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RESEARCH

Use of non-invasive ventilation to wean critically ill adults offinvasive ventilation: meta-analysis and systematic review

Karen E A Burns, clinical scientist,1 scientist,2 assistant professor of medicine,3 Neill K J Adhikari, intensivist,4

associate scientist,5 lecturer,6 Sean P Keenan, head,7 clinical assistant professor of medicine,8 Maureen

Meade, associate professor of medicine9

ABSTRACT

Objective To summarise theevidence for early extubation

with immediate application of non-invasive ventilation

compared with continued invasive weaning on importantoutcomes in intubated adults with respiratory failure.

Design Systematic review and meta-analysis of

randomised and quasi-randomised controlled trials.

SettingIntensive care units.

Participants Critically ill adults receiving invasive

ventilation.

Study selection criteria We searched Medline, Embase,

and CENTRAL, proceedings from four conferences, and

reference lists of relevant studies to identify relevant

trials. Two reviewers independently selected trials,

assessed trial quality, and abstracted data.

Results We identified 12 trials enrolling 530 participants,

mostly with chronic obstructive pulmonary disease.Compared with invasive weaning, non-invasive weaning

was significantly associated with reduced mortality

(relative risk 0.55, 95%confidence interval 0.38 to 0.79),

ventilator associated pneumonia (0.29, 95% 0.19 to

0.45),length of stay in intensivecare unit (weightedmean

difference 6.27 days, 8.77 to 3.78) and hospital (7.

19 days, 10.80 to 3.58), total duration of ventilation,

and duration of invasive ventilation. Non-invasive

weaning had no effect on weaning failures or weaning

time. Benefits on mortality and weaning failures were

non-significantly greater in trials that exclusively enrolled

patients with chronic obstructive pulmonary disease

versus mixed populations.Conclusions Current trials in critically ill adults show a

consistent positive effect of non-invasive weaning on

mortality and ventilator associated pneumonia, though

the net clinical benefits remain to be fully elucidated.

Non-invasive ventilation should preferentially be used in

patients with chronic obstructive pulmonary disease in a

highly monitored environment.

INTRODUCTION

Patients with respiratory failure often require mechan-ical ventilation to unload the respiratory muscles andsupport gas exchange until the pathophysiology lead-

ing to respiratory failure improves. Invasive ventila-tion maintains a patent airway but when used over a

prolonged period of time might lead to ventilator asso-ciated pneumonia.1 This, in turn, is associated withincreased morbidity and trends towards increased

mortality.2

For these reasons, clinicians caring forpatients who need invasive ventilation strive to reducethe duration of invasive ventilation while optimisingthe chance for successful extubation.3

Non-invasive ventilation provides an alternativemethod of supporting a patients respiration by usingpositive pressure ventilation with either an oronasal,nasal, or total face mask at the patient-ventilator inter-face. Non-invasive ventilation preserves the patientsability to speak and cough4 and has been shown toreduce complications related to intubation, especiallyventilator associated pneumonia.5 6 Similar to invasiveventilation, non-invasive ventilation can reduce the fre-

quency of breathing, augment tidal volume, improvegas exchange, and rest the muscles of respiration.7 8

Non-invasive ventilation has been widely investigatedas an initial treatment to prevent intubation and intuba-tion related complications and improve clinical out-comes in selected patients.9 10 Many patients withsevere respiratory failure, impaired sensorium, haemo-dynamic instability, or difficulty clearing secretions,however, undergo direct intubation or intubation aftera failed attempt at non-invasive ventilation.

