Extubation Failure in Brain-injured Patients

Risk Factors and Development of a Prediction Score in a

Preliminary Prospective Cohort Study
Thomas Godet, M.D., Ph.D., Russell Chabanne, M.D., Julien Marin, M.D., Sophie Kauffmann, M.D.,
M.Sc., Emmanuel Futier, M.D., Ph.D., Bruno Pereira, Ph.D., Jean-Michel Constantin, M.D., Ph.D.

ABSTRACT

Background: The decision to extubate brain-injured patients with residual impaired consciousness holds a high degree of uncer-
tainty of success. The authors developed a pragmatic clinical score predictive of extubation failure in brain-injured patients.
Methods: One hundred and forty brain-injured patients were prospectively included after the first spontaneous breathing trial
success. Assessment of multiparametric hemodynamic, respiratory, and neurologic functions was performed just before extu-
bation. Extubation failure was defined as the need for ventilatory support during intensive care unit stay. Extubation failure
within 48h was also analyzed. Neurologic outcomes were recorded at 6 months.
Results: Extubation failure occurred in 43 (31%) patients with 31 (24%) within 48h. Predictors of extubation failure con-
sisted of upper-airway functions (cough, gag reflex, and deglutition) and neurologic status (Coma Recovery Scale-Revised
visual subscale). From the odds ratios, a four-item predictive score was developed (area under the curve, 0.85; 95% CI, 0.77
to 0.92) and internally validated by bootstrap. Cutoff was determined with sensitivity of 92%, specificity of 50%, positive
predictive value of 82%, and negative predictive value of 70% for extubation failure. Failure before and beyond 48h shared
similar risk factors. Low consciousness level patients were extubated with 85% probability of success providing the presence
of at least two operating airway functions.
Conclusions: A simplified clinical pragmatic score assessing cough, deglutition, gag reflex, and neurologic status was devel-
oped in a preliminary prospective cohort of brain-injured patients and was internally validated (bootstrapping). Extubation
appears possible, providing functioning upper airways and irrespective of neurologic status. Clinical practice generalizability
urgently needs external validation. (Anesthesiology 2017; 126:104-14)

T he decision to extubate brain-injured patients with

residual impaired consciousness holds a high degree of
uncertainty of success and undesirability of incorrect pre-
What We Already Know about This Topic
In mechanically ventilated brain-injured patients who have
undergone successful breathing trials, there is a high rate of
diction.1,2 Risk factors of extubation failure are common extubation failure.
in this setting: severity of initial critical illness, emergent, The management of such patients might be improved signifi-
and often prehospital tracheal intubation that favors stri- cantly if the clinical parameters that are predictive of extuba-
dor, prolonged mechanical ventilation (MV), altered con- tion success are identified.

sciousness with impaired airway protective reflexes such as
cough and deglutition, neuromuscular weakness or paraly-
sis, and hypersecretion.3 In general critical care medicine,
it is usually assumed that restored conscious behavior is a
prerequisite to extubation.46 While separation from MV is
generally easily acquired in brain-injured patients without
other comorbidity,7 extubation failure is frequent.8 Never-
theless, some patients with severe alteration of conscious-
ness could be extubated with success, and burden may be
associated with extubation delay.9 Few studies investigated
predictive factors implicated in extubation failure with
What This Article Tells Us That Is New
A simplified score, comprised coughing, swallowing, and gag
function, in combination with visual function subscale of the
Coma Recovery Scale Revised, was developed; the total
score was correlated with successful tracheal extubation.
This clinically pragmatic score can be easily developed. External
validation of its predictive value, however, is necessary.
focalization on different components of the problem: ven-
tilatory parameters or global neurologic evaluation without
clear predictors.1,8,1013 For example, Glasgow Coma Scale

This article is featured in This Month in Anesthesiology, page 1A. Supplemental Digital Content is available for this article. Direct URL
citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided
in the HTML text of this article on the Journals Web site (www.anesthesiology.org). T.G. and R.C. contributed equally to this article.
Submitted for publication April 4, 2016. Accepted for publication September 6, 2016. From the Department of Perioperative Medicine
(T.G., R.C., J.M., S.K., E.F., J.-M.C.) and Biostatistics Unit, DRCI, Gabriel Montpied Hospital (B.P.), University Hospital of Clermont-Ferrand,
Clermont-Ferrand, France; and Retinoids, Reproduction and Developmental Disease (R2D2) Unit, EA 7281, University of Clermont-Ferrand
1, Clermont-Ferrand, France (T.G., E.F., J.-M.C.).
Copyright 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. All Rights Reserved. Anesthesiology 2017; 126:104-14

