safety and efficacy of high-flow nasal cannula therapy in ...safety and efficacy of high-flow...

14
Safety and Efcacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRD a , Roshan Adappa, MRCPCH, MD b , Nakul Gupta, MRCPCH b , W. John Watkins, PhD a , Sailesh Kotecha, FRCPCH, PhD a , Mallinath Chakraborty, MRCPCH, PhD a,b abstract BACKGROUND AND OBJECTIVE: High-ow therapy is the most recent, and popular, mode of respiratory support in neonates. However, the evidence supporting its efcacy and safety has not yet been established. We conducted a systematic review and meta-analysis of clinical trials comparing efcacy and safety of high-ow therapy compared with other modes of noninvasive ventilation (NIV) in preterm infants. METHODS: Articles were indexed by using Medline, Embase, Scopus, OpenSIGLE, Health Management Information Consortium, and Cochrane Central Register of Controlled Trials. Randomized or quasi- randomized clinical trials involving preterm infants, comparing high-ow therapy with other modes of NIV, and reporting extractable data on relevant outcomes, were selected. Data on efcacy, safety, and other common neonatal outcomes were extracted on predesigned forms. RESULTS: In this analysis, we included 1112 preterm infants, participating in 9 clinical trials. High-ow therapy was similar in efcacy to other modes of NIV in preterm infants when used as primary support (odds ratio of failure of therapy, 1.02 [95% condence interval: 0.55 to 1.88]), as well as after extubation (1.09 [0.58 to 2.02]). There were no signicant differences in odds of death (0.48 [0.18 to 1.24]) between the groups. Preterm infants supported on high- ow had signicantly lower odds of nasal trauma (0.13 [0.02 to 0.69]). CONCLUSIONS: High-ow therapy appears to be similar in efcacy and safety to other conventional modes of NIV in preterm infants. It is associated with signicantly lower odds of nasal trauma. Caution needs to be exercised in extreme preterm infants because of the paucity of published data. a Department of Child Health, Cardiff University, Cardiff, United Kingdom; and b Department of Neonatology, University Hospital of Wales, Cardiff, United Kingdom Ms Kotecha designed the search strategy and ran the searches, collected and analyzed data, and reviewed and revised the manuscript; Dr Adappa and Dr Gupta shortlisted articles and reviewed and revised the manuscript; Dr Watkins undertook statistical analysis and reviewed and revised the manuscript; Professor Kotecha supervised searches, data collection and analysis, and critically reviewed the manuscript; Dr Chakraborty conceptualized and designed the study, supervised searches, shortlisted articles, supervised data analysis, and drafted the initial manuscript; and all authors approved the nal manuscript as submitted. www.pediatrics.org/cgi/doi/10.1542/peds.2015-0738 DOI: 10.1542/peds.2015-0738 Accepted for publication Jun 17, 2015 Address correspondence to Mallinath Chakraborty, MRCPCH, PhD, Department of Child Health, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2015 by the American Academy of Pediatrics FINANCIAL DISCLOSURE: The authors have indicated they have no nancial relationships relevant to this article to disclose. FUNDING: No external funding. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conicts of interest to disclose. REVIEW ARTICLE PEDIATRICS Volume 136, number 3, September 2015 by guest on June 12, 2020 www.aappublications.org/news Downloaded from

Upload: others

Post on 05-Jun-2020

6 views

Category:

Documents


0 download

TRANSCRIPT

Page 1: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

Safety and Efficacy of High-Flow NasalCannula Therapy in Preterm Infants:A Meta-analysisSarah J. Kotecha, BSc, SRDa, Roshan Adappa, MRCPCH, MDb, Nakul Gupta, MRCPCHb, W. John Watkins, PhDa,Sailesh Kotecha, FRCPCH, PhDa, Mallinath Chakraborty, MRCPCH, PhDa,b

abstract BACKGROUND AND OBJECTIVE: High-flow therapy is the most recent, and popular, mode of respiratorysupport in neonates. However, the evidence supporting its efficacy and safety has not yet beenestablished. We conducted a systematic review and meta-analysis of clinical trials comparingefficacy and safety of high-flow therapy compared with other modes of noninvasive ventilation(NIV) in preterm infants.

METHODS: Articles were indexed by using Medline, Embase, Scopus, OpenSIGLE, Health ManagementInformation Consortium, and Cochrane Central Register of Controlled Trials. Randomized or quasi-randomized clinical trials involving preterm infants, comparing high-flow therapy with other modesof NIV, and reporting extractable data on relevant outcomes, were selected. Data on efficacy, safety,and other common neonatal outcomes were extracted on predesigned forms.

RESULTS: In this analysis, we included 1112 preterm infants, participating in 9 clinical trials.High-flow therapy was similar in efficacy to other modes of NIV in preterm infants when usedas primary support (odds ratio of failure of therapy, 1.02 [95% confidence interval: 0.55 to1.88]), as well as after extubation (1.09 [0.58 to 2.02]). There were no significant differences inodds of death (0.48 [0.18 to 1.24]) between the groups. Preterm infants supported on high-flow had significantly lower odds of nasal trauma (0.13 [0.02 to 0.69]).

CONCLUSIONS: High-flow therapy appears to be similar in efficacy and safety to other conventionalmodes of NIV in preterm infants. It is associated with significantly lower odds of nasal trauma.Caution needs to be exercised in extreme preterm infants because of the paucity of published data.

aDepartment of Child Health, Cardiff University, Cardiff, United Kingdom; and bDepartment of Neonatology, University Hospital of Wales, Cardiff, United Kingdom

Ms Kotecha designed the search strategy and ran the searches, collected and analyzed data, and reviewed and revised the manuscript; Dr Adappa and Dr Gupta shortlistedarticles and reviewed and revised the manuscript; Dr Watkins undertook statistical analysis and reviewed and revised the manuscript; Professor Kotecha supervised searches,data collection and analysis, and critically reviewed the manuscript; Dr Chakraborty conceptualized and designed the study, supervised searches, shortlisted articles,supervised data analysis, and drafted the initial manuscript; and all authors approved the final manuscript as submitted.

www.pediatrics.org/cgi/doi/10.1542/peds.2015-0738

DOI: 10.1542/peds.2015-0738

Accepted for publication Jun 17, 2015

Address correspondence to Mallinath Chakraborty, MRCPCH, PhD, Department of Child Health, Cardiff University, Heath Park, Cardiff CF14 4XN, United Kingdom. E-mail:[email protected]

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

Copyright © 2015 by the American Academy of Pediatrics

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

FUNDING: No external funding.

