[

Original Research Critical Care

Ventilator-Associated Pneumonia During Weaning

From Mechanical Ventilation
Role of Fluid Management
Armand Mekontso Dessap, MD, PhD; Sandrine Katsahian, MD; Ferran Roche-Campo, MD, PhD; Hugo Varet, PhD;
Achille Kouatchet, MD; Vinko Tomicic, MD; Gaetan Beduneau, MD; Romain Sonneville, MD, PhD;
Samir Jaber, MD, PhD; Michael Darmon, MD, PhD; Diego Castanares-Zapatero, MD; Laurent Brochard, MD;
and Christian Brun-Buisson, MD

Pulmonary edema may alter alveolar bacterial clearance and infectivity.

Manipulation of fluid balance aimed at reducing fluid overload may, therefore, influence
ventilator-associated pneumonia (VAP) occurrence in intubated patients. The objective
of the present study was to assess the impact of a depletive fluid-management strategy on
ventilator-associated complication (VAC) and VAP occurrence during weaning from mechanical ventilation.

BACKGROUND:

We used data from the B-type Natriuretic Peptide for the Fluid Management of
Weaning (BMW) randomized controlled trial performed in nine ICUs across Europe and
America. We compared the cumulative incidence of VAC and VAP between the biomarkerdriven, depletive fluid-management group and the usual-care group during the 14 days
following randomization, using specific competing-risk methods (the Fine and Gray model).

METHODS:

RESULTS: Among the 304 patients analyzed, 41 experienced VAP, including 27 (17.8%) in the
usual-care group vs 14 (9.2%) in the interventional group (P 5 .03). From the Fine and Gray
model, the probabilities of VAC and VAP occurrence were both significantly reduced with the
interventional strategy while adjusting for weaning outcome as a competing event (subhazard ratios [25th-75th percentiles], 0.44 [0.22-0.87], P 5 .02 and 0.50 [0.25-0.96], P 5 .03,
respectively).

Using proper competing risk analyses, we found that a depletive fluidmanagement strategy, when initiating the weaning process, has the potential for lowering VAP
risk in patients who are mechanically ventilated.

CONCLUSIONS:

TRIAL REGISTRY:

ClinicalTrials.gov; No.: NCT00473148; URL: www.clinicaltrials.gov

CHEST 2014; 146(1):58-65

Manuscript received October 29, 2013; revision accepted February 5,

2014; originally published Online First March 20, 2014.
ABBREVIATIONS: AWS 5 automated weaning system; BMW 5 B-type
Natriuretic Peptide for the Fluid Management of Weaning; BNP 5
B-type natriuretic peptide; PEEP 5 positive end-expiratory pressure;
VAC 5 ventilator-associated complication; VAP 5 ventilator-associated
pneumonia
AFFILIATIONS: From the Service de Ranimation Mdicale (Drs
Mekontso Dessap, Roche-Campo, and Brun-Buisson), and Unit de
Recherche Clinique (Drs Katsahian and Varet), AP-HP, CHU Henri
Mondor, Crteil, F-94010, France; Facult de Mdecine (Drs Mekontso
Dessap and Brun-Buisson), Universit Paris Est Crteil, Crteil, F-94010,
France; INSERM (Drs Mekontso Dessap and Brun-Buisson), Unit
U955, Crteil, F-94010, France; Servei de Medicina Intensiva (Dr Roche-

Campo), Hospital de Sant Pau, Barcelona, Spain; Service de Ranimation Mdicale (Dr Kouatchet), CHU dAngers, Angers, France; Departamento de Paciente Crtico (Dr Tomicic), Clinica Alemana, Santiago de
Chile, Chile; Service de Ranimation Mdicale and UPRES-EA 3830
(Dr Beduneau), CHU de Rouen, Rouen, France; Service de Ranimation
Mdicale et des Maladies Infectieuses (Dr Sonneville), AP-HP, CHU
Bichat-Claude Bernard, Univ Paris Diderot, Sorbonne Paris Cit, Paris,
France; Ranimation DAR B (Dr Jaber), CHU Saint Eloi, INSERM U1046,
Montpellier, France; Service de Ranimation Mdicale (Dr Darmon),
AP-HP, CHU Saint Louis, Paris, France; Service de Soins Intensifs
(Dr Castanares-Zapatero), Hpital Universitaire Saint-Luc, Bruxelles,
Belgium; Critical Care Department (Dr Brochard), St. Michaels Hospital,
Toronto, ON, Canada; and Interdepartmental Division of Critical Care
Medicine (Dr Brochard), University of Toronto, Toronto, ON, Canada.