Anesthesiology, V 126 No 1 104 January 2017

Copyright 2016, the American Society of Anesthesiologists, Inc. Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
<zdoi;10.1097/ALN.0000000000001379>
 CRITICAL CARE MEDICINE
(GCS), in which low values often appear as limitative factors
to extubation, is difficult to evaluate in intubated patients
and patients ability to be an indicator of precise neurologic
function is limited.14,15 As a consequence, no guideline
exists in this specific population and practice variations are
frequent between institutions.1 To characterize risk factors
associated with extubation failure in brain-injured patients,
we conducted a prospective, monocentric, observational
study with multiparametric assessment of demographic,
neurologic, hemodynamic, and respiratory functions. The
objective of the study was to develop and internally validate
a simplified pragmatic score predictive of extubation failure
in this category of patients. Some of the results of this study
have been previously reported in the form of an abstract.16,17
Materials and Methods
Additional details are provided in the online Supplemen-
tal Digital Content (http://links.lww.com/ALN/B322).
Clinical trial is registered with http://www.clinicaltrials.gov
(NCT 02235376).
Ethics Statement
Protocol was approved by Regional Ethics Committee
(Comit dEthique des Centres dInvestigation Clinique,
Rhne-Alpes-Auvergne, Grenoble, France, IRB 5921) on
June 19, 2013. Because of the observational design of this
study, which consisted of routine care in the studied intensive
care units (ICUs), the need for written consent was waived.
An information letter concerning the study was given to the
patient or a next of kin after recovery.
Patients and Setting
The study was performed in a 13-bed neuro-ICU and 2
general ICUs (17 and 15 beds, respectively) of a university
hospital. All consecutives brain-injured adult patients with
initial GCS less than or equal to 12 (before tracheal intu-
bation), intubated for neurologic reason and ventilated for
more than 48h, were screened between June 2013 and Feb-
ruary 2015 (18-month period). Patients with brain struc-
tural lesions (isolated traumatic brain injury, subarachnoid
hemorrhage, supra- or infratentorial spontaneous intrace-
rebral hematoma, supra- or infratentorial acute ischemic
stroke, or hypoxicischemic encephalopathy due to cardiac
arrest) eligible for extubation were included. Patients with
spinal cord injury, status epilepticus, disorder of conscious-
ness caused by alcohol or other intoxication, central nervous
system infection, tracheostomy, autoextubation, and with-
drawal of care due to ethical reason were not included. Fol-
low-up of included patients was 6 months to assess Glasgow
Outcome Scale.
Weaning and Extubation Protocol
Detailed protocols are provided in the online Supplemental
Digital Content (http://links.lww.com/ALN/B322).
Anesthesiology 2017; 126:104-14 105 Godet et al.
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Medical, paramedical, and physiotherapist staff were
aware of the study protocol, which consisted of routine care
in the studied ICUs.
Since all three ICUs were affiliated with the Depart-
ment of Perioperative Medicine of the University Hospital
of Clermont-Ferrand, Clermont-Ferrand, France, with the
same medical and paramedical leadership and steward-
ship, protocols related to brain-injured patients were the
same. The weaning protocol followed European guidelines
of weaning from MV for general ICU patients.4 Notably,
it was assumed that no tracheostomy was performed before
any extubation attempt, unless the patient failed more than
three spontaneous breathing trials (SBT). After resolution of
acute organ dysfunctions notably increased intracranial pres-
sure and sedative drugs withdrawal, eligibility for a SBT was
daily assessed. Patients were extubated when they succeeded
SBT irrespective of their neurologic status and upper-airway
function.9 At the end of a successful SBT, previous venti-
latory parameters were resumed during clinical evaluation
related to the study. Extubation and respiratory care fol-
lowed regular guidelines and were provided by a respiratory
therapist during daytime. No prophylactic noninvasive ven-
tilation (NIV) was used. If needed, standard oxygen therapy
was initiated after extubation without high-flow devices.
Time between the end of a successful SBT and extubation
did not last more than 1h. Local standard of care prevented
delayed extubation after a passed SBT. All SBT procedures
were reviewed on electronic patient records by two investiga-
tors not in charge of patient care (J.M.C. and E.F.) in order
to look for possible delayed extubations. Additionally, data
from tracheostomized patients were also reviewed in order to
verify they previously failed at least three SBTs.
Extubation failure was defined as the need for ventila-
tory support after extubation using tracheal intubation or
NIV4 during ICU stay. Respiratory failure necessitating
reventilation was defined as the occurrence of at least two
signs among oxygen therapy greater than 9 Lmin1 to main-
tain oxygen saturation measured by pulse oximetry greater
than 90%, respiratory rate greater than 35min1 with acces-
sory respiratory muscles involvement, respiratory or cardiac
arrest, major tracheal secretions with inadequate cough,
Paco2 greater than 50 mmHg with pH less than 7.35, heart
rate greater than 120min1, systolic blood pressure greater
than 200 mmHg or less than 90 mmHg. Analyses of extuba-
tion failure before 48h as classically defined4 and at any time
during ICU stay were performed. Justifications of those tim-
ings are presented in the Discussion.
Numerous clinical and paraclinical data were collected
before extubation (see Methods and Data Collection in
Supplemental Digital Content, http://links.lww.com/ALN/
B322, which extensively expose collected clinical and para-
clinical data). Of note, neurologic assessment included GCS
with one point for verbal (total score on 10 points due to
inability to assess verbal component of the score with tracheal
intubation),18 Full Outline of UnResponsiveness (FOUR)