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

REVIEW ARTICLE PEDIATRICS Volume 136, number 3, September 2015 by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 2: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

Respiratory failure, requiring invasivesupport with mechanical ventilation(MV) or noninvasive support withnasal modes of ventilation, remains themost common morbidity of preterminfants after birth.1 Recent studiessuggest increased rates of survival ofextreme preterm infants,1,2 withgreater numbers needing respiratorysupport. Traditionally, this support hasbeen in the form of invasive (throughan endo-tracheal tube) MV. Morerecently, randomized controlled clinicaltrials have established the benefits ofprimary noninvasive ventilation (NIV)support, especially for nasalcontinuous positive airway pressure(nCPAP)3,4 when compared with MV.5

After extubation from MV, nCPAP isalready established as an effectivemode of support.6 Other modes of NIVin preterm infants include bilevelnCPAP (BiPAP)/noninvasive positivepressure ventilation (NIPPV) andheated humidified high-flow nasalcannula (HHHFNC) therapy. The use ofBiPAP/NIPPV as a primary mode ofrespiratory support seems to beequally efficacious,7 and clinicallysuperior after extubation from MV,8

when compared with nCPAP.

The most recent mode of respiratorysupport to be introduced fornewborn infants, HHHFNC, however,has quickly gained popularityamong clinicians worldwide,9–13

although evidence supporting itsuse is not fully established.14–16

Several clinical trials over the lastdecade have collected evidence ofthe use of HHHFNC in preterminfants, both as a primary mode ofsupport at birth and after extubationfrom MV. We conducteda systematic review and meta-analysis to collect all publishedinformation, to be able to guideclinical practice.

METHODS

Objectives

Our objective was to assess theefficacy and safety of HHHFNC as

respiratory support for preterminfants (,37 weeks’ gestational age[GA] at birth), when compared withother modes of NIV including nCPAP,and NIPPV or BiPAP.

Inclusion Criteria

We included prospective, randomizedor quasi randomized controlled trialsinvolving preterm infants born at,37 weeks’ GA. Trials involvingmixed groups of infants (bothpreterm and term) were included ifseparate data for preterm infantswere available (reported in the text,extracted from the data, or obtainedfrom authors). No trials wereexcluded based on diagnosis ofdisease condition in the infants.Subgroups analyses were plannedprospectively for ,32 weeks’ GA(#1500 g birth weight [BW]) and,28 weeks’ GA (#1000 g BW), ifstratified data were available. Forstudies using BW as inclusion criteria,1000 g was used as a surrogate for28 weeks, 1500 g for 32 weeks, and2000 g for 36 weeks. Trials wereincluded if participating infantsintended to be managed onnoninvasive respiratory support, andrandomly assigned to HHHFNC orany other form of noninvasiverespiratory support within 24 hoursof birth, after extubation from MVor while weaning from noninvasiverespiratory support. At least 1 ormore of the relevant review outcomes(see below) should have beenreported in the results to considerinclusion.

Search Strategy

We developed a search strategy byusing keywords and Medical SubjectHeadings (MeSH) terms, as detailedin the Supplemental Information,from 6 databases: Embase, HealthManagement InformationConsortium (HMIC), Medline, Scopus,OpenSIGLE, and Cochrane CentralRegister of Controlled Trials(CENTRAL). The databases weresearched in May 2014. References inincluded studies were also screened

for inclusion. The search includedarticles in all languages from allcountries.

Outcomes

Primary outcomes were failure oftherapy to establish efficacy, anddeath, pulmonary air leaks, and nasaltrauma to establish safety. Anydefinition of failure of therapy wasconsidered, because there weredifferences in how variousresearchers defined it in trials. Dataon several secondary outcomes werecollected, including respiratoryoutcomes (respiratory complications,mode, and length of respiratorysupport, bronchopulmonarydysplasia [BPD]), intraventricularhemorrhage (IVH), and other relevantneonatal outcomes (sepsis,necrotizing enterocolitis [NEC],patent ductus arteriosus [PDA],retinopathy of prematurity [ROP],etc).

Definitions

BPD was defined as respiratorysupport and/or supplementaloxygen requirement at 36 weeks’corrected GA. If a room-oxygen testwas undertaken at 36 weeks’corrected GA before categorizing asBPD, then only infants failing the testwere considered to have BPD.17

Grades of IVH were as classified byPapile et al.18 Classification of NECwas as by Bell et al19 and modifiedby Walsh et al.20 For the purposes ofthis review, HHHFNC was defined asheated humidified flows in excess of2 L/min (low flows are defined as,2 L/min). However, most recentarticles have used flow rates from5 to 8 L/min.

Data Collection

Data were collected oncharacteristics of studies andplanned outcomes, using astandardized data collection form(Supplemental Table 5) by at least2 authors independently, and thencross-checked for accuracy. Attempts

PEDIATRICS Volume 136, number 3, September 2015 543 by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 3: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

were made to clarify methods andrequest gestation-stratified datafrom corresponding authors inarticles, where both preterm andterm infants were included. Theseare mentioned in the relevant tablesin the Results section.

Statistical Analysis

Measurement of Treatment Effect

Statistical analysis was conducted byusing Review Manager (RevMan)version 5.3 (The Nordic CochraneCentre, The Cochrane Collaboration,2014, Copenhagen, Denmark). Forcontinuous data, the mean and SD(such as duration of respiratorysupport) were collected andanalyzed by using weighted meandifferences (WMDs). For categoricaldata (such as death or treatmentfailure), data were extracted for eachintervention group and odds ratios(ORs) were calculated, along with95% confidence intervals (CIs).Significance was set at P , .05.

One study21 revealed outcomes asmedians and interquartile ranges.Means and SDs were calculated fromthis data by using methods publishedpreviously.22,23 For 1 study,24 somedata were read from publishedfigures. Whenever this data wereused for pooled estimates ofoutcome in the meta-analysis,a sensitivity assessment wasundertaken to test for differences inestimates.

Assessment of Bias in Included Studies

All studies included in final analysiswere assessed for risk of bias byusing a domain-based flow-sheet(as used by the CochraneCollaboration). Specific domainsexamined included selection bias,performance bias, detection bias,attrition bias (low risk: adequateif ,10% missing data; high risk:inadequate if .10% missing data),reporting bias, and any other formof bias specific to the design of thestudy. For each domain, risk of biaswas categorized as low risk, high

risk, or unknown/unclear risk (ifinadequate details were reportedin the methods). For each domain,a judgment was made on likelymagnitude and direction of thebias, and its likely impact on theoutcomes. Disagreements wereresolved by consensus. A judgmentwas made on the overall risk ofbias on the basis of the abovedomains.

Assessment of Heterogeneity

Heterogeneity was quantified byusing Inaccuracy2 (I2) statistic(http://handbook.cochrane.org/) andstratified as insignificant (I2 #49%)or significant (I2 .50%). In thepresence of .50% heterogeneity,a sensitivity analysis was conductedto explain the source of heterogeneity.To calculate pooled estimate of effectsize, a fixed-effect model was usedif insignificant heterogeneity wasdetected, and a random-effect modelwas used if significant heterogeneitywas detected.

