Infants With Bronchiolitis: What Treatment Is Best?

William T. Basco, Jr., MD, MS

Aug 23, 2013

Racemic Adrenaline and Inhalation Strategies in Acute Bronchiolitis

Skjerven HO, Hunderi JO, Brügmann-Pieper SK, et al

N Engl J Med. 2013;368:2286-2293

Study Summary

Although inhaled epinephrine (adrenaline) has been found to reduce the need for hospitalization when given to patients with bronchiolitis in the emergency department, it is not clear whether continuing nebulized epinephrine in the hospital will alter the hospital course of bronchiolitis in children. This multicenter, double-blind trial, conducted in Norway, used a 2 x 2 factorial design in which both the inhaled substance (epinephrine vs saline) and the frequency of delivery (on demand vs scheduled) were randomized. This resulted in 4 study groups of children who received the 2 different interventions in different combinations.

A total of 404 children (59% boys) were enrolled in 2010 and 2011. All children were younger than 12 months (mean age, 4.2 months) and met a clinical definition of bronchiolitis; all had significant symptoms, meaning that patients with mild symptoms were generally excluded. Most (81%) of the infants had bronchiolitis due to respiratory syncytial virus. The trial excluded patients with chronic medical conditions that would otherwise potentially alter treatment, as well as any who had received steroids within 4 weeks of presenting. In Norway, hospitalized children with bronchiolitis do not receive glucocorticoids or beta-adrenergic agonists.

The primary outcome of interest was hospital length of stay. The investigators evaluated several secondary outcomes, including whether nasogastric tube feedings were used and whether patients required oxygen or ventilatory support.

Study Findings

The randomization was roughly equal, resulting in approximately 100 patients in each of the 4 factorial groups. The discontinuation rate was approximately equal among the groups, except in the group that received inhaled saline on a fixed schedule; 26% of the infants in that cohort discontinued the study, compared with 17%-20% in the remaining 3 groups. Overall, 321 infants completed the study (82% of the racemic epinephrine groups and 77% of the inhaled saline groups).

Length of stay did not differ between the infants who received inhaled racemic epinephrine and those who received saline, with Kaplan-Meier plots of the 2 groups closely or completely overlapping through almost all of the inpatient period. In contrast, there was a slight divergence between the Kaplan-Meier curves for infants who received on-demand inhalation therapy and those who received fixed inhalation, and the curves favored those who received on-demand therapy. The infants who received on-demand therapy received a mean of 12 inhalations, compared with 17 among those who received inhalations on a fixed schedule.

When secondary outcomes grouped by inhalation substance were examined, there were no differences between the infants who received racemic epinephrine vs saline, including need for oxygen supplementation, nasogastric tube feeding, or ventilatory support. However, when secondary outcomes were grouped by inhalation schedule, the infants who received inhalation on a fixed schedule more commonly received oxygen (48.7% vs 38.3% of those who received on-demand therapy) and also had a higher frequency of receiving ventilatory support (10.8% vs 4.0%).

Length of stay was an average of 13.7 hours shorter for infants who received inhalations on demand. Age was related to length of stay, with younger infants generally staying longer. However, subgroup analysis by age did not reveal a difference in the effectiveness of racemic epinephrine.

The benefit of on-demand inhalations appeared to be confined to the younger infants (< 3 months old), and length of stay was shorter if treatments were given on demand. Among infants 3 months of age or older, inhalation frequency was not related to hospital length of stay.

Skjerven and colleagues concluded that among infants with acute bronchiolitis, inhalations of adrenaline did not shorten hospital length of stay. On-demand administration of inhalations seemed to decrease the duration of hospitalization.

Viewpoint

Skjerven and colleagues are correct to point out in the discussion section that one should be careful to remember the sample of infants in which this intervention was tested. First, the interventions were tested among infants with bronchiolitis, so it is not clear whether one might expect similar outcomes in older toddlers with bronchiolitis. Furthermore, these were young infants with bronchiolitis, not infants with viral-induced symptoms that may or may not be classic bronchiolitis.

I don't point out these limitations on generalizability to suggest that I am optimistic that inhaled racemic epinephrine offers promise for other potential age groups of children with bronchiolitis. In fact, I would characterize the general landscape of bronchiolitis trials as follows: For almost any therapeutic approach tested in the past 15 years (systemic corticosteroids, inhaled hypertonic saline, inhaled beta-agonists, or inhaled racemic epinephrine), initial small, single-center studies have often appeared promising. For the most part, however, these initial, smaller studies were followed by more extensive, multicenter, double-blind studies that have not generally shown any benefit of aggressive intervention once a young infant has been admitted to the hospital for bronchiolitis. So, the state-of-the-art care for these infants is still mostly supportive.