Noninvasive Ventilation and Weaning in Patients

with Chronic Hypercapnic Respiratory Failure

A Randomized Multicenter Trial
Christophe Girault1,2, Michael Bubenheim3, Fekri Abroug4, Jean Luc Diehl5, Souheil Elatrous6,
Pascal Beuret7, Jack Richecoeur8, Erwan LHer9, Gilles Hilbert10, Gilles Capellier11, Antoine Rabbat12,
Mohamed Besbes13, Claude Guerin14, Philippe Guiot15, Jacques Benichou3,16, and Guy Bonmarchand1,2,
for the VENISE Trial Group*
1
Department of Medical Intensive Care, Rouen University Hospital, Rouen, France; 3Department of Biostatistics, Rouen University Hospital, Rouen,
France; 2UPRES EA 3830-IFRMP.23, Institute for Biomedical Research, Rouen University, Rouen, France; 4Medical Intensive Care Unit, Monastir
University Hospital, Monastir, Tunisia; 5Medical Intensive Care Unit, Georges Pompidou University Hospital, Paris, France; 6Medical Intensive Care
Unit, Mahdia University Hospital, Mahdia, Tunisia; 7Medico-surgical Intensive Care Unit, Roanne Hospital, Roanne, France; 8Medico-surgical
Intensive Care Unit, Pontoise Hospital, Pontoise, France; 9Medical Intensive Care Unit, Brest University Hospital, Brest, France; 10Medical Intensive
Care Unit, Bordeaux University Hospital, Bordeaux, France; 11Medical Intensive Care Unit, Besancon University Hospital, Besancon, France;
12
tel-Dieu University Hospital, Paris, France; 13Medical Intensive Care Unit, Ariana University
Respiratory and Medical Intensive Care Unit, Ho
Hospital, Ariana, Tunisia; 14Medical Intensive Care Unit, Lyon University Hospital, Lyon, France; 15Medical Intensive Care Unit, Mulhouse Hospital,
Mulhouse, France; and 16INSERM U 657, Rouen University, Rouen, France

Rationale: The use of noninvasive ventilation (NIV) as an early

weaning/extubation technique from mechanical ventilation
remains controversial.
Objectives: To investigate NIV effectiveness as an early weaning/
extubation technique in difficult-to-wean patients with chronic hypercapnic respiratory failure (CHRF).
Methods: In 13 intensive care units, 208 patients with CHRF intubated for acute respiratory failure (ARF) who failed a first spontaneous breathing trial were randomly assigned to three groups:
conventional invasive weaning group (n 69), extubation followed
by standard oxygen therapy (n 70), or NIV (n 69). NIV was
permitted as rescue therapy for both non-NIV groups if postextubation ARF occurred. Primary endpoint was reintubation within 7 days
after extubation. Secondary endpoints were: occurrence of postextubation ARF or death within 7 days after extubation, use of rescue
postextubation NIV, weaning time, and patient outcomes.
Measurements and Main Results: Reintubation rates were 30, 37, and
32% for invasive weaning, oxygen-therapy, and NIV groups, respectively (P 0.654). Weaning failure rates, including postextubation ARF,

(Received in original form January 7, 2011; accepted in final form May 19, 2011)
This study was funded by the Rouen University Hospital and supported by the
National Clinical Research Hospital Program 01/012-HP-PHRC (French Ministry of
Health).
Funding and support agencies were not involved in the study design, data collection, data analysis and interpretation, writing or approval of the manuscript.
Presented in part at the American Thoracic Society International Conference in
San Diego, May 1520, 2009.
Author contributions: C.G.: idea of the study; study design and conception;
obtaining funding, administrative, and material support; study supervision; literature research; data collection; data analysis and interpretation; manuscript writing; final approval. M.B.: statistical analysis, data analysis and interpretation, final
approval. F.A., J.L.D., S.E., P.B., J.R., E.L., G.H., G.C., A.R., M.B., C.G., P.G.: data
collection, data analysis and interpretation, final approval. J.B.: study design and
conception, statistical analysis, data analysis and interpretation, final approval.
G.B.: study design and conception, administrative and material support, study
supervision, data analysis and interpretation, final approval.
*A complete list of members may be found before the beginning of the REFERENCES.
Correspondence and requests for reprints should be addressed to Christophe
pital Charles Nicolle, Centre
Girault, M.D., Service de Reanimation Medicale, Ho
pitaux de Rouen, 1, rue de Germont 76031 Rouen,
Hospitalier Universitaire-Ho
CEDEX, France. E-mail: Christophe.Girault@chu-rouen.fr
Am J Respir Crit Care Med Vol 184. pp 672679, 2011
Originally Published in Press as DOI: 10.1164/rccm.201101-0035OC on June 16, 2011
Internet address: www.atsjournals.org

AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject

The use of noninvasive ventilation (NIV) as an early

weaning/extubation technique from invasive mechanical
ventilation remains controversial.
What This Study Adds to the Field

