nebulized hypertonic saline for acute bronchiolitis: a...

Nebulized Hypertonic Saline for AcuteBronchiolitis: A Systematic ReviewLinjie Zhang, MD, PhDa, Raúl A. Mendoza-Sassi, MD, PhDa, Terry P. Klassen, MDb, Claire Wainwright, MDc

abstractBACKGROUND AND OBJECTIVE: The mainstay of treatment for acute bronchiolitis remains supportivecare. The objective of this study was to assess the efficacy and safety of nebulized hypertonicsaline (HS) in infants with acute bronchiolitis.

METHODS: Data sources included PubMed and the Virtual Health Library of the Latin Americanand Caribbean Center on Health Sciences Information up to May 2015. Studies selected wererandomized or quasi-randomized controlled trials comparing nebulized HS with 0.9% salineor standard treatment.

RESULTS:We included 24 trials involving 3209 patients, 1706 of whom received HS. Hospitalizedpatients treated with nebulized HS had a significantly shorter length of stay compared withthose receiving 0.9% saline or standard care (15 trials involving 1956 patients; meandifference [MD] 20.45 days, 95% confidence interval [CI] 20.82 to 20.08). The HS group alsohad a significantly lower posttreatment clinical score in the first 3 days of admission (5 trialsinvolving 404 inpatients; day 1: MD 20.99, 95% CI 21.48 to 20.50; day 2: MD 21.45, 95% CI22.06 to 20.85; day 3: MD 21.44, 95% CI 21.78 to 21.11). Nebulized HS reduced the risk ofhospitalization by 20% compared with 0.9% saline among outpatients (7 trials involving 951patients; risk ratio 0.80, 95% CI 0.67–0.96). No significant adverse events related to HSinhalation were reported. The quality of evidence is moderate due to inconsistency in resultsbetween trials and study limitations (risk of bias).

CONCLUSIONS: Nebulized HS is a safe and potentially effective treatment of infants with acutebronchiolitis.

aFaculty of Medicine, Federal University of Rio Grande, Rio Grande, Brazil; bManitoba Institute of Child Health; Children’s Hospital Research Institute of Manitoba; Department of Pediatrics,University of Manitoba, Winnipeg, Canada; and cQueensland Children’s Medical Research Institute; Department of Respiratory and Sleep Medicine, Lady Cilento Children’s Hospital; School ofMedicine, University of Queensland, Brisbane, Australia

Dr Zhang conceptualized and designed the study, participated in trial selection, quality assessment, data collection and data analysis, and drafted the protocol and thereview article; Dr Mendoza-Sassi provided input for study design, critically reviewed the protocol and the review article, and participated in trial selection, qualityassessment, and data collection; Drs Klassen and Wainwright provided input for study design, and critically reviewed the protocol and review article; and all authorsapproved the final manuscript as submitted and agree to be accountable for all aspects of the work.

www.pediatrics.org/cgi/doi/10.1542/peds.2015-1914

DOI: 10.1542/peds.2015-1914

Accepted for publication Jul 24, 2015

Address correspondence to Linjie Zhang, MD, PhD, CNPq research fellow, Faculty of Medicine, Federal University of Rio Grande, Rua Visconde de Paranagua 102, Centro,Rio Grande-RS, Brazil 96200-190. E-mail: [email protected]; [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.

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Acute bronchiolitis in infancy, mainlycaused by respiratory syncytial virus(RSV), is the most common lowerrespiratory infection and the leadingcause of hospitalization in childrenyounger than 2 years. In the UnitedStates, acute bronchiolitis in infancyis responsible for ∼150 000hospitalizations each year at anestimated cost of $500 million.1,2

From 1992 to 2000, bronchiolitisaccounted for ∼1 868 000 emergencydepartment (ED) visits for childrenyounger than 2 years.3 In the UnitedKingdom, hospital admissions foracute bronchiolitis increased from21 330 in 2004 and 2005 to 33 472 in2010 and 2011.4

Globally, it has been estimated that,in 2005, at least 33.8 millionepisodes of RSV-associated acutelower respiratory infections (ALRIs)occurred in children younger than5 years, with incidence in developingcountries more than twice that ofindustrialized countries.5 In the sameyear, RSV-associated severe ALRIswere responsible for ∼3.4 millionhospitalizations and 66 000 to 199000 deaths in young childrenworldwide, with 99% of thesedeaths occurring in developingcountries.

Despite its high incidence andmorbidity, there are few effectivetherapies for acute bronchiolitis ininfancy, and the mainstay oftreatment remains supportive care.6,7

Given the theoretical effects ofhypertonic saline (HS) in reducingairway edema, unblocking mucusplugging, and improving mucociliaryclearance, HS administered vianebulizer has been proposed asa potentially effective therapy foracute bronchiolitis in infants.8 Thefirst randomized trial, published in2002, showed a significant effect ofnebulized 3% saline solution inimproving symptom scores among 65outpatients with acute bronchiolitis,as compared with 0.9% normal saline(NS).9 Over the past decades,a growing number of randomized

trials have been undertaken to assessthe effects and safety of nebulized HSin infants with acutebronchiolitis.10–19 The Cochranereview published in 2013 including11 randomized trials shows thatnebulized 3% saline may significantlyreduce the length of stay (LOS) inhospitalized infants with acutebronchiolitis and improve the clinicalseverity score (CSS) in bothoutpatient and inpatientpopulations.20 Since then, new trialswith conflicting results have beenpublished, and an updated synthesisof the literature is needed.21 Wedecided to conduct a new systematicreview of currently availablerandomized trials to assess theefficacy and safety of nebulized HS ininfants with acute bronchiolitis and toexplore possible reasons forinconsistent results across trials. Wehypothesize that nebulized HS may beless effective than previously claimedfor acute bronchiolitis and effect sizeof HS may mainly depend ondiagnostic accuracy of bronchiolitisand the treatment regimen.

METHODS

We followed the recommendations ofthe Preferred Reporting Items forSystematic Reviews and Meta-Analyses statement for writing thissystematic review and meta-analysis.22 The full review protocol isavailable in the supplementarymaterial. We used different datasources, search strategy, andstatistical techniques than that usedin the 2013 Cochrane review.20

Data Sources and Search Strategy

We searched PubMed and the VirtualHealth Library of the Latin Americanand Caribbean Center on HealthSciences Information (BIREME),which contains Medline, CENTRAL,LILACS, IBECS, and .20 otherdatabases (www.bireme.br). Alldatabases were searched frominception until May 2015. The searchstrategy on PubMed was as follows:(bronchiolitis OR “acute wheezing”

OR “respiratory syncytial virus” ORRSV OR “parainfluenza virus”) AND(“hypertonic saline” OR “salinesolution” OR 3% saline OR 5% salineOR saline). We used the limits ofstudy type: clinical trial, randomizedcontrolled trial (RCT). The searchstrategy on the Virtual Health Libraryof BIREME was as follows:bronchiolitis AND “hypertonic saline.”There was no restriction on languageof publication. We also conducteda search of the ClinicalTrials.gov trialsregistry to identify completed butunpublished trials. We checkedreference lists of all primary studiesand review articles for additionalrelevant trials.

