Bronchiolitis, a disorder in infants most commonly resulting from viral
lower respiratory tract infection, is associated with acute inflammation, small
airway involvement with epithelial cell necrosis, bronchospasm and increased
Respiratory syncytial virus is the most common etiology, although other
viruses can also produce bronchiolitis, including adenovirus and influenza.
Treatment of bronchiolitis remains mostly supportive. Several pharmacotherapies
(bronchodilators, ribavirin and corticosteroids) have been evaluated, and
although some are commonly used, their use remains controversial and not
clearly defined. Hypertonic saline (HTS) nebulizations have more recently been
evaluated and are increasingly being used in the clinical setting. This
month’s column will review published studies of HTS use in infants with
Edward A. Bell
Several published trials of HTS have evaluated 3% sodium chloride given
by nebulization. These trials differ in clinical setting, HTS dosing schedule,
coadministration with bronchodilators and outcome criteria. Sarrell and
colleagues compared nebulized HTS (3%) plus terbutaline (5 mg), a
beta-2–adrenergic bronchodilator, to 0.9% saline plus terbutaline, given
three times daily for 5 days, in 65 ambulatory infants (aged younger than 24
months) with mild bronchiolitis in Israel. Changes in the use of a validated
clinical scoring scale were used for assessment of outcome, besides the need
for hospitalization. Infants were assessed daily upon return to the clinic.
The treatment and control groups, similar at baseline, were compared in
a randomized, double blind manner. Infants receiving HTS plus terbutaline
demonstrated significantly greater clinical scoring improvements than control
infants on each day of the study, although most improvements were noted in the
first 2 days of treatment (P< .05). There was no difference in need
for hospitalization between the groups. No differences in adverse effects
between the groups were noted, although these were not well defined. Although
this was a randomized controlled trial, its findings are limited by poorly
defined inclusion criteria and statistical analysis, besides unknown treatment
The same group of investigators evaluated hospitalized infants with
bronchiolitis in a similar manner (Mandelberg). This randomized, double blind
study included 52 hospitalized infants (aged younger than 12 months) with
moderate bronchiolitis. Infants in the treatment group received nebulized
epinephrine (1.5 mg) plus 3% HTS, and control infants received nebulized
epinephrine plus 0.9% saline, with both treatment regimens given three times
daily until hospital discharge.
The same clinical scoring scale was used as the trial by Sarrell.
Outcome measures included change in clinical scoring and duration of
hospitalization. Control infants did not demonstrate improvement in clinical
scoring on days 1 through 3, whereas infants in the treatment group
demonstrated clinical scoring improvement on days 1 through 3. Infants in the
treatment group additionally demonstrated a significant decrease in hospital
stay, by approximately 1 day, as compared with control infants (3 days vs. 4
days, respectively). No differences in adverse effects were noted between the
groups. The findings of this study are similarly limited by poorly defined
inclusion criteria and statistical analysis; hospital discharge decisions made
by differing attending physicians with no defined criteria for discharge also
limit this trial.
Recruiting an additional 41 hospitalized infants and pooling data from
the previous study (Mandelberg) resulted in a third published trial (Tal).
Study methodology was similar to the Mandelberg trial. Infants receiving
nebulized HTS 3% plus epinephrine demonstrated improved clinical scores on days
1 and 2, as compared with control infants receiving 0.9% saline plus
epinephrine (P< .05). Pooled data from both trials (n=93)
demonstrated a reduction in hospital stay from 3.6 to 2.8 days in infants
receiving nebulized HTS 3% plus epinephrine compared with nebulized 0.9% saline
plus epinephrine, respectively (P< .05).
In a trial of 96 hospitalized infants aged younger than 18 months with
moderate bronchiolitis, nebulized HTS 3% was compared with 0.9% saline in a
randomized, double blind manner in Canada (Kuzik). Dosing schedules differed in
this trial, with nebulized active and control treatments given every 2 hours
for three doses, every 4 hours for five doses, and then every 6 hours until
hospital discharge. The primary outcome measure was length of hospital stay,
determined by protocol defined discharge criteria (including a clinical scoring
scale) — used for 55% of discharged infants — or by independent
clinical status determination by the attending physician — used for 45% of
Other medications were allowed, including nebulized bronchodilators,
nebulized corticosteroids and systemic corticosteroids (14% to 17% of infants).
