Research

JAMA Pediatrics | Original Investigation

Evaluating the Placebo Status of Nebulized Normal Saline

in Patients With Acute Viral Bronchiolitis
A Systematic Review and Meta-analysis
Samantha A. House, DO, MPH; Anne M. Gadomski, MD, MPH; Shawn L. Ralston, MD, MS

Supplemental content
IMPORTANCE In therapeutic trials for acute viral bronchiolitis, consistent clinical improvement
in groups that received nebulized normal saline (NS) as placebo raises the question of
whether nebulized NS acts as a treatment rather than a placebo.

OBJECTIVE To measure the short-term association of nebulized NS with physiologic measures

of respiratory status in children with bronchiolitis by analyzing the changes in these measures
between the use of nebulized NS and the use of other placebos and the changes before and
after nebulized NS treatment.

DATA SOURCES MEDLINE and Scopus were searched through March 2019, as were
bibliographies of included studies and relevant systematic reviews, for randomized clinical
trials evaluating nebulized therapies in bronchiolitis.

STUDY SELECTION Randomized clinical trials comparing children 2 years or younger with
bronchiolitis who were treated with nebulized NS were included. Studies enrolling a
treatment group receiving an alternative placebo were included for comparison of NS
with other placebos.

DATA EXTRACTION AND SYNTHESIS Data abstraction was performed per PRISMA guidelines.
Fixed- and random-effects, variance-weighted meta-analytic models were used.

MAIN OUTCOMES AND MEASURES Pooled estimates of the association with respiratory scores,
respiratory rates, and oxygen saturation within 60 minutes of treatment were generated for
nebulized NS vs another placebo and for change before and after receiving nebulized NS.

RESULTS A total of 29 studies including 1583 patients were included. Standardized mean
differences in respiratory scores for nebulized NS vs other placebo (3 studies) favored
nebulized NS by −0.9 points (95% CI, −1.2 to −0.6 points) at 60 minutes after treatment
(P < .001). There were no differences in respiratory rate or oxygen saturation comparing
nebulized NS with other placebo. The standardized mean difference in respiratory score
(25 studies) after nebulized NS was −0.7 (95% CI, −0.7 to −0.6; I2 = 62%). The weighted
mean difference in respiratory scores using a consistent scale (13 studies) after nebulized
NS was −1.6 points (95% CI, −1.9 to −1.3 points; I2 = 72%). The weighted mean difference
in respiratory rate (17 studies) after nebulized NS was −5.5 breaths per minute (95% CI,
−6.3 to −4.6 breaths per minute; I2 = 24%). The weighted mean difference in oxygen
saturation (23 studies) after nebulized NS was −0.4% (95% CI, −0.6% to −0.2%; I2 = 79%).
Author Affiliations: Department of
CONCLUSIONS AND RELEVANCE Nebulized NS may be an active treatment for acute viral Pediatrics, Children’s Hospital at
bronchiolitis. Further evaluation should occur to establish whether it is a true placebo. Dartmouth-Hitchcock Medical
Center, Lebanon, New Hampshire
(House); Department of Pediatrics,
Geisel School of Medicine, Dartmouth
College, Hanover, New Hampshire
(House); Research Institute,
Bassett Medical Center,
Cooperstown, New York (Gadomski);
Department of Pediatrics, Johns
Hopkins Medical School, Baltimore,
Maryland (Ralston).
Corresponding Author: Shawn L.
Ralston, MD, MS, Department of
Pediatrics, Johns Hopkins Medical
School, 1800 Orleans Ave,
JAMA Pediatr. doi:10.1001/jamapediatrics.2019.5195 Bloomberg 8470, Baltimore, MD
Published online January 6, 2020. 21287 (sralsto3@jhmi.edu).

