Articles

Continued enteral nutrition until extubation compared with

fasting before extubation in patients in the intensive care
unit: an open-label, cluster-randomised, parallel-group,
non-inferiority trial
Mickaël Landais*, Mai-Anh Nay*, Johann Auchabie*, Noemie Hubert, Aurélien Frerou, Aihem Yehia, Alain Mercat, Maud Jonas, Frédéric Martino,
Mikael Moriconi, Anne Courte, Vincent Robert-Edan, Alexandre Conia, Florent Bavozet, Pierre-Yves Egreteau, Cédric Bruel, Anne Renault,
Olivier Huet, Marc Feller, Nicolas Chudeau, Martine Ferrandiere, Anne Rebion, Alain Robert, Bruno Giraudeau, Jean Reignier, Arnaud W Thille,
Elsa Tavernier, Stephan Ehrmann, on behalf of the REVA network and CRICS-TriggerSEP F-CRIN research network†

Summary
Background Fasting is frequently imposed before extubation in patients in intensive care units, with the aim to reduce Lancet Respir Med 2023;
risk of aspiration. This unevaluated practice might delay extubation, increase workload, and reduce caloric intake. We 11: 319–28

aimed to compare continued enteral nutrition until extubation with fasting before extubation in patients in the Published Online
January 21, 2023
intensive care unit.
https://doi.org/10.1016/
S2213-2600(22)00413-1
Methods We conducted an open-label, cluster-randomised, parallel-group, non-inferiority trial in 22 intensive care See Comment page 298
units in France. Patients aged 18 years or older were eligible for enrolment if they had received invasive mechanical For the Chinese translation of the
ventilation for at least 48 h in the intensive care unit and received prepyloric enteral nutrition for at least 24 h at the abstract see Online for
time of extubation decision. Centres were randomly assigned (1:1) to continued enteral nutrition until extubation or appendix 1
6-h fasting with concomitant gastric suctioning before extubation, to be applied for all patients within the unit. *Contributed equally
Masking was not possible because of the nature of the trial. The primary outcome was extubation failure (composite †Contributors are listed in
criteria of reintubation or death) within 7 days after extubation, assessed in both the intention-to-treat and per-protocol appendix 2 (pp 3–4)
populations. The non-inferiority margin was set at 10%. Pneumonia within 14 days of extubation was a key secondary Réanimation Polyvalente,
Centre Hospitalier du Mans,
endpoint. This trial is now complete and is registered with ClinicalTrials.gov, NCT03335345.
Le Mans, France (M Landais MD,
N Chudeau MD, A Robert PhD);
Findings Between April 1, 2018, and Oct 31, 2019, 7056 patients receiving enteral nutrition and mechanical ventilation Médecine Intensive
were admitted to the intensive care units and 4198 were assessed for eligibility. 1130 patients were enrolled and Réanimation, Centre
Hospitalier Régional d’Orléans,
included in the intention-to-treat population and 1008 were included in the per-protocol population. In the intention-
Orléans Cedex 2, France
to-treat population, extubation failure occurred in 106 (17·2%) of 617 patients assigned to receive continued enteral (M-A Nay MD); Réanimation,
nutrition until extubation versus 90 (17·5%) of 513 assigned to fasting, meeting the a priori defined non-inferiority Centre Hospitalier Cholet,
criterion (absolute difference –0·4%, 95% CI –5·2 to 4·5). In the per-protocol population, extubation failure occurred Cholet, France (J Auchabie MD);
Réanimation de Chirurgie
in 101 (17·0%) of 595 patients assigned to receive continued enteral nutrition versus 74 (17·9%) of 413 assigned to
Cardiaque, Hôpital de la Pitié
fasting (absolute difference –0·9%, 95% CI –5·6 to 3·7). Pneumonia within 14 days of extubation occurred in Salpêtrière, Paris, France
ten (1·6%) patients assigned to receive continued enteral nutrition and 13 (2·5%) assigned to fasting (rate ratio 0·77, (N Hubert MD); Médecine
95% CI 0·22 to 2·69). Intensive Réanimation et
Maladies Infectieuses, CHU de
Rennes, Rennes, France
Interpretation Continued enteral nutrition until extubation in critically ill patients in the intensive care unit was non- (A Frerou MD); Médecine
inferior to a 6-h fasting maximum gastric vacuity strategy comprising continuous gastric tube suctioning, in terms of Intensive Réanimation, CHD
extubation failure within 7 days (a patient-centred outcome), and thus represents a potential alternative in this Vendée, La Roche sur Yon,
France (A Yehia MD); Médecine
population. Intensive Réanimation, CHU
Angers, France
Funding French Ministry of Health. (Prof A Mercat PhD); Médecine
Intensive Réanimation, CH de
Saint-Nazaire, Saint-Nazaire,
Copyright © 2023 Elsevier Ltd. All rights reserved. France (M Jonas MD);
Réanimation, CHU de la
Introduction despite meeting mechanical ventilation weaning Guadeloupe, Point-à-Pitre,
Extubation is a key procedure in the intensive care unit in criteria,6–8 and intubation is also associated with a risk of France (F Martino MD);
Réanimation, CH de Quimper,
the course of critical illness recovery.1,2 Because aspiration.9 A strong association is observed between Quimper, France
oropharyngeal dysfunction can last for several hours after extubation failure and occurrence of nosocomial (M Moriconi MD); Réanimation,
removal of the tracheal tube protecting the airways, the pneumonia, which might occur because of aspiration of CH de Saint-Brieuc, Saint-
extubation procedure is associated with a risk of gastric digestive secretions.10,11 To favour gastric vacuity, many Brieuc, France (A Courte MD);
Réanimation Chirurgicale,
content aspiration.3–5 Extubation failure and repeat practitioners impose an enteral fasting period in patients Hôpital Nord, CHU de Nantes,
intubation within a week occurs in up to 20% of patients, in the intensive care unit, interrupting enteral nutrition