To mitigate the effect of complications associatedwith protracted invasive ventilation, investigatorshave explored the role of non-invasive ventilation in

weaning patients from invasive ventilation. Non-inva-sive weaning involves extubating patients directly tonon-invasive ventilation for the purpose of weaningto reducethe duration of invasive ventilation and, con-sequently, complications related to intubation. SinceUdwadia and colleagues published the first reportdescribing use of non-invasive ventilation to facilitateliberation of patients with weaning failure from inva-sive ventilation in 1992,11 several uncontrolled, pro-spective studies,12-15 early randomised controlledtrials,w1-w5 and an early meta-analysis16 have examinedits use to facilitate weaning. Thatmeta-analysisshowedsignificant benefit of the non-invasive approach on

length of stay in hospital and the total duration of ven-tilation. Non-invasive weaning also reduced mortality

1Interdepartmental Division ofCritical Care, St Michaels Hospital,Toronto, ON, Canada M5B 1W82Keenan Research Centre, Li Ka

Shing Knowledge Institute,Toronto, ON, Canada3Divisions of Respiratory andCritical Care Medicine, Universityof Toronto, Toronto, ON, Canada4Department of Critical CareMedicine, Sunnybrook HealthSciences Centre, Toronto, ON,Canada5Sunnybrook Research Institute,Toronto, ON6Interdepartmental Division ofCritical Care, University ofToronto, Toronto,d ON7Department of Critical Care,Royal Columbian Hospital, New

Westminster, BC8Division of Critical Care Medicine,Department of Medicine,Vancouver, BC9Department of ClinicalEpidemiology and Biostatics,McMaster University, Hamilton,ON

Correspondence to: K E A BurnsBurnsk@smh.toronto.on.ca

Cite this as: BMJ2009;338:b1574doi:10.1136/bmj.b1574

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and ventilator associated pneumonia compared withinvasive weaning, however there were few events.

In light of newevidence we critically appraised, sum-marised, and updated current work on the effect ofnon-invasive weaning compared with invasive wean-ing on the primary outcome of mortality and second-ary outcomes including ventilator associatedpneumonia, length of stay in intensive care and in hos-pital, and duration of ventilator support in critically illmechanically ventilated adults.

METHODS

Data sources and searches

We updated a previously conductedsearch of Medline(January 1966-April 2008), Embase (January 1980-April 2008), and the Cochrane Central Register ofControlled Trials (Cochrane Library, Issue 2, 2008)without language restrictions. Details of the searchstrategy and terms are available from the authors.Two reviewers (KEAB, NKJA) screened citation titlesand abstracts independently. All potentially eligiblestudies were retrieved in full and translated into Eng-lish, as required. One reviewer (SPK) updated manualsearches of abstracts from intensive care conferenceproceedings published in the American Journal of Respiratory and Critical Care Medicine, Intensive Care Med-icine, Critical Care Medicine, and Chest from January2003 to April 2008. We reviewed bibliographies ofall retrieved articles to identify potentially relevanttrialsand contactedauthors of included studies to iden-tifyunpublished studies andobtain additional informa-tion regarding study methods, where needed.

Study selectionWe included randomised trials that enrolled adultswith respiratory failure who required invasivemechanical ventilation for at least 24 hours. The trialsexamined extubation with immediate application ofnon-invasive ventilation compared with continuedinvasive weaning. We included trials reporting atleast one of mortality (primary outcome), ventilatorassociated pneumonia, weaning failure (using authorsdefinitions), length of stay in intensive care or hospital,total duration of ventilation (invasive and non-inva-sive), duration of ventilation related to weaning (afterrandomisation), duration of invasive ventilation,

adverse events, or quality of life. We also includedquasi-randomised controlled trialsfor example,those that allocated patients by hospital registry num-ber or day of the week. We excluded studies that com-pared non-invasive with invasive weaning in theimmediate postoperative setting, compared non-inva-sive ventilation with unassisted oxygen supplementa-tion, and investigated use of non-invasive ventilationafter unplanned extubation. Two authors (KEAB,NKJA) independently selected articles meeting theinclusion criteria.