score with three components (eyes, motor, and brainstem
reflexes)19 (respiration item systematically rated 1 with tra-
cheal intubation and breathes above ventilator rate for every
patient in our cohort since they sustain pressure support ven-
tilation), and Coma Recovery Scale-Revised (CRS-R) with
its six components (auditory, visual, motor, oromotor/ver-
bal, communication, and arousal),20 with specificity related
to inability to vocalize due to the endotracheal tube (item
2 of the oromotor/verbal function scale [vocalization/oral
movement] was validated if oral movement compatible with
vocalization attempt was observed and item 3 [intelligible
verbalization] was validated if one could recognize words on
patient lips or if the patient was able to write words). Data
collection before extubation and follow-up were exclusively
done by four senior intensivists working in the three ICUs
(R.C., T.G., S.K., and J.M.) in a specifically designed and
standardized case report form.
Statistical Analysis
It seemed difficult to propose a sample size estimation
according to literature in order to develop and validate a sim-
plified pragmatic score predictive of extubation failure in this
category of patients. Numerous rules of thumb have been
suggested for determining the minimum number of sub-
jects required to conduct multiple regression analyses, but
they are heterogeneous and are often with minimal empiri-
cal evidence. For multiple regression models, some authors
suggested variable ratios of 15:1 or 30:1 when generaliza-
tion was critical.2124 Considering these works and expected
extubation failure rate between 20 and 30%, we proposed to
include at least 120 subjects to highlight three to five predic-
tive factors. All analyses were performed using Stata software
(version 13; StataCorp, USA) and done for a two-sided type
I error of = 5%. Patients characteristics were described
by numbers and percentages for categorical parameters. For
quantitative values, mean and SDs or median with inter-
quartile range were calculated and presented according to
statistical distribution (normal distribution of quantitative
values was checked by ShapiroWilk test). Categorical data
were compared using chi-square test. Quantitative data were
compared between independent groups (extubation suc-
cess/failure) using Students t test or MannWhitney U test
when assumptions of t test were not met (normality studied
using ShapiroWilk test and homoscedasticity using Fisher
Snedecor test). A multivariate analysis was performed using
logistic regression models by stepwise approach according to
univariate results (P < 0.10)25,26 and clinical relevance.27,28
Results were expressed with odds ratios (OR) and 95% CI.
The final model was validated by a two-step bootstrapping
process. For each step, bootstrap samples with replacements
(n = 1,000) were generated from the training set. In the first
phase, the percentage of models including each initial vari-
able was determined by usual stepwise approach. Then, in
the second phase, parameters of generalized linear regression
(logistic for dichotomous-dependent variable) of the final
Anesthesiology 2017; 126:104-14 106 Godet et al.
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Extubation Failure in Brain-injured Patients
model were independently estimated. The bootstrap esti-
mates associated with each covariate regression coefficient,
and their associated standard errors (SEs), were finally aver-
aged from replicates. Log-likelihood measured the good-
ness-of-fit of a model. After these multivariate analyses, a
receiver operating characteristic (ROC) curve was plotted for
the final model, and area under the curve (AUC) was esti-
mated.29 A score predicting the extubation failure was esti-
mated according to OR values. The threshold value of this
score was determined according to usual recommendations
by estimating several indexes as Youden, Liu, and efficiency.
Sensitivity, specificity, and negative/positive predictive val-
ues were presented with 95% CI. A sensitivity analysis was
performed to study patterns of patients with missing data
and considered after analyses as not missing at random. An
analysis of extubation failure before 48h was also performed.
Our study conforms to the recent set of reporting guidelines:
Transparent Reporting of a multivariable prediction model
for Individual Prognosis Or Diagnosis.30
Results
See the Supplemental Digital Content (http://links.lww.
com/ALN/B322) for more information. One hundred and
forty patients eligible to extubation were included between
June 2013 and February 2015 (fig. 1). Extubation failure
occurred in 43 (31%) patients (31 patients [24%] before
48h). Data of extubation failure before 48h are presented in
online supplementary material (Tables E1 and E2, Supple-
mental Digital Content, http://links.lww.com/ALN/B322,
presenting data about patients with extubation failure before
48h). Further presented data correspond to extubation fail-
ure at any time during ICU stay. Missing data were investi-
gated. Among the failure group, 361 of 4,730 (7.6%) and
among the success group, 915 of 10,670 (8.6%) data were
missing (P = 0.45). Total percentage of missing data was
8.3%. These aspects had no impact on results. No data were
missing for the primary outcome.
There was no difference related to demographic data,
general and neurologic initial severity scores, type of neuro-
logic injury, pupillary status, brainstem reflexes, comorbid-
ity, or characteristic of tracheal intubation between success
and failure groups. More patients had alcohol abuse in the
failure group (table 1). Characteristics of patients on success-
ful SBT day are presented in Table E3 (Supplemental Digital
Content, http://links.lww.com/ALN/B322, presenting char-
acteristics of patients on successful SBT day). No difference
between characteristics of patients was observed on success-
ful SBT day. Intercurrent events (neurologic, respiratory,
or hemodynamic) and notably intercurrent pneumonia or
adult respiratory distress syndrome had no effect on extuba-
tion outcome. Duration of MV, number of failed SBT, and
arterial blood gases had no impact.
Patients outcomes are presented in table 2. ICU mortal-
ity and length of stay were increased in the failure group.
There was no difference in hospital length of stay. Glasgow
 CRITICAL CARE MEDICINE

