Nebulized 5% or 3% Hypertonic or 0.

9% Saline for Treating Acute

Bronchiolitis in Infants
Khalid Al-Ansari, MD, FRCPC, FAAP(PEM), Mahmoud Sakran, MD, Bruce L. Davidson, MD, MPH, Rafah El Sayyed, MD,
Hella Mahjoub,
Mahjoub, MD, and Khalid Ibrahim,
Ibrahim, MD

Objective To compcompararee the

the effica
efficacy
cy and
and safe
safety
ty of 5%,
5%, 3%,
3%, and
and 0.9%
0.9% sali
saline
ne solu
soluti
tion
on for
for trea
treati
ting
ng acut
acute e bron
bronchchio
ioliliti
tiss
in the prehospital setting.
Study design This was a double-blind trial including consecutive infants aged <18 months treated in an urban
urgent care setting. A total of 165 patients were randomized to receive nebulized 5%, 3%, or 0.9% (normal) saline
with epinephrine every 4 hours. The primary efficacy outcome was bronchiolitis severity score improvement at 48
hours ( c2 analysis). Scores and oxygen saturation immediately before and after each treatment were recorded to
assess safety.
Results A total of 187 previously healthy infants (median age, 3.1 months) diagnosed with bronchiolitis were
enrolled. Positivity for respiratory syncytial virus was similar in the 3 treatment groups (mean, 56%). At 48 hours,
the mean severity score for the 5% saline group was 3.69 Æ 1.09, and that for the 0.9% saline group was 4.12 Æ
1.11 ( P = .04; difference, 0.43, 95% confidence interval for the difference, 0.02-0.88). The mean severity score
for
for the
the 3% sali
saline
ne grou
groupp was
was inte
interm
rmed
edia
iate
te at 4.00
4.00 Æ 1.22
1.22.. Revi
Revisi
sitt rate
ratess afte
afterr disc
discha
harge
rge were
were simi
simila
larr in the
the 3 trea
treatm
tmenentt
groups. No adverse reactions or other safety concerns were identified.
Conclusions Nebuli
Nebulizat
zation
ion with
with 5% hypert
hypertoni
onicc saline
saline is saf
safe,
e, can
can be widely
widely genera
generaliz
lizabl
able,
e, and may be be superi
superioror to
current treatment for early outpatient treatment of bronchiolitis. (J Pediatr 2010;157:630-4) .

B
ronchiolitis is among the most cocommon and serious lower respiratory tract infection
infectionss in young children, affecting
mainly
mainly infants months.1,2 Incidence peaks between December and March.3,4 In the United States in 2002,
infants aged 2-5 months.
149 000 patients with bronchiolitis required hospitalization, with a mean hospital stay of 3.3 days and admission costs
of $500 million.5 In Qatar in 2008, about 4600 patients made about 6100 visits to pediatric emergency centers for bronchiolitis;
20% of these patients were hospitalized.
The mainstay of treatment remains supportive care, with supplemental ox  ygen and hydration if needed, and a trial of bron-
chodilator therapy (albuterol/salbutamol or epinephrine) as an option.6-8 Using the bronchiolitis severity score to assess
patien
patients
ts over
over time,
time, inhale
inhaled
d 3% hypert
hypertoni
onicc saline
saline with
with epinep
epinephri
hrine
ne admini
administestered
red by nebuli
nebuliza
zation
tion every
every 6-8 hours
hours has been
been found
found
to improve the bronchiolitis seve
severity
rity score and reduce the length of hospital stay in hospita
hospitalized patients when compared with
0.9% saline with epinephrine;9-13 this treatment is not routinely recommended, however.8 In patients with cystic fibrosis, hy-
pertonic saline concentration of 3%, 7%, and 12% have shown promisepromise inin a dose-response pattern for improving mucociliary 
14,15
clearance and maintaining lung function compared with 0.9% saline. Cough and chest tightness at the time of hypertonic
saline administration were reported in those patients, however.
Early, prehospital intervention for bronchiolitis with a safe, effective, and inexpensive agent might save lives, reduce com-
plications and hospitalizations, and be applicable for use worldwide, including small communities where hospital care is
not available. We reasoned that a hypertonic saline concentration >3% could be safe and more efficacious, alleviating severe
symptoms and avoiding the need f or or hospitalization in some instances. To build on the therapeutic benefit of 3% saline for
inpatients with acute bronchiolitis,9-13 we applied the dose-response and safety data from stable patients with cystic fibrosis,
cautiously focusing on 5% rather than higher concentrations for our infant patients. We compared 5% saline with 3% saline
and 0.9% (normal) saline in terms of efficacy and safety in treating acute bronchiolitis in the outpatient, early treatment*infir-
mary setting.