RESULTS

Selection of Studies

Search results and filtering atdifferent stages is represented inFig 1. Full details of search terms,with the search sequence, ispresented in the SupplementalInformation section.

Description of Studies

Eighteen studies published as full-text articles21,24–40 and 8 studiespublished as abstracts41–48 wereinitially considered for the review.Of the studies published as full-textarticles, 2 used nonheated high-flowtherapy,25,36 7 were randomized-sequence cross-overstudies,28,30,31,35–37,39 2 compareddifferent modes of high-flowtherapy,32,39 and 1 expressed datafor nasal trauma as scores.26 Of thestudies published as abstracts, 2 wererandomized-sequence cross-overtrials,41,47 2 had no raw data suitablefor pooling,42,48 1 compared HHHFNC

FIGURE 1Flow diagram describing stages of search results and filtering process, as per Preferred ReportingItems for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

544 KOTECHA et al by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 4: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

with MV,46 and 1 study included termand preterm infants, without separatedata for preterm infants.43 These17 studies were excluded because wewere unable to extract relevant datafor our analysis (SupplementalTable 8). Thus, 7 studies published asfull-text articles and 2 studiespublished as abstracts were includedin the final review (Table 1).

All included studies comparedHHHFNC with nCPAP, except 140

that compared infants on HHHFNCwith those on NIPPV. All of thestudies involved preterm infantswho were ,37 weeks’ gestation, but2 studies only included infants bornat ,32 weeks’ gestation.21,27 Onestudy included both term andpreterm infants, but stratified datafor the preterm infants weresupplied by the authors.38

Two studies compared HHHFNC withnCPAP both as a primary mode ofrespiratory support and as supportafter extubation from MV.33,38

Stratified data for preterm infantssupported on HHHFNC as primarymode or after extubation wereavailable from the authors for only1 of the studies.38 Thus, the finalanalysis included 6 studies whereHHHFNC was compared with otherforms of NIV as a primary mode ofrespiratory support29,33,38,40,44,45 and3 studies where these 2 modalitieswere compared after extubation fromMV.21,27,33 One study compared the2 modes while weaning fromrespiratory support.24 One study wasonly published as an abstract inEnglish, but as full-text article inPersian.29 Google Translate wasused for an automated translationfrom Persian to English (GoogleInc, Mountain View, CA). Characteristicsand clinical details of all includedstudies are presented in Table 1.

Risk of Bias in Included Studies

Eight of the studies were randomizedcontrolled trials, whereas 1 wasa quasi-randomized trial.33 There wasvariability of the risk of bias in the

included studies (Fig 2), with 6 studieswith an overall low risk ofbias,21,24,27,38,40,45 2 studies witha high risk of bias because of unclearpublished methods,29,33 and 1 hadinadequate information in the abstractto make an informed judgment.44

Efficacy of HHHFNC

Efficacy of HHHFNC, compared withother forms of NIV, was assessedprimarily by analyzing failure oftherapy. Because HHHFNC has beenused both as a primary mode ofrespiratory support as well as afterextubation from MV in preterminfants, we conducted separateanalyses to compare failure rates.Four studies, involving 321 preterminfants,38,40,44,45 compared efficacyof HHHFNC with other NIV whenused as a primary mode ofrespiratory support. Pooledestimates of OR for failure of therapyfor these studies was 1.02 (95% CI:0.55 to 1.88; Fig 3A), and 1.12 (0.51to 2.50) when the study comparingHHHFNC and NIPPV40 was excluded.One of the trials in the primary usegroup had an uncertain risk ofbias44; excluding this from theanalysis gave a pooled estimate offailure of 0.85 (0.43 to 1.69). Threetrials involving 661 preterminfants21,27,38 compared failure ratesof HHHFNC with that of other NIV(all used nCPAP) when used asrespiratory support after extubation.The pooled OR was 1.09 (0.58 to2.02; Fig 3B), although there wasmoderate heterogeneity in theincluded trials (I2 = 56%).

When all 8 eligible trials revealingfailure of therapy (any definition) wereincluded, involving 1112 preterminfants, the pooled OR of failure oftherapy for HHHFNC versus any otherNIV was 1.10 (0.82 to 1.49; Fig 4A).Restricting this analysis to include the6 studies with overall low risk of biasinvolving 950 preterm infants, thepooled OR was 1.09 (0.79 to 1.49;Fig 4B). To compare efficacy ofHHHFNC versus nCPAP, the trialcomparing HHHFNC with NIPPV40 was

excluded from the analysis. However,this did not significantly change the OR(OR for all studies 1.13 [95% CI: 0.82to 1.55]; OR for studies with low riskof bias 1.12 [95% CI: 0.80 to 1.56]).

As planned in our protocol, weconducted analyses on gestationalsubgroups for failure rates of HHHFNC.All of the included studies in our reviewincluded infants born at,32 weeks’ GA.However, stratified data on infants bornat ,32 weeks’ GA was available fromonly 3 studies.21,27,38 Two studiescompared efficacy of HHHFNC withnCPAP after extubation from MV,21,27

whereas the third study used HHHFNCas primary support as well as afterextubation from MV.38 Pooling all datafrom these 3 studies, which involved585 infants, gave an estimated OR offailure of HHHFNC 0.89 (0.42 to 1.89).Including only the 2 studies thatcompared HHHFNC with nCPAP afterextubation (435 infants) gave anestimated OR of failure of HHHFNC, ininfants born ,32 weeks’ GA, as 1.12(0.74 to 1.69). Four studies includedinfants born at,28 weeks’ GA,21,27,40,45

whereas 2 more possibly includedinfants ,28 weeks’ GA as derived fromtheir results table.33,38 Stratified datawere available from 1 of the abovestudies,27 comparing HHHFNC withnCPAP after extubation from MV, givingan OR of 0.54 (0.19 to 1.53, total59 infants). No stratified data wereavailable from any of the other studieson infants born at ,28 weeks’ GA.

To assess time to failure of therapy,we compared failure rates at 3 andat 7 days after study entry. Twostudies, involving 443 infants,38,44

reported failure of therapy ofHHHFNC versus NIV (both nCPAP)#72 hours, with a pooled OR of 1.24(0.66 to 2.32; Supplemental Fig 8A).Four studies, involving a total of 814infants,21,27,38,45 reported failure oftherapy of HHHFNC versus NIV (allnCPAP) by 7 days after study entry,with an estimated pooled OR of 1.06(0.75 to 1.50; Supplemental Fig 8B).

