning curve; its “ancillary techniques” allow sampling
from the lung and mediastinum, such as BAL, protected specimen brushing (PSB),
transbronchial needle aspiration (TBNA) and transbronchial lung biopsy (TBLB) [1, 2, 4].
By transmitting images from the tip of the instrument to a video camera instead of an
eyepiece, video bronchoscopy is of help in performing FBO procedures that can be better
followed by all the team members. Although rigid bronchoscopy has a narrower range of
applications, it maintains a crucial role when performing interventional procedures, such as
ablative therapies (e.g. laser, argon plasma coagulation, electrocautery and cryotherapy),
airway stenting, as well as in removing foreign bodies [3, 4].

This chapter will focus on the acute clinical indications for bronchoscopy in adults both in
the bronchoscopy unit and the ICU/RHDCU, the pathophysiological pitfalls of bronchoscopy

Pulmonology and Respiratory Intensive Care Unit, San Donato Hospital, Arezzo, Italy.

Correspondence: Raffaele Scala, Pulmonology and Respiratory Intensive Care Unit, San Donato Hospital, Via Nenni 20, 52100 Arezzo,
Italy. E-mail: raffaele_scala@hotmail.com

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 209–228. DOI: 10.1183/2312508X.10002616 209

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

in nonventilated and ventilated patients, as well as the role of NIV and/or high-flow nasal
cannula (HFNC) oxygen in “assisting” high-risk patients during bronchoscopy.

Clinical indications for acute bronchoscopy

The main indications for acute bronchoscopy and listed in table 1 and include: 1) to help/
guide procedures for airway management (e.g. difficult intubation and percutaneous
dilatational tracheostomy (PDT)) [5–7], 2) to support the diagnosis of infective and
noninfective lung infiltrates in nonventilated and ventilated patients [1, 8–12], 3) to manage
airway obstruction of various aetiology (e.g. such as mucous plugs, foreign bodies and benign/
malignant tracheobronchial diseases) [3, 4, 13], and 4) to manage massive haemoptysis [14].

Acute bronchoscopy in the bronchoscopy unit

Pneumonia

Even if FBO is not routinely recommended in nonventilated patients with suspected or

known severe community-acquired (CAP) or hospital-acquired pneumonia (HAP) because
its risks may outweigh the benefit of determining the responsible pathogen(s), early BAL
and/or PSB should be strongly considered in immunosuppressed patients and/or in patients
potentially infected with multidrug-resistant microorganisms [1, 8, 9].

Acute interstitial lung diseases

The two most common scenarios of acute interstitial lung diseases (ILDs) are: 1) rapid
deterioration of a previously diagnosed ILD and 2) initial presentation with rapidly
progressive ILD [10]. In the former scenario, the differential diagnosis should consider either
a progression of the known underlying ILD, or a superimposed infection or other

Table 1. Indications for acute bronchoscopy

Bronchoscopy unit Intensive care settings

Diagnostic tool Diagnostic tool

Acute intrathoracic tumours Ventilator-associated pneumonia
Severe community/hospital-acquired Severe community/hospital-acquired
pneumonia pneumonia#
Acute interstitial lung diseases Acute interstitial lung diseases#
Therapeutic tool in airway obstruction Intrathoracic tumours#
Atelectasis due to mucous plug Therapeutic tool in airway obstruction
Benign or malignant central airway Atelectasis due to mucous plug#
obstruction Supportive tool for interventional procedures
Inhaled foreign body Endotracheal intubation in difficult airways
Management of massive haemoptysis Percutaneous dilatational tracheostomy
Positioning of double-lumen endotracheal
tube
Risky extubation
#
: in mechanically ventilated patients by means of noninvasive or invasive ventilation support.

210

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

noninfective causes. In the latter scenario, the acute presentation may represent the
exacerbation of a previously unrecognised ILD (e.g. idiopathic pulmonary fibrosis (IPF)) or a
“de novo” condition such as acute interstitial pneumonia, fulminant organising pneumonia,
acute eosinophilic pneumonia, or, less frequently, diffuse alveolar damage in occult
connective tissue disease, vasculitis or hypersensitivity pneumonia. However, the differential
diagnosis in “de novo” presentation should always consider processes other than primary ILD
(e.g. infection, cardiogenic pulmonary oedema, alveolar haemorrhage syndromes or
drug-induced pneumopathy). Considering the diagnostic flow chart in acute ILDs,
high-resolution CT should be always done before performing bronchoscopy to increase the
diagnostic yield of BAL and TBLB [10].

BAL plays a crucial role in the diagnosis of infective ILD, especially in immunosuppressed
patients [1, 15], and may be helpful for excluding infection in “acceleration” of IPF or other
ILDs [10, 16–18]. In the case of progression of known progressive fibrotic ILD, FBO
procedures are not appropriate and palliative approach is warranted [18].

The added value of TBLB in patients with acute respiratory failure (ARF) undergoing BAL
is controversial, especially in the case of known idiopathic ILDs [1, 10, 19–23]. Conversely,
in severely immunosuppressed patients with pulmonary infiltrates, granulomatous diseases
(e.g. sarcoidosis) and lymphangitis carcinomatosis, TBLB may be more diagnostically
sensitive than BAL [19, 21].

Transbronchial lung cryobiopsy (TBLC) has been recently proposed as a less invasive
alternative to surgical lung biopsy (SLB) in ILD [24]. TBLC yields larger and
better-preserved specimens as compared with TBLB, but smaller specimens than SLB.
Diagnostic yields, mortality and complication rates for TBLC fall somewhere between those
observed for TBLB and those observed for SLB [25, 26]. Despite its potential benefits, there
are no data regarding the use of TBLC in ARF [24–26]. In hypoxaemic patients, TBLC may
be safely performed under HFNC oxygen or NIV in units where its life-threatening
complications can be quickly treated.

Intrathoracic tumours

Challenges in performing acute FBO for the diagnosis and staging of intrathoracic tumours are
correlated with the presence of chronic respiratory failure, central airway obstruction (CAO),
severe bleeding, superior vena cava syndrome and extrapulmonary metastases [1, 13, 14, 27].

Severely hypoxaemic patients with/without hypercapnia may safely undergo diagnostic

bronchoscopy under the assistance of NIV or HFNC oxygen [28, 29]. Management of CAO
due to malignant infiltration and/or extrinsic compression (e.g. bulky adenopathies) and
treatment of severe haemoptysis are reported later in this chapter. The impaired systemic
venous return due to superior vena cava syndrome may facilitate FBO-correlated
haemorrhagic complications [27]. Furthermore, coexisting chronic cardiopulmonary
diseases and the use of anticoagulant and/or antiplatelet therapy increase the likelihood of
periprocedural hypoxaemia and bleeding, respectively [1]. The risk of neurological
complications (e.g. epilepsy and intracranial hypertension) during acute FBO is greater in
patients with cerebral metastases for whom a prophylactic treatment should be considered.
In the case of liver and/or renal failure, doses of sedatives and local lidocaine should be
carefully adjusted [1, 27].

211

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Haemoptysis

Massive haemoptysis causing ARF and/or haemodynamic instability is a life-threatening

emergency with a mortality ranging from 7% to 80% [14]. The usefulness of bronchoscopy
for the management of haemoptysis (e.g. identification of sources of bleeding and
endobronchial treatments) varies depending on the clinical scenario [30, 31].

CT and bronchoscopy should be performed in every case of haemoptysis, if the origin and
cause of the bleeding are not already known. In peripheral bleeding, diagnostic
bronchoscopy is necessary to identify the origin in order to guide either radiological
intervention with bronchial arterial coils or surgical resection. In life-threatening acute
bleeding, waiting for the CT scan is not recommended and the patient should be transferred
directly to the bronchoscopy unit [31]. The priority in patients with ongoing massive
haemoptysis is the immediate protection of the airways by means of endotracheal intubation
with either an endotracheal tube (ETT) or rigid bronchoscopy [3, 4, 32]. Performing FBO
through an ETT or rigid bronchoscopy may be helpful for suctioning and exploring the
bronchial tree as well as for implementing acute strategies to stop the bleeding. The bleeding
can be efficiently controlled by means of rigid (with or without flexible) bronchoscopy in
the case of peripheral bleeding (e.g. blocker balloon, tamponade or spigot) or central
bleeding (e.g. argon plasma coagulation or laser ablation) [31]. Interventional bronchoscopic
procedures are effective to manage massive bleeding of endoscopically visible bronchogenic
carcinoma [3, 4, 14].

Despite bronchoscopic instillation of adrenaline and other substances [33–35] and

endobronchial tamponade with balloon catheters [36] having been attempted to stop
bleeding, the efficacy of these empirical therapies is unproven [1, 14, 31]. Furthermore,
FBO may facilitate selective intubation of the unaffected lung with a single- or
double-lumen ETT [32, 37], thus buying time to address the bleeding in the affected lung.
In nonmassive haemoptysis, FBO is usually performed within 24–48 h in stable patients
[38]. Localisation of the site of bleeding can be achieved in a larger proportion of cases by
combining FBO with CT [39, 40]. FBO may also be useful when haemoptysis occurs in
invasively ventilated patients (e.g. diffuse alveolar haemorrhage).

Atelectasis

Despite the widespread clinical use of FBO in the bronchoscopy unit to treat atelectasis in
nonventilated patients, there are no published studies in favour of this practice [41]. This
does not mean that FBO is not indicated to remove mucous plugs, but simply that the
effectiveness of this procedure remains unproven [1]. In this scenario, FBO may be useful
to exclude the coexistence of benign or malignant endobronchial stenosis.

Central airway obstruction

In the case of malignant or benign CAO, patients should undergo interventional

bronchoscopy as early as possible in experienced hands before invasive mechanical ventilation
(IMV) becomes necessary. Interventional procedures lead to quick symptom relief and are
beneficial to enable further etiological therapy [13]. In patients with CAO of different
aetiologies necessitating IMV and admission to the ICU/RHDCU, preliminary data suggest
that rigid bronchoscopy procedures (i.e. ablative therapies and/or airway stenting) are a

212

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

feasible, safe and successful means of weaning from ventilation, providing potential benefits in
terms of prolonging survival, reducing hospital stay, allowing additional cancer treatments and
palliating symptoms [42–44].

Inhaled foreign bodies

In contrast to children, tracheobronchial foreign body aspiration is uncommon in adults

[45]. However, life-threatening ARF could be a dramatic presentation of foreign bodies in
adults, especially in those with dysphagia, neurological disorders, and alcohol and sedative
abuse [46]. The tracheobronchial tree should be quickly examined with FBO in all
suspected cases. The oral route should be used as foreign bodies may not pass through the
nasal cavity when retrieved from the tracheobronchial tree. FBO extraction should be
attempted by a trained physician in a setting where rigid bronchoscopy is readily feasible in
the case of CAO, failure, complications (e.g. haemorrhage and displacement) or need for
ventilatory support [46]. Physicians should be careful not to push foreign bodies more
distally during FBO extraction as it may become impossible to remove them
endoscopically, making thoracotomy necessary. Displacement of the foreign body or a
fragment of it into the contralateral lung or trachea with subsequent complete CAO is a
potentially lethal complication. Rigid bronchoscopy allows better control of the airway and
easier manipulation of foreign bodies with different types of forceps or cryotherapy probes
[45]. This is why foreign body extraction should be primarily performed using rigid
bronchoscopy whenever possible. Performing FBO through rigid bronchoscopy allows
identification of distal foreign bodies. FBO is preferable to rigid bronchoscopy in
mechanically ventilated patients or in the case of spine/craniofacial fractures that prevent
the manipulations required for rigid bronchoscopy [45]. The success rate of FBO extraction
in adults ranges from 60% to 90% [45–47].

