Noninvasive ventilation to prevent respiratory failure after

extubation in high-risk patients*

Stefano Nava; Cesare Gregoretti; Francesco Fanfulla; Enzo Squadrone; Mario Grassi; Annalisa Carlucci;
Fabio Beltrame; Paolo Navalesi

Objective: Compared with standard medical therapy (SMT),

noninvasive ventilation (NIV) does not reduce the need for reintubation in unselected patients who develop respiratory failure
after extubation. The goal of this study was to assess whether
early application of NIV, immediately after extubation, is effective
in preventing postextubation respiratory failure in an at-risk population.
Design: Multiple-center, randomized controlled study.
Setting: Multiple hospitals.
Patients: Ninety-seven consecutive patients with similar baseline characteristics, requiring >48 hrs of mechanical ventilation and considered at risk of developing postextubation respiratory failure (i.e., patients who had hypercapnia,
congestive heart failure, ineffective cough and excessive tracheobronchial secretions, more than one failure of a weaning
trial, more than one comorbid condition, and upper airway
obstruction).

ostextubation respiratory failure is a rather common event

after discontinuation of mechanical ventilation, reintubation being needed in about 10% of patients (1, 2), with a range between 4% (3)
and 24% (4).
Nonrandomized studies (5, 6) suggested that noninvasive mechanical ventilation (NIV) may be successfully used,
especially in patients with hypercapnic
postextubation respiratory failure (6), as
a curative therapy to avoid reintubation. However, two subsequent randomized studies doused enthusiasm for this

*See also p. 2685.

From Respiratory Units, Fondazione S. Maugeri,
Istituto Scientifico di Pavia (SN, AC, PN), Istituto Scientifico di Montescano (FF), IRCCS, CTO Hospital,
Torino (CG), S. Luigi Gonzaga Hospital, Orbassano (ES),
Ospedale S. Maria Della Misericordia, Udine (FB), and
Department of Health Sciences, Section of Medical
Statistics & Epidemiology (MG), University of Pavia.
All the authors involved have no financial interest
to disclose.
Copyright 2005 by the Society of Critical Care
Medicine and Lippincott Williams & Wilkins
DOI: 10.1097/01.CCM.0000186416.44752.72

Crit Care Med 2005 Vol. 33, No. 11

Interventions: After a successful weaning trial, the patients

were randomized to receive NIV for >8 hrs a day in the first 48
hrs or SMT. Primary outcome was the need for reintubation
according to standardized criteria. Secondary outcomes were
intensive care unit and hospital mortality, as well as time spent
in the intensive care unit and in hospital.
Measurements and Main Results: Compared with the SMT
group, the NIV group had a lower rate of reintubation (four of 48
vs. 12 of 49; p .027). The need for reintubation was associated
with a higher risk of mortality (p < .01). The use of NIV resulted
in a reduction of risk of intensive care unit mortality (10%, p <
.01), mediated by the reduction for the need of reintubation.
Conclusions: NIV was more effective than SMT in preventing
postextubation respiratory failure in a population considered at risk
of developing this complication. (Crit Care Med 2005; 33:24652470)
KEY WORDS: standard medical therapy; noninvasive ventilation; reintubation; respiratory failure

strategy. Keenan et al. (7) reported no

difference in mortality and reintubation
rate when NIV was compared with standard medical therapy. Later Esteban et al.
(8) showed that NIV did not avoid the
need for reintubation and indeed that it
was associated with a higher intensive
care unit (ICU) mortality rate than was
standard medical treatment.
The length of time elapsed before reintubation is associated with mortality
rate (9), and therefore the treatment of
postextubation failure should be started
very early.
It has also been shown (2, 9) that there
is a clearly identified subset of patients
(i.e., those with comorbid conditions, increased work of breathing at the time of
failure, and upper airway obstruction) at
high risk of requiring reintubation.
We postulated that in comparison
with standard medical treatment, the
preventive use of NIV for the first 48 hrs
after extubation would reduce the need
for intubation and related complications
in these patients at risk. We tested this
hypothesis in a randomized, controlled
multiple-center study.