58 Original Research
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C H E S T J U LY 2 0 1 4

Ventilator-associated pneumonia (VAP) is the most

common hospital-acquired infection in the ICU.
Although there is debate about its impact on mortality,1,2 VAP is clearly associated with increased duration of mechanical ventilation, ICU and hospital stays,
antibiotic consumption, and costs.3 The cumulative risk
of developing VAP increases for the whole duration of
mechanical ventilation.4 Many other risks factors for
VAP have been described, including witnessed aspiration and exposure to paralytic agents.4
The concept of ventilator-associated complications
(VACs) was recently proposed as a measure of respiratory deterioration in patients under mechanical ventilation.5 These complications, which are driven by
atelectasis, pulmonary edema, and VAP, may overlap in
some patients. VAP is a common complication of permeability pulmonary edema, with a prevalence ranging
from 40% to 60% during moderate to severe ARDS.6-8
The association of pneumonia with hydrostatic pulmo-

Materials and Methods

Patients
This randomized controlled trial was conducted in nine ICUs in Europe
and South America between May 2007 and July 2009. A detailed
description of the BMW study design (NCT00473148) has been published
previously with supplemental information on patients and methods.11
Inclusion criteria were those allowing early initiation of ventilator
weaning: endotracheal mechanical ventilation for at least 24 h, transcutaneous oxygen saturation 90% with Fio2 50% and positive
end-expiratory pressure (PEEP) 8 cm H2O, hemodynamic stability
during the past 12 h, sedation stopped or decreased over the past
48 h, stable neurologic status with Ramsay score 5, and body temperature . 36.0C and , 39.0C. Permanent noninclusion criteria were
pregnancy or lactation, age , 18 years, known allergy to furosemide
or sulfonamides, tracheostomy on inclusion, hepatic encephalopathy,
cerebral edema, acute hydrocephalus, myasthenia gravis, acute idiopathic polyradiculoneuropathy, decision to withdraw life support, and
prolonged cardiac arrest with a poor neurologic prognosis. Temporary
noninclusion criteria were extubation scheduled on the same day; persistent, acute, right ventricular failure; renal insufficiency (defined as
any of the following: need for renal replacement therapy, plasma urea
level . 25 mmol/L, plasma creatinine level . 180 mmol/L, creatinine
clearance , 30 mL/min, or . 25% increase in plasma creatinine over

FUNDING/SUPPORT:

This project was funded by the French Ministry

of Health research program (Programme Hospitalier de Recherche Clinique) [contract 05104]. Biosite France supplied the BNP assay devices
and kits (Triage MeterPlus) for the study. Drger provided the AWSequipped ventilators for the study.
CORRESPONDENCE TO: Armand Mekontso Dessap, MD, PhD, Service
de Ranimation Mdicale, Centre Hospitalo-Universitaire Henri Mondor;
51, avenue du Mal de Lattre de Tassigny 94 010 Crteil Cedex, France;
e-mail: armand.dessap@hmn.aphp.fr
2014 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of
this article is prohibited without written permission from the American
College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.13-2564

nary edema is also frequent.9 Pulmonary edema may

predispose patients to pneumonia via several mechanisms that alter the alveolar microenvironment, including enhanced bacterial colonization and infectivity,
decreased host bactericidal capacities, or both.10 A fluidmanagement strategy aimed at lowering lung fluid balance may, therefore, prove useful in amending both the
risk of VAC and of VAP. We tested this hypothesis in
the context of weaning from mechanical ventilation
using data from the B-type Natriuretic Peptide for the
Fluid Management of Weaning (BMW) study, which compared a biomarker-guided, depletive fluid-management
strategy to usual care in patients who were in the ICU
and mechanically ventilated. Since weaning outcome
and VAP act as competing risks,4 we designed the present work with a competing-risk approach to properly
estimate the effect of a depletive fluid-management
strategy on VAP risk among patients enrolled in the
BMW study.

