Critical care
Original research
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Correspondence to
Dr Karen E A Burns, Critical
Care, Unity Health Toronto,
Toronto, Canada;
​karen.​burns@​unityhealth.​to
Received 5 February 2021
Accepted 15 September 2021
Published Online First
29 October 2021
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To cite: Burns KEA,
Stevenson J, Laird M, et al.
Thorax 2022;77:752–761.
752   Burns KEA, et al. Thorax 2022;77:752–761. doi:10.1136/thoraxjnl-2021-216993
Non-­invasive ventilation versus invasive weaning in
critically ill adults: a systematic review and meta-­
analysis
Karen E A Burns  ‍ ‍,1,2,3,4,5 James Stevenson,6 Matthew Laird,6 Neill K J Adhikari,1,7,8
Yuchong Li,2,5 Cong Lu,2,5 Xiaolin He,5 Wentao Wang,9 Zhenting Liang,8 Lu Chen,2,5
Haibo Zhang,1,2,5,10 Jan O Friedrich1,2,3,5
ABSTRACT
Background  Extubation to non-­invasive ventilation Key messages
(NIV) has been investigated as a strategy to wean
critically ill adults from invasive ventilation and reduce What is the key question?
ventilator-r­ elated complications. ⇒ What is the effect of non-­invasive and invasive
Methods  We searched MEDLINE, EMBASE, the weaning in randomised or quasi-­randomised
trials of critically ill adults on mortality (primary
Cochrane Central Register of Controlled Trials,
proceedings of four conferences and bibliographies (to outcome), pneumonia, weaning failures and
June 2020) for randomised and quasi-­randomised trials other clinically important outcomes?
that compared extubation with immediate application
What is the bottom line?
of NIV to continued invasive weaning in intubated
⇒ High-­quality evidence suggests that non-­
adults and reported mortality (primary outcome) or
invasive (vs invasive) weaning significantly
other outcomes. Two reviewers independently screened
reduced mortality, pneumonia and the
citations, assessed trial quality and abstracted data.
proportion of weaning failures, and subgroup
Results  We identified 28 trials, of moderate-­to-­good
analyses found that non-­invasive weaning
quality, involving 2066 patients, 44.6% with chronic
reduced mortality, pneumonia, reintubation
obstructive pulmonary disease (COPD). Non-­invasive
and intensive care unit length of stay in trials
weaning significantly reduced mortality (risk ratio (RR)
enrolling chronic obstructive pulmonary disease
0.57, 95% CI 0.44 to 0.74; high quality), weaning
(COPD) (vs mixed) populations.
failures (RR 0.59, 95% CI 0.43 to 0.81; high quality),
pneumonia (RR 0.30, 95% CI 0.22 to 0.41; high Why read on?
quality), intensive care unit (ICU) (mean difference (MD) ⇒ Pooled data support the net clinical benefits
−4.62 days, 95% CI −5.91 to −3.34) and hospital stay associated with the non-­invasive approach
(MD −6.29 days, 95% CI −8.90 to −3.68). Non-­invasive to weaning on important clinical outcomes,
weaning also significantly reduced the total duration of particularly in patients with COPD, while more
ventilation, duration of invasive ventilation and duration careful patient selection is required in non-­
of ventilation related to weaning (MD −0.57, 95% CI COPD patients.
−1.08 to −0.07) and tracheostomy rate. Mortality,
pneumonia, reintubation and ICU stay were significantly
lower in trials enrolling COPD (vs mixed) populations. health-­related quality of life,4 5 post-­traumatic stress
Conclusion  Non-­invasive weaning significantly reduced disorder,6 7 depression,8 delirium9 and cognitive
mortality, pneumonia and the duration of ventilation impairment.10 Consequently, minimising patients’
related to weaning, particularly in patients with COPD. exposure to invasive mechanical ventilation has been
Beneficial effects are less clear (or more careful patient
identified as a key research priority by critical care
selection is required) in non-­COPD patients. societies.11
PROSPERO registration number  CRD42020201402. Non-­invasive ventilation (NIV), administered with
a patient–ventilator interface, can provide partial
ventilator support to patients with ARF without the
need for an artificial airway. Interfaces include nasal
INTRODUCTION mask, oronasal mask, full face masks, mouthpiece,
Mechanical ventilation is often required to support nasal pillows and helmets.12 NIV does not provide
critically ill patients with acute respiratory failure airway protection. Similar to invasive ventilation,
(ARF). Although life-­ saving, invasive ventilation is NIV can augment tidal volumes, reduces respiratory
associated with ventilator-­ related complications, rates, apply positive end-­ expiratory pressure and
such as ventilator-­associated pneumonia (VAP). VAP, improve gas exchange.12 13 Unlike invasive mechanical
in turn, is associated with attributable mortality of ventilation, NIV preserves patient’s ability to cough,
approximately 13%.1 Cumulative exposure to inva- swallow and speak.14 Patients who are treated with
sive mechanical ventilation is associated with long-­ NIV may receive less invasive monitoring and seda-
term sequelae including muscle weakness,2 3 reduced tion15 and experience less psychological distress.16

For these reasons, investigators have studied NIV as a method to
reduce patient’s exposure to invasive mechanical ventilation during
weaning. With this technique, patients who do not meet conven-
tional criteria for extubation (ie, fail a spontaneous breathing trial
(SBT) or are not ready to undergo an SBT) are extubated directly
to NIV. Non-­invasive support is then reduced over time, minimising
patients’ exposure to invasive ventilation and related complications.