Study Selection

To be included in this review, studieshad to meet all of the followingcriteria: (1) study design: RCTs orquasi-RCTs; (2) participants: infantsup to 24 months of age with diagnosisof acute bronchiolitis; we classifiedparticipants into “inpatients” whowere admitted to the hospital and“outpatients” who attended at anambulatory care unit or ED; (3)interventions and comparisons:nebulized HS ($3%) alone or mixedwith bronchodilator, compared withnebulized NS alone or mixed withsame bronchodilator, or standardtreatment; (4) outcome measures:primary outcomes included LOS inhospital for inpatients defined astime to actual discharge or time takento be ready for discharge, andadmission rate for outpatients, andsecondary outcomes included CSSs,rate of readmission to hospital orED, oxygen saturation, respiratoryrate, heart rate, time for theresolution of symptoms/signs,duration of oxygen supplementation,results of pulmonary function tests,radiologic findings, and adverseevents (AEs). We excluded studiesthat included patients who had hadrecurrent wheezing or wereintubated and ventilated, and studiesthat assessed pulmonary functionalone.

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Two review authors (RM and LZ)independently assessed the titles andabstracts of all citations identified bythe searches. We obtained the fullarticles when they appeared to meetthe inclusion criteria or there wereinsufficient data in the title andabstract to make a clear decision fortheir inclusion. The definitiveinclusion of trials was made afterreviewing the full-text articles. Weresolved any disagreements betweenthe 2 review authors about studyinclusion by discussion andconsensus.

Data Extraction and Management

One review author (LZ) extractedstudy details from the included trialsby using a standardized dataextraction form. These were checkedby another review author (RM). Weresolved any disagreements bydiscussion and consensus. Weextracted the following data: (1)study characteristics: year ofpublication, and country and settingof study; (2) methods: study design,methods of random sequencegeneration, allocation concealmentand blinding, and description ofwithdrawal; (3) participants: samplesize, age, gender, and inclusion andexclusion criteria; (4) interventionsand controls: concentration andvolume of saline, type of nebulizer,interval of administration, treatmentduration, and cointerventions; (5)outcomes: primary and secondaryoutcomes as described previously.For continuous outcomes, weextracted sample size, mean (median)and precision of measurements (SD,SE, 95% confidence interval [CI], orinterquartile range) of each treatmentarm. For dichotomous outcomes, weextracted number of events and totalnumber of participants of eachtreatment arm. We contacted theprincipal investigators of 5trials10,12,18,23,24 for methodologicaldetails and additional trial data, ofwhom 310,12,18 provided therequested data. We used Engaugedigitizing software (digitizer.

sourceforge.net) to extract the 25thand 75th percentiles of LOS inhospital from the figure of 1 paper.24

For 2 trials,24,25 we estimated meanand SD from median and interquartilerange of LOS in hospital by using themethod described by Wan et al.26

When the trial recruited multiplegroups, we combined them into HSand NS groups.14,15,17,24,27

Assessment of Risk of Bias

Two reviewers (RM and LZ)independently assessed the risk ofbias in included trials by examiningthe 6 key domains according to therecommendations of the CochraneCollaboration.28 We graded eachpotential source of bias as yes, no, orunclear, relating to whether thepotential for bias was low, high, orunknown. We resolved anydisagreements between the 2 reviewauthors by discussion and consensus.

Data Synthesis and StatisticalAnalysis

We performed meta-analysis forquantitative data synthesis wheneverthere were available data from theprimary studies. For continuousoutcomes, we used weighted meandifference (MD) between treatment

groups and 95% CI as the metrics ofeffect size. Dichotomous data weresynthesized by using risk ratios (RR)and 95% CIs as the effect measures.We used the random-effects modelfor meta-analyses.

We assessed heterogeneity in resultsbetween studies by using theCochrane Q test (P , .1 consideredsignificant) and the I2 statistic. The I2

statistic ranges from 0% to 100% andmeasures the degree of inconsistencyacross studies, with values of 25%,50%, and 75% corresponding to low,moderate, and high heterogeneity,respectively.29

We conducted a priori subgroupanalysis based on the treatmentregimen. We also conducted post hocsubgroup analyses according todiagnosis criteria for bronchiolitis(presence of wheeze as essentialdiagnostic criteria and availability ofvirological testing) and risk of bias inthe trials. We performed post hocsensitivity analyses excluding opentrials, trials in which mean and SDwere estimated from median andinterquartile range, trials with highrisk of attrition bias (withdrawal rate.20% or data obtained from a part ofstudy sample), and trials that did not

FIGURE 1Flow diagram of study selection.

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TABLE1

Characteristicsof

Included

Trials

StudyID

andCountry

Setting

InclusionCriteriaof

Participants

RSVPositivity

InterventionandControl

Treatm

entRegimen

Outcom

es

Al-Ansari2010,14

Qatar

Outpatient

(ED)

Infants#18

mowith

moderateto

severe

bronchiolitis,d

efinedas

aprodromal

historyof

viralRTI

followed

bywheezingand/or

crackles

andWangCSSof

$4.

56.1%

(96/171)

25mL3%

saline+1.5mgepinephrine

(n=58)

Salinesolutions

givenon

enrollm

entand

every4h

thereafter.

-Primary:WangCSSat

48h.

25mL5%


(n=57)

-Secondary:W

angCSSat

24and72

h,LOSin

ED,revisitto

ED,AEs.

25mL0.9%

saline+1.5mg

epinephrine(n

=56)

Anil2010,15Turkey

Outpatient

(ED)

Infants6wkto

24mowith

first

episodeof

bronchiolitis,definedby

symptom

sof

upperRTIand

presence

ofbilateralw

heezingand/

orcrackles

onauscultationand

WangCSSbetween1and9.

NA24mL3%


(n=39)

Salinesolutions

givenat

0and30

min.

-Primary:WangCSSat

0,30,60,

120min.

24mL0.9%

saline+1.5mg

epinephrine(n

=38)

-Secondary:SAO 2

inroom

airand

heartrate

at0,30,60and

120min,AEs.

23%

saline+2.5mgsalbutam

ol(n

=36)

24mL0.9%

saline+2.5mg

salbutam

ol(n

=36)

24mL0.9%

saline(n

=37)

Everard2014,4

EnglandandWales

Inpatient

Children,12

mowith

diagnosisof

bronchiolitisdefinedas

apparent

viralRTIw

ithairw

ayobstruction

(hyperinflation,tachypnea,and

subcostalrecession)

and

widespreadcrepitations,needing

O 2with

SaO 2

,92%.