the past 24 h); injection of iodinated contrast agent in the past 6 h;

blood sodium level . 150 mEq/L; blood potassium level , 3.5 mEq/L;
or metabolic alkalosis with arterial pH . 7.50. When inclusion was
delayed because of a temporary noninclusion criterion, enrollment could
be performed after correction of the abnormal value. The protocol was
approved by our institutions local ethics committee (Comit de Protection des Personnes Ile-de-France IX, approval number 06-035), and
informed consent was signed by the patient or a close relative. The primary end point was the time from randomization to successful extubation. Successful extubation was defined as the patient alive and without
reintubation 72 h after extubation.11
Patient Management
To standardize the weaning process, all patients were ventilated using a
computer-driven, automated weaning system (AWS) (Evita Smart Care
System; Drger). Patients were assigned to one of two groupsB-type
natriuretic peptide (BNP)-guided depletive fluid management or usual
care based on clinical evaluationvia an independent, Internet-based,
centralized block randomization with stratification on the center and
underlying disease. A blood sample was collected each morning for a
BNP assay in all randomized patients during the weaning phase. In the
control group, the clinicians were blinded to the BNP assay results, and
all treatments, including diuretics, were carried out according to usual
care. In the interventional group, on days with a BNP level 200 pg/mL,12
fluid intake was restricted (baseline infusion 500 mL/24 h, parenteral
nutrition 1,000 mL/24 h, no saline solutions apart from nutrition
and drugs) and furosemide was administered (as IV bolus doses of
10-30 mg every 3 h, to achieve a target urine output of 4.5-9 mL/kg/3 h).
During ventilation in both groups, the AWS gradually decreased the
pressure support level while maintaining the patient within a zone of
respiratory comfort, as previously described.13 When the AWS declared
the patient ready for separation, extubation was performed as soon
as possible (including during the night), provided the patient met the
other criteria required for extubation, namely, transcutaneous oxygen
saturation 90% with Fio2 40% and PEEP 5 cm H2O, hemodynamic stability, Ramsay score 3 with continuous sedation stopped
or minimal (analgesic medication could be continued), audible cough
(spontaneously or during aspiration), need for fewer than three endotracheal suctionings during the last 4 h, and no scheduled procedure

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59

Acknowledgments
Author contributions: A. M. D. served as
principal author, had full access to all of the
data in the study, and takes responsibility for
the integrity of the data and the accuracy of
the data analysis. A. M. D., L. B., and C. B.-B.
contributed to study concept and design;
A. M. D., F. R.-C., A. K., V. T., G. B., R. S., S. J.,
M. D., and D. C.-Z. contributed to patient
recruitment; A. M. D., F. R.-C., A. K., V. T.,
G. B., R. S., S. J., M. D., and D. C.-Z. contributed to data collection; A. M. D., S. K., H. V.,
L. B., and C. B.-B. contributed to data
analysis and interpretation; A. M. D., S. K.,
L. B., and C. B.-B. contributed to the drafting
of the manuscript; and A. M. D., S. K., F. R.-C.,
H. V., A. K., V. T., G. B., R. S., S. J., M. D.,
D. C.-Z., L. B., and C. B.-B. contributed to
the review, revision, and approval of the final
version.
Financial/nonfinancial disclosures: The
authors have reported to CHEST the
following conflicts of interest: Dr Brochard
has been a consultant for Drger, and his
research laboratory has received research
grants from Covidien, General Electric,
Drger, and Vygon. The remaining authors
have reported that no potential conflicts of
interest exist with any companies/organizations whose products or services may be
discussed in this article.
Role of sponsors: The study sponsors had no
role in study design, data collection, data
analysis, data interpretation, or writing of the
report.

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Dupont WD, Morris JA, Bernard GR.
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65

TABLE 1

] Baseline Characteristics

Characteristics
Age, y
Sex, No. (% male)
SAPS II at ICU admission

Usual Care Group (n 5 152)

65 (52-74)
102 (67.1)
44 (34-56)

Interventional Group (n 5 152)

P Value

66 (55-76)

.18

93 (61.2)

.28

43 (34-54)

Immunosuppressiona

.66
.64

Solid cancer with metastases

4 (2.7)

7 (4.9)

Hematologic malignancy

8 (5.5)

6 (4.2)

AIDS

3 (2.1)

5 (3.5)

Cardiopulmonary disease

.79

COPD

38 (25.0)