Fig. 1. Flow chart of patients screening and recruitment. AIS = supra- or infratentorial acute ischemic stroke; GCS = Glasgow
Coma Scale; HIE = hypoxicischemic encephalopathy; ICH = supra- or infratentorial spontaneous intracerebral hematoma;
ICU = intensive care unit; SAH = subarachnoid hemorrhage; TBI = traumatic brain injury.

Table 1. Admission Characteristics of Patients (n = 140)

Extubation Success (n = 97) Extubation Failure (n = 43) P Value

Age, yr 5616 5817 0.40

Male sex, n (%) 62 (64) 26 (78) 0.70
Body mass index, kgm2 275 265 0.52
GCS, median (IQR) 8 (511) 6 (49) 0.19
Type of neurologic insult, n (%)
TBI 43 (44) 19 (44) 0.99
SAH 20 (21) 8 (19) 0.78
ICH 23 (22) 7 (16) 0.50
 Supratentorial 21 (22) 6 (14)
 Infratentorial 2 (2) 1 (2)
AIS, n (%) 5 (5) 7 (16) 0.10
 Supratentorial 5 (5) 5 (12)
 Infratentorial 0 2 (5)
HIE, n (%) 6 (6) 2 (5) 0.72
SAPS II 4915 5216 0.30
SOFA 63 63 0.65
Medical history
Cardiac 43 (44) 19 (44) 0.99
Respiratory 12 (12) 8 (19) 0.33
Neurology 24 (25) 15 (35) 0.22
Diabetes mellitus 17 (17) 8 (19) 0.88
Smoking 29 (29) 14 (33) 0.81
Alcohol 17 (17) 16 (37) 0.03
Characteristics of tracheal
intubation
Prehospital 38 (39) 20 (35) 0.42
Difficult 1 (1) 2 (5) NA

Data are presented as mean SD unless otherwise indicated. Percentages may not exactly total 100% because of rounding.
AIS = acute ischemic stroke; GCS = Glasgow Coma Scale; HIE = hypoxic-ischemic encephalopathy; ICH = spontaneous intracerebral hematoma; IQR
= interquartile range; NA = not appropriate; SAH = subarachnoid hemorrhage; SAPS = simplified acute physiologic score; SOFA = sequential organ
failure assessment; TBI = traumatic brain injury.

Outcome Scale was significantly higher (meaning better Causes of extubation failure are presented in Table E4
recovery) in the extubation success group at ICU discharge (Supplemental Digital Content, http://links.lww.com/
and at 6 months. ALN/B322, presenting causes of extubation failure).

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 Extubation Failure in Brain-injured Patients

Table 2. Patients Follow-Up and Outcomes

Extubation Success (n = 97) Extubation Failure (n = 43) P Value

Extubation failure delay, days 0 1.41.9 NA

Extubation failure < 48h, n (%) 0 31 (72) NA
Noninvasive ventilation, n (%) 0 12 (28) NA
Tracheostomy, n (%) 0 9 (21) NA
Death in ICU, n (%) 1 (1) 8 (19) < 0.0001
Total MV, days 17 (1025) 25 (1935) < 0.0001
ICU length of stay, days 23 (1436) 30 (2248) < 0.001
Hospital length of stay, days 51 (3585) 55 (37 84) 0.69
GOS
ICU discharge 3.90.8 3.21.2 0.002
6 months 4.31.5 3.31.8 0.009

Data are presented as mean SD or median (interquartile range).

GOS = Glasgow Outcome Scale; ICU = intensive care unit; MV = mechanical ventilation; NA = not appropriate.