Acute bronchoscopy in intensive care settings

Ventilator-associated pneumonia

Except for some scenarios (e.g. severe sepsis, multiorgan dysfunction and shock) for which
antibiotic therapy should not be delayed while awaiting microbiological results, all patients
with suspected ventilator-associated pneumonia (VAP) should undergo lower respiratory
tract sampling before any introduction/change of antibiotics [11, 12, 48]. In suspected VAP,
bronchoscopic or “invasive” (e.g. BAL and/or PSB) and nonbronchoscopic or “noninvasive”
techniques (e.g. tracheobronchial aspiration or mini-BAL) are used to obtain respiratory
samples [12, 49, 50]. Both “invasive” and noninvasive” samples can be analysed either
“quantitatively” with a threshold count of bacterial growth to differentiate between infection
and colonisation (e.g. PSB: 103 CFU·mL−1; BAL: 104 CFU·mL−1; endotracheal aspirates:
105 CFU·mL−1) or “qualitatively” ( presence or absence of pathogenic germs) [51, 52].
Uncontrolled studies [53–58] showed great heterogeneity (e.g. gold standard for diagnosis,
microbiological thresholds and employed techniques), a wide range of sensitivities of
bronchoscopic techniques (51–100%) and variable comparison with “noninvasive”
techniques [1]. A recent systematic review [12], including five RCTs [55, 59–62] for a total
of 1367 immunocompetent patients with VAP, did not show any significant differences in
mortality rates, influence on antibiotic change, days of IMV and length of ICU stay
between either “quantitative” versus “qualitative” analysis or “invasive” versus “noninvasive”
sampling techniques. According to the evidence, FBO should be considered only if

213

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

“noninvasive” techniques fail to identify a responsible organism. The available data do not
address the issue of diagnosis of “non-VAP” in ventilated patients (e.g. severe CAP that
requires subsequent ventilation) [1, 12] (figure 1).

Acute interstitial lung diseases

The choice of admitting acute ILD patients in the ICU/RHDCU and performing FBO
procedures is strongly dependent on the likelihood of a successful outcome, based on
reasonable clinical judgement and a high-resolution CT pattern showing that the
underlying ILD (“non-IPF” diseases) and/or the superimposed trigger (e.g. opportunistic
infection) are likely to be reversible [10]. Evidence of extensive fibrotic alterations or of an
“IPF pattern” without superimposed acute disease usually indicates that FBO procedures
and IMV are highly unlikely to be successful [18].

Similar to its use in the bronchoscopy unit, BAL plays a crucial role in the ICU for the
diagnosis of infection in either previously known ILDs or in “de novo” ILDs, especially in
high-risk conditions (e.g. neutropenia, immunosuppressive therapy and haematological
malignancies) [10]. Moreover, BAL may be helpful in excluding infection and supporting
the diagnosis of “acceleration” of a known IPF [10, 18]. BAL may also be safely performed
under NIV in severely hypoxaemic ILD patients [28, 63]. BAL findings may be useful in
the delicate decision-making process dealing with withholding or withdrawing ventilation.
The added value of TBLB to BAL in ILD patients admitted to the ICU/RHDCU should be
carefully weighed against its potential risks [10, 18]. In nonintubated patients, the rate of
TBLB complications (e.g. pneumothorax and haemorrhage) may be acceptable (<5%)
assuming that SLB could be avoided. Conversely, pneumothorax following TBLB in IMV
patients may lead to life-threatening deterioration in gas exchange [22]. In a series of 13
invasively ventilated patients with progressive infiltrates [20], TBLB established the
diagnosis in six cases, but significant complications occurred in four cases (n=2
pneumothorax requiring drainage, n=1 pulmonary haemorrhage and n=1 arrhythmia). On
the basis of this limited evidence, TBLB should be used cautiously in highly selected IMV
patients. In a pilot study [63], TBLB allowed a definite diagnosis in five out six severely
hypoxaemic ILD patients (n=2 malignancy, n=1 lymphoma, n=1 sarcoidosis and n=1
Pneumocystis pneumonia) requiring NIV, with one subject intubated for haemoptysis.

Suspected CAP/HAP Suspected VAP

High-risk hosts? “Noninvasive” techniques

(Immunosuppressed status, MDR) are conclusive?

No Yes Yes No

“Noninvasive” FBO “Noninvasive” FBO

management sampling management sampling

Figure 1. Role of bronchoscopic techniques in the diagnosis of pneumonia in nonventilated and ventilated
patients. CAP: community-acquired pneumonia; HAP: hospital-acquired pneumonia; VAP: ventilator-associated
pneumonia; MDR: multidrug resistance; FBO: flexible bronchoscopy.

214

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

Intrathoracic tumours

The risk of performing FBO in IMV patients with suspected lung cancer is correlated with
the patient’s condition, reduced calibre of the ETT and complications of bronchoscopic
sampling [1]. Concerning the latter, while TBLB may be associated with catastrophic
complications in IMV patients, this is not the case for TBNA. In a retrospective study of
eight invasively ventilated patients with abnormal lymph nodes [64], TBNA showed a
sensitivity of 83% and a specificity of 100%; in five cases (63%), TBNA led to a change in
management without complications. Even though there are no available data in ARF,
endobronchial ultrasound-guided TBNA could be easily performed in ventilated patients
and is of higher diagnostic value than “blind” TBNA [65].

Atelectasis

Although FBO is widely used to treat atelectasis due to mucous plugs in intubated patients,
the evidence for its usefulness is scant [1, 41]. Small case series [66–68] reported variable
success rates (19–89%) of FBO in IMV patients, showing a better response for lobar than
for subsegmental atelectasis. Some earlier studies suggested, but did not prove, that BAL or
high-pressure insufflations though a balloon-tipped catheter may be of additional benefit to
reverse atelectasis [1, 41]. Two small RCTs [69, 70] performed in intubated patients
demonstrated a similar efficacy of FBO versus aggressive chest physiotherapy either for
prevention of post-lobectomy atelectasis or as treatment for atelectasis after physiotherapy
failure [71, 72]. Accordingly, FBO may be considered only in selected intubated patients
who develop lobar atelectasis that does not resolve with physiotherapy [1, 41].

Difficult intubation

Intubation with FBO (i.e. fibreoptic intubation (FOI)) is considered a mainstay of

anticipated and unanticipated elective difficult airways management in awake,
spontaneously breathing patients [5, 71–73]. The advantages of FOI over the other
techniques are particularly evident in patients with cervical spine injury, such as
maintenance of the head and neck in a neutral position, reduction of the risk of aspiration,
identification of a coexistent airway trauma, and avoidance of complications due to
incorrect ETT placement [74, 75]. In comparative studies, no differences was seen in terms
of the rate of successful intubation between FOI and other techniques, such as a laryngeal
mask airway (LMA) and video laryngoscopy; conversely, FOI was associated with longer
intubation times and a higher incidence of hypoxaemia [76–78]. In clinical scenarios in
which nonemergency intubation is deemed necessary and mask or supraglottic ventilation
(e.g. a LMA) is unlikely to be successful or poses an aspiration risk, awake FOI is
recommended because the drawbacks of general anaesthesia are avoided (e.g. inadequate
ventilation and loss of upper airway patency) [5]. Pitfalls of FOI in an emergency should be
carefully considered (table 2). The success and safety of FOI presuppose adequate time for
preparation, a cooperative spontaneously breathing patient, as well as experience in
handling FBO. Consequently, this technique is not indicated in an anticipated “cannot
intubate/cannot ventilate” situation. In acute patients who require immediate intubation
(e.g. severe respiratory distress, impending respiratory arrest, cardiovascular instability and
burden of airway secretions), it is crucial to assess the feasibility of either bag manual
ventilation or NIV to safely support patients during FOI. In the case of an unanticipated

215

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 2. Indications of intubation under the guidance of flexible bronchoscopy and pitfalls in the
emergency setting

Indications
Known or suspected difficult laryngoscopy (e.g. macroglossia, limited mouth opening, receding
lower jaw, short thyromental distance, protruding teeth, Mallampati class III/IV and obesity)
Known or suspected cervical spine instability
Anatomic abnormalities (e.g. congenital airway deformities, head and neck malformations,
and cancers)
Head, neck, spine and upper airway trauma
Pitfalls
Time-consuming procedure requiring expertise in handling the bronchoscope
Not a feasible procedure in “cannot intubate/cannot ventilate” scenarios
Need for adequate oxygenation and ventilation (i.e. manual bag ventilation, noninvasive
ventilation and ventilation via supraglottic devices) during the procedure
High risk of failure in the case of deep analgo-sedation due to reduced airway
visibility (i.e. tongue obstruction)

“cannot intubate/cannot ventilate” condition, FOI should be attempted only when

ventilation may be guaranteed with supraglottic devices [5, 77, 78].

FOI can be performed in awake patients with topical anaesthesia alone using the
“spray-as-you-go” technique [5, 79]. Analgo-sedation may be considered judiciously [5, 80–
82]. If “conscious sedation” with preserved spontaneous breathing increases the patient’s
cooperation and facilitates FOI, a deeper sedation may cause fall back of the tongue with
reduced airway visibility and severe hypoxaemia. Concerning the route of access, the nasal
approach is anatomically favourable in that the laryngeal opening is more easily seen with
the fibrescope [5], particularly in patients with a large tongue, limited mouth opening,
receding lower jaw or tracheal deviation. If nasal introduction is difficult, the oral route
should be chosen to prevent bleeding. If performed orally, FOI may be facilitated by either
manual manoeuvres (e.g. jaw thrust and tongue protrusion), or various oral bite blocks,
intubating airway and supraglottic devices or a laryngoscope blade [5, 77]. Additionally,
specialised face masks allow oxygen administration, and manual masks and NIV maintain
ventilation during FOI attempts. For both nasal and oral access, a video laryngoscope or
rigid/semirigid bronchoscope can be used in combination with FBO to perform the
intubation under direct vision, thereby avoiding airway trauma [5]. Adequate size matching
between the ETT and the external diameter of the bronchoscope (gap ⩽1.5 mm) permits
less play between them and may avoid the ETT becoming caught at the level of the
epiglottis or the arytenoid cartilages [5]. Any resistance to advancement should be
overcome by rotating the ETT 90° counterclockwise. Potential complications of FOI include
epistaxis, laryngotracheal trauma, laryngospasm, gastric distention and aspiration [5].

Tracheostomy and other applications

PDT has almost completely replaced surgical tracheostomy in the ICU/RHDCU because of
its advantages, such as bedside feasibility and fewer complications (e.g. haemorrhage,
pneumothorax, emphysema, tracheomalacia and stenosis). Compared with the “blinded”
manoeuvre, “FBO-guided” PDT reduces the rate of pneumothorax, uncorrected placement
of cannulae and tracheal back wall damage [6, 7]. Furthermore, FBO prevents accidental
extubation, allows removal of secretions and treats endobronchial haemorrhage [6, 7, 83].

216

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

However, there are some pitfalls of “FBO-guided” PDT: 1) hypercarbia with increased
intracranial pressure in neurological patients, 2) risk of bleeding or malplacement in
patients with difficult anatomy, coagulopathy, obesity or previous tracheostomy and 3) high
repair costs due to accidental needle puncture of the bronchoscope [84]. Real-time
ultrasound guidance is a safer alternative to FBO in these high-risk conditions [6, 83, 84].

Among other applications, FBO is helpful for positioning double-lumen ETTs,

endobronchial blockers, tubes and stents in patients with CAO and massive haemoptysis.
FBO is also useful in risky extubation, specifically to assess pharyngeal airway swelling,
vocal cord function and subglottic stenosis [85].