MATERIALS AND METHODS

Patients
Ninety-seven patients admitted to three
ICUs who had been ventilated 48 hrs and
who were considered at risk of developing
postextubation respiratory failure were enrolled. The enrolment criteria are shown in
Table 1. A weak cough was assessed using the
Airway Care Score (10). Chronic heart failure
(CHF) was defined according to the New York
Heart Association criteria (11). The presence
of comorbidities was classified as previously
described (12); CHF has been considered a
stand-alone risk factor of reintubation (2).
Weaning from mechanical ventilation was performed according to standardized protocols
using gradual daily reduction of pressure support or a single daily T-tube trial (13, 14). A
weaning trial was done once the patient had
reached a phase of clinical stability and met
the following criteria: a) normal sensorium; b)
absence of hyperthermia (core temperature38) and sepsis; c) PaO2 60 mm Hg at
a FIO2 40% with an external positive endexpiratory pressure (PEEPext) 5 cm H2O; d)
no cardiac ischemia or arrhythmias; e) a cuff
leak volume 110 mL (15). The patients able

2465

Table 1. Criteria for enrollment

Mechanical ventilation 48 hrs
Successful weaning trial
Plus one or more of the following high-risk scenarios for reintubation features:
1. More than one consecutive failure of weaning trial
2. Chronic heart failure
3. PaCO2 45 mm Hg after extubation
4. More than one comorbidity (excluding chronic heart failure)
5. Weak cough defined as Airway Care Score (10) values 8 and 12
6. Upper airways stridor at extubation not requiring immediate reintubation

to tolerate the spontaneous breathing trial for

1 hr, in accordance with published criteria,
were reconnected to the ventilator for 1 or 2
hrs and then extubated (13, 14).
Criteria for exclusion from the study were
coma, inability to protect the airways defined
as a Airway Care Score 12 (10) or a documented swallowing problem, cervical spine injury, neuromuscular diseases, lack of informed consent, agitated or uncooperative
state, anatomical abnormalities interfering
with the mask fit, uncontrolled cardiac ischemia or arrhythmias, and failure of more than
two organs. Patients overweight (i.e., body
mass index 30), those with documented or
suspected sleep apnea, and those already on
home noninvasive mechanical ventilation
were excluded from the study to avoid confounding factors. The study was approved by
the institutional Ethics Committee, and informed written consent was obtained from patients or their next of kin.

Protocol
One hour after successful extubation, Arterial blood gases were repeated, and the patients were randomized to either standard
medical therapy or NIV. The randomization
sequence was generated by a computer program with a variable block size.
Noninvasive Ventilation. All the patients
were ventilated using either a ventilator specifically designed for NIV (BiPAP Vision, Respironics) or an ICU ventilator, using a pressure support ventilation mode with the
addition of a PEEPext.
For patients who were hypercapnic, the
inspiratory pressure was adjusted according to
the patients tolerance and with a PEEPext 6
cm H2O. For the nonhypercapnic patients, the
PEEPext was initially set at 5 cm H2O and
could be increased until oxygen saturation was
constantly 92%, whereas the inspiratory
pressure support was initially set at 10 cm
H2O and then increased to the maximum tolerated.
In either case, both settings were aimed to
achieve respiratory rate25 breaths/min and
satisfactory gas exchange, that is, arterial oxygen saturation (SaO2) 92%, with pH 7.35.
The fractional concentration of oxygen was
such to achieve an SaO2 92%.