Hypersecretion was the main reported reason accounting for
67% of extubation failure. Stridor was the cause in 14%.
No patient was reintubated due to any acute neurologic
complication.
Extubation failure rates associated with total GCS and
eye and motor subscales are presented in Figure E1 (Supple-
mental Digital Content, http://links.lww.com/ALN/B322,
presenting extubation failure rates associated with total and
eye and motor subscales of GCS). Some patients with GCS
as low as 3 could be extubated with success.
In univariate analysis, as shown in table3, assessment of
ocular functions in FOUR and CRS-R scores significantly
differentiated success and failure. None of the motor
responses was significant irrespective to scores. Communica-
tion and oromotor responses from CRS-R did not appear
discriminative. Brainstem and arousal capabilities assessed by
FOUR, GCS, and CRS-R were associated with extubation
failure. Agitation and pain assessed by Richmond Agitation
and Sedation Scale and Behavioral Pain Scale, respectively,
did not accurately predict extubation outcome. Confusion of
patients, as assessed by confusion assessment method for the
intensive care unit, was significantly associated with extuba-
tion failure. Classical respiratory and general parameters like
respiratory rate, rapid shallow breathing index, weight varia-
tion, and heart rate were not significant. Assessment of airway
management criteria, illustrated by the capability to cough,
the deglutition ability, and the gag reflex, were strongly asso-
ciated with extubation failure when absent.
In multivariate analyses, GCS and FOUR as total scores
or as their different components, as well as alcohol consump-
tion history, were not significant. CRS-R subscales were col-
linear. Related to practical ability in intubated patients, the
decision was made to keep CRS-R visual. Multivariate
analysis was computed, and results are presented in table4.
According to statistical distribution and clinical relevance,
CRS-R visual subscore was dichotomized as presented
in Figure E2 (Supplemental Digital Content, http://links.
lww.com/ALN/B322, presenting CRS-R visual subscore
dichotomization).
Starting from this model, we created a score with weight-
ing related to ORs and ranging from 1 to 14 (table5). Boot-
strap validation was performed for the construction of ROC
curve presented in figure2. AUC was 0.82 (95% CI, 0.73 to
0.91) for CRS-R visual subscale-based multivariate model.
In our cohort, at the cutoff point of 9 determined by ROC
analysis, positive and negative predictive values for extuba-
tion failure were 89 and 66% with a sensitivity of 84% and
a specificity of 75%, respectively (table6).
Extubation failure rates across the original cohort are pre-
sented in figure3. Scores beyond presented cutoff of 9 show
low extubation failure incidences. Patients presenting with at
least two operating airway components succeeded extubation
in 90 versus 10% if less (fig.4A). In each subgroup of operat-
ing airway functions (0, 1, 2, or 3), extubation success rates
were 38, 32, 67, and 90%, respectively, independent of the
type of operating function: gag reflex, cough, or deglutition
(fig.4B).
ROC curve of model including only airways function
has an AUC of 0.79 and was not significantly different from
ROC curve of model integrating neurologic status (AUC,
0.82). Notwithstanding, this last model is more parsimoni-
ous with lower log-likelihood (55 vs. 60). When consider-
ing patients with low consciousness levels (CRS-R visual
scores 0, 1, and 2), predictions of extubation success were 38
versus 85% when considering operating airways functions
(fig. 5). No extubation delays or erroneous primary trache-
ostomy indications were revealed by retrospective analysis of
electronic patient records.
Discussion
This study identified risk factors associated with extubation
failure in a cohort of neurocritical care patients with severe
brain injuries. A pragmatic predictive clinical score, easy to
perform at the bedside, was elaborated and validated.
Weaning of MV requires two successive steps: weaning
of pressure support (ventilator) and liberation of the airway
from the endotracheal tube. Brain-injured patients, usually
not affected by cardiopulmonary incompetency as a cause of

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 CRITICAL CARE MEDICINE

Table 3. Results of Univariate Analysis

Extubation Success (n = 97) Extubation Failure (n = 43) P Value

Neurologic examination before extubation

GCS, median (IQR) 9 (810) 9 (710) 0.10
Item eye, median (IQR) 3.70.6 3.50.8 0.03
Item motor, median (IQR) 5.11.4 4.81.6 0.32
RASS, median (IQR) 0 (1 to 0) 1 (1 to 0) 0.09
BPS, median (IQR) 3 (33) 3 (33) 0.77
FOUR score, median (IQR) 12 (1113) 11 (1013) 0.004
FOUR item eye 3.60.8 3.11.1 0.001
FOUR item motor 3.21.1 3.01.2 0.25
FOUR item brainstem 4.00.1 3.80.6 0.004
CRS-R, median (IQR) 15 (1019) 11 (815) 0.003
CRS-R item auditory 2.61.4 2.21.5 0.08
CRS-R item visual 3.11.4 2.21.3 < 0.001
CRS-R item motor 3.71.6 3.31.4 0.15
CRS-R item oromotor/verbal 1.30.7 1.10.7 0.06
CRS-R item communication 0.90.9 0.70.8 0.47
CRS-R item arousal 2.50.7 1.80.9 < 0.0001
Confusion (CAM-ICU), n (%) 54 (56) 34 (79) 0.01
Respiratory examination before extubation
RR, min1 19.15.5 19.55.2 0.68
RSBI, RR/Vt, min1L1 3919 3817 0.82
Airways management, n (%)
Cough 75 (77) 23 (53) 0.007
Gag reflex 83 (86) 27 (63) < 0.001
Deglutition 76 (78) 17 (40) < 0.001
Miscellaneous
Weight variation, kg 0.47.9 0.66.4 0.88
HR, min1 88.416.3 84.015.1 0.15