NIV used as an early weaning/extubation technique in

difficult-to-wean patients with chronic respiratory failure did
not reduce the reintubation rate within 7 days as compared
with conventional weaning and early extubation with standard oxygen therapy. Nevertheless, NIV may improve the
weaning results in these patients by shortening the intubation
duration and reducing the risk of postextubation acute respiratory failure The potential benefit of rescue postextubation NIV in these patients needs further study

were 54, 71, and 33%, respectively (P , 0.001). Rescue NIV success
rates for invasive and oxygen-therapy groups were 45 and 58%, respectively (P 0.386). By design, intubation duration was 1.5 days
longer for the invasive group than in the two others. Apart from a longer weaning time in NIV than in invasive group (2.5 vs. 1.5 d; P 0.033),
no significant outcome difference was observed between groups.
Conclusions: No difference was found in the reintubation rate between the three weaning strategies. NIV decreases the intubation
duration and may improve the weaning results in difficult-to-wean
patients with CHRF by reducing the risk of postextubation ARF. The
benefit of rescue NIV in these patients deserves confirmation.
Clinical trial registered with www.clinicaltrials.gov (NCT 00213499).
Keywords: noninvasive ventilation; weaning; extubation; acute respiratory failure; chronic obstructive pulmonary disease

Noninvasive ventilation (NIV) has been recently developed for

the management of weaning/extubation from invasive mechanical ventilation (MV) and postextubation acute respiratory failure (ARF) (1), the main goal being to shorten intubation time
and to prevent or avoid reintubation and subsequent complications (2, 3). The weaning/extubation period represents an important clinical issue for clinicians and patients, and prediction

Girault, Bubenheim, Abroug, et al.: Noninvasive Ventilation and Weaning

of its outcome may be difficult in most weak patients. Difficult

weaning requiring a progressive withdrawal from MV may occur, in fact, in 25% of intensive care unit (ICU) patients (4, 5)
and in 40 to 60% of patients with chronic obstructive pulmonary
disease (COPD) (6, 7). The weaning time may also account for
up to 40% of the total invasive MV duration (8, 9). Moreover,
reintubation may be necessary within 48 to72 hours in 5 to 25%
of planned extubation, even if a spontaneous breathing trial
(SBT) has been successful (3, 10). Reintubation represents per
se an independent risk factor for nosocomial pneumonia, increasing ICU and hospital stay as well as mortality (3, 8).
Hence, the ICU clinician has to find the optimal compromise
between the risks of unduly prolonged intubation and those of
too early weaning and extubation process (11, 12). Therefore,
any strategy with the aim of reducing morbidity and mortality of
prolonged invasive MV or reintubation appears relevant and
should be developed to improve patient prognosis.
Consequently, NIV has been evaluated as an early weaning
and extubation technique in difficult-to-wean patients (1317).
Despite encouraging results regarding the incidence of reintubation, complications, and patient outcome, the role of NIV in
this indication remains debated (11, 18, 19). A recent metaanalysis found that a noninvasive weaning strategy could be of potential benefit as compared with conventional invasive weaning,
particularly in patients with COPD (20). However, these authors
acknowledged that larger controlled trials were still needed. In
addition, despite the negative results of NIV to treat postextubation ARF (i.e., rescue postextubation NIV) in medical patients
(21, 22), the interest of this approach probably requires further
evaluation in more selected medical populations.
We conducted a prospective randomized multicenter study
to investigate the effectiveness of NIV as an early weaning/
extubation technique in patients with chronic hypercapnic respiratory failure (CHRF) considered difficult to wean from invasive
MV. We also evaluated the role of rescue postextubation NIV
when a postextubation ARF occurred in these patients.
Some of the results of this study have been previously reported in the form of an abstract (23).

METHODS
The study was approved by the Local Ethics Committee of Rouen University Hospital and all patients or their families gave their signed informed consent before inclusion. The methodology used has been
previously published elsewhere (24).

Patient Selection
Patients were consecutively recruited between January 2002 and March
2006 from 13 French and Tunisian ICUs experienced in NIV for more
than 5 years. Eligible patients were those with known or suspected CHRF
based on their clinical history (COPD, persistent asthma, bronchiectasis,
obesity-hypoventilation syndrome, chest wall deformity, sequelae of pulmonary tuberculosis), chest X-ray, arterial blood gases (ABG) in steady
state, and/or admission bicarbonates level, as well as previous pulmonary
function tests if available. They had to be intubated for at least 48 hours
for ARF regardless of etiology. They also had to be clinically stable for at
least 24 hours to undergo an SBT after they had met the following weaning criteria based on a daily screening evaluation: PaO2/FIO2 greater than
or equal to 150 mm Hg, positive end expiratory pressure (PEEP) less
than or equal to 5 cm H2O, no vasopressor or sedation and Glasgow
Coma Score greater than or equal to 12, effective cough (11). Patients
were included in the study only if they exhibited SBT intolerance, administered via a T-piece, occurring between 5 minutes and 2 hours (7).
SBT intolerance was based on one of the following clinical and/or ABG
criteria if available: sweats, agitation, somnolence, or consciousness impairment; respiratory rate greater than 35/min or greater than or equal to
50% increase relative to baseline; decrease in SaO2 greater than or equal