To better understand the net clinical benefits associated with
non-­invasive weaning, we sought to critically appraise, summarise
and update a prior systematic review and meta-­analysis17 of the
effect of non-­invasive weaning compared with invasive weaning on
important outcomes in light of new evidence.
METHODS
Data sources and searches
We updated a previously conducted search of MEDLINE (January
1966 to July 2021), EMBASE (January 1980 to July 2021) via
Ovid SP and the Cochrane Central Register of Controlled Trials
(CENTRAL) (the Cochrane Library 2012, July 2021) without
language restrictions. Details of the search strategies used are
provided in online supplemental appendix 1. Two reviewers (JS,
ML) independently screened citation titles and abstracts. One
reviewer (JOF) updated manual searches of abstracts from confer-
ence proceedings published in the American Journal of Respiratory
and Critical Care Medicine, Intensive Care Medicine, Critical Care
Medicine and Chest from June 2013 to August 2020. We reviewed
bibliographies of retrieved articles to identify potentially relevant
trials, contacted authors to obtain additional information regarding
study methods where needed and searched for ongoing trials on
www.isrctn.com and www.clinicaltrials.gov.
Study selection
We included randomised and quasi-­ randomised trials that (1)
enrolled adults with respiratory failure who required invasive
mechanical ventilation for at least 24 hours but before they met
conventional criteria for extubation, (2) compared extubation with
immediate application of NIV to continue the ventilation weaning
process with continued invasive weaning and (3) reported at least
one of mortality (primary outcome), VAP, weaning failure (using
authors’ definitions), intensive care unit (ICU) or hospital length of
stay, total duration of ventilation, duration of ventilation related to
weaning, duration of invasive ventilation, adverse events or quality
of life. We excluded trials that compared non-­invasive with inva-
sive weaning in the immediate postoperative setting (typically with
less than 24 hours of invasive ventilation), compared NIV with
unassisted oxygen supplementation and investigated NIV after
unplanned extubation.
Data abstraction and risk of bias assessment
Two unblinded authors (JS, ML) abstracted data regarding risk
of bias (randomisation, allocation concealment, completeness of
follow-­up, selective outcomes reporting) using a standardised
data abstraction form. We did not formally assess blinding in
these necessarily unblinded trials. Disagreements regarding
study selection and data abstraction were resolved by consensus
and arbitration with a third author (KEAB).
Data synthesis and statistical analysis
We pooled data across studies using random effects models. We
derived summary estimates of risk ratio (RR) and mean differ-
ence (MD) with 95% CIs for binary and continuous outcomes,
respectively, using Review Manager V.5.4 (Cochrane Collabora-
tion, Oxford).18 If an outcome was reported at two different times,
Burns KEA, et al. Thorax 2022;77:752–761. doi:10.1136/thoraxjnl-2021-216993
Critical care
we included the more protracted measure in pooled analyses (eg,
mortality).
We evaluated the impact of statistical heterogeneity among
pooled studies for each outcome using the Cochran Q statistic
(threshold p<0.10)19 20 and the I2 statistic21 22 with threshold
values of 0%–40%, 30%–60%, 50%–90% and >75% representing
heterogeneity that might not be important or represent moderate,
substantial or considerable heterogeneity, respectively.22 If a hetero-
geneity value overlapped two categories, we assigned it the higher
heterogeneity rating. In sensitivity analyses, we assessed the impact
of excluding quasi-­randomised trials on estimates of mortality and
VAP. We planned subgroup analyses to compare the effects of non-­
invasive weaning on mortality and weaning failures in studies of
patients with chronic obstructive pulmonary disease (COPD) only
compared with mixed populations (any non-­COPD) and in studies
that enrolled >50% versus <50% patients with COPD. We assessed
for differences between subgroup summary estimates using the χ2
test.23 We examined funnel plots visually for evidence of publica-
tion bias. We used the principles of grades of recommendation,
assessment, development, and evaluation (GRADE)24 to assess the
quality of the body of evidence associated with specific outcomes
(mortality, weaning failure, VAP, duration of ventilation related to
weaning and reintubation).