Criteria associated with extubation failure. Data are presented as mean SD unless otherwise noted. Score items are presented as mean SD to be more
illustrative of differences. FOUR-item respiratory equals 1 for all patients according to the definition in intubated patients.
BPS = behavioral pain scale; CAM-ICU = confusion assessment method for the intensive care unit; CRS-R = Coma Recovery Scale-Revised; FOUR = full
outline of unresponsiveness; GCS = Glasgow Coma Scale; HR = heart rate; IQR = interquartile range; RASS = Richmond Agitation and Sedation Scale;
RR = respiratory rate; RSBI = rapid shallow breathing index; Vt = tidal volume.

Table 4. Results of Multivariate Analysis Table 5. Score Calculation Worksheet

OR (95% CI) P Value Factors Points

CRS-R item visual 3.4 (1.38.6) 0.012 Airways management

Gag reflex 4.2 (1.314.1) 0.02 Cough 4
Deglutition 3.2 (1.28.4) 0.021 Deglutition 3
Cough 3.8 (1.49.8) 0.007 Gag reflex 4
AUC 0.82 (0.730.91) Neurologic examination
CRS-R item visual
Criteria independently associated with extubation failure.
 012 1
AUC = area under the curve; CRS-R = Coma Recovery Scale-Revised; OR
= odds ratio.  345 3
Total 14

The presence of any factor allows the attribution of corresponding points.

their critical illness, generally succeed in the first step, but The absence of any factor of airway management implies the attribution
extubation per se remains challenging. of 0 point.
In our cohort, eligibility for the first SBT was prolonged CRS-R = Coma Recovery Scale-Revised.

related to the severity of the patients. Comparable duration of

MV is classical in this type of population.31 As expected and
despite prolonged MV, autonomy from the ventilator could
be obtained easily with less than two failed SBT before extu-
bation, and no difference between groups (Table E3, Supple-
mental Digital Content, http://links.lww.com/ALN/B322,
presenting characteristics of patients on successful SBT day).
Extubation failure in our work reached 31% (24% within
48h). This rate is consequent and is in accordance with lit-
erature with reported values of 20 to 40% in neurocritical
care.7,8 As a comparison, extubation failure in general ICU
patients ranges between 10 and 20%.3 It has to be mentioned
that some studies in this field found some surprising low rates

Anesthesiology 2017; 126:104-14 109 Godet et al.

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 Extubation Failure in Brain-injured Patients

Fig. 2. Receiver operating characteristic (ROC) curve of multivariate model based on Coma Recovery Scale-Revised item
visual and airways items. Area under the curve = 0.82 (95% CI, 0.73 to 0.91).

Table 6. Diagnostic Performances of Predictive Score of patients unable to tolerate multiple weaning trials related to
Extubation Failure infratentorial ischemic stroke, with bulbar respiratory drive
Score
palsy in three patients and prolonged neuromuscular weak-
ness in one patient.
CRS-R Item Visual In this population, from extended epidemiologic, clinical,
Cutoff 9 and biologic criteria concerning neurologic, hemodynamic,
Sensitivity 84% (95% CI, 0.750.91) and ventilatory functions, we identified few independently
Specificity 75% (95% CI, 0.580.88) associated with extubation failure: predominantly loss of
Positive predictive value 89% (95% CI, 0.800.95) upper-airway protective reflexes and to a lesser extent loss of
Negative predictive value 66% (95% CI, 0.490.80) minimal behavioral clinical evidence of consciousness.
CRS-R = Coma Recovery Scale-Revised. Coplin et al.9 demonstrated that brain-injured patients
meeting standard weaning criteria could be extubated irre-
spective of their upper-airway function and their mental sta-
tus could be evaluated with the GCS. In their cohort, some
patients with a GCS as low as 4 tolerated extubation. Extu-
bations delay was associated with increased risk of pneu-
monia and prolonged length of stay. In our cohort, patients
with low GCS could also sustain extubation.
Nevertheless, Namen et al.8 identified GCS to be the best
independent factor associated with extubation failure. ROC
curve analysis identified a cutoff beyond GCS greater than
or equal to 8 for extubation success (AUC, 0.681; OR, 4.9;
95% CI, 2.8 to 8.3; P < 0.001). Other studies found GCS
with a threshold value of 8 to be a good indicator of extuba-
Fig. 3. Percentages of extubation failure according to predic- tion tolerance,3234 and American guidelines suggest wean-
tive score. N = number of patients in the cohort with a par- ing when adequate mentation defined as GCS greater than
ticular score range. or equal to 13 is present.5 However, other studies did not
recognize GCS as a predictor,13,35 and in our cohort, GCS
in extubation failure.10,13 It could be related to population was not independently associated with extubation failure.
disparities, for example, elective neurosurgical patients with Indeed, GCS lacks information to differentiate subtle dis-
short duration of MV or exclusions of tracheostomy without orders of consciousness, does not assess brainstem reflexes,
any extubation attempt for severe patients in some studies. In and is not evaluable in intubated patients.15 Identical GCS
our cohort, no tracheostomy was performed unless the patient with total sum of scale components could indicate very dif-
was not able to sustain SBT. It happened in four nonincluded ferent neurologic conditions.18 Therefore, results based on

Anesthesiology 2017; 126:104-14 110 Godet et al.