Pitfalls and remedies of bronchoscopy in nonventilated and

ventilated patients

Bronchoscopy in nonventilated patients

FBO induces important cardiopulmonary effects in nonintubated patients (figure 2) [1, 2, 4,

86–88]. By occupying 10–20% of the normal tracheal lumen, FBO increases airway resistance
and causes “air trapping” (i.e. intrinsic PEEP), both of which may reduce gas exchange and
augment work of breathing. FBO-induced hypoxaemia becomes worse when BAL is
performed and suction is applied, due to ventilation–perfusion mismatch and end-expiration

Trachea

80–90%

10–20%
Flexible
bronchoscope

Change from laminar to

Bronchospasm
turbulent flow
Air
trapping
Airway
resistance

Heart Work of
workload breathing Elastance

BAL
PaO2
Sedation PaCO2 Suction

Figure 2. Pathophysiology of cardiopulmonary changes during bronchoscopy.

217

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

alveolar closure, respectively. FBO causes PaO2 to decrease by 10–20 mmHg [1, 2, 4, 86–88].
Additionally, analgo-sedation during FBO may induce hypoventilation [89]. These
pulmonary changes persist after the procedure and the time that the gas exchange takes to
normalise ranges from 15 min in normal subjects to >24 h in patients with cardiopulmonary
diseases [90]. Furthermore, bleeding and pneumothorax complicating biopsy procedures may
precipitate life-threatening ARF [1, 2, 87]. FBO-induced sympathetic stimulation and
hypoxaemia could increase cardiac output. Decreased intrathoracic pressure caused by the
augmented respiratory muscle effort produces an increase in right ventricular preload and
left ventricular afterload. Consequently, FBO may trigger cardiac arrhythmias, and, less
frequently, cardiogenic pulmonary oedema and acute coronary syndrome [91]. These
cardiopulmonary changes are more exaggerated during rigid bronchoscopy procedures
because of the greater size of the instrument, prolonged suctioning, low FIO2 (to prevent
combustion hazard during laser resection) and deeper analgo-sedation [92].

Despite these relevant cardiopulmonary effects, the findings of the studies evaluating the
risks of FBO in hypoxaemic nonventilated patients are contrasting [87, 88]. It was reported
that BAL performed in the ICU did not significantly increase intubation requirements in
critically ill cancer patients, as compared with “noninvasive” diagnostic tests [93]. In a
prospective study performed in 169 nonintubated hypoxaemic patients undergoing FBO, a
third of the procedures were complicated by increased ventilatory support: NIV for
“oxygen-supported” patients and IMV for “noninvasively supported” patients. Intubation
was required in 15% of cases, but it occurred 2 h after FBO in 4% of cases [94].
Nevertheless, FBO is not recommended if hypoxaemia cannot be corrected to at least PaO2
75 mmHg or to SpO2 >90% with supplemental oxygen [1, 95]. When FBO is mandatory,
IMV can ensure adequate ventilation during the manoeuvre, but exposes patients to the risk
of severe complications (e.g. baro/volutrauma, VAP and prolonged weaning) [1, 28, 87].

Bronchoscopy during NIV

There is a strong pathophysiological rationale for combining FBO and NIV in critically ill
patients because the limitations of one technique may be counterbalanced by the properties
of the other [28, 87]. NIV prevents FBO-induced cardiopulmonary alterations by means of
unloading respiratory muscles, and improving gas exchange and heart performance.
Moreover, keeping the patient on NIV after FBO may prevent the risk of post-procedural
pulmonary complications. Conversely, thanks to the possibility of clearing the airways
under NIV, FBO may improve gas exchange and, potentially, reduce the need for
endotracheal intubation [87].

The literature [63, 96–113] reports different acute scenarios of synergistic interaction
between FBO and NIV (figure 3).

The majority of the published studies used NIV (with the inclusion of CPAP) to prevent
respiratory deterioration in spontaneously breathing ARF patients undergoing diagnostic
FBO (table 3) [63, 96–113]. Most of them were uncontrolled heterogeneous studies in
terms of severity and type of ARF, underlying diseases, setting of treatment, modes of
ventilation, NIV interface, method of performing FBO during NIV and FBO procedures.
Rates of success in avoiding intubation varied from 89% to 100%. Two RCTs compared the
efficacy and safety of NIV versus oxygen in “assisting” nonventilated patients receiving
FBO. In the first RCT conducted on 30 patients (PaO2 ⩽125 mmHg under an oxygen

218

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

T/D-FBO
Severe FBO intubation
under NIV

Stage of ARF
D-FBO
Moderate
under NIV

Mild D-FBO
under NIV

Oxygen NIV

Baseline support

Figure 3. Different acute scenarios of a synergistic interaction between flexible bronchoscopy (FBO) and NIV.
Mild: pH >7.35 and/or PaO2/FIO2 200–300 mmHg; moderate: pH 7.25–7.35 and/or PaO2/FIO2 100–200 mmHg;
severe: pH <7.25 and PaO2/FIO2 <100 mmHg. ARF: acute respiratory failure; D: diagnostic; T: therapeutic.
Modified from [87].

mask) with suspected pneumonia, MAITRE et al. [98] showed significantly higher SpO2
values during and 30 min after FBO with CPAP compared with oxygen therapy. Not only
did the patients in the oxygen group develop hypoxaemia during FBO, but five patients in
the oxygen group (compared with none in the CPAP group) also required ventilatory
assistance within 6 h following the procedure. In another RCT involving 26 patients with
HAP (PaO2/FIO2 ⩽200 mmHg), ANTONELLI et al. [99] reported that compared with the
oxygen group, the NIV group showed higher PaO2/FIO2 values during and 60 min after
FBO, as well as lower heart rate and mean arterial pressure values after FBO. One patient
in the NIV group and two patients in the oxygen group required nonemergency intubation.
Accordingly, prophylactic NIV is able to ensure adequate gas exchange during FBO in
spontaneously breathing hypoxaemic patients, thus preventing intubation [1, 87].

Two uncontrolled studies [103, 104] investigated the feasibility, effectiveness and safety of
FBO with BAL in hypoxaemic patients (PaO2/FIO2 <200 mmHg) requiring NIV before the
procedure. The rate of intubation at 48 h after FBO was much higher (39–45%) than that
reported in studies dealing with prophylactic NIV during FBO (0–11%). According to the
limited data, patients requiring NIV prior to FBO are at high risk of intubation and therefore
FBO should be considered only in selected cases if intubation is available promptly [1, 87].

One case–control study [105] reported the effectiveness of early therapeutic FBO to avoid
NIV failure for excessive secretions as compared with FBO after IMV in 30 acidotic COPD
patients with hypercapnic encephalopathy. 2 h of NIV plus FBO significantly improved gas
exchange, “sensorium” and cough efficiency without major complications. Improvement in
acidosis, as well as hospital mortality, and durations of hospitalisation and ventilation were
similar in the NIV-FBO versus IMV-FBO group. The NIV-FBO strategy significantly
reduced infectious complications and requirement for tracheostomy. Even if this strategy
may be a successful alternative to IMV in selected COPD patients, larger RCTs are
necessary to confirm this result.

219

FB:Cardiologia Siglo XXI

220

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 3. Studies evaluating the combined use of flexible bronchoscopy (FBO) and NIV in different acute respiratory failure (ARF) scenarios

First author Year Study Patients n Type of ARF and Support Indication for FBO ETI at 48 h %
[ref.] population pre-FBO FBO procedures

ANTONELLI [96] 1996 Prospective, NIV: 8 Hypoxaemic, Oxygen Diagnostic BAL NIV: 0
observational suspected pneumonia
DA CONCEICAO 2000 Prospective, NIV: 10 Hypoxaemic– Oxygen Diagnostic BAL NIV: 0
[97] observational hypercapnic, COPD
MAITRE [98] 2000 RCT Oxygen: 15; Hypoxaemic, Oxygen Diagnostic BAL, BB Oxygen: 46.7;
CPAP: 15 suspected pneumonia CPAP: 6.7
ANTONELLI [99] 2002 RCT Oxygen: 13; Hypoxaemic, Oxygen Diagnostic BAL Oxygen: 15.4;
NIV: 13 suspected pneumonia NIV: 7.7
BOURGAIN [106] 2007 RCT Oxygen: 16; Ear, nose and throat None Difficult ETI FBO-assisted NA
NIV: 16 surgery ETI
CHINER [101] 2010 Prospective, NIV: 35 Hypoxaemic, Oxygen Diagnostic BW, PSB, BAL, NIV: 0
observational miscellaneous BB
HEUNKS [102] 2010 Prospective, NIV: 12 Hypoxaemic, Oxygen Diagnostic BAL NIV: 8.3
observational miscellaneous
SCALA [105] 2010 Prospective, NIV: 15; Hypoxaemic– NIV Diagnostic/ BAL NIV: 20
case–control IMV: 15 hypercapnic, COPD therapeutic
BAUMANN [103] 2011 Prospective, NIV: 40 Hypoxaemic, NIV Diagnostic BAL NIV: 10
observational miscellaneous
CLOUZEAU [113] 2011 Prospective, NIV: 23 Hypoxaemic, NIV Diagnostic BAL NIV: 17.4
observational miscellaneous
AGARWALL [63] 2012 Prospective, NIV: 6 Hypoxaemic, acute Oxygen Diagnostic BAL, TBLB NIV: 1.7
observational ILDs
CRACCO [94] 2013 Prospective, Oxygen and Hypoxaemic, Oxygen and Diagnostic BAL Oxygen and
observational NIV: 169 miscellaneous NIV NIV: 15
BARJAKTAREVIC 2015 Prospective, NIV: 10 Hypoxaemic, NA NIV ETI in NIV FBO-assisted NA
[108] observational failure ETI
KORKMAZ EKREN 2016 Prospective, NIV: 28 Hypoxaemic, NIV Diagnostic BAL NIV: 39.3
[104] observational miscellaneous

ETI: endotracheal intubation; BB: bronchial biopsy; BW: bronchial washing; PSB: protected specimen brushing; IMV: invasive mechanical ventilation;
ILD: interstitial lung disease; TBLB: transbronchial lung biopsy; NA: not available.

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

The combined use of FBO and NIV may be useful to perform intubation in two contexts:
difficult airways and NIV failure. First, according to a RCT performed on 32 patients with
anticipated difficult intubation in ear, nose and throat surgery [106], NIV was more
effective than spontaneous breathing to improve ventilation during FOI performed under
propofol. This issue may be particularly critical in obstructive sleep apnoea syndrome
because of the risk of severe hypoxaemia due to upper airway collapse under sedation;
working as “functional airways stenting”, NIV/CPAP may facilitate FOI [109]. Second,
intubation is challenging in severely hypoxaemic patients who deteriorate under NIV due
to risk of major cardiovascular complications when the mask is removed [110]. Two small
pilot studies [107, 108] reported the feasibility and safety of FOI under sedation during
NIV in patients with either hypercapnic and/or hypoxaemic ARF who had developed NIV
failure. These preliminary findings require confirmation by large RCTs comparing
conventional versus FBO-guided intubation under NIV in patients with either predicted or
proven difficult direct laryngoscopy, or with NIV failure due severe hypoxaemia.

Synergistic use of rigid bronchoscopy and NIV has been reported in two RCTs [111, 112]
showing that as compared with both assisted spontaneous breathing and external
high-frequency oscillation, NIV delivered by a poncho-wrap to support rigid bronchoscopy
procedures under general anaesthesia was associated with lower incidence and severity of
acidosis, lower requirement for increased oxygen supply, lower use of opioids, shorter
recovery time, and reduced need for assisted manual ventilation. The applicability of this
technique is limited as these favourable results were obtained by only one expert centre.