673

to 5%; increase in heart rate or systolic blood pressure greater than or

equal to 20%; PaO2 less than or equal to 60 mm Hg (8 kPa) with FIO2 of
40% and/or pH less than 7.35. For the purpose of the study, these
patients, who failed a first SBT, were considered as difficult to wean from
MV. In the event of SBT intolerance within 5 minutes, suggesting insufficient ventilatory autonomy, the patient was reventilated in assist-controlled
mode and SBT was attempted again the next day. The noninclusion
criteria were as follows: good SBT tolerance for at least 2 hours, the
patient being then extubated; hemodynamic and/or clinical respiratory
instability; initial intubation considered as difficult; suspected swallowing disorders; ineffective cough and/or persistent bronchial hypersecretion at the time of weaning; uncooperative patient; contraindications
for the use of a face mask (skin lesions, etc.); recent gastrointestinal
surgery or myocardial infarction; home NIV; tracheostomy; refusal of
consent or participation in another study (Figure 1).
In cases of SBT intolerance, patients were randomized into the following three groups: conventional invasive weaning group, extubation
followed by standard oxygen therapy, and extubation followed by NIV.
The weaning strategy was allocated based on a computer-generated randomization table using variable blocks of four, sealed and opaque envelopes according to center stratification.

Weaning Procedure According to the Randomization Arm

Conventional invasive weaning was performed using one of the following techniques: one or more daily SBT with T-piece or pressure support
ventilation (PSV) with or without PEEP, and a progressive decrease in
PSV level until less than or equal to 7 cm H2O. Regardless of the
technique, FIO2 was set to maintain SaO2 greater than or equal to
90%. Patients whose SBT was successful were then extubated. In contrast, patients were reventilated according to the ventilatory mode previously used, and invasive weaning was continued on the following
days.
For both oxygen-therapy and NIV groups, SBT failure was followed
by a reventilation period of at least 30 minutes, and extubation, performed the day of randomization after informed consent was obtained,
was followed either by standard oxygen therapy to maintain SaO2
greater than or equal to 90% or immediate NIV after the technique
was explained to the patient. NIV was applied via a face mask as first
choice, with an ICU or a specific NIV ventilator depending on the
center practice. NIV was performed in a semirecumbent position for
a daily duration greater than or equal to 6 hours, as continuous initially,
then intermittently with oxygen spontaneous breathing (SB) periods.
The preferred recommended ventilatory mode was PSV 6 PEEP or
bilevel positive airway pressure, initially set to obtain an expiratory
tidal volume greater than 7 ml/kg and a respiratory rate less than 30
cycles/min. The oxygen flow on SB, FIO2, and PEEP with NIV were set
to maintain SaO2 greater than or equal to 90%. These initial settings,
type of mask, and NIV sequences were secondarily adjusted to the
patients comfort and tolerance, presence of air leaks, and ABG controls. Criteria to discontinue NIV were as follows: daily need less than 6
hours or respiratory stability with standard oxygen therapy for at least
12 hours, thus allowing for a PaO2 greater than or equal to 64 mm Hg
(8.5 kPa) with pH greater than or equal to 7.35 and PaCO2 less than or
equal to 60 mm Hg (8 kPa).
The use of NIV was permitted as rescue therapy, before eventual
reintubation, in both invasive and oxygen-therapy groups in cases of
postextubation ARF occurrence (rescue postextubation NIV) defined
by at least two of the following criteria: tachypnea greater than 30/min
or bradypnea less than 12/min; hypoxemia under O2 greater than or
equal to 6 L/min or FIO2 greater than or equal to 50% with a Venturi
mask (i.e., SaO2 , 90% or PaO2 , 64 mm Hg [8.5 kPa] or PaO2/FIO2 <
130 mmHg); hypercapnia with respiratory acidosis under nasal O2
less than or equal to 3 L/min (i.e., increase of PaCO2 > 10% relative to
pre-extubation value [SBT] and pH < 7.35); clinical signs of ARF
(i.e., cyanosis, sweats, involvement of accessory respiratory muscles, paradoxical abdominal motion, consciousness impairment). NIV application
and discontinuation modalities were similar to that of the NIV weaning
group.
For the three weaning groups, the reintubation decision was based
either on (1) one of the following major criteria: respiratory or cardiac
arrest, persistent severe hypoxemia (PaO2/FIO2 < 130 mm Hg) despite
NIV, hemodynamic instability with systolic blood pressure less than or

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Figure 1. Flowchart of the trial. * For the

main outcome criterion. hemod.
hemodynamic; NIV noninvasive ventilation; resp. respiratory; SBT spontaneous breathing trial.

equal to 85 mm Hg despite adequate vascular filling, severe cardiac

arrhythmia; or (2) at least two of the following minor criteria: ineffective ventilation due to agitation and/or major air leaks under NIV;
clinical signs of severe ARF with tachypnea greater than 35/min
and/or pH less than 7.20; occurrence, persistence, or worsening of
ARF under NIV (tachypnea, sweats, cyanosis, involvement of accessory respiratory muscles, paradoxical abdominal motion, and/or respiratory acidosis impairment); consciousness deterioration or respiratory
encephalopathy score (0: normal consciousness; 1: mild flapping
tremor; 2: severe flapping tremor and mild confusion; 3: severe confusion with diurnal sleepiness or mild agitation; 4: coma or major agitation) worsening (> 3) under NIV; bronchial hypersecretion under NIV;
development of other organ failure. In all cases, the attending physician
made the final decision regarding reintubation as needed.
In all three groups, weaning from invasive MV was associated with
continuous noninvasive respiratory and hemodynamic monitoring as
well as optimized medical treatment determined by the attending physician in light of the underlying conditions and the cause of ARF responsible for intubation.

