Bronchiolitis Trial and Tribulation

How to treat an infant with a first episode of wheeze accompanying a viral infection has been a longstanding but unresolved question in the medical literature. Obvious similarity in physical findings between these bronchiolitic infants and older asthmatic children has resulted in the widespread use of bronchodilators.1 However, systematic meta-analyses and expert opinion as voiced in clinical practice guidelines suggest that only a minority of children respond transiently, with no impact on the overall course of illness.2 The heterogeneous nature of bronchiolitis may explain the failure of many infants to respond, since there is often a prominent contribution from airway inflammation and mucus that are not affected by beta-agonists. Epinephrine has been hypothesized to have a potential for additional benefit, perhaps due to its alpha-adrenergic properties. Studies to date have been inconclusive, and a systematic review has noted the need for further large clinical trials.3 In this issue of Academic Emergency Medicine, Walsh et al.4 describe a large double-blind randomized trial of albuterol versus epinephrine conducted at two emergency departments (EDs).4 The investigators enrolled 703 children under 18 months of age with acute wheezing following an upper respiratory infection. Subjects were randomized to three repeated doses of nebulized albuterol or a single dose of epinephrine followed by two doses of saline over a 1-hour period. The primary outcome was “successful discharge” defined as discharge after the observation period without need for further bronchodilators in the ED or a subsequent hospitalization. The investigators found no difference in the primary outcome in unadjusted analysis. However, they reported a modest increase in successful discharge in the albuterol group (corresponding to about an 8% absolute increase above the epinephrine discharge rate of 46%) after adjusting for baseline severity using a severity score that they had previously validated. The methodologic issue of whether to use an adjusted or unadjusted analysis is controversial. With randomization and a large sample size, the probability that confounders will distribute unevenly enough between treatment groups to impact the final results should be low. If a particular factor is expected to be associated with the outcome (as with baseline severity here), an optimal approach would be to stratify randomization on that factor to ensure balance between the groups. However, the authors make the case that, with the fairly complex score used here, it was not practical to stratify at the time of enrollment. Apparently they planned to adjust for the score before conducting their trial, and therefore they use the adjusted analysis as the bottom line in reporting their results. Assessing severity of bronchiolitis is not a straightforward task, and the authors correctly note that there is no criterion standard. The Respiratory Distress Assessment Instrument (RDAI), an auscultatory score originally developed in a study of subcutaneous epinephrine, has been used widely in key studies of bronchiolitis but has not been well validated.5–8 The score used in the study by Walsh et al. was developed in an Irish population and later shown to have acceptable interobserver reliability; it includes age, physical findings related to respiratory status, and a subjective assessment of hydration.9,10 Not fully examined here is the potential that there is an interaction between severity and response to albuterol; the values in Table 2 of the article suggest that the difference in discharge rate for albuterol over epinephrine is greatest in mild patients (12.8%, or a number needed to treat of 8) with declining difference as severity increases. This would suggest that future studies focus on use of epinephrine in more severe patients, which would also reflect current clinical practice. Beyond trial methodology, there are a variety of clinical issues that have vexed investigators studying bronchiolitis and remain relevant here. First, there is the question of how to define the condition. Some infants with bronchiolitis go on to develop recurrent wheezing, suggesting that there may be heterogeneity within the population that could potentially determine treatment response. In fact, long-term prospective studies have identified three distinct phenotypes of childhood wheezing, and genetic research will likely identify many factors contributing to heterogeneity.11 To reduce this concern, prior investigators have often limited studies of bronchiolitis to a first episode of wheeze. Here the authors included infants with prior wheezing, who represented about 30% of the sample. Infants with prior episodes of wheeze were 36% more likely to be discharged overall, suggesting a better response to bronchodilators in this subgroup. Apparently, the overall results favoring albuterol did not change when these infants were excluded, although details of this subanalysis are not provided. The appropriate age range has also been controversial, since children with first wheeze after 1 year are more likely to develop asthma; here the authors chose to enroll up to 18 months. At the other end of the age spectrum, very young infants are at risk for apnea and may be admitted purely for that reason (as apparently was recommended for all those under 2 months at these institutions). Although recent evidence suggests the risk of apnea for full-term infants is limited to the first month of life,12 it may be wiser to exclude these infants since the outcome may be largely predetermined. Finally, the design of the study by Walsh et al. may have favored albuterol, as three doses were given over the first hour, and may have remained active at the 2-hour assessment, when the single dose of epinephrine may have worn off. Some prior studies have focused on shorter time periods and demonstrated increased effect of epinephrine. To make conclusions about transient effects would require an assessment when both drugs would be expected to be active. How should the results of this study be interpreted in the context of the overall literature? Overall, the results would support current guidelines recommending albuterol as the appropriate first agent for a trial of bronchodilators.2 This approach also makes practical sense, since epinephrine does not have an approved option to continue at home if a response was observed. The role of epinephrine as a secondary agent in infants with severe wheeze who do not respond to albuterol remains an open question that will need to be addressed by future studies. Although bronchiolitis may frustrate clinicians, it has contributed to one positive recent trend: the impetus to join together in multicenter research. A study showing no efficacy for corticosteroids in bronchiolitis was the first trial attempted by the Pediatric Emergency Care Applied Research Network (PECARN), and a study of steroids and epinephrine will soon be reported by the Pediatric Emergency Research Canada (PERC) network.8,13 Although these efforts may fail to produce a silver bullet for bronchiolitis, the systems and collaborations developed in these networks have the potential to improve emergency care for children in a broad and sustained manner.

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