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 Research Original Investigation
A
cute viral bronchiolitis, one of the most common child-
hood illnesses, has no established, evidence-based
nebulized therapy, to our knowledge.1-8 In most ran-
domized clinical trials, nebulized normal saline (NS) is used
as the placebo, which is logical given that NS is also used as
the vehicle for nebulization of the active treatment. How-
ever, consistent improvement above expected rates in pa-
tients receiving placebo has been noted across bronchodila-
tor trials.9 The waxing and waning nature of bronchiolitis may
explain these findings, but given the strong trend toward im-
provement, it is also possible that nebulized NS is acting as an
effective treatment.
Nebulized NS has historically been used as a placebo in
other conditions as well, typically in studies examining
bronchodilator medications and sputum expectorants.10 A
small amount of evidence exists to suggest that nebulized
NS may be an active treatment for adults with chronic
obstructive pulmonary disease. In a randomized clinical trial
of 40 patients with chronic obstructive pulmonary disease,
investigators used a technique of “inefficient” nebulization
to blind participants to treatment allocation and demon-
strated significant improvements in dyspnea scores favoring
NS nebulized through the effective nebulizer vs the ineffi-
cient nebulizer. 10 Randomized clinical trials comparing
nebulized NS with inhaled terbutaline and with inhaled
furosemide among patients with dyspnea have also found
similar improvement in breathlessness scores among groups
receiving active treatment and those receiving NS.11,12 How-
ever, in another very small trial of laboratory-induced dysp-
nea in 5 healthy volunteers that was specifically designed to
reduce expectation of dyspnea relief, only 1 in 5 patients
experienced relief, which investigators ascribed to the pla-
cebo effect.12
The concept of the placebo effect has recently undergone
reconsideration and refinement. The 1955 article by Beecher13
that first established the idea of the approximately equal to
30% placebo response rate has been critically reassessed,
suggesting that the reported findings were influenced by the
natural fluctuations of the diseases studied.14,15 Further-
more, 2 large meta-analyses of randomized clinical trials
comparing placebo vs no treatment failed to detect signifi-
cant placebo effects in many types of studies. In particular, the
more objective the outcome assessment, the less likely that
there was any measurable placebo effect detected.15,16 Less is
known about the effect of placebos on infants, in whom any
improvement is necessarily determined by external assess-
ment rather than self-report.
In this context, we sought to examine the hypothesis
that nebulized NS may be an active treatment rather than a
placebo for patients with acute viral bronchiolitis. We
undertook a systematic review and meta-analysis of ran-
domized clinical trials in acute viral bronchiolitis using
nebulized NS with 2 objectives: to compare nebulized NS
with other forms of placebo (eg, nonnebulized placebo or
sham nebulization) and to estimate the association of nebu-
lized NS with short-term physiologic measures of respira-
tory status in randomized clinical trials in which it was used
as the placebo.
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Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis
Key Points
Question Does nebulized normal saline have an association with
physiologic measures of respiratory status in patients with acute
viral bronchiolitis?
Findings This systematic review and meta-analysis found that
patients with bronchiolitis treated with nebulized normal saline
showed significant improvement in respiratory rate and
respiratory score after therapy, although oxygen saturation
remained unchanged. In addition, when compared with patients
treated with other placebos, those treated with nebulized normal
saline showed greater improvements in posttreatment respiratory
scores.
Meaning Nebulized normal saline may not be an inert placebo for
patients with bronchiolitis and should be further studied to
establish the clinical significance of any potential treatment
outcome.
Methods
Eligibility Criteria
Studies were considered for inclusion if they reported results
of a clinical trial of patients 2 years or younger with a primary
diagnosis of acute viral bronchiolitis who were treated with
nebulized NS. For trials comparing nebulized NS with an-
other placebo, at least 1 treatment group receiving only the al-
ternative form of placebo was additionally required for inclu-
sion. Only published studies were considered for this review.
Information Sources and Search Strategy
This study was conducted in accordance with the Preferred Re-
porting Items for Systematic Reviews and Meta-analyses
(PRISMA) reporting guideline. We searched MEDLINE from 1946
to March 2019 and Scopus from 1976 to March 2019. Search
terms are shown in eFigure 1 in the Supplement. Bibliographies
of qualifying studies and relevant systematic reviews were also
hand searched for additional candidate studies. A review
protocol was not registered prior to study completion.
Study Selection
Studies identified from the initial search results underwent title
and abstract review conducted by 2 independent reviewers
(S.A.H. and S.L.R.). Any discrepancies regarding inclusion were
resolved by consensus. Studies were then excluded through
full-text review if they failed to provide information on short-
term physiologic measures of respiratory status, which were
defined as composite respiratory score, respiratory rate, and/or
oxygen saturation values within the first hour after treat-
ment. Further exclusion criteria were inclusion of children older
than 2 years and receipt of another nebulized medication in
the NS group within 1 hour of study entry. For studies with in-
complete data and those excluded owing to lack of reporting
of short-term physiologic outcomes in which the study pro-
tocol suggested these data were collected, corresponding au-
thors were contacted via email to determine whether these ad-
ditional data were available. Foreign language studies were
translated into English.
jamapediatrics.com
 Table. Characteristics of Included Studies
Patients
Severity of Baseline Score, Receiving
a
Source Country Study Description Score Used Illness Included Mean (SD) Placebo, No.
Outpatient Studies

