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Nebulized Hypertonic Saline for Acute

Bronchiolitis: A Systematic Review


Linjie Zhang, MD, PhDa, Raúl A. Mendoza-Sassi, MD, PhDa, Terry P. Klassen, MDb, Claire Wainwright, MDc

The mainstay of treatment for acute bronchiolitis remains supportive


BACKGROUND AND OBJECTIVE: abstract
care. The objective of this study was to assess the efficacy and safety of nebulized hypertonic
saline (HS) in infants with acute bronchiolitis.
METHODS:Data sources included PubMed and the Virtual Health Library of the Latin American
and Caribbean Center on Health Sciences Information up to May 2015. Studies selected were
randomized or quasi-randomized controlled trials comparing nebulized HS with 0.9% saline
or standard treatment.
RESULTS: We included 24 trials involving 3209 patients, 1706 of whom received HS. Hospitalized
patients treated with nebulized HS had a significantly shorter length of stay compared with
those receiving 0.9% saline or standard care (15 trials involving 1956 patients; mean
difference [MD] 20.45 days, 95% confidence interval [CI] 20.82 to 20.08). The HS group also
had a significantly lower posttreatment clinical score in the first 3 days of admission (5 trials
involving 404 inpatients; day 1: MD 20.99, 95% CI 21.48 to 20.50; day 2: MD 21.45, 95% CI
22.06 to 20.85; day 3: MD 21.44, 95% CI 21.78 to 21.11). Nebulized HS reduced the risk of
hospitalization by 20% compared with 0.9% saline among outpatients (7 trials involving 951
patients; risk ratio 0.80, 95% CI 0.67–0.96). No significant adverse events related to HS
inhalation were reported. The quality of evidence is moderate due to inconsistency in results
between trials and study limitations (risk of bias).
CONCLUSIONS:Nebulized HS is a safe and potentially effective treatment of infants with acute
bronchiolitis.

a
Faculty 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 of
Medicine, 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 the
review article; Dr Mendoza-Sassi provided input for study design, critically reviewed the protocol and the review article, and participated in trial selection, quality
assessment, and data collection; Drs Klassen and Wainwright provided input for study design, and critically reviewed the protocol and review article; and all authors
approved 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: lzhang@furg.br; linjie.zhang@pq.cnpq.br
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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PEDIATRICS Volume 136, number 4, from http://pediatrics.aappublications.org/ by guest on October 22, 2017
October 2015 REVIEW ARTICLE
Acute bronchiolitis in infancy, mainly trials have been undertaken to assess OR “respiratory syncytial virus” OR
caused by respiratory syncytial virus the effects and safety of nebulized HS RSV OR “parainfluenza virus”) AND
(RSV), is the most common lower in infants with acute (“hypertonic saline” OR “saline
respiratory infection and the leading bronchiolitis.10–19 The Cochrane solution” OR 3% saline OR 5% saline
cause of hospitalization in children review published in 2013 including OR saline). We used the limits of
younger than 2 years. In the United 11 randomized trials shows that study type: clinical trial, randomized
States, acute bronchiolitis in infancy nebulized 3% saline may significantly controlled trial (RCT). The search
is responsible for ∼150 000 reduce the length of stay (LOS) in strategy on the Virtual Health Library
hospitalizations each year at an hospitalized infants with acute of BIREME was as follows:
estimated cost of $500 million.1,2 bronchiolitis and improve the clinical bronchiolitis AND “hypertonic saline.”
From 1992 to 2000, bronchiolitis severity score (CSS) in both There was no restriction on language
accounted for ∼1 868 000 emergency outpatient and inpatient of publication. We also conducted
department (ED) visits for children populations.20 Since then, new trials a search of the ClinicalTrials.gov trials
younger than 2 years.3 In the United with conflicting results have been registry to identify completed but
Kingdom, hospital admissions for published, and an updated synthesis unpublished trials. We checked
acute bronchiolitis increased from of the literature is needed.21 We reference lists of all primary studies
21 330 in 2004 and 2005 to 33 472 in decided to conduct a new systematic and review articles for additional
2010 and 2011.4 review of currently available relevant trials.
randomized trials to assess the
Globally, it has been estimated that,
efficacy and safety of nebulized HS in Study Selection
in 2005, at least 33.8 million
infants with acute bronchiolitis and to To be included in this review, studies
episodes of RSV-associated acute
explore possible reasons for had to meet all of the following
lower respiratory infections (ALRIs) inconsistent results across trials. We
occurred in children younger than criteria: (1) study design: RCTs or
hypothesize that nebulized HS may be quasi-RCTs; (2) participants: infants
5 years, with incidence in developing less effective than previously claimed
countries more than twice that of up to 24 months of age with diagnosis
for acute bronchiolitis and effect size of acute bronchiolitis; we classified
industrialized countries.5 In the same of HS may mainly depend on
year, RSV-associated severe ALRIs participants into “inpatients” who
diagnostic accuracy of bronchiolitis were admitted to the hospital and
were responsible for ∼3.4 million and the treatment regimen.
hospitalizations and 66 000 to 199 “outpatients” who attended at an
000 deaths in young children ambulatory care unit or ED; (3)
METHODS interventions and comparisons:
worldwide, with 99% of these
deaths occurring in developing We followed the recommendations of nebulized HS ($3%) alone or mixed
countries. the Preferred Reporting Items for with bronchodilator, compared with
Systematic Reviews and Meta- nebulized NS alone or mixed with
Despite its high incidence and Analyses statement for writing this same bronchodilator, or standard
morbidity, there are few effective systematic review and meta- treatment; (4) outcome measures:
therapies for acute bronchiolitis in analysis.22 The full review protocol is primary outcomes included LOS in
infancy, and the mainstay of available in the supplementary hospital for inpatients defined as
treatment remains supportive care.6,7 material. We used different data time to actual discharge or time taken
Given the theoretical effects of sources, search strategy, and to be ready for discharge, and
hypertonic saline (HS) in reducing statistical techniques than that used admission rate for outpatients, and
airway edema, unblocking mucus in the 2013 Cochrane review.20 secondary outcomes included CSSs,
plugging, and improving mucociliary rate of readmission to hospital or
clearance, HS administered via Data Sources and Search Strategy ED, oxygen saturation, respiratory
nebulizer has been proposed as We searched PubMed and the Virtual rate, heart rate, time for the
a potentially effective therapy for Health Library of the Latin American resolution of symptoms/signs,
acute bronchiolitis in infants.8 The and Caribbean Center on Health duration of oxygen supplementation,
first randomized trial, published in Sciences Information (BIREME), results of pulmonary function tests,
2002, showed a significant effect of which contains Medline, CENTRAL, radiologic findings, and adverse
nebulized 3% saline solution in LILACS, IBECS, and .20 other events (AEs). We excluded studies
improving symptom scores among 65 databases (www.bireme.br). All that included patients who had had
outpatients with acute bronchiolitis, databases were searched from recurrent wheezing or were
as compared with 0.9% normal saline inception until May 2015. The search intubated and ventilated, and studies
(NS).9 Over the past decades, strategy on PubMed was as follows: that assessed pulmonary function
a growing number of randomized (bronchiolitis OR “acute wheezing” alone.