41 (27.0)

LVD

24 (15.8)

20 (13.2)

Neither

90 (59.2)

91 (59.9)

Reason for intubation

.38

Coma

22 (14.5)

15 (9.9)

Septic shock

18 (11.8)

21 (13.8)

COPD exacerbation

10 (6.6)

15 (9.9)

Cardiogenic pulmonary edema

19 (12.5)

14 (9.2)

Pneumonia

40 (26.3)

50 (32.9)

Cardiac arrest

10 (6.6)

Surgery

19 (12.5)

Other

14 (9.2)

6 (3.9)
23 (15.1)
8 (5.3)

Events between ICU admission and randomization

Septic shockb

61 (40.1)

70 (46.1)

.30

Ventilator-associated pneumonia

32 (21.1)

25 (16.4)

.30

ARDSb

55 (36.2)

53 (34.9)

.81

Use of neuromuscular blockers

35 (23.0)

32 (21.1)

.68

Steroid treatment

53 (34.9)

60 (39.5)

.41

Duration of invasive mechanical ventilation before

inclusion, d

4.4 (2.7-7.8)

5.0 (3.0-9.1)

.25

14 (10-15)

13 (10-15)

.96

Ventilation settings at randomization

Pressure support level, cm H2O
PEEP level, cm H2O
PaO2/FIO2 ratio, mm Hg
SOFA score at randomization
Ramsay score at randomization
Temperature at randomization, C

5 (5-8)
218 (176-266)
4 (2-6)
2.0 (2.0-4.0)
37.0 (36.5-37.8)

5 (5-6)
225 (174-297)
4 (3-5)
2.0 (2.0-3.0)
37.1 (36.6-37.6)

.42
.40
.67
.39
.96

Data given as No. (%) or median (interquartile range) unless otherwise indicated. LVD 5 left ventricular systolic dysfunction; PEEP 5 positive endexpiratory pressure; SAPS 5 Simplied Acute Physiology Score; SOFA 5 Sequential Organ Failure Assessment.
aData were missing for 14 patients (six and eight cases in the usual-care group and in the interventional group, respectively).
bAt admission or later during the ICU stay.

adjusting for weaning outcome as a competing event

(subhazard ratio, 0.44 [0.22-0.87]; P 5 .02). The weaning
time, ICU length of stay, and hospital length of stay were
significantly longer in patients with VAP as compared
with those without, whereas no difference was found for
ICU mortality or hospital mortality (Table 4).

Discussion
Previous studies of goal-directed fluid management in
critically ill patients who are mechanically ventilated
have shown beneficial respiratory effects of interventions aimed at lowering fluid balance.19-22 However,
none of these studies reported on VAP rate. To our

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61

TABLE 2

] Main Outcomes of the B-type Natriuretic Peptide for the Fluid Management of Weaning Study

Measure

Usual Care Group (n 5 152)

Interventional Group (n 5 152)

P Value

Median (IQR)

47.7 (22.9-124.8)

39.8 (20.0-72.4)

.019

Mean (SD)

92.8 (110.2)

70.6 (106.8)

58.6 (23.3-139.8)

42.4 (20.8-107.5)

Time to first extubation, h

Time to successful extubation, h

Median (IQR)
Mean (SD)

112.2 (147.1)

86.2 (127.9)

.034

Time to successful weaning from invasive and

noninvasive ventilation, h
Median (IQR)
Mean (SD)

74.4 (31.7-160.5)
134.3 (187.6)

49.3 (21.9-140.6)
107.1 (141.0)

.051

Ventilator-free days from randomization to day 14, d

Median (IQR)

9.7 (2.3-12.9)

Mean (SD)

8.2 (5.2)

12.0 (6.5-13.1)
9.3 (4.9)

.026

Ventilator-free days from randomization to day 28, d

Median (IQR)

23.3 (14.7-26.7)

25.9 (19.3-27.1)

Mean (SD)

18.9 (10.4)

20.3 (10.4)

Median (IQR)

54.9 (38.7-58.3)

57.9 (50.4-59.1)

Mean (SD)

42.8 (23.7)

45.7 (22.7)

.038

Ventilator-free days from randomization to day 60, d

.015

ICU stay length, d

Median (IQR)
Mean (SD)

8.0 (4.0-13.0)