2466

A full face mask was used in all the patients

but five to start NIV and then, in some cases,
substituted by a nasal one after the first few
hours of ventilation.
NIV was applied following the so-called sequential protocol, modified from the protocol
proposed by Hilbert et al. (16). After the first
48 hrs of the protocol, if the patient was clinically stable, NIV was withdrawn; otherwise it
was ventilated ad libitum.
Standard Medical Therapy. Oxygen therapy was delivered to achieve SaO2 92%. Patients also received standard medical treatment, decided by the attending physicians.
Both groups received the same care by
nurses and respiratory therapists during the
ICU stay. In particular one daily session of
physiotherapy was provided to all the patients.
This included chest clapping, passive and active mobilization, and postural drainage, when
indicated.
Criteria for Intubation. In both study
groups, after patients had undergone the assigned treatment for 1 hr, they were reintubated if they met at least one of the following
major criteria usually employed in patients
developing postextubation respiratory failure
(8, 9): a) respiratory acidosis (pH 7.35 with a
PaCO2 45 mm Hg or in the presence of hypercapnia at the time of extubation, a PaCO2
increase 15%); and b) hypoxemia (i.e., SaO2
90% for FIO2 50%). Minor criteria for intubation were a) an increase in respiratory
rate 20% from the time of extubation and in
any case 35 breaths/min; b) clinical signs of
incipient respiratory muscle fatigue (use of
accessory muscles, inward movements of the
abdomen during inspiration); c) severe dyspnea; and c) inability to remove secretions
(Airway Care Score 12) (10). Patients had to
meet one of the major criteria or at least two
of the minor criteria to be intubated. Clearly,
endotracheal intubation was also promptly
performed in emergency situations such as
coma, cardiac or respiratory arrest, or severe
hypotension.
Measurements. The following variables
were recorded at enrollment: age, gender,
number and types of comorbidities, Simplified
Acute Physiology Score II (17), and reasons for
mechanical ventilation. Respiratory rate and
SaO2 were recorded continuously on the monitors, whereas arterial blood gases were analyzed once a day at 8 am and a) in the case of

any change either in the ventilatory settings

or in the FIO2; b) at the time of reintubation;
and c) at discharge from the ICU. Airway Care
Score was routinely monitored every 6 hrs. We
also recorded the effective hours/day on NIV,
the total days on mechanical ventilation before extubation, the total days of ICU and hospital stay, and the causes of intubation (9) and
death.
Outcomes. The primary end point was the
need for reintubation in the ICU. Secondary
end points were ICU and hospital mortality
and length of stay in the ICU and in hospital.

Statistical Analysis
The trial was designed to enter a maximum
number of patients in each treatment group of
97 to detect a decrement in reintubation frequency of 15% in the NIV group vs. the postulated 25% frequency of intubation in the
conventionally treated group (i.e., chronic obstructive pulmonary disease [COPD], acute respiratory failure (18, 19), and congestive heart
failure) (20) with a power of 80% at two-sided
p .05 (21). Two-stage ad-interim analysis
was planned after having recruited half of the
scheduled patients (22) using the equal-alpha
stopping rule of Pocock (23). This rule was
based on risk differences of primary outcome
(i.e., reintubation in this study) between the
two treatment groups, where the fixed nominal p value needed to stop the trial at stage 1
should be .0296. In the interim analysis, the
observed risk difference for intubation in the
NIV group was lower than that in the standard
therapy group and the p value was less than
the cutoff value of .03 (p .027), and the trial
was therefore stopped.
Results are presented as mean SD and
frequencies (percentages). Significance tests
of the patients differences at enrollment and
at the time of randomization were computed
by Students t-test and chi-square test, when
appropriate. Univariate analysis was performed to assess the association between NIV
and reintubation, NIV and ICU mortality, and
reintubation and ICU mortality. Subsequently,
a multivariate analysis was performed. The
associations between the variables, reintubation, ICU mortality, and NIV were fitted by
generalized linear models with binomial distribution and identity link, performed on an
intention-to-treat basis.
To assess the interaction between the socalled direct or indirect NIV effect on ICU
mortality (NIV on ICU mortality direct effect; NIV on ICU mortality mediated by the
NIV effect on reintubation indirect effect),
we applied a Mendelian randomization model
(24).

RESULTS
As shown in Figure 1, 122 patients
were considered to be at risk of postextuCrit Care Med 2005 Vol. 33, No. 11

Figure 1. Trial profile. Seven patients were not recruited because of an omission by the attending physician. NIV, noninvasive ventilation.