Data extraction and quality assessment

Twoauthors (KEAB, NKJA), notblinded to thesourceof the reports, used a standardised data abstraction

form to independently abstract data regarding studymethods (randomisation, allocation concealment,cointerventions, blinded outcome assessment, com-pleteness of follow-up, and adherence to the intentionto treat principle). Additionally, we assessed featuresunique to the design and implementation of weaningtrials, includinguse of daily screening to identify wean-ing candidates, criteria to identify weaning readiness,explicit weaning protocols (both groups), criteria fordiscontinuing mechanical ventilation (both groups),and reintubation. Disagreements regarding studyselection and data abstraction were resolved by con-sensus and arbitration with a third author (SPK orMM).

Data synthesis and statistical analysis

When there were no compelling differences in studypopulations, interventions, and outcomes we pooleddata across studies using random effects models.17

We derived summary estimates of relative risk andweighted mean difference with 95% confidence inter-vals for binary and continuous outcomes, respectively,usingReviewManager4.2.10software(CochraneCol-laboration, Oxford). If an outcome was reported at twodifferent time points, we included the more protractedmeasure in pooled analyses.

Wedeterminedthepresenceandimpactofstatisticalheterogeneity among studies using the Cochran Qstatistic18 (threshold P

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randomised trials on mortality and ventilator asso-ciated pneumonia. We planned subgroup analyses tocompare the effects of non-invasive weaning on mor-tality and weaning failures in exclusively chronicobstructive pulmonary disease compared with non-chronic populations and on mortality in studies that

enrolled

50% versus 88% on FiO2 40%

Day 3 + weaning criteria BilevelNIV (pressure mode) Invasive PS

Ferrer,w5 2003 43 Acute respiratory f ailure a nd persistentweaning failure. Intubated for at least 72 hrs

2 hr SBT failure on 3consecutive days

Bilevel NIV in ST modedelivered withface ornasal mask

AC or invasive PS

Rabie,w6

2004 37 Exacerbation of COPD 2 hr SBT failure NIV (proportional assist in timed mode)delivered by face or nasal mask

Invasive PS

Wang,w7 2004 28 COPD. Bronchopulmonary infection PIC window NIV ( pressure mode) delivered by mask

(unspecified)

SIMV+PS

Zheng,w8 2005 33 COPD. Severe pulmonary infection PIC window Bilevel NIV (pressure mode) delivered by faceor nasal mask

Invasive PS

Zou,w9 2006 76 COPD with s evere r espiratory f ailure.Pulmonary infection

PIC window Bilevel NIV (pressure,ST mode) delivered bynasal or oronasal mask

SIMV+PS

Wang,w10 2005 90 COPD w ith s evere h ypercapnic r espiratoryfailure. Pneumonia or purulent bronchitis. Age85. Capable of self carein past year

PIC window Bilevel NIV (pressure mode) SIMV+PS

Trevisan,w112008 65 Invas ively ventilated >48 h ours 30 m in SB T failure Bilevel N IV ( pressure mode) delivered b yfacemask

Invasive mechanicalventilation

Shiva Prasadw12 30 COPD. Hypercapnic respiratory failure 2 hrSBT failure Bilevel NIV (pressure mode) deliveredby fullface mask

Invasive PS

COPD=chronic obstructive pulmonary disease; SBT=spontaneous breathing trial; PS=pressure support; NIV=non-invasive ventilation; PIC=pulmonary infection control; AC=assist control;SIMV=synchronised intermittent mechanical ventilation; VPAP=ventilator positive airway pressure.