jamapediatrics.com
Schuh et al,19 1990 Canada Albuterol vs normal saline Other (each 0-3)b No minimum severity 1.6 (0.1), 19
1.8 (0.1)
Klassen et al,21 1991 Canada Albuterol vs normal saline RDAI (0-17) RDAI score 4-15 8.5 (2.9) 41
24
Schweich et al, 1992 United States Albuterol vs normal saline RDAI (0-17) No minimum severity 7.9 (2.2) 12
Gadomski et al,27 1994c United States Albuterol vs normal saline vs oral albuterol vs oral placebo Study specific (0-27) No minimum severity 10 (5) 18d
Gadomski et al,26 1994c Egypt Albuterol vs normal saline vs oral albuterol vs oral placebo Study specific (0-27) No minimum severity 14.2 (6.2) 32d
Van Bever et al,31 1995 Belgium Furosemide vs normal saline Tal (0-12) No minimum severity 5.1 (1.5) 14
Can et al,32 1998 Turkey Albuterol vs normal saline vs mist tent Other (0-20) Score ≥5 11.3 (3.6) 52d
34
Hariprakash et al, 2003 United Kingdom Epinephrine vs normal saline RDAI (0-17) RDAI score ≥3 7.6 (4) 36
Khashabi et al,35 2005 Iran Epinephrine vs salbutamol vs normal saline Other (0-26) Score 9-18 10.6 (3.8) 24
Ralston et al,36 2005 United States Epinephrine vs albuterol vs normal saline RDAI (0-17) RDAI score ≥4 8 (2) 25
39
Plint et al, 2009 Canada Epinephrine and oral dexamethasone vs epinephrine and oral placebo RDAI (0-17) RDAI score 4-15 8 (3) 201
vs normal saline and oral dexamethasone vs normal saline and
oral placebo
Anil et al,42 2010 Turkey Epinephrine in normal saline vs epinephrine in 3% saline vs albuterol Wang (0-12) Wang score 1-9 3.6 (1) 37
in normal saline vs albuterol in 3% saline vs normal saline
Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis

Ipek et al,43 2011 Turkey Nebulized albuterol in normal saline vs albuterol in 3% saline Wang (0-12) Wang score 4-8 4.7 (1) 30
vs 3% saline vs normal saline
Angoulvant et al,47 2017c France 3% Hypertonic saline vs normal saline RDAI (0-17) Moderate to severe 7.7 (3.4) 378
Inpatient Studies
Lines et al,20 1990 Australia Salbutamol vs normal saline RDAI (0-17) No minimum severity 7.7 (2) 23
22 b
Ho et al, 1991 Australia Salbutamol vs normal saline None No minimum severity NA 8
Lines et al,23 1992 Australia Ipratropium bromide vs normal saline RDAI (0-17)b No minimum severity NR 14
Kristjánsson et al,25 1993 Sweden Racemic adrenaline vs normal saline Other (0-10) Score ≥4 4.5 (1) 14
and Norway

© 2020 American Medical Association. All rights reserved.

Chowdhury et al,29 1995 Saudi Arabia Salbutamol vs ipratropium bromide vs combined salbutamol and Modified RDAI (0-20) Moderate 10 (2.4) 22

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ipratropium bromide vs normal saline
Reijonen et al,28 1995 Finland Racemic epinephrine followed by normal saline vs albuterol followed RDAI (0-17) No minimum severity 9.2 (3.3) 49
by normal saline vs normal saline followed by racemic epinephrine
vs normal saline followed by albuterol
Chevallier et al,30 1995 France Salbutamol vs normal saline Study specific (each 0-3)b Moderate 2.4 (0.5), 17
2.1 (0.7)
Abul-Ainine et al,33 2002 United Kingdom Adrenaline vs normal saline RDAI (0-17) Moderately severe 11.2 (3.3) 19
Karadag et al,37 2008 Turkey Salbutamol vs ipratropium bromide vs normal saline Wang (0-12) Wang score ≥6 8.8 (1.3) 23
Bar et al,38 2008 Israel Furosemide vs normal saline RDAI (0-17) No minimum severity 8.9 (5) 16

(continued)

(Reprinted) JAMA Pediatrics Published online January 6, 2020

Original Investigation Research

E3
 Research Original Investigation Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis

Data Collection Process

Reflects the number of patients receiving nebulized normal saline only; other placebo groups include 32 patients
receiving oral placebo (Gadomski et al27), 22 patients receiving oral placebo (Gadomski et al26), and 52 patients
Placebo, No.
Data abstraction was performed independently by 2 study in-

Receiving
Patients
vestigators (S.A.H. and S.L.R.) using a standardized data extrac-

201
tion sheet, cross-checked for agreement, and referred to a third

19
10

26

97
investigator (A.M.G.) for any disagreements. Data elements ex-
tracted included study setting and geographical location, types
Baseline Score,

of interventions, mean or median age of patients, illness sever-

Mean (SD)
7.4 (2.4)
3.1 (2.3)

4.3 (1.5)

3.5 (2.1)
4.9 (1) ity criteria for study entry, respiratory scores, respiratory rates,
and oxygen saturation. For all outcome measures, the mean and
SD of baseline and posttreatment values were collected when
available and calculated or imputed from presented data when
not directly available using methods provided in the Cochrane
No minimum severity

No minimum severity
Handbook.17 Sixty-minute posttherapy measures were used
RDAI score 4-15
Illness Included

Wang score ≥3

preferentially; 20- to 30-minute posttreatment measures were

Severity of

Analysis includes unpublished data provided by authors.

used when 60-minute measures were unavailable.