RESULTS
Trial identification
We previously identified 16 trials25–40 meeting our eligibility criteria.
In updated searches of 971 records (online supplemental appendix
1), we assessed 20 new articles for eligibility (figure 1). Of these, we
included 12 new trials41–52 that evaluated NIV as a weaning strategy.
One trial28 was previously assessed to be quasi-­randomised. We were
unable to clarify whether another trial42 reported as ‘randomised’
was truly randomised or quasi-­ randomised. One trial did not
include outcomes data by group and only contributed data to the
quality assessment.41 In summary, we included 28 trials reporting on
2066 patients in our updated review.
Of the 28 included trials, 4 trials were published only in abstract
form,27 30 41 43 8 trials were published in Chinese,28 31 33 34 42 48 49 52
1 trial was a dissertation subsequently published in full36 and
another was a pilot randomised controlled trial (RCT).40 We
excluded 19 studies53–71 including 8 newly excluded publications
(figure 1).72–79 The two reviewers (JS, ML) achieved complete
agreement on study selection.
Fourteen trials included exclusively COPD (n=922) patients
(table 1).25 28 30–34 36 38 42 43 45 47 52 Of non-­COPD trials, COPD
was diagnosed in approximately 75% of patients in three
trials,26 29 37 approximately one-­third of patients in two trials,27 35
over 20% of patients in another trial39 46 and unspecified in a
final trial.41 Three trials excluded patients with COPD40 49 51 and
one trial each focused exclusively on specific patient populations
including after cardiac surgery,44 elderly patients with severe
community-­acquired pneumonia49 and adults with acute respira-
tory distress syndrome48 or hypoxemic respiratory failure.51 The
largest trial stratified on the presence of COPD but included less
than 4% of patients with COPD.50
Patients were considered difficult to wean in two trials26 37 and
persistent weaning failures in another trial.29 Five trials31–34 43
included COPD patients with respiratory failure due to pulmo-
nary infection. No included trials evaluated high-­ flow nasal
cannulae in the intervention group.
Quality assessment
Overall, the quality of the included trials was moderate-­to-­good
(figure 2). In most trials, allocation to treatment group was
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Figure 1  Trial selection process. This review represents an update of a previously conducted systematic review and meta-­analysis.16
by random assignment with one quasi-­randomised confirmed
to allocate patients according to hospital admission order.28
We judged allocation concealment to be adequate in 13
trials,25 27 29 30 37–40 44 47 50–52 unclear in 14 trials26 31–36 41–43 45 46 48 49
and inadequate in a quasi-­randomised trial.28 In three trials,33 34 41
denominators were not provided in binary outcomes to ensure
complete outcomes reporting. One trial49 was deemed to be at
high risk of bias due to incomplete outcomes reporting as >5%
of the patients (4 NIV arm, 1 control arm) were excluded post
randomisation. With regard to selective outcomes reporting
two trials were deemed to be at high risk of bias29 41 and three
trials were deemed to be at unclear risk of bias28 44 45 (online
supplemental appendix 2). On inspection of a funnel plot for
the primary outcome, we noted the potential absence of small
negative trials (online supplemental appendix 3).
Primary outcome: mortality
Twenty-­seven trials involving 2042 patients (increase of
1048) provided mortality data. Mortality was reported at
30 days,36 39 45 50 60 days,25 49 90 days,26 29 50 180 days,50
ICU37 40 46 47 50–52 and hospital discharge26 30 32–35 38 40–44 46 50 51
and at undefined times.27 28 31 48 There was strong evidence that
non-­invasive weaning reduced mortality (RR 0.57, 95% CI 0.44
754
to 0.74; p≤0.0001; high quality) with moderate heterogeneity
(I2=27%) (figure 3).
Secondary outcomes
Eleven trials involving 829 patients, using variable defi-
nitions, reported the proportion of patients successfully
weaned.25–27 30 37–40 43 46 51 The pooled data demonstrated a
significant reduction in the proportion of weaning failures using
non-­invasive weaning (RR 0.59, 95% CI 0.43 to 0.81; p=0.001;
high quality) with low heterogeneity (I2=22%).
Pooled data from 23 trials involving 1581 (increase of 628)
patients25 26 28–39 42 43 45–49 51 52 that reported VAP for which criteria
for the diagnosis were provided in 10 trials25 28 29 31–36 39 42 45–48 50 51
showed that non-­invasive weaning was associated with decreased
VAP (RR 0.30, 95% CI 0.22 to 0.41; p<0.00001; high quality)
with low heterogeneity (I2=24%) (figure 4).