RESEARCH

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improvement in white blood cell count (or percentageof neutrophils), and reduced volume and tenacity ofsecretions,w7-w10 with improved haemodynamics,cough, and level of consciousnessw7 w9 or reduced venti-lator settings.w10

Invasive weaning

Patients in the control groups were variably weanedwith pressure support,w1-w6 w8 w12 assist control,w5 orsynchronised intermittent mandatory ventilation withpressure support.w7 w9 w10 The level of support was gra-

dually decreased in two studiesw1 w5

and trials of spon-taneous breathing, using T-piece or continuouspositive airway pressure of less than 5 cm H2O, wereperformed twice dailyw1 or dailyw5 w11 until extubation.One study included at least two observation periodsper day during pressure support weaning withoptionaltrials of spontaneous breathing.w2 One study eachtitrated pressure support either by 2 cm H2O everyfour hours according to clinical tolerance, saturations,and respiratory ratew12 or by 2-4 cm H2O per day.w6

Patients were considered weaned when they remainedstable for at least four hours with a synchronised inter-mittent mandatoryventilation rateof 5 breaths/minute

with pressure support of 5-7 cm H2Ow10

; blood gaseswere normalised, and patients could breathe sponta-neously for more than three hours with low oxygenrequirements (fractional concentration of inspiredoxygen (FiO2) 0.40), acceptable saturations (pulseoximetry saturation (SpO2) 90%), and a normal pH(pH 7.35)w7; or when pressure support was titrated to8 cm H2O

w8 or 10 cm H2Ow9 w12 with positive end

expiratory pressure of 5 cm H2O,w12 and satisfactoryblood gases,w12 saturations,w8 w9 respiratory rate,w8 w9w12 tidal volume (about 8 ml/kg body weight),w8 w9

and partial pressure of carbon dioxide (PaCO2,between 45 and 60 mm Hg or at baseline levels) on

low FiO2w8 w9 w12

for more than four hours.w8 w9

To dis-continue invasive ventilation, patients successfully

completed a spontaneous breathing trial of either twohours,w3 w5 three hours,w1 w4 w7 or unspecified dura-tion,w11 or two periods of observation with optionalspontaneous breathing trials.w2

Non-invasive weaning

Similar to invasive weaning, trials applied differentprotocols for non-invasive weaning. After extubation,in 11 studies non-invasive ventilation was adminis-tered in pressure mode,w1-w5 w7-w12 of which five speci-fied a spontaneous timed modew2 w3 w5 w9 w12 or flow

mode.w2 Another study used proportional assist venti-lation in timed mode.w6 Non-invasive ventilation wasdelivered by face maskw1-w3 w5 w6 w8-w12 or nasal mask.w2w3 w5 w6 w8 w9 Initial support was delivered continuouslyin five studies,w1 w3-w5 w12 intermittently in one study,w2

for at least two hours during the initial application inone study,w9 or until tolerated for 20-22 hours a day(spaced by periods of spontaneous ventilation duringmeals and for expectoration) in one study.w6 The levelof support was gradually decreased and the durationon non-invasive ventilation gradually reduced.w8 w9

Some trials permitted fixed or gradually increasingperiods of spontaneous breathing,w1 w6 with at leasttwow1 w6 specifying two periods of spontaneous breath-ing a day. In some studies, clinicians titrated pressuresupportby2cmH2O every four hours

w12 orby2-4cmH2Oeachday

w6 accordingtothepatientstolerance.Insome studies, clinicians decreased the level of inspira-tory and expiratory positive airway pressure to 8 cmand4cmH2O, respectively,w12 while in others, inspira-tory pressure was reduced to

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breathing or at least two periods of spontaneousbreathing observed by an attending physician.w2

Quality assessment

We contacted authors to confirm and supplementinformation related to study methods where needed;nine study authors responded.w1-w3 w5 w6 w9 w11 w12 Over-all, the included studies were of moderate to high qual-ity (table 2).

Primary outcome: mortality

All 12 trials (530 patients) provided mortality data,reported at 30 days,w12 60 days,w1 90 days,w2 w5 at hos-

pital discharge,w6 w9-w11

or at an undefined time.w3 w4 w7

There was strong evidence that non-invasive weaningwas associated with reduced mortality (relative risk0.55, 95% confidence interval 0.38 to 0.79, P=0.001),with no heterogeneity (table 3, fig 2).

