Avoiding Endotracheal Ventilation to PreventBronchopulmonary Dysplasia: A Meta-analysis

abstractBACKGROUND AND OBJECTIVE: Mechanical ventilation via an endotra-cheal tube is a risk factor for bronchopulmonary dysplasia (BPD), oneof the most common morbidities of very preterm infants. Our objectivewas to investigate the effect that strategies to avoid endotracheal me-chanical ventilation (eMV) have on the incidence of BPD in preterminfants ,30 weeks’ gestational age (GA).

METHODS: In February 2013, we searched the databases Medline,Embase, and the Cochrane Central Register of Controlled Trials. Studyselection criteria included randomized controlled trials published inpeer-reviewed journals since the year 2000 that compared preterminfants ,30 weeks’ GA treated by using a strategy aimed atavoiding eMV with a control group in which mechanical ventilationvia an endotracheal tube was performed at an earlier stage. Datawere extracted and analyzed by using the standard methods of theCochrane Neonatal Review Group. The authors independentlyassessed study eligibility and risk of bias, extracted data andcalculated odds ratios and 95% confidence intervals, employingRevMan version 5.1.6.

RESULTS: We identified 7 trials that included a total of 3289 infants. Thecombined odds ratio (95% confidence interval) of death or BPD was0.83 (0.71–0.96). The number needed to treat was 35. The studyresults were remarkably homogeneous. Avoiding eMV had no influ-ence on the incidence of severe intraventricular hemorrhage.

CONCLUSIONS: Strategies aimed at avoiding eMV in infants ,30weeks’ GA have a small but significant beneficial impact on preventingBPD. Pediatrics 2013;132:e1351–e1360

AUTHORS: Hendrik S. Fischer, MD, and Christoph Bührer,MD, PhD

Department of Neonatology, Charité University Medical Center,Berlin, Germany

KEY WORDSrespiratory distress syndrome, bronchopulmonary dysplasia,newborn, mechanical ventilation, surfactant

ABBREVIATIONSBPD—bronchopulmonary dysplasiaCENTRAL—Cochrane Central Register of Controlled TrialsCI—confidence intervalCNRN—Colombian Neonatal Research NetworkeMV—endotracheal mechanical ventilationFIO2—fraction of inspired oxygenGA—gestational ageINSURE—intubation, surfactant, extubationIVH—intraventricular hemorrhagenCPAP—nasal continuous positive airway pressurenHFOV—nasal high frequency oscillatory ventilationNICHD—National Institute of Child Health and HumanDevelopmentnIPPV—nasal intermittent positive pressure ventilationNNT—number needed to treatRCT—randomized controlled trialRDS—respiratory distress syndrome

Drs Fischer and Bührer developed the concept and design of thestudy; they independently searched for relevant studies andextracted, assessed, and analyzed the data; Dr Fischer draftedthe manuscript; Dr Bührer critically reviewed and revised themanuscript; and both authors approved the final manuscript assubmitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2013-1880

doi:10.1542/peds.2013-1880

Accepted for publication Aug 27, 2013

Address correspondence to Hendrik S. Fischer, MD, Klinik fürNeonatologie, Charité Universitätsmedizin Berlin, AugustenburgerPlatz 1, 13353 Berlin, Germany. E-mail: hendrik.fischer@charite.de

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2013 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they haveno financial relationships relevant to this article to disclose.

FUNDING: No external funding.

POTENTIAL CONFLICT OF INTEREST: The authors have indicatedthey have no potential conflicts of interest to disclose.