84%

(179/212)

24mL3%

saline+standard

care

(n=

142)

HSgivenevery6huntil

primaryoutcom

eachieved.

-Primary:fitfordischarge(75%

ofusualintake

andSaO 2

$92%

for6hat

room

air).

-Standard

care

(n=149)

-Secondary:actual

timeto

discharge,

readmission

within

28dfrom

random

ization,healthcare

usage,

durationof

respiratorysymptom

spostdischarge,ITQoL,AEs.

Florin

2014,31USA

Outpatient

(ED)

Children,24

mowith

firstepisodeof

bronchiolitis,d

efinedas

first

episodeof

wheezingassociated

with

signsandsymptom

sof

upper

RTIand

respiratorydistress

measuredby

RDAIscorebetween4

and15.

NA24mL3%

saline(n

=31)

Onedose

ofsaline

solutions

givenat

0min.-Primary:RACS

at1hafterinhalation.

24mL0.9%

saline(n

=31)

-Secondaryoutcom

es:vitalsigns,

SaO 2,hospitalizationrate,physician

clinical

impression,parental

assessment,AEs.

Grew

al2009,13Canada

Outpatient

(ED)

Children6wkto

12mowith

diagnosis

ofbronchiolitis,d

efinedas

first

episodeof

wheezingandsymptom

sof

viralRTI,initial

SAO 2

85%–96%

andinitial

RDAI

score$4.

82.2%

(37/45)

22.5mL3%

saline+0.5mL2.25%

racemicepinephrine(n

=24)

Onedose

salinesolutions

givenat

0min.

-Primary:RACS

0–120min,changein

SAO 2

0–120min.

22.5mL0.9%

saline+0.5mL2.25%


=24)

-Secondary:admission

tohospital,

return

toED,AEs.

Ipek

2011,17Turkey

Outpatient

(ED)

Children,2ywith

historyof

precedingviralupperRTIfollowed

bywheezingandcrackles

onauscultationandWangCSSbetween

4and8.

NA24mL3%

saline+0.15

mg/kg

salbutam

ol(n

=30)

Salinesolutions

givenat

0,20,40min.

-Primary:WangCSS,useof

corticosteroid,hospitalization,

clinical

assessment48–72

h.24mL0.9%

saline+0.15

mg/kg

salbutam

ol(n

=30)

-Secondary:SAO 2,respiratory

rate,

heartrate.

24mL3%

saline(n

=30)

24mL0.9%

saline(n

=30)



TABLE1

Continued

StudyID

andCountry

Setting

InclusionCriteriaof

Participants

RSVPositivity


Treatm

entRegimen

Outcom

es

Jacobs

2014,32USA

Outpatient

(ED)

Children6wkto

,18

mowith


viralRTI

andfirstepisodeofwheezing,Wang

CSS$4andSaO 2

.85%.

60.3%

(41/68)

23mL7%

saline+0.5mL2.25%


=52)

Onedose

ofsaline

solutions

givenat

0min.-Primary:WangCSSbefore

andafter

treatm

entandat

disposition.

23mL0.9%

saline+0.5mL2.25%


=49)

-Secondary:hospitalizationrate,

proportionof

admitted

patients

discharged

at23

h,LOS,AEs.

Kuzik2007,12Abu

DhabiandCanada

Inpatient

Children#18

mowith

historyof

precedingviralu

pper

RTI,wheezing

orcrackles

onchestauscultation,

plus

either

SaO 2

of94%inroom

air

orsignificant

respiratorydistress

asmeasuredby

RDAI

score$4.

68.8%

(55/80)

24mL3%

saline(n

=47)

3dosesgivenevery2h,

followed

byevery4hfor

5doses,followed

byevery6huntil

discharge.

-Primary:LOSdefinedas

time

betweenstudyentryandtim

eat

which

theinfant

either

reached

protocol-defineddischargecriteria

(RDAIscore

,4andSaO 2

$95%in

room

airfor4h)

ordischarged

byattendingphysician,

whichever

camefirst.

24mL0.9%

saline(n

=49)

-Secondary:AEs.

Li2014,35China

Outpatient

(Ambulatory

care

unit)

Children2–18

mowith

firstepisodeof

bronchiolitis(WangCSS$4).

NA22mL3%

saline(n

=42)

Salinesolutions

giventwice

daily

for3d.

-Primary:WangCSS24,48,72

hafter

treatm

ent.

22mL5%

saline(n

=40)

-Secondary:AEs.

22mL0.9%

saline(n

=42)

Luo2010,18China

Inpatient

Wheezinginfantswith

mild

tomoderateviralbronchiolitis,

measuredby

WangCSS.

69.9%

(65/93)

24mL3%


ol(n

=50)

Salinesolutions

givenevery

8huntil

discharge.

LOS(discharge

decidedby

attending

physician),timeforresolutionof

wheezing,cough,pulmonarymoist

andcrackles,W

angCSS,AEs.

24mL0.9%

saline+2.5mg

salbutam

ol(n

=43)

Luo2011,19China

Inpatient

Children,24

mowith

firstepisodeof

wheezingdiagnosedas

moderateto

severe

bronchiolitisaccording

WangCSS.

73.2%

(82/112)

24mL3%

saline(n

=57)

3dosesgivenevery2h,

followed

byevery4hfor

5doses,followed

byevery6huntil

discharge.

LOS(discharge

decidedby

attending

physician),timeforresolutionof

wheezing,cough,pulmonarymoist

andcrackles,W

angCSS,AEs.

24mL0.9%

saline(n

=55)

Mandelberg2003,10

Israel

Inpatient

Children#12

mowith

clinical

presentationof

viralbronchiolitis,

temperature

.38°C

andSaO 2

$85%.

87%

(47/52)

24mL3%


(n=27)

Salinesolutions

givenevery

8huntil

discharge.

-Primary:LOS(discharge

decidedby

attendingphysician),W

angCSS.

24mL0.9%

saline+1.5mg

epinephrine(n

=25)

-Secondary:radiograph

score,AEs.

Miraglia

2012,16Italy

Inpatient

Childrenunder24

mowith

diagnosis

ofbronchiolitis,d

efinedas

first

episodeof

wheezingandclinical

symptom

sof

viralRTI,SAO 2

,94%

inroom

airandsignificant

respiratorydistress

measuredby

WangCSS.

82.1%

(87/106)

-?mL3%


(n=52)

Salinesolutions

givenevery

6h.

-Primary:LOSdefinedas

time

betweenstudyentryandtim

eof

discharge.

-?mL0·9%

saline+1.5mg

epinephrine(n

=54)

-Secondary:WangCSSon

each

treatm

entday.