www.thelancet.com/respiratory Vol 11 April 2023 319

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 Articles
Nantes, France
(V Robert-Edan MD);
Réanimation, CH de Chartres,
Chartres, France (A Conia MD);
Médecine Intensive
Réanimation, CH de Dreux,
Dreux, France (F Bavozet MD);
Réanimation Polyvalente, CH
de Morlaix, Morlaix, France
(P-Y Egreteau MD); Médecine
Intensive Réanimation, Hôpital
Saint Joseph, Paris, France
(C Bruel MD); Médecine
Intensive Réanimation
(A Renault MD) and
Réanimation Chirurgicale
(Prof O Huet PhD), CHU de
Brest, Brest, France;
Réanimation Médico-
Chirurgicale, CH de Blois, Blois,
France (M Feller MD);
Réanimation Chirurgicale,
CHRU de Tours, Tours, France
(M Ferrandierre MD); Clinical
Investigation Centre, INSERM
1415, CHRU Tours, Tours,
France (A Rebion MSc);
Universities of Tours and
Nantes, INSERM 1246-SPHERE,
Tours, France
(Prof B Giraudeau PhD,
E Tavernier PhD); Clinical
Investigation Centre, INSERM
1415, CHRU Tours, Tours,
France (Prof B Giraudeau,
E Tavernier); Service de
Médecine Intensive
Réanimation, Centre
Hospitalier Universitaire de
Nantes, Nantes, France
(Prof J Reignier PhD); CHU de
Poitiers, Médecine Intensive
Réanimation, INSERM CIC 1402
ALIVE, Université de Poitiers,
Poitiers, France
(Prof A W Thille PhD); Médecine
Intensive Réanimation, CHRU
Tours, CIC INSERM 1415,
CRICS-TriggerSep F-CRIN
Research Network, Tours,
France (Prof S Ehrmann PhD);
INSERM, Centre d’Etude des
Pathologies Respiratoires,
U1100, Tours, France
(Prof S Ehrmann); Université de
Tours, Tours, France
(Prof S Ehrmann)
Correspondence to:
Prof Stephan Ehrmann,
Médecine Intensive
Réanimation, CHRU Tours, CIC
INSERM 1415, CRICS-TriggerSep
F-CRIN Research Network, Tours
F37044, France
stephan.ehrmann@univ-tours.
fr
See Online for appendix 2
320
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Research in context
Evidence before this study
Fasting and nutrition practice before extubation in intensive
care units and its effect on patient-centred outcomes has
scarcely been evaluated. We searched PubMed on April 1, 2018,
with no language or date restrictions, with the terms “enteral
nutrition”, “fasting”, “intensive care”, “extubation”, and
“ventilator weaning” to identify relevant studies. Three cohort
studies showed a caloric intake deficit related to intubation or
extubation procedures and showed that extubation and
ventilator weaning represent a frequent cause of nutrition
interruption among critically ill patients. Two surveys among
intensive care unit practitioners showed high heterogeneity in
practice concerning nutrition before extubation, with patient
fasting durations ranging from 2 h to 12 h. No evaluation of the
effect on patient-centred outcomes had been conducted and
the topic is not covered by current guidelines.
Added value of this study
To our knowledge, this is the largest randomised clinical trial to
evaluate continuation of enteral nutrition until extubation
and sometimes suctioning the gastric content via the
gastric tube, before extubation.12 This practice is partly
based on guidelines for scheduled surgery but has never
been evaluated among patients who are extubated in the
intensive care unit after critical illness requiring invasive
mechanical ventilation.9 Fasting before extubation is not
devoid of potential harms, such as delayed extubation and
reduced nutritional intake with associated metabolic
disturbances, as well as potential extra nursing workload.13
We aimed to compare continued enteral nutrition until
extubation with fasting before extubation in patients in
the intensive care unit.
Methods
Study design
We conducted a pragmatic, open-label, cluster-ran­
domised, parallel-group, non-inferiority trial in
22 intensive care units in France, with each unit being
a cluster. The cluster randomisation design was
motivated by the assessed intervention being a care
practice intervention, with a risk of group contamination
that is highly deleterious in a non-inferiority trial; to
further limit the risk of contamination, no crossover
was implemented between clusters. The published
study protocol14 was approved by the relevant ethics
committee (Comité de Protection des Personnes Sud
Mediterranée; 2017.10.02 bis) for all centres. Express
informed consent was obtained from all participants or,
in case of impossibility, from their next of kin or
another surrogate decision maker according to French
law. In all cases, the patient was informed about the
trial, and express consent was obtained as soon as
possible.
compared with fasting as part of a maximum gastric vacuity
strategy, including gastric content suctioning when feasible,
in the immediate timeframe before extubation in the critical
care setting. This study shows the overall safety of pursuing
enteral nutrition until extubation, given the non-inferior rate
of extubation failure—a patient-centred endpoint evaluating
the overall safety of the procedure. These results support
changes in clinical practice because extubation, as part of
airway management, represents a very frequent cause of
enteral nutrition interruption. Furthermore, continued enteral
nutrition until extubation might reduce side-effects and
improve patient outcomes.
Implications of all the available evidence
The available evidence shows that continued enteral nutrition
until extubation in critically ill patients in the intensive care
unit is a practice that could be safe to implement and be
associated with potential benefits, thus clinical practice
change should be considered.
Participants
Patients aged 18 years or older were eligible for enrolment
if they had received invasive mechanical ventilation for at
least 48 h in the intensive care unit and received
prepyloric enteral nutrition for at least 24 h at the time of
extubation decision.
Exclusion criteria were pregnancy, breastfeeding,
do-not-reintubate order, guardianship or trusteeship,
absence of social security coverage, tracheostomy, post-
pyloric enteral nutrition (jejunal tube), and previous
inclusion in the trial.
Randomisation and masking
Clusters were randomly assigned (1:1) to continued
enteral nutrition until extubation or 6-h fasting with
concomitant gastric suctioning before extubation. All
intensive care units were randomised at one time, before
the first inclusion with stratification on whether the
centre was university-affiliated and on predominant
recruitment case mix to reduce potential recruitment bias
related to medical and surgical case mix. A statistician not
involved in participant recruitment prepared a computer-
generated randomisation list. Each unit applied the
strategy assigned by randomisation (continued enteral
nutrition until extubation or fasting before extubation) to
all the patients included within the unit during the entire
trial. Masking was not possible because of the nature of
the trial; however, nosocomial pneumonia diagnosis was
adjudicated by a centralised masked committee.
Procedures
Before the decision to extubate, weaning of mechanical
ventilation and performance of spontaneous breathing
www.thelancet.com/respiratory Vol 11 April 2023