In summary, although failure rateswere slightly lower in the other NIV

PEDIATRICS Volume 136, number 3, September 2015 545 by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 5: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

TABLE1

Characteristicsof

Included

Studies

Investigators(Study

Identifier)

StudyDesign

Population

WhenRandom

ized

Outcom

esComments

Completed

studiespublished

asfull-text

Abdel-Hadyet

al201124

RCT,HH

HFNC

(2L/min)versus

nCPAP(5

cmH 2O)

Preterm

$28

wkGA,60

infants

Weaning

from

nCPAP

Primary:Durationof

oxygen

therapyin

days

“HF”

restricted

to2L/min

Secondary:Durationof

respiratorysupport,nCPAP,

hospitalization,weaning;w

eaning

success,need

for

intubation,

complications

Objectivefailure

criteria

Collins

etal

201327

RCT,HH

HFNC

(8L/min)versus

nCPAP(8

cmH 2O)

Preterm

,32

wkGA,132

infants

Postextubation

Primary:Extubationfailure

upto

7d

Objectivefailure

criteria

Secondary:Nasaltrauma,durationof

respiratory

supportandsupplementalO

2,BPD(36wk),IVH,NEC,

timeto

fullfeeds

Boy.

girlin

nCPAP

Data

stratified

byGA

Iranpour

etal

201129

RCT,HH

HFNC

versus

nCPAP

Preterm

infants30–35

wk

GA,70infants

Within

24hof

birth

Death,NEC,PDA,IVH,

CLD,

pneumothorax,pulmonary

hemorrhage,apnea,sepsis,d

urationof

hospitalization,durationof

fullenteralfeeding,and

durationof

O 2need

Norawdata

inabstract.U

sed

translation.

Kugelman

etal

201540

RCT,HH

HFNC

(1–5L/min)

versus

NIPPV(ventilator

generated)

Preterm

infants,35

wk

GAand.1000

gBW

,76

infants

Primarysupportafter

birth

Primary:Treatm

entfailure

(intubationor

othermodeof

NIV)

Objectivefailure

criteria

Secondary:clinical

features

during

treatm

ent,

respiratorystatus

before

MVifneeded,“tim

etostop

nasalsupport,”IVH,

BPD,

nasaltraum

a,airleaks,GI

perforation

Manleyet

al201321

RCT,HH

HFNC

(5–8L/min)

versus

bubble

nCPAP

(5–8cm

H 2O)

Preterm

infants,32

wk

GA,303

infants

Onfirstextubation

(,36

wk)

Primary:Treatm

entfailure

in7d

Designed

asnoninferioritytrial

Secondary:reintubationduring

theprimary-outcom

eperiod,death

before

hospitaldischarge,BPD(36

wk),pneum

othoraxaftertrialentry,totaldays

ofany

respiratorysupportaftertrialentry,durationof

oxygen

supplementationaftertrialentry,length

ofhospitaladmission,nasal

trauma,sepsis,N

EC,R

OP,

IVH,

andPVL.

Objectivefailure

criteria

HHHFNC

“rescued”by

nCPAP;

ITTanalysis

NIPPVallowed

fornCPAPgroup

Phadtare

etal

200933

Quasi-randomized

prospectivecontrolled

trial,HH

HFNC

versus

nCPAP

Preterm

infants,37

wk

GA,70infants

PrimarytherapyforRD

Sandat

extubation

Death,failure

oftherapy,intubationandventilation,

days

onMV/nCPAP/High-flow

,cause

offailure,

durationof

hospitalstay,and

complications.

Subjectivefailure

criteria

Yoderet

al201338

RCT,HH

HFNC

versus

nCPAP

Neonates

$1000

gBW

and

$28

wkGA

432infants

Atbirthandpostextubation

within

96hage

Primary:Failure

ofsupportwithin

3d

Included

term

infants

Secondary:Death,ventilationdays,oxygendays,need

fordelayedintubation,

system

icadverseevents,

localnasaltrauma,infant

comfort,B

PD,timeto

full

feeds

Stratified

results

notpublished

Objectivefailure

criteria

Studiespublishedas

abstractsonly

Lavizzariet

al201344

RCT,HH

HFNC

(4–6L/min)

versus

nCPAP4–6cm

H 2O)

Preterm

infants29

–36

+6 ,

92infants

Atbirthon

diagnosisof

RDS

Primary:intubationwithin

3d

Failure

criterianotspecified

Secondary:need

ofsurfactant,total

durationof

respiratoryassistance

andNIV,length

ofhospitalization

NairandKarna200545

RCT,HH

HFNC

versus

nCPAP

Preterm

infants27–34

wk

GA,28infants

nCPAPat

6hof

age

Primary:Respiratoryfailure

within

7d

CLD,

chroniclung

disease;GI,gastrointestinal;ITT,intentionto

treat;PVL,periventricularleukom

alacia;R

CT,randomized

controlledtrial.

546 KOTECHA et al by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 6: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

group compared with HHHFNC, it wasnot statistically significant, regardlessof the timing of use of HHHFNC(primary support or after extubation)or the timing of assessment for failureof therapy (3 days or 7 days).

Safety of HHHFNC

Safety was assessed by comparingrates of deaths and pulmonary airleaks in the infants supported onHHHFNC and on other modes of NIV.There was no statistically significantdifference in the rate of deaths in thegroup of preterm infants randomly

assigned to receive HHHFNCcompared with other NIV in the5 studies revealing this outcomeinvolving 922 infants (OR: 0.48 [0.18to 1.24]; Fig 5).21,24,27,38,40 Similarly,no statistically significant differencebetween the groups was found in theincidence of any pulmonary air leaks,as reported by 6 trials involving 992preterm infants,21,24,27,33,38,40 withan OR of 0.72 (0.28 to 1.83; Fig 6).

Nasal Trauma

Injury of the nasal mucosa or externalnares is often reported on preterm

infants who are supported onnCPAP.49,50 Five studies involving857 infants21,29,33,38,40 revealed theincidence of nasal trauma in infantssupported on HHHFNC comparedwith other forms of NIV. One moretrial26 revealed nasal trauma, but asscores rather than events, and couldnot be included in the analysis.Pooled OR for incidence of nasaltrauma in preterm infants receivingHHHFNC was 0.13, which wassignificantly lower (P = .02) thaninfants supported on other forms ofNIV (95% CI: 0.02 to 0.69; Fig 7),although significant heterogeneitywas detected between the trials.Excluding the 2 trials with a high riskof bias, OR for nasal trauma was stillsignificantly lower in infants (total717) supported on HHHFNC (0.33;0.13 to 0.87, P = .02).

Secondary Outcomes

Other relevant outcomes of preterminfants were compared between thegroups, as planned in our analysis(Table 2). Odds of all secondaryoutcomes analyzed were comparablein the 2 groups of infants.