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Bronchopulmonary dysplasia (BPD)was first described by Northway et al1

as a pulmonary sequela of prolongedartificial ventilation and oxygen treat-ment in 32 neonates treated for severerespiratory distress syndrome (RDS).Affected infants had a prolonged clini-cal course of their lung disease, char-acteristic radiologic features, anda high mortality. Since that time, ante-natal steroids,2 exogenous surfactanttreatment,3 gentler ventilation strate-gies,4,5 and other advances in neonatalintensive care have increased the sur-vival of very premature infants andhave reduced the rate of BPD.6 Al-though only a small number of preterminfants reveal the classic clinicalcourse of BPD today, a recent studyrevealed a considerable BPD incidenceof 42% in a large cohort of infants withgestational ages (GAs) of 220/7 to 28

6/7weeks7 as defined by oxygen use at 36weeks’ postmenstrual age.8 This wasattributed to a subset of infants whohad an atypical pattern of chronic lungdisease that was marked by delayeddeterioration of pulmonary gas ex-change in the absence of initial re-spiratory distress or only after clinicalsymptoms and radiologic signs of RDShad resolved9,10: This so-called “newBPD”11 is characterized by a milderclinical course and a maturational ar-rest of extremely immature lungs, andeven occurs in the absence of markedhyperoxia and high ventilation settings.12

Cohort studies suggest that avoidingendotracheal mechanical ventilation(eMV) and stabilizing very prematureinfants on early nasal continuous posi-tive airway pressure (nCPAP) in the de-livery room may be one way of reducingthe new BPD.5,7 Randomized controlledtrials (RCTs) have revealed that post-natal nCPAP is feasible and safe in pre-mature infants between 240/7 and 28

6/7weeks’ GA, but they have not reporteda significant reduction in BPD.13–16 Newtechniques to apply surfactant via a thinendotracheal catheter combine nCPAP

and endotracheal surfactant instillationwithout any need for eMV,17,18 and a re-cently published RCT revealed that thistechnique reduced moderate to severeBPD in a subgroup analysis of infants#28 weeks’ GA.19

Presumably, avoiding endotracheal ven-tilation prevents volutrauma and therebyattenuates direct lung injury and thesubsequent activation of the inflam-matory process in the lung that precedesBPD.20,21 Although there is a consensusthat gentle ventilation strategies, in-cluding nCPAP, have been effective in re-ducing the incidence of classic BPD,4,11 itis still unclear what the best strategy isfor preventing BPD in premature infants,30 weeks’ GA. To date, several RCTshave compared “invasive” approaches topostnatal respiratory care with ap-proaches designed to avoid eMV in thisGA group. Therefore, the aim of the cur-rent study was to conduct a meta-analysis investigating the effect thatavoiding eMVhas on the incidence of BPDin premature infants,30 weeks’ GA.

METHODS

Criteria for Considering Studies forThis Review

Randomized controlled clinical trialsinvestigating strategies for avoidingeMV in preterm neonates ,30 weeks’GA were eligible for the meta-analysis.RCTs including more mature infantswere eligible if .50% of the studypatients were,30 weeks’ GA and if thestudy authors provided stratified datafor these infants. For trials to be in-cluded, they had to compare an in-tervention that avoided eMV (eg,nCPAP) with a control group in whichmechanical ventilation by an endotra-cheal tube was performed at an earlierstage (eg, prophylactic mechanicalventilation or intubation, surfactant,extubation [INSURE]). The study designhad to prescribe randomization within24 hours after birth. Only studies pub-lished in full in peer-reviewed journals

were accepted. No language restric-tions applied. We included studies pub-lished in 2000 and thereafter becausethey were considered to better reflectcurrent practice, especially with regardto the use of antenatal steroids.22

Types of Outcome Measures

The primary outcomewas death or BPDat 36 weeks’ GA. BPD was defined as theneed for oxygen treatment at 36 weeks’GA, which corresponds to moderate tosevere BPD under the National Instituteof Child Health and Human Development(NICHD) workshop consensus defini-tion.8 If the study authors did notprovide clinical data about oxygentreatment at 36 weeks’ GA, but did pre-scribe a standardized room air chal-lenge to define oxygen requirement,data based on this physiologic definitionof BPD23 were accepted. As a secondaryoutcome, the incidence of severe in-traventricular hemorrhage (IVH) wasinvestigated. Severe IVH was defined asIVH grade 3 or 4.24