trials was left to the discretion of the attending physician.
Patients were included after the decision to extubate was
made.
In clusters assigned to continued enteral nutrition
until extubation, enteral nutrition was continued until
extubation without changing the flow rate. No suctioning
via the gastric tube was performed before, during, or
after extubation. Aspiration prevention measures, such
as head-of-bed elevation, as well as the nutrition strategy
before study inclusion, were left to the discretion of the
attending physician.
In clusters assigned to fasting before extubation, a
strategy of maximal gastric vacuity was implemented at
least 6 h before planned extubation, comprising an
interruption of enteral nutrition and concomitant
continuous suctioning via the gastric tube when feasible
(ie, tube of sufficient diameter), as fasting alone might
not guarantee gastric vacuity.
In both groups, after extubation, the choice to maintain
the gastric tube, the conduct of nutrition via the gastric
tube, and parenteral or oral route was left to the discretion
of the attending physician. In case of reintubation and
subsequent extubation, patients were managed according
to the initial allocation group. All data were entered and
stored in a secured online clinical record file database.
Outcomes
The primary outcome was extubation failure, defined as a
composite criteria of reintubation or death, within 7 days
after extubation. The choice of a composite outcome was
made to account for the minority of patients who might
die without being reintubated. The decision of reintubation
was left to the discretion of the attending physician.
Key secondary outcomes were hypoglycaemia and
hyperglycaemia, nosocomial pneumonia, nursing workl­
oad (visual analog scale from 0 to 100 with higher score
indicating higher workload), duration between the first
successful spontaneous breathing trial and extubation and
intensive care unit discharge (duration of intensive care
unit stay), and intensive care unit mortality. Nosocomial
pneumonia diagnosis was adjudicated by a centralised
independent masked committee on the basis of clinical,
radiological, and bacteriological data. The incidence of
nosocomial pneumonia in the intensive care unit within
the 14 days following extubation was compared between
groups, as well as: the occurrence of respiratory failure
within 7 days of extubation (unplanned oxygen therapy or
non-invasive ventilation, or tachypnoea with greater than
30 breaths per min); total calorie intake for the day before
extubation, the day of extubation, and the day after
extubation; extubation failure within 48 h and within 72 h;
and extubation failure attributable to aspiration at 7 days.
Detailed secondary outcomes are provided in
appendix 2 (pp 6–8).
The simplified acute physiology score 2 was calculated
from 17 variables at admission;15 the score ranges from
0 to 163, with higher scores indicating more severe
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Articles
disease and higher mortality risk. Coexisting conditions
were assessed according to the Charlson comorbidity
index,16 in which 19 clinical conditions and age are scored
with regard to the risk of death; the score ranges from 0
to 41, with higher scores indicating a higher risk of death.
Statistical analysis
Analyses were performed in accordance with the
pre-established statistical analysis plan, according to both
the intention-to-treat and per-protocol principles (no
nutrition interruption of more than 30 min or nutrition
flow rate reduction of more than 50%, and no gastric
tube suctioning interruption of more than 30 min;
appendix 2 pp 9–10). In both populations, the difference
in extubation failure rates between the two groups was
estimated and a two-tailed 95% CI with corrected
variances taking into account the cluster design was
calculated. The upper limit of this CI was then compared
with the a priori defined 10% non-inferiority margin. The
relative risk (RR) was also calculated (mixed effect log-
binomial model). Time from the first successful spon­
taneous breathing trial to extubation was represented by
Kaplan-Meier curves and the difference between groups
was tested with a clustered log-rank test. Time from the
first successful spontaneous breathing trial to intensive
care unit discharge was represented by cumulative
incidence curves and compared between groups using a
competing risk model, with death as the competing event.
Quantitative outcomes were compared between groups
using a linear mixed effects model. Count outcomes were
compared between groups using a mixed effect Poisson
regression with the duration in the intensive care unit as
the offset. All estimates of the secondary outcomes were
reported with a 95% CI taking into account clustering
with a random effect for each cluster in the mixed effects
regressions (appendix 2 pp 9–12).17,18
Absolute difference in the primary outcome between
groups, adjusted on potential confounders (ie, steroids
use, respiratory physiotherapy, age, disease severity,
number of spontaneous breathing trial failures, cough
evaluation, tracheal secretion abundance, risk factors of
extubation failure, comorbidities), was evaluated by post-
hoc univariate and multivariate mixed linear model
sensitivity analyses (appendix 2 p 12).
Based on an expected incidence of extubation failure of
16% in the control group, with a non-inferiority margin
of 10%, a one-sided type I error of 2·5% and a power of
80%, and an intraclass correlation coefficient of 0·03,
1100 participants needed to be included in 22 clusters
(appendix 2 p 13).19 All analyses were performed using R.
This trial is registered with ClinicalTrials.gov,
NCT03335345.
Role of the funding source
The funder of the study had no role in study design, data
collection, data analysis, data interpretation, or writing of
the report.
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22 intensive care units (clusters) were enrolled

and randomly assigned

11 assigned to fasting group 11 assigned to continued enteral nutrition

2 medical group
2 surgical 4 medical
7 medical-surgical 1 surgical
6 medical-surgical

