Easily identified at-risk patients for extubation failure may benefit from noninvasive ventilation: a prospective before-after study
Thille et al. Critical Care
Easily identified at-risk patients for extubation failure may benefit from noninvasive ventilation: a prospective before-after study
Arnaud W. Thille 1 2 3 4 7
Florence Boissier 0 1 2 3 4 7
Hassen Ben-Ghezala 0 7
Keyvan Razazi 7
Armand Mekontso-Dessap 7
Christian Brun-Buisson 7
Laurent Brochard 5 6
0 Equal contributors
1 INSERM CIC 1402 (ALIVE group) , Poitiers , France
2 CHU de Poitiers , Réanimation Médicale, Poitiers , France
3 Université de Poitiers, Faculté de Médecine , Poitiers , France
4 CHU de Poitiers , Réanimation Médicale, Poitiers , France
5 Keenan Research Institute and Department of Critical Care Medicine, St. Michael's Hospital , Toronto, ON , Canada
6 Interdepartmental Division of Critical Care Medicine, University of Toronto , Toronto, ON , Canada
7 AP-HP, Hôpital Henri Mondor, DHU A-TVB, Service de Réanimation Médicale, CARMAS Research Group , Créteil 94010 , France
Background: While studies have suggested that prophylactic noninvasive ventilation (NIV) could prevent postextubation respiratory failure in the intensive care unit, they appear inconsistent with regard to reintubation. We assessed the impact of a prophylactic NIV protocol on reintubation in a large population of at-risk patients. Methods: Prospective before-after study performed in the medical ICU of a teaching referral hospital. In the control cohort, we determined that patients older than 65 years and those with underlying cardiac or respiratory disease were at high-risk for reintubation. In the interventional cohort, we implemented a protocol using prophylactic NIV in all patients intubated at least 24 h and having one of these risk factors. NIV was immediately applied after planned extubation during at least the first 24 hours. Extubation failure was defined by the need for reintubation within seven days following extubation. Results: We included 83 patients at high-risk among 132 extubated patients in the control cohort (12-month period) and 150 patients at high-risk among 225 extubated patients in the NIV cohort (18-month period). The reintubation rate was significantly decreased from 28 % in the control cohort (23/83) to 15 % (23/150) in the NIV cohort (p = 0.02 log-rank test), whereas the non-at-risk patients did not significantly differ in the two periods (10.2 % vs. 10.7 %, p = 0.93). After multivariate logistic-regression analysis, the use of prophylactic NIV protocol was independently associated with extubation success. Conclusions: The implementation of prophylactic NIV after extubation may reduce the reintubation rate in a large population of patients with easily identified risk factors for extubation failure.
Extubation is a critical decision in an ICU and extubation
failure is associated with high mortality [
having successfully passed a weaning readiness test, 15 %
of patients on average and up to 20–25 % of those at
highrisk may need reintubation [
Several studies have suggested that prophylactic
noninvasive ventilation (NIV) could help to prevent
postextubation respiratory failure in patients at high-risk for
extubation failure [
]. In these studies, NIV was
applied during the 24–48 hours following extubation and
seemed particularly effective in cases of hypercapnia [
while its use appeared pointless in patients at low-risk for
extubation failure . Among the six randomized
controlled studies of prophylactic NIV, two studies found
a reduction in reintubation rate [
], whereas the others
found no significant difference [
8, 9, 11, 12
reintubation is the major event independently associated
with poor outcome [
], and the main objective of
prophylactic NIV should be to avoid reintubation in the
most at-risk patients. The studies that have found
beneficial effects of NIV in hypercapnic patients included a
selected population with chronic pulmonary disease
admitted in specialized pulmonary units [
more than 30 % of these patients were hypercapnic at the
time of extubation [
], a finding which may be less
prevalent in a general ICU.
We previously determined a subset of patients at
highrisk for reintubation, comprising patients older than
65 years and/or having underlying cardiac or respiratory
]. Easily identifiable, these criteria represent a
large population that could potentially benefit from
post-extubation NIV. Therefore, we aimed to assess the
risk of reintubation up to seven days after extubation in
patients at high-risk for extubation failure after
implementation of a specific prophylactic NIV program.