Meta-­analysis also supported that non-­ invasive weaning
significantly reduced ICU (MD −4.62 days, 95% CI −5.91 to
−3.34; p<0.00001, I2=80%) and hospital (MD −6.29 days,
95% CI −8.90 to −3.68; p<0.00001, I2=75%) stay, total dura-
tion of mechanical ventilation (MD −5.26 days, 95% CI −7.86
to −2.67; p<0.0001, I2=83%) and duration of invasive venti-
lation (MD −7.75 days, 95% CI −9.86 to −5.64; p<0 00 001,
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Table 1  Populations and interventions in studies of non-­invasive ventilation (NIV) in critically ill adults
No. of Inclusion criteria
Study patients Inclusion criteria (patients) (weaning eligibility) Experimental strategy Control strategy
25
Nava et al 50 Exacerbation of COPD. Intubated for at least Simple weaning criteria, 1 hour SBT Non-­invasive PS on conventional Invasive PS
36–48 hours failure ventilator delivered with face
mask
Girault et al26 33 Acute-­on-­chronic respiratory failure (COPD, Simple weaning criteria, 2 hours SBT Flow or pressure mode with Flow or pressure
restrictive or mixed populations). Intubated for failure nasal or face mask mode (PS)
at least 48 hours
Hill et al27 21 Acute respiratory failure (ARF) 30 min SBT failure NIV using VPAP in ST-­A mode Invasive PS
28
Chen et al 24 Exacerbation of COPD. Intubated for at least Day 3+ weaning criteria Bilevel NIV (pressure mode)  Invasive PS
48–60 hours. Saturations>88% on FiO2 40%
Ferrer et al29 43 ARF and persistent weaning failure. Intubated 2 hours SBT failure on 3 consecutive Bilevel NIV in ST mode delivered AC or invasive PS
for at least 72 hours days with face or nasal mask
Rabie et al30 37 Exacerbation of COPD 2 hours SBT failure NIV (proportional assist in timed Invasive PS
mode) delivered by face or nasal
mask
Wang et al31 28 COPD. Bronchopulmonary infection PIC window NIV (pressure mode) delivered SIMV+PS
by mask (unspecified)
Wang et al32 90 COPD with severe hypercapnic respiratory PIC window Bilevel NIV (pressure mode) SIMV+PS
failure. Pneumonia or purulent bronchitis.
Age≤85 years. Capable of self-­care in past year
Zheng et al33 33 COPD. Severe pulmonary infection PIC window Bilevel NIV (pressure mode) Invasive PS
delivered by face or nasal mask
Zou et al34 76 COPD with severe respiratory failure. PIC window Bilevel NIV (pressure, ST mode) SIMV +PS
Pulmonary infection delivered by nasal or oronasal
mask
Trevisan et al35 65 Invasively ventilated >48 hours 30 min SBT failure Bilevel NIV (pressure mode) Invasive MV
delivered by face mask
Prasad et al36 30 COPD. Hypercapnic respiratory failure 2 hours SBT failure Bilevel NIV (pressure mode) Invasive PS
delivered by full face mask
Girault et al37 138 Chronic hypercapneic respiratory failure 2 hours SBT failure Non-­invasive PS±PEEP or bilevel Invasive PS with
invasively ventilated for at least 48 hours NIV with face mask (initial once daily SBT with
choice) T-­piece or PS±PEEP
Rabie Agmy et al38 264 Acute on chronic exacerbation of COPD 2 hours SBT failure NIV (pressure, ST mode) Invasive PS
Tawfeek and Ali-­ 42 Invasively ventilated for >48 hours 2 hours SBT failure Non-­invasive PAV ventilation SIMV
Elnabtity39 delivered by face mask
Vaschetto et al40 20 Hypoxemic respiratory failure invasively PS with PEEP +inspiratory support, Helmet NIV Invasive PS with
ventilated for at least 48 hours <25 cmH2O and PEEP 8–13 cmH2O; SBT when P/F
PaO2/FiO2 200–300 mm Hg with ratio >250 mm Hg
FiO2≤0.6
Charra et al41 24 Invasively ventilated for greater than 48 hours T-­piece SBT failure Face mask bilevel NIV Classic wean with
in medical intensive care unit invasive PS
Rong42 64 COPD with respiratory failure PIC window Bilevel positive airway pressure SIMV+PS
Mohamed and 30 COPD with infective exacerbation Not reported NIV Invasive MV
Ibrahim43
Laiq et al44 60 Cardiac surgery patients invasively ventilated 30 min T-­piece SBT failure NIPPV Invasive MV with
greater than 48 hours daily SBT
El-­Shimy et al45 40 COPD on MV 30 min–2 hours T-­piece SBT failure NIV (BiPAP) SIMV+PS
46
Carron et al 64 Intubated for  ARF≥48 hours 30 min PSV SBT failure Helmet NIV PSV weaning
Mishra et al47 50 COPD exacerbation requiring invasive MV for T-­piece SBT failure Full face mask NIPPV (BiPAP) PSV