3223 patients receiving enteral nutrition and 3833 patients receiving enteral nutrition and
mechanical ventilation were admitted mechanical ventilation were admitted
to participating intensive care units to participating intensive care units

1367 not assessed for eligibility 1491 not assessed for eligibility
874 had been receiving mechanical ventilation for 943 had been receiving mechanical ventilation for
less than 48 h less than 48 h
477 had been receiving enteral nutrition for less 535 had been receiving enteral nutrition for less
than 24 h than 24 h
16 were younger than 18 years 13 were younger than 18 years

1856 patients were assessed for eligibility 2342 patients were assessed for eligibility

846 patients were excluded 1054 patients were excluded

274 died before inclusion 345 died before inclusion
363 were in a moribund condition or had do not 439 were in a moribund condition or had do not
resuscitate orders resuscitate order
27 had no social security coverage 18 had no social security coverage
3 were pregnant 7 were pregnant
71 were under guardianship 105 were under guardianship
82 had tracheostomy 95 had tracheostomy
12 had post-pyloric enteral nutrition 22 had post-pyloric enteral nutrition
14 were already included in the trial 23 were already included in the trial
497 were eligible but not randomly assigned 671 were eligible but not randomly assigned
48 did not consent 54 did not consent
63 were transferred to another centre 51 were transferred to another centre
386 due to investigator unavailability or other reason 566 due to investigator unavailability or other reason

513 patients were assigned to fasting and 617 patients were assigned to continued
included in the intention-to-treat enteral nutrition and included in the
population intention-to-treat population

Within 6 h before extubation: Within 6 h before extubation:

23 patients received enteral nutrition 9 patients had enteral nutrition interrupted more than
77 patients had gastric tube suctioning interrupted 30 min before extubation
more than 30 min before extubation 13 patients had a decrease in flow rate of greater than
50% within 6 h before extubation

413 patients were included in the 595 patients were included in the
per-protocol population per-protocol population

Figure 1: Trial profile

Results two groups (table 1; appendix 2 pp 15–16). Charac­teristics

Between April 1, 2018, and Oct 31, 2019, 7056 patients
receiving enteral nutrition and mechanical ventilation
were admitted to the intensive care units and 4198 were
assessed for eligibility. 1130 patients were enrolled and
included in the intention-to-treat population and 1008 were
included in the per-protocol population (figure 1). The
baseline characteristics of the patients were similar in the
before extubation were similar except for the adminis­
tration of steroids to prevent laryngeal oedema, which was
more frequent in the fasting group (table 2); however, no
significant interaction was observed (post-hoc interaction
p=0·88). Also, the proportion of patients with a weak or
ineffective cough (as compared with effective or very
effective) was higher in the fasting group than in the

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Continued enteral Fasting group Continued enteral Fasting group

nutrition group (n=513) nutrition group (n=513)
(n=617) (n=617)
Age, years 61·7 (13·5) 64·1 (13·3) Number of spontaneous breathing trial failures
Sex 0 395 (64·9%) 374 (74·5%)
Female 199 (32·3%) 191 (37·2%) 1 117 (19·2%) 77 (15·3%)
Male 418 (67·7%) 322 (62·8%) 2 48 (7·9%) 26 (5·2%)
Simplified acute physiology score 2 50·9 (17·2) 49·9 (17·8) ≥3 49 (8·0%) 25 (5·0%)
Height, cm 168·5 (9·2) 168·8 (9·3) Systolic blood pressure, mmHg 135·1 (20·7) 137·5 (22·9)
Weight, kg 77·8 (19·5) 79·1 (19·2) Diastolic blood pressure, mmHg 72·2 (14·5) 68·7 (14·0)
BMI, kg/m² 27·4 (6·6) 27·7 (6·3) Heart rate, beats per min 93·8 (18·1) 91·2 (16·7)
Type of admission Respiratory rate, breaths per min 23·9 (6·4) 23·0 (6·2)
Unscheduled surgical 69 (11·2%) 63 (12·3%) Oxygen saturations 96·1% (2·9) 96·1% (2·9)
Scheduled surgical 12 (1·9%) 28 (5·5%) Arterial blood pH 7·45 (0·05) 7·45 (0·05)
Medical 536 (86·9%) 422 (82·3%) Arterial partial pressure of oxygen, 75·5 (16·6) 84·9 (36·7)
Charlson comorbidity index 4·4 (2·6) 4·6 (2·7) mmHg

Comorbidities Arterial partial pressure of carbon 40·4 (9·3) 40·3 (7·4)

dioxide, mmHg
Chronic obstructive pulmonary 89 (14·4%) 65 (12·7%)
disease Hypercapnia* 11 (30·6%) 24 (21·4%)