Practical issues

NIV-assisted FBO may be performed not only in the ICU/RHDCU, but also in other
settings (i.e. the bronchoscopy unit) by physicians with expertise in both NIV and FBO
who could also deal with cardiopulmonary complications and airways management [28,
87]. In nonventilated patients, NIV should be initiated at least 15–20 min before FBO and
kept for 30–90 min after the procedure. The easiest mode of “assisting” FBO in hypoxaemic
patients consists of delivering CPAP by means of a Boussignac system with an orofacial
mask because this device remains open to the atmosphere [98]. When FBO is performed
under NIV, initial low levels of pressure support (i.e. 10 cmH2O) and PEEP (i.e. 5 cmH2O)
are suggested. With ICU ventilators (i.e. a double-tube circuit, ventilatory monitoring and
FIO2 setting), pressure support could be titrated in order to achieve an expiratory tidal
volume of 8–10 mL·kg−1 and respiratory rate <25 breaths·min−1. In the case of
hypoventilation, air leaks should be minimised; then, if the mask fitting is fine, pressure
support could be increased. FIO2 is set to achieve SpO2 >90%. Patients who remain
hypoxaemic despite high FIO2 and PEEP levels are not good candidates for NIV-assisted
FBO. Although many interfaces have been applied for NIV-FBO procedures, the most
widely used is the orofacial mask (figure 4). The bronchoscope could be introduced
through the nasal or oral route depending on the mask used and the operator’s experience
[28, 87]. The oral route requires direct introduction of the bronchoscope through a sealed
connector inserted between the mask and the circuit; a mouthpiece is recommended to
prevent damage to the instrument. Conversely, nasal access is challenging as the
bronchoscope has to be considerably manipulated with risks of injuring both the nasal
mucosa and instrument. In additional to topical anaesthesia, analgo-sedation may be
considered for facilitating NIV-assisted FBO [113]. Risks of the NIV-FBO approach are
related to both NIV (e.g. gastro-distension, pulmonary aspiration, hypoventilation and skin

221

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Figure 4. Flexible bronchoscopy under NIV assistance via a face mask.

breakdown) and FBO procedures (e.g. cardiovascular events, hypoxaemia, bleeding and
pneumothorax), as well to analgo-sedation [28, 87, 114].

Bronchoscopy during HFNC oxygen therapy

HFNC oxygen has been increasingly applied to different patterns of hypoxaemic ARF, due to
its advantages over conventional oxygen therapy (e.g. delivery of high FIO2, adequate
humidification, patient comfort and provision of low PEEP values) [115]. Few studies have
assessed HFNC oxygen during FBO [29, 115–117]. In a RCT comparing HFNC oxygen
versus conventional oxygen therapy in 45 mildly hypoxaemic patients undergoing FBO [116],
oxygenation was significantly better at the end of the procedure with HFNC oxygen at a
higher flow rate (60 L·min−1) compared with HFNC oxygen at a lower flow rate (40 L·min−1)
or oxygen through a Venturi mask. In another RCT [117], NIV was superior to HFNC
oxygen with regard to oxygenation before, during and after FBO performed in 40 patients
with moderate-to-severe hypoxaemia; no differences in intubation rate were observed at 24 h
after the FBO between patients treated with NIV and HFNC oxygen. Further evidence is
required to define the role of HFNC oxygen to support nonventilated patients during FBO.

Bronchoscopy during IMV

Cardiopulmonary changes induced by FBO are similar in spontaneously breathing and

invasively ventilated patients. During IMV, the degree of these effects is dependent on
the gap between the external diameter of the bronchoscope and the internal diameter of
the ETT/tracheostomy tube. Bronchoscopes in nonintubated patients occupy 10–20% of the
cross-sectional area of the trachea. In contrast, a 5.7-mm bronchoscope occupies 40% of a
9-mm ETT and 66% of a 7-mm ETT. Failure to recognise this matching may lead to
inadequate ventilation with “air trapping” and damage to the bronchoscope [1]. The LMA

222

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

accommodates a larger bronchoscope, generating lower flow resistance values than the
corresponding sizes of ETTs [118]. The external diameter of a bronchoscope should be
carefully selected according to the size and type of the airway device used during IMV
(ETT, tracheostomy tube or LMA) [1].

In IMV patients, pre-oxygenation with a FIO2 of 1.0 is recommended during and immediately
after FBO. The ventilator should be adjusted to a mandatory setting, avoiding triggered modes
that are not reliable in maintaining ventilation during FBO. The ventilator pressure limit
should be increased to ensure that adequate tidal volumes are delivered during each respiratory
cycle and the ventilator rate increased if necessary. A special swivel connector with a perforated
diaphragm, through which the bronchoscope can be inserted, allows maintenance of PEEP/
CPAP, which is crucial in severe ARDS patients [1]. Small studies [119–121] have supported
the use of jet and high-frequency positive-pressure ventilation during FBO in intubated
patients, but more RCTs are needed to confirm any potential benefit of these techniques.

FBO should be undertaken cautiously in ventilated patients with head injury, as intracranial
pressure may increase significantly due to carbon dioxide retention [122, 123]. A small
RCT [124] showed that hyperventilation is useful in reducing the rise in intracranial
pressure during FBO in IMV patients with closed head injury.

Conclusions

Bronchoscopy plays a fundamental role for the management of acute patients, both in
the bronchoscopy room and in the ICU/RHDCU. Knowledge of the pitfalls and indications
of bronchoscopy in ventilated and nonventilated patients is necessary to obtain the benefits
and avoid the potentially life-threatening complications. The setting where acute
bronchoscopy is performed should be able to adequately monitor patients, and to manage
airway difficulties and cardiopulmonary emergencies. Acute bronchoscopy is useful to
facilitate/guide procedures for airway management (e.g. FOI and PDT), support diagnosis
of lung infiltrates in nonventilated and ventilated patients (e.g. VAP and ILD), and manage
severe CAO and massive haemoptysis. Although the evidence that exists in favour of the
combined use of NIV and bronchoscopy in different scenarios is variable, the best evidence
supports prophylactic NIV to prevent intubation during FBO in nonventilated hypoxaemic
patients. The role of HFNC oxygen in “assisting” FBO needs to be further investigated.

References
1. Du Rand IA, Blaikley J, Booton R, et al. British Thoracic Society guideline for diagnostic flexible bronchoscopy in
adults: accredited by NICE. Thorax 2013; 68: Suppl. 1, i1–i44.
2. Dellinger RP, Bandi V. Fiberoptic bronchoscopy in the intensive care unit. Crit Care Clin 1992; 8: 755–772.
3. Wain JC. Rigid bronchoscopy: the value of a venerable procedure. Chest Surg Clin N Am 2001; 1: 691–699.
4. Wahidi MM, Herth FJ, Ernst A. State of the art: interventional pulmonology. Chest 2007; 131: 261–274.
5. Collins SR, Blank RS. Fiberoptic intubation: an overview and update. Respir Care 2014; 59: 865–878.
6. Cheung NH, Napolitano LM. Tracheostomy: epidemiology, indications, timing, technique, and outcomes.
Respir Care 2014; 59: 895–915.
7. Al-Ansari MA, Hijazi MH. Clinical review: percutaneous dilatational tracheostomy. Crit Care 2006; 10: 202.
8. Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society
Consensus Guidelines on the Management of Community-Acquired Pneumonia in Adults. Clin Infect Dis 2007;
44: Suppl. 2, S27–S72.
9. Lim WS, Baudouin SV, George RC, et al. BTS guidelines for the management of community acquired pneumonia
in adults: update 2009. Thorax 2009; 64: Suppl. 3, iii1–iii55.

223

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

10. Bradley B, Branley HM, Egan JJ, et al. Interstitial lung disease guideline: the British Thoracic Society in
collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax
2008; 63: Suppl. 5, v1–v58.
11. American Thoracic Society, Infectious Diseases Society of America. Guidelines for the management of adults with
hospital-acquired, ventilator-associated, and healthcare associated pneumonia. Am J Respir Crit Care Med 2005; 171:
388–416.
12. Berton DC, Kalil AC, Teixeira PJ. Quantitative versus qualitative cultures of respiratory secretions for clinical
outcomes in patients with ventilator-associated pneumonia. Cochrane Database Syst Rev 2014; 4: CD006482.
13. Murgu S, Egressy K, Laxmanan B, et al. Central airway obstruction: benign strictures, tracheobronchomalacia and
malignancy-related obstruction. Chest 2016; 150: 426–441.
14. Theron J, Diacon AH, Bolliger CT. Management of massive haemoptysis. In: Nava S, Welte T, eds. Respiratory
Emergencies (ERS Monograph). Sheffield, European Respiratory Society, 2006; pp. 95–107.
15. Stover DE, Zaman MB, Hajdu SI, et al. Bronchoalveolar lavage in the diagnosis of diffuse pulmonary infiltrates in
the immunosuppressed host. Ann Intern Med 1984; 101: 1–7.
16. Song JW, Hong SB, Lim CM, et al. Acute exacerbation of idiopathic pulmonary fibrosis: incidence, risk factors
and outcome. Eur Respir J 2011; 37: 356–363.
17. Ryerson CJ, Cottin V, Brown KK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the
paradigm. Eur Respir J 2015; 46: 512–520.
18. Papiris SA, Manali ED, Kolilekas L, et al. Clinical review: idiopathic pulmonary fibrosis acute exacerbations –
unravelling Ariadne’s thread. Crit Care 2010; 14: 246.
19. Cazzadori A, Di Perri G, Todeschini G, et al. Transbronchial biopsy in the diagnosis of pulmonary infiltrates in
immunocompromised patients. Chest 1995; 107: 101–106.
20. Pincus PS, Kallenbach JM, Hurwitz MD, et al. Transbronchial biopsy during mechanical ventilation. Crit Care
Med 1987; 15: 1136–1139.
21. Rao VK, Ritter J, Kollef MH. Utility of transbronchial biopsy in patients with acute respiratory failure:
a postmortem study. Chest 1998; 114: 549–555.
22. O’Brien JD, Ettinger NA, Shevlin D, et al. Safety and yield of transbronchial biopsy in mechanically ventilated
patients. Crit Care Med 1997; 25: 440–446.
23. Martin C, Papazian L, Payan MJ, et al. Pulmonary fibrosis correlates with outcome in adult respiratory distress
syndrome. A study in mechanically ventilated patients. Chest 1995; 107: 196–200.
24. Poletti V, Ravaglia C, Tomassetti S. Transbronchial cryobiopsy in diffuse parenchymal lung diseases. Curr Opin
Pulm Med 2016; 22: 289–296.
25. Sharp C, McCabe M, Adamali H, et al. Use of transbronchial cryobiopsy in the diagnosis of interstitial lung
disease – a systematic review and cost analysis. QJM 2016; in press [DOI: 10.1093/qjmed/hcw142].
26. Raparia K, Aisner DL, Allen TC, et al. Transbronchial lung cryobiopsy for interstitial lung disease diagnosis: a
perspective from members of the Pulmonary Pathology Society. Arch Pathol Lab Med 2016; 140: 1281–1284.
27. Detterbeck FC, Zelman Lewis S, Diekemper R, et al. Executive Summary: Diagnosis and management of lung
cancer, 3rd ed: American College of Chest Physicians evidence based clinical practice guidelines. Chest 2013; 143:
Suppl. 5, 7S–37S.
28. Esquinas A, Zuil M, Scala R, et al. Bronchoscopy during non-invasive mechanical ventilation: a review of
techniques and procedures. Arch Bronconeumol 2013; 49: 105–112.
29. Lomas C, Roca O, Alvarez A, et al. Fibroscopy in patients with hypoxemic respiratory insufficiency: utility of the
high-flow nasal cannula. Respir Med CME 2009; 2: 121–124.
30. Lordan JL, Gascoigne A, Corris PA. The pulmonary physician in critical care. Illustrative case 7: assessment and
management of massive haemoptysis. Thorax 2003; 58: 814–819.
31. Yendamuri S. Massive airway hemorrhage. Thorac Surg Clin 2015; 25: 255–260.
32. Conlan AA, Hurvitz SS. Management of massive hemoptysis with the rigid bronchoscope and cold saline lavage.
Thorax 1980; 35: 901–904.
33. Tüller C, Tüller D, Tamm M, et al. Hemodynamic effects of endobronchial application of ornipressin versus
terlipressin. Respiration 2004; 71: 397–401.
34. Tsukamoto T, Sasaki H, Nakamura H. Treatment of hemoptysis patients by thrombin and fibrinogen-thrombin
infusion therapy using a fiberoptic bronchoscope. Chest 1989; 96: 473–476.
35. de Gracia J, de la Rosa D, Catalan E, et al. Use of endoscopic fibrinogen-thrombin in the treatment of severe
hemoptysis. Respir Med 2003; 97: 790–795.
36. Freitag L, Telkolf E, Stamatis G, et al. Three years experience with a new balloon catheter for the management of
haemoptysis. Eur Respir J 1994; 7: 2033–2037.
37. Klein U, Karzai W, Bloos F, et al. Role of fiberoptic bronchoscopy in conjunction with the use of double-lumen
tubes for thoracic anesthesia: a prospective study. Anesthesiology 1998; 88: 346–350.
38. Jean-Baptiste E. Clinical assessment and management of massive haemoptysis. Crit Care Med 2000; 28: 1642–1647.