Methods From the Division of Pediatric Emergency Medicine,

Department of Pediatrics, Hamad Medical Corporation,
Doha, Qatar (K.A., M.S., R.E., H.M., K.I.); Weill Cornell
We conducted a double-blinded, randomized, parallel-group clinical trial to Medical
Medical College,Doha,
College,Doha, Qatar(K.A.,B.D.); andDivisionof 
compare the efficacy and safety of 5% and 3% hypertonic saline versus 0.9% Pulmonary and Critical Care Medicine, University of 
Washington School of Medicine, Seattle, WA (B.D.)
(normal) saline for the treatment of acute bronchiolitis. The study was con- Supported by Hamad Medical Corporation which em-
ploys all of the physicians except B.D., who also worked
at Hamad. The authors declare no conflicts of interest.
Registered at clinicaltrials.gov
clinicaltrials.gov:: ID# NCT01016249.
NCT01016249.
ICU Intensive care unit
RSV
RSV Resp
Respir
irat
ator
oryy sync
syncyt
ytia
iall viru
viruss 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc.
  All rights reserved. 10.1016/j.jpeds.2010.04.074

630

ducted between September 2007 and December 2008 in the
short-stay unit of the Pediatric Emergency Center of Hamad
General Hospital, the only pediatric emergency facility in
Qatar. The center serves an average of 200 000 patients
annually and manages 42 beds in a short-stay unit. Patients
admitted to the unit are assessed at least every 6 hours by a pe-
diatrician to determine readiness for discharge. The length of  hospital admission.
stay in the unit for bronchiolitis ranges from 6 to 168 hours.
Infants aged #18 months presenting to the unit for the
treatment of moderate to severe viral bronchiolitis were eligi-
ble for the study. Inclusion criteria were a prodromal history  minimal or absent wheezing, crackles, and chest retractions,
consistent with viral upper respiratory tract infection fol-
lowed by wheezing and/or crackles on auscultation and
a Wang bronchiolitis severity score16 of  $4 (Table I;
available at www.jpeds.com) on presentation.
Patients were excluded from the study if they had one or
more of the following characteristics: born at #34 weeks’ ges-
tation, previous history of wheezing, steroid use within 48
hours of presentation, obtundation and progressive respira-
tory failure requiring intensive care unit (ICU) admission,
history of apnea within 24 hours before presentation, oxygen
saturation #85% on room air at the time of recruitment, his-
tory of a diagnosis of chronic lung disease, congenital heart
disease, or immunodeficiency. The 6 attending physicians
covering the 18 beds in the respiratory section of the short-
stay unit were trained on using the Wang bronchiolitis sever-
ity score and its practical application on 4 patients with bron-
chiolitis before the start of the study. Written informed
consent, sought from a parent or legal guardian as soon as
the patient was admitted to the unit, was obtained for every  ity score for each treatment group at 48 hours. Secondary
participant. The study was approved by the hospital’s Institu-
tional Review Board.
Study Procedures
Patients were examined on presentation in the Pediatric
Emergency Center’s examination area, and those needing
further treatment or observation were admitted to the
short-stay unit. Patients with bronchiolitis were assessed
for study eligibility within 2 hours of the initial physician as-
sessment. In patients for whom consent was obtained, plain
chest radiography was performed, and nasopharyngeal
swabs were taken for detection of respiratory syncytial virus
(RSV) (RSV Respi-Strip; Coris Bioconcept, Gembloux, Bel-
gium). Then a computer-generated list of random numbers
was used by the enrolling physicians in consecutive order to
identify a sealed envelope containing 1 of 3 codes identifying
1 of 3 different 500-mL bags of sterilely prepared blinded
study solution containing 5%, 3%, or 0.9% saline, prepared
fresh each morning by a pharmacist blinded to patient
assignment.
Patients received 5mL of the study nebulization mixed
with 1.5 mL of epinephrine in a double-blinded fashion on
enrollment and every 4 hours thereafter until they were ready  improvement in severity score at 48 hours for not-yet-
for discharge. Inhaled medications were delivered through
a tight-fitting face mask by pressurized oxygen with the
flow meter set at 10 L/min. Additional nebulized epinephrine
(5 mL) delivered in the same way could be administered with
Vol. 157, No. 4  October 2010
blinded study solution at a maximum frequency of every 
hour, and additional treatment (eg, supplementary oxygen,
hydration) could be given at the discretion of the treating
physician. Patients were withdrawn from the study if oxygen
saturation within 30 min after nebulization fell below 85% on
room air or if clinical deterioration was deemed to warrant
A patients could be discharged when the treating physician
determined she or he did not need supplementary oxygen,
was feeding adequately without intravenous fluids, and had
provided that oxygen saturation was $ 94% and the severity 
score was <4. However, quite frequently, the actual time of 
discharge was determined based on social factors, such as
availability and consensus of family members. At discharge,
patients were sent home with an albuterol metered-dose in-
haler with an appropriately sized Aerochamber and mask at-
tachment (Forest Laboratories, Dublin, Ireland). Daily 
telephone follow-up by a study nurse was mandatory for 1
week after discharge. A patient could return to the Pediatric
Emergency Center earlier if desired or necessary.
Study Measurements and Outcomes
Immediately before each scheduled nebulization (initial and
every 4 hours), immediately after, and 2 hours after, the fol-
lowing measurements were collected for each patient: bron-
chiolitis severity score, oxygen saturation on room air, and
heart rate. The primary efficacy outcome in this double-
blinded study was mean prenebulization bronchiolitis sever-
 