Secondary outcomes

Pooled data from 11 studies (509 patients)w1 w2 w4-w12

showed that non-invasive weaning was associatedwith decreased ventilator associated pneumonia (rela-tive risk 0.29, 0.19 to 0.45, P

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studies enrolling50% (10 studies) versus

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single adequately powered randomised controlled trialdirectly comparing the alternative weaning strategieslimits the strength of our inferences.

While surviving admission to hospital is undoubt-edly an important outcome for patients and healthcareproviders, it can be influenced by many factors result-ing in highly variable lengths of stay. Patients mightremain in hospital at arbitrary time points (such as60 days) because of factors related and unrelated tothe initial illness that precipitated admission. This

might not only influence the distribution of eventsbetween two treatment arms but might also underesti-mate mortality (biasing towards a mortality benefit).Conversely, extended follow-up might be influencedbyadditionaldeathsunrelatedtothetreatmentofinter-est(biasingagainstamortalitybenefit).Toexaminethepotential influence of measuring mortality at varioustime points, we pooled study estimates of mortalityusing random effects models in three categories: mor-tality or time in intensive care not specified (six trials)(relative risk 0.63, 0.32 to 1.25, P=0.18); hospital, inpa-tient, or 30 day mortality (seven trials) (0.56, 0.31 to1.01, P=0.05); and 60-90 day mortality (three trials)

(0.42, 0.21 to 0.80, P=

0.009). While underpowered todetect differences (with fewer events and trials at eachtime point), the pooled results support a qualitativelysimilar direction of treatment effect in favour of non-invasive weaning.

The included studies varied in the methods used toidentify candidates for weaning and to titrate and dis-continue mechanical support. Multidisciplinary proto-cols to identify candidates for weaning and for theconduct of dailytrials of spontaneous breathingreducethe duration of mechanical ventilation.27-33 In ourmeta-analysis, while only three trials screened dailyfor readiness for trials of spontaneous breathing, four

additional trials conducted pre-randomisation trials ofspontaneous breathing, and four trials assessed for

resolution of pulmonary infection to identify weaningreadiness. The latter strategy prioritises resolution ofthe cause of respiratory failure (bronchopulmonaryinfection) over meeting conventional weaning criteriaand represents a novel approach to identifying candi-dates for weaning in selected populations. In trials thatdid not include a trial of spontaneous breathing afterrandomisation, however, some invasively ventilatedpatients might have been ventilated longer than neces-sary. While methods for identifying candidates for

weaning might affect study estimates of the durationof ventilation, they represent pre-randomisationstudy design considerations and areless likely to resultin important performance bias. Conversely, unequalor inconsistent use of weaning protocols and the fre-quency with which periods of spontaneous breathing(non-invasive strategy) or trials of spontaneous breath-ing(invasivestrategy)werepermittedrepresentimpor-tant post-randomisation study design considerationsthat could bias estimates of the duration of ventilationin unblinded weaning trials. Opportunities for com-parable reductions in mechanical support were pro-vided by using weaning protocols or guidelines in

both treatment groups in seven trials with variableuse of periods of spontaneous breathing (or trials ofspontaneous breathing) among the included studies.Whereas 11 trials reported use of criteria to discon-tinue mechanical ventilation in both groups, only sixreported explicit reintubation criteria after a failedattempt at extubation. While recent literature supportsthat administration of sedation is an important consid-eration in study design, with the potential to affectlength of ventilation,34 only one study in our reviewused a sedation protocol.w3 Overall, most trialsincluded measures to reduce bias after randomisationand were of moderateto high quality, thoughvariation

among trials in adopting these measures limits inter-pretation of some of the pooled results.