This is a prospective before-after study aimed at
assessing the effects of a protocol for the routine use of
prophylactic NIV after planned extubation in patients at
high-risk for reintubation. All patients admitted to the
13-bed medical ICU of our teaching hospital in Créteil
and who had undergone planned extubation were
prospectively screened. In a first cohort treated from May
2005 to May 2006 (control cohort) we identified a
population at high-risk for reintubation as noted in our previously
published analysis [
]. After implementing prophylactic
NIV following extubation, we prospectively collected data
from November 2010 to April 2012 to analyze the risk of
extubation failure in these patients and compare it to
clinicians’ predictions [
]. In the current before-after study we
wish to compare the efficacy of this prophylactic NIV
protocol. This study was approved by the ethics committee
of Henri Mondor hospital (CPP Ile-de-France IX). Signed
informed consent was waived because of the observational
nature of the study; patients or relatives were nonetheless
provided with an informational letter on the aims and
conduct of the study.
All ventilated patients were screened every morning by
the nurse in charge and a weaning test was
systematically performed in those who fulfilled the following
weaning criteria: patient awake without continuous infusion
of sedatives, SpO2 ≥ 90 % with FiO2 ≤ 40 % and positive
end-expiratory pressure (PEEP) ≤ 5 cmH2O, and no need
for vasopressors. Failure of the weaning test was defined
as the development within 1 hour of any of the
following: respiratory rate above 35 breaths/min, SpO2
persistently below 90 %, heart rate persistently above 130
beats/min, systolic blood pressure below 90 mmHg or
above 180 mmHg, clinical signs suggesting respiratory
distress, profuse sweating, agitation or depressed mental
status. When the weaning test was well-tolerated,
patients were extubated after 1 hour. In the control
cohort the weaning test was performed using a T-piece
whereas in the NIV cohort it was performed using a
pressure-support (PS) around 7 cm H2O without PEEP.
Moreover, a blood gas test was systematically performed
at the end of the weaning test in the NIV cohort.
In the control cohort, we found that patients older than
65 years and those having any underlying cardiac or
respiratory disease were at high-risk for extubation failure
with a reintubation rate exceeding 20 % in patients who
had one of these two factors, and greater than 30 %
when the two factors were combined [
]. Therefore, we
decided to implement a protocol for the systematic use
of prophylactic NIV within the first 24 hours following
planned extubation in all patients who fulfilled at least
one of these criteria [
]. Patients intubated less than
24 h and those with a do-not reintubate order were
Underlying cardiac diseases included left ventricular
dysfunction defined by left ventricular ejection fraction ≤ 45 %,
ischemic heart disease or chronic atrial fibrillation, history
of cardiogenic pulmonary edema, or severe valvulopathy.
Chronic lung diseases included chronic obstructive
pulmonary disease, obesity-hypoventilation syndrome or
restrictive pulmonary disease.
Prophylactic NIV protocol
The study was conducted after the implementation of
a nurse-driven NIV protocol to adjust the ventilatory
settings and to improve the patient’s tolerance to NIV
following a simple decision algorithm. NIV was
immediately applied after extubation for periods of at least
1 hour, with a minimal duration of 8 hours within the
first 24 hours following extubation. NIV was initiated
using a PS level of 8 cm H2O and a PEEP level of 5 cm
H2O. The nurse could then gradually adjust the PS
level to target a tidal volume at around 6-8 ml/kg of
predicted body weight. An algorithm was used by
nurses in case of leaks, which successively included
repositioning of the mask, reducing the PEEP level at
2 cm H2O, and reducing the PS level by steps of 2 cm
H2O. NIV was performed via a non-vented full-face
mask with an ICU ventilator using a dedicated NIV
mode, equipped with a heated humidifier. Ventilator
settings, ventilatory parameters, and blood gases were
prospectively collected 1 hour after NIV initiation, as
well as the number and duration of NIV sessions.
Between NIV sessions patients received standard oxygen
therapy; high-flow oxygen therapy was never used,
either in the control cohort or in the NIV cohort.