outcomes were the severity scores at 24 hours and trend
over time to 72 hours, 2-hour postnebulization severity 
scores trending over time, and safety measures. The latter in-
cluded severity scores and oxygen saturation levels immedi-
ately before versus after nebulization, number of patients
requiring ICU admission, number requiring readmission to
the short-stay unit, and the number revisiting the Pediatric
Emergency Center in the week after discharge.
Statistical Analysis
We predicted a dose response with a superior (lower) severity 
score at 48 hours for patients not already discharged in the
5% saline group compared with the 0.9% saline group,
with an intermediate value for the 3% saline group. We
also predicted that mean scores starting at about 16 hours af-
ter the start of treatment would confirm this relationship. We
predicted that by 72 hours, the group mean differences would
disappear, due to relatively refractory illness among remain-
ing patients regardless of saline group assignment. Given that
pervious studies of hospitalized patients with bronchiolitis
had severity scores of ~7, we estimated that our less ill outpa-
tients’ mean severity scores would be ~6. We felt that a 10%
discharged patients randomized to the 5% saline group
compared with the 0.9% saline group would be clinically sig-
nificant. Assuming that the 0.9% saline group remained at
a score of 6, a reduction to 5.4 for the 5% saline group and
631
THE JOURNAL OF PEDIATRICS  www.jpeds.com
to an intermediate value for the 3% saline group would con-
firm our hypothesis. We calculated descriptive statistics
(mean, standard deviation and frequency) with percentages
for relevant variables, using c2 tests for categorical variables
and one-way analysis of variance with post hoc Bonferroni
correction for continuous variables. We used SPSS 14.0 sta-
tistical packages (SPSS Inc., Chicago, Illinois) for all data en-
try and analysis.
We calculated that having 45 patients per group would
provide 80% power to show a mean severity score improve-
ment of 10% for the 5% saline group versus the 0.9% saline
group, assuming a standard deviation of about 1 for each
mean severity score. We did not intend to definitively com-
pare the 5% and 3% saline groups. To account for patients
discharged before the 48-hour time point, we added 10 pa-
tients to each group, for a sample size of 55 patients per
group. Patients properly enrolled with outcome data at 48
hours were included in the analysis.
Results
A total of 187 previously healthy infants diagnosed with viral
bronchiolitis, median age 3.1 months (range, 9 days to 14.7
months), were enrolled in the study. Sixteen infants were ex-
cluded from the analysis; 9 should have been excluded from
enrollment (4 born at #34 weeks’ gestational age, 2 with
a history of apnea with cyanosis before enrollment, 1 with
previously known severe laryngomalacia, and 2 who had
received steroids within 24 hours before enrollment), 1 infant
was enrolled twice in the study (the second enrollment was
excluded from the analysis), and 6 infants were electively re-
moved by their parents. Of the 171 infants remaining, 57
were randomized to receive 5% hypertonic saline, 58 to re-
ceive 3% hypertonic saline, and 56 to receive 0.9% saline.
Subjects’ baseline characteristics before enrollment were sim-
ilar in the 3 treatment arms (Table II).
Efficacy  cyanosis, or decreased oxygen saturation. No patient re-
Figure 1 shows bronchiolitis severity scores from baseline to
72 hours. At the primary outcome time point of 48 hours, the