There were no differences in these treatments between the active and control
groups. Infants given bronchodilators received about five doses per day,
besides the mean of nine nebulized active or control saline nebulized
treatments per day. Length of hospital stay was reduced by 26%, approximately 1
day, in infants receiving HTS 3% (P< .05). Adverse effects were mild
and did not differ between groups. This trial, although more controlled than
the other trials, is limited by the use of several additional therapies and
non-protocol discharge criteria.
In the only negative trial published, nebulized HTS 3% plus epinephrine
(11.3 mg) was compared with nebulized 0.9% saline plus epinephrine (11.3 mg) in
46 infants aged younger than 12 months with mild-moderate bronchiolitis in an
ED setting in Canada, in a randomized, double blind manner (Grewal). At the
discretion of the attending physician, a second dose of study treatment was
available for administration. A validated clinical scoring scale was used and
assessed at baseline and at four time points (up to 120 minutes) after
treatment nebulization. The primary outcome measure was change in clinical
scoring. Although both groups improved from baseline with treatment, there was
no difference in improvement by clinical scoring between the groups at 120
minutes post-treatment, nor did the groups differ in improvement of oxygen
saturation, need for a second nebulized dose, return to the ED or need for
hospitalization. This trial evaluated a higher nebulized epinephrine dose than
the previous studies.
A Cochrane database review performed a meta-analysis of data from seven
trials (n=581), with nebulized HTS 3% compared with 0.9% saline in infants aged
younger than 24 months with mild-moderate bronchiolitis in inpatient,
outpatient and ED settings. Infants treated with HTS 3% improved as compared
with infants receiving 0.9% saline, with decreased hospital stays
(approximately 1 day) and improved clinical scores (P< .05). Two
trials in the ED setting did not demonstrate significant clinical improvement
(up to 120 minutes post-nebulization) of HTS 3% as compared with 0.9% saline.
No significant adverse effects of HTS 3% were seen in these data.
Results of the trials discussed indicate that nebulized HTS 3% may be
able to impart clinical improvement to infants with mild-moderate bronchiolitis
in inpatient and outpatient settings. Trials of HTS 3% in the ED setting have
failed to show significant benefit after one to two doses. Although data from
these trials demonstrate that nebulized HTS 3% may be beneficial, several
questions remain, including: the most effective dosing schedule, comparative
efficacy of HTS alone and with concomitantly administered nebulized
bronchodilators, and the role of HTS 3% in more severe bronchiolitis. The use
of concomitant therapy with nebulized bronchodilators (eg, albuterol,
epinephrine) is interesting to consider, as this pharmacotherapy is generally
regarded as an optional treatment with equivocal efficacy that should not be
Optimal bronchodilator dosing and the most effective agent to use remain
poorly defined. Adverse effects from nebulized HTS 3% use have been mild. A
recently published retrospective study of nebulized HTS 3% given without
concomitant bronchodilators revealed a low rate of adverse effects (Ralston).
Results of the trials discussed here suggest a beneficial effect of nebulized
HTS 3% therapy. However, additional data from more controlled trials are
needed, including the role of HTS 3% given alone, the role of concomitantly
administered nebulized bronchodilator therapy, and the most effective HTS 3%
- Grewal S. Arch Pediatr Adolesc Med. 2009;163:1007-1012.
- Kuzik BA. J Pediatr. 2007;151:266-270.
- Mandelberg A. Chest. 2003;123:481-487.
- Ralston S. Pediatrics. 2010;126:e520-e525.
- Sarrell EM. Chest. 2002;122:2015-2020.
- Tal G. Isr Med Assoc J. 2006;8:169-173.
- Zhang L. Cochrane Database Syst Rev. 2008;4:CD006458.
Edward A. Bell, PharmD, BCPS, is professor of clinical sciences at
Drake University College of Pharmacy, Blank Children’s Hospital, in Des
Moines, Iowa. He is also a member of the Infectious Diseases in Children
Editorial Board. Disclosure: Dr. Bell reports no relevant financial