TABLE1

Continued

StudyID

andCountry

Setting

InclusionCriteriaof

Participants

RSVPositivity


Treatm

entRegimen

Outcom

es

Ojha

2014,33Nepal

Inpatient

Children.6wkto

,24

mowith

first

episodeof


wheezingassociated

with

upperRTI,

tachypnea,increasedrespiratory

effort,clinical

scoringof

respiratorydistress

$4andSaO 2

$85%.

NA24mL3%

saline(n

=36)

Salinesolutions

givenevery

8huntil

discharge.

-Primary:LOScalculated

from

timeof

entryto

timeof

discharge(no

supplementalO 2,feeding

adequately,m

inimal

orabsent

ofwheezing,crackles,and

retractions,

S aO 2

$95%at

room

airfor4hand

severityscorewas

,4).

24mL0.9%

saline(n

=36)

-Secondary:durationof

supplemental

O 2,clinical

scores.

Pandit2013,34India

Inpatient

Children2–12

mowith

acute


short

historyof

coughwith

orwithout

fever,7dandfirstepisodeof

wheezing.

NA24mL3%

saline+1mLadrenaline(n

=51)

3dosesgivenevery1h,

followed

byevery6h

until

discharge.


criteria:

respiratoryrate

,60/m

in,w

ithout

retractions

andwheezing).

24mL0.9%

saline+1mLadrenaline

(n=49)

-Secondary:improvem

entin

RDAI

score,respiratoryrate,SaO

2,heart

rate,num

berof

addon

treatm

ent,

AEs.

Sarrel2002,9Israel

Outpatient

(Ambulatory

care

unit)

Children#24

mowith

clinical

presentationof

mild

tomoderate

bronchiolitisandSaO2

,96%.

80%

(52/65)

22mL3%

saline+5mgterbutaline

(n=33)

Salinesolutions

givenevery

8hfor5d.

-Primary:hospitalizationrate,W

ang

CSS.

22mL0.9%

saline+5mgterbutaline

(n=32)


score,AEs.

Sharma2012,23India

Inpatient

Children1–24

mowith

moderate

(WangCSS3–6)

acutebronchiolitis

definedas

firstepisodeofwheezing

with

prodromeof

upperRTI.

NA24mL3%


ol(n

=125)

Salinesolutions

givenevery

4huntil

discharge.

-Primaryoutcom

e:LOSdefinedas

timefrom

admission

toWangCSS

,3.

24mL0.9%

saline+2.5mg

salbutam

ol(n

=123)

-Secondary:WangCSS,AEs.

Tal2006,11Israel

Inpatient

Children#12

mowith

clinical

presentationof

viralbronchiolitis

leadingto

hospitalizationandSaO 2

$85%.

80%

(33/41)

24mL3%


(n=21)

Salinesolutions

givenevery

8huntil

discharge.


decidedby

attendingphysician),W

angCSS.

24mL0.9%

saline+1.5mg

epinephrine(n

=20)


score,AEs.

Teunissen2013,24The

Netherlands

Inpatient

Children0–24

mowith

moderateto

severe

(WangCSS$3)

bronchiolitis

definedas

upperRTIw

ithwheezing,

tachypnea,anddyspnea.

88%

(212/241)

24mL3%


ol(n

=84)

Salinesolutions

givenevery

8huntil

discharge.

-Primaryoutcom

e:LOSdefinedas

timebetweenthefirstdose

ofmedications

andclinicaldecision

todischarge(protocol-defined

dischargecriteria:no

supplemental

O 2,notube-feedingor

intravenous

fluids).

24mL6%


ol(n

=83)

-Secondary:transfer

toICU,

durationof

supplementalO 2

ortube-feeding,AEs.

24mL0.9%

saline+.·5

mg

salbutam

ol(n

=80)



use 0.9% saline as the control. Allmeta-analyses were performed byusing Stata version 11.0 (Stata Corp,College Station, TX).

RESULTS

Literature Search and StudySelection

The search strategy identified 97unique records from PubMed and 125records from BIREME. After screeningthe titles and abstracts, we retrieved26 potentially relevant full-textarticles for further evaluation. Fivearticles were excluded for reasonsshown in Fig 1. We obtained the datafrom clinical trials registry(ClinicalTrials.gov) to assess theeligibility of 3 completed butunpublished trials and all met theinclusion criteria. No additional trialswere found by checking the referencelists of primary studies and reviewarticles. Thus, a total of 24trials4,9–19,23–25,27,30–37 involving3209 patients were included in thereview. All but 2 trials14,35

contributed data to the meta-analyses.

Study Characteristics and Risk ofBias

Table 1 summarizes thecharacteristics of the 24 includedtrials. All studies were parallel-groupRCTs except 1 that was a quasi-RCT.17 The criteria for diagnosisof bronchiolitis were clearlydefined by 19 trials. Eighteentrials12–19,23,24,27,31–37 definedbronchiolitis as the first episode ofwheezing associated with viralrespiratory infection in children ,2years of age. In 1 trial,4 bronchiolitiswas defined as an apparent viralrespiratory tract infection associatedwith airways obstruction manifestby hyperinflation, tachypnea,and subcostal recession withwidespread crepitations onauscultation. Virologicalinvestigation was available in 13trials4,9–14,16,18,19,24,30,32 andthe positive rate for RSV variedTA

BLE1

Continued

StudyID

andCountry

Setting

InclusionCriteriaof

Participants

RSVPositivity


Treatm

entRegimen

Outcom

es

Tinsa2014,27Tunis

Inpatient

Children1to

12mowith

diagnosisof

bronchiolitis,d

efinedas

first

episodeof

wheezingassociated

with

acuteRTIand

Wangscore$3.

NA24mL5%

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=31)

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givenevery

4huntil

discharge.

-Primary:WangCSSat

30,60and120

min.

22mL5%

saline+2mLepinephrine

(n=37)

-Secondary::LOS

(discharge

criteria:

nosupplementalO 2,adequatefluid

intake,W

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24mL0.9%

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=26)

Wu2014,30USA

Outpatient

(ED)

Children,24

mowith

firstepisodeof

bronchiolitisduring

bronchiolitis

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62·2%(84/135)

24mL3%

saline(n

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20min

toamaximum

of3doses.Admitted

patients:every8huntil

discharge.

-Primary:admission

rate,LOS.

24mL0.9%

saline(n

=197)

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AIscore,need

for

supplementaltherapy,AEs.

NCT01276821,36

Nepal

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(ED)

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2ywith

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definedas

firstepisodeofwheezing

andWangCSSbetween1and9.

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(n=50)

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givenat

0,30

min.

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24mL0.9%

saline+1.5mg

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=50)

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,respiratoryrate,

heartrate

at30,60,120min,

transfer

toICU,dischargerate

after

120min,revisitto

EDwithin

1wk,

AEs.