respectively) (4, 5, 13, 14, 25), and anticipating a postrandomization

secondary exclusion risk of approximately 5% (e.g., death before extubation), the sample size was 66 patients in each group, leading to a total
of 208 allocated patients. An interim analysis was planned for the
primary endpoint after the 99th patient was included, based on a type
1 risk of 2.94%. The trial was monitored by an independent data and
safety monitoring board.
All endpoints were analyzed applying the intention-to-treat principle. Continuous data were reported as median with 1st and 3rd quartiles
(Q1Q3) and categorical data as absolute number with percentage.
Comparisons between the three groups were performed with the
Kruskal-Wallis test for ordinal variables, and Fisher exact, FreemanHalton, or the likelihood ratio test for nominal variables as appropriate. Time-to-event analyses were based on the actuarial method for
estimation and the log-rank test for the overall comparisons of several
independent groups. A P value less than 0.05 was considered statistically significant. In addition, a center effect was controlled for using the
Cochran-Mantel-Haenszel test. Analyses were performed using the
SAS 9.2 statistical software (SAS Institute Inc., Cary, NC).

Data Collection and Evaluation Criteria

RESULTS

The following characteristics were recorded on admission: demographic

data, simplified acute physiological score II (SAPS II), McCabe score,
underlying CHRF type, cause of ARF, home oxygen therapy, NIV failure before intubation. The following characteristics were collected on
randomization: duration of prior hospitalization and invasive MV, number of prior SBTs, duration of tolerance for the last SBT, ABG data after
SBT failure if available, initial weaning technique and settings.
We evaluated the weaning/extubation results according to the weaning strategy allocated. The primary endpoint of the study was defined as
the need for reintubation within 7 days after extubation for all three
groups. Causes and time to reintubation were recorded.
The secondary endpoints were: secondary occurrence of postextubation ARF (as defined above) or death from all causes within 7 days after
extubation. To assess more globally the weaning failure, we then determined a composite criterion including postextubation ARF, reintubation, or death occurrence within 7 days after extubation. We also
evaluated the time to rescue postextubation NIV and its related success
rate (i.e., the probability of reintubation or death within 7 days after its
initiation), duration of the weaning procedure, weaning or invasive MV
complications, ICU and hospital length of stay and survival, and respiratory condition on hospital discharge. Patients were followed up until
Day 28 or hospital discharge. In addition, we performed a post hoc
analysis for the subgroup of patients with CHRF due to COPD regarding the weaning results and survival.

Statistical Analysis
According to a two-sided 5% type 1 error and 80% power to detect a difference in the reintubation rate of at least 10% between each group
based on previous data (i.e., for weaning failure rates of 20, 30, and
10% for the invasive weaning, oxygen-therapy, and NIV groups,

Of the 388 eligible patients, 180 (46%) were not included, mainly
due to SBT success in 127 patients (71%) (Figure 1). The
remaining 208 patients were randomized as follows: 69 in the
invasive weaning group, 70 in the oxygen-therapy group, and 69
in the NIV group. Two and one patient died before reintubation
in the first and third group, respectively. As a result, 67 and 68
patients in these two groups were kept in the primary endpoint
analysis (Figure 1).
There was no significant difference between the characteristics of the three groups on admission and randomization (Table
1). The underlying CHRF was mainly due to COPD (69%). For
the invasive group, the weaning technique was primarily SBT
with T-piece (80%) then PSV (20%). A PS mode was used for
97% of patients in the NIV group, with median levels of PS and
PEEP of 15 (1218) and 4 (35) cm H2O, respectively.
The main weaning results are shown in Table 2 and Figure 2.
The probability of reintubation was not significantly different
between the three weaning strategies, even when including the
occurrence of death within 7 postextubation days. Causes and
time for reintubation were similar for the three groups. Regarding the primary endpoint, no significant center effect was observed (P 0.654).
Weaning results differed significantly between groups, favoring the interventional NIV group, when postextubation ARF occurrence was considered in the weaning outcome. Thus, NIV
significantly decreased the incidence of postextubation ARF
as compared with both non-NIV groups (log-rank test, P ,

Girault, Bubenheim, Abroug, et al.: Noninvasive Ventilation and Weaning

675

TABLE 1. PATIENTS CHARACTERISTICS ON BOTH ADMISSION AND RANDOMIZATION

Parameters
Characteristics on admission
Age, yr
Sex, M/F
SAPS II
McCabe score
CHRF type
Obstructive
Restrictive
Mixed
Unknown
LTO (yes/no/unknown), n
ARF causes
Acute exacerbation
Pneumonia
ACPE
Other
NIV failure before ETMV
Characteristics at randomization
Duration of prior hospital stay, d
Duration of prior ICU stay, d
Duration of prior ETMV, d
Number of SBT before randomization
Duration of last SBT tolerance, min
ABG for SBT intolerance
FIO2 used, %
PaO2/FIO2, mm Hg
PaO2, mm Hg
SaO2, %
pH
PaCO2, mm Hg
HCO32, mmol/L

Invasive Weaning Group (n 69)

O2 Group (n 70)

NIV Group (n 69)

P Value

70 [6075]
42 (61)/27 (39)
40 [3457]
2 [12]

72 [6579]
55 (78)/15 (22)
40 [3450]
1 [12]