Asthma 28 (4·5%) 32 (6·2%) Administration of steroids before 103 (16·7%) 248 (48·3%)
extubation
Obesity hypoventilation 24 (3·9%) 19 (3·7%)
syndrome For prevention of laryngeal 17 (2·8%) 161 (31·4%)
oedema
Obstructive sleep apnoea 39 (6·3%) 45 (8·8%)
syndrome requiring continuous Other indication 86 (14·0%) 87 (17·0%)
positive pressure therapy Cough evaluation
Long-term oxygen therapy 6 (1·0%) 12 (2·3%) Ineffective 10 (1·7%) 36 (7·5%)
Non-invasive ventilation at 8 (1·3%) 6 (1·2%) Weak 102 (17·0%) 125 (25·9%)
home Effective 407 (67·7%) 281 (58·2%)
Left ventricular dysfunction 41 (7·0%) 32 (7·1%) Very effective 82 (13·6%) 41 (8·5%)
Ischaemic heart disease 85 (13·8%) 69 (13·5%) Tracheal secretion evaluation
Atrial fibrillation 67 (10·9%) 66 (12·9%) Absent 26 (4·3%) 34 (6·8%)
History of cardiogenic pulmonary 20 (3·2%) 19 (3·7%) Low abundance 321 (53·1%) 247 (49·2%)
oedema
Abundant 219 (36·3%) 190 (37·8%)
Severe valvular heart disease 13 (2·2%) 34 (7·3%)
Great abundance 38 (6·3%) 31 (6·2%)
Data are mean (SD) or n (%). Percentages might sum to more than 100% because
Respiratory physiotherapy 201 (32·8%) 137 (28·1%)
of several conditions being present in one patient and rounding. Additional
baseline characteristics are provided in the appendix 2 (pp 15–16). Risk factors of extubation failure†
0 400 (64·8%) 316 (61·6%)
Table 1: Patient characteristics at randomisation
≥1 217 (35·2%) 197 (38·4%)
Median volume of enteral intake 375 (252–438) 0
continued enteral nutrition group (161 [31·4%] of 6 h before extubation, mL (IQR)
513 patients vs 112 [18·1%] of 617). The duration of Median volume of gastric 0 20 (2–200)
mechanical ventilation before extubation was similar in contents suctioned 6 h before
extubation, mL (IQR)
both groups (table 2; appendix 2 pp 15–16). 217 (35·2%) of
Median duration of invasive 8·4 (5·4–13·4) 8·3 (5·3–12·4)
617 patients in the continued enteral nutrition group and mechanical ventilation before
197 (38·4%) of 513 patients in the fasting group had one or extubation, days (IQR)‡
more risk factors for extubation failure, such as stroke, Data are n (%) or mean (SD) unless otherwise stated. Percentages might sum to
neuromuscular disease, CNS infection, severe head more than 100% because of several conditions being present in one patient and
trauma, diaphragmatic dysfunction, depressive disorders, rounding. Additional baseline characteristics are provided in the appendix 2
(pp 15–16). *Hypercapnia was defined by an arterial partial pressure of carbon
or delirium (table 2; appendix 2 pp 15–16). 395 (64·9%) dioxide of greater than 45mmHg; arterial blood gas analysis at the end of the
patients in the continued enteral nutrition group and spontaneous breathing trial was left to the discretion of the attending physician.
374 (74·5%) in the fasting group passed their first †Predefined specific risk factors of extubation failure recorded in the study were
spontaneous breathing trial. The median volume of stroke, neuromuscular disease, CNS infection, severe head trauma, diaphragmatic
dysfunction, depressive disorders, and delirium.14 ‡Time from intubation to
enteral intake in the 6 h before extubation in the continued extubation was analysed with a mixed-effects Cox regression, with a random
enteral nutrition group was 375 mL (IQR 252–438). The effect for each cluster; the hazard ratio was 0·93 (95% CI 0·77–1·11).
median volume of gastric contents suctioned in the 6 h
Table 2: Patient characteristics at extubation
before extubation in the fasting group was 20 mL
(IQR 2–200; table 2). Caloric intake on the day of

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Continued enteral Fasting group (n=513) Between-group Relative risk or rate