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 CRITICAL CARE MEDICINE

A B

Fig. 4. (A) Percentages of extubation success according to the number of operating airways functions in the whole popula-
tion. The presence of at least two operating airways functions (cough, deglutition, or gag reflex) allow the prediction of 90%
of extubation success. (B) Percentages of extubation success according to the number of operating airways function in each
subgroup of functioning airway. NS = number of patients presenting with extubation success; NT = total number of patients in
each subgroup of operating airways function.

to discriminate these clinical signs, visual assessment was

Fig. 5. Evolution of extubation success percentages in low
consciousness level patients (Coma Recovery Scale-Revised
[CRS-R] item visual 0, 1, or 2) according to the number of
effective airways (AW). If two or more airways functions are
present, extubation success rate is not different from the
overall intensive care unit population.
the global GCS in the aforementioned studies could be
questionable. FOUR score that evaluates brainstem reflexes,
respiratory function, and nonverbal signs of consciousness
was developed for intubated patients in the ICU.19 FOUR
was not independently associated with extubation failure in
our cohort as in the study by Ko et al.10
CRS-R20 allows clinical diagnosis of vegetative state,
minimally conscious state (MCS), emergence of conscious-
ness, and locked-in syndrome by means of behavioral
assessment in patients with depressed mental status. It is a
reference scale in neurorehabilitation. Even if CRS-R could
be difficult to use in an acute care setting,36,37 its validation
in different countries and languages frequently included
ICU patients.3840 Notably, Schnakers et al.37 included 22
intubated patients in ICU among 60 patients with disor-
ders of consciousness. In this study, the authors concluded
that FOUR score was not as accurate as CRS-R to diagnose
vegetative state and MCS even in an acute care setting. In
our cohort, CRS-R total score was not statistically signifi-
cant in multivariate analysis. CRS-R subscales visual and
arousal were significant but collinear, meaning they bear
identical information. Due to clinical relevance with facility
integrated in our model. We found a change in extubation
tolerance related to neurologic status when the patient was
able to sustain visual pursuit (follow a mirror without loss of
fixation). Recent works speculated that visual pursuit was a
key surrogate of neurologic progression to MCS.41,42
Ability to follow stereotyped commands was a strong pre-
dictor of extubation success in a study by Anderson et al.13
Nevertheless, neither motor item of the GCS, FOUR, or
CRS-R was predictive of extubation tolerance in our cohort.
This type of response involves upper cognitive processing.
Our different and more severe population could explain this
discrepancy.
Airway function and especially ability to clear secretions
by cough and swallow is fundamental to succeed weaning
after liberation from the endotracheal tube.43 These func-
tions are frequently impaired in this setting due to inherent
neurologic lesions44 and prolonged critical illness under MV
with artificial airway.45,46
Few components of upper-airway control have been
studied in the literature, and quality of data are scarce.3
The ability to cough on demand,13 spontaneously,9 or dur-
ing endotracheal suctioning12,47 was associated with bet-
ter extubation outcomes. One could argue that cough on
demand only reflects neurologic status. A landmark study
from Coplin et al.9 reported that comatose patients (GCS
less than or equal to 8) with absent or weak gag and/or
cough reflex sustained extubation, while the presence of
spontaneous cough and low suctioning frequency were
associated with better extubation outcomes.9 In order to
have pragmatic objective clinical factors, we decided not
to monitor volume and quality of secretions or suction-
ing frequency as reported elsewhere.9,13,48 Spontaneous
deglutition screening is used especially in stroke patients to

Anesthesiology 2017; 126:104-14 111 Godet et al.