71 [6676]
52 (75)/17 (25)
46 [3456]
1 [12]

0.188
0.051
0.495
0.453
0.215

50 (73)
7 (10)
9 (13)
3 (4)
21/45/3
n 66
27 (41)
21 (32)
4 (6)
14 (21)
15 (23)

46 (66)
8 (11)
14 (20)
2 (3)
16/52/2
n 68
24 (35)
22 (32)
5 (7)
17 (25)
19 (28)

48 (69)
2 (3)
15 (22)
4 (6)
16/49/4
n 65
33 (51)
12 (18)
4 (6)
16 (25)
16 (25)

10
6
6
1
50

[515]
[412]
[411]
[13]
[3080]
n 46
40 [4040]
195 [158221]
73 [6085]
994 [9097]
7.37 [7.327.43]
52 [4666]
31 [2934]

10
7
7
1
45

[717]
[413]
[511]
[12]
[2090]
n 52
40 [4050]
171 [152213]
73 [6185]
94 [8896]
7.36 [7.307.40]
53 [4764]
31 [2933]

8
6
6
1
45

[514]
[49]
[410]
[12]
[1760]
n 40
40 [4050]
183 [145233]
77 [6090]
94 [9196]
7.36 [7.317.40]
53 [4561]
29 [2633]

0.521
0.493

0.787
0.421
0.669
0.721
0.927
0.362
0.445
0.523
0.760
0.503
0.436
0.859
0.131

Definition of abbreviations: ABG arterial blood gases; ACPE acute cardiogenic pulmonary edema; ARF acute respiratory failure; CHRF chronic hypercapnic
respiratory failure; ETMV endotracheal mechanical ventilation; ICU intensive care unit; LTO long-term oxygen therapy; NIV noninvasive ventilation; Q
quartile; SAPS Simplified Acute Physiologic Score; SBT spontaneous breathing trial.
Data are presented as median [Q1Q3] or n (%) unless otherwise noted.

0.001) (Table 2, Figure 2). In cases of postextubation ARF,

rescue postextubation NIV was used more frequently in the
oxygen-therapy (57%) than in the invasive group (45%), but
this difference was not significant. The time for rescue therapy
was similar between these two groups. In both non-NIV groups,
the use of rescue postextubation NIV avoided reintubation or
death in 37 of 71 patients overall (52%) without any difference
in the success rates between the two groups. By design, intubation

duration was found to be longer for the invasive group by 1.5 (0.5
3.5) days than for the two other groups. The duration of ventilatory support for weaning was significantly longer for the initial
NIV group than the invasive group (P 0.033).
Apart from the intubation and ventilatory support for weaning durations, no difference was observed between the three
weaning strategies regarding invasive MV and weaning complications during the study or for other outcomes (Table 3, Figure 3).

Figure 2. Probability of weaning failure within the first 7 days after extubation for the overall population according to study group. ARF acute
respiratory failure; NIV noninvasive ventilation.

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TABLE 2. WEANING RESULTS ACCORDING TO STUDY GROUP

Parameters
Weaning results
Reintubation < 7 d
Reintubation or death < 7 d
Postextubation ARF or death < 7 d
Postextubation ARF, reintubation, or death < 7 d
Rescue NIV for postextubation ARF
Success rate (no reintubation or death < 7 d)
Causes of reintubation
Consciousness deterioration or encephalopathy score > 3
Persistent severe hypoxemia
ARF occurrence, persistence. or worsening under NIV
Hypotension/shock
Arrhythmia
Other organ failure
Time to reintubation, d
Time to postextubation NIV, d
Duration of intubation, d
Duration of ventilatory support for weaning, dx
Weaning results in patients with COPD
Reintubation < 7 d
Reintubation or death < 7 d
Postextubation ARF or death < 7 d
Postextubation ARF, reintubation, or death < 7 d

Invasive Weaning Group (n 69)

O2 Group (n 70)

NIV Group (n 69)

P Value

20/67 (30)*
22/69 (32)
32/69 (46)
37/69 (54)
31/69 (45)
14/31 (45)
n 20
15 (75)
8 (40)
13 (65)
4 (20)
0
2 (1)
1.5 [0.53.5]
0.5 [0.51.5]
1.5 [0.53.5]
1.5 [0.53.5]
n 50
12/48 (25)*
14/50 (28)
21/50 (42)
24/50 (48)

26/70 (37)
26/70 (37)
41/70 (59)
50/70 (71)
40/70 (57)
23/40 (58)
n 26
16 (62)
15 (58)
16 (61.5)
3 (12)
2 (8)
1(4)
0.5 [0.53.5]
0.5 [0.50.5]
0

n 46
17/46 (37)
17/46 (37)
24/46 (52)
32/46 (70)

22/68 (32)*
23/69 (33)
6/69 (9)
23/69 (33)

n 22
11 (50)
10 (45)
15 (68)
1 (5)
0
0
0.5 [0.51.5]

0
2.5 [0.53.5]
n 48
13/47 (28)*
14/48 (29)
4/48 (8)
14/48 (29)

0.654
0.758
,0.001
,0.001
0.176
0.386
0.239
0.513
0.949
0.323
0.328
0.380
0.141
0.139

0.033
0.420
0.516
,0.001
,0.001

Definition of abbreviations: ARF acute respiratory failure; CHRF chronic hypercapnic respiratory failure; NIV noninvasive ventilation; Q quartile.
Data are presented as median [Q1Q3] or n (%) unless otherwise noted.
* Due to two and one deaths before reintubation within 7 d in invasive weaning and NIV groups respectively.
y
Only the first event was considered for one patient.
z
All reintubations were justified by one or more causes per patient.
x
By excluding the time for ventilatory support in cases of rescue postextubation NIV or reintubation, defined as the time from randomization to extubation for the
invasive group and to NIV stop or reintubation for the NIV group.