688 Downloaded from http://pediatrics.aappublications.org/ by guest on October 22, 2017 ZHANG et al


Two review authors (RM and LZ) sourceforge.net) to extract the 25th groups and 95% CI as the metrics of
independently assessed the titles and and 75th percentiles of LOS in effect size. Dichotomous data were
abstracts of all citations identified by hospital from the figure of 1 paper.24 synthesized by using risk ratios (RR)
the searches. We obtained the full For 2 trials,24,25 we estimated mean and 95% CIs as the effect measures.
articles when they appeared to meet and SD from median and interquartile We used the random-effects model
the inclusion criteria or there were range of LOS in hospital by using the for meta-analyses.
insufficient data in the title and method described by Wan et al.26 We assessed heterogeneity in results
abstract to make a clear decision for When the trial recruited multiple between studies by using the
their inclusion. The definitive groups, we combined them into HS Cochrane Q test (P , .1 considered
inclusion of trials was made after and NS groups.14,15,17,24,27 significant) and the I2 statistic. The I2
reviewing the full-text articles. We statistic ranges from 0% to 100% and
Assessment of Risk of Bias
resolved any disagreements between measures the degree of inconsistency
the 2 review authors about study Two reviewers (RM and LZ)
across studies, with values of 25%,
inclusion by discussion and independently assessed the risk of
50%, and 75% corresponding to low,
consensus. bias in included trials by examining
moderate, and high heterogeneity,
the 6 key domains according to the
respectively.29
Data Extraction and Management recommendations of the Cochrane
Collaboration.28 We graded each We conducted a priori subgroup
One review author (LZ) extracted analysis based on the treatment
potential source of bias as yes, no, or
study details from the included trials regimen. We also conducted post hoc
unclear, relating to whether the
by using a standardized data subgroup analyses according to
potential for bias was low, high, or
extraction form. These were checked diagnosis criteria for bronchiolitis
unknown. We resolved any
by another review author (RM). We (presence of wheeze as essential
disagreements between the 2 review
resolved any disagreements by diagnostic criteria and availability of
authors by discussion and consensus.
discussion and consensus. We virological testing) and risk of bias in
extracted the following data: (1) Data Synthesis and Statistical the trials. We performed post hoc
study characteristics: year of Analysis sensitivity analyses excluding open
publication, and country and setting We performed meta-analysis for trials, trials in which mean and SD
of study; (2) methods: study design, quantitative data synthesis whenever were estimated from median and
methods of random sequence there were available data from the interquartile range, trials with high
generation, allocation concealment primary studies. For continuous risk of attrition bias (withdrawal rate
and blinding, and description of outcomes, we used weighted mean .20% or data obtained from a part of
withdrawal; (3) participants: sample difference (MD) between treatment study sample), and trials that did not
size, age, gender, and inclusion and
exclusion criteria; (4) interventions
and controls: concentration and
volume of saline, type of nebulizer,
interval of administration, treatment
duration, and cointerventions; (5)
outcomes: primary and secondary
outcomes as described previously.
For continuous outcomes, we
extracted sample size, mean (median)
and precision of measurements (SD,
SE, 95% confidence interval [CI], or
interquartile range) of each treatment
arm. For dichotomous outcomes, we
extracted number of events and total
number of participants of each
treatment arm. We contacted the
principal investigators of 5
trials10,12,18,23,24 for methodological
details and additional trial data, of
whom 310,12,18 provided the
requested data. We used Engauge FIGURE 1
digitizing software (digitizer. Flow diagram of study selection.

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TABLE 1 Characteristics of Included Trials

690
Study ID and Country Setting Inclusion Criteria of Participants RSV Positivity Intervention and Control Treatment Regimen Outcomes
Al-Ansari 2010,14 Qatar Outpatient (ED) Infants #18 mo with moderate to 56.1% (96/171) 25 mL 3% saline + 1.5 mg epinephrine Saline solutions given on - Primary: Wang CSS at 48 h.
severe bronchiolitis, defined as (n = 58) enrollment and every 4 h
a prodromal history of viral RTI 25 mL 5% saline + 1.5 mg epinephrine thereafter. - Secondary: Wang CSS at 24 and 72 h,
followed by wheezing and/or (n = 57) LOS in ED, revisit to ED, AEs.
crackles and Wang CSS of $4. 25 mL 0.9% saline + 1.5 mg
epinephrine (n = 56)
Anil 2010,15 Turkey Outpatient (ED) Infants 6 wk to 24 mo with first NA 24 mL 3% saline + 1.5 mg epinephrine Saline solutions given at - Primary: Wang CSS at 0, 30, 60,
episode of bronchiolitis, defined by (n = 39) 0 and 30 min. 120 min.
symptoms of upper RTI and 24 mL 0.9% saline + 1.5 mg - Secondary: SAO2 in room air and
presence of bilateral wheezing and/ epinephrine (n = 38) heart rate at 0, 30, 60 and
or crackles on auscultation and 23% saline + 2.5 mg salbutamol 120 min, AEs.
Wang CSS between 1 and 9. (n = 36)
24 mL 0.9% saline + 2.5 mg
salbutamol (n = 36)
24 mL 0.9% saline (n = 37)
Everard 2014,4 Inpatient Children ,12 mo with diagnosis of 84% (179/212) 24 mL 3% saline + standard care (n = HS given every 6 h until - Primary: fit for discharge (75% of
England and Wales bronchiolitis defined as apparent 142) primary outcome usual intake and SaO2 $92%
viral RTI with airway obstruction achieved. for 6 h at room air).
(hyperinflation, tachypnea, and - Standard care (n = 149) - Secondary: actual time to discharge,
subcostal recession) and readmission within 28 d from
widespread crepitations, needing O2 randomization, healthcare usage,
with SaO2 ,92%. duration of respiratory symptoms
postdischarge, ITQoL, AEs.
Florin 2014,31 USA Outpatient (ED) Children ,24 mo with first episode of NA 24 mL 3% saline (n = 31) One dose of saline - Primary: RACS at 1 h after inhalation.
bronchiolitis, defined as first 24 mL 0.9% saline (n = 31) solutions given at 0 min. - Secondary outcomes: vital signs,
episode of wheezing associated SaO2, hospitalization rate, physician
with signs and symptoms of upper clinical impression, parental
RTI and respiratory distress assessment, AEs.
measured by RDAI score between 4
and 15.
Grewal 2009,13 Canada Outpatient (ED) Children 6 wk to 12 mo with diagnosis 82.2% (37/45) 22.5 mL 3% saline + 0.5 mL 2.25% One dose saline solutions - Primary: RACS 0–120 min, change in
of bronchiolitis, defined as first racemic epinephrine (n = 24) given at 0 min. SAO2 0–120 min.
episode of wheezing and symptoms 22.5 mL 0.9% saline + 0.5 mL 2.25% - Secondary: admission to hospital,
of viral RTI, initial SAO2 85%–96% racemic epinephrine (n = 24) return to ED, AEs.
and initial RDAI score $4.