mean severity score for the 5% saline group was 3.69 Æ 1.09,
and that for the 0.9% saline group was 4.12 Æ 1.11 (P  = .04;
Table II. Baseline characteristics of enrolled infants
0.9% saline
Characteristics (n = 56)
Age, months, mean Æ3.30
2.43
Duration of symptoms before enrollment, (days) 3.6 Æ 1.87
Male/female, n 31/26
Baseline severity score 5.77 Æ 1.37
Baseline O2 saturation, % 97.36 Æ1.16
RSV-positivity, n (%) 31 (55.4%)
Chest X-ray, n (%)
Normal 42 (75%)
Viral pneumonia 11 (19.6%)
Collapse/consolidation 3 (5.4%)
632
Vol. 157, No. 4
difference, 0.43; 95% confidence interval for the difference,
0.02-0.88). The mean severity score for the 3% saline group
was intermediate, at 4.00 Æ 1.22. At 24 hours after
randomization, the mean severity score for the 5% saline
group was 3.75 Æ 1.27, and that for the 0.9% saline group
was 3.97 Æ 1.40 (P  = .38). The mean severity score for the
3% saline group at 24 hours was 4.00 Æ 0.98. Figure 1
shows a consistent trend favoring 5% saline starting about
8 hours after randomization and continuing to 72 hours.
Additional epinephrine doses were prescribed for 3 infants
(5.3%) in the 5% saline group, 1 infant (1.7%) in the 3%
saline group, and 3 infants (5.4%) in the 0.9% saline group
(P  = .53).
Follow-Up
The mean length of stay was 1.56 Æ 1.38 days for the 5% sa-
line group, 1.4 Æ 1.41 days for the 3% saline group, and 1.88
Æ 1.76 days for the 0.9% saline group ( P  = .36). Time to dis-
charge for the 3 groups is displayed in Figure 2. Three infants
(1.6%) were lost to follow-up after discharge, 2 in the 5%
saline group and 1 in the 0.9% saline group.
The rate of revisits to the Pediatric Emergency Center in
the 7 days after discharge was high and similar in the 3 treat-
ment groups: 35 (61%) in the 5% saline group, 35 (59%) in
the 3% saline group, and 35 (63%) in the 0.9% saline group
(P  = .91). Short-stay readmission was required for 10 infants
(18%) in the 5% saline group, 8 infants (14%) in the 3%
saline group, and 7 infants (13%) in the 0.9% saline group
(P  = .73). One infant in the 0.9% saline group required
a 2-day stay in the ICU during a hospital admission in the
week after the study visit. Antibiotic usage was similar in
the 3 groups: 19% in the 5% saline group, 22% in the 3%
saline group, and 18% in the 0.9% saline group. No study 
subjects received corticosteroid therapy.
Safety 
No patient was withdrawn from the study because of apnea,
quired hospital or ICU admission during their study visit
for bronchiolitis. Severity scores immediately after and im-
mediately before nebulization and oxygen saturations imme-
diately after and immediately before nebulization were
3% saline 5% saline
(n = 58) (n = 57) P  value
3.84 Æ 2.84 4.02 Æ 2.56 .32
4.7 Æ 4.34 4.6 Æ 3.22 .14
39/19 31/26 .35
6.16 Æ 1.53 5.65 Æ 1.14 .11
97 Æ 1.39 97.42 Æ 1.15 .15
34 (58.6%) 31 (54.4%) .89
44 (75.9%) 44 (77.2%)
13 (22.4%) 10 (17.5%) .81
1 (1.7%) 3 (5.3%)
Al-Ansari et al
October 2010
Figure 1. Mean bronchiolitis severity score assessments
over time. At 48 hours, the time of primary outcome assess-
ment, a significant difference between 5% saline and 0.9%
saline was seen (standard deviations not shown).
obtained for each patient at baseline and 24, 48, and 72 hours
after study entry, and the difference between the each set of  the infirmary. This instrument has been previously validated
prenebulization and postnebulization values was calculated
to explore whether nebulization negatively affected either
measurement in any of the treatment groups. The results
were similar among the 3 groups and demonstrated no