bation respiratory failure and therefore

eligible for the study. Twenty-five were
excluded so that 97 patients were randomly assigned to receive standard medical therapy or NIV.
The groups did not differ significantly
at the time of intubation (Table 2) and at
the time of randomization, which occurred 12 hrs after the weaning trial
(Table 3). In the NIV group, the ventilator
was set with the following pressures:
13.18 4.54 for the inspiratory support
and 5.29 1.61 for PEEPext. Of the 48
patients randomized to receive NIV, only
one did not tolerate the procedure,
whereas two did not achieve the minimal
hours of daily NIV, required by the protocol (8 hrs/day). Fourteen patients enrolled for NIV developed nose-skin redness or abrasion, two eye irritation, one
oral dryness, and two nasal congestion.
The primary diagnosis of admission,
the reasons for reintubation, and the
time it was done are illustrated for the
two groups in Table 4.
In the univariate model (Table 5), we
found that the use of NIV determined a
16% reduction on the risk for reintubation (p .027), whereas the protective
effect on ICU mortality (risk difference
12%) was close to achieve a statistical
significance (p .064). The need for reintubation was associated with a 60% increase in the risk of ICU mortality (p
.001). Patients needing reintubation had
a statistically higher ICU length of stay
compared with those who did not (23.89
29.51 vs. 8.64 5.19, p .001).
The multivariate analysis (Table 5)
confirms the results of the univariate
Crit Care Med 2005 Vol. 33, No. 11

model; in particular, after adjusting for

the reintubation rate, NIV did not show
any direct effect on ICU mortality (risk
difference 0.7%, p not significant).
However, taking in account the direct
and indirect effect, the use of NIV determined a statistically significant reduction
in risk of ICU mortality (10%) as shown
by this equation: direct effect indirect
effect 0.01 0.160.59 0.10 (p .01).
Finally, hospital mortality (12% vs.
18% for NIV and standard treatment, respectively) and time spent in the ICU (8.9
5.7 days vs. 11.6 14.9) or hospital
(23.3 16.4 vs. 25.5 21.4) were not
different between the two groups.

DISCUSSION
The main finding of this study is that
preventive application of NIV in a cohort
of patients at risk of postextubation failure after having passed a spontaneous
breathing trial may reduce the need for
reintubation. The need for reintubation
was associated with a higher risk of ICU
mortality, and the use of NIV resulted in
a reduction of risk of ICU mortality, mediated by the reduction for the need of
reintubation.
The incidence of reintubation is relatively high, being about 10 15% (1, 2),
among patients undergoing mechanical
ventilation for 48 hrs, so it is important
to identify those patients at risk.
Some important information was provided by Epstein and Ciubotaru (9), who
demonstrated how the etiology of extubation failure and the time to reintubation
are both strong predictors of outcome.

These authors postulated that if the need

of reintubation was the primary explanation for mortality, then the latter should
not vary according to the different causes
of extubation failure. They also concluded
that the timely reinstitution of ventilatory support has the potential to reduce
the increased mortality and that the
need to test accuracy of predictors of
early reintubation may be less important
if NIV proves to be an effective therapy for
extubation respiratory failure.
Two randomized controlled studies
were therefore recently performed in a
nonselected population of patients to assess the hypothesis that NIV may be an
effective curative strategy for postextubation respiratory failure.
In a single-center study, Keenan et al.
(7) showed in a heterogeneous group of
81 patients who developed respiratory
distress during the first 48 hrs after extubation that treatment with NIV did not
improve the outcome, compared with
standard medical therapy. The criteria for
defining postextubation failure were not
based on deterioration of arterial blood
gases but mainly on clinical signs such as
an increased respiratory rate or the presence of accessory muscle recruitment
and abdominal paradox.
To expand the clinical meaning of this
relatively small study, a larger international multiple-center randomized study
was performed in 221 patients. Esteban
and coworkers (8) found that the curative
application of NIV to treat an episode of
postextubation respiratory failure did not
reduce mortality or the need for reintubation, but quite the contrary, that the
2467

Table 2. Baseline characteristics at the time of institution of mechanical ventilation

NIV
(n 48)

Standard Treatment
(n 49)

p Value

56.0 19.3
17/31
31.4 0.3

53.2 19.5
19/30
32.5 2.6

.47
.65
.60

8 (17)
6 (13)
4 (8)
4 (8)
4 (8)
NYHA II (2)
NYHA III (1)
NYHA IV (1)
17 (36)
3 (6)
2 (4)

9 (18)
5 (10)
4 (8)
4 (8)
6 (12)
NYHA II (2)
NYHA III (3)
NYHA IV (1)
15 (31)
5 (11)
1 (2)