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Ipek 2011,17 Turkey Outpatient (ED) Children ,2 y with history of NA 24 mL 3% saline + 0.15 mg /kg Saline solutions given at 0, - Primary: Wang CSS, use of
preceding viral upper RTI followed salbutamol (n = 30) 20, 40 min. corticosteroid, hospitalization,
by wheezing and crackles on clinical assessment 48–72 h.
auscultation and Wang CSS between 24 mL 0.9% saline + 0.15 mg /kg - Secondary: SAO2, respiratory rate,
4 and 8. salbutamol (n = 30) heart rate.
24 mL 3% saline (n = 30)
24 mL 0.9% saline (n = 30)

ZHANG et al
TABLE 1 Continued
Study ID and Country Setting Inclusion Criteria of Participants RSV Positivity Intervention and Control Treatment Regimen Outcomes
Jacobs 2014,32 USA Outpatient (ED) Children 6 wk to , 18 mo with 60.3% (41/68) 23 mL 7% saline + 0.5 mL 2.25% One dose of saline - Primary: Wang CSS before and after
bronchiolitis defined as viral RTI racemic epinephrine (n = 52) solutions given at 0 min. treatment and at disposition.
and first episode of wheezing, Wang 23 mL 0.9% saline + 0.5 mL 2.25% - Secondary: hospitalization rate,
CSS $4 and SaO2 .85%. racemic epinephrine (n = 49) proportion of admitted patients
discharged at 23 h, LOS, AEs.
Kuzik 2007,12 Abu Inpatient Children #18 mo with history of 68.8% (55/80) 24 mL 3% saline (n = 47) 3 doses given every 2 h, - Primary: LOS defined as time
Dhabi and Canada preceding viral upper RTI, wheezing followed by every 4 h for between study entry and time at
or crackles on chest auscultation, 5 doses, followed by which the infant either reached
plus either SaO2 of 94% in room air every 6 h until protocol-defined discharge criteria
or significant respiratory distress discharge. (RDAI score , 4 and SaO2 $95% in

PEDIATRICS Volume 136, number 4, October


as measured by RDAI score $4. room air for 4 h) or discharged by
attending physician, whichever

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came first.
24 mL 0.9% saline (n = 49) - Secondary: AEs.
Li 2014,35 China Outpatient (Ambulatory Children 2–18 mo with first episode of NA 22 mL 3% saline (n = 42) Saline solutions given twice - Primary: Wang CSS 24, 48, 72 h after
care unit) bronchiolitis (Wang CSS $4). daily for 3 d. treatment.
22 mL 5% saline (n = 40) - Secondary: AEs.
22 mL 0.9% saline (n = 42)
Luo 2010,18 China Inpatient Wheezing infants with mild to 69.9% (65/93) 24 mL 3% saline + 2.5 mg salbutamol Saline solutions given every LOS (discharge decided by attending
moderate viral bronchiolitis, (n = 50) 8 h until discharge. physician), time for resolution of
measured by Wang CSS. 24 mL 0.9% saline + 2.5 mg wheezing, cough, pulmonary moist
salbutamol (n = 43) and crackles, Wang CSS, AEs.
Luo 2011,19 China Inpatient Children ,24 mo with first episode of 73.2% (82/112) 24 mL 3% saline (n = 57) 3 doses given every 2 h, LOS (discharge decided by attending
wheezing diagnosed as moderate to 24 mL 0.9% saline (n = 55) followed by every 4 h for physician), time for resolution of
severe bronchiolitis according 5 doses, followed by wheezing, cough, pulmonary moist
Wang CSS. every 6 h until and crackles, Wang CSS, AEs.
discharge.
Mandelberg 2003,10 Inpatient Children #12 mo with clinical 87% (47/52) 24 mL 3% saline + 1.5 mg epinephrine Saline solutions given every - Primary: LOS (discharge decided by
Israel presentation of viral bronchiolitis, (n = 27) 8 h until discharge. attending physician), Wang CSS.
temperature .38°C and SaO2 24 mL 0.9% saline + 1.5 mg - Secondary: radiograph score, AEs.
$85%. epinephrine (n = 25)
Miraglia 2012,16 Italy Inpatient Children under 24 mo with diagnosis 82.1% (87/106) - ? mL 3% saline + 1.5 mg epinephrine Saline solutions given every - Primary: LOS defined as time
of bronchiolitis, defined as first (n = 52) 6 h. between study entry and time of
episode of wheezing and clinical discharge.
symptoms of viral RTI, SAO2 ,94% - ? mL 0·9% saline + 1.5 mg - Secondary: Wang CSS on each

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in room air and significant epinephrine (n = 54) treatment day.
respiratory distress measured by
Wang CSS.