DISCUSSION

From our analysis, supportingpreterm infants on HHHFNC wasequivalent in efficacy as any otherform of NIV (NIPPV or nCPAP). Thisefficacy was mainly observed in themoderate to late preterm infants($28 weeks’ gestation at birth), andafter extubation from MV. HHHFNChad similar failure rates to the othermodes when used both as a primarymode of respiratory support afterbirth, as well as support afterextubation from MV, although thenumber of infants who weresupported on HHHFNC at birth waslimited. Efficacy was maintained overtime, as assessed by failure of therapyat 3 days and at 7 days after trialentry. There were no statisticallysignificant differences in the odds ofdeath or air leaks in infantssupported on HHHFNC compared

FIGURE 2Risk of bias diagram for each study (represented on left y-axis) as assessed on specific domains(represented on upper x-axis). Green circles with “+” represent low risk of bias, red circles with “2”

represent high risk of bias, and open circles represent unclear risk of bias.

PEDIATRICS Volume 136, number 3, September 2015 547 by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 7: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

with other modes of NIV. However,significantly fewer infants had nasaltrauma as a complication whensupported on HHHFNC comparedwith other forms of NIV.

We have assessed efficacy bycomparing rates of failure of therapyof a particular mode of support.“Failure of therapy” was variablydefined by different studies. Six of

the studies included in our analysishad published objective criteriain the methods to define failureof therapy, which included acombination of clinical (observation

FIGURE 3Pooled estimates of odds of failure of therapy of HHHFNC compared with other modes of NIV in preterm infants, when used as (A) primary mode ofrespiratory support, and (B) after extubation from MV.

FIGURE 4Pooled estimate of odds of failure of therapy in preterm infants supported on HHHFNC compared with other modes of NIV (A) including all eligible studies,and (B) studies with a low risk of bias only.

548 KOTECHA et al by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 8: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

of vitals, respiratory effort, apneas,oxygen requirement) and biochemical(blood gas characteristics)criteria.21,24,27,38,40,45 Although therewere minor differences in thethresholds, the criteria published bythese trials were largely similar(Supplemental Table 9). The 3 otherstudies did not publish objectivecriteria in their methods to definefailure of therapy.29,33,44 All 3 of thesestudies were deemed to have a highrisk of performance and detection bias.However, on separate analysis, bothincluding and excluding the studieswith a high risk of bias, the pooled ORfor failure of therapy remained verysimilar (results section “efficacy oftherapy”). Nevertheless, it is importantthat future studies attempt to define“failure” more accurately anduniformly, for results to be easilycomparable between different studies.

Studies with a low risk of bias (Fig 4B)defined failure of therapy by objectivecriteria. However, not all failuresnecessarily resulted in reintubation forMV,26,27 suggesting that “failure of 1

mode of NIV” is not the same as “failureof NIV.” In our opinion, this is animportant distinction to make, asoverall the neonatal community seemsto be moving toward increased use ofNIV, which has shown clinical benefit.5

A time-based definition of failure has itsown disadvantages, as some infantscontinue to “fail” even after the definedstudy period,51 especially the extremepreterm group.

A common complication amongpreterm infants supported on nCPAP isnasal injury,49 which can vary from20% to 60%. The higher rates wereobserved in the smaller and extremepreterm infants. Our analysis suggestssignificantly lower odds of nasal trauma(defined and measured variably) inpreterm infants supported on HHHFNC,compared with other modes of nCPAP.In addition, preterm infants are thoughtto be more comfortable on HHHFNC byneonatal nurses compared withnCPAP,52 although no difference inpatient comfort was detected while onHHHFNC as compared with nCPAP ina recent trial.30

HHHFNC is the most recent mode ofNIV in adults and neonatal patients.However, the precise mechanism ofaction, resulting in clinical benefit,has not been fully evaluated.Proposed theories include washoutof anatomic dead space in the upperairways because of the flow of gas,improvement in conductance of gasbecause of humidification, reductionin metabolic demands of the airwaysfrom the warm and humidified gas,and provision of distending pressureto the lungs.9,53 Extrathoracicanatomic dead space is related toage and is higher in small infants(.3 mL/kg) compared with adults.54

Thus, continuous washout of thisrelatively large space with a supplyof fresh gas could be of clinicalbenefit, especially in the neonatalperiod. In contrast to nCPAP (orBiPAP), which depend on a seal toprovide distending pressure, a seal atthe upper airways is not required forHHHFNC. Thus, the distendingpressure provided by HHHFNC isdynamic, depending on the phase ofthe respiratory cycle.55,56 All of these

FIGURE 5Pooled estimate of odds of death in preterm infants supported on HHHFNC compared with other modes of NIV.

FIGURE 6Pooled estimate of odds of pulmonary air leaks in preterm infants supported on HHHFNC compared with other modes of NIV.

PEDIATRICS Volume 136, number 3, September 2015 549 by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 9: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

mechanisms, in theory, suggestHHHFNC could be suited to theanatomy and physiology of preterminfants. Additionally, HHHFNC seemsto cause less nasal trauma in preterminfants, and seems to be preferred bynurses52 and parents.30 However,because of the physiology of thelungs in early respiratory distresssyndrome (RDS), the continuousdistending pressure provided bynCPAP, in theory, could make it moresuitable as a mode of respiratorysupport than HHHFNC.

HHHFNC systems have been in use inboth adults and infants since theearly 2000s. To our knowledge, thisis the first detailed systematic reviewcomparing HHHFNC with othermodes of NIV in preterm infants,with a view to pooling all of the datatogether and providing evidentialbasis for this popular mode ofrespiratory support. Except for 1, alltrials in this meta-analysis havecompared HHHFNC with nCPAP.Although our analysis demonstrated

a slightly higher odds of failure ofHHHFNC compared with nCPAP, andto all other modes of NIV combined,this was not statistically significant.Majority of the infants included inthe studies in our analysis weremoderate (28–32 weeks’ GA) to late(.32 weeks’ GA) preterms. Only 4 ofthe studies in our analysis includedpreterm infants ,28 weeks’ GA atbirth,21,27,40,45 and the 2 largestudies used HHHFNC at this GA onlyafter extubation.21,27 The study byNair and Karna45 used HHHFNC asa primary mode of support inpreterm infants ,28 weeks’ GA, butno stratified data were available forthese infants. Collins et al27 reportedreintubation of infants ,28 weeks’GA, which was comparable betweenthe HHHFNC and nCPAP groups. Thetrial by Manley et al21 revealedhigher failure rates for infants bornat ,26 weeks’ GA (81% for HHHFNCcompared with 61% for nCPAP).Thus, the evidence for efficacy ofHHHFNC in the extreme preterm

infants (,28 weeks’ GA at birth),compared with other modes of NIV,

remains scanty, and this needsto be the subject of future studies.

Until then, this form of respiratorysupport cannot be recommended

in extremely preterm infants, eitheras primary support or after

extubation.