NCT01488448,25

USA

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NA24mL3%

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24mL0.9%

saline(n

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within

30d,

transfer

toICU,

AEs.

NCT01238848,37

Argentina

Inpatient

Children1–24

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forfirst

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bronchiolitis,w

ithseverityscore$5andoxygen

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NA23mL3%

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23mL0.9%

saline+albuterol0.25

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(n=45)

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O 2,AEs.

ITQoL,Infant

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from 56% to 88%. Theconcentration of HS was definedat 3% in all but 5 trials, in which5%14,27,35 (n = 165), 6%24 (n = 83),and 7%32 saline (n = 52) wasused. Treatment regimen ofnebulized HS varied across studies,especially outpatient trials(Table 1).

All trials were double-blind except 3open trials,4,34,37 in whichperformance bias and detection biasmight occur (Supplemental Table 5).All trials but 117 were stated asrandomized; however, 11trials9–12,15,16,18,25,30,35,37 did notdescribe the methods for randomsequence generation and/orallocation concealment. Attributionbias might occur in 3 trials25,32,37

because of high and unbalancedwithdrawal rate after randomization.

Efficacy of Nebulized HS in Inpatients

LOS in Hospital

Among 14 inpatient trials,139–12,16,18,19,23–25,33,34,37 used LOSas the primary outcome and 127usedLOS as the secondary outcome. OneED trial30 involving 408 patientsprovided the data of LOS among 145hospitalized patients. We includedthe data of these 145 inpatients in themeta-analysis. The pooled results of15 trials with a total of 1956inpatients showed a statisticallysignificant shorter mean LOS amonginfants treated with HS comparedwith those treated with 0.9% salineor standard care (MD of 20.45 days,

95% CI 20.82 to 20.08, P = .01)(Fig 2). There was significantheterogeneity in results betweenstudies (I2 statistic = 82%). Thedata were suitable for conducting5 subgroup analyses (Table 2).Nine trials4,10–12,16,18,19,24,30 inwhich virological investigationwas available showed significanteffects of HS on reducing LOS,whereas 6 trials23,25,27,33,34,37 inwhich such testing was notavailable did not show significantbenefits (P = .02 for subgroupcomparison). The effect size ofHS on LOS appeared to be greaterin trials10–12,16,18,25,30,37 withunclear or high risk of selection bias,compared with trials4,19,23–25,27,33

with low risk of selection bias.

FIGURE 2Effects of nebulized HS on reduction of LOS among inpatients.


http://pediatrics.aappublications.org/lookup/suppl/doi:10.1542/peds.2015-1914/-/DCSupplemental


However, the difference betweensubgroups was not statisticallysignificant.

Four sensitivity analyses, excluding 2trials24,25 with estimated mean andSD of LOS, 3 trials25,33,37 with highrisk of attrition bias, 2 open trials,4,34

and 1 trial4 that did not use 0.9%saline as the control, did notsignificantly affect the results of themeta-analysis.

Improvement in CSSs

Eleven inpatient trials usedbronchiolitis severity scores asoutcome measure. Two trials12,34

used Respiratory Distress AssessmentInstrument (RDAI)38 scores based onwheezing and retractions, but 112 didnot report the results and the other34

reported RDAI scores only on day 1 ofadmission. One trial33 used a clinicalscore based on respiratory rate,wheezing, retractions, and oxygensaturation. This trial did not finda significant difference between HSand NS groups in clinical scoresthrough day 1 to day 4 of admission.All the remaining 8 trials used Wang’sclinical scores,39 grading respiratoryrate, wheezing, retractions, and

general condition from 0 to 3.However, only 5 trials10,11,16,18,19

with a total of 404 patients providedsuitable data for the meta-analysis,showing a significant effect of HS inimproving clinical scores on day 1(MD of 20.99, 95% CI 21.48 to20.50, P , .0001, I2 statistic = 67%),day 2 (MD of 21.45, 95% CI 22.06 to20.85, P , .0001, I2 statistic = 79%),and day 3 of admission (MD of 21.44,95% CI 21.78 to 21.11, P , .0001, I2

statistic = 53%).

Other Efficacy Outcomes

Three trials24,33,37 used duration ofin-hospital oxygen supplementationas efficacy outcome. Other efficacyoutcomes used by at least 1 trialincluded duration of tube feeding,time for the resolution of respiratorysymptoms and signs, radiographscores, measurement of respiratoryrate, heart rate and oxygensaturation, readmission within 28days from randomization, and infantand parental quality-of-lifequestionnaire. Two trials18,19

reported a shorter duration ofrespiratory symptoms and signs(cough, wheezing, and crackles) inpatients treated with HS compared

with those receiving NS. None of thetrials showed significant effects of HSon other previously mentionedoutcomes.

Efficacy of Nebulized HS inOutpatients

Admission Rate

Seven outpatient trials with a total of951 patients assessed the efficacy ofnebulized 3% saline on reducing therisk of hospitalization. The pooled RRwas 0.80 (95% CI 0.67–0.96, P = .01)(Fig 3). There was no significantheterogeneity in results betweenstudies (I2 statistic = 2%). The datawere available for conducting 4subgroup analyses (Table 2). Theeffect size of HS on the risk ofhospitalization was significantlygreater in trials9,13,30,32 in whichvirological investigation was availableand in trials9,17,30 in which multipledoses ($3) of saline solutions wereadministered, compared withtrials15,17,31 in which virologicaltesting was not available andtrials13,15,31,32 by using only 1 to 2doses of saline solutions, respectively.Four trials9,15,17,30 with unclear orhigh risk of selection bias showed

TABLE 2 Subgroup Analyses on LOS (Inpatients) and Admission Rate (Outpatients)

Subgroups LOS, d Admission rate, %

Trial, n Patients,n

Effect Size:MD (95% CI)

SubgroupComparison,a

P Value

Trial, n Patients,n

Effect Size:RR (95% CI)

SubgroupComparison,a

P Value

Virological investigation .02 .06Available 9 1183 20.74 (21.32 to 20.16) 4 620 0.71 (0.58–0.88)Not available 6 773 0.01 (20.17–0.19) 3 331 1·04 (0.75–1.44)

Wheeze as diagnostic criteria .42 —

Yes 11 1427 20.40 (20.84–0.04) 5 478 0.92 (0.72–1.16)No 1 291 20.03 (20.80–0.74) 0 0 —

HS mixed withbronchodilatorb

.80 .71

Yes 9 1019 20.42 (20.89–0.05) 5 481 0.76 (0.55–1.06)No 7 937 20.52 (21.18–0.14) 2 470 0.85 (0.52–1.40)

Treatment regimenc .79 .07A 6 840 20.52 (21.14–0.09) 4 358 0.93 (0.73–1.20)B 9 1116 20.41 (20.93–0.10) 3 593 0.67 (0.52–0.87)

Selection bias .31 .13Low 7 1151 20.26 (20.82–0.30) 3 209 0.91 (0.68–1.23)Unclear/high 8 805 20.65 (21.14 to 20.15) 4 742 0.68 (0.52–0.87)

a Subgroup comparison using x2 test (degrees of freedom = 1) with P , .1 considered as statistically significant.b One trial had 2 interventions compared with NS: HS mixed with epinephrine and HS alone. We included 2 comparisons, splitting the number of NS group in half for each comparison.c For inpatients: regimen A, every 4 h or 3 initial doses given every 1–2 h followed by every 4–6 h; regimen B, every 6–8 h. For outpatients: regimen A, 1 to 2 doses; regimen B, multipledoses ($3).



significant effects of HS on reducingthe risk of hospitalization, whereas 3trials13,31,32 with low risk of selectionbias did not show significant benefitsof HS; however, the differencebetween subgroups was notstatistically significant.