For the subgroup of patients with COPD, similar weaning and

survival results were found as in the overall population (Table 2).

DISCUSSION
In the present study, which focused on NIV as an early weaning/
extubation technique in difficult-to-wean CHRF population, we
found no statistically significant difference in the probability of
reintubation between the three weaning strategies. However, the
study demonstrates that NIV may improve weaning results in
these patients by reducing the risk of postextubation ARF occurrence. Although the duration of intubation was shortened, the
ventilatory support time dedicated to weaning was found to
be slightly increased with NIV. Our results also suggest that rescue NIV might be useful to avoid reintubation when postextubation ARF occurs in these patients.
The clinical benefit of NIV is well recognized for the initial
management of hypercapnic ARF (18, 19, 26), leading to its
increasing use in France (27), Europe (28), and worldwide (8).
Several randomized trials have assessed NIV as a weaning/
extubation technique relative to conventional methods in
patients with initial (13, 14, 16, 17) or persistent (15) weaning
difficulties from invasive MV. As expected, these studies demonstrated a reduction in the invasive MV duration with NIV,
but they also showed some discrepancies in terms of weaning
success or failure, incidence of reintubation, total MV duration,
complications, and patient outcome. These controversial results
have been recently underlined in a metaanalysis involving 12
randomized studies and 530 patients (20).
The VENISE trial (VEntilation Non Invasive et SEvrage) involved a large cohort of patients with CHRF considered as
potentially difficult to wean based on the first SBT failure,
69% of whom were patients with COPD. No significant difference was found between the three weaning strategies regarding
the incidence of reintubation, even in the subgroup of patients

with COPD. These findings are consistent with those previously

published (1317), as well as with conclusions of the aforementioned metaanalysis (20). Not surprisingly for the oxygen-therapy
group, we also observed relatively high rates of reintubation in
the two other groups as compared with those previously
reported (47, 10, 11). Nevertheless, the interpretation of this
finding should consider that the study involved difficult-to-wean
patients with CHRF, the time between randomization and SBT
was relatively short, as well as the fact we have observed the
reintubation incidence within a 7-day period after extubation.
Furthermore, in line with previous studies (1317, 20) and by
design, NIV allowed decrease of the intubation duration as
compared with invasive weaning without increasing the risk
of weaning failure in terms of reintubation. In contrast to two
previous studies (13, 15), this benefit was obtained at the expense of an obviously increased ventilatory support time related
to weaning with NIV. Similar results have been previously
reported (14), suggesting that NIV might, in fact, allow earlier
extubation but not necessarily more rapid de-ventilation in
difficult-to-wean patients with CHRF according to their severity. In addition, our study demonstrated that NIV used as an
early weaning/extubation technique may be useful to prevent or
avoid the risk of postextubation ARF as compared with conventional weaning and early extubation with standard oxygentherapy groups. In these two latter groups, we can reasonably
assume that some patients would have been reintubated for
postextubation ARF if NIV was not applied as rescue therapy.
These positive results with NIV for reducing postextubation
ARF occurrence appear, in fact, very similar to those reported
in studies assessing the preventive effect of postextubation NIV
in patients who successfully passed an SBT but were considered
at high risk for extubation failure (2932). Interestingly, these
latter patients were also hypercapnic during or after the successful SBT.

Girault, Bubenheim, Abroug, et al.: Noninvasive Ventilation and Weaning

677

Figure 3. Probability of intensive care unit and hospital survival for the overall population according to study group. ICU intensive care unit;
NIV noninvasive ventilation.

The study also suggests a potential benefit of rescue NIV applied in cases of postextubation ARF occurrence in our selected
population. Indeed, it was applied frequently in the two non-NIV
groups and reduced the risk of reintubation or death in 45% of
patients assigned invasive weaning and 58% of those assigned to
the oxygen-therapy group. Furthermore, the reintubation rate
was not different between the three weaning strategies, nor
was rescue postextubation NIV time between the two nonNIV groups. Rescue NIV for the management of postextubation
ARF is currently not recommended for medical patients (11, 19)
based on no proven benefit to avoid reintubation and potential
harmful reintubation delay on mortality (21, 22). However,
these randomized studies were conducted in very heterogeneous

populations, including mainly hypoxemic postextubation ARF

and only 10% (21) to 12% (22) of patients with COPD. Moreover, they were performed in centers that were sometimes poorly
experienced with NIV. Although our encouraging results enhance those previously reported in hypercapnic patients with
CHRF (30, 33), because our patients were not randomized on
postextubation ARF occurrence, prospective randomized trials
are therefore still necessary to further demonstrate the benefit
of rescue postextubation NIV in this particular population.
By contrast to previous studies (13, 1517), we did not observe any benefit of NIV in terms of MV complications, length
of stay, and patient outcomes. One explanation could be the
frequent use of rescue postextubation NIV in both non-NIV

