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.
PEDIATRICS Volume 136, number 4, October 2015 REVIEW ARTICLE by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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.
688 ZHANG et al by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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.
PEDIATRICS Volume 136, number 4, October 2015 689 by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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%
saline+1.5mgepinephrine
(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%
saline+1.5mgepinephrine
(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%
racemicepinephrine(n
=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)
690 ZHANG et al by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
TABLE1
Continued
StudyID
andCountry
Setting
InclusionCriteriaof
Participants
RSVPositivity
InterventionandControl
Treatm
entRegimen
Outcom
es
Jacobs
2014,32USA
Outpatient
(ED)
Children6wkto
,18
mowith
bronchiolitisdefinedas
viralRTI
andfirstepisodeofwheezing,Wang
CSS$4andSaO 2
.85%.
60.3%
(41/68)
23mL7%
saline+0.5mL2.25%
racemicepinephrine(n
=52)
Onedose
ofsaline
solutions
givenat
0min.-Primary:WangCSSbefore
andafter
treatm
entandat
disposition.
23mL0.9%
saline+0.5mL2.25%
racemicepinephrine(n
=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%
saline+2.5mgsalbutam
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%
saline+1.5mgepinephrine
(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%
saline+1.5mgepinephrine
(n=52)
Salinesolutions
givenevery
6h.
-Primary:LOSdefinedas
time
betweenstudyentryandtim
eof
discharge.
-?mL0·9%
saline+1.5mg
epinephrine(n
=54)
-Secondary:WangCSSon
each
treatm
entday.
PEDIATRICS Volume 136, number 4, October 2015 691 by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
TABLE1
Continued
StudyID
andCountry
Setting
InclusionCriteriaof
Participants
RSVPositivity
InterventionandControl
Treatm
entRegimen
Outcom
es
Ojha
2014,33Nepal
Inpatient
Children.6wkto
,24
mowith
first
episodeof
bronchiolitisdefinedas
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
bronchiolitisdefinedas
short
historyof
coughwith
orwithout
fever,7dandfirstepisodeof
wheezing.
NA24mL3%
saline+1mLadrenaline(n
=51)
3dosesgivenevery1h,
followed
byevery6h
until
discharge.
-Primary:LOS(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)
-Secondary:radiograph
score,AEs.
Sharma2012,23India
Inpatient
Children1–24
mowith
moderate
(WangCSS3–6)
acutebronchiolitis
definedas
firstepisodeofwheezing
with
prodromeof
upperRTI.
NA24mL3%
saline+2.5mgsalbutam
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%
saline+1.5mgepinephrine
(n=21)
Salinesolutions
givenevery
8huntil
discharge.
-Primary:LOS(discharge
decidedby
attendingphysician),W
angCSS.
24mL0.9%
saline+1.5mg
epinephrine(n
=20)
-Secondary:radiograph
score,AEs.
Teunissen2013,24The
Netherlands
Inpatient
Children0–24
mowith
moderateto
severe
(WangCSS$3)
bronchiolitis
definedas
upperRTIw
ithwheezing,
tachypnea,anddyspnea.
88%
(212/241)
24mL3%
saline+2.5mgsalbutam
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%
saline+2.5mgsalbutam
ol(n
=83)
-Secondary:transfer
toICU,
durationof
supplementalO 2
ortube-feeding,AEs.
24mL0.9%
saline+.·5
mg
salbutam
ol(n
=80)
692 ZHANG et al by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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
InterventionandControl
Treatm
entRegimen
Outcom
es
Tinsa2014,27Tunis
Inpatient
Children1to
12mowith
diagnosisof
bronchiolitis,d
efinedas
first
episodeof
wheezingassociated
with
acuteRTIand
Wangscore$3.
NA24mL5%
saline(n
=31)
Salinesolutions
givenevery
4huntil
discharge.
-Primary:WangCSSat
30,60and120
min.
22mL5%
saline+2mLepinephrine
(n=37)
-Secondary::LOS
(discharge
criteria:
nosupplementalO 2,adequatefluid
intake,W
angCSS,3),AEs.
24mL0.9%
saline(n
=26)
Wu2014,30USA
Outpatient
(ED)
Children,24
mowith
firstepisodeof
bronchiolitisduring
bronchiolitis
season.