691
TABLE 1 Continued

692
Study ID and Country Setting Inclusion Criteria of Participants RSV Positivity Intervention and Control Treatment Regimen Outcomes
Ojha 2014,33 Nepal Inpatient Children .6 wk to ,24 mo with first NA 24 mL 3% saline (n = 36) Saline solutions given every - Primary: LOS calculated from time of
episode of bronchiolitis defined as 8 h until discharge. entry to time of discharge (no
wheezing associated with upper RTI, supplemental O2, feeding
tachypnea, increased respiratory adequately, minimal or absent of
effort, clinical scoring of wheezing, crackles, and retractions,
respiratory distress $4 and SaO2 SaO2 $95% at room air for 4 h and
$85%. severity score was , 4).
24 mL 0.9% saline (n = 36) - Secondary: duration of supplemental
O2, clinical scores.
Pandit 2013,34 India Inpatient Children 2–12 mo with acute NA 24 mL 3% saline + 1 mL adrenaline (n 3 doses given every 1 h, - Primary: LOS (discharge criteria:
bronchiolitis defined as short = 51) followed by every 6 h respiratory rate ,60/min, without
history of cough with or without until discharge. retractions and wheezing).
fever ,7 d and first episode of 24 mL 0.9% saline + 1 mL adrenaline - Secondary: improvement in RDAI
wheezing. (n = 49) score, respiratory rate, SaO2, heart
rate, number of add on treatment,
AEs.
Sarrel 2002,9 Israel Outpatient (Ambulatory Children #24 mo with clinical 80% (52/65) 22 mL 3% saline + 5 mg terbutaline Saline solutions given every - Primary: hospitalization rate, Wang
care unit) presentation of mild to moderate (n = 33) 8 h for 5 d. CSS.
bronchiolitis and SaO2 ,96%. 22 mL 0.9% saline + 5 mg terbutaline - Secondary: radiograph score, AEs.
(n = 32)
Sharma 2012,23 India Inpatient Children 1–24 mo with moderate NA 24 mL 3% saline + 2.5 mg salbutamol Saline solutions given every - Primary outcome: LOS defined as
(Wang CSS 3–6) acute bronchiolitis (n = 125) 4 h until discharge. time from admission to Wang CSS
defined as first episode of wheezing , 3.
with prodrome of upper RTI. 24 mL 0.9% saline + 2.5 mg - Secondary: Wang CSS, AEs.
salbutamol (n = 123)
Tal 2006,11 Israel Inpatient Children #12 mo with clinical 80% (33/41) 24 mL 3% saline + 1.5 mg epinephrine Saline solutions given every - Primary: LOS (discharge decided by
presentation of viral bronchiolitis (n = 21) 8 h until discharge. attending physician), Wang CSS.
leading to hospitalization and SaO2 24 mL 0.9% saline + 1.5 mg - Secondary: radiograph score, AEs.
$85%. epinephrine (n = 20)
Teunissen 2013,24 The Inpatient Children 0–24 mo with moderate to 88% (212/241) 24 mL 3% saline + 2.5 mg salbutamol Saline solutions given every - Primary outcome: LOS defined as
Netherlands severe (Wang CSS $3) bronchiolitis (n = 84) 8 h until discharge. time between the first dose of
defined as upper RTI with wheezing, medications and clinical decision to
tachypnea, and dyspnea. discharge (protocol-defined
discharge criteria: no supplemental
O2, no tube-feeding or intravenous

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fluids).
24 mL 6% saline + 2.5 mg salbutamol - Secondary: transfer to ICU,
(n = 83) duration of supplemental O2 or
tube-feeding, AEs.
24 mL 0.9% saline + .·5 mg
salbutamol (n = 80)

ZHANG et al
TABLE 1 Continued
Study ID and Country Setting Inclusion Criteria of Participants RSV Positivity Intervention and Control Treatment Regimen Outcomes
Tinsa 2014,27 Tunis Inpatient Children 1 to 12 mo with diagnosis of NA 24 mL 5% saline (n = 31) Saline solutions given every - Primary: Wang CSS at 30, 60 and 120
bronchiolitis, defined as first 4 h until discharge. min.
episode of wheezing associated 22 mL 5% saline + 2 mL epinephrine - Secondary:: LOS (discharge criteria:
with acute RTI and Wang score $3. (n = 37) no supplemental O2, adequate fluid
intake, Wang CSS ,3), AEs.
24 mL 0.9% saline (n = 26)
Wu 2014,30 USA Outpatient (ED) Children ,24 mo with first episode of 62·2% (84/135) 24 mL 3% saline (n = 211) Saline solutions given every - Primary: admission rate, LOS.
bronchiolitis during bronchiolitis 24 mL 0.9% saline (n = 197) 20 min to a maximum of - Secondary: RDAI score, need for
season. 3 doses. Admitted supplemental therapy, AEs.
patients: every 8 h until

PEDIATRICS Volume 136, number 4, October


discharge.
NCT01276821,36 Nepal Outpatient (ED) Children 6 wk to 2 y with bronchiolitis NA 24 mL 3% saline + 1.5 mg epinephrine Saline solutions given at 0, - Primary: Wang CSS at 30, 60, 120 min.

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defined as first episode of wheezing (n = 50) 30 min.
and Wang CSS between 1 and 9. 24 mL 0.9% saline + 1.5 mg - Secondary: SaO2, respiratory rate,
epinephrine (n = 50) heart rate at 30, 60, 120 min,
transfer to ICU, discharge rate after
120 min, revisit to ED within 1 wk,
AEs.
NCT01488448,25 USA Inpatient Children 0–12 mo admitted to hospital NA 24 mL 3% saline (n = 93) Saline solutions given every - Primary: LOS.
with a diagnosis of bronchiolitis. 24 mL 0.9% saline (n = 97) 4 h until discharge. - Secondary: readmission within 30 d,
transfer to ICU, AEs.
NCT01238848,37 Inpatient Children 1–24 mo hospitalized for first NA 23 mL 3% saline + albuterol 0·25 mg/ - Primary: LOS.
Argentina episode of bronchiolitis, with kg/day (n = 37)
severity score $5 and oxygen 23 mL 0.9% saline + albuterol 0.25 - Secondary: duration of supplemental
saturation $97%. mg/kg/day (n = 45) O2, AEs.
ITQoL, Infant Toddler Quality of Life; NA, not applicable; RACS, Respiratory Assessment Change Score; RTI, respiratory tract infection; SaO2, oxygen saturation.