Search Methods for Identificationof Studies

The standard search methods of theCochrane Collaboration were used.25

The authors independently searchedthe databases Medline, Embase, andthe Cochrane Central Register of Con-trolled Trials (CENTRAL), starting fromJanuary 2000 and continuing up tothe last access on February 24, 2013.This search was combined with cross-referencing of previous reviews and tri-als, the use of information from experts,and occasional access to newer kinds ofresources such as clinicaltrials.gov. Ahighly sensitive search strategy wasused, as outlined in the CochraneHandbook for Systematic Reviews ofInterventions, and followed specific rec-ommendations for identifying RCTs inMedline and Embase.25,26 Searches werecarried out to identify RCTs concernedwith (1) neonates OR prematurity OR

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BPD, (2) surfactant OR ventilatory sup-port, and (3) randomized controlled tri-als. These 3 concepts were linked by the“AND” operator. A variety of search termswas usedwithin each concept. Both free-text and subject-headings (ExcerptaMedica Tree terms for Embase, MeSHterms for Medline and CENTRAL) wereused. To reduce the number of dupli-cates, the Embase search was restrictedto trials not indexed in Medline. Medlinewas available via PubMed, Embase viaOvidSP, andCENTRAL viaDIMDI (DeutschesInstitut für medizinische Dokumentationund Information). The format of thesearches was adapted as necessary andcan be viewed online as SupplementalInformation. Results were reported inline with the recommendations of thePreferred Reporting Items for Systematicreviews and Meta-Analyses (PRISMA)group statement.27

Assessment of MethodologicalQuality

The assessment of methodological qual-ity compliedwithCochranecriteria25: riskof selection bias (quality of randomiza-tion, allocation concealment), perfor-mance bias (blinding of intervention),detection bias (blinding of outcome as-sessment), attrition bias (completenessof follow-up), selective reporting (re-porting bias), and other features of thestudy implying a potential for bias wereassessed and categorized as low risk,high risk, or unclear risk. Plans existedto contact the study authors and ask foradditional information about their trialsif necessary.

Data Collection and Analysis

Theauthorsof thepresentmeta-analysisworked independently of each other onselecting the studies, assessing themethodological quality, and extractingthe data. At each stage, the authorsdiscussed and resolved any differencesthat arose. RevMan version 5.1.6 wasused for data analysis. The effect that

strategies foravoidingventilationhadonprimary and secondary outcomes wascalculated by using a random effectsmodel. Odds ratios and 95% confidenceintervals (CIs) were reported for all in-cludedstudiesand for the pooleddata. Alevel of statistical significance of P, .05was accepted. For the primary outcome,a number needed to treat (NNT) wascalculated. Heterogeneity was esti-mated by using the x2 test and the I2

value. To assess for publication bias, thetreatment effects that avoiding ventila-tion had on BPD were plotted against SE(log[odds ratio]) in a funnel plot.25,28

RESULTS

The authors identified 3692 recordsthrough database searches, and 24records through other sources (Fig 1).Because of the high number of recordsretrieved and the different serversused to access the different databases,removing duplicates at this stage wasnot practicable. A total of 3716 recordswere therefore screened for eligibility.Of those, 3702 were excluded becausethey were off-topic or did not meet theinclusion criteria. The remaining 14records were obtained as full-textarticles and assessed for eligibility. Of

these articles, 11 were in English and 3in Chinese.