Score ≥4

Quality Assessment and Risk of Bias

The revised Cochrane risk of bias tool for randomized clinical
trials was used to screen for overall risk of bias within each in-
cluded study at the level of the outcomes investigated in our
meta-analysis. Two investigators (S.A.H. and S.L.R.) evalu-
receiving mist tent (Can et al32).

ated each study using this tool; discrepancies were referred to

Other (0-10)

Wang (0-12)
RDAI (0-17)
RDAI (0-17)

RDAI (0-17)

the third study author (A.M.G.) for resolution.

Score Used

Summary Measures and Data Synthesis

For studies evaluating nebulized NS vs another placebo, the
study-weighted mean differences in outcomes between treat-
5% Hypertonic saline vs mixed 5% hypertonic saline with standard

ment groups were calculated. For studies providing data on

(fixed schedule) vs normal saline (on demand) vs normal saline

treatment with nebulized NS over time, the study-weighted

d
c

mean differences in outcomes within the first 60 minutes of the

Racemic adrenaline (on demand) vs racemic adrenaline

study vs study baseline were calculated. Standardized mean dif-

ferences were used when combining respiratory scores for the
component (Schuh et al19 and Chevallier et al30), no score used (Ho et al22), or no baseline score reported
Excluded from score analysis owing to a 2-component score structure with baseline scores for each score

full study cohort because study-specific scores use different

scales; however, the scale was preserved in subgroup analysis
Abbreviations: NA, not applicable; NR, not reported; RDAI, respiratory distress assessment index.
3% Hypertonic saline vs normal saline

of studies using a consistent score. The point estimates and 95%

epinephrine 0.1% vs normal saline

CIs were computed with inverse-variance–weighted fixed- and

random-effects models using Comprehensive Meta-Analysis 2.0.
Terbutaline vs normal saline
Albuterol vs normal saline

Heterogeneity was assessed using the I2 statistic.

a
Study Description

Additional Analyses
(fixed schedule)

Preplanned subgroup analyses were conducted based on

whether the study population was outpatients vs inpatients
and in studies using the same respiratory scoring tool when
All medications were nebulized unless otherwise specified.
Table. Characteristics of Included Studies (continued)

more than 5 studies met this criterion. Sensitivity analyses were

performed by removing 1 study sequentially, removing outli-
ers as defined by failure of the individual study CI to overlap
either end of the CIs generated for the point estimates, and by
United States

United States

removing studies at high risk of bias based on the revised Coch-

Country

Norway
Tunisia

Tunisia

rane risk of bias tool for randomized trials.18

Results
Skjerven et al,41 2013
Scarlett et al,44 2012

Silver et al,46 2015c

Tinsa et al,40 2009

Tinsa et al,45 2014

Study Selection
(Lines et al23).

A total of 1084 citations were identified in the initial database

search. Bibliography review of included studies and relevant
Source

meta-analyses resulted in an additional 26 candidate stud-

ies. After duplicate removal, 874 studies were screened, with
b
a

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 Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis Original Investigation Research

Figure 1. Summary of Differences in Respiratory Score After Treatment With Nebulized Normal Saline

Source
Inpatient
Lines et al,20 1990
Scarlett et al,44 2012
Kristjánsson et al,25 1993
Reijonen et al,28 1995
Chowdhury et al,29 1995
Abul-Ainine et al,33 2002
Bar et al,38 2008
Karadag et al,37 2008
Tinsa et al,40 2009
Skjerven et al,41 2013
Tinsa et al,45 2014
Silver et al,46 2015
Fixed
Random
Outpatient
Klassen et al,21 1991
Schweich et al,24 1992
Gadomski et al,27 1994
Gadomski et al,26 1994
Van Bever et al,31 1995
Can et al,32 1998
Hariprakash et al,34 2003
Ralston et al,36 2005
Khashabi et al,35 2005
Plint et al,39 2009
Anil et al,42 2010
Ipek et al,43 2011
Angoulvant et al,47 2017
Fixed
Random
Overall
Fixed
Random
Improvement No Improvement
Mean Standard With Normal With Normal
Difference (95% CI) Saline Saline
–0.3 (–0.9 to 0.3)
–0.1 (–1.0 to 0.7)
–0.2 (–0.9 to 0.6)
–0.7 (–1.1 to –0.3)
–1.5 (–2.1 to –0.8)
–1.0 (–1.7 to –0.3)
–0.4 (–1.1 to 0.3)
–0.2 (–0.8 to 0.3)
–1.0 (–1.7 to –0.4)
–1.1 (–1.3 to –0.9)
–0.2 (–0.7 to 0.4)
–0.1 (–0.4 to 0.2)
–0.7 (–0.8 to –0.5)
–0.6 (–0.9 to –0.3)
–0.8 (–1.2 to –0.3)
–0.6 (–1.4 to 0.3)
–0.8 (–1.3 to –0.3)
–1.2 (–1.8 to –0.5)
–0.9 (–1.7 to –0.2)
–0.4 (–0.8 to –0.0)
–0.2 (–0.6 to 0.3)
–0.4 (–1.0 to 0.2)
–0.6 (–1.2 to –0.0)
–0.6 (–0.8 to –0.4)
–0.9 (–1.4 to –0.4)
–0.9 (–1.4 to –0.3)
–0.7 (–0.9 to –0.6)
–0.7 (–0.7 to –0.6)
–0.6 (–0.8 to –0.5)
–0.7 (–0.7 to –0.6)
–0.6 (–0.7 to –0.5)