at least 48 hours
Wang et al48 53 Surgical patients requiring invasive MV for PaO2/FiO2 200–250 mm Hg with NIV Invasive MV with
acute respiratory distress syndrome PEEP 8 and PS 12 cmH2O, acute daily SBT
infiltrates resolved
Guo et al49 96 (5 Age≥75 years and community-­acquired Failed SBT NIV PSV weaning with
excluded) pneumonia requiring MV SBT
Perkins et al50 364 Invasive MV for >48 hours SBT failure Face mask NIV Invasive MV with
daily SBT

Continued

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 Critical care
Table 1  Continued
No. of
Study patients Inclusion criteria (patients)
Vaschetto et al51 130 Hypoxemic respiratory failure invasively
ventilated for at least 48 hours
 Chen et al52 106 COPD exacerbation requiring invasive MV
AC, assist control; BiPAP, bilevel positive airway pressure; COPD, chronic obstructive pulmonary disease; GCS, Glasgow Coma Scale; IBW, ideal body weight; MV, mechanical
ventilation; PEEP, postive end-­expiratory pressure; P/F, partial pressure of oxygen/fractional concentration of oxygen; PIC, pulmonary infection control; PS, pressure support; PSV,
pressure support ventilation; SBT, spontaneous breathing trial; SIMV, synchronised intermittent mandatory ventilation; ST, spontaneous timed; ST-­A, spontaneous timed; VPAP,
variable positive airway pressure; Vt, tidal volume.
I2=94%), all with considerable heterogeneity. Non-­ invasive
weaning significantly reduced the duration of mechanical venti-
lation related to weaning (MD −0.57 days, 95% CI −1.08 to
−0.07; p=0.03; moderate quality due to inconsistency with
I2=88%) favouring non-­invasive weaning (figure 5). No study
reported quality of life (table 2).
Adverse events
The pooled result showed no difference in arrhythmias (RR
0.70, 95% CI 0.41, 1.20; four trials, 565 patients),26 36 37 50
non-­significantly lower reintubation (RR 0.69, 95% CI 0.47 to
1.01; 14 trials, moderate quality due to inconsistency, 1336
patients)26–29 32 34 35 37–40 46 48 50 and tracheostomy rates (RR 0.25,
95% CI 0.10 to 0.61; 10 trials, 1130 patients)26 29 35 37–40 46 50 51
with variable heterogeneity (table 2).
Sensitivity and subgroup analyses
Exclusion of two potentially quasi-­randomised trials28 42 main-
tained significant reductions in mortality (RR 0.62, 95% CI 0.47
to 0.80) and VAP (RR 0.30, 95% CI 0.22 to 0.43) both favouring
non-­invasive weaning.
We noted a significant difference in RR between subgroups
(p=0.0003) evaluating non-­ invasive weaning on mortality in
COPD (RR 0.36, 95% CI 0.25 to 0.51; 14 trials, 922 patients;
p<0.00001, I2=0%) versus mixed population (RR 0.81, 95% CI
0.62 to 1.05; 13 trials, 1120 patients; p=0.11, I2=7%). A
subgroup analysis that compared trials enrolling at least 50% (RR
0.44, 95% CI 0.31 to 0.63; 18 trials, 1200 patients) versus less
than 50% patients with COPD (RR 0.80, 95% CI 0.61 to 1.06;
nine trials, 842 patients) also showed a larger and statistically
significant (p=0.009) mortality reduction in subgroup analysis
favouring COPD trials. The effect of non-­invasive weaning on
weaning failures did not differ significantly between COPD and
mixed populations and trials enrolling at least 50% versus less
Figure 2  Risk of bias of the included trials. Green, yellow and red
circles represent low, unclear and high risk of bias, respectively.
756
Inclusion criteria
(weaning eligibility) Experimental strategy Control strategy
PS with PEEP +inspiratory support, Oral-­nasal or full face mask NIV Invasive PS with
<25 cmH2O and PEEP 8–13 cmH2O; 30 min PS 5/PEEP
PaO2/FiO2 200–300 mm Hg with 5 SBT when P/F
FiO2≤0.6; PaCO2 ≤50 mm Hg and ratio >250 mm Hg
pH ≥7.35,  risk ratio≤30, Vt≤8 mL/kg
IBW, T<38.5°C, GCS 10T, suction <2/
hour
Criteria for moving to NIV in NIV Invasive MV until
intervention group not clear successful SBT
than 50% patients with COPD. Similarly, we found significant
differences between subgroups evaluating non-­invasive weaning
on VAP and ICU length of stay in COPD versus mixed popula-
tions. A post hoc subgroup analysis demonstrated significantly
lower reintubation rate (p=0.02) in COPD trials (RR 0.48,
95% CI 0.34 to 0.67) versus mixed patient populations (RR
0.89. 95% CI 0.59 to 1.35) (table 3).