nutrition group (n=617) difference* (95% CI) ratio (95% CI)
Primary outcome
Extubation failure within 7 days after extubation† 106 (17·2%) 90 (17·5%) –0·4% (–5·2 to 4·5) 0·98 (0·74 to 1·29)
Secondary outcomes
Nosocomial pneumonia‡ 10 (1·6%) 13 (2·5%) NA 0·77 (0·22 to 2·69)
Duration from the first successful spontaneous 2·0 (1·0 to 4·4) 17·6 (3·4 to 26·8) NA NA
breathing trial to extubation, h§
Duration from the first successful spontaneous 4·0 (2·0 to 8·0) 6·6 (3·0 to 11·1) NA NA
breathing trial to intensive care unit discharge,
days¶
Total nutritional intake (enteral and parenteral), kcal
The day before extubation 1775·0 (1455·0 to 2150·0) 1505·0 (1065·0 to 1876·0) 284·0 (132·0 to 435·2) NA
The day of extubation, before extubation|| 482·0 (260·0 to 890·0) 236·0 (26·0 to 823·0) 200 (–11·4 to 411·5) NA
The day of extubation, after extubation|| 155·0 (48·0 to 575·0) 75·0 (13·0 to 321·0) 49·3 (–217·9 to 314·9) NA
The day after extubation 200·0 (50·0 to 996·0) 300·0 (93·0 to 1260·0) –186·7 (–531·1 to 155·4) NA
Death in the intensive care unit 24 (3·9%) 35 (6·8%) –2·9% (–6·4 to 0·5) 0·56 (0·32 to 0·99)
Tachypnoea** 364 (59·0%) 277 (54·0%) NA 1·41 (1·05 to 1·89)
Curative oxygen therapy†† 208 (33·7%) 249 (48·5%) NA 0·82 (0·57 to 1·19)
Extubation failure at 48 h 77 (12·5%) 44 (8·6%) 3·9% (–0·1 to 7·9) 1·46 (1·02 to 2·07)
Extubation failure at 72 h 91 (14·7%) 54 (10·5%) 4·2% (–0·1 to 8·6) 1·40 (1·02 to 1·93)
Hypoglycaemia‡‡
The day before extubation 18 (2·9%) 17 (3·3%) –0·4% (–3·7 to 2·9) 0·86 (0·31 to 2·37)
The day of extubation, before extubation 2 (0·3%) 16 (3·1%) –2·8% (–5·2 to –0·4) 0·11 (0·02 to 0·52)
The day of extubation, after extubation 16 (2·6%) 11 (2·1%) 0·4% (–1·5 to 2·4) 1·13 (0·62 to 2·04)
The day after extubation 21 (3·4%) 19 (3·7%) –0·3% (–2·6 to 2·0) 0·91 (0·47 to 1·75)
Hyperglycaemia§§
The day before extubation 113 (18·3%) 136 (26·5%) –8·2% (–15·3 to –1·1) 0·69 (0·53 to 0·89)
The day of extubation, before extubation 69 (11·2%) 78 (15·2%) –4·0% (–10·1 to 2·1) 0·75 (0·49 to 1·16)
The day of extubation, after extubation 77 (12·5%) 60 (11·7%) 0·8% (–4·2 to 5·8) 1·02 (0·68 to 1·53)
The day after extubation 85 (13·8%) 98 (19·1%) –5·3% (–11·2 to 0·6) 0·72 (0·51 to 1·00)
Data are n (%) or median (IQR) unless otherwise stated. Risk differences were not reported (ie, NA) in cases where a Poisson model was used to analyse count data, taking into
account the exposure time (intensive care unit length of stay). NA= not applicable. *The difference is expressed as percentage points for binary variables, and mean difference
for quantitative variables. †The primary outcome was assessed in the intention-to-treat population; the intraclass correlation coefficient was 0·002 (95% CI 0·000–0·043) in
the continued enteral nutrition group and 0·008 (0·000–0·066) in the fasting group. ‡Nosocomial pneumonia diagnosis was adjudicated by a centralised independent masked
committee based on clinical, radiological, and bacteriological data. §The p value associated with the clustered log-rank test was <0·0001. ¶The median duration was analysed
with a competing risks model; the model was a population average regression taking into account the correlation across individuals within a cluster; the hazard ratio was 1·39
(95% CI 1·13–1·71). ||Overall total nutritional intake on the day of extubation was 880 kcal (IQR 513–1539) in the continued enteral nutrition group and 700 kcal (241–1118) in
the fasting group. **Defined as a respiratory rate of greater than 30 breaths per min, that occurred during the first 7 days after extubation. ††Defined as unplanned oxygen
delivery with a flow rate of 5 L/min or with high flow nasal cannula for respiratory failure, that occurred during the first 7 days after extubation. ‡‡Defined as unplanned
implementation in response to respiratory failure, that occurred during the first 7 days after extubation. §§Presence of at least one episode during the period.

Table 3: Primary outcome and key secondary outcomes in the intention-to-treat population

extubation was low in both groups (880 kcal [IQR 513–1539]
in the continued enteral nutrition group and 700 kcal
[241–1118] in the fasting group).
In the intention-to-treat population, 106 (17·2%) of
617 patients in the continued enteral nutrition group and
90 (17·5%) of 513 in the fasting group had extubation
failure within 7 days after extubation (absolute
difference –0·4%, 95% CI –5·2 to 4·5; table 3). In the per-
protocol population, 101 (17·0%) of 595 patients in the
continued enteral nutrition group and 74 (17·9%) of 413 in
the fasting group had extubation failure within 7 days after
extubation (absolute difference –0·9%, 95% CI –5·6 to 3·7).
In both populations, the upper limit of the 95% CI was
within the a priori defined 10% non-inferiority margin,
thus meeting the criteria for non-inferiority (figure 2). A
minority of patients (less than 2% of the study population)
died without being reintubated (11 patients in the
continued enteral nutrition group and nine in the fasting
group; appendix 2 p 16; appendix 2 p 18 shows extubation
failure rates per participating units and clusters).
The post-hoc sensitivity analysis assessing absolute
difference between groups in the primary outcome
adjusted on various potential confounders confirmed the
non-inferiority results of the primary analysis (appendix 2
pp 24–27).
There was no difference between groups in the incidence
of nosocomial pneumonia after extubation (ten [1·6%]
patients in the continued enteral nutrition group vs

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13 [2·5%] in the fasting group; rate ratio 0·77, 95% CI Events, n (%) Risk difference
0·22–2·69; table 3; appendix 2 p 17). The median duration (95% CI)
Continued enteral Fasting group
from the first successful spontaneous breathing trial to nutrition group
extubation was significantly shorter in the continued
Intention-to-treat analysis 106 (17·2%) 90 (17·5%) Non- –0·4 (–5·2 to 4·5)
enteral nutrition group than in the fasting group (2·0 h inferiority –0·9 (–5·6 to 3·7)
Per-protocol analysis 101 (17·0%) 74 (17·9%)
[IQR 1·0–4·4] vs 17·6 h [3·4–26·8]; figure 3). The median margin
duration from the first successful spontaneous breathing –10 –5 0 5 10
trial to alive discharge from the intensive care unit was
Favours continued Favours fasting
shorter in the continued enteral nutrition group than in enteral nutrition
the fasting group (4·0 days [IQR 2·0–8·0] vs 6·6 days
[3·0–11·1]; hazard ratio 1·45, 95% CI 1·19–1·77; figure 3). Figure 2: Extubation failure within the 7 days after extubation (primary outcome)
Aspiration prompting reintubation occurred in eight Error bars show 95% CI.