Excluded Studies

After full assessment, 7 studies wereexcluded. One of thosewas not an RCT.29

Another, the trial of Chu et al,30 com-pared prophylactic intubation andsurfactant application with rescuesurfactant in 100 premature infants of,32 weeks’ GA, but did not report onBPD or IVH as outcomes. The remaining5 studies were excluded because theyfocused on premature infants .30weeks’GAwithmild tomoderateRDS.31–35

Included Studies

The characteristics of the 7 RCTs in-cluded in the meta-analysis are shownin Table 1. The authors of 6 studies werecontacted, and additional informationabout 4 trials was obtained.15,19,36,37 Wevery much appreciate the cooperationof 2 authors who provided us with pre-viously unpublished, stratified datafrom their studies.19,37 The includedRCTs differed from each other withregard to patient maturity, inclusioncriteria, and prescribed treatment (Ta-ble 1). Although the early trials com-pared nCPAP with INSURE and/or

FIGURE 1Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) flow diagram.27

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longer-termmechanical ventilation,13–16,37

themore recent studies investigated sur-factant application during nCPAP via athin catheter as an alternative to endo-tracheal intubation and surfactant.19,36

Risk of Bias in the Included Studies

Selection Bias: Random sequence gen-eration was found to be adequate inmost trials (low risk), but 2 of thestudies did not describe it in detail(unclear risk).14,16 Allocation conceal-ment was adequate in all RCTs (lowrisk). Performance bias and detectionbias: All studies were nonblinded, im-plying a high risk of bias. One RCT usedonly the physiologic definition of BPD,without blinding the outcome assess-ment.36 Attrition bias: In the ColombianNeonatal Research Network (CNRN)study, 1 patient was lost to follow-upand excluded from the analysis (lowrisk).37 In the Delivery Room Manage-ment (DRM) study, 3% of the studypatients did not receive a cranial ul-trasound (low risk).15 The outcomedata of all other studies were complete(low risk). Reporting bias: Six studyprotocols were registered at in-dependent trial registries before orduring the recruitment period (lowrisk), and the CNRN study was regis-tered only after recruitment was com-plete (unclear risk). Other sourcesof bias: Several study protocols gave

cause for concern regarding samplingbias. The DRM study was stopped pre-maturely after an interim analysisrevealed that no statistically significantdifferences in major outcomes were insight (low risk).15 There was unclearrisk for sampling bias in the Continu-ous Positive Airway Pressure or In-tubation at Birth (COIN), CNRN, and TakeCare trials because clinical judgmentof the patient’s respiratory status waspart of the study entry criteria.13,19,37

Additional issues were identified in theAvoiding Mechanical Ventilation (AMV)trial (parental consent and patient re-cruitment up to 12 hours of age, unclearrisk)36 and the CNRN trial (neonates notrecruited if expected to be transferredto another hospital because of theparents’ health insurance, unclearrisk).37 No other potential sources ofbias were detected. The funnel plot of allstudies with regard to BPD revealsa symmetrical distribution of effectsizes around the mean, indicating a lowrisk of publication bias. This funnel plot,as well as a detailed characterization ofall included studies and of the assess-ment of methodological quality, isavailable as supplementary material.

Effects of Intervention

The meta-analysis revealed that apply-ing diverse strategies for avoiding eMVresulted in a statistically significant

reduction of death or BPD (P = .01;Fig 2). The odds ratio (95% CI) was 0.83(0.71–0.96) with an NNT of 35. AvoidingeMV had no influence on the incidenceof severe IVH (P = .35; Fig 3). Measuresof heterogeneity did not indicate a het-erogeneity problem (x2 , df and P ..60 in both analyses, as shown in Figs 2and 3).

DISCUSSION

The present meta-analysis of 7 RCTscomprising 3289 patients revealed thatavoiding eMV reduced the combinedoutcome of death or BPD in preterminfants ,30 weeks’ GA. The risk of de-veloping severe IVH was unchanged.