TABLE 3. COMPLICATIONS AND OUTCOME RESULTS FOR THE OVERALL POPULATION ACCORDING TO STUDY GROUP
Parameters
ETMV or weaning complications
Type of complications*
Autoextubation
Postextubation stridor
Tube obstruction
Respiratory encephalopathy
Bronchial hypersecretion
Nosocomial pneumonia
Sinusitis
Atelectasis
Cardiac arrhythmia
Hemodynamic collapse
ACPE
Paralytic ileus
Gastric distension
Mask intolerance
ICU stay, d
Hospital stay < 28 d
ICU survival
Hospital survival < 28 d
Respiratory support at discharge in last surviving patients
SB in ambient air
SB with oxygen therapy
NIV
Tracheostomy
Unknown

Invasive Weaning Group (n 69)

O2 Group (n 70)

NIV Group (n 69)

P Value

35 (51)

43 (61)

33 (52)

0.247

5
11
1
4
7
10
1
1
6
7
2
3

(7)
(16)
(1)
(6)
(10)
(14)
(1)
(1)
(9)
(10)
(3)
(4)

7.5 [4.514.5]
18.5 [9.528]
64 (93)
60 (87)
n 55
30 (55)
12 (22)
8 (15)
3 (5)
2 (4)

6 (9)
14 (20)

7 (10)
12 (17)
17 (24)
2 (3)
3 (4)
5 (7)
9 (13)
1 (1)
3 (4)

7.5 [4.517.5]
19.5 [12.528]
61 (87)
61 (87)
n 54
25 (46)
19 (35)
7 (13)
2 (4)
1 (2)

6 (9)
6 (9)
1 (1)
6 (9)
6 (9)
9 (13)
1 (1)
2 (3)
5 (7)
12 (17)
1 (1)
1 (1)
5 (7)
5 (7)
7.5 [4.515.5]
17.5 [9.528]
56 (81)
53 (77)
n 50
20 (40)
22 (44)
4 (8)
2 (4)
2 (4)

1.000
0.161
0.551
0.735
0.308
0.184
1.000
0.873
0.949
0.462
0.848
0.703

0.691
0.616
0.101
0.154
0.512

Definition of abbreviations: ACPE acute cardiogenic pulmonary edema; ETMV endotracheal mechanical ventilation; ICU intensive care unit; NIV noninvasive
ventilation; Q quartile; SB spontaneous breathing.
Data are presented as median [Q1Q3] or n (%) unless otherwise noted.
* One or more complications per patient.

678

AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE

groups, particularly in the oxygen-therapy group, and its benefit

to avoid reintubation. Indeed, this might have contributed to
narrowing the difference in outcome between the three groups.
Nevertheless, the difference in ICU and hospital survival observed between groups, although not significant, may require
further studies sufficiently powered for these outcome criteria.
The process of discontinuing invasive MV represents an important clinical issue for the ICU physician, particularly in
patients with COPD. The rate of weaning success/failure may
vary widely according to various studies, weaning techniques,
and modes of ventilation used, as well as the definition of weaning outcome (49). This definition has been recently revised and
weaning failure should no longer be limited as either SBT failure or the need for reintubation within 48 hours after extubation (11). In fact, the need for postextubation NIV should also
be considered now as part of the weaning outcome. To our
knowledge, the weaning failure, including reintubation and/or
the need for rescue NIV in cases of postextubation ARF, has
been applied in only one previous study (13). Finally, the recently recommended definition of weaning outcome (11) should
certainly be considered in the interpretation of our results and
its comparison with previous (20) and future studies.
The VENISE trial is currently the largest prospective randomized multicenter study on the use of NIV for early
weaning/extubation from invasive MV. One major feature of
the study is the design that included a control group that received
standard oxygen therapy only. As the real need for programmed
NIV for weaning/extubation may have been questioned in previous studies (13, 14), we did not use this group as another way
to perform weaning but to demonstrate more objectively the
real usefulness of NIV in this indication. Interestingly, additional information is also provided by the oxygen-therapy
group, because a substantial number of patients who failed
SBT were successfully extubated on the same day. The study
also involved a selected population of patients with CHRF considered as difficult to wean, mainly due to COPD. Moreover, we
followed the weaning results up to 7 days after extubation to
better track the late occurrence of NIV failure (34) and consider
patients with a potentially prolonged weaning (11). Nevertheless, several limitations of the present study should be acknowledged. First, it was not possible, for obvious reasons, to conduct
a double-blind investigation. Despite clearly predefined evaluation criteria and interventional procedures during the trial, the
impact of such a bias cannot be definitely excluded. However,
most attending physicians were not directly involved in the
study. Moreover, the oxygen-therapy group enabled us to better
control this bias and underscored the interest of NIV in the
interventional group. Second, the use of rescue NIV in cases
of postextubation ARF might have contributed to reduce the
difference in patient outcome between the three groups, mainly
for the primary endpoint. Indeed, as stated above, reintubation
would have been highly likely if rescue NIV was not allowed in
the two non-NIV groups. Nevertheless, based on previously
published data (30, 33) and for ethical reasons, we felt it was
difficult not to offer the possibility of rescue NIV before reintubating the patient. Furthermore, we cannot formally exclude
that some patients of the three weaning groups, particularly
those of the interventional NIV group, might have experienced
ARF worsening under NIV but benefited from NIV intensification, and hence were not reintubated. Last, the trial was conducted in centers with extensive experience with NIV. Therefore,
present results could probably not apply to those centers less
experienced with this technique. In our view, in agreement with
other authors (1, 20, 30), a skilled team is a major determinant to
efficiency and safety of NIV applied within the weaning and
postextubation period.