62·2%(84/135)
24mL3%
saline(n
=211)
Salinesolutions
givenevery
20min
toamaximum
of3doses.Admitted
patients:every8huntil
discharge.
-Primary:admission
rate,LOS.
24mL0.9%
saline(n
=197)
-Secondary:RD
AIscore,need
for
supplementaltherapy,AEs.
NCT01276821,36
Nepal
Outpatient
(ED)
Children6wkto
2ywith
bronchiolitis
definedas
firstepisodeofwheezing
andWangCSSbetween1and9.
NA24mL3%
saline+1.5mgepinephrine
(n=50)
Salinesolutions
givenat
0,30
min.
-Primary:WangCSSat30,60,120min.
24mL0.9%
saline+1.5mg
epinephrine(n
=50)
-Secondary:S aO 2
,respiratoryrate,
heartrate
at30,60,120min,
transfer
toICU,dischargerate
after
120min,revisitto
EDwithin
1wk,
AEs.
NCT01488448,25
USA
Inpatient
Children0–12
moadmitted
tohospital
with
adiagnosisof
bronchiolitis.
NA24mL3%
saline(n
=93)
Salinesolutions
givenevery
4huntil
discharge.
-Primary:LOS.
24mL0.9%
saline(n
=97)
-Secondary:readmission
within
30d,
transfer
toICU,
AEs.
NCT01238848,37
Argentina
Inpatient
Children1–24
mohospitalized
forfirst
episodeof
bronchiolitis,w
ithseverityscore$5andoxygen
saturation$97%.
NA23mL3%
saline+albuterol0·25mg/
kg/day
(n=37)
-Primary:LOS.
23mL0.9%
saline+albuterol0.25
mg/kg/day
(n=45)
-Secondary:durationof
supplemental
O 2,AEs.
ITQoL,Infant
ToddlerQuality
ofLife;N
A,notapplicable;R
ACS,RespiratoryAssessmentChange
Score;RTI,respiratorytractinfection;
SaO 2,oxygensaturation.
PEDIATRICS Volume 136, number 4, October 2015 693 by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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.
694 ZHANG et al by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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).
PEDIATRICS Volume 136, number 4, October 2015 695 by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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.
696 ZHANG et al by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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)
PEDIATRICS Volume 136, number 4, October 2015 697 by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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.
698 ZHANG et al by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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
REFERENCES
1. Pelletier AJ, Mansbach JM, Camargo CAJr. Direct medical costs of bronchiolitishospitalizations in the United States.Pediatrics. 2006;118(6):2418–2423
2. Shay DK, Holman RC, Newman RD, Liu LL,Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among USchildren, 1980-1996. JAMA. 1999;282(15):1440–1446
3. Mansbach JM, Emond JA, Camargo CA Jr.Bronchiolitis in US emergencydepartments 1992 to 2000: epidemiologyand practice variation. Pediatr EmergCare. 2005;21(4):242–247
4. Everard ML, Hind D, Ugonna K, et al;SABRE Study Team. SABRE: a multicentrerandomised control trial of nebulisedhypertonic saline in infants hospitalisedwith acute bronchiolitis. Thorax. 2014;69(12):1105–1112
5. Nair H, Nokes DJ, Gessner BD, et al.Global burden of acute lower respiratoryinfections due to respiratory syncytialvirus in young children: a systematic
PEDIATRICS Volume 136, number 4, October 2015 699 by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
review and meta-analysis. Lancet. 2010;375(9725):1545–1555
6. Wohl ME, Chernick V. Treatment of acutebronchiolitis. N Engl J Med. 2003;349(1):82–83
7. Wainwright C. Acute viral bronchiolitis inchildren—a very common condition withfew therapeutic options. Paediatr RespirRev. 2010;11(1):39–45, quiz 45
8. Mandelberg A, Amirav I. Hypertonicsaline or high volume normal saline forviral bronchiolitis: mechanisms andrationale. Pediatr Pulmonol. 2010;45(1):36–40
9. Sarrell EM, Tal G, Witzling M, et al.Nebulized 3% hypertonic saline solutiontreatment in ambulatory children withviral bronchiolitis decreases symptoms.Chest. 2002;122(6):2015–2020