Improvement in CSSs

All 10 outpatient trials usedbronchiolitis severity scores as theoutcome measure. Variation inscoring methods and time points ofassessment makes it inappropriate toconduct meta-analyses. Thus, wenarratively summarized the mainresults of 9 trials in terms of effects ofHS on improving clinical scores(Table 3). These trials did not showsignificant effects of nebulized HS inimproving clinical scores, except 3 ofthe trials. One9 showed significant

benefits of 3% saline compared withNS on each of 3 treatment days, thesecond14 showed consistent trendfavoring 5% saline compared with3% and 0.9% saline solutions from 8to 72 hours after randomization, andthe third34 showed the superiority ofboth 5% and 3% saline solutions overNS on each of 3 treatment days, butno significant difference was foundbetween 5% and 3% saline groups.

Rate of Readmission to Hospital or ED

Five outpatient trials reported therate of readmission to hospital and/or the ED 24 hours to 1 week afterdischarge. The meta-analysis did notshow significant effects of HS inreducing the risk of readmission tohospital (4 trials13–15,31 with 428patients, RR of 1.45, 95% CI0.67–3.14, P = .34, I2 statistic = 1%)

and to ED (5 trials13–15,31,36 with 523patients, RR of 0.78, 95% CI0.46–1.32, P = .36, I2 statistic = 29%).

Other Efficacy Outcomes

Oxygen saturation was used as anefficacy outcome by 4 trials.13,15,17,31

Other efficacy outcomes used by atleast 1 trial included duration ofoxygen supplementation,measurement of respiratory rate andheart rate, radiograph scores, andparental perception of improvement.None of the trials showed beneficialeffects of HS on previously mentionedoutcomes.

Safety of Nebulized HS

Of 24 trials included in this review, 21reported safety data among 2897participants, 1557 of whom receivedHS (3% saline: n = 1257; 5% saline:

FIGURE 3Effects of nebulized HS on reducing the risk of hospitalization among outpatients.



n = 165; 6% saline: n = 83; 7%saline: n = 52). Fourteentrials9–11,14,15,18,23,25,27,31,32,34,36,37

did not find any significant AEsamong a total of 1548 participants,of whom 828 received nebulized HS(mixture with bronchodilators: n =673, 81.3%; HS alone: n = 155,18.7%). In the remaining 7trials4,12,13,19,24,30,35 involving 1324participants of whom 729 receivednebulized HS (mixture withbronchodilators: n = 190, 26%; HSalone: n = 539, 74%), at least 1 AEwas reported. Variation in reportingand in outcomes precluded thepossibility of conducting meta-analysis of safety data. We

narratively summarized the safetydata of 7 trials (Table 4). VariousAEs were reported in both HS andcontrol groups. In most of cases, AEswere mild and resolvedspontaneously. Only 1 inpatient trial4

involving 142 patients receiving 3%saline alone without bronchodilatorreported 1 serious AE (bradycardiaand desaturation) possibly related toHS inhalation but resolved thefollowing day.

DISCUSSION

This new systematic review andmeta-analysis shows a modest butstatistically significant benefit of

nebulized 3% saline in reducingLOS in infants hospitalized for acutebronchiolitis. The review alsoshows that nebulized HS couldreduce the risk of hospitalization by20% compared with normalsaline among outpatients withbronchiolitis.

The results of this new reviewconfirmed our hypothesis thatnebulized HS may be less effectivethan previously claimed for infantswith acute bronchiolitis. The effectsize of nebulized HS on reducingLOS in hospitalized patients shownby the present review is onlyapproximately one-third of thatshown by the 2013 Cochranereview,20 which included 6 inpatienttrials involving 500 patients (MD21.15 days, 95% CI 21.49 to 20.82days). It is interesting to note thatall 8 trials4,23–25,27,30,33,34 publishedin 2013 and thereafter, including 2European multicenter studies4,24

with relatively large sample size, didnot find significant effects ofnebulized HS on LOS amonginpatients with bronchiolitis. Foroutpatients, this new review showeda 20% reduction on the risk ofhospitalization associated withnebulized HS in contrast witha 37% non–statistically significantreduction shown by the 2013Cochrane review,20 which included4 outpatient trials involving 380participants (RR 0.63, 95% CI0.37–1.07).

We conducted subgroup analyses toexplore potential effect modifiers andsources of heterogeneity in theresults across studies. We found thattrials in which virologicalinvestigation was available showeda significantly greater effect size ofnebulized HS than trials without suchtesting in both inpatients andoutpatients, measured by reduction ofLOS and risk of hospitalization. Thesedata suggest that diagnostic accuracyof bronchiolitis may affect thetreatment outcomes with HS. Thenumber and frequency of saline

TABLE 3 Narrative Summary of the Main Findings of 10 Outpatient Trials in Terms of Effects of HSon Improving Clinical Scores

Trial Scoring Methods Main Findings

Al-Ansari 201014 Wang score - Mean scores (SD) 24 h after randomization: 5% saline vs 0.9%saline: 3.75 (1.27) vs 3.97 (1.40), P . .05; 3% saline vs 0.9%saline: 4.0 (0.98) vs 3.75 (1.27), P . .05.

- Mean scores (SD) 48 h after randomization: 5% saline vs 0.9%saline: 3.69 (1.09) vs 4.12 (1.11), P = .04; 3% saline vs 0.9%saline: 4.0 (1.22) vs 4.12 (1.11), P . .05.

- Consistent trend favoring 5% saline from 8 to 72 h afterrandomization.

Anil 201015 Wang score There was no significant difference between 3% and 0·9%saline groups in terms of clinical scores at 30, 60, and120 min of assessment.

Florin 201431 RDAI score - Mean RDAI scores (95% CI) 1 h after saline administration: 3%saline vs 0.9% saline: 6.6 (5.5–7.6) vs 5.1 (4.1–6.2), P = .05.