The main limitation of our study isthat we were unable to conductadequate stratified analysis on thelower GAs, as planned in our methods.This is due to the limited amount ofdata on the use of HHHFNC in infants,32 weeks’ GA, and more so oninfants ,28 weeks’ GA. The vast

majority of infants ,28 weeks’ GA atbirth need some form of respiratory

support, both at birth and afterextubation. More so, these are theinfants at highest risk of nasal

trauma49 resulting in long-term nasaldeformities,57 and if HHHFNC proves

to be efficacious in the extremelypreterm infants, the incidence of such

deformities could be minimized.

Due to our study design, we haveincluded trials with high risk of bias intheir methods, as well as studiespublished as abstracts only.Throughout the article, we havepresented results both including andexcluding studies with a high risk ofbias, as part of sensitivity analysis. Ourresults reveal that the effect size orstatistical significance did not changeon sensitivity analysis. Although we areconfident of our scientific methods, itis our opinion that clinical practice

TABLE 2 Summary of Secondary Outcomes

Outcome Total Numberof Infantsa

StudyReference

PooledEstimateb

95% CI

Total duration of respiratory supportc 818 21,24,38,40,45 1.28 20.91 to 3.48Length of stay on neonatal unitc 860 21,24,33,38,40 0.81 22.38 to 4.01BPDd 932 21,27,33,38,40 0.93 0.67 to 1.28PDA, anyd 870 21,29,33,38,40 0.97 0.66 to 1.42PDA requiring treatmentd 654 21,38 0.84 0.55 to 1.30IVH, anyd 711 21,24,27,29,33,38,40 0.63 0.31 to 1.28IVH, grade III/IVd 495 21,24,27 0.48 0.19 to 1.21ROP, anyd 720 21,38 0.97 0.38 to 2.46Sepsisd 860 21,24,29,38,40 1.07 0.69 to 1.65a All infants in included studies.b High-flow versus NIV.c Weighted mean difference in days.d OR.

FIGURE 7Pooled estimate of odds of nasal trauma in preterm infants supported on HHHFNC compared with other modes of NIV.

550 KOTECHA et al by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 10: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

should be based on data from studieswith a low risk of bias.

Results of our analysis suggest thatHHHFNC is not inferior to othermodes of NIV in preterm infants. Dueto significantly lower odds ofnasal trauma, and no significantdifferences in other commonneonatal outcomes, HHHFNC may bea preferred method in this GA group.Caution needs to be exercised inthe more preterm infants, whereefficacy and safety of HHHFNC,either as a primary mode of supportor after extubation, are not yetthoroughly tested.

Future research needs to concentrateon the extreme preterm group ofinfants, who would benefit most frommodes of NIV. Weaning of NIV isanother area of practice thatneeds further research, as a recentreview on weaning of HHHFNC inpreterm infants was unable to identifyany eligible studies on this subject.58

We feel that our data provide evidenceto consider HHHFNC as a mode ofrespiratory support in preterm infantsby clinicians.

ABBREVIATIONS

BiPAP: bilevel nasal continuouspositive airway pressure

BPD: bronchopulmonary dysplasiaBW: birth weightCI: confidence intervalGA: gestational ageHHHFNC: heated humidified high-

flow nasal cannulaIVH: intraventricular hemorrhageMeSH: Medical Subject HeadingsMV: mechanical ventilationnCPAP: nasal continuous positive

airway pressureNEC: necrotizing enterocolitisNIPPV: noninvasive positive

pressure ventilationNIV: noninvasive ventilationOR: odds ratioPDA: patent ductus arteriosusRDS: respiratory distress

syndromeROP: retinopathy of prematurity

REFERENCES

1. Stoll BJ, Hansen NI, Bell EF, et al; EuniceKennedy Shriver National Institute ofChild Health and Human DevelopmentNeonatal Research Network. Neonataloutcomes of extremely preterm infantsfrom the NICHD Neonatal ResearchNetwork. Pediatrics. 2010;126(3):443–456

2. Costeloe KL, Hennessy EM, Haider S,Stacey F, Marlow N, Draper ES. Shortterm outcomes after extreme pretermbirth in England: comparison of twobirth cohorts in 1995 and 2006 (theEPICure studies). BMJ. 2012;345:e7976

3. Morley CJ, Davis PG, Doyle LW, Brion LP,Hascoet JM, Carlin JB; COIN TrialInvestigators. Nasal CPAP or intubationat birth for very preterm infants. N EnglJ Med. 2008;358(7):700–708

4. Finer NN, Carlo WA, Walsh MC, et al;SUPPORT Study Group of the EuniceKennedy Shriver NICHD NeonatalResearch Network. Early CPAP versussurfactant in extremely preterm infants.N Engl J Med. 2010;362(21):1970–1979

5. Schmölzer GM, Kumar M, Pichler G, AzizK, O’Reilly M, Cheung PY. Non-invasiveversus invasive respiratory support inpreterm infants at birth: systematicreview and meta-analysis. BMJ. 2013;347:f5980

6. Davis PG, Henderson-Smart DJ. Nasalcontinuous positive airways pressureimmediately after extubation forpreventing morbidity in preterm infants.Cochrane Database Syst Rev. 2003; (2):CD000143

7. Kirpalani H, Millar D, Lemyre B, Yoder BA,Chiu A, Roberts RS; NIPPV Study Group. Atrial comparing noninvasive ventilationstrategies in preterm infants. N Engl JMed. 2013;369(7):611–620

8. Lemyre B, Davis PG, De Paoli AG,Kirpalani H. Nasal intermittent positivepressure ventilation (NIPPV) versusnasal continuous positive airwaypressure (NCPAP) for preterm neonatesafter extubation. Cochrane DatabaseSyst Rev. 2014;9:CD003212

9. Ward JJ. High-flow oxygenadministration by nasal cannula foradult and perinatal patients. RespirCare. 2013;58(1):98–122

10. Manley BJ, Owen L, Doyle LW, Davis PG.High-flow nasal cannulae and nasalcontinuous positive airway pressure use

in non-tertiary special care nurseries inAustralia and New Zealand. J PaediatrChild Health. 2012;48(1):16–21

11. Ojha S, Gridley E, Dorling J. Use of heatedhumidified high-flow nasal cannulaoxygen in neonates: a UK wide survey.Acta Paediatr. 2013;102(3):249–253

12. Nath P, Ponnusamy V, Willis K, Bissett L,Clarke P. Current practices of high andlow flow oxygen therapy andhumidification in UK neonatal units.Pediatr Int. 2010;52(6):893–894

13. Hochwald O, Osiovich H. The use of highflow nasal cannulae in neonatalintensive care units: Is clinical practiceconsistent with the evidence? J NeonatalPerinatal Med. 2010;3(3):187–191

14. Shetty S, Greenough A. Review findsinsufficient evidence to support theroutine use of heated, humidified high-flow nasal cannula use in neonates. ActaPaediatr. 2014;103(9):898–903