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assess dysphagia and aspiration risk.49 Gag reflex could be
a simple indicator of aspiration risk50 but has been assessed
in few studies.9,13 No exact detail of evaluation technique
was provided. Besides being challenging to test in intu-
bated patients, a previous study reported that gag reflex
was absent in 37% of healthy subjects despite preserved
pharyngeal sensations.51 Such an observation might create
confusion in interpretation of results of published studies,
and further investigation is needed.
As with cough, we did not evaluate qualitative aspects of
gag reflex and deglutition. We simply assessed airway fac-
tors on a yes/no basis more compatible with daytime clinical
practice.
Criteria associated with hemodynamics, medical history,
and interestingly respiratory functions did not correlate with
extubation failure in this population. Indeed, as already
reported, standard weaning parameters do not predict extu-
bation failure of neurocritical care patients.10
Finally, our study highlights that extubation of brain-
injured patients relies on a minimal level of consciousness and
more importantly on maintenance of airway protective reflexes
(gag reflex, cough, and deglutition). This observation corrobo-
rates the work by Manno et al.,52 where neuro-ICU patients
who sustained SBT and had favorable airway characteristics
according to the airway care score (sputum quantity, charac-
ter and viscosity, cough to suction, and suctioning frequency)
were randomized to early or delayed extubation regardless of
GCS. They observed that early extubation of patients with
impaired mental status was feasible, without increase in nei-
ther reintubation rate nor mortality. This is in accordance with
our results and results of others9; if airway is functional, low
consciousness level does not alter extubation tolerance.
We used an extended time definition of extubation fail-
ure. Indeed, current trends tend to enlarge the definition to
5 to 7 days3 compared to the classical 48h even if variability
in definition is frequent.53 We considered this cutoff more
appropriate for this population. Early failure might explore
cardiorespiratory incompetency, whereas delayed reintuba-
tion could reflect neurologic and airway impairment. How-
ever, we performed subgroup analyses before and beyond
48h to stick with international guidelines4 and found no dif-
ference (Tables E1 and E2, Supplemental Digital Content,
http://links.lww.com/ALN/B322, presenting data about
patients with extubation failure before 48h).
Relatively low observed rates of stridor in our study
could be explained by differences in endpoint definition and
patients selection from other studies.12,54 Notably, extended
timepoint beyond 48h was taken to define extubation fail-
ure, and no selection was done on the cuff leak test or ability
to cough and deal with bronchial secretions. Strict monitor-
ing every 4h of the cuff pressure was a part of the protocol
in the three ICUs. Even lower stridor rates could be found in
the neurocritical care setting.13,55
Anesthesiology 2017; 126:104-14 112 Godet et al.
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Extubation Failure in Brain-injured Patients
Limitations
Our study has several limitations that deserve discussion.
First, observational and monocentric design limits generaliza-
tion of results. However, the initial goal was the development
of a prediction score. Even if statistical bootstrap validation is
an accepted method, prospective, multicentric validation on
a larger cohort remains the definitive standard and is urgently
mandated. However, because it does not require distribu-
tional assumptions (such as normally distributed errors), the
bootstrap can provide more accurate inferences when the data
are not well behaved or when the sample size is small.56 The
lack of an external cohort validation is the main limitation
of the study. However, this preliminary study was intended
to explore inherent bias, feasability of the generalization to
a larger multicentric trial. Moreover, this preliminary study
allowed the selection of pertinent criteria involved in the
extubation success among a very large panel of hypothetic
ones. Second, deglutition was not assessed with paraclinic
examinations such as fibroscopy or videofluoroscopy, which
could have been more sensitive45 but not routinely available
and difficult with orotracheal intubation. Third, cough was
determined as present spontaneously or during suctioning.
Few studies reported the use of peak flow systems to evaluate
cough strength and found a good correlation with extubation
success.47,48 Quantitative evaluation on demand was limited
in our severe brain-injured patients. Fourth, the incidence of
pneumonia was high (greater than 70%). In a recent study,
Asehnoune et al.31 reported an incidence of 68% in a cohort
of severe brain-injured patients with comparable MV dura-
tion. Fifth, physicians assessed patients at a unique time point
even if fluctuations notably in neurologic examination might
exist.57 Sixth, NIV in brain-injured patients might be con-
sidered inadequate related to upper-airway dysfunction.58
Twelve patients (28%) in the extubation failure group were
concerned. This therapy was administered with strict clinical
observation. Not surprisingly, every patient treated with NIV
was promptly intubated (within a few hours). Ultimately, one
could argue that early tracheostomy before any extubation
attempt could be beneficial in this population, but optimal
timing still has to be demonstrated.1
Conclusion
In this preliminary study, extubation of brain-injured patients
with impaired mental status seems reasonably possible pro-
viding a tight control and functioning of protective airway
reflexes. The use of a pragmatic predictive clinical scoring
system could help decision-making. External validation in a
large, multicentric, prospective fashion is urgently needed.
Acknowledgments
The authors acknowledge the nurses, respiratory thera-
pists, and critical care fellows and staff who participated
in patients management and care from the Department of
Perioperative Medicine, University Hospital of Clermont-
Ferrand, Clermont-Ferrand, France.
 CRITICAL CARE MEDICINE
Research Support
Support was provided solely from institutional and/or de-
partmental sources.
Competing Interests
The authors declare no competing interests.
Correspondence
Address correspondence to Dr. Constantin: Department of
Perioperative Medicine, University Hospital of Clermont-
Ferrand, 1 Place Lucie Aubrac, 63000 Clermont-Ferrand,
France. jmconstantin@chu-clermontferrand.fr. This article
may be accessed for personal use at no charge through the
Journal Web site, www.anesthesiology.org.
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