Quality of Evidence

Assessment of the included RCTs in-dicated that all studies were of goodmethodological quality with mostly lowrisk for bias. The only major issue wasthe lack of blinding. Although it is vir-tually impossible to blind clinicians tothe intervention, it might be possible toreduce detection bias in the future byusing the physiologic definition ofBPD,23,38 which involves a standardized,time-limited room air challenge withoxygen saturation monitoring for allinfants receiving a fraction of inspiredoxygen (FIO2) #30% at 36 weeks’ post-menstrual age. Still, even with this

TABLE 1 Characteristics of Included Studies

Author Study Name Year Intervention Any eMV Except INSURE, % GA Randomization n Recruitment

Morley et al13 COIN 2008 nCPAP versus mechanical ventilation 59 vs 100 25 0/7–286/7 At 5 min of age 610 1999–2006

Rojas et al37 a CNRN 2009 nCPAP versus INSURE 43 vs 39 27 0/7–296/7 15–60 min of age 146b 2004–2006

Finer et al14 SUPPORT 2010 nCPAP versus mechanical ventilation 83 vs 100 24 0/7–276/7 ,1 h of age 1316 2005–2009

Sandri et al16 CURPAP d 2010 nCPAP versus INSURE 31 vs 33c 25 0/7–286/7 ,30 min of age 208 2007–2008

Dunn et al15 DRM 2011 3 groups: nCPAP versus INSUREversus mechanical ventilation

52 vs 59 vs 96 26 0/7–296/7 Before delivery 648 2003–2009

Göpel et al36 AMV 2011 nCPAP 6 surfactant duringspontaneous breathing versusnCPAP 6 mechanical ventilation

33 vs 73 26 0/7–286/7 ,12 h of age 220 2007–2009

Kanmaz et al19 a Take Care 2013 nCPAP 6 surfactant duringspontaneous breathingversus nCPAP 6 INSURE

42 vs 52a #296/7 ,2 h of age 141b 2010–2011

a Previously unpublished, stratified data for infants ,30 0/7 weeks’ GA.b Number of infants ,30 0/7 weeks’ GA only.c Need for any eMV except INSURE in the first 5 d of live.d Combining prophylactic surfactant and early nasal continuous positive airway pressure study.

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definition, complete blinding of out-come assessment would be challeng-ing. Furthermore, several studies haverevealed that the physiologic definitiondiagnoses fewer infants with BPD.7,14,38

Advocates of the severity-based con-sensus definition point out that thisdefinition correlates with long-termclinical outcomes39 and that the morerigorous physiologic definition of BPDmay miss infants with moderate re-spiratory impairment that still warrant

closer follow-up.40 In summary, a con-siderable risk of performance and de-tection bias is present in all includedstudies, with a special set of problemssurrounding the use of supplementaloxygen as a diagnostic criteria for BPD.

Theriskofsamplingbias instudiesusingclinical criteria for postnatal patientrecruitment is consideredaminorpoint.In connection with the Surfactant, Posi-tive Pressure, and Pulse Oximetry Ran-domizedTrial(SUPPORT),however, itwas

found that protocols prescribing ante-natal parental consent also bias thestudypopulation(in thiscasebyskewingit toward newborns who were receivingantenatal steroids and whose parentscould be approached without languagebarriers).41 Although it is possible thatsome study populations differed fromthose intended, this was unlikely to re-duce the external validity of the meta-analysis because the protocol explicitlyallowed inclusion of a broad spectrum

FIGURE 2Effect of avoiding eMV on death or BPD.

FIGURE 3Effect of avoiding eMV on IVH.

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of patients ,30 0/7 weeks’ GA with dif-ferent degrees of immaturity and se-verity of lung disease.