Bias
RESULTS

analyses.
Selection

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College Station, TX).

Table 1 summarizes the

auscultation. Virological
from clinical trials registry

review. All but 2 trials14,35


articles. Thus, a total of 24

widespread crepitations on
of bronchiolitis were clearly

by hyperinflation, tachypnea,
and subcostal recession with
Literature Search and Study

eligibility of 3 completed but

defined by 19 trials. Eighteen


contributed data to the meta-

trials12–19,23,24,27,31–37 defined

trials4,9–14,16,18,19,24,30,32 and
wheezing associated with viral
26 potentially relevant full-text

(ClinicalTrials.gov) to assess the

RCTs except 1 that was a quasi-


RCT.17 The criteria for diagnosis
trials4,9–19,23–25,27,30–37 involving

the positive rate for RSV varied


was defined as an apparent viral
The search strategy identified 97

characteristics of the 24 included


meta-analyses were performed by

unpublished trials and all met the

investigation was available in 13


use 0.9% saline as the control. All

with airways obstruction manifest


Study Characteristics and Risk of
articles were excluded for reasons
articles for further evaluation. Five

bronchiolitis as the first episode of


lists of primary studies and review

3209 patients were included in the

respiratory infection in children ,2


using Stata version 11.0 (Stata Corp,

respiratory tract infection associated


the titles and abstracts, we retrieved

years of age. In 1 trial,4 bronchiolitis


trials. All studies were parallel-group
records from BIREME. After screening
unique records from PubMed and 125

inclusion criteria. No additional trials


shown in Fig 1. We obtained the data

were found by checking the reference

693
from 56% to 88%. The because of high and unbalanced 95% CI 20.82 to 20.08, P = .01)
concentration of HS was defined withdrawal rate after randomization. (Fig 2). There was significant
at 3% in all but 5 trials, in which heterogeneity in results between
5%14,27,35 (n = 165), 6%24 (n = 83), Efficacy of Nebulized HS in Inpatients studies (I2 statistic = 82%). The
and 7%32 saline (n = 52) was LOS in Hospital data were suitable for conducting
used. Treatment regimen of Among 14 inpatient trials, 5 subgroup analyses (Table 2).
nebulized HS varied across studies, 139–12,16,18,19,23–25,33,34,37 used LOS Nine trials4,10–12,16,18,19,24,30 in
especially outpatient trials as the primary outcome and 127used which virological investigation
(Table 1). LOS as the secondary outcome. One was available showed significant
All trials were double-blind except 3 ED trial30 involving 408 patients effects of HS on reducing LOS,
open trials,4,34,37 in which provided the data of LOS among 145 whereas 6 trials23,25,27,33,34,37 in
performance bias and detection bias hospitalized patients. We included which such testing was not
might occur (Supplemental Table 5). the data of these 145 inpatients in the available did not show significant
All trials but 117 were stated as meta-analysis. The pooled results of benefits (P = .02 for subgroup
randomized; however, 11 15 trials with a total of 1956 comparison). The effect size of
trials9–12,15,16,18,25,30,35,37 did not inpatients showed a statistically HS on LOS appeared to be greater
describe the methods for random significant shorter mean LOS among in trials10–12,16,18,25,30,37 with
sequence generation and/or infants treated with HS compared unclear or high risk of selection bias,
allocation concealment. Attribution with those treated with 0.9% saline compared with trials4,19,23–25,27,33
bias might occur in 3 trials25,32,37 or standard care (MD of 20.45 days, with low risk of selection bias.

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

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TABLE 2 Subgroup Analyses on LOS (Inpatients) and Admission Rate (Outpatients)
Subgroups LOS, d Admission rate, %

Trial, n Patients, Effect Size: Subgroup Trial, n Patients, Effect Size: Subgroup
n MD (95% CI) Comparison,a n RR (95% CI) Comparison,a
P Value P Value
Virological investigation .02 .06
Available 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 with .80 .71
bronchodilatorb
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 .07
A 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 .13
Low 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 x 2 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, multiple

doses ($3).

However, the difference between general condition from 0 to 3. with those receiving NS. None of the
subgroups was not statistically However, only 5 trials10,11,16,18,19 trials showed significant effects of HS
significant. with a total of 404 patients provided on other previously mentioned
Four sensitivity analyses, excluding 2 suitable data for the meta-analysis, outcomes.
trials24,25 with estimated mean and showing a significant effect of HS in
SD of LOS, 3 trials25,33,37 with high improving clinical scores on day 1 Efficacy of Nebulized HS in
risk of attrition bias, 2 open trials,4,34 (MD of 20.99, 95% CI 21.48 to Outpatients
and 1 trial4 that did not use 0.9% 20.50, P , .0001, I2 statistic = 67%),
Admission Rate
saline as the control, did not day 2 (MD of 21.45, 95% CI 22.06 to
20.85, P , .0001, I2 statistic = 79%), Seven outpatient trials with a total of
significantly affect the results of the
and day 3 of admission (MD of 21.44, 951 patients assessed the efficacy of
meta-analysis.
95% CI 21.78 to 21.11, P , .0001, I2 nebulized 3% saline on reducing the
statistic = 53%). risk of hospitalization. The pooled RR
Improvement in CSSs was 0.80 (95% CI 0.67–0.96, P = .01)
Eleven inpatient trials used Other Efficacy Outcomes (Fig 3). There was no significant
bronchiolitis severity scores as Three trials24,33,37 used duration of heterogeneity in results between
outcome measure. Two trials12,34 in-hospital oxygen supplementation studies (I2 statistic = 2%). The data
used Respiratory Distress Assessment as efficacy outcome. Other efficacy were available for conducting 4
Instrument (RDAI)38 scores based on outcomes used by at least 1 trial subgroup analyses (Table 2). The
wheezing and retractions, but 112 did included duration of tube feeding, effect size of HS on the risk of
not report the results and the other34 time for the resolution of respiratory hospitalization was significantly
reported RDAI scores only on day 1 of symptoms and signs, radiograph greater in trials9,13,30,32 in which
admission. One trial33 used a clinical scores, measurement of respiratory virological investigation was available
score based on respiratory rate, rate, heart rate and oxygen and in trials9,17,30 in which multiple
wheezing, retractions, and oxygen saturation, readmission within 28 doses ($3) of saline solutions were
saturation. This trial did not find days from randomization, and infant administered, compared with
a significant difference between HS and parental quality-of-life trials15,17,31 in which virological
and NS groups in clinical scores questionnaire. Two trials18,19 testing was not available and
through day 1 to day 4 of admission. reported a shorter duration of trials13,15,31,32 by using only 1 to 2
All the remaining 8 trials used Wang’s respiratory symptoms and signs doses of saline solutions, respectively.
clinical scores,39 grading respiratory (cough, wheezing, and crackles) in Four trials9,15,17,30 with unclear or
rate, wheezing, retractions, and patients treated with HS compared high risk of selection bias showed