8.0 (4.0-14.0)

11.6 (12.3)

11.4 (11.2)

Median (IQR)

20.0 (12.0-33.0)

20.0 (13.0-33.0)

Mean (SD)

27.3 (37.3)

24.0 (14.2)

.995

Hospital stay length, d

.796

ICU mortality

19 (12.5%)

18 (11.8%)

.861

Hospital mortality

25 (16.4%)

20 (13.2%)

.433

Day-60 mortality

28 (18.4%)

21 (13.8%)

.275

IQR 5 interquartile range.

knowledge, the present study is the first to assess the

effect of fluid management on VAP occurrence in
patients on ventilation in the ICU. Using competing
risks analysis, we found that a depletive fluid-management
strategy was associated with a significant reduction of
VAP cumulative incidence, while adjusting for extubation outcome as a competing risk.
When recording complications during the 14 days
following randomization in the BMW study, we found
significantly lower rates of VAC and VAP in the depletive fluid-management group as compared with usual
care. The clinical significance of this observation was
not straightforward, with several possible explanations
and a potential ascertainment bias. First, worsening
respiratory symptoms due to pulmonary edema may

have been mistaken for VAP in some patients. However,

the strict criteria used to diagnose pneumonia limited
this possibility. Second, the earlier separation from the
ventilator achieved with the depletive fluid-management
strategy decreased the risk exposure to VAP. Although
the daily hazard rate of VAP has been shown to decrease
after day 5, its cumulative risk increases over time
throughout the entire duration of mechanical ventilation.4 Therefore, weaning outcome and VAP act as competing risks. Specific statistical tools based on
cumulative incidence estimates have been developed to
analyze data suffering from competing risks.16,17 These
approaches have been previously used in ICU studies to
evaluate nonfatal end points or even mortality associated with intercurrent events.15,23,24 Applying this methodology to data from the BMW randomized controlled

62 Original Research
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[ 146#1

C H E S T J U LY 2 0 1 4

TABLE 3

] Microorganisms Responsible for VentilatorAssociated Pneumonia During Weaning

Pathogen

Usual Care
Group (n 5 27)

Interventional
Group (n 5 14)

Staphylococcus species

2 (7.4)

1 (7.1)

Streptococcus species

4 (14.8)

1 (7.1)

Enterobacteriaceae

10 (37.0)

6 (42.9)

Nonfermentative
gram-negative bacilli

13 (48.1)

5 (35.7)

Other gram-negative
bacteria

0 (0.0)

1 (7.1)

Polymicrobiala

7 (25.9)

6 (42.9)

Data are given as No. (% of pathogens).

aIncluding two cases of mixed oropharyngeal ora in the usual-care
group and three cases in the interventional group.

trial, we found that a depletive fluid-management

strategy was associated with lower cumulative incidences of VAC and VAP while controlling for successful extubation as a competing risk. The incidence
density of VAP, which is the number of observed
events divided by population-time at risk, is misleading

if competing risks are present, which is the case of this

study.25
Several factors may confer an advantage to a depletive
fluid-management strategy over the usual clinical
approach in reducing the incidence of VAP. First, the
edematous lung may be more susceptible to bacterial
infection. Studies in rodents have shown impaired, in
vivo, intrapulmonary bacterial inactivation in animals
with pulmonary edema.26 Crystalloid infusion has been
shown to markedly depress lung bacterial clearance of
Staphylococcus aureus and Klebsiella pneumoniae in animals.10 The degree of impairment of lung bacterial clearance by intraalveolar fluid may, however, vary from one
pathogen to another.27 Second, pulmonary edema may
exert a direct effect on bacterial colonization and infectivity. Pathogens in the Pseudomonadaceae account
for the predominant cause of late-onset VAP3 and
represented 44% of isolated species in our study.
Because these organisms are particularly well adapted to
wet or damp conditions,28,29 their virulence and infectivity may be enhanced in the context of wet lungs.
There is currently no practical guide to fluid management

Figure 1 Cumulative incidence function of successful extubation (bold lines) and VAP (dotted lines) during the first 14 d following randomization
in patients managed according to the interventional fluid-management strategy (red) or according to usual care (black). BNP 5 B-type natriuretic
peptide; VAP 5 ventilator-associated pneumonia.