Effect on BPD

In spite of substantial differencesbetween study protocols, the meta-analysis results for the primary out-come death or BPD were remarkablyhomogenous. Regardless of the pop-ulation studied and the strategy used,avoiding eMV consistently led to a re-duction in the incidence of death or BPDin all trials, with odds ratios rangingfrom 0.63 to 0.97 (Fig 2) and a statisti-cally significant effect in the meta-analysis (odds ratio, 0.83 [95% CI,0.71–0.96]). This matches large obser-vational studies, which revealed thatan increase in the primary use ofnCPAP over time was associated witha lower BPD risk in infants,29 weeks’GA7 and in extremely low birth weightinfants.5 A recently updated Cochranereview conducted a subgroup analysisthat compared prophylactic surfactantadministration with selective surfac-tant treatment of established RDS inpreterm infants ,30 weeks’ GA.42 TheCochrane authors identified 2 studiesthat prescribed routine application ofnCPAP in the control group (SUPPORTand the DRM trial). In conformity withour results, their meta-analysis re-vealed an increase in death or BPDwhen endotracheal intubation and sur-factant were applied prophylactically(risk ratio, 1.12 [95% CI, 1.02–1.24]).

So although there is a consensus thatinfantswho require early eMV for severeRDS should be given surfactant in atimely fashion,43 available data indicatethat stabilizing premature infants ,30weeks’ GA on nCPAP alone, therebyavoiding eMV altogether, is a viable andeffective way of reducing BPD. This ob-servation is in line with the currentunderstanding of the pathogenesis ofBPD. A considerable number of studiesin animal and human neonates have

revealed that a pulmonary inflamma-tory response is a crucial factor in BPDdevelopment.21 Pulmonary inflamma-tion might be of antenatal origin44 butmight also be provoked by eMV,20,45

supplemental oxygen,46 or postnatalinfections.44 In an extremely pretermlung, eMV triggers an inflammatorycascade, which involves chemokinesand other proinflammatory cytokines,transmigration of inflammatory cells toairspaces, secondary lung injury byproteases, and dysregulation of growthfactors, leading to fibrosis and abnor-mal lung development.12,21,45 Animalstudies reveal that only 2 hours ofpostnatal pressure-limited ventilationinduced an inflammatory response inthe alveolar wash fluid of prematurelambs,45 and lambs receiving 2 hours ofcontinuous positive airway pressurewere found to have lower indicatorsof acute lung injury and better lungcompliance than lambs that weremechanically ventilated.20 This supportsthe hypothesis that avoiding the in-flammatory response secondary toeMVmay reduce BPD. As preterm lungsappear to be particularly vulnerableduring the first few hours of life,47,48

early intubation should be avoided.Special caution should be exercisedduring newborn resuscitation, asseemingly gentle mask ventilation mayalso overexpand the lungs.49

Other mechanisms may contribute,albeit toa lowerextent, toBPDreductionin infants who are never intubated.Firstly, noninvasive respiratory supportmay prevent direct complications ofa difficult intubation, such as vocal corddysfunction or subglottic stenosis,whichmay lead toprolonged ventilationand ventilator-induced lung injury.50,51

Secondly, the absence of an endotra-cheal tube may avoid reflex-inducedapnea occurring in response to me-chanical stimulation of the laryngealmucosa.52 Thirdly, noninvasive respira-tory support preserves normal laryngeal

function, allows normal mucociliaryclearance of lung secretions, and mayprevent secondary lung damage byreducing the incidence of ventilator-associated pneumonia.44,53

Effect on IVH

Avoiding eMV in very premature infantsmeans that a considerable number ofthem will later need rescue intubationbecause of hypercapnic respiratoryfailure. On the one hand, there aresubstantiated concerns about the as-sociation between hypercapnia and IVHin preterm infants,54 especially duringthe first days of life.55 Moreover, hyper-capnia can go unnoticed if respiratorydrive is poor, and transcutaneous CO2monitoring is not popular because theelectrodes can cause heat damage onextremely immature skin.56 On the otherhand, mild hypercapnia has long beenregarded as safe in premature infants,1000 g, and permissive hypercapniacan be used as a way of reducing eMVand improving pulmonary outcomes.57

The results of the present meta-analysisrevealed no difference in the incidenceof severe IVH between the interventiongroup and the control group, whichindicates that the strategies applied toavoid eMV in the included RCTs weregenerally safe (Fig 3). The measures ofheterogeneity suggest that differentodds ratios for IVH in individual studiesmay be explained by chance alone, andthere was no apparent relationship be-tween prescribed PCO2-thresholds forintubation and higher incidences of IVH.