evidence of toxicity.
Discussion
In our study group, nebulization with 5% hypertonic saline
proved superior to 0.9% saline for improving the bronchio-
litis severity score in patients with viral bronchiolitis in the
early treatment setting, and possibly superior to 3% saline
Figure 2. Actual times of discharge from the pediatric
emergency center for the 3 treatment groups. Discharge time
was affected by medical and social factors.
Nebulized 5% or 3% or Hypertonic or 0.9% Saline for Treating Acute Bronchiolitis in Infants
ORIGINAL ARTICLES
as well. If our results are confirmed, we believe this simple,
inexpensive, easily applied, safe, and apparently effective
treatment could be generalized for use worldwide in clinics,
infirmaries, and hospitals caring for pediatric patients. Bron-
chiolitis morbidity 1,17 might be minimized by systematic in-
troduction of this helpful early intervention. However,
a multicenter trial with a larger sample size and relevant clin-
ical outcome is needed to confirm and extend our results.
Grewal et al18 reported no difference in efficacy between
nebulized 3% and 0.9% saline in the emergency department
at 2 hours after randomization. Our study found no differ-
ences that early. Grewal et al did find a difference in hospital-
ization rate that was clinically significant, but not statistically 
significant due to their limited sample size.18
Our study has some limitations. The relatively small num-
ber of patients enrolled does not allow us to distinguish the
efficacy of 3% saline and 5% saline in a definitive way. In
addition, although our primary measure was the calculated
bronchiolitis severity score, objectively determined by phys-
ical examination and blinded with respect to treatment as-
signment, this is not the only measure that determines
clinical (as opposed to social) readiness for discharge from
for its relationship to disease improvement, interobserver, in-
traobserver, and intrasubject variation, however.16,19 Finally,
it is possible that some of our patients had early presentation
of asthma rather than acute bronchiolitis. We tried to limit
the likelihood of enrolling subjects with asthma by following
strict inclusion criteria. The proportion of our patients with
a positive RSV assay was similar to that reported for other
bronchiolitis populations1 and is higher than what would
be expected for asthma. Moreover, if asthma were prevalent
among our patients, then we would have expected to see
worsening of clinical symptoms on exposure to hypertonic
saline.
We conclude that nebulization with 5% hypertonic saline
is safe and may be superior to current treatment for early in-
firmary outpatient treatment of bronchiolitis. Planning for
a multicenter trial to explore the clinical benefit of this ther-
apy with a larger sample size is underway. n
Submitted for publication Dec 3, 2009; last revision received Feb 22, 2010;
accepted Apr 29, 2010.
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October 2010 ORIGINAL ARTICLES

Table I. Determination of bronchiolitis severity scores

Score 0 1 2 3
Respiratory rate, breaths/minute <30 31-45 46-60 >60
Wheezing None Terminal expiratory or only Entire expiration or audible on Inspiration and expiration without stethoscope
with stethoscope expiration without stethoscope
Retraction None Intercostals only Tracheosternal Severe with nasal flaring
General condition Normal - - Irritabity, lethargy,
poor feeding

Nebulized 5% or 3% or Hypertonic or 0.9% Saline for Treating Acute Bronchiolitis in Infants 634.e1