Epinephrine Plus Dexamethasone May Reduce Hospitalizations for Children With Bronchiolitis

Laurie Barclay, MD

May 13, 2009

May 13, 2009 — Combined epinephrine plus dexamethasone treatment may significantly reduce hospital admissions in children with bronchiolitis seen in the emergency department, according to the results of a multicenter, double-blind, placebo-controlled trial reported in the May 14 issue of the New England Journal of Medicine.

"Although numerous studies have explored the benefit of using nebulized epinephrine or corticosteroids alone to treat infants with bronchiolitis, the effectiveness of combining these medications is not well established," write Amy C. Plint, MD, MSc, from Children's Hospital of Eastern Ontario in Ottawa, Canada, and colleagues. "The current study was undertaken in response to the continued controversy concerning the use of nebulized epinephrine and systemic corticosteroids in the treatment of bronchiolitis in infants and in recognition of the substantial burden that the care of infants with this disease adds to the health care system."

In this study, 800 infants aged 6 weeks to 12 months who were seen in the pediatric emergency department for bronchiolitis were randomly assigned to 1 of 4 groups. The epinephrine-dexamethasone group received 2 treatments of nebulized epinephrine (3 mL of epinephrine in a 1:1000 solution per treatment) and a total of 6 oral doses of dexamethasone (1.0 mg/kg of body weight in the emergency department and 0.6 mg/kg for an additional 5 days). The epinephrine-alone group received nebulized epinephrine and oral placebo, the dexamethasone-alone group received nebulized placebo and oral dexamethasone, and the placebo group received nebulized placebo and oral placebo. The main endpoint of the study was hospitalization within 7 days from the day when the child was first seen in the emergency department and enrolled.

All 4 groups were well balanced in baseline clinical characteristics. Hospitalization occurred by day 7 in 34 infants (17.1%) in the epinephrine-dexamethasone group, 47 (23.7%) in the epinephrine group, 51 (25.6%) in the dexamethasone group, and 53 (26.4%) in the placebo group. Compared with the placebo group, only the infants in the epinephrine-dexamethasone group were significantly less likely to be admitted by day 7 (relative risk, 0.65; 95% confidence interval, 0.45 - 0.95; P = .02), based on the unadjusted analysis. This result was no longer significant after adjustment for multiple comparisons (P = .07). No serious adverse events were observed.

"Among infants with bronchiolitis treated in the emergency department, combined therapy with dexamethasone and epinephrine may significantly reduce hospital admissions," the study authors write. "These results were not modified by RSV [respiratory syncytial virus] status, presence or absence of a history of atopy, or the severity or the duration of illness."

Limitations of this study include enrollment restricted to infants who had wheezing for the first time, limiting generalizability; infants enrolled at academic centers; failure of the study design to anticipate the synergism between epinephrine and dexamethasone; and multiple comparisons present in the factorial study design.

"Given the unexpected synergy we found between epinephrine and dexamethasone and the lack of any apparent benefit when either drug is used alone, our results should be considered exploratory," the study authors conclude. "Although some clinicians consider a trial of a bronchodilator to be standard therapy, published data show, at most, mild transient clinical benefits and no effect on the admission rate. Therefore, confirmation of our findings by a study powered specifically to compare combined epinephrine and dexamethasone therapy with placebo is needed."

In an accompanying editorial, Urs Frey, MD, PhD, from University Hospital of Bern in Bern, Switzerland, and Erika von Mutius, MD, MSc, from University Children's Hospital in Munich, Germany, note the small effect size of the study (11 infants would have to be treated to prevent 1 hospital admission).

"It does not seem practical to apply the treatment, especially considering the potential effects of high-dose corticosteroids on brain and lung development in such young children," Drs. Frey and von Mutius write. "We need to assess risk factors and symptom history and make sure that we identify and treat children with unremitting wheezing. In these children, particularly those presenting with signs of atopy, maintenance treatment can be initiated with inhaled corticosteroids, administered through an appropriate spacer, or with leukotriene-receptor antagonists."

The Canadian Institutes of Health Research and Alberta Children's Hospital Foundation supported this study. Two of the study authors have disclosed various financial relationships with the Canadian Institutes of Health Research or Cumberland Pharmaceuticals. The other study authors have disclosed no relevant financial relationships.

Dr. Frey has received a travel grant from GlaxoSmithKline and research support from VoluSense. Dr. von Mutius has received consulting fees from GlaxoSmithKline, UCB, and ProtectImmun; lecture fees from Novartis and Alk-Scherax; and grant support from Airsonett. Dr. von Mutius has been named as an inventor on a pending patent for protection from allergies and inflammatory disorders.

N Engl J Med. 2009;360:2079-2089; 2130-2133.


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