Clinical Implications

Although avoidance of eMV reduced thecombined outcome of death or BPD inthe meta-analysis, deciding to managea very premature infant solely withnoninvasive respiratory support is of-ten extremely difficult because we lackevidence-based thresholds for intuba-tion and surfactant treatment. In themeta-analysis, the effect on BPD of

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avoiding eMV was consistent across allstudies included in spite of the differentstrategies they applied to avoid eMV.From a safety point of view, early nCPAPcarries an increased risk of pneumo-thorax if thresholds to administersurfactant are set high (9% in the COINand CNRN trials), whereas pneumo-thorax rates decrease to 2% to 3% ifsurfactant is given during the first hourof life.13,37 In this regard, nCPAP withsurfactant treatment during sponta-neous breathing is a promising optionbecause it allows to combine avoid-ance of eMV with early surfactant ad-ministration.17–19,36 It is worth notingthat 33% to 83% of study patients in thenoninvasive treatment groups neededeMV at some point during their clinicalcourse (Table 1). It is possible thatthese patients still benefited withregard to BPD reduction because eMVwas avoided during the postnatal tran-sition period when their lungs wereparticularly vulnerable.20,47,48 That said,only a subset of moderately ill patientswill benefit from the doctor’s intentionto withhold intubation, because stablenewborns will be managed with non-invasive respiratory support anyway,whereas critically ill patients will stillrequire immediate intubation. In thepresent meta-analysis, this is reflectedby the moderate influence on the pri-mary outcome of death or BPD and bythe high NNT of 35.

Consequently, a modern approach toBPD prevention in premature infants,30 weeks’ GA does not overestimatethe value of avoiding eMV, but appliesa sophisticated, individualized clini-cal strategy. This may include estab-lished measures such as low oxygenresuscitation46 and early use of caf-feine.58 It could also involve inter-ventions that have been investigatedmore recently, such as macrolidetreatment of preterm infants colo-nized with ureaplasma,59 and volume-targeted ventilation.60

Implications for Research

Although 5 of the 7 RCTs in the meta-analysis investigated nCPAP withoutsurfactant as a way of avoiding eMV ininfants of ,30 weeks’ GA, more dataare needed about other noninvasivetreatment methods and their effect onBPD.

Nasal intermittent positive pressureventilation (nIPPV) has been shown toincrease the beneficial effects of nCPAPin the treatment of apnea of pre-maturity61,62 and in the prevention ofneonatal extubation failure.63 Severalsingle-center RCTs indicate that nIPPVmay also be a viable alternative tonCPAPasan initial treatment of RDS.62,64–66

Recent meta-analyses have revealedthat, compared with nCPAP, nIPPV re-duced the need for eMV within the first72 hours of life67 and reduced thecombined outcome of death or BPD.68

However, the individual study resultsvaried considerably. SynchronizednIPPV was not associated with furtherbenefits when compared with conven-tional nIPPV in a retrospective study.69

More recently, 2 crossover studieshave revealed that neurally adjustedventilatory assist, where the ventilatoris triggered by the electrical activity ofthe diaphragm, improves synchroniza-tion and gas exchange in preterminfants.70,71 Future RCTs need to revealwhether this new technology also im-proves long-term outcomes. Nasal highfrequency oscillatory ventilation (nHFOV)is another promising form of nonin-vasive respiratory support, which avoidsthe problem of breath synchronization.Bench testing revealed that CO2-elimination was more effective duringnHFOV than during nIPPV.72 A smallinterventional study in 14 very low birthweight infants on nCPAP revealed simi-lar benefits when PCO2 was measuredbefore and after 2 hours of nHFOV.73

Other observational studies revealedsuccessful use of nHFOV as rescuetherapy for nCPAP failure74 and in the

postextubation period.75 To explore thefuture role that nHFOV could play in thetreatment of RDS, further research oneffectiveness and safety is needed.