–2.0 –1.0 0 1.0

Mean Standard Difference (95% CI)

118 potentially meeting inclusion criteria after title and ab-
stract screening. Eighty-nine studies were excluded by full-
text review. The most frequent reason for trial exclusion in full-
text review was that the study did not report data on outcomes
of interest. Twenty-nine studies met inclusion criteria based
on reported outcomes.19-47 Additional data were requested by
email from 5 authors, and 3 responded with unpublished data
for 4 included studies.26,27,46,47 Study selection is depicted in
eFigure 1 in the Supplement. Three studies enrolling a group
receiving nonnebulized placebo were identified.26,27,32
Study Characteristics
The Table provides detailed information on the included stud-
ies. These 29 trials were performed in numerous countries and
evaluate a range of active therapies, including nebulized epineph-
rine, albuterol, hypertonic saline, terbutaline, ipratropium, and
furosemide. Fifteen studies were conducted in the inpatient
setting,20,22,23,25,28-30,33,37,38,40,41,44-46 and 14 were conducted in
the outpatient setting.19,21,24,26,27,31,32,34-36,39,42,43,47 In total, there
were 1477 patients who received nebulized NS and 106 patients
who received a nonnebulized placebo. The Respiratory Distress
Assessment Index (RDAI)48 was the most commonly used
scoring system in 14 trials.20,21,23,24,28,33,34,36,38-40,44,46,47 About
half of the trials specified a minimum level of severity of disease
for study entry.21,25,29,30,32-37,39-41,43,45,47
Risk of Bias
Most studies were categorized as having some concern for
bias, although 8 studies were found to be at high risk for
bias20,23,25,29,31,32,41,44 (eFigure 2 in the Supplement).
Nebulized NS vs Other Placebo
Three studies compared nebulized NS with a nonnebulized
placebo, including 2 using an oral placebo and 1 using a mist
tent.26,27,32 Standardized mean differences in scores for the
NS group (n = 102) vs other placebo group (n = 106) favored
NS by −0.9 points (95% CI, −1.2 to −0.6 points) at 60 minutes
after therapy (P < .001). The study protocols in the 2 studies

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 Research Original Investigation Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis

Figure 2. Summary of Differences in Respiratory Score After Nebulized Normal Saline

for All Studies Reporting Respiratory Distress Assessment Index Scores

Source
Inpatient
Lines et al,20 1990
Scarlett et al,44 2012
Reijonen et al,28 1995
Abul-Ainine et al,33 2002
Bar et al,38 2008
Tinsa et al,40 2009
Silver et al,46 2015
Fixed
Random
Outpatient
Klassen et al,21 1991
Schweich et al,24 1992
Hariprakash et al,34 2003
Ralston et al,36 2005
Plint et al,39 2009
Angoulvant et al,47 2017
Fixed
Random
Overall
Fixed
Random
Improvement No Improvement
Mean Difference With Normal With Normal
(95% CI) Saline Saline
–0.6 (–1.8 to 0.6)
–0.3 (–2.3 to 1.7)
–2.7 (–4.2 to –1.1)
–3.7 (–6.1 to –1.3)
–1.5 (–4.4 to 1.4)
–1.9 (–3.1 to –0.7)
–0.2 (–0.8 to 0.4)
–0.9 (–1.4 to –0.4)
–1.4 (–2.3 to –0.4)
–2.3 (–3.6 to –1.0)
–1.3 (–3.1 to 0.5)
–0.7 (–2.5 to 1.1)
–1.0 (–2.4 to 0.4)
–1.7 (–2.2 to –1.1)
–2.4 (–2.9 to –1.9)
–2.0 (–2.3 to –1.6)
–1.8 (–2.3 to –1.3)
–1.6 (–1.9 to –1.3)
–1.7 (–2.2 to –1.2)