Table 3 | Summary estimates of effect of non-invasive ventilation in critically ill adults

OutcomeNo studies (No of

patients) Summary estimate (95% CI)P value (summary

estimate)P value

(heterogeneity) I2 (%)

Mortality 12 (530) 0.55* (0.38 to 0.79) 0.001 0.49 0

VAP 11 (509) 0.29* (0.19 to 0.45)

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This review was strengthened by an extensivesearchfor relevant trials. We conducted duplicate indepen-dent citation screening and data abstraction and corre-sponded with lead investigators to clarify studymethods where needed. In addition to appraising thequality of randomised trials, we also assessed metho-

dological features specific to weaning trials that mightinfluence estimates of treatment effect. We used ran-dom effects models in pooling data, which take intoconsideration variation both between and within stu-dies. Pooling results in a meta-analysis implicitlyassumes that the studies are sufficiently similar withrespect to their populations, study interventions, out-comes, and methodological quality that one could rea-sonably expect a comparable underlying treatmenteffect. A priori, we planned sensitivity and subgroupanalyses to explain the differences amongstudy resultsand anticipating heterogeneity in pooling across stu-dies for selected outcomes.

Conclusion

Current trials of non-invasive weaning, while limitedby inclusion of small numbers of patients mostly withchronic obstructive pulmonary disease, consistentlyshow positive effects on mortality and ventilator asso-ciated pneumonia. The evidence of benefit is promis-ing, but additional trials are required to fully evaluatethe net clinical benefits on clinical outcomesassociatedwith non-invasive weaning, especially the risks asso-ciated with extubation and the impact of reintubationafter a failed attempt at extubation on clinical out-comes. If consideration is being given to weaning

patients with non-invasive ventilation, we suggest thatit be preferentially used in patients with chronicobstructive pulmonary disease and applied in a highlymonitored environment. A well designed, adequatelypowered randomised controlled with explicitlydefined end points comparing the alternativeapproaches to weaning is justified.

We thank Haibo Zhang, Haibo Qiu, Wei Ehr Cheng, and Zhuxian Feng for

their assistance in contacting authors to clarify publication and study

design issues.

Contributors: KEAB conducted the literature searches, screenedabstracts, selected studies meeting inclusion criteria, extracted data,

assessed study quality, prepared initial and subsequent drafts of the

manuscript, and integrated comments from other authors into revised

versions of the manuscript. NKJA screened abstracts, selected studiesmeeting inclusion criteria, extracted data, and assessed study quality.

SPK screened abstracts from conference proceedings, arranged for

translation of foreign language publications, and adjudicated

disagreements between reviewers. MM provided methodological

guidance on drafting the manuscript and adjudicated disagreements

between reviewers. All authors revised and approved the final version of

the manuscript. KEAB is guarantor.

Funding: KEAB holds a clinician scientist award from the CanadianInstitutes of Health Research.

Competing interests: SPK has received an unrestricted grant fromRespironics Inc to support development of a non-invasive ventilationguideline for the Canadian Critical Care Trials Group.

Ethical approval: Not required.

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WHAT IS ALREADY KNOWN ON THIS TOPIC

Non-invasive ventilation has been widely investigated as an initial treatment to preventintubation and intubation related complications

Many patients with severe respiratory failure, impaired sensorium, haemodynamicinstability, or difficulty clearing secretions undergo direct intubation or intubation after afailed attempt at non-invasive ventilation

WHAT THIS STUDY ADDS

Non-invasive weaning was associated with decreased mortality, ventilator associatedpneumonia, length of stay in intensive care and hospital, total durationof mechanicalventilation, and duration of invasive ventilation

RESEARCH

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COPD patients. Intensive Care Med1995;21:871-9.

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28 Ely EW, Baker AM, Dunagan DP, Burke HL, Smith AC, Kelly PT, et al.Effect on the duration of mechanical ventilation of identifyingpatients capable of breathing spontaneously. N EnglJ Med1996;335:1864-9.

29 KollefMH,Shapiro SD, SilverP, StJohn RE, PrenticeD, Sauer S,et al.A randomized, controlled trial of protocol-directed versus physician-

directed weaning from mechanical ventilation. Crit Care Med1997;25:567-74.

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Accepted: 16 January 2009

RESEARCH

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