Duration of NIV and criteria for reintubation
In the absence of acute respiratory failure symptoms
24 hours after planned extubation, NIV was
discontinued. If moderate respiratory failure appeared or
persisted 24 hours after extubation, prophylactic NIV
was continued for periods of 24 hours and reassessed
daily until complete disappearance of acute
respiratory failure criteria, including: 1) respiratory rate > 25/
min, 2) clinical signs suggesting increased work of
breathing, 3) respiratory acidosis defined as pH < 7.35
and PaCO2 > 45 mmHg, and 4) SpO2 < 90 % despite
In the two cohorts, patients were reintubated if they
met at least one of the following criteria: 1) clear
worsening of respiratory failure with a respiratory rate
above 40 breaths per minute, SpO2 persistently below
90 % despite supplemental oxygen, worsening pH and
PaCO2 values with depressed mental status, or
persistent inability to remove copious airway secretions;
2) hemodynamic failure (defined as systolic blood
pressure < 90 mmHg) without response to a fluid
challenge and need for vasoactive drugs, 3)
neurological failure defined as altered consciousness, coma
or psychomotor agitation, or 4) cardiac or respiratory
In the literature, the time interval used to define
extubation failure varies between 48 [
6, 15, 16
] and 72 hours
], or up to one week [
3, 17, 20, 21
]. Since use
of NIV may delay reintubation time [
], we defined
extubation failure as the need for reintubation within seven
days following extubation.
Continuous variables were expressed as mean ± standard
deviation and compared using Student’s t-test.
Dichotomous variables were expressed as percentage and
compared using the Chi-2 test. Our main objective was to
compare the rate of extubation failure in the two cohorts
using the rate of reintubation ≤ 7 days as the primary
end point. Kaplan-Meier curves were plotted to assess
time from extubation to reintubation in patients at
highrisk in the two cohorts and compared by the log-rank
test. We performed a multivariate analysis using a
backward step-down logistic regression model including the
non-collinear variables associated with extubation failure
with a p value <0.15 using univariate analysis. We
considered two-tailed p values <0.05 as significant.
All in all, 132 patients in the control cohort (12-month
period) and 225 patients in the NIV cohort (18-month
period) experienced planned extubation (Fig. 1).
Sixtyone of the 357 extubated patients (17 %) needed
reintubation at some time in the ICU, of whom 74 % (n = 45),
82 % (n = 50) and 97 % (n = 59) were reintubated within
the first 48 hours, 72 hours and seven days following
extubation, respectively. Acute respiratory failure was the main
reason for reintubation (69 %, 42/61). The mortality of
patients who needed reintubation reached 51 % (31/61).
Patients at high-risk for extubation failure
In the control cohort, 83 of the 132 extubated patients
(63 %) were at high-risk for extubation failure (Fig. 1),
and none of them received any prophylactic NIV. In the
NIV cohort, 150 of the 225 extubated patients (67 %)
were at high-risk and eligible to receive prophylactic
NIV. Patients’ characteristics did not differ between the
two cohorts (Table 1).
All in all, reintubation within seven days following
extubation occurred in 46 of the 233 patients considered
at high-risk (20 %). This rate was significantly lower in
the NIV cohort than in the control cohort, decreasing
from 28 % (23/83) to 15 % (23/150), p = 0.02 log-rank
test (Fig. 2) whereas the non-at-risk patients did not
significantly differ during the two periods: 10.2 % (5/49) vs.
10.7 % (8/75), p = 0.93. The rate of reintubation in
patients at high-risk treated with NIV was not significantly
higher than that in patients at low-risk overall: 15.3 %
(23/150) vs. 10.5 % (13/124), p = 0.24.
Use of NIV
Among the 150 patients considered at high-risk for
reintubation in the NIV cohort, 139 (93 %) actually received
prophylactic NIV after extubation. In the 11 remaining
patients the prophylactic NIV protocol was not followed
by the physician or refused by the patient (these patients
were kept in the analysis of the NIV cohort performed
on an intention-to-treat basis). Given the fact that none
of these 11 patients needed reintubation, the rate of
extubation failure reached 17 % (23/139) among all
patients treated with NIV but remained significantly
lower than in patients at high-risk in the control cohort
(p = 0.04 log-rank test).
The median duration of NIV within the first 24 h
following extubation was 490 min [interquartile range,
353-559] and 54 % of the patients (75/139) received more
Values are given as mean ± standard deviation (SD) or as median [interquartile range, from 25th to 75th percentiles]
NIV noninvasive positive pressure ventilation, SAPS II Simplified Acute Physiology Score II, SOFA Sequential Organ Failure Assessment, MV mechanical ventilation,
ICU intensive care unit
than eight hours of NIV. NIV was prolonged beyond
the first 24 hours in 24 % of the cases (33/139)
because of persistent respiratory failure with a rate of
extubation failure of 21 % (7/33).