VOL 184

2011

In conclusion, NIV used as an early weaning/extubation technique in difficult-to-wean patients with CHRF did not reduce the
reintubation rate within 7 days as compared with conventional
weaning and early extubation with standard oxygen therapy.
Nevertheless, NIV may improve the weaning results in these
patients by shortening the intubation duration and reducing the
risk of postextubation ARF. Our results should support the implementation of NIV in clinical practice to manage weaning difficulties in patients with CHRF (20). The potential benefit of
postextubation NIV used as a rescue therapy requires confirmation by further randomized trials in this specific population.
Author Disclosure: C.G. receives honoraria from Philips Health Care-Respironics
France for a NIV educational program. M.B. does not have a financial relationship
with a commercial entity that has an interest in the subject of this manuscript.
F.A. does not have a financial relationship with a commercial entity that has an
interest in the subject of this manuscript. J.L.D. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.E. does not have a financial relationship with a commercial entity that
has an interest in the subject of this manuscript. P.B. does not have a financial
relationship with a commercial entity that has an interest in the subject of this
manuscript. J.R. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. E.L. does not have a financial
relationship with a commercial entity that has an interest in the subject of this
manuscript. G.H. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. G.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this
manuscript. A.R. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. M.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this
manuscript. C.G. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. P.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this
manuscript. J.B. does not have a financial relationship with a commercial entity
that has an interest in the subject of this manuscript. G.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this
manuscript.
The coinvestigators of the VENISE (VEntilation Non Invasive et SEvrage) Trial
Group: Tunisia: Fekri Abroug, M.D., Ph.D., Lamia Besbes, M.D. (Medical ICU,
Monastir University Hospital); Souheil Elatrous, M.D. (Medical ICU, Mahdia
University Hospital); Mohamed Besbes, M.D. (Medical ICU, Ariana University
Hospital).
France: Jean-Luc Diehl, M.D., Ph.D., Christophe Faisy, M.D., Emmanuel Guerot,
M.D. (Medical ICU, Georges Pompidou University Hospital, Paris); Guy Bonmarchand, M.D., Ph.D., Fahmi Dachraoui, M.D., Christophe Girault, M.D., Bouchra
Lamia, M.D., Fabienne Tamion M.D., Ph.D. (Department of Medical Intensive
Care, Rouen University Hospital); Pascal Beuret, M.D., Marie-Jose Carton, M.D.,
Mahmoud Kaaki, M.D. (Medico-surgical ICU, Roanne Hospital); Jack Richecoeur,
M.D., Eleonore Klebeev, M.D. (Medico-surgical ICU, Pontoise Hospital); Erwan
LHer, M.D., Ph.D. (Medical ICU, Brest University Hospital); Gilles Hilbert, M.D.,
Ph.D., Hoang-Nam Bui, M.D. (Medical ICU, Bordeaux University Hospital); Gilles
Capellier, M.D., Ph.D. (Medical ICU, Besancon University Hospital); Antoine Rabbat, M.D., Aurelie Lefebvre, M.D., Christine Lorut, M.D. (Respiratory and Medical
ICU, Hotel-Dieu University Hospital, Paris); Claude Guerin, M.D., Ph.D., Michel
Badet, M.D. (Medical ICU, Lyon University Hospital); Philippe Guiot, M.D. (Medical ICU, Mulhouse Hospital).
Data Monitoring and Management Board: Veronique Chambaretaud, Abdesslam
Chajara, Patrice Testut, Karim Lallouche (Clinical Research Assistants, Rouen University Hospital); Marie-France Hellot (Biostatistician, Rouen University Hospital);
Philippe Lagoutte (Data-manager, Rouen University Hospital).
Safety Monitoring Board: Herve Levesque, M.D., Ph.D. (Department of Internal
Medicine, Rouen University Hospital); Dominique Robert, M.D. (Medical ICU,
Lyon University Hospital); Benoit Veber, M.D., Ph.D. (Surgical ICU, Rouen University Hospital).
Mechanical Ventilation Research Group from the Societe de Reanimation de
Langue Francaise (SRLF): Laurent Brochard, M.D., Ph.D. (Medical ICU, Creteil
University Hospital); Alain Mercat, M.D., Ph.D (Medical ICU, Angers University
Hospital); Jean-Christophe Richard, M.D., Ph.D. (Medical ICU, Rouen University
Hospital); Jordi Mancebo, M.D., Ph.D. (Medical ICU, Barcelona University Hospital, Spain).
Acknowledgment: The authors thank the medical and nursing staff of all
the participating centers for their valuable cooperation in this trial, as well
as Richard Medeiros, Rouen University Hospital Medical Editor, for editing
the manuscript. They also thank the Mechanical Ventilation Research Group
from the Societe de Reanimation de Langue Francaise for their help in designing the study.

Girault, Bubenheim, Abroug, et al.: Noninvasive Ventilation and Weaning

679

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