Pediatrics

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 mucous production.

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 bronchiolitis. 

Edward A. Bell

Clinical trials

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 adherence.

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 discharged infants.

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.

Conclusion

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 used routinely.

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% dosing schedule.

References:

• 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 disclosures.