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

significant effects of HS on reducing benefits of 3% saline compared with and to ED (5 trials13–15,31,36 with 523
the risk of hospitalization, whereas 3 NS on each of 3 treatment days, the patients, RR of 0.78, 95% CI
trials13,31,32 with low risk of selection second14 showed consistent trend 0.46–1.32, P = .36, I2 statistic = 29%).
bias did not show significant benefits favoring 5% saline compared with
of HS; however, the difference 3% and 0.9% saline solutions from 8 Other Efficacy Outcomes
between subgroups was not to 72 hours after randomization, and Oxygen saturation was used as an
statistically significant. the third34 showed the superiority of efficacy outcome by 4 trials.13,15,17,31
both 5% and 3% saline solutions over Other efficacy outcomes used by at
Improvement in CSSs NS on each of 3 treatment days, but least 1 trial included duration of
All 10 outpatient trials used no significant difference was found oxygen supplementation,
bronchiolitis severity scores as the between 5% and 3% saline groups. measurement of respiratory rate and
outcome measure. Variation in heart rate, radiograph scores, and
scoring methods and time points of Rate of Readmission to Hospital or ED parental perception of improvement.
assessment makes it inappropriate to Five outpatient trials reported the None of the trials showed beneficial
conduct meta-analyses. Thus, we rate of readmission to hospital and/ effects of HS on previously mentioned
narratively summarized the main or the ED 24 hours to 1 week after outcomes.
results of 9 trials in terms of effects of discharge. The meta-analysis did not
HS on improving clinical scores show significant effects of HS in Safety of Nebulized HS
(Table 3). These trials did not show reducing the risk of readmission to Of 24 trials included in this review, 21
significant effects of nebulized HS in hospital (4 trials13–15,31 with 428 reported safety data among 2897
improving clinical scores, except 3 of patients, RR of 1.45, 95% CI participants, 1557 of whom received
the trials. One9 showed significant 0.67–3.14, P = .34, I2 statistic = 1%) HS (3% saline: n = 1257; 5% saline:

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TABLE 3 Narrative Summary of the Main Findings of 10 Outpatient Trials in Terms of Effects of HS nebulized 3% saline in reducing
on Improving Clinical Scores LOS in infants hospitalized for acute
Trial Scoring Methods Main Findings bronchiolitis. The review also
Al-Ansari 201014 Wang score - Mean scores (SD) 24 h after randomization: 5% saline vs 0.9% shows that nebulized HS could
saline: 3.75 (1.27) vs 3.97 (1.40), P . .05; 3% saline vs 0.9% reduce the risk of hospitalization by
saline: 4.0 (0.98) vs 3.75 (1.27), P . .05. 20% compared with normal
- Mean scores (SD) 48 h after randomization: 5% saline vs 0.9%
saline among outpatients with
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. bronchiolitis.
- Consistent trend favoring 5% saline from 8 to 72 h after The results of this new review
randomization.
Anil 201015 Wang score There was no significant difference between 3% and 0·9%
confirmed our hypothesis that
saline groups in terms of clinical scores at 30, 60, and nebulized HS may be less effective
120 min of assessment. than previously claimed for infants
Florin 201431 RDAI score - Mean RDAI scores (95% CI) 1 h after saline administration: 3% with acute bronchiolitis. The effect
saline vs 0.9% saline: 6.6 (5.5–7.6) vs 5.1 (4.1–6.2), P = .05.
size of nebulized HS on reducing
- 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 LOS in hospitalized patients shown
(25.3 to 22.7), P = .01. by the present review is only
Grewal 200913 RDAI score Mean RACS scores (95% CI) from 0 to 120 min: 3% saline vs approximately one-third of that
0.9% saline: 4.39 (2.64–6.13) vs 5.13 (3.71–6.55), P . .05. shown by the 2013 Cochrane
Ipek 201117 Wang score There was no significant difference between 3% and 0.9%
review,20 which included 6 inpatient
saline groups in terms of clinical scores at 60 min of
assessment. trials involving 500 patients (MD
Jacobs 201432 Wang score - Mean change in scores (SD) at ED disposition: 7% saline 21.15 days, 95% CI 21.49 to 20.82
vs 0.9% saline: 2.6 (1.9) vs 2.4 (2.3), P = .21. days). It is interesting to note that
- Mean change in scores (SD) after first nebulization in ED all 8 trials4,23–25,27,30,33,34 published
disposition: 7% saline vs 0.9% saline: 2.06 (1.7) vs 2.0 (1.9),
P = .06.
in 2013 and thereafter, including 2
Li 201435 Wang score Median scores (interquartile range): 5%, 3% vs 0.9% saline. European multicenter studies4,24
224 h after treatment: 6 (1), 6 (1) vs 7 (1); P , .05 with relatively large sample size, did
(5% vs 0.9%; 3% vs 0.9%). not find significant effects of
248 h after treatment: 5 (1), 5 (1) vs 6 (0.2), P , .05
nebulized HS on LOS among
(5% vs 0.9%).
272 h after treatment: 3.5 (1), 4 (1) vs 7 (0), P , 0·05 inpatients with bronchiolitis. For
(5% vs 0.9%; 3% vs 0.9%). outpatients, this new review showed
Sarrell 20029 Wang score Mean scores differed significantly, in favor of 3% saline a 20% reduction on the risk of
compared with 0.9% saline, on each of the treatment days. hospitalization associated with
Wu 201430 RDAI score Mean scores (SD): 3% saline vs 0.9% saline: 5.32 (3.14) vs 4.88
(2.95), P . .05.
nebulized HS in contrast with
NCT 0127682136 Wang score Mean change in scores (SD) after 2 sessions of nebulization: a 37% non–statistically significant
3% saline vs 0.9% saline: 3.52 (1.41) vs 2.26 (1.15) reduction shown by the 2013
Cochrane review,20 which included
4 outpatient trials involving 380
n = 165; 6% saline: n = 83; 7% narratively summarized the safety
participants (RR 0.63, 95% CI
saline: n = 52). Fourteen data of 7 trials (Table 4). Various
0.37–1.07).
trials9–11,14,15,18,23,25,27,31,32,34,36,37 AEs were reported in both HS and
did not find any significant AEs control groups. In most of cases, AEs We conducted subgroup analyses to
among a total of 1548 participants, were mild and resolved explore potential effect modifiers and
of whom 828 received nebulized HS spontaneously. Only 1 inpatient trial4 sources of heterogeneity in the
(mixture with bronchodilators: n = involving 142 patients receiving 3% results across studies. We found that
673, 81.3%; HS alone: n = 155, saline alone without bronchodilator trials in which virological
18.7%). In the remaining 7 reported 1 serious AE (bradycardia investigation was available showed
trials4,12,13,19,24,30,35 involving 1324 and desaturation) possibly related to a significantly greater effect size of
participants of whom 729 received HS inhalation but resolved the nebulized HS than trials without such
nebulized HS (mixture with following day. testing in both inpatients and
bronchodilators: n = 190, 26%; HS outpatients, measured by reduction of
alone: n = 539, 74%), at least 1 AE LOS and risk of hospitalization. These
was reported. Variation in reporting DISCUSSION data suggest that diagnostic accuracy
and in outcomes precluded the This new systematic review and of bronchiolitis may affect the
possibility of conducting meta- meta-analysis shows a modest but treatment outcomes with HS. The
analysis of safety data. We statistically significant benefit of number and frequency of saline