224

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

39. Dupree HJ, Lewejohann JC, Gleiss J, et al. Fiberoptic bronchoscopy of intubated patients with life-threatening
hemoptysis. World J Surg 2001; 25: 104–107.
40. Khalil A, Soussan M, Mangiapan G, et al. Utility of high-resolution chest CT scan in the emergency management
of haemoptysis in the intensive care unit: severity, localization and aetiology. Br J Radiol 2007; 80: 21–25.
41. Kreider ME, Lipson DA. Bronchoscopy for atelectasis in the ICU: a case report and review of the literature.
Chest 2003; 124: 344–350.
42. Colt HG, Harrell JH. Therapeutic rigid bronchoscopy allows level of care changes in patients with acute
respiratory failure from central airways obstruction. Chest 1997; 112: 202–206.
43. Boyd M, Rubio E. The utility of interventional pulmonary procedures in liberating patients with
malignancy-associated central airway obstruction from mechanical ventilation. Lung 2012; 190: 471–476.
44. Murgu S, Langer S, Colt H. Bronchoscopic intervention obviates the need for continued mechanical ventilation in
patients with airway obstruction and respiratory failure from inoperable non-small-cell lung cancer. Respiration
2012; 84: 55–61.
45. Baharloo F, Veyckemans F, Francis C, et al. Tracheobronchial foreign bodies: presentation and management in
children and adults. Chest 1999; 115: 1357–1362.
46. Delage A, Marquette CH. Airway foreign bodies: clinical presentation, diagnosis and treatment. In: Strausz J,
Bollinger CT, eds. Interventional Pulmonology (ERS Monograph). Sheffield, European Respiratory Society, 2010;
pp. 135–148.
47. Chen CH, Lai CL, Tsai TT, et al. Foreign body aspiration into the lower airway in Chinese adults. Chest 1997;
112: 129–133.
48. Bouza E, Burillo A, Cercenado E. New approaches to the aetiological diagnosis of VAP. In: Torres A, Ewig S, eds.
Nosocomial and Ventilator-Associated Pneumonia (ERS Monograph). Sheffield, European Respiratory Society,
2011; pp. 11–23.
49. de Jaeger A, Litalien C, Lacroix J, et al. Protected specimen brush or bronchoalveolar lavage to diagnose bacterial
nosocomial pneumonia in ventilated adults: a meta-analysis. Crit Care Med 1999; 27: 2548–2560.
50. Torres A, El-Ebiary M. Bronchoscopic BAL in the diagnosis of ventilator-associated pneumonia. Chest 2000; 117:
Suppl. 2, 198S–202S.
51. Bartlett JG, Finegold SM. Bacteriology of expectorated sputum with quantitative culture and wash technique
compared to transtracheal aspirates. Am Rev Respir Dis 1978; 117: 1019–1027.
52. Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 2002; 165: 867–903.
53. Pugin J, Auckenthaler R, Mili N, et al. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of
bronchoscopic and nonbronchoscopic ‘blind’ bronchoalveolar lavage fluid. Am Rev Respir Dis 1991; 143: 1121–1129.
54. Rodriguez de Castro F, Sole-Violan J, Aranda Leon A, et al. Do quantitative cultures of protected brush
specimens modify the initial empirical therapy in ventilated patients with suspected pneumonia? Eur Respir J
1996; 9: 37–41.
55. Sanchez-Nieto JM, Torres A, Garcia-Cordoba F, et al. Impact of invasive and noninvasive quantitative culture sampling
on outcome of ventilator-associated pneumonia: a pilot study. Am J Respir Crit Care Med 1998; 157: 371–376.
56. Souweine B, Veber B, Bedos JP, et al. Diagnostic accuracy of protected specimen brush and bronchoalveolar
lavage in nosocomial pneumonia: impact of previous antimicrobial treatments. Crit Care Med 1998; 6: 236–244.
57. Torres A, el-Ebiary M, Padro L, et al. Validation of different techniques for the diagnosis of ventilator-associated
pneumonia. Comparison with immediate postmortem pulmonary biopsy. Am J Respir Crit Care Med 1994; 149:
324–331.
58. Kirtland SH, Corley DE, Winterbauer RH, et al. The diagnosis of ventilator-associated pneumonia: a comparison
of histologic, microbiologic, and clinical criteria. Chest 1997; 112: 445–457.
59. Ruiz M, Torres A, Ewig S, et al. Noninvasive versus invasive microbial investigation in ventilator-associated
pneumonia: evaluation of outcome. Am J Respir Crit Care Med 2000; 162: 119–125.
60. Sole Violan J, Fernandez JA, Benitez AB, et al. Impact of quantitative invasive diagnostic techniques in the
management and outcome of mechanically ventilated patients with suspected pneumonia. Crit Care Med 2000;
28: 2737–2741.
61. Fagon JY, Chastre J, Wolff M, et al. Invasive and noninvasive strategies for management of suspected ventilator
associated pneumonia. A randomized trial. Ann Intern Med 2000; 132: 621–630.
62. The Canadian Clinical Care Trials Group. A randomized trial of diagnostic techniques for ventilator-associated
pneumonia. N Engl J Med 2006; 355: 2619–2630.
63. Agarwal R, Khan A, Aggarwal AN, et al. Bronchoscopic lung biopsy using noninvasive ventilatory support: case
series and review of literature of NIV-assisted bronchoscopy. Respir Care 2012; 57: 1927–1936.
64. Ghamande S, Rafanan A, Dweik R, et al. Role of transbronchial needle aspiration in patients receiving mechanical
ventilation. Chest 2002; 122: 985–989.
65. Dhooria S, Aggarwal AN, Gupta D, et al. Utility and safety of endoscopic ultrasound with bronchoscope-guided
fine-needle aspiration in mediastinal lymph node sampling: systematic review and meta-analysis. Respir Care
2015; 60: 1040–1050.

225

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

66. Haenel JB, Moore FA, Moore EE, et al. Efficacy of selective intrabronchial air insufflation in acute lobar collapse.
Am J Surg 1992; 164: 501–505.
67. Tsao TC, Tsai YH, Lan RS, et al. Treatment for collapsed lung in critically ill patients. Selective intrabronchial air
insufflation using the fiberoptic bronchoscope. Chest 1990; 97: 435–438.
68. Tabboush ZS, Ayash RH, Badran HM. When fiberoptic bronchoscopy is indicated in the management of
postoperative atelectasis. Acta Anaesthesiol Scand 1998; 42: 384.
69. Jaworski A, Goldberg SK, Walkenstein MD, et al. Utility of immediate postlobectomy fiberoptic bronchoscopy in
preventing atelectasis. Chest 1988; 94: 38–43.
70. Marini JJ, Pierson DJ, Hudson LD. Acute lobar atelectasis: a prospective comparison of fiberoptic bronchoscopy
and respiratory therapy. Am Rev Respir Dis 1979; 119: 971–978.
71. Henderson JJ, Popat MT, Latto IP, et al. Difficult airway society guidelines for management of the unanticipated
difficult intubation. Anaesthesia 2004; 59: 675–694.
72. Petrini F, Accorsi A, Adrario E, et al. Recommendations for airway control and difficult airway management.
Minerva Anestesiol 2005; 71: 617–657.
73. Apfelbaum JL, Hagberg CA, Caplan RA, et al. Practice guidelines for management of the difficult airway: an
updated report by the American Society of Anesthesiologists Task Force on Management of the Difficult Airway.
Anesthesiology 2013; 118: 251–270.
74. Houde BJ, Williams SR, Cadrin-Chênevert A, et al. A comparison of cervical spine motion during orotracheal
intubation with the Trachlight or the flexible fiberoptic bronchoscope. Anesth Analg 2009; 108: 1638–1643.
75. Cleiman P, Nemeth J, Vetere P. A significant cervical spine fracture: think of the airway. J Emerg Med 2012; 42:
e23–e25.
76. Langeron O, Semjen F, Bourgain JL, et al. Comparison of the intubating laryngeal mask airway with the fiberoptic
intubation in anticipated difficult airway management. Anesthesiology 2001; 94: 968–972.
77. Dhar P, Osborn I, Brimacombe J, et al. Blind orotracheal intubation with the intubating laryngeal mask versus
fiberoptic guided orotracheal intubation with the Ovassapian airway. A pilot study of awake patients.
Anaesth Intensive Care 2001; 29: 252–254.
78. Aoyama K, Yasunaga E, Takenaka I, et al. Positive pressure ventilation during fiberoptic intubation: comparison of the
laryngeal mask airway, intubating laryngeal mask and endoscopy mask techniques. Br J Anaesth 2002; 88: 246–254.
79. Simmons ST, Schleich AR. Airway regional anesthesia for awake fiberoptic intubation. Reg Anesth Pain Med 2002;
27: 180–192.
80. Bergese SD, Bender SP, McSweeney TD, et al. A comparative study of dexmedetomidine with midazolam and
midazolam alone for sedation during elective awake fiberoptic intubation. J Clin Anesth 2010; 22: 35–40.
81. Puchner W, Egger P, Puhringer F, et al. Evaluation of remifentanil as single drug for awake fiberoptic intubation.
Acta Anaesthesiol Scand 2002; 46: 350–354.
82. Pean D, Floch H, Beliard C, et al. Propofol versus sevoflurane for fiberoptic intubation under spontaneous
breathing anesthesia in patients difficult to intubate. Minerva Anestesiol 2010; 76: 780–786.
83. Cabrini L, Monti G, Landoni G, et al. Percutaneous tracheostomy, a systematic review. Acta Anaesthesiol Scand
2012; 56: 270–281.
84. Rudas M, Seppelt I, Herkes R, et al. Traditional landmark versus ultrasound guided tracheal puncture during
percutaneous dilatational tracheostomy in adult intensive care patients: a randomised controlled trial. Crit Care
2014; 18: 514.
85. Campos JH. Update on tracheobronchial anatomy and flexible fiberoptic bronchoscopy in thoracic anesthesia.
Curr Opin Anaesthesiol 2009; 22: 4–10.
86. Lindholm CE, Ollman B, Snyder J, et al. Flexible fiberoptic bronchoscopy in critical care medicine. Diagnosis,
therapy and complications. Crit Care Med 1974; 2: 250–261.
87. Scala R. Flexible bronchoscopy during non-invasive positive pressure mechanical ventilation: are two better than
one? Panminerva Med 2016; 58: 211–221.
88. Murgu SD, Pecson J, Colt HG. Bronchoscopy during noninvasive ventilation: indications and technique.
Respir Care 2010; 55: 595–600.
89. Dreher M, Ekkernkamp E, Storre JH, et al. Sedation during flexible bronchoscopy in patients with pre-existing
respiratory failure: midazolam versus midazolam plus alfentanil. Respiration 2010; 79: 307–314.
90. Bauer TT, Torres A, Ewig S, et al. Effects of bronchoalveolar lavage volume on arterial oxygenation in
mechanically ventilated patients with pneumonia. Intensive Care Med 2001; 27: 384–393.
91. Katz AS, Michelson EL, Stawicki J, et al. Cardiac arrhythmias, frequency during fiberoptic bronchoscopy and
correlation with hypoxemia. Arch Intern Med 1981; 141: 603–606.
92. Vitacca M, Natalini G, Cavaliere S, et al. Breathing pattern and arterial blood gases during Nd-YAG laser
photoresection of endobronchial lesions under general anesthesia: use of negative pressure ventilation:
a preliminary study. Chest 1997; 112: 1466–1473.
93. Azoulay E, Mokart D, Lambert J, et al. Diagnostic strategy for hematology and oncology patients with acute
respiratory failure: randomized controlled trial. Am J Respir Crit Care Med 2010; 182: 1038–1046.