- Mean RACS scores (95% CI) 1 h after saline administration:3% saline vs 0.9% saline: 21.5 (23.1–0.2) vs 24.0(25.3 to 22.7), P = .01.

Grewal 200913 RDAI score Mean RACS scores (95% CI) from 0 to 120 min: 3% saline vs0.9% saline: 4.39 (2.64–6.13) vs 5.13 (3.71–6.55), P . .05.

Ipek 201117 Wang score There was no significant difference between 3% and 0.9%saline groups in terms of clinical scores at 60 min ofassessment.

Jacobs 201432 Wang score - Mean change in scores (SD) at ED disposition: 7% salinevs 0.9% saline: 2.6 (1.9) vs 2.4 (2.3), P = .21.

- Mean change in scores (SD) after first nebulization in EDdisposition: 7% saline vs 0.9% saline: 2.06 (1.7) vs 2.0 (1.9),P = .06.

Li 201435 Wang score Median scores (interquartile range): 5%, 3% vs 0.9% saline.224 h after treatment: 6 (1), 6 (1) vs 7 (1); P , .05(5% vs 0.9%; 3% vs 0.9%).

248 h after treatment: 5 (1), 5 (1) vs 6 (0.2), P , .05(5% vs 0.9%).

272 h after treatment: 3.5 (1), 4 (1) vs 7 (0), P , 0·05(5% vs 0.9%; 3% vs 0.9%).

Sarrell 20029 Wang score Mean scores differed significantly, in favor of 3% salinecompared with 0.9% saline, on each of the treatment days.

Wu 201430 RDAI score Mean scores (SD): 3% saline vs 0.9% saline: 5.32 (3.14) vs 4.88(2.95), P . .05.

NCT 0127682136 Wang score Mean change in scores (SD) after 2 sessions of nebulization:3% saline vs 0.9% saline: 3.52 (1.41) vs 2.26 (1.15)



inhalations may also appear toinfluence the effect size of HS. Trialsundertaken in an outpatient setting inwhich multiple doses ($3) of salinesolutions were administrated showeda significantly greater reduction onthe risk of hospitalization comparedwith trials that used 1 to 2 doses ofsaline solutions. However, for

inpatients, no significant differencewas observed in reduction of LOSbetween trials that used morefrequent saline inhalations (3 initialdoses given every 1–2 hours,followed by every 4–6 hours) andthose in which saline solutions weregiven every 6 to 8 hours. Anotherfactor that could possibly influence

the effect size of HS was risk ofselection bias. Trials with unclear orhigh risk of selection bias showedsignificant effects of HS on reducingLOS and risk of hospitalization,whereas trials with low risk ofselection bias did not show significantbenefits of HS on these outcomes.This does cast some doubt on theoverall effect estimates of HS;however, the difference betweensubgroups was not statisticallysignificant. A tight seal betweenthe mask and the infant’s face iscrucial for an effective drug deliverywith nebulizer.40 The performanceof the nebulizer may also affectdrug delivery.41 Thus, variability indrug delivery could be consideredone of the potential sources ofheterogeneity across studies;however, lack of data from primarystudies did not allow us to includethis important factor for subgroupanalyses.

Clinical score is generally considereda relatively objective measure toassess the severity of illness. Eleveninpatient trials used bronchiolitisseverity scores as the efficacyoutcome, but only 5 trials that usedWang’s clinical scores providedsuitable data for meta-analysis. Thepooled results of these 5 trialsshowed a significant effect of HS inimproving clinical scores through day1 to day 3 of admission. However,the inability to include another 6inpatient trials in the meta-analysismay have affected the results of theanalysis. Seven of 10 outpatient trialsdid not show significant effects ofnebulized HS in improving clinicalscores.

Potential adverse effects ofintervention with nebulized HS, suchas acute bronchospasm, remaina potential concern. In this review,there were 14 trials involving 828patients receiving nebulized HS thatdid not report any significant AEs. In81.3% of these patients, salinesolutions were mixed withbronchodilators. In contrast, there

TABLE 4 Narrative Summary of AEs of Treatment Reported by 7 Trials

Trial HS (n) vs Controls (n) Main Findings

Everard 20144 3% saline (n = 142) vsstandard care (n = 143)

Six AEs were possibly related to salinetreatment, including 1 serious AE (SAE),bradycardia and desaturation, whichresolved the following day.The remaining 5 non-SAEs were bradycardia(self-correcting), desaturation, coughing fit,and increased respiratory rate (all ofwhich were resolved within 1 d), and achest infection that resolved after 6 d.

Grewal 200913 3% saline + epinephrine(n = 23) vs 0.9% saline +epinephrine (n = 23)

AEs were noted in 4 infants (vomiting, 3;diarrhea, 1); all were enrolled in the HSgroup. No additional bronchodilators weregiven to any enrolled patient during thestudy period.

Kuzik 200712 3% saline (n = 47) vs 0.9%saline (n = 49)

No infants were withdrawn by the medicalstaff due to AEs, although 5 infants werewithdrawn at parents’ request because ofperceived AEs, only 2 from the HS group,of whom 1 presented with vigorouscrying and another with agitation.

Li 201435 5% saline (n = 40), 3% saline(n = 42) vs 0.9% saline(n = 42)

No AEs were observed in the 3% and 0.9%saline groups. Four patients from the 5%saline group presented with paroxysmalcough during saline inhalation.

Luo 201119 3% saline (n = 57) vs 0.9%saline (n = 55)

No infants were withdrawn by the medicalstaff because of AEs. Coughing andwheezing never worsened during salineinhalation, although 5 infants had hoarsevoices, only 2 from the HS group, and thesymptom disappeared after 3–4 d.

Teunissen 201424 3%, 6% saline + salbutamol(n = 167) vs 0.9% +salbutamol (n = 80)

A substantial number of AEs (eg, cough,bronchospasm, agitation, desaturation)were noted in all treatment groups. Exceptfor cough, which occurred significantlymore in the HS groups (P = .03), nodifferences were found between groups.Withdrawals due to AEs did not differbetween groups (4.3%, 6.1% and 7.9%in the 3%, 6% and 0.9% saline groups,respectively, P = .59).

Wu 201430 3% saline (n = 211) vs 0.9%saline (n = 197)

Three patients in the NS group and 4 in theHS group withdrew owing to parent request.Of these parent requests, 1 in the NS groupand 2 in the HS group were attributed toworsening cough. For these 3 patients,pretreatment and posttreatment vital signsand RDAI score were the same or improved,and no intervention or additional treatmentwas necessary.



were 7 trials involving 729 patientstreated with nebulized HS of which74% received HS alone and reportedat least 1 AE. Most AEs were mildand resolved spontaneously. Theseresults suggest that nebulized HS isa safe treatment in infants withbronchiolitis, especially whenadministered in conjunction witha bronchodilator.