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TABLE 4 Narrative Summary of AEs of Treatment Reported by 7 Trials the effect size of HS was risk of
Trial HS (n) vs Controls (n) Main Findings selection bias. Trials with unclear or
Everard 20144 3% saline (n = 142) vs Six AEs were possibly related to saline
high risk of selection bias showed
standard care (n = 143) treatment, including 1 serious AE (SAE), significant effects of HS on reducing
bradycardia and desaturation, which LOS and risk of hospitalization,
resolved the following day. whereas trials with low risk of
The remaining 5 non-SAEs were bradycardia selection bias did not show significant
(self-correcting), desaturation, coughing fit,
and increased respiratory rate (all of
benefits of HS on these outcomes.
which were resolved within 1 d), and a This does cast some doubt on the
chest infection that resolved after 6 d. overall effect estimates of HS;
Grewal 200913 3% saline + epinephrine AEs were noted in 4 infants (vomiting, 3; however, the difference between
(n = 23) vs 0.9% saline + diarrhea, 1); all were enrolled in the HS
subgroups was not statistically
epinephrine (n = 23) group. No additional bronchodilators were
given to any enrolled patient during the significant. A tight seal between
study period. the mask and the infant’s face is
Kuzik 200712 3% saline (n = 47) vs 0.9% No infants were withdrawn by the medical crucial for an effective drug delivery
saline (n = 49) staff due to AEs, although 5 infants were with nebulizer.40 The performance
withdrawn at parents’ request because of
perceived AEs, only 2 from the HS group,
of the nebulizer may also affect
of whom 1 presented with vigorous drug delivery.41 Thus, variability in
crying and another with agitation. drug delivery could be considered
Li 201435 5% saline (n = 40), 3% saline No AEs were observed in the 3% and 0.9% one of the potential sources of
(n = 42) vs 0.9% saline saline groups. Four patients from the 5%
heterogeneity across studies;
(n = 42) saline group presented with paroxysmal
cough during saline inhalation. however, lack of data from primary
Luo 201119 3% saline (n = 57) vs 0.9% No infants were withdrawn by the medical studies did not allow us to include
saline (n = 55) staff because of AEs. Coughing and this important factor for subgroup
wheezing never worsened during saline analyses.
inhalation, although 5 infants had hoarse
voices, only 2 from the HS group, and the Clinical score is generally considered
symptom disappeared after 3–4 d. a relatively objective measure to
Teunissen 201424 3%, 6% saline + salbutamol A substantial number of AEs (eg, cough, assess the severity of illness. Eleven
(n = 167) vs 0.9% + bronchospasm, agitation, desaturation)
salbutamol (n = 80) were noted in all treatment groups. Except
inpatient trials used bronchiolitis
for cough, which occurred significantly severity scores as the efficacy
more in the HS groups (P = .03), no outcome, but only 5 trials that used
differences were found between groups. Wang’s clinical scores provided
Withdrawals due to AEs did not differ
suitable data for meta-analysis. The
between groups (4.3%, 6.1% and 7.9%
in the 3%, 6% and 0.9% saline groups, pooled results of these 5 trials
respectively, P = .59). showed a significant effect of HS in
Wu 201430 3% saline (n = 211) vs 0.9% Three patients in the NS group and 4 in the improving clinical scores through day
saline (n = 197) HS group withdrew owing to parent request. 1 to day 3 of admission. However,
Of these parent requests, 1 in the NS group
and 2 in the HS group were attributed to
the inability to include another 6
worsening cough. For these 3 patients, inpatient trials in the meta-analysis
pretreatment and posttreatment vital signs may have affected the results of the
and RDAI score were the same or improved, analysis. Seven of 10 outpatient trials
and no intervention or additional treatment
did not show significant effects of
was necessary.
nebulized HS in improving clinical
scores.
Potential adverse effects of
inhalations may also appear to inpatients, no significant difference intervention with nebulized HS, such
influence the effect size of HS. Trials was observed in reduction of LOS as acute bronchospasm, remain
undertaken in an outpatient setting in between trials that used more a potential concern. In this review,
which multiple doses ($3) of saline frequent saline inhalations (3 initial there were 14 trials involving 828
solutions were administrated showed doses given every 1–2 hours, patients receiving nebulized HS that
a significantly greater reduction on followed by every 4–6 hours) and did not report any significant AEs. In
the risk of hospitalization compared those in which saline solutions were 81.3% of these patients, saline
with trials that used 1 to 2 doses of given every 6 to 8 hours. Another solutions were mixed with
saline solutions. However, for factor that could possibly influence bronchodilators. In contrast, there