If rescue surfactant is administeredwithout endotracheal intubation formore severe RDS, its benefits couldpossibly be combined with those ofnoninvasive respiratory support. Sur-factant can be administered via a thinendotracheal catheter placed intra-tracheally by using a laryngoscope anda Magill forceps during spontaneousbreathing and ongoing nCPAP treat-ment.17 Alternatively, a semirigid vas-cular catheter can be guided throughthe vocal cords without a trochar orforceps.18 Laryngeal mask airwayshave been used for surfactant ad-ministration in a study of prematureinfants between 880 and 2520 g,76 anda recent RCT has confirmed that thistechnique achieves effective surfac-tant delivery.77 Aerosolized surfactantwould be the least invasive andprobably most desirable way of ad-ministering surfactant. Progress hasrecently been made toward solvingthe technical problems of surfactantnebulization by using vibrating mem-brane nebulizers,78–80 but more clini-cal data are needed on the efficacy ofaerosolized surfactant and of otherinnovative methods of administeringsurfactant. Moreover, future RCTsshould investigate the optimal timingof surfactant administration. With re-spect to the study design, the mode ofrespiratory support should be similarwhen surfactant timing is studied, andvice versa.

RCTs have also revealed that sustainedinflations81 and heliox82 reduce the riskof infants having to undergo eMV, andlate recurrent dosing of surfactant hasshown some promise for shorteningthe duration of eMV in intubatedinfants.83 These interventions need tobe investigated as complementarystrategies for reducing BPD.

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Limitations of the Meta-analysis

Thereareseveral limitations to thismeta-analysis. Firstly, the exclusion of ab-stracts and conference proceedingsimplies a risk of publication bias. How-ever, the funnel plot does not indicate anysuch bias, and our method ensured thatthe included RCTs had undergone a rig-orous peer review. Secondly, as the RCTsdiffered with regard to inclusion criteria,treatment protocol, and number ofpatients recruited in each study, thismighthave impactedtheeffectsizeofBPDreduction in the meta-analysis. The dif-ferences included the study patients’ GA,the strategy used to avoid eMV, andtiming and dosage of methylxanthineand surfactant treatment. Thirdly, due toconstraints of time and resources, themeta-analysis was designed to only in-vestigate severe IVH as a secondary

outcome. A more detailed meta-analysisneeds to investigate the impact thatavoiding intubation has on other adverseoutcomes of prematurity and on clinicalcomplications such aspneumothorax.13,37

Because eMV has been associated withreduced cerebral blood flow and cere-bral palsy in very premature infants,84,85

future meta-analyses should includeneurodevelopmental outcomes.

CONCLUSIONS

The present meta-analysis indicatesthat avoiding eMV reduces the in-cidence of death or BPD in prematureinfants ,30 weeks’ GA without in-creasing the risk of IVH. However,with an NNT of 35, the beneficial effectwas small. Avoiding intubation andsubsequent ventilation through an en-dotracheal tube may only be one

component of a comprehensive strat-egy to reduce BPD in this population.Future studies need to explore the roleof nIPPV and nHFOV in the primarytreatment of neonates in the deliveryroom and to investigate alternativemethods of administering surfactant.

ACKNOWLEDGMENTSThe authors would like to thank DrMario Rojas (CNRN) and Dr H. GözdeKanmaz (Take Care) for providing pre-viously unpublished data and addi-tional information on their trials; DrMichael Dunn (DRM) and Dr EgbertHerting (AMV) for providing additionalinformation about their studies; DrYuwei Zhao for accessing and translat-ing articles published in Chinese; andJenMetcalf for linguistic revision of themanuscript.

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