.87
.76
.81
.81
.49

Characteristics
Age, yrs
Gender, female/male
SAPS II
Reason for initiation of mechanical
ventilation, n (%)
Pneumonia
ARDS
Postsurgical respiratory failure
Trauma
CHF

COPD exacerbation
Neurosurgery
Others

.36
.44
.55

NIV, noninvasive ventilation; SAPS, Simplified Acute Physiology Score; ARDS, acute respiratory
distress syndrome; CHF, congestive heart failure; NYHA, New York Heart Association classification
(no. of patients); COPD, chronic obstructive pulmonary disease.
The p values were obtained by 2 test or t-test, when appropriate.

survival rate tended to be higher in the

group of patients undergoing medical
treatment and that the time interval between development of respiratory failure
and reintubation was significantly higher

with NIV. This study was again performed

in an unselected group of patients, so
that the authors concluded there was the
potential that selected patients (i.e., those
with COPD) may still benefit from NIV.

Table 3. Characteristics of the patients at the time of randomization and the number of reintubation
for each risk group

Characteristics
Duration of endotracheal mechanical
ventilation, days
Respiratory rate, breaths/min
Heart rate, beats/min
pH
PaCO2, mm Hg
PaO2/FIO2
Bicarbonates, mml/L
Methods of weaning from mechanical
ventilation, n (%)
Gradual reduction of pressure support
Single daily trial of spontaneous breathing
Reason to be considered at risk for
reintubation, n (%) and no. of
reintubationsa
More than one weaning trial failure
CHF
PaCO2 45 mm Hg
More than one comorbidity
Weak cough
Upper airways stridor at extubation

NIV (n 48)
6.14 7

Standard Treatment
(n 49)

p Value

7.46 6

21.5 12.3
89.5 3.5
7.44 0.06
41.7 4.26
246.9 59.8
28.7 5.97

23.2 11.0
92.6 28.8
7.44 0.05
39.4 5.65
269.8 73.0
27.2 5.44

.65
.52
.95
.09
.11
.19

30 (62)
18 (38)

33 (67)
16 (33)

.34
.27

9 (19)
1
4 (8)
0
18 (37)
1
18 (37)
1
2 (4)
1
2 (4)
0

11 (22)
2
6 (12)
2
15 (31)
4
14 (20)
2
3 (6)
2
1 (2)
0

.33

CHF, congestive heart failure.

a
May be more than one. The p values were obtained by 2 test or t-test, when appropriate.

2468

.24

.29
.40
.27
.19
.15

The etiology of extubation failure is an

independent factor influencing the need
for reintubation (2), patients considered
at risk, consisting mainly of those with
chronic diseases (i.e., mainly COPD or
CHF), and increased work of breathing at
the time of extubation (9). In these subsets of patients, NIV has been shown to be
of benefit even to shorten the duration of
intubation compared with the standard
weaning procedure (2527) and to fully
mimic, when properly set, the physiologic changes observed during endotracheal mechanical ventilation.
In contrast to the previous studies,
assessing the curative treatment with
NIV, once postextubation respiratory failure was overt, the present investigation
was designed to assess the preventive effects of NIV in avoiding reintubation.
Years ago, Jiang et al. (28) evaluated
the effects of preventive NIV immediately
after extubation, in a randomized study
comparing this strategy with standard
medical therapy. They were unable to
show any statistical difference in the patients outcome, but again the population
was unselected, so that their results may
theoretically have underestimated the effect of NIV in a more specific subset of
patients.
Contrary to the previous and other
investigations (7, 8), most of the highrisk patients enrolled in our study were
affected by persistent hypercapnia (i.e.,
COPD), CHF, or other comorbidities. The
benefits of NIV in preventing reintubation in COPD patients were already described, compared with standard medical
treatment, in a nonrandomized study by
Hilbert et al. (6).
Patients with CHF are also likely to
benefit from the application of continuous expiratory pressure and inspiratory
support delivered noninvasively (29), especially during the first phase of unsupported breathing when the cardiocirculatory pump is under stress (30).
Our study also involved few high-risk
postoperative patients. Most of the previous studies assessing the specific use of
NIV as a preventive treatment in these
patients demonstrate an improvement in
physiologic variables, but no benefits on
the clinical outcome were reported (31
33). This was likely to be due to the relatively small sample size of the studies.
To support the findings of our study, it
was very recently demonstrated that the
application of noninvasive continuous
positive pressure was more effective compared with standard treatment in preCrit Care Med 2005 Vol. 33, No. 11