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were 7 trials involving 729 patients a placebo, as high-volume NS
treated with nebulized HS of which inhalation could potentially have
ABBREVIATIONS
74% received HS alone and reported physiologic effects by improving AEs: adverse events
at least 1 AE. Most AEs were mild airway mucociliary clearance, which ALRIs: acute lower respiratory
and resolved spontaneously. These may have beneficial effects on acute infections
results suggest that nebulized HS is bronchiolitis.8 Use of NS as the BIREME: Latin American and
a safe treatment in infants with control may tend to minimize the Caribbean Center on
bronchiolitis, especially when effect size of HS. Health Sciences
administered in conjunction with Information
In conclusion, this new systematic
a bronchodilator. CI: confidence interval
review shows that nebulized HS is
CSS: clinical severity score
This systematic review included associated with a mean reduction
ED: emergency department
trials conducted in both high-income of 0.45 days (∼11 hours) in LOS
GRADE: Grading of
and low-income countries and in among infants admitted for acute
Recommendations,
different settings (inpatient, bronchiolitis and a mean reduction of
Assessment, Development
ambulatory care unit, and ED). Thus, 20% in the risk of hospitalization
and Evaluations
evidence derived from the review among outpatients. This review
HS: hypertonic saline
may have a wide applicability. also suggests that nebulized HS is
LOS: length of stay
However, the quality of evidence a safe treatment in infants with
MD: mean difference
could be graded only as moderate, bronchiolitis, especially when
NS: normal saline
mainly due to inconsistency in the administered in conjunction with
RACS: respiratory assessment
results between studies and risk of a bronchodilator. Given the high
change score
bias in some trials, according to prevalence of bronchiolitis in infants
RCTs: randomized controlled trials
the Grading of Recommendations, and huge burden on health care
RDAI: respiratory distress
Assessment, Development and systems throughout the world,
assessment instrument
Evaluations (GRADE) criteria.42 benefits of nebulized HS shown by
RR: risk ratio
Moreover, all but 3 trials excluded this review, even though smaller than
RSV: respiratory syncytial virus
patients requiring mechanical previously estimated, may still be
RTI: respiratory tract infection
ventilation, intensive care, or having considered clinically relevant.
an oxygen saturation reading ,85% Moreover, good safety profile and low
on room air, so caution should be cost make nebulized HS a potential
taken when extrapolating the attractive therapeutic modality for REFERENCES
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145(1):106–109 volume, nebulizer flow, and 151–157

BACON FROM THE SEA: Recently, a friend prepared lunch for me. He toasted some
bread and then layered tomatoes, lettuce, and some dried leaves he had briefly pan
fried. The sandwich was delicious, but what really surprised me was that the
sandwich tasted just like a bacon, lettuce, and tomato sandwich – without any bacon.
When I asked him what gave the sandwich the bacon flavor, he responded with
a smile, “seaweed”.
As reported in Bon Appetit (Test Kitchen: July 30, 2015), the type of seaweed my
friend was referring to is called “dulse.” Dulse is an edible seaweed, much like nori
and kelp, which looks like leafy red lettuce and is packed with fiber, protein, and
minerals. It grows wild on the northern Atlantic and Pacific coasts, and is harvested
at low tide from early summer to early fall. Dulse is usually immediately dried and
sold either in whole leaf or powder form. Fresh dulse tastes a bit salty and has
mineral overtones suggestive of the ocean from which it came, while dried dulse can
take on a variety of flavors. However, when pan-fried, whole-leaf dulse becomes
smoky and savory, and tastes remarkably similar to bacon.
I like to cook with bacon, and will 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

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PEDIATRICS Volume 136, number 4, October 2015 from http://pediatrics.aappublications.org/ by guest on October 22, 2017 701
Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review
Linjie Zhang, Raúl A. Mendoza-Sassi, Terry P. Klassen and Claire Wainwright
Pediatrics 2015;136;687
DOI: 10.1542/peds.2015-1914 originally published online September 28, 2015;

Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/136/4/687
Supplementary Material Supplementary material can be found at:
http://pediatrics.aappublications.org/content/suppl/2015/09/22/peds.2
015-1914.DCSupplemental
References This article cites 38 articles, 7 of which you can access for free at:
http://pediatrics.aappublications.org/content/136/4/687.full#ref-list-1
Subspecialty Collections This article, along with others on similar topics, appears in the
following collection(s):
Pulmonology
http://classic.pediatrics.aappublications.org/cgi/collection/pulmonolo
gy_sub
Bronchiolitis
http://classic.pediatrics.aappublications.org/cgi/collection/bronchiolit
is_sub
RSV
http://classic.pediatrics.aappublications.org/cgi/collection/rsv_sub
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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
60007. Copyright © 2015 by the American Academy of Pediatrics. All rights reserved. Print
ISSN: .

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ERRATUM

E R R AT U M Zhang et al, Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic


Review. 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 Saline
for Acute Bronchiolitis: A Systematic Review” published in the October 2015 issue
of Pediatrics (2015;136[4]:687–701; doi:10.1542/peds.2015-1914).

On page 689, under Data Synthesis and Statistical Analysis, paragraph 3, on lines
14–15, “withdrawal rate .20%” should have read: “withdrawal rate .15% and
intention-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 trial
from the meta-analysis changes the results of hypertonic saline on length of stay
from an MD of –0.45 days (95% confidence interval 20.82 to 20.08) to MD of –0.51
days (95% confidence interval 20.91 to 20.11). Exclusion of this trial from the
subgroup analyses does not significantly affect the results.
doi:10.1542/peds.2016-0017

PEDIATRICS Volume 137, Number 4, April 2016 1


Nebulized Hypertonic Saline for Acute Bronchiolitis: A Systematic Review
Linjie Zhang, Raúl A. Mendoza-Sassi, Terry P. Klassen and Claire Wainwright
Pediatrics 2015;136;687
DOI: 10.1542/peds.2015-1914 originally published online September 28, 2015;

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/136/4/687

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

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

Downloaded from http://pediatrics.aappublications.org/ by guest on October 22, 2017