Factors associated with extubation failure in high-risk patients
A comparison of patients in cases of success or failure of
extubation is given in Table 2. After adjustment using
multivariate logistic-regression, patients with a more
prolonged duration of mechanical ventilation prior to
extubation were more likely to experience extubation
failure, whereas the implementation of a prophylactic
NIV protocol was independently associated with
extubation success (Table 3).
In the NIV cohort, the proportion of hypercapnic
patients (PaCO2 > 45 mmHg) at the end of the weaning
test was 16 % overall (35/225) and 20 % among the
patients at high-risk (30/150).
In this prospective before-after study we assessed the
impact of NIV on patient outcome after planned
extubation. The implementation of a prophylactic NIV protocol
significantly reduced the rate of reintubation in patients
identified as at high-risk of extubation failure. Our NIV
protocol was applied in a large population of patients at
high-risk based on particularly easily identifiable criteria,
including those older than 65 years or with underlying
cardiac or respiratory disease.
Several studies have suggested that prophylactic NIV
could reduce the risk of post-extubation respiratory
failure, particularly in hypercapnic patients [
]. In these
studies, the rate of reintubation assessed within the 48–72
hours following extubation ranged from 19 to 24 % with
standard oxygen and from 8 to 11 % with prophylactic
]. While reintubation rates were higher in our
population, we defined extubation failure as reintubation
up to seven days after extubation. When assessed within
the first 48 hours following extubation, our reintubation
rates are similar to those reported in previous studies
(22 % in the control cohort and 11 % in the NIV cohort).
To date, only two studies have found a significant
reduction in the rate of reintubation [
]. In the study
by Nava and colleagues, prophylactic NIV applied at
least eight hours per day during the first 48 hours
following extubation significantly reduced the rate of
reintubation from 24 % to 8 % (p = 0.027). Another study
observed a decrease in reintubation rate from 39 % to
only 5 % in the group receiving NIV (p = 0.016) .
However, only 38 patients were included in this
singlecenter study and the rate of reintubation reported in the
control group receiving standard oxygen (39 %) was
inordinately high [
In the study by Ferrer and colleagues, prophylactic
NIV helped to reduce the risk of post-extubation
respiratory failure and to decrease mortality, even though
the reintubation rate was not significantly decreased [
Indeed, as NIV could be used as rescue therapy in case
of respiratory distress, it enabled a number of patients
from the control group receiving standard oxygen to
avoid reintubation. As NIV was chiefly beneficial in
hypercapnic patients with chronic respiratory disorders,
the same group conducted a second trial including 106
hypercapnic patients [
]. The results confirmed those of
the previous study, and use of prophylactic NIV avoided
post-extubation respiratory failure [
]. Although 90-day
mortality was significantly lower in patients receiving
prophylactic NIV, neither in-ICU mortality nor
inhospital mortality differed between the two groups, and
it would perhaps be premature to attribute the difference
in long-term outcome to the use of NIV immediately
after extubation. In our study, although we found a
significant decrease in the reintubation rate (13 %), ICU
mortality did not differ between patients treated with
NIV and those receiving standard oxygen.
Whereas NIV seems beneficial in patients considered
at high-risk for reintubation, it is probably pointless in
patients at low-risk. In a large multicenter trial including
nearly 400 patients intubated for more than 48 hours,
the use of prophylactic NIV had no impact on outcome
]. The patients included in this study were not really
at high-risk for reintubation, and the overall reintubation
rate did not exceed 10 %.
In studies including patients considered at high-risk for
extubation failure [
], the inclusion criteria were highly
heterogeneous and differed from one study to another.
Nava and colleagues included patients with hypercapnia
(34 % of the patients) as well as patients with chronic
cardiac failure, several comorbidities, weak cough, stridor, or
having failed several weaning tests before extubation [
Ferrer and colleagues included patients aged ≥ 65 years or
more, a high severity score, or intubated for cardiac failure
]. The same group subsequently conducted a second trial
including only patients with hypercapnia [
]. In another
study, prophylactic NIV was used only in patients
intubated at least three days for acute respiratory failure [
However, in these studies many of the factors constituting
inclusion criteria to start prophylactic NIV are not variables
clearly associated with reintubation.