DISCUSSION
In this updated systematic review, we identified 28 trials
(2066 patients) enrolling mechanically ventilated patients that
compared weaning with extubation to non-­invasive ventilation
to ongoing weaning on mechanical ventilation. Compared with
invasive weaning, non-­invasive weaning reduced mortality (high
quality), VAP (high quality), weaning failures (high quality),
length of stay in the ICU and hospital and tracheostomy. More-
over, non-­invasive (vs invasive weaning) significantly reduced
the duration of invasive ventilation, total duration of ventilation
and the duration of ventilation related to weaning. The effects
on mortality and VAP remained significant after exclusion of
quasi-­randomised trials. Subgroup analysis suggested that the
benefits of non-­invasive weaning were higher in COPD versus
mixed patient populations, with significant between-­ group
differences in mortality, ICU length of stay and reintubation
favouring patients with COPD.
Compared with our previous review, this update includes
data from 12 additional trials and 1072 additional patients.17
Patients with COPD accounted for half the trials and 44.6%
of the patients overall. Overall trials included in the current
review were of moderate-­to-­good quality. Lack of blinding and
the inconsistent use of standardised weaning protocols in both
arms and absence of a sedation protocol in the invasive weaning
arm raise the possibility that control patients in some trials
may not have received optimal care, biasing in favour of non-­
invasive weaning. The largest trial included patients with vari-
able reasons for ARF and carefully protocolised weaning in both
groups.50 Similar to our systematic review, Perkins et al found
significant differences in the duration of invasive ventilation and
total duration of ventilation. Unlike our review, this study did
not find differences in rates of mortality or tracheostomy.50 The
low proportion of patients with COPD included in their trial
(4% COPD) versus the larger number of patients with COPD
included in our review (44.6%) may, at least in part, explain the
discordant findings. In general, results of large trials have been
found to agree with meta-­analyses to which they contribute,80
but differences between large trials and meta-­analyses of smaller
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Figure 3  Effect of non-­invasive weaning on mortality. COPD, chronic obstructive pulmonary disease; M-­H, Mantel-­Haenszel.

Figure 4  Effect of non-­invasive weaning on ventilator-­associated pneumonia. COPD, chronic obstructive pulmonary disease; M-­H, Mantel-­Haenszel.
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Figure 5  Effect of non-­invasive weaning on duration of ventilation related to weaning. COPD, chronic obstructive pulmonary disease; IV,
intravenous.

trials addressing the same question have been demonstrated in large-­scale observational studies of weaning practices83 84 should
some fields81 and may depend on the selection of included trials, provide more data on the real-­world use of non-­invasive weaning.
methods used to summarise data and outcomes reported.82 Clinicians weighing the trade-­off between the risks associated with
Non-­invasive weaning may be particularly suitable for patients failed extubation versus prolonged invasive ventilation can be reas-
with COPD, whose failure to wean is characterised by respiratory sured that non-­invasive weaning is superior to invasive weaning, for
muscle weakness and gas trapping leading to intrinsic positive end-­ patients with COPD. However, enthusiasm should be tempered by
expiratory pressure, both of which are assisted by non-­ invasive considerations of experience required among physicians, nurses and
ventilation. In contrast, patients with non-­hypercapneic respiratory respiratory therapists to safely implement non-­invasive weaning,
failure may fail a SBT for other reasons (eg, excess sputum) or may reintubation if required, and the need for standalone non-­invasive
have other reasons why extubation should be deferred (eg, low ventilators or ventilators capable of both forms of ventilation. This
level of consciousness). A survey of self-­reported practices found is particularly important in non-­COPD patients where benefits are
that intensivists commonly reported using non-­invasive weaning in less clear based on our subgroup analyses.