–8.0 –6.0 –4.0 –2.0 0 2.0 4.0

Mean Difference (95% CI)

comparing NS with oral placebo were identical because they
were performed by the same team of investigators in 2 dif-
ferent countries; thus, we subanalyzed these data with the
respiratory score scale preserved.26,27 Weighted mean differ-
ences in scores for the NS group (n = 50) vs oral placebo
group (n = 54) favored NS by −1.6 points (95% CI, −0.8 to
−0.03 points) on a study-specific respiratory score (scale,
0-20) at 60 minutes after therapy (P = .04). There were no
differences in respiratory rate or oxygen saturation between
the group receiving nebulized NS and the group receiving
the other placebos.
Association of Nebulized NS With Respiratory Scores
A total of 25 studies reported composite respiratory scores over
time for patients receiving nebulized NS.20,21,24-29,31-47 The stan-
dardized mean difference in scores within 60 minutes after
nebulized NS decreased by −0.7 (95% CI, −0.7 to −0.6; I2 = 62%;
P < .001) (Figure 1). Random-effects modeling and subgroup
analysis by study setting did not substantively alter the point
estimates; however, heterogeneity appeared to be associat-
edwith inconsistency in the inpatient subgroup (outpatient
I2 = 4%; inpatient I2 = 79%).
Association of Nebulized NS With RDAI Score
The RDAI (scale, 0-17 points) was the only score used in enough
studies to perform subgroup analysis preserving scale. A total
of 13 studies reported RDAI data20,21,24,28,33,34,36,38-40,44,46,47;
1 study used this scoring system, but baseline scores could not
be ascertained, and thus the score was not analyzed for this
study.23 The weighted mean difference in scores within 60 min-
utes after nebulized NS decreased by −1.6 points (95% CI, −1.9
to −1.3 points; I2 = 72%; P < .001) (Figure 2). Subgroup analy-
sis demonstrated a −2.0-point (95% CI, −2.3 to −1.6 points) de-
crease in the outpatient subgroup vs a −0.9-point (95% CI, −1.4
to −0.4 points) decrease in the inpatient subgroup. Random-
effects modeling did not substantively alter the point esti-
mates, whereas heterogeneity appeared to be associated with
inconsistency in the inpatient subgroup (outpatient I2 = 42%;
inpatient I2 = 72%).
Association of Nebulized NS With Respiratory Rate
In the 17 studies providing data on respiratory rates,19-21,23,
24,26-28,30,33-35,38-40,43,47
the weighted mean difference within
60 minutes after nebulized NS decreased by −5.5 breaths per
minute (95% CI, −6.3 to −4.6 breaths per minute; I2 = 24%;
P < .001) (Figure 3). Fixed-effects vs random-effects model-
ing and subgroup analyses by study setting did not substan-
tively alter the point estimates, and heterogeneity was low in
the overall analysis.
Association of Nebulized NS With Oxygen Saturation
In the 23 studies providing data on oxygen saturation,19-28,
30,32-40,42,43,47
the weighted mean difference within 60 min-
utes after nebulized NS decreased by −0.4% (95% CI, −0.6%
to −0.2%; I2 = 79%; P < .001) (Figure 4). Random-effects
modeling substantively altered the overall point estimate
toward nonsignificance (mean difference, −0.3%; P = .10).
Subgroup analysis also produced a nonsignificant point esti-

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 Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis Original Investigation Research

Figure 3. Summary of Differences in Respiratory Rate After Treatment With Nebulized Normal Saline

Source
Inpatient
Lines et al,20 1990
Lines et al,23 1992
Chevallier et al,30 1995
Reijonen et al,28 1995
Abul-Ainine et al,33 2002
Bar et al,38 2008
Tinsa et al,40 2009
Fixed
Random
Outpatient
Schuh et al,19 1990
Klassen et al,21 1991
Schweich et al,24 1992
Gadomski et al,27 1994
Gadomski et al,26 1994
Hariprakash et al,34 2003
Khashabi et al,35 2005
Plint et al,39 2009
Ipek et al,43 2011
Angoulvant et al,47 2017
Fixed
Random
Overall
Fixed
Random
Improvement No Improvement
Mean Difference With Normal With Normal
(95% CI) Saline Saline
–3.2 (–10.9 to 4.5)
–5.5 (–9.3 to –1.7)
–4.7 (–11.6 to 2.2)
–6.9 (–11.3 to –2.5)
–4.2 (–9.7 to 1.3)
–3.3 (–13.0 to 6.4)
–3.4 (–11.7 to 4.9)
–5.1 (–7.3 to –3.0)
–5.1 (–7.3 to –3.0)
–8.7 (–10.6 to –6.8)
–2.0 (–6.8 to 2.8)
–1.4 (–9.4 to 6.6)
–5.0 (–7.9 to –2.1)
–7.0 (–13.9 to –0.1)
–4.0 (–9.1 to 1.1)
–7.2 (–11.8 to –2.6)
–3.0 (–5.5 to –0.5)
–4.0 (–7.6 to –0.4)
–5.2 (–6.8 to –3.6)
–5.5 (–6.5 to –4.6)
–5.1 (–6.7 to –3.5)
–5.5 (–6.3 to –4.6)
–5.1 (–6.4 to –3.9)