15. Lee JH, Rehder KJ, Williford L, Cheifetz IM,Turner DA. Use of high flow nasalcannula in critically ill infants, children,and adults: a critical review of theliterature. Intensive Care Med. 2013;39(2):247–257

16. Manley BJ, Dold SK, Davis PG, Roehr CC.High-flow nasal cannulae for respiratorysupport of preterm infants: a review ofthe evidence. Neonatology. 2012;102(4):300–308

17. Jobe AH, Bancalari E. Bronchopulmonarydysplasia. Am J Respir Crit Care Med.2001;163(7):1723–1729

18. Papile LA, Burstein J, Burstein R, KofflerH. Incidence and evolution ofsubependymal and intraventricularhemorrhage: a study of infants withbirth weights less than 1,500 gm. JPediatr. 1978;92(4):529–534

19. Bell MJ, Ternberg JL, Feigin RD, et al.Neonatal necrotizing enterocolitis.Therapeutic decisions based uponclinical staging. Ann Surg. 1978;187(1):1–7

20. Walsh MC, Kliegman RM. Necrotizingenterocolitis: treatment based onstaging criteria. Pediatr Clin North Am.1986;33(1):179–201

21. Manley BJ, Owen LS, Doyle LW, et al. High-flow nasal cannulae in very preterminfants after extubation. N Engl J Med.2013;369(15):1425–1433

PEDIATRICS Volume 136, number 3, September 2015 551 by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 11: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

22. Hozo SP, Djulbegovic B, Hozo I. Estimatingthe mean and variance from the median,range, and the size of a sample. BMCMed Res Methodol. 2005;5:13

23. Kotecha SJ, Edwards MO, Watkins WJ,et al. Effect of preterm birth on laterFEV1: a systematic review and meta-analysis. Thorax. 2013;68(8):760–766

24. Abdel-Hady H, Shouman B, Aly H. Earlyweaning from CPAP to high flow nasalcannula in preterm infants is associatedwith prolonged oxygen requirement:a randomized controlled trial. Early HumDev. 2011;87(3):205–208

25. Campbell DM, Shah PS, Shah V, Kelly EN.Nasal continuous positive airwaypressure from high flow cannula versusInfant Flow for Preterm infants. JPerinatol. 2006;26(9):546–549

26. Collins CL, Barfield C, Horne RS, Davis PG.A comparison of nasal trauma inpreterm infants extubated to eitherheated humidified high-flow nasalcannulae or nasal continuous positiveairway pressure. Eur J Pediatr. 2014;173(2):181–186

27. Collins CL, Holberton JR, Barfield C, DavisPG. A randomized controlled trial tocompare heated humidified high-flownasal cannulae with nasal continuouspositive airway pressure postextubationin premature infants. J Pediatr. 2013;162(5):949–954

28. de Jongh BE, Locke R, Mackley A, et al.Work of breathing indices in infants withrespiratory insufficiency receiving high-flow nasal cannula and nasal continuouspositive airway pressure. J Perinatol.2014;34(1):27–32

29. Iranpour R, Sadeghnia A, Hesaraki M.High-flow nasal cannula versus nasalcontinuous positive airway pressure inthe management of respiratory distresssyndrome. J Isfahan Med School. 2011;29(143):761–771

30. Klingenberg C, Pettersen M, Hansen EA,et al. Patient comfort during treatmentwith heated humidified high flow nasalcannulae versus nasal continuouspositive airway pressure: a randomisedcross-over trial. Arch Dis Child FetalNeonatal Ed. 2014;99(2):F134–F137

31. Lavizzari A, Veneroni C, Colnaghi M, et al.Respiratory mechanics during NCPAPand HHHFNC at equal distendingpressures. Arch Dis Child Fetal NeonatalEd. 2014;99(4):F315–F320

32. Miller SM, Dowd SA. High-flow nasalcannula and extubation success in thepremature infant: a comparison of twomodalities. J Perinatol. 2010;30(12):805–808

33. Phadtare R, Joshi R, Rajhans A, Patil S,Dominic S, Devaskar U. High flow nasalcannula oxygen (Vapotherm) inpremature neonates with respiratorydistress syndrome: is it better than theconventional nasal continuous positiveairway pressure (NCPAP)? Perinatology.2009;11(1):8

34. Roberts CT, Dawson JA, Alquoka E, et al.Are high flow nasal cannulae noisierthan bubble CPAP for preterm infants?Arch Dis Child Fetal Neonatal Ed. 2014;99(4):F291–F295

35. Saslow JG, Aghai ZH, Nakhla TA, et al.Work of breathing using high-flow nasalcannula in preterm infants. J Perinatol.2006;26(8):476–480

36. Sreenan C, Lemke RP, Hudson-Mason A,Osiovich H. High-flow nasal cannulae in themanagement of apnea of prematurity:a comparison with conventional nasalcontinuous positive airway pressure.Pediatrics. 2001;107(5):1081–1083

37. Woodhead DD, Lambert DK, Clark JM,Christensen RD. Comparing two methodsof delivering high-flow gas therapy bynasal cannula following endotrachealextubation: a prospective, randomized,masked, crossover trial. J Perinatol.2006;26(8):481–485

38. Yoder BA, Stoddard RA, Li M, King J,Dirnberger DR, Abbasi S. Heated,humidified high-flow nasal cannulaversus nasal CPAP for respiratorysupport in neonates. Pediatrics. 2013;131(5). Available at: www.pediatrics.org/cgi/content/full/131/5/e1482

39. Collins CL, Holberton JR, König K.Comparison of the pharyngeal pressureprovided by two heated, humidified high-flow nasal cannulae devices inpremature infants. J Paediatr ChildHealth. 2013;49(7):554–556

40. Kugelman A, Riskin A, Said W, Shoris I,Mor F, Bader D. A randomized pilot studycomparing heated humidified high-flownasal cannulae with NIPPV for RDS.Pediatr Pulmonol. 2015;50(6):576–583

41. Hough J, Shearman A, Jardine L.Humidified high flow nasal cannula inpreterm infants: a trial of randomisedflow rate on cardiorespiratory

parameters. In: Pediatric AcademicSocieties Annual Meeting; April 28–May1, 2012; Boston, MA

42. Hua C, McEwan A, Callander I. Hiflowcompared to CPAP from 30 weeksgestation at Liverpool hospital. JPaediatr Child Health. 2013;49:131[conference abstract]

43. Joshi RRA, Patil S, Dominic S, Phadtare R,Devaskar U. High flow oxygen in neonatalrespiratory failure: is it better than CPAP.In: Pediatric Academic Societies AnnualMeeting; May 3–6, 2008; Honolulu, HI

44. Lavizzari ACM, Mercadante D, Pierro M,Mosca F. High flow nasal cannula versusnasal CPAP in the management ofrespiratory distress syndrome:preliminary data. In: Pediatric AcademicSocieties Annual Meeting; May 3–7, 2013;Washington, DC