10. Mandelberg A, Tal G, Witzling M, et al.Nebulized 3% hypertonic saline solutiontreatment in hospitalized infants withviral bronchiolitis. Chest. 2003;123(2):481–487
11. Tal G, Cesar K, Oron A, Houri S, Ballin A,Mandelberg A. Hypertonic saline/epinephrine treatment in hospitalizedinfants with viral bronchiolitis reduceshospitalization stay: 2 yearsexperience. Isr Med Assoc J. 2006;8(3):169–173
12. Kuzik BA, Al-Qadhi SA, Kent S, et al.Nebulized hypertonic saline in thetreatment of viral bronchiolitis ininfants. J Pediatr. 2007;151(3):266–270,270.e1
13. Grewal S, Ali S, McConnell DW,Vandermeer B, Klassen TP. A randomizedtrial of nebulized 3% hypertonic salinewith epinephrine in the treatment ofacute bronchiolitis in the emergencydepartment. Arch Pediatr Adolesc Med.2009;163(11):1007–1012
14. Al-Ansari K, Sakran M, Davidson BL, ElSayyed R, Mahjoub H, Ibrahim K.Nebulized 5% or 3% hypertonic or 0.9%saline for treating acute bronchiolitis ininfants. J Pediatr. 2010;157(4):630–634,634.e1
15. Anil AB, Anil M, Saglam AB, Cetin N, Bal A,Aksu N. High volume normal saline aloneis as effective as nebulized salbutamol-normal saline, epinephrine-normalsaline, and 3% saline in mildbronchiolitis. Pediatr Pulmonol. 2010;45(1):41–47
16. Miraglia Del Giudice M, Saitta F, LeonardiS, et al. Effectiveness of nebulizedhypertonic saline and epinephrine inhospitalized infants with bronchiolitis.Int J Immunopathol Pharmacol. 2012;25(2):485–491
17. Ipek IO, Yalcin EU, Sezer RG, Bozaykut A.The efficacy of nebulized salbutamol,hypertonic saline and salbutamol/hypertonic saline combination inmoderate bronchiolitis. Pulm PharmacolTher. 2011;24(6):633–637
18. Luo Z, Liu E, Luo J, et al. Nebulizedhypertonic saline/salbutamol solutiontreatment in hospitalized children withmild to moderate bronchiolitis. PediatrInt. 2010;52(2):199–202
19. Luo Z, Fu Z, Liu E, et al. Nebulizedhypertonic saline treatment inhospitalized children with moderate tosevere viral bronchiolitis. Clin MicrobiolInfect. 2011;17(12):1829–1833
20. Zhang L, Mendoza-Sassi RA, WainwrightC, Klassen TP. Nebulized hypertonicsaline solution for acute bronchiolitis ininfants. Cochrane Database Syst Rev.2008;(4):CD006458
21. Grewal S, Klassen TP. The tale of 2 trials:disentangling contradictory evidenceon hypertonic saline for acutebronchiolitis. JAMA Pediatr. 2014;168(7):607–609
22. Liberati A, Altman DG, Tetzlaff J, et al. ThePRISMA statement for reportingsystematic reviews and meta-analyses ofstudies that evaluate healthcareinterventions: explanation andelaboration. BMJ. 2009;339:b2700
23. Sharma BS, Gupta MK, Rafik SP.Hypertonic (3%) saline vs 0.93% salinenebulization for acute viral bronchiolitis:a randomized controlled trial. IndianPediatr. 2013;50(8):743–747
24. Teunissen J, Hochs AH, Vaessen-VerberneA, et al. The effect of 3% and 6%hypertonic saline in viral bronchiolitis:a randomised controlled trial. Eur RespirJ. 2014;44(4):913–921
25. NCT01488448 trial. Available at: https://clinicaltrials.gov/ct2/show/NCT01488448.Accessed January 5, 2015
26. Wan X, Wang W, Liu J, Tong T. Estimatingthe sample mean and standard deviationfrom the sample size, median, rangeand/or interquartile range. BMC MedRes Methodol. 2014;14:135
27. Tinsa F, Abdelkafi S, Bel Haj I, et al.A randomized, controlled trial of nebulized5% hypertonic saline and mixed 5%hypertonic saline with epinephrine inbronchiolitis. Tunis Med. 2014;92(11):674–677
28. Higgins JPT, Green S, editors. CochraneHandbook for Systematic Reviews ofInterventions version 5.1.0 [updatedMarch 2011]. The CochraneCollaboration, 2011. Available at: www.cochrane-handbook.org. Accessed May 1,2013