Table 4. Clinical outcome (reintubation) of patients

NIV

Standard Medical Treatment

No. of
Patients
(n 4)

Time from
Randomization,
Hrs

Incapacity to remove secretions

1 (Ns)
1 (COPD)

14
26

Changes in mental status

Refractory hypoxia

1 (Tr)

31

Cardiac arrest
Emergency surgery
High ventilatory demand

1 (ARDS)

Reasons for Reintubation

Upper airway obstruction

Mean

No. of
Patients
(n 12)
1
1
1
1
1
1
1
1
1
1
1
1

26

24.2 7.2

SD

Time from
Randomization, Hrs

(Ns)
(Ns)
(COPD)
(COPD)
(ARDS)
(Pne)
(CHF)
(Post-s)
(COPD)
(COPD)
(Pne)
(ARDS)

2
26
18
38
18
27
5
40
16
27
8
3
19.0 13.0

NIV, noninvasive ventilation; Ns, neurosurgery patient; COPD, chronic obstructive pulmonary
disease; Tr, trauma; ARDS, acute respiratory distress syndrome; Pne, pneumonia; CHF, chronic heart
failure; Post-s, postsurgical respiratory failure.
a
Stridor with resolution on reintubation (Ref. 2). Values are number of patients (primary diagnosis
on admission).

venting the need for intubation in patients who developed initial hypoxemia
after elective major abdominal surgery
(34).
The criteria of reintubation adopted in
the study, although they were similar to
those reported in the literature (8, 9),
may have been too strict, especially for
COPD patients. We should note, however,
that a pH 7.35 should have been also
accompanied with a Pa CO 2 increase
15% from that recorded at the time of
extubation. For this reason, the highest
pH of COPD patients needing intubation
was 7.31 (one patient), whereas in the
remaining COPD patients the pH values
ranged from 7.27 to 7.30.
Last, we are well aware of the possible
problem of tolerance and complications

when applying NIV to critically ill patients. The tolerance to NIV was quite
high in our study, in keeping with our
previous experiences (25, 35) and the rate
of complications, rather similar to those
described in the literature (36).

CONCLUSIONS
In this study, performed in patients
considered at risk of developing postextubation respiratory failure, we demonstrated that the preventive application of
NIV immediately after extubation is associated with a lower need for endotracheal
intubation than in patients treated with
standard medical therapy. The use of NIV
itself was independently associated with a
reduced risk of developing postextubation

Table 5. Risk difference of univariate and multivariate equations calculated with the generalized linear
models
Response
Variable Y
Univariate
Reintubation
ICU mortality
ICU mortality
Multivariate
Reintubation
ICU mortality
ICU mortality

Predictor
Variable X, n (%)
NIV
4/48 (8)
NIV
3/48 (6)
Reintubation
10/16 (63)
NIV
4/48 (8)
NIV
6/48 (12)
Reintubation
10/16 (62)

No NIV
12/49 (24)
No NIV
9/49 (18)
No reintubation
2/81 (3)
No NIV
12/49 (24)
No NIV
6/49 (13)
No reintubation
2/81 (3)

Risk
Difference, %

95% CI

16

(2, 31)

.027

12

(25, 0.7)

.064

60

(36, 84)

.001

16

(2, 31)

.027

(8, 6)

.845

60

(37, 83)

CI, confidence interval; NIV, noninvasive ventilation; ICU, intensive care unit.

Crit Care Med 2005 Vol. 33, No. 11

p Value

.001

oninvasive ventilation was more

effective

than

standard medical therapy in

preventing postextubation respiratory failure in a population considered at risk of developing this complication.

failure, whereas the act of reintubation

per se was a strong predictor of mortality.
This study demonstrates that despite
the recent negative studies about the use
of NIV to treat postextubation respiratory
failure, preventive application of NIV may
be of clinical benefit in a very selected
population of patients at high risk of developing postextubation respiratory distress.

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Crit Care Med 2005 Vol. 33, No. 11