45. Nair G, Karna P. Comparison of theeffects of Vapotherm and nasal CPAP inrespiratory distress in preterm infants.In: Pediatric Academic Societies AnnualMeeting; May 14–17, 2005; Washington,DC

46. Ovalle OO, Gomez T, Troncoso G, PalaciosJ, Ortiz E. High flow nasal cannula aftersurfactant treatment for infantrespiratory distress syndrome inpreterm infants ,30 weeks. In: PediatricAcademic Societies Annual Meeting; May14–17, 2005; Washington, DC

47. Pyon KH, Aghai ZH, Nakhla TA, Stahl GE,Saslow JG. High Flow Nasal Cannula inPreterm Infants: Effects of High FlowRates on Work of Breathing. PediatricAcademic Society; 2008

48. Yang CY, Lien R, Yang PH, Chiang MC, ChuSM. Weaning of the ventilatory supportin VLBW infants: the role of peep, O2 flowand high flow air. In: 50th AnnualMeeting of the European Society forPaediatric Research; October 9–12, 2009;Hamburg, Germany

49. Newnam KM, McGrath JM, Estes T, JalloN, Salyer J, Bass WT. An integrativereview of skin breakdown in the preterminfant associated with nasal continuouspositive airway pressure. J ObstetGynecol Neonatal Nurs. 2013;42(5):508–516

50. Fischer C, Bertelle V, Hohlfeld J, Forcada-Guex M, Stadelmann-Diaw C, Tolsa JF. Nasaltrauma due to continuous positive airwaypressure in neonates. Arch Dis Child FetalNeonatal Ed. 2010;95(6):F447–F451

552 KOTECHA et al by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 12: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

51. Giaccone A, Jensen E, Davis P, Schmidt B.Definitions of extubation success in verypremature infants: a systematic review.Arch Dis Child Fetal Neonatal Ed. 2014;99(2):F124–F127

52. Roberts CT, Manley BJ, Dawson JA, DavisPG. Nursing perceptions of high-flownasal cannulae treatment for verypreterm infants. J Paediatr Child Health.2014;50(10):806–810

53. Dysart K, Miller TL, Wolfson MR, ShafferTH. Research in high flow therapy:

mechanisms of action. Respir Med. 2009;103(10):1400–1405

54. Numa AH, Newth CJ. Anatomic deadspace in infants and children. J ApplPhysiol (1985). 1996;80(5):1485–1489

55. Mündel T, Feng S, Tatkov S, Schneider H.Mechanisms of nasal high flow onventilation during wakefulness andsleep. J Appl Physiol (1985). 2013;114(8):1058–1065

56. Parke R, McGuinness S, Eccleston M.Nasal high-flow therapy delivers low

level positive airway pressure. Br JAnaesth. 2009;103(6):886–890

57. Li Y, Sepulveda A, Buchanan EP. Latepresenting nasal deformities after nasalcontinuous positive airway pressureinjury: 33-year experience. J PlastReconstr Aesthet Surg. 2015;68(3):339–343

58. Farley RC, Hough JL, Jardine LA.Strategies for the discontinuation ofhumidified high flow nasal cannula(HHFNC) in preterm infants. CochraneDatabase Syst Rev. 2015;6:CD011079

MEASURINGSCREAMS: Iwas recently at aplay I had seenbefore. I knew that itwassuspenseful and that soon a screamwould be heard. I was somewhat prepared but,nonetheless, the sudden piercing scream made me flinch. Around me, many in theaudience practically jumped from their seats and programs were sent flying. Thescene made me wonder why we all were so startled by the noise.According to The New York Times (Science: July 16, 2015), researchers have de-termined what makes us react to screams. Surprisingly, at least to me, it isn’tnecessarily the loudness,pitch,or shrillness thatmakesusreact. Scientistsanalyzingscreams in movies and those recorded in a laboratory found that during a scream,the loudness of the sound changes. During normal conversation, the loudness ofspeech rangesbetween4and5hertz. In a scream, the loudness can range from30 to150 hertz. Roughness, which describes how fast the loudness of a sound changes, isa critical component of what makes a scream alarming - or scary. The greater theroughness of the scream, the more alarming it is. Researchers have studied theeffects of screams on brain function using functional magnetic resonance imaging.Screams trigger activity in the amygdala, an area of the brain that registers andremembers fears. The greater the roughness of the scream, the greater the activitytriggered in the amygdala. Sounds in the environment associated with a lot ofroughness turnouttobethoseused inemergencyvehiclessuchasambulances.Whileambulance sirens were not necessarily designed with roughness in mind, they are,like the screamin theplay Iwaswatching, quiteattentiongetting -which, in the caseof getting out of the way of an oncoming ambulance, is a good thing to do.

Noted by WVR, MD

PEDIATRICS Volume 136, number 3, September 2015 553 by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 13: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

DOI: 10.1542/peds.2015-0738 originally published online August 17, 2015; 2015;136;542Pediatrics 

and Mallinath ChakrabortySarah J. Kotecha, Roshan Adappa, Nakul Gupta, W. John Watkins, Sailesh Kotecha

Meta-analysisSafety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A

ServicesUpdated Information &

http://pediatrics.aappublications.org/content/136/3/542including high resolution figures, can be found at:

Referenceshttp://pediatrics.aappublications.org/content/136/3/542#BIBLThis article cites 51 articles, 12 of which you can access for free at:

Subspecialty Collections

http://www.aappublications.org/cgi/collection/neonatology_subNeonatologysubhttp://www.aappublications.org/cgi/collection/fetus:newborn_infant_Fetus/Newborn Infantine_subhttp://www.aappublications.org/cgi/collection/evidence-based_medicEvidence-Based Medicinefollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtmlin its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or

Reprintshttp://www.aappublications.org/site/misc/reprints.xhtmlInformation about ordering reprints can be found online:

by guest on June 12, 2020www.aappublications.org/newsDownloaded from

Page 14: Safety and Efficacy of High-Flow Nasal Cannula Therapy in ...Safety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A Meta-analysis Sarah J. Kotecha, BSc, SRDa,

DOI: 10.1542/peds.2015-0738 originally published online August 17, 2015; 2015;136;542Pediatrics 

and Mallinath ChakrabortySarah J. Kotecha, Roshan Adappa, Nakul Gupta, W. John Watkins, Sailesh Kotecha

Meta-analysisSafety and Efficacy of High-Flow Nasal Cannula Therapy in Preterm Infants: A

http://pediatrics.aappublications.org/content/136/3/542located on the World Wide Web at:

The online version of this article, along with updated information and services, is

http://pediatrics.aappublications.org/content/suppl/2015/08/11/peds.2015-0738.DCSupplementalData Supplement at:

ISSN: 1073-0397. 60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

by guest on June 12, 2020www.aappublications.org/newsDownloaded from