226

FB:Cardiologia Siglo XXI

 ACUTE BRONCHOSCOPY | R. SCALA

94. Cracco C, Fartoukh M, Prodanovic H, et al. Safety of performing fiberoptic bronchoscopy in critically ill
hypoxemic patients with acute respiratory failure. Intensive Care Med 2013; 39: 45–52.
95. Goldstein RA, Rohatgi PK, Bergofsky EH, et al. Clinical role of bronchoalveolar lavage in adults with pulmonary
disease. Am Rev Respir Dis 1990; 142: 481–486.
96. Antonelli M, Conti G, Riccioni L, et al. Noninvasive positive-pressure ventilation via face mask during
bronchoscopy with BAL in high-risk hypoxemic patients. Chest 1996; 110: 724–728.
97. Da Conceiçao M, Genco G, Favier JC, et al. Fiberoptic bronchoscopy during noninvasive positive-pressure
ventilation in patients with chronic obstructive lung disease with hypoxemia and hypercapnia. Ann Fr Anesth
Reanim 2000; 19: 231–236.
98. Maitre B, Jaber S, Maggiore SM, et al. Continuous positive airway pressure during fiberoptic bronchoscopy in
hypoxemic patients. A randomized double-blind study using a new device. Am J Respir Crit Care Med 2000; 162:
1063–1067.
99. Antonelli M, Conti G, Rocco M, et al. Noninvasive positive-pressure ventilation vs conventional oxygen
supplementation in hypoxemic patients undergoing diagnostic bronchoscopy. Chest 2002; 121: 1149–1154.
100. Antonelli M, Pennisi MA, Conti G, et al. Fiberoptic bronchoscopy during noninvasive positive pressure
ventilation delivered by helmet. Intensive Care Med 2003; 29: 126–129.
101. Chiner E, Sancho-Chust JN, Llombart M, et al. Fiberoptic bronchoscopy during nasal non-invasive ventilation in
acute respiratory failure. Respiration 2010; 80: 321–326.
102. Heunks LM, de Bruin CJ, van der Hoeven JG, et al. Noninvasive mechanical ventilation for diagnostic
bronchoscopy using a new face mask: an observational feasibility study. Intensive Care Med 2010; 36: 143–147.
103. Baumann HJ, Klose H, Simon M, et al. Fiber optic bronchoscopy in patients with acute hypoxemic respiratory
failure requiring noninvasive ventilation – a feasibility study. Crit Care 2011; 15: R179.
104. Korkmaz Ekren P, Basarik Aydogan B, Gurgun A, et al. Can fiberoptic bronchoscopy be applied to critically ill
patients treated with noninvasive ventilation for acute respiratory distress syndrome? Prospective observational
study. BMC Pulm Med 2016; 16: 89.
105. Scala R, Naldi M, Maccari U. Early fiberoptic bronchoscopy during non-invasive ventilation in patients with
decompensated chronic obstructive pulmonary disease due to community-acquired-pneumonia. Crit Care 2010;
14: R80.
106. Bourgain JL, Billard V, Cros AM. Pressure support ventilation during fibreoptic intubation under propofol
anaesthesia. Br J Anaesth 2007; 98: 136–140.
107. Da Conceiçao M, Favier JC, Bidallier I, et al. Fiberoptic intubation with non-invasive ventilation with an
endoscopic facial mask. Ann Fr Anesth Reanim 2002; 21: 256–262.
108. Barjaktarevic I, Berlin D. Bronchoscopic intubation during continuous nasal positive pressure ventilation in the
treatment of hypoxemic respiratory failure. J Intensive Care Med 2015; 30: 161–166.
109. Corso RM, Gregoretti C, Braghiroli A, et al. Practice guidelines for the perioperative management of patients with
obstructive sleep apnea: navigating through uncertainty. Anesthesiology 2014; 121: 664–665.
110. Delclaux C, L’Her E, Alberti C, et al. Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency
with continuous positive airway pressure delivered by a face mask: a randomized controlled trial. JAMA 2000;
284: 2352–2360.
111. Natalini G, Cavaliere S, Vitacca M, et al. Negative pressure ventilation vs. spontaneous assisted ventilation during
rigid bronchoscopy. A controlled randomised trial. Acta Anaesthesiol Scand 1998; 42: 1063–1069.
112. Natalini G, Cavaliere S, Seramondi V, et al. Negative pressure ventilation vs external high frequency oscillation
during rigid bronchoscopy. A controlled randomized trial. Chest 2000; 118: 18–23.
113. Clouzeau B, Bui HN, Guilhon E, et al. Fiberoptic bronchoscopy under noninvasive ventilation and propofol
target-controlled infusion in hypoxemic patients. Intensive Care Med 2011; 37: 1969–1975.
114. Murgu SD, Pecson J, Colt HG. Flexible bronchoscopy assisted by noninvasive positive pressure ventilation.
Crit Care Nurse 2011; 31: 70–76.
115. Papazian L, Corley A, Hess D, et al. Use of high-flow nasal cannula oxygenation in ICU adults: a narrative
review. Intensive Care Med 2016; 42: 1336–1349.
116. Simon M, Braune S, Frings D, et al. High-flow nasal cannula oxygen versus non-invasive ventilation in patients
with acute hypoxaemic respiratory failure undergoing flexible bronchoscopy – a prospective randomised trial.
Crit Care 2014; 18: 712.
117. Lucangelo U, Vassallo FG, Marras E, et al. High-flow nasal interface improves oxygenation in patients undergoing
bronchoscopy. Crit Care Res Pract 2012; 2012: 506382.
118. Brimacombe J, Dunbar-Reid K. The effect of introducing fibreoptic bronchoscopes on gas flow in laryngeal masks
and tracheal tubes. Anaesthesia 1996; 51: 923–928.
119. MacIntyre NR, Ramage JE, Follett JV. Jet ventilation in support of fiberoptic bronchoscopy. Crit Care Med 1987;
15: 303–307.
120. Ramanathan S, Sinha K, Arismendy J, et al. Humidification and airway pressures during high-frequency jet ventilation
delivered through the suction-biopsy channel of a flexible bronchofiberscope. Crit Care Med 1984; 12: 820–823.

227

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

121. Flatau E, Lewinsohn G, Konichezky S, et al. Mechanical ventilation in fiberoptic-bronchoscopy: comparison

between high frequency positive pressure ventilation and normal frequency positive pressure ventilation. Crit Care
Med 1982; 10: 733–735.
122. Kerwin AJ, Croce MA, Timmons SD, et al. Effects of fiberoptic bronchoscopy on intracranial pressure in patients
with brain injury: a prospective clinical study. J Trauma 2000; 48: 878–882.
123. Peerless JR, Snow N, Likavec MJ, et al. The effect of fiberoptic bronchoscopy on cerebral hemodynamics in
patients with severe head injury. Chest 1995; 108: 962–965.
124. Previgliano IJ, Ripoll PI, Chiappero G, et al. Optimizing cerebral perfusion pressure during fiberoptic
bronchoscopy in severe head injury: effect of hyperventilation. Acta Neurochir Suppl 2002; 81: 103–105.

Disclosures: None declared.

228

FB:Cardiologia Siglo XXI

 | Chapter 16
Chest tube insertion
Sanjay Adlakha, Mark Roberts and Nabeel Ali

Chest tube placement into the pleural cavity is performed to drain abnormal collections of air
or fluid, or as a means to instil medications to perform pleurodesis. The choice of chest tube
and insertion site depends on the indication for placement and the nature of the fluid/air to
be drained. Small drains should be used for pneumothorax, free-flowing pleural effusions and
pleural infection, and analgesia should be considered as a pre-medication. It is strongly
recommended that all chest tubes for fluid should be inserted under image guidance. The
tube should be inserted using full aseptic technique, and substantial force should never be
used. Blunt dissection should be employed in cases of trauma or insertion of large-bore
drains. Chest tubes should be managed on wards familiar with their management, and
checked daily for fluid drainage volumes and any signs of wound infection, and documented
for swinging and/or bubbling. The chest tube should be removed once pneumothorax has
resolved and fluid drainage has decreased to <200 mL per day.

C hest tube insertion is a procedure in which a tube is placed through the chest wall into
the pleural cavity, primarily to drain an air, fluid or blood collection from the pleural
space.

Hippocrates’ writings described how open drainage of the thorax was frequently performed
in the fifth century BC [1]. The first clear evidence of a chest tube procedure can be found
in Wolfram von Eschenbach’s Parzival, written between 1210 and 1220 [2]. In 1873,
Playfair first described the closed drainage of the pleura in a 7-year-old child suffering from
thoracic empyema [3]. Following the First World War, rib resection and open drainage was
attempted, but it was not until the late 1950s that tube drainage became widely used [4, 5].

Insertion of a chest tube is a relatively simple procedure but with the potential to cause
significant morbidity and mortality if performed by inexperienced doctors [6]. Elective chest
tube insertion should be avoided out of normal hours, except in the case of significant
respiratory or cardiovascular compromise, because the rate of complications is higher [7].

Here, we will review the indications and contraindications and use of imaging for chest
tube insertion, and the techniques, management and complications of chest tubes.

Dept of Respiratory Medicine, Sherwood Forest Hospitals NHS Foundation Trust, Sutton in Ashfield, UK.

Correspondence: Nabeel Ali, Dept of Respiratory Medicine, King’s Mill Hospital, Mansfield Road, Sutton in Ashfield, NG17 4JL, UK.
E-mail: nabeel.ali@sfh-tr.nhs.uk

Copyright ©ERS 2016. Print ISBN: 978-1-84984-073-6. Online ISBN: 978-1-84984-074-3. Print ISSN: 2312-508X. Online ISSN: 2312-5098.

ERS Monogr 2016; 74: 229–239. DOI: 10.1183/2312508X.10011116 229

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Indications and contraindications

Chest tube placement is indicated for the conditions shown in table 1.

