Epinephrine

Hartling L, Wiebe N, Russell K, Patel H, Klassen TP. A meta-analysis of randomized controlled trials evaluating the efficacy of epinephrine for the treatment of acute viral bronchiolitis. Arch Pediatr Adolesc Med 2003; 157:957-964.

* BACKGROUND

Inhaled epinephrine is the most frequently prescribed bronchodilator for acute viral bronchiolitis. It stimulates alpha-receptors in the bronchiolar vasculature and may potentially be more effective than other commonly used bronchodilators (ie, albuterol and ipratropium). Although some data suggest that epinephrine is more effective than placebo in ambulatory patients, its benefit has not been universally accepted due to inconsistent findings in clinical trials and a lack of demonstrated response in hospitalized patients.

* POPULATION STUDIED

In this meta-analysis, the researchers included randomized, double-blind, clinical trials evaluating the efficacy of epinephrine vs placebo or epinephrine vs other bronchodilators in the treatment of bronchiolitis for hospitalized or ambulatory patients aged 2 years or younger. Bronchiolitis was defined as wheezing (with or without cough, tachypnea, and increased respiratory effort) associated with clinical evidence of a viral infection (eg, coryza and fever).

* STUDY DESIGN AND VALIDITY

One researcher searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and reference lists from articles to identify eligible clinical trials. Non-English-language publications were translated for evaluation. The researcher included a study if it reported at least 1 of the following outcome measures: clinical score, oxygen saturation (via oximetry), admission rates, length of hospital stay, respiratory rate, heart rate, and results of pulmonary function tests.

Two reviewers independently evaluated trials for inclusion, and only those that both agreed upon were selected. A standard form was used to note study characteristics, participants, intervention, outcomes, funding sources, and results (specifically, clinical scores of efficacy). Clinical scores were converted to standardized mean differences, since the trials used 6 different clinical scores. The Jadad scale (a validated 5-point quality assessment tool) was used to assess randomization, double-blinding, withdrawals, and dropouts from included studies. Quality ranged from very poor to very good, and all studies were included.

This research has several limitations, some of which are common to meta-analysis methodology. There is no universally accepted assessment tool for evaluating clinical response in bronchiolitis. The endpoints and reported clinical results from these studies varied. Clinical scores of efficacy were established to provide some common marker of response. They were derived by extracting data from tables, recalculations of reported results (eg, 95% confidence intervals, standard deviations, means, medians), graphs, and, in some instances, by requesting additional data from the original investigators.

Only a few studies had common clinical scores, resulting in a small number of subjects included in the multiple comparisons. A statistically significant heterogeneity was seen among the trials, and most clinical scores reflected only short-term markers of efficacy (up to 4 hours post-treatment). Additionally, the method to attain consensus for discrepancies between the 2 independent investigators that reviewed studies for inclusion was not described. (Level of evidence: 1a-)

* OUTCOMES MEASURED

Inpatient and outpatient study data were compared independently. Clinical scores of response at different times after treatment, changes in oxygen saturation, "improvement," length of stay, and pallor after treatment were reported. The researchers converted the data into standardized mean differences in clinical scores (effect size).

* RESULTS

Fourteen clinical trials (7 inpatient, 6 outpatient, and 1 unknown) were included in this meta-analysis. All the studies were small, with the largest including only 194 patients.

Compared with placebo, epinephrine showed no difference in clinical scores 30 minutes after treatment, oxygenation, or length of stay in the inpatient studies. Clinical scores modestly improved 60 minutes after treatment. In the outpatient studies, epinephrine produced modest improvement in clinical scores compared with placebo 60 minutes after treatment, but not at 30 minutes. Oxygenation modestly improved after 30 minutes but no difference in oxygenation was seen after 60 minutes.

For the vague global outcome of "improvement," the number needed to treat was 1.7 (95% confidence interval, 1.3-2.5). No difference was seen in admission rates.

When comparing epinephrine with albuterol, no differences were seen in any measured outcomes in inpatients; however, some outcomes were different among outpatients. Changes in oxygenation after 60 minutes, "improvement," and pallor were statistically better with epinephrine compared with albuterol.

* PRACTICE RECOMMENDATIONS

Epinephrine provides small short-term benefits in ambulatory patients with acute bronchiolitis; however, it is not definitely better than albuterol.

Data do not support using epinephrine for inpatient bronchiolitis. This question remains unanswered due to the small size of the studies included in this meta-analysis and the absence of a reliable clinical scoring system to measure response in bronchiolitis.

Joseph J. Saseen, PharmD, University of Colorado Health Sciences Center, Departments of Clinical Pharmacy and Family Medicine, Denver E-mail: joseph.saseen@uchsc.edu.

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