–12.0 –6.0 0 0.6 12.0

Mean Difference (95% CI)

mate in the outpatient subgroup (mean difference, 0.3%; estimates, although it did produce a modest decrease in hetero-
P = .38). Furthermore, heterogeneity was high in the out- geneity (I2 = 60%).
patient subgroup (I 2 = 83%) vs the inpatient subgroup
(I2 = 49%).

Sensitivity Analyses
Sensitivity analyses removing 1 study did not alter the overall
point estimates for any of the analyses. For the RDAI, sensi-
tivity analysis removing outliers46 reduced heterogeneity to
acceptable levels (I2 = 42%) while producing a similar point es-
timate (mean difference, −1.9; 95% CI, −2.2 to −1.6). For respi-
ratory rate, sensitivity analysis removing outliers19 did not sub-
stantively alter findings. For oxygen saturation, sensitivity
analysis removing outliers23,32,35,47 produced an overall point
estimate of −0.2%, which was not statistically significant
(P = .10), with acceptable heterogeneity (I2 = 24%).
Sensitivity analysis removing studies at high risk of bias
in the respiratory score analysis20,25,29,31,32,41,44 did not sub-
stantively alter the point estimate, although it reduced hetero-
geneity (I2 = 47%). Removal of studies at high risk of bias in
the RDAI analysis20,44 did not substantively alter the point es-
timate or measures of heterogeneity. Removal of studies at high
risk of bias from the respiratory rate analysis20,23 did not sub-
stantively alter the point estimate or measures of heteroge-
neity. Removing studies at high risk of bias from the oxygen
saturation analysis20,23,25,32 did not substantively alter the point
Discussion
In this systematic review of randomized clinical trials using
nebulized NS as a placebo, we encountered direct and indi-
rect evidence that NS may be an active treatment rather than
a placebo. The direct evidence comes from 3 studies involv-
ing more than 200 patients, in which nebulized NS was evalu-
ated vs other placebos and significantly improved respira-
tory scores. The indirect evidence comes from significantly
improved assessments of respiratory scores and respiratory
rates before and after nebulized NS in several randomized clini-
cal trials. Although the quality of this evidence is not strong
owing to the small number of studies in the first analysis and
the absence of a comparator group in the second, it is consis-
tent across a wide variety of trials and is concordant. Finally,
there was an equivocal association with oxygen saturation
noted in the meta-analysis, with high heterogeneity in the
broad sample; subgroup analysis and sensitivity analysis re-
solving this heterogeneity suggest that nebulized NS has no
association with oxygen saturation.
There are several potential explanations for our findings.
It is possible that nebulized NS is truly not a placebo; that is,

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 Research Original Investigation Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis

Figure 4. Summary of Differences in Oxygen Saturation After Treatment With Nebulized Normal Saline

Source
Inpatient
Lines et al,20 1990
Ho et al,22 1991
Lines et al,23 1992
Kristjánsson et al,25 1993
Chevallier et al,30 1995
Reijonen et al,28 1995
Abul-Ainine et al,33 2002
Bar et al,38 2008
Karadag et al,37 2008
Tinsa et al,40 2009
Fixed
Random
Outpatient
Schuh et al,19 1990
Klassen et al,21 1991
Schweich et al,24 1992
Gadomski et al,27 1994
Gadomski et al,26 1994
Can et al,32 1998
Hariprakash et al,34 2003
Ralston et al,36 2005
Khashabi et al,35 2005
Plint et al,39 2009
Anil et al,42 2010
Ipek et al,43 2011
Angoulvant et al,47 2017
Fixed
Random
Overall
Fixed
Random
Improvement No Improvement
Mean Difference With Normal With Normal
(95% CI) Saline Saline
–1.0 (–2.1 to 0.1)
0.3 (–1.0 to 1.6)
–1.9 (–2.5 to –1.3)
–0.2 (–1.9 to 1.5)
–0.9 (–1.8 to 0.0)
–0.4 (–1.3 to 0.5)
–0.2 (–2.1 to 1.7)
0.0 (–2.7 to 2.7)
–0.5 (–2.8 to 1.8)
–0.5 (–1.7 to 0.7)
–1.0 (–1.3 to –0.6)
–0.7 (–1.3 to –0.2)
–0.5 (–1.6 to 0.6)
0.0 (–1.7 to 1.7)
0.7 (–0.1 to 1.5)
0.0 (–2.0 to 2.0)
0.0 (–1.0 to 1.0)
1.6 (1.1 to 2.5)
0.0 (–0.9 to 0.9)
–1.5 (–4.3 to 1.3)
2.5 (0.9 to 4.1)
–0.8 (–1.4 to –0.2)
1.0 (0.0 to 2.0)
1.0 (–0.5 to 2.5)
–1.0 (–1.4 to –0.6)
–0.1 (–0.4 to 0.1)
0.3 (–0.4 to 0.9)
–0.4 (–0.6 to –0.2)
–0.3 (–0.7 to 0.1)