29. Higgins JPT, Thompson SG, Deeks JJ,Altman DG. Measuring inconsistency inmeta-analyses. BMJ. 2003;327(7414):557–560
30. Wu S, Baker C, Lang ME, et al. Nebulizedhypertonic saline for bronchiolitis:a randomized clinical trial. JAMA Pediatr.2014;168(7):657–663
31. Florin TA, Shaw KN, Kittick M, YakscoeS, Zorc JJ. Nebulized hypertonic salinefor bronchiolitis in the emergencydepartment: a randomized clinicaltrial. JAMA Pediatr. 2014;168(7):664–670
32. Jacobs JD, Foster M, Wan J, Pershad J.7% Hypertonic saline in acutebronchiolitis: a randomized controlledtrial. Pediatrics. 2014;133(1). Available at:www.pediatrics.org/cgi/content/full/133/1/e8
33. Ojha AR, Mathema S, Sah S, Aryal UR.A comparative study on use of 3%saline versus 0.9% saline nebulizationin children with bronchiolitis. JNepal Health Res Counc. 2014;12(26):39–43
34. Pandit S, Dhawan N, Thakur D. Utility ofhypertonic saline in the management ofacute bronchiolitis in infants:a randomized controlled study. Int J ClinPediatr. 2013;2(1):24–29
35. Li G, Zhao J. Effectiveness of inhaledhypertonic saline in children withbronchiolitis [in Chinese]. Zhonghua ErKe Za Zhi. 2014;52(8):607–610
36. NCT01276821 trial. Available at: https://clinicaltrials.gov/ct2/show/NCT01276821.Accessed January 5, 2015
37. NCT01238848 trial. Available at: https://clinicaltrials.gov/ct2/show/NCT01238848.Accessed January 5, 2015
38. Lowell DI, Lister G, Von Koss H, McCarthyP. Wheezing in infants: the response to
700 ZHANG et al by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
epinephrine. Pediatrics. 1987;79(6):939–945
39. Wang EE, Milner RA, Navas L, Maj H.Observer agreement for respiratorysigns and oximetry in infantshospitalized with lower respiratoryinfections. Am Rev Respir Dis. 1992;145(1):106–109
40. Amirav I, Newhouse MT. Aerosol therapyin infants and toddlers: past, presentand future. Expert Rev Respir Med. 2008;2(5):597–605
41. Hess D, Fisher D, Williams P, Pooler S,Kacmarek RM. Medication nebulizerperformance. Effects of diluentvolume, nebulizer flow, and
nebulizer brand. Chest. 1996;110(2):498–505
42. Guyatt G, Oxman AD, Sultan S, et al.GRADE guidelines: 11. Making an overallrating of confidence in effect estimatesfor a single outcome and for alloutcomes. J Clin Epidemiol. 2013;66(2):151–157
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
PEDIATRICS Volume 136, number 4, October 2015 701 by guest on May 23, 2018http://pediatrics.aappublications.org/Downloaded from
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
ServicesUpdated Information &
http://pediatrics.aappublications.org/content/136/4/687including high resolution figures, can be found at:
Supplementary Material
015-1914.DCSupplementalhttp://pediatrics.aappublications.org/content/suppl/2015/09/22/peds.2Supplementary material can be found at:
Referenceshttp://pediatrics.aappublications.org/content/136/4/687.full#ref-list-1This article cites 38 articles, 7 of which you can access for free at:
Subspecialty Collections
http://classic.pediatrics.aappublications.org/cgi/collection/rsv_subRSVis_subhttp://classic.pediatrics.aappublications.org/cgi/collection/bronchiolitBronchiolitisgy_subhttp://classic.pediatrics.aappublications.org/cgi/collection/pulmonoloPulmonologyfollowing collection(s): This article, along with others on similar topics, appears in the
Permissions & Licensing
https://shop.aap.org/licensing-permissions/in its entirety can be found online at: Information about reproducing this article in parts (figures, tables) or
Reprintshttp://classic.pediatrics.aappublications.org/content/reprintsInformation about ordering reprints can be found online:
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
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
Top Related