Contraindications are relative and depend greatly on the urgency with which the tube needs
to be placed. Use of anticoagulants, and known bleeding disorders or abnormal coagulation,
are all relative contraindications. Ideally, anticoagulation will be reversed or withheld while
the procedure is performed. Non-urgent chest drain insertions should be avoided in
anticoagulated patients until the international normalised ratio (INR) is <1.5 [7]. In more
urgent cases, attempts to correct severe coagulation defects should be undertaken in
consultation with a haematologist.

Long-acting antiplatelet agents may be safe to continue when placing a small-bore tube, but
there is no good RCT evidence [8, 9].

Use of imaging

Chest radiography

The plain chest radiograph features of pleural effusion or pneumothorax are usually
characteristic. In the case of pneumothorax, the chest radiograph demonstrates a visible
visceral pleural edge seen as a very thin, sharp, white line. No lung markings are visible
peripherally to this line, and the peripheral space is radiolucent compared with the adjacent
lung. In a pleural effusion, the posteroanterior chest radiograph will show at least blunting of
the costophrenic angle, and potentially no lung markings may be visible. There is often dense
opacification of the hemithorax, without air bronchograms. Sometimes, there is a mediastinal
shift away from the side of the effusion.

Table 1. Indications for chest tube insertion

Pneumothorax
Large primary spontaneous pneumothorax persisting after needle aspiration
Secondary spontaneous pneumothorax
Traumatic pneumothorax: large symptomatic iatrogenic pneumothorax, most commonly due to
lung biopsy or central line placement/pacemaker insertion
All patients on mechanical ventilation
Tension pneumothorax
Post-operative bronchopleural fistula/post-thoracoscopy
Pleurodesis for treatment of secondary pneumothorax in patients unfit for operative
intervention
Pleural effusion
Infected effusion (i.e. parapneumonic effusion, empyema)
Symptomatic malignant effusion
Chylothorax
Other effusions: symptomatic effusions of other aetiology (e.g. cardiac failure, renal failure,
hepatic effusion), considering and balancing benefits versus risks
Pleurodesis for the treatment of refractory effusion (predominantly malignancy)
Post-operative following thoracic or upper abdominal surgery
Haemothorax
Chest trauma (blunt or penetrating)
Post-operative following thoracic or upper abdominal surgery

230

FB:Cardiologia Siglo XXI

 CHEST TUBE INSERTION | S. ADLAKHA ET AL.

Ultrasound

Thoracic ultrasound guidance is strongly recommended for all pleural procedures for
pleural fluid [7]. Ultrasound guidance not only improves the rate of successful chest tube
insertion but also reduces the risks associated with the procedure [10].

CT

CT is helpful in tube placement in complex pneumothorax/loculated fluid/adhesions and to

distinguish a bulla from a pneumothorax. It is also helpful in diagnosing occult
pneumothorax in mechanically ventilated patients. Sometimes, tubes may need to be placed
under direct guidance.

Pre-procedure preparation

Training

All doctors who perform chest tube insertion should be appropriately trained and should
have been supervised initially by an experienced trainer. A survey of UK National Health
Service Trusts showed that the majority did not have a formal training policy for chest
drain insertion in 2008 [4].

Consent

Written information should be provided before the consent process, except in emergency
situations. Written informed consent should be taken where the patient is competent and
should be obtained by a member of staff trained in the procedure or adequately trained to take
consent.

Clotting disorders and anticoagulation

Non-urgent chest drain insertions should be avoided in anticoagulated patients until the
INR is <1.5 [5].

Antibiotic prophylaxis

Antibiotic prophylaxis is not indicated for nontrauma patients requiring a chest drain [11].
Antibiotic prophylaxis should be considered for trauma patients requiring chest drains,
especially after penetrating trauma [12].

Equipment

The equipment used for chest tube insertion is listed in table 2. Equipment for the
Seldinger technique is also available in a packed kit form (figure 1).

231

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 2. Equipment used for chest tube insertion

Ultrasound machine for effusions

Sterile gloves and gown
Skin antiseptic solution (i.e. iodine or chlorhexidine in alcohol)
Sterile drapes
Local anaesthetic (e.g. lidocaine 1%)
A selection of syringes (10–20 mL) and needles (21–25 G)
Scalpel and blade
Suture (e.g. 0 or 1–0 silk)
Instrument for blunt dissection if required (e.g. artery forceps)
Guide wire and dilators for Seldinger technique
Chest tube
Connecting tubing
Closed drainage system (including sterile water if an underwater seal is being used)
Gauze swabs and dressings

Tube selection

There is no consensus regarding the size of chest tube that should be inserted for
pneumothorax, pleural effusion, empyema or haemothorax (figure 2).

Overall, small tubes should be used as the first-line therapy for pneumothorax, free-flowing
pleural effusions and pleural infection [7]. Small-bore tubes have significantly lower pain
scores and analgesia requirements and a greater degree of comfort than in comparable
patients in whom large-bore catheters have been inserted for the same indication [13–16].
Recent randomised trial data showed placement of 12-French chest tubes was associated
with a statistically significant but clinically modest reduction in pain when compared with
24-French chest tubes [16].

Figure 1. Prepacked 12-French Seldinger chest tube kit (Rocket Medical, Washington, UK).

232

FB:Cardiologia Siglo XXI

 CHEST TUBE INSERTION | S. ADLAKHA ET AL.

Figure 2. Argyle chest tubes of different sizes (Covidien, Tullamore, Ireland).

In trauma, INABA et al. [17] performed a prospective analysis of 28–32-French versus

36–40-French chest tube sizes and showed that chest tube size did not have an impact
upon the clinically relevant outcomes. Specifically, there was no difference in the efficacy of
drainage, rate of complications including retained haemothorax, need for additional tube
drainage or invasive procedures. Furthermore, tube size did not affect the pain felt by
patients at the site of insertion in this particular study; however, these would all be
considered large drains [17].

For patients at risk of a large air leak due to bronchopleural fistulae (e.g. on mechanical
ventilation, bronchial dehiscence), a larger-bore tube is generally believed to be superior
(e.g. 24-French), although scientific evidence is lacking [18, 19].

If a small-bore tube fails, large-bore tubes may be successful, although other studies suggest
image-guided small-bore catheters can be therapeutically successful when large-bore tubes
fail [20, 21].

Analgesia and sedation

Chest tube insertion can be associated with pain and anxiety [22]. To reduce the pain
associated with chest drains, analgesia should be considered as pre-medication. Analgesia
should be prescribed for all patients with a chest drain in place. The patient needs to be
reassured before and during the procedure to reduce the anxiety associated with the
procedure. Good local anaesthesia is key in reducing pain.

In addition to local analgesia with lidocaine, in a haemodynamically stable patient,

conscious sedation with an opioid or a benzodiazepine (as per local policy) may be
considered. Patients given conscious sedation must be appropriately monitored from a
cardiorespiratory perspective.

233

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Figure 3. The “triangle of safety”. A: lateral edge of pectoris major; B: base of axilla; C: lateral edge of
latissimus dorsi; D: fifth intercostal space.

Insertion site

Ideally, insertion should be in the “triangle of safety”, an area bordered by the lateral edge
of the latissimus dorsi, the lateral border of the pectoralis major muscle and a line superior
to the horizontal level of the nipple (figure 3) [7]. If the chest tube is to be inserted into a
loculated pleural effusion, the site of insertion should be guided by imaging. For apical
pneumothoraces, the second intercostal space in the mid-clavicular line may be more
appropriate but is not recommended routinely. It may be the preferred site when using a
small drain with an ambulatory drainage system.

Ideally, patients should be in the lateral decubitus position, slightly rotated, and with the
arm on the side of the lesion placed behind the patient’s head. Sometimes patients are
more comfortable in a semi-recumbent position. An alternative is for the patient to sit
upright leaning over an adjacent table with a pillow under the arms if the drain needs to be
inserted posteriorly (under ultrasound guidance).

Techniques

Local anaesthesia is first performed, as described in table 3. Once the site is prepared and
anaesthetised, one of two techniques is then commonly used to place a chest tube. The
standard technique employs blunt dissection to access the pleural space (table 4). In
contrast, the Seldinger technique uses serial dilation over a guidewire (table 5) and has
become the most widespread method of tube insertion. The Seldinger technique is useful

234

FB:Cardiologia Siglo XXI

 CHEST TUBE INSERTION | S. ADLAKHA ET AL.

Table 3. Procedure for local anaesthesia

Step Procedure

1 Chest tube insertion should take place in a clean area using full aseptic technique
including gowns, drapes, sterile gloves and skin cleansing.
2 Place the patient in the preferred position as described in the main text.
3 Perform a pleural ultrasound prior to chest tube insertion and mark the site of
insertion.
4 Perform a surgical hand wash, and put on a surgical gown, mask and sterile gloves.
5 Open the chest drain pack.
6 Clean the skin using an antiseptic skin preparation, such as chlorhexidine, and swab
in a circular motion from the point of insertion outwards in a circular motion.
7 Place sterile drapes to maintain the sterile field.
8 Insert local anaesthetic initially, with an orange needle (25 G); this will make a bleb of
anaesthetic just below the skin surface. Change to a green needle (21 G) and
anaesthetise the intercostal muscles, other soft tissues and pleura. Once free air or
fluid is aspirated, withdraw the needle a few millimetres until aspiration ceases.
Then inject 1–2 mL of local anaesthetic.
9 Aspirate as the needle is inserted to prevent injection into a vessel and to help locate
fluid or air in the pleural cavity.

Table 4. Procedure for blunt dissection following local anaesthesia

Step Procedure

1 Once free air or fluid has been aspirated, make an appropriate incision in the skin
with the incision length just greater than the diameter of the tube at the site of the
lidocaine injection parallel to the intercostal space.
2 Perform blunt dissection using artery forceps through the subcutaneous tissues (open
and close forceps to separate rather than cut tissues). This is to avoid injury to the
neurovascular bundle that runs along the inferior aspect of the rib.
3 After a few passes, you should feel a sudden give and sometimes a hiss of air or flow
of fluid.
4 Insert a finger through the tract into the pleural space to confirm proper position and
make sure there are no adhesions between the lung and the pleural surface.
5 Insert the tube through the tract and advance the chest tube until the last drainage
hole is within the thoracic cavity by at least 2 cm.
6 Aim the drain towards the apex in the case of pneumothorax, or inferiorly and
posteriorly for effusion.
7 Confirm that the chest tube is in the thoracic cavity by observing condensation within
the tube with respiration, or drainage from the tube.
8 Place a suture to anchor the chest tube. Attach the end of the tube onto the
underwater drainage system. Check that the water in the chest drain is bubbling or
fluctuating (“swinging”); if in doubt, ask the patient to cough gently.
9 Remove the drapes. Secure the drain to the skin using some cut swabs and a dry
adhesive dressing.
10 Dispose of all waste and sharps appropriately.
11 Obtain a chest radiograph to confirm position of the chest tube, and document the
findings in the clinical notes.
12 Start a chart for recording chest tube activity (swinging, bubbling and drainage).
13 After the procedure, inform the patient regarding chest tube advice. They should be
advised to make sure that the chest drainage system is kept below the level of the
chest at all times.