patients with COPD (>50% of respondents in most regions) but
were less likely to do so (<30% in most regions) for other indica-
tions such cardiogenic pulmonary oedema or postoperatively.83 Two Comparison with other studies
A clinical practice guideline that cited our previous review85
gave a conditional recommendation in favour of non-­invasive
Table 2  Summary estimates of effect of non-­invasive ventilation in weaning for patients with hypercapneic respiratory failure but
critically ill adults made no recommendation for patients with hypoxemic respira-
No. of studies Summary estimate tory failure. Compared with the 2018 review by Yeung et al,86
Outcome (no. of patients) (95% CI) I2 (%) we included five additional trials.27 30 38 51 52 Similar to their
Mortality 26 (2042) 0.57 (0.44 to 0.74) 26 study, we documented beneficial effects of NIV on mortality,
VAP, duration of invasive ventilation and ICU stay.86 In a sensi-
VAP 23 (1581) 0.30 (0.22 to 0.41) 24
tivity analysis of nine trials (n=788 patients who failed an initial
Weaning failures 11 (829) 0.59 (0.43 to 0.81) 22 SBT), they reported beneficial effects of non-­invasive weaning
Length of stay on hospital mortality but wide ‘highest posterior density inter-
 Intensive care  22 (1804) −4.6 (−5.9 to −3.3) 80 vals’, from Bayesian estimates, precluded a definitive statement
 Hospital  13 (1061) −6.3 (−8.9 to −3.7) 75
of the effect of NIV on this outcome. Unlike their study, we also
identified beneficial effects of non-­invasive (vs invasive) weaning
Duration of mechanical ventilation
in reducing the proportion of weaning failures and tracheos-
 Total  12 (687) −5.3 (−7.9 to −2.7) 83 tomies, as well as, hospital length of stay and the duration of
 Related to weaning  13 (1163) −0.6 (−1.1 to −0.1) 88 ventilation related to weaning with considerable heterogeneity.
 Invasive ventilation  19 (1214) −7.8 (−9.9 to −5.6) 94 Moreover, we found significant effects of non-­invasive weaning,
compared with invasive weaning on mortality, VAP, ICU stay and
Adverse events
reintubation in COPD versus mixed populations. Similar to our
 Reintubation  14 (1336) 0.69 (0.47 to 1.01) 59 previous meta-­analysis,17 we found that non-­invasive weaning
 Tracheostomy  10 (1130) 0.25 (0.10 to 0.61) 56 significantly reduced mortality, weaning failure, VAP, ICU and
 Arrhythmia  4 (565) 0.70 (0.41 to 1.20) 0 hospital lengths of stay, total duration of ventilation and reintu-
*Risk ratio. bation compared with invasive weaning. In this updated review,
†Mean difference. we also found that non-­invasive (vs invasive) weaning signifi-
‡Invasive ventilation. cantly reduced the duration of ventilation related to weaning but
VAP, ventilator-­associated pneumonia. did not significantly reduce the rate of reintubation. Although
758 Burns KEA, et al. Thorax 2022;77:752–761. doi:10.1136/thoraxjnl-2021-216993
 Critical care

Table 3  Secondary analysis of summary estimates of effect of non-­invasive ventilation by subgroup

Outcome Subgroups No. of trials Effect estimate Test for subgroup differences
Mortality COPD 14 RR 0.36 (0.25, 0.51) P=0.0003
Mixed 12 RR 0.81 (0.62, 1.05)
Weaning failure COPD 4 RR 0.52 (0.37, 0.73) P=0.56
Mixed 7 RR 0.62 (0.37, 1.06)
Ventilator-a­ ssociated pneumonia COPD 14 RR 0.22 (0.15, 0.33) P=0.03
Mixed 9 RR 0.42 (0.28, 0.64)
ICU length of stay COPD 12 MD −6.1 (−8.1, –4.0) P=0.03
Mixed 10 MD −3.1 (−5.0, –1.1)
Hospital length of stay COPD 7 MD −7.4 (−10.9, –4.0) P=0.16
Mixed 6 MD −4.0 (−7.4, –0.6)
Total duration of mechanical ventilation COPD 7 MD −6.4 (−10.4, –2.4) P=0.15
Mixed 5 MD −3.2 (−5.0, –1.4)
Duration of ventilation related to weaning COPD 6 MD −1.3 (−2.2, –0.4) P=0.17
Mixed 7 MD 0.3 (−1.8, 2.3)
Duration of invasive ventilation COPD 11 MD −8.0 (−11.0, –5.1) P=0.81
Mixed 8 MD −7.4 (−11.3, –3.6)
Reintubation COPD 4 RR 0.48 (0.34, 0.67) P=0.02
Mixed 10 RR 0.89 (0.59, 1.35)
Tracheostomy COPD 1 RR 0.04 (0.00, 0.60) P=0.15
Mixed 9 RR 0.31 (0.13, 0.71)
Arrhythmia COPD 1 RR 2.00 (0.20, 19.78) P=0.36
Mixed 3 RR 0.66 (0.38, 1.15)
COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; MD, mean difference; RR, risk ratio.

our prior review noted a significant difference in mortality
between COPD versus mixed populations overall, it did not find
significant differences comparing trials in which at least 50% of
enrolled patients had COPD with trials in which less than 50%
of patients had COPD. By contrast, in our updated review, we
found significant differences between COPD versus mixed popu-
lations in four outcomes (mortality, VAP, ICU stay and reintuba-
tion) and in mortality in a subgroup analysis that compared trials
enrolling at least 50% versus less than 50% patients with COPD.