This systematic review includedtrials conducted in both high-incomeand low-income countries and indifferent settings (inpatient,ambulatory care unit, and ED). Thus,evidence derived from the reviewmay have a wide applicability.However, the quality of evidencecould be graded only as moderate,mainly due to inconsistency in theresults between studies and risk ofbias in some trials, according tothe Grading of Recommendations,Assessment, Development andEvaluations (GRADE) criteria.42

Moreover, all but 3 trials excludedpatients requiring mechanicalventilation, intensive care, or havingan oxygen saturation reading ,85%on room air, so caution should betaken when extrapolating thefindings of this review to infantswith more severe bronchiolitis. Theunderlying airway pathologicchanges may vary between infantswith different severity ofbronchiolitis, so different responsesto treatments with HS may beexpected in more severe cases. Theresults of meta-analysis for effectsof HS on clinical scores amonginpatients may be biased becauseonly 5 of 11 trials measuring thisoutcome were included in theanalysis. The number of trials andpatients in outpatient settings islimited, and 1 trial30 witha relatively large sample size hascontributed 43% of weight to theoverall summary estimate of effectsof HS on reduction of risk ofhospitalization. All but 1 trial4 usedNS as the comparison. The use of NSallows the trial to be double-blind;however, NS is not technically

a placebo, as high-volume NSinhalation could potentially havephysiologic effects by improvingairway mucociliary clearance, whichmay have beneficial effects on acutebronchiolitis.8 Use of NS as thecontrol may tend to minimize theeffect size of HS.

In conclusion, this new systematicreview shows that nebulized HS isassociated with a mean reductionof 0.45 days (∼11 hours) in LOSamong infants admitted for acutebronchiolitis and a mean reduction of20% in the risk of hospitalizationamong outpatients. This reviewalso suggests that nebulized HS isa safe treatment in infants withbronchiolitis, especially whenadministered in conjunction witha bronchodilator. Given the highprevalence of bronchiolitis in infantsand huge burden on health caresystems throughout the world,benefits of nebulized HS shown bythis review, even though smaller thanpreviously estimated, may still beconsidered clinically relevant.Moreover, good safety profile and lowcost make nebulized HS a potentialattractive therapeutic modality forbronchiolitis in infants. However,further large multicenter trials arestill warranted to confirm benefits ofnebulized HS in both inpatients andoutpatients with bronchiolitis, giventhe limited number of available trials,the small sample sizes of mostprevious trials, and conflicting resultsacross studies. Further trialsshould use the most widely acceptedclinical criteria and virologicalinvestigation for diagnosis ofbronchiolitis. When LOS in hospitaland admission rate are used asthe primary efficacy outcomes,well-defined admission and dischargecriteria should be used. Multipledoses of saline inhalations shouldbe administered in outpatients;however, the optimal treatmentregimen of nebulized HS for infantswith bronchiolitis remains to bedetermined by further trials in bothinpatients and outpatients.

ABBREVIATIONS

AEs: adverse eventsALRIs: acute lower respiratory

infectionsBIREME: Latin American and

Caribbean Center onHealth SciencesInformation

CI: confidence intervalCSS: clinical severity scoreED: emergency departmentGRADE: Grading of

Recommendations,Assessment, Developmentand Evaluations

HS: hypertonic salineLOS: length of stayMD: mean differenceNS: normal salineRACS: respiratory assessment

change scoreRCTs: randomized controlled trialsRDAI: respiratory distress

assessment instrumentRR: risk ratioRSV: respiratory syncytial virusRTI: respiratory tract infection

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BACON FROMTHE SEA: Recently, a friend prepared lunch forme. He toasted somebread and then layered tomatoes, lettuce, and some dried leaves he had briefly panfried. The sandwich was delicious, but what really surprised me was that thesandwichtasted just likeabacon, lettuce,andtomatosandwich–withoutanybacon.When I asked him what gave the sandwich the bacon flavor, he responded witha smile, “seaweed”.As reported in Bon Appetit (Test Kitchen: July 30, 2015), the type of seaweed myfriend was referring to is called “dulse.” Dulse is an edible seaweed, much like noriand kelp, which looks like leafy red lettuce and is packed with fiber, protein, andminerals. It growswild on the northern Atlantic and Pacific coasts, and is harvestedat low tide from early summer to early fall. Dulse is usually immediately dried andsold either in whole leaf or powder form. Fresh dulse tastes a bit salty and hasmineral overtones suggestive of the ocean fromwhich it came,while dried dulse cantake on a variety of flavors. However, when pan-fried, whole-leaf dulse becomessmoky and savory, and tastes remarkably similar to bacon.I like to cook with bacon, andwill have to try pan-fried dulse in some of my tomato-based dishes to see if I can get the same undertones without the fat of bacon.

Noted by WVR, MD



DOI: 10.1542/peds.2015-1914 originally published online September 28, 2015; 2015;136;687Pediatrics

Linjie Zhang, Raúl A. Mendoza-Sassi, Terry P. Klassen and Claire WainwrightNebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review

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Zhang et al, Nebulized Hypertonic Saline for Acute Bronchiolitis: A SystematicReview. Pediatrics. 2015;136(4):687–701; doi:10.1542/peds.2015-1914.

An error occurred in the article by Zhang et al, titled “Nebulized Hypertonic Salinefor Acute Bronchiolitis: A Systematic Review” published in the October 2015 issueof Pediatrics (2015;136[4]:687–701; doi:10.1542/peds.2015-1914).

On page 689, under Data Synthesis and Statistical Analysis, paragraph 3, on lines14–15, “withdrawal rate .20%” should have read: “withdrawal rate .15% andintention-to-treat analysis not used.”

The authors also note that they erroneously included 1 unpublished inpatient trial(NCT01488448) that included patients with previous wheeze. Removal of this trialfrom the meta-analysis changes the results of hypertonic saline on length of stayfrom an MD of –0.45 days (95% confidence interval 20.82 to 20.08) to MD of –0.51days (95% confidence interval 20.91 to 20.11). Exclusion of this trial from thesubgroup analyses does not significantly affect the results.

doi:10.1542/peds.2016-0017

ERRATUM

PEDIATRICS Volume 137, Number 4, April 2016 1

ERRATUM

DOI: 10.1542/peds.2015-1914 originally published online September 28, 2015; 2015;136;687Pediatrics

Linjie Zhang, Raúl A. Mendoza-Sassi, Terry P. Klassen and Claire WainwrightNebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review

http://pediatrics.aappublications.org/content/136/4/687located on the World Wide Web at:

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

http://pediatrics.aappublications.org//content/137/4/e20160017.full.pdf An erratum has been published regarding this article. Please see the attached page for:

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

by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from

http://pediatrics.aappublications.org/content/136/4/687

http://pediatrics.aappublications.org//content/137/4/e20160017.full.pdf


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