(1·3%) patients in the continued enteral nutrition group

and 15 (2·9%) in the fasting group (appendix 2 p 17). Death A
in the intensive care unit was significantly less frequent in 100
the continued enteral nutrition group than in the fasting
group (24 [3·9%] patients vs 35 [6·8%]; RR 0·56, 95% CI
0·32–0·99; table 3; appendix 2 p 23). 75
Cumulative incidence (%)

Tachypnoea within 7 days after extubation was more

frequent in the continued enteral nutrition group than in
the fasting group (364 [59·0%] patients vs 277 [54·0%]; 50
rate ratio 1·41, 95% CI 1·05–1·89). The use of unplanned
oxygen therapy or unplanned non-invasive ventilation
(curative oxygen therapy) within 7 days after extubation 25
did not differ significantly between groups (table 3). The Fasting group
Continued enteral nutrition group
extubation failure rate at 48 h was higher in the continued Log-rank p<0·0001
enteral nutrition group than in the fasting group 0
0 24 48 72 96 120 144 168 192 216 240
(77 [12·5%] patients vs 44 [8·6%]; RR 1·46, 95% CI
Number at risk
1·02–2·07). The extubation failure rate at 72 h was also (number censored)
higher in the continued enteral nutrition group than in Continued enteral 602 (0) 67 (0) 32 (0) 18 (0) 14 (0) 11 (0) 11 (0) 10 (0) 7 (0) 7 (0) 5 (0)
the fasting group (91 [14·7%] patients vs 54 [10·5%]; nutrition group
Fasting group 485 (0) 161 (0) 76 (0) 37 (0) 26 (0) 20 (0) 14 (0) 9 (0) 8 (0) 6 (0) 4 (0)
RR 1·40, 95% CI 1·02–1·93; table 3). Results for other
prespecified respiratory exploratory outcomes are B
detailed in the appendix 2 (p 19). 100
Hypoglycaemia before extubation on the day of extu­
bation was significantly less frequent in the continued
enteral nutrition group than in the fasting group 75
Cumulative incidence (%)

(two [0·3%] patients vs 16 [3·1%]; RR 0·11, 95% CI

0·02–0·52; table 3). There was no difference between
groups in the incidence of hypoglycaemia at other 50
timepoints. Hyperglycaemia on the day before extubation
was significantly less frequent in the continued enteral
nutrition group than in the fasting group (113 [18·3%] 25
patients vs 136 [26·5%]; RR 0·69, 95% CI 0·53–0·89;
table 3). There was no difference between groups in the Hazard ratio 1·45 (95% CI 1·19–1·77)
incidence of hyperglycaemia at other timepoints. Results 0
0 7 14 21 28 35 42
for other prespecified nutritional exploratory outcomes Time since first successful spontaneous breathing trial (h)
are detailed in the appendix 2 (p 19). Number at risk
(number censored)
Continued enteral 602 (0) 182 (0) 75 (0) 42 (0) 29 (0) 18 (0) 13 (0)
Discussion nutrition group
Fasting group 485 (0) 234 (0) 111 (0) 62 (0) 35 (0) 24 (0) 15 (0)
This pragmatic, multicentre, open-label, cluster-
randomised, parallel-group, non-inferiority trial showed Figure 3: Cumulative incidence of extubation and intensive care unit discharge over time after the first
that continued enteral nutrition until extubation was successful spontaneous breathing trial
non-inferior to 6-h fasting with concomitant gastric tube (A) Extubation incidence. (B) Intensive care unit discharge incidence.
suctioning before planned extubation in the intensive
care unit in terms of extubation failure (reintubation or
death within 7 days). Patients who received continued