These findings underscore the greater net clinical benefits asso-
ciated with the non-­invasive approach to weaning for patients
with COPD. The findings of our updated review extend the
findings of our previous review by identifying beneficial effects
of non-­invasive (vs invasive) weaning in reducing the duration
of ventilation related to weaning, hospital length of stay and
the proportions of weaning failures and tracheostomies. More-
over, they highlight the robustness and stability of the evidence
favouring non-­invasive weaning for patients with COPD as new
trials were added to the prior pool of trials. At present, however,
our analyses do not support the use of non-­invasive weaning in
mixed populations. Aligned with our findings, a recent system-
atic review and individual patient meta-­analysis in six trials high-
lighted the potential beneficial effect of non-­invasive ventilation
after early extubation in reducing total days spent on invasive
mechanical ventilation, though this was not associated with a
significant reduction in ICU mortality.87
Strengths and limitations
This review was strengthened by a comprehensive trial search
and standard systematic review methods to reduce risk of bias.
Limitations of this work include this risk of bias in primary
trials, primarily driven by potential publication bias, specifically
the absence of small negative trials and imprecision. Overall, the
quality of the evidence was graded as high for key outcomes
in our review including mortality, weaning failure and VAP.
Notwithstanding, some outcomes, in particular VAP, were
subject to ascertainment bias, since microbiological confirmation
via sputum culture is easier in intubated patients. Highly vari-
able control group event rates for mortality and VAP may reflect
heterogeneity in the patient populations included and selection
criteria used between studies or different usual care practices and
contribute to indirectness of evidence.
CONCLUSION
Pooled data support the net clinical benefits associated with
the non-­ invasive approach to weaning on a wide range of
clinical outcomes. In subgroup analysis, we found significant
benefit of non-­invasive weaning in trials enrolling COPD versus
mixed populations on mortality and other important outcomes
including pneumonia, reintubation and ICU length of stay.
Author affiliations
1
Interdepartmental Division of Critical Care Medicine, Temerty Faculty of Medicine,
University of Toronto, Toronto, Ontario, Canada
2
Departments of Critical Care and Medicine, Unity Health Toronto – St. Michael’s
Hospital, Toronto, Ontario, Canada
3
The Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
4
Department of Clinical Epidemiology and Biostatistics, McMaster University,
Hamilton, Ontario, Canada
5
Keenan Research Centre for Biomedical Science and the Li Ka Shing Knowledge
Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
6
The School of Medicine, Royal College of Surgeons, Dublin, Ireland
7
Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto,
Ontario, Canada

Burns KEA, et al. Thorax 2022;77:752–761. doi:10.1136/thoraxjnl-2021-216993 759

 Critical care
8
Institute of Health Policy, Management, and Evaluation, University of Toronto,
Toronto, Ontario, Canada
9
The Department of Critical Care Medicine, The Second Affiliated Hospital of
Zhengzhou University, Zhengzhou, China
10
Department of Anesthesia and Physiology, University of Toronto, Toronto, Ontario,
Canada
Correction notice  This article has been corrected since it was published Online
First. Some affiliations were listed incorrectly and a minor error was noted in Table 3.
Twitter Karen E A Burns @karenburnsk
Collaborators  Not applicable.
Contributors  KEAB conducted the literature searches, resolved discrepancies
between citation reviewers, selected studies meeting inclusion criteria, assessed
study quality, conducted risk of bias assessments, double checked data entry,
prepared initial and subsequent drafts of the manuscript and integrated comments
into revised versions of the manuscript. JS and ML screened abstracts, selected
studies meeting inclusion criteria, abstracted data, assessed study quality, conducted
risk of bias assessments and integrated comments into revised versions of the
manuscript. YL, CL, ZL and LC assisted with screening articles for inclusion. YL, CL,
XH, ZL, WW, LC and HZ translated articles, abstracted data, assessed study quality
and conducted risk of bias assessments. NKJA provided methodologic guidance,
aided with drafting the manuscript and integrated comments into revised versions
of the manuscript. JOF provided methodologic guidance, assessed study quality and
conducted risk of bias assessments, hand searched conference proceedings and
integrated comments into revised versions of the manuscript. All authors revised and
approved the final version of the manuscript.
Funding  KEAB holds a career award from the Physician Services Incorporated
Foundation.
Competing interests  None declared.
Patient consent for publication  Not applicable.
Ethics approval  Not required.
Provenance and peer review  Not commissioned; externally peer reviewed.
Data availability statement  Data are available from KEAB. Data are available
from Dr. Burns (0000-­0002-9­ 967-­5424).
ORCID iD
Karen E A Burns http://orcid.org/0000-0002-9967-5424
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