235

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

Table 5. Procedure for the Seldinger technique following local anaesthesia

Step Procedure

1 Insert an introducer needle into the pleural space and confirm that either fluid or air
is returned. If this does not occur, do not proceed.
2 If fluid or air is returned, the syringe is removed.
3 Insert the guidewire through the introducer needle into the pleural space. The wire
should pass without resistance. If this is not the case, the needle can be
repositioned if this is practical. Otherwise, the procedure should be abandoned.
4 The introducer needle is then removed, leaving the guidewire in position.
5 Pass the dilators sequentially over the guidewire to dilate the tract in a slight twisting
action. Never use force.
6 Remove the dilator (or serial dilators).
7 Pass the chest tube into the pleural space over the guide wire.
8 Remove the guidewire and any tube stiffeners, leaving the chest tube in place.
9 Secure the tube in place with a suture, dress with gauze, connect the drainage
system, obtain a chest radiograph to confirm the tube position and assess lung
expansion, and monitor the initial drainage from the tube as described in the
main text.

for the placement of smaller-bore tubes that drain air and nonviscous fluids, and must be
performed with the aid of ultrasound for fluids.

Management

Drainage

Drainage must be monitored. Some examples of drainage systems are given in table 6.

Level of suction

In medical situations, there is no evidence to recommend or discourage the use of suction.

However, suction is common practice, especially in the treatment of nonresolving

Table 6. Drainage systems

System Description

Underwater seal bottle Tube is placed under water at a depth of ∼3 cm with a side vent,
which allows the escape of air or which may be connected to
a suction pump
Heimlich valve [23, 24] Ambulatory drainage system
Flutter bag Ambulatory drainage system
Digital chest drainage Provides regulated negative pressure close to the patient’s
system# [25, 26] chest
Shows actual air leak data
Patients enjoy freedom of mobility without being attached to
wall suction
Timely decision regarding chest drainage management
#
: Thopaz Digital Chest Drainage System; Medela Inc. Healthcare, McHenry, IL, USA.

236

FB:Cardiologia Siglo XXI

 CHEST TUBE INSERTION | S. ADLAKHA ET AL.

pneumothorax. A persistent air leak, without incomplete re-expansion of the pneumothorax

on a chest radiograph, is the usual reason for applying (or increasing) suction [27]. If suction
is required, this may be done by the underwater seal at a level of 10–20 cmH2O. Higher levels
of suction may be associated with significant discomfort.

Removal of the chest tube

The presence of an air leak or fluid drainage should be assessed daily to determine whether
the tube can be removed. To reduce the risk of infection complications, the tube should be
removed as soon as it is safe to do so.

For pneumothorax, when the lung is fully expanded and there is no visible air leak without
suction, the chest tube can be removed. As a general rule, the chest tube should not be
clamped. This is the safe approach in most instances to avoid clamping being carried out
inappropriately by less experienced clinicians.

For pleural effusion, once the daily output of drainage fluid is <200 mL per day and the
lung is fully expanded, the chest tube may be removed. However, there is little evidence as
to the minimum fluid volume associated with successful removal [28, 29].

Removal technique

If the above removal criteria are met, the suction is eliminated (if applied). While some
advocate pulling the chest tube at end-inspiration, others advocate end-expiration. A small
study comparing these two techniques did not show a difference in post-pull
pneumothorax [30]. The procedure should be explained to the patient. The patient should
rehearse this several times prior to the actual tube removal. Remove the chest tube quickly
while placing a dry sterile dressing over the opening. Once the tube has been removed,
secure the dressing with tape.

There is no evidence that a chest radiograph should be performed routinely in medical

patients, although this is common practice in some areas. Case series in cardiac surgery
patients suggest that it is not required [31–33].

Complications

Complications from chest tube placement are related to the indication for insertion,
circumstances (i.e. elective versus emergency), experience and training of the clinician [34].

Complications of chest tube placement include malposition, infection (e.g. empyema),

organ injury (e.g. lung, diaphragm, heart, liver or spleen) and pulmonary oedema related to
rapid pulmonary expansion (reducing the volume drained to 1.5 L at a time appears to
mitigate this) [27, 28, 35, 36].

The incidence of these complications ranges from 1% to 6% and is related to the diameter
of the tube, with small-bore tubes having fewer complications [37].

237

FB:Cardiologia Siglo XXI

ERS MONOGRAPH | PULMONARY EMERGENCIES

References
1. Hochberg LA. Thoracic Surgery before the 20th Century. New York, Vantage Press, 1960.
2. Hughes J. Battlefield medicine in Wolfram’s Parzival. J Mediev Mil Hist 2010; 8: 119–130.
3. Playfair GE. Case of empyema treated by aspiration and subsequently by drainage: recovery. Br Med J 1875; 1: 45.
4. Monaghan SF, Swan KG. Tube thoracostomy: the struggle to the “standard of care”. Ann Thorac Surg 2008; 86:
2019–2022.
5. Munnell ER. Thoracic drainage. Ann Thorac Surg 1997; 63: 1497–1502.
6. Harris A, O’Driscoll B, Turkington P. Survey of major complications of intercostal chest drain insertion in the UK.
Postgrad Med J 2010; 86: 68–72.
7. Havelock T, TeoH R, Laws D, et al. Pleural procedures and thoracic ultrasound: British Thoracic Society Pleural
Disease Guideline 2010. Thorax 2010; 65: Suppl. 2, ii61–ii76.
8. Dammert P, Pratter M, Boujaoude Z. Safety of ultrasound-guided small-bore chest tube insertion in patients on
clopidogrel. J Bronchology Interv Pulmonol 2013; 20: 16–20.
9. Abouzgheib W, Shweihat YR, Meena N. Is chest tube insertion with ultrasound guidance safe in patients using
clopidogrel? Respirology 2012; 17: 1222–1224.
10. Lee WY, Faruqi S, Kastelik J, et al. Ultrasound guided pleural aspiration and chest drain insertion – a prospective
study. Eur Respir J 2011; 38: Suppl. 55, 465.
11. Olgac G, Aydogmus U, Mulazimoglu L, et al. Antibiotics are not needed during tube thoracostomy for
spontaneous pneumothorax: an observational case study. J Cardiothorac Surg 2006; 1: 43.
12. Sanabria A, Valdivieso E, Gomez G, et al. Prophylactic antibiotics in chest trauma: a meta-analysis of high-quality
studies. World J Surg 2006; 30: 1843–1847.
13. Clementsen P, Evald T, Grode G, et al. Treatment of malignant pleural effusion: pleurodesis using a small
percutaneous catheter. A prospective randomized study. Respir Med 1998; 92: 593–596.
14. Chetty GK, Battula NR, Govindaswamy R, et al. Comparative analysis of the Bonanno catheter and tube
thorocostomy in effective aspiration of pleural effusion. Heart Surg Forum 2006; 9: E731–E734.
15. Light RW. Pleural controversy: optimal chest tube size for drainage. Respirology 2011; 16: 244–248.
16. Rahman NM, Pepperell J, Rehal S, et al. Effect of opioids vs NSAIDs and larger vs smaller chest tube size on pain
control and pleurodesis efficacy among patients with malignant pleural effusion: the TIME1 Randomized Clinical
Trial. JAMA 2015; 314: 2641–2653.
17. Inaba K, Lustenberger T, Recinos G, et al. Does size matter? A prospective analysis of 28–32 versus 36–40 French
chest tube size in trauma. J Trauma Acute Care Surg 2012; 72: 422–427.
18. Baumann M, Strange C, Heffner J, et al. Management of spontaneous pneumothorax: an American College of
Chest Physicians Delphi Consensus Statement. Chest 2001; 119: 590–602.
19. Baumann M, Sahn S. Medical management and therapy of bronchopleural fistulas in mechanically ventilated
patient. Chest 1990; 97: 721–728.
20. Silverman SG, Mueller PR, Saini S, et al. Thoracic empyema: management with image-guided catheter drainage.
Radiology 1988; 169: 5–9.
21. van Sonnenberg E, Nakamoto SK, Mueller PR, et al. CT- and ultrasound-guided catheter drainage of empyemas
after chest-tube failure. Radiology 1984; 151: 349–353.
22. Luketich JD, Kiss M, Hershey J, et al. Chest tube insertion: a prospective evaluation of pain management. Clin J
Pain 1998; 14: 152–154.
23. Heimlich HJ. Heimlich valve for chest drainage. Med Instrum 1983; 17: 29–31.
24. Heimlich HJ. Valve drainage of the pleural cavity. Dis Chest 1968; 53: 282–287.
25. Pompili C, Detterbeck F, Papagiannopoulos K, et al. Multicenter international randomized comparison of objective
and subjective outcomes between electronic and traditional chest drainage systems. Ann Thorac Surg 2014; 98:
490–497.
26. Mier JM, Molins L, Fibla J. The benefits of digital air leak assessment after pulmonary resection: prospective and
comparative study. Cir Esp 2010; 87: 385–389.
27. MacDuff A, Arnold A, Harvey J. Management of spontaneous pneumothorax: British Thoracic Society pleural
disease guideline 2010. Thorax 2010; 65: ii18–ii31.
28. Adegboye VO, Falade A, Osinusi K. Reexpansion pulmonary oedema as a complication of pleural drainage.
Niger Postgrad Med J 9: 214–220.
29. Roberts M, Neville E, Berrisford R. Management of a malignant pleural effusion: British Thoracic Society Pleural
Disease Guideline 2010. Thorax 2010; 65: Suppl. 2, ii32–ii40.
30. Bell RL, Ovadia P, Abdullah F, et al. Chest tube removal: end-inspiration or end-expiration? J Trauma 2001; 50:
674–677.
31. McCormick JT, O’Mara MS, Papasavas PK, et al. The use of routine chest X-ray films after chest tube removal in
postoperative cardiac patients. Ann Thorac Surg 2002; 74: 2161–2164.

238

FB:Cardiologia Siglo XXI

 CHEST TUBE INSERTION | S. ADLAKHA ET AL.

32. Sepehripour AH, Farid S, Shah R. Is routine chest radiography indicated following chest drain removal after
cardiothoracic surgery? Interact Cardiovasc Thorac Surg 2012; 14: 834–838.
33. Pacharn P, Heller DND, Kammen BF, et al. Are chest radiographs routinely necessary following thoracostomy tube
removal? Pediatr Radiol 2002; 32: 138–142.
34. Ball CG, Lord J, Laupland KB, et al. Chest tube complications: how well are we training our residents? Can J Surg
2007; 50: 450–458.
35. Kwiatt M, Tarbox A, Seamon M, et al. Thoracostomy tubes: a comprehensive review of complications and related
topics. Int J Crit Illn Inj Sci 2014; 4: 143–155.
36. Mao M, Hughes R, Papadimos TJ, et al. Complications of chest tubes: a focused clinical synopsis. Curr Opin Pulm
Med 2015; 21: 376–386.
37. Collop NA, Kim S, Sahn SA. Analysis of tube thoracostomy performed by pulmonologists at a teaching hospital.
Chest 1997; 112: 709–713.

Disclosures: None declared.

239

FB:Cardiologia Siglo XXI

 Pulmonary Emergencies
ERS monograph

ERS monograph

This Monograph, written by well recognised experts in the

Pulmonary
field, provides a comprehensive overview of pulmonary
emergencies. A broad range of different respiratory
emergencies is covered, from pneumothorax, pulmonary
Emergencies
embolism, right heart failure and haematothorax to acute
exacerbations of diseases such as asthma and chronic
obstructive pulmonary disease. Recent developments in
treatment strategies for acute pulmonary problems are also
Edited by Leo Heunks,
discussed in detail, with chapters on topics such as high-flow Alexandre Demoule
nasal cannula oxygen therapy, extracorporeal carbon dioxide
removal and noninvasive ventilation. and Wolfram Windisch

ERS monograph 74

Print ISSN: 2312-508X ISBN 978- 1- 84984- 073- 6

Online ISSN: 2312-5098
Print ISBN: 978-1-84984-073-6
Online ISBN: 978-1-84984-074-3

December 2016

€60.00 9 781849 840736

FB:Cardiologia Siglo XXI