–4.0 –2.0 0 2.0 4.0

Mean Difference (95% CI)

it provides a small beneficial effect on young children with
acute viral bronchiolitis through improvement in hydration of
airway surfaces and mucous clearance and decreased upper
airway resistance. It is also possible that the clinical course of
bronchiolitis waxes and wanes independent of nebulized NS
or other therapies being evaluated. Patients may be given an-
tipyretics or nasal suction or simply settle down after the ini-
tial evaluation phase, thus appearing improved. Several stud-
ies have noted that respiratory rate and respiratory score are
correlated with a patient’s state (eg, awake, asleep, or
crying).25-27,33 It is not possible to isolate the relative effect of
additional symptomatic therapies or patient state vs that of
nebulized NS on the outcomes evaluated in this data set. A third
possibility is that the primary method of evaluation (respira-
tory score) is a biased tool that is susceptible to psychological
effects in the evaluator and that these repeated measures tend
to regress toward the mean. Modern thinking about the pla-
cebo effect has become more nuanced, and it appears that
any potentially subjective symptom measurement tool (such
as pain or depression scales) is more likely to demonstrate a
placebo effect than objective outcomes.15 This phenomenon
could be associated with the findings on the respiratory scor-
ing tools in our study as well.
We cannot draw firm conclusions regarding treatment from
our results owing to the wide range of potential explanations
described and the inherent bias associated with pretreatment
and posttreatment evaluation. Our data should not affect the
current consensus that the active therapies evaluated in acute
viral bronchiolitis do not alter the disease course. Although the
presence of a treatment effect from a medication given in an an-
cillary manner to both treatment groups in a randomized clini-
cal trial (either as the placebo therapy or the vehicle for active
therapy) may complicate study power analyses, there is no com-
pelling reason to believe that it would interfere with the treat-
ment effect from other active medications. At a minimum, our
data should highlight the need for future randomized clinical
trials of this disease to account for the fact that short-term physi-
ologic measures will strongly trend toward improvement. Thus,
power analyses will need to account for decreased sensitivity
to changes in these measures.

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 Placebo Status of Nebulized Normal Saline in Patients With Acute Viral Bronchiolitis Original Investigation Research

Limitations more reflective of overall disease course and severity, such

This meta-analysis has some limitations, including the
heterogeneity of the included trials, with varying maximum
ages, populations, and criteria for severity of illness for
study entry. Study heterogeneity was excessive for some of
our aggregate analyses, although we managed to resolve it to
acceptable levels with subgroup and sensitivity analyses
without changing the overall conclusions. It is highly likely
that severity of illness would have a significant association
with our study outcomes because patients with mild disease
may have a small margin for improvement given their rela-
tively normal vital signs and low distress scores at baseline.
In addition, the clinical significance of the short-term physi-
ologic outcomes that we propose from treatment with nebu-
lized NS is unclear. Although reductions in respiratory score
and respiratory rate may signal short-term clinical improve-
ment, we did not evaluate other relevant clinical outcomes
as hospitalization rates or hospital length of stay. Finally, we
made no effort to include unpublished abstracts; thus, it is
possible that missing data could alter our conclusions,
although this possibility is unlikely given the numbers of
patients and studies included.
Conclusions
This meta-analysis suggests that nebulized NS could be an ac-
tive treatment for acute viral bronchiolitis rather than an in-
ert placebo. Further evaluation of nebulized NS vs sham nebu-
lization and/or oral placebo should occur to establish whether
or not nebulized NS is a true placebo. Future study designs
should factor in the potential treatment effect of nebulized
NS on short-term outcomes.

ARTICLE INFORMATION
Accepted for Publication: September 9, 2019.
Published Online: January 6, 2020.
doi:10.1001/jamapediatrics.2019.5195
Author Contributions: Drs House and Ralston
had full access to all the data in the study and take
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: All authors.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important
intellectual content: All authors.
Statistical analysis: All authors.
Administrative, technical, or material support:
House, Gadomski.
Conflict of Interest Disclosures: None reported.
Additional Contributions: Paige N. Scudder, MLIS,
Biomedical Libraries, Dartmouth College, assisted
with the initial literature search. She was not
compensated for her contribution.
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