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TABLE 4

] Main Outcomes of Patients With or Without VAP During Weaning

VAP
No (n 5 263)

Yes (n 5 41)

P Value

Time to successful extubation, h

Outcomes

43.9 (20.7-117.3)

141.6 (49.1-330.9)

, .0001

Ventilator-free days from

randomization to day 14, d

11.9 (6.9-13.1)

1.4 (0.0-11.2)

, .0001

ICU length of stay,a d

7.0 (4.0-14.0)

15.0 (9.0-47.0)

, .0001

ICU survivors length of stay (n 5 267),a d

7.0 (4.0-12.5)

15.0 (9.0-51.5)

, .0001

Hospital length of stay, d

22.5 (13.8-43.0)

48.0 (17.0-60.0)

.003

Hospital survivors length of stay (n 5 258),a d

23.0 (14.0-46.0)

59.0 (21.5-60.0)

.001

ICU mortality, No. (%)

30 (11.4)

7 (17.1)

.31

Hospital mortality,b No. (%)

39 (14.8)

7 (17.1)

.71

Data are given as median (IQR) unless otherwise indicated. VAP 5 ventilator-associated pneumonia. See Table 2 legend for expansion of other
abbreviation.
aPatients still in ICU or in hospital at last follow-up (day 60) were attributed a 60-d length of stay in ICU or hospital, respectively.
bMortality analyses are unadjusted for dierences in acuity or mortality risk.

in guidelines for VAP prevention.30 Whether incorporating a depletive fluid-management strategy into a
bundle of preventive measures may favorably alter
patients outcomes needs further research.
Our study has some limitations. First, we recorded VAP
episodes occurring during weaning from mechanical
ventilation, which started after a median of 5 days
following intubation. Therefore, we could not assess the
effect of fluid-balance management on early-onset VAP.
Second, the generalizability of our study (ie, its external
validity) may be limited by the specific inclusion and
exclusion criteria used in the BMW trial, especially the
exclusion of patients with renal failure because of the
influence of renal function on BNP levels. Third, we
could not control for implementation of VAP preventive measures in both groups, but the study was ran-

domized. Fourth, the overall rate of VAP was relatively

high in our study; this may be explained by the inclusion of the majority of patients in the first week of
mechanical ventilation and the high proportion of
patients with ARDS, a subgroup at very high risk of
such complication.3,6,7 Last, although we used a standard
and commonly accepted research definition for VAP,
based on a combination of clinical criteria and microbiologic confirmation, this characterization is still prone
to both false positives and false negatives.
In conclusion, using a competing risks analysis, we
found that a biomarker-driven, depletive-fluid strategy
decreases the cumulative incidence of VAP during the
weaning period, which may have contributed to reducing
its duration. This finding may encourage innovative
strategies aimed at preventing VAP in patients in the ICU.

64 Original Research
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[ 146#1

C H E S T J U LY 2 0 1 4

Acknowledgments
Author contributions: A. M. D. served as
principal author, had full access to all of the
data in the study, and takes responsibility for
the integrity of the data and the accuracy of
the data analysis. A. M. D., L. B., and C. B.-B.
contributed to study concept and design;
A. M. D., F. R.-C., A. K., V. T., G. B., R. S., S. J.,
M. D., and D. C.-Z. contributed to patient
recruitment; A. M. D., F. R.-C., A. K., V. T.,
G. B., R. S., S. J., M. D., and D. C.-Z. contributed to data collection; A. M. D., S. K., H. V.,
L. B., and C. B.-B. contributed to data
analysis and interpretation; A. M. D., S. K.,
L. B., and C. B.-B. contributed to the drafting
of the manuscript; and A. M. D., S. K., F. R.-C.,
H. V., A. K., V. T., G. B., R. S., S. J., M. D.,
D. C.-Z., L. B., and C. B.-B. contributed to
the review, revision, and approval of the final
version.
Financial/nonfinancial disclosures: The
authors have reported to CHEST the
following conflicts of interest: Dr Brochard
has been a consultant for Drger, and his
research laboratory has received research
grants from Covidien, General Electric,
Drger, and Vygon. The remaining authors
have reported that no potential conflicts of
interest exist with any companies/organizations whose products or services may be
discussed in this article.
Role of sponsors: The study sponsors had no
role in study design, data collection, data
analysis, data interpretation, or writing of the
report.

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