From our standpoint, future research efforts should
focus on identifying patients at high-risk for reintubation
who may benefit from NIV in various ICU settings. On
All variables significantly associated with extubation failure with a p value < 0.15 were included in the model including: male sex, SAPS II, hypercapnia, duration of
mechanical ventilation (MV) prior to extubation, and application of prophylactic NIV protocol (NIV cohort)
SAPS II Simplified Acute Physiology Score II, NIV noninvasive positive pressure ventilation
aValues of adjusted odds ratio are taken from the final model including only variables independently associated with extubation failure. Logistic regression was
performed using 233 observations and the final model had an area under a Receiver Operating Curve of 0.726 (Hosmer-Lemeshow test 0.683)
the other hand, classification of patients according to
the difficulty of their weaning process [
] seems of
little help in prediction of extubation failure since the
reintubation rate between patients with simple weaning
and those with difficult weaning is somewhat similar [
]. By contrast, we have found that prolonged
duration of mechanical ventilation prior to extubation was
a strong predictor of extubation failure, and that
patients intubated more than seven days may probably be
considered as at high-risk of extubation failure .
Since our first study [
], we decided to initiate NIV in a
large subset of patients, who were at once particularly
easy to identify, and at unacceptably high-risk for
reintubation and mortality. Among these patients, only
20 % had hypercapnia during the weaning test and
would have received prophylactic NIV in the event that
only this criterion had been used.
First, our study was performed in a single center in which
our population may have differed from those of other
centers in terms of demographic or primary reason for
intubation, a factor that limits the generalizability of our
results. Although cohort studies obviously do not have the
strength of a randomized controlled study, our study was
prospective and included the largest number of patients at
high-risk treated with prophylactic NIV to date (n = 139).
The reintubation rate in the non-at-risk patients remained
exactly similar between the two periods.
Second, the weaning readiness tests were not
performed in the same way in the two cohorts. Low levels
of PS were used during the NIV cohort, which may
have resulted in lower levels of work of breathing than
with T-piece as performed in the first cohort [
However, clinical studies have found no difference between
the two approaches in terms of extubation outcome
] and, if anything, the low pressure-support
approach could result in a higher extubation rate and
potentially more patients in need of reintubation in the
Third, the data from the NIV cohort were collected
four years after the end of the control cohort.
Therefore, other changes may have impacted the
reintubation rate, such as modification in sedation practice, use
of diuretics, special attention paid to patients at
highrisk, and our result could be due to an improvement in
the process of weaning including prophylactic NIV
rather than the implementation of NIV alone. However,
the duration of mechanical ventilation prior to
extubation was not significantly different between cohorts
and the use of the NIV protocol remained
independently associated with extubation success, even after
adjustment on prior duration of mechanical ventilation.
Moreover, the percentage of patients at high-risk was
not significantly different between cohorts, thereby
suggesting a relatively similar clinical practice.
As a final limitation, the trend toward a lower
proportion of hypercapnic patients in the NIV cohort may
have partially contributed to the lower reintubation
rate compared to the control cohort. However,
although it was previously shown that weaning may be
more prolonged in hypercapnic patients, it was not
significantly associated with extubation failure [
our second cohort, hypercapnia at the end of the
weaning test was associated with extubation failure in
univariate analysis, but was not an independent
predictor of reintubation after adjustment on multiple
risk factors [
Although our results support the use of NIV rather
than standard oxygen in patients at-risk, the beneficial
effects found in this study might not be extrapolated to
patients treated by high-flow oxygen therapy [
Prophylactic NIV applied immediately after extubation
could reduce the reintubation rate in a large population
of patients at high-risk for extubation failure including
those aged 65 years or older and/or having underlying
cardiac or respiratory disease.
The implementation of a protocol using prophylactic
noninvasive ventilation immediately after extubation
may reduce the reintubation rate in a large population
of patients with easily identified risk factors for
These patients were older than 65 years and presented
with underlying cardiac or respiratory disease.
The authors declare that they have no competing interests.
AWT has 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. Conception and
design: AWT; Acquisition of data: FB, HBG, KR; Analysis and interpretation of
data: AWT, FB, HBG, KR, AMD, CBB, LB; Drafting the manuscript or revising it
critically for important intellectual content: AWT, FB, HBG, KR, AMD, CBB, and
LB. All authors have read and approved the final manuscript.
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