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enteral nutrition until extubation were extubated earlier,
had shorter intensive care unit stay, had fewer
hypoglycaemia and hyperglycaemia episodes, and even
showed improved survival (reduced intensive care unit
deaths) compared with those who had 6-h fasting. The
early extubation failure rate (ie, reintubation within 48 h
or 72 h) was higher in the continued enteral nutrition
group than in the fasting group. The patient-centred
clinical significance of this result is questionable, given
the similar extubation failure rate observed at 7 days in
both groups.
Overall, the low rate of aspiration prompting reintu­
bation, the low rate of nosocomial pneumonia after
inclusion, and the low caloric intake on the day of
extubation in both groups contributed to the non-
inferiority of continued enteral nutrition before
extubation. The low caloric intake after extubation in both
groups represents an additional argument for avoiding
fasting before extubation. The non-inferiority of continued
enteral nutrition until extubation in terms of overall safety
of extubation, as measured through extubation failure,
needs to be put into perspective with the potential absence
of efficacy of fasting. Indeed, an ultrasonographic study
evaluating gastric vacuity before extubation in critically ill
patients showed that a quarter of patients had substantial
persisting gastric contents despite fasting and observed
no association between fasting and decreased gastric
contents volume.20 Furthermore, the secondary outcome
of a significantly longer time interval between the first
successful spontaneous breathing trial and extubation in
the fasting group than in the continued enteral nutrition
group raises concern of disbenefit for the patient
associated with the fasting strategy. Although the study
included a large population of critically ill patients,
comprising 15% of scheduled and unscheduled surgical
patients, our results might not be directly generalisable to
the specific context of major abdominal surgery.
The pathophysiology of hospital-acquired pneumonia,
and particularly its relationship with extubation in the
intensive care unit and the potential aspiration of
oropharyngeal and digestive secretions, remains
debated.1,7–9,14,21,22 This trial shows non-inferiority of the
continued enteral nutrition until extubation strategy but
does not enable us to precisely decipher direct and
indirect mechanisms linking fasting and nutrition to
secondary outcomes, such as time to extubation and
incidence of pneumonia. Hospital-acquired pneumonia
occurred in 23 (2·0%) patients overall; thus, those
pathophysiological hypotheses underpinning the
rationale for a fasting period before extubation are
associated with a very low event rate, of questionable
clinical relevance compared with other mechanisms of
extubation failure (appendix 2 pp 21–22).
The patients included in the study were at high risk of
extubation failure, with a substantial proportion of
patients older than 65 years and with respiratory and
cardiovascular comorbidities, one-third of patients had
326
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one or more risk factors for extubation failure, 40% of
patients had abundant or greatly abundant tracheal
secretions, and a quarter had an ineffective or weak
cough.6–8 The overall extubation failure rate of
17·3% observed in the present study, in the upper range
of extubation failure rates reported in the literature, is in
accordance with studies that have evaluated patients at
high risk of extubation failure and the initial sample size
calculation,1,6–8 which reinforces the external validity of the
study. However, only 24·1% of patients in the continued
enteral nutrition group and 27·1% in the fasting group
received preventive non-invasive ventilation after
extubation, an intervention that has been shown to reduce
extubation failure.23 Conversely, 14·4% of patients in the
continued enteral nutrition group and 19·5% in the
fasting group received unplanned curative non-invasive
ventilation within 7 days of extubation, a practice
potentially associated with poor outcomes.24 Intensive
care unit mortality was lower in the continued enteral
nutrition group than in the fasting group; this secondary
outcome is only hypothesis-generating, especially given
the relatively small between-group difference in overall
nutritional intake. Continued enteral nutrition until
extubation is unlikely to have a direct beneficial effect on
patient survival; however, as it hastened extubation and
discharge from the intensive care unit, it might be
indirectly beneficial, reducing the exposure to invasive,
potentially deleterious, intensive care unit techniques.
To our knowledge, the present study is the largest
randomised trial to evaluate continuation of nutrition
compared with fasting in the immediate timeframe
before extubation in the critical care setting. This study
shows the overall safety of continued enteral nutrition
until extubation given the non-inferior rate of extubation
failure, a patient-centred endpoint used to evaluate the
overall safety of the procedure.25 These results support
changes in clinical practice because extubation, as part of
airway management, represents a very frequent cause of
enteral nutrition interruption.12,13,26,27
This study has several limitations. The study was not
blinded, due to the nature of the intervention and the
pragmatic design with cluster randomisation at the level
of the intensive care unit. The primary composite
outcome of extubation failure is in part influenced by the
physicians’ decision to intubate patients. However, the
long observation period of 7 days decreases potential
bias. The primary composite outcome is to be considered
as objectively measured but potentially influenced by
clinician judgement, which is associated with a low risk
of bias.28
The open-label, cluster-randomised design might not
fully control for all potential recruitment bias and
confounding factors. Some potential confounders could
have favoured extubation failure in the fasting group—
eg, patients in the fasting group were 2 years older on
average and more frequently presented with weak or
ineffective cough than those in the continued enteral
www.thelancet.com/respiratory Vol 11 April 2023

nutrition group. Conversely, patients in the continued
enteral nutrition group were more severely ill, as
measured by the simplified acute physiology score, had
more frequently not passed their first spontaneous
breathing trial, and had less frequently received steroids
to prevent laryngeal oedema, all of which might have
favoured extubation failure in this group. More frequent
steroid administration in the fasting group might be due
to the available time to administer the therapy before
extubation because of the 6-h fasting duration,29 but one
cannot formally exclude a patient-related or unit-related
bias given the potential heterogeneity in care in the peri-
extubation period across centres. The slight group
imbalances, which in part counterbalance each other,
should not distract from the pragmatic finding of the
present large-scale study showing an equal risk of
extubation failure among 1130 patients whether they
undergo fasting or not before extubation. Of note, the
post-hoc sensitivity analysis of the primary composite
outcome adjusted for potential confounders, including,
among others, steroid administration and cough
effectiveness, confirmed the non-inferiority of the
continued enteral nutrition until extubation strategy in
all cases (appendix 2 p 24).
In conclusion, in the studied population, continued
enteral nutrition until extubation in the intensive care
unit was non-inferior to a 6-h fasting maximum gastric
vacuity strategy before extubation, comprising
continuous gastric tube suctioning when feasible. The
non-inferiority of continued enteral nutrition until
extubation, in terms of extubation failure within 7 days (a
patient-centred outcome), supports change in clinical
practice towards this safe alternative.
Contributors
ML, M-AN, JA, ET, and SE conceived and coordinated the design and
overall study conduct, data analysis, and manuscript writing, and vouch
for the data analysis accuracy. NH participated in initial study design.
AReb and ARo supervised methodology, study recruitment, and data
management. JR and AWT participated in study design, data
interpretation, and manuscript drafting, as nutrition and mechanical
ventilation experts. ET and BG supervised methodology and did the
statistical analysis. All other authors participated in patient recruitment
and study conduct. All authors revised the manuscript for important
intellectual content and approved the final manuscript. ML, M-AN, JA,
ET, SE, and BG had direct access to the data and are responsible for the
decision to submit for publication.
Declaration of interests
SE reports grants, lecture fees, travel support, and receipt of equipment
from Aerogen and Fisher & Paykel Healthcare, and consulting fees and
advisory board participation at Aerogen. M-AN reports grants, receipt of
equipment, and lecture fees from Fisher & Paykel Healthcare.
AWT reports grants from the French Ministry of Health, lectures fees
from Sigher & Paykel and Philips, and travel support from Fisher &
Paykel, GE Healthcare, and Sedana. All other authors declare no
competing interests.
Data sharing
Study data, including individual participant data, will be made available
upon reasonable requests made to the corresponding author.
Acknowledgments
The trial was funded with a grant from the French Ministry of Health
(API16/A/063; Groupement Interrégional de Recherche Clinique
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Articles
et d’Innovation Grand Ouest). We thank all patients and relatives, as
well as clinical, administrative, and research staff involved in the
conduct of this study. We sincerely thank Julie Mankikian,
Adrien Auvet, and Christophe Cracco for participating in the
pneumonia adjudication committee.
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