A Meta-analysis of Randomized Controlled Trials Evaluating the Efficacy of Epinephrine for the Treatment of Acute Viral Bronchiolitis FREE

BRONCHIOLITIS, THE most common lower respiratory tract infection in infants, is characterized by fever, coryza, cough, expiratory wheezing, and respiratory distress (ie, increased respiratory rate, chest wall indrawing, thoracoabdominal asynchrony).¹ It is most commonly associated with viruses, with the leading cause being the respiratory syncytial virus.^{1 - 2} Overall, it is estimated that 11% to 12% of all infants are affected in the first year of life, with 1% to 2% requiring hospitalization.³ Because of the prevalence and morbidity associated with bronchiolitis, the economic burden placed on health care services is substantial.²

Despite the frequency of the condition, considerable controversy remains regarding its management. Historically, children have been offered supportive care, including oxygen and supplemental fluids.^{1 - 2} Recent clinical trials have provided conflicting evidence regarding the benefit of pharmacological interventions. Much of the debate involves the role of bronchodilators.²

Although in common use, the efficacy of bronchodilators in this patient group has not been universally accepted. Two recent systematic reviews have found insufficient empirical support for widespread use of bronchodilators.^{3 - 4} Flores and Horwitz³ reviewed 8 randomized controlled trials (RCTs) to evaluate the efficacy of β₂-agonists in bronchiolitis. Among 3 inpatient studies, the results were contradictory with respect to improved clinical scores, duration of hospital stay, and oxygen saturation. Among the 5 outpatient studies, there was no benefit in terms of hospitalization rate or respiratory rate. The reviewers found a statistically significant improvement in oxygen saturation and heart rate, but the results were deemed to be not clinically significant.

Kellner and colleagues⁴ reviewed 20 RCTs, 18 of which examined β₂-agonists and 2, epinephrine hydrochloride. The review grouped all bronchodilators and compared these with placebo; they did not examine the relative efficacy of different bronchodilators. The reviewers found modest short-term improvements in clinical score among children with mild and moderate bronchiolitis. The results for oxygen saturation were inconclusive owing to heterogeneity between studies. They found no significant improvement in rate or duration of hospitalization. These authors concluded that bronchodilators could not be recommended for routine management in first-time wheezers.

Although different nebulized bronchodilators such as albuterol sulfate (salbutamol), ipratroprium bromide, and epinephrine are being used in the treatment of bronchiolitis, research to date supports epinephrine as the bronchodilator of choice.¹ Along with the β-adrenergic effects of bronchodilation, epinephrine adds α-adrenergic properties and is believed to offer the supplemental benefits of vasoconstriction in the bronchiolar vasculature. Along with others, Wohl and Chernick⁵ have suggested that this vasoconstriction may reduce edema and mucous production, hallmarks in the pathology of acute viral bronchiolitis. Because of the unique mechanism of action of epinephrine and its increasing use in infants with bronchiolitis, we chose to specifically investigate the efficacy of this drug in the treatment of bronchiolitis. Thus, the objective of this study was to review RCTs that compared the effects of inhaled or systemic epinephrine vs placebo or other bronchodilators in infants and young children (age, ≤2 years) with bronchiolitis.

All RCTs evaluating the efficacy of epinephrine vs placebo or of epinephrine vs other bronchodilators in the treatment of bronchiolitis were considered for inclusion, regardless of language or publication status. All studies involving infants and young children 2 years or younger were eligible for inclusion. 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). Studies of inpatients and outpatients were included. Studies were included if they reported on at least 1 of the following outcome measures: clinical score, oxygen saturation (oximetry), admission to the hospital (rate of hospitalization), length of hospital stay, respiratory rate, heart rate, and results of pulmonary function tests.

Searches of MEDLINE (January 1966 through December 2000), EMBASE (January 1988 through December 2000), and The Cochrane Central Register of Controlled Trials were conducted using the following terms: epinephrine, bronchiolitis, respiratory syncytial viruses, respiratory syncytial Pneumovirus, respiratory syncytial virus, and adrenalin. The complete search strategies are available from the authors on request. We examined the reference lists of all selected articles for relevant studies. Primary authors of relevant trials were contacted for information on additional trials. We searched PubMed at the end of the project (September 2002) to identify any recent studies.

The initial search of all of the databases and reference lists was screened independently by 2 of us (L.H. and K.R.) to identify citations with potential relevance. The full text of selected articles was obtained. The 2 reviewers independently decided on trial inclusion using a standard form with predetermined eligibility criteria. Disagreements were resolved by consensus reached after discussion.

Study quality for English-language studies was assessed independently by 2 of us (reviewers K.R., T.P.K., or L.H.); study quality of the Turkish reports was assessed by an independent reviewer. Quality was assessed on the basis of published reports in peer-reviewed journals when available; for 1 trial,⁶ quality assessment was based on the abstract and unpublished information from the author, as the manuscript was not yet available. Each study was evaluated using the Jadad 5-point scale to assess randomization (0-2 points), double blinding (0-2 points), and withdrawals and dropouts (0-1 point).⁷ The Jadad scale was chosen because it is the only quality assessment tool, to the best of our knowledge, that has been validated, and it incorporates components that are directly related to the control of bias. Concealment of allocation was assessed as adequate, inadequate, or unclear.⁸ Differences in quality ratings were resolved through discussion.

Data from the English-language studies were extracted independently by 2 of us (L.H. and K.R.); data were extracted from the Turkish reports by a single individual. Additional data were requested from authors as necessary. A standard form was used that described the following: characteristics of the study (design, method of randomization, and withdrawals/dropouts), participants (age and sex), intervention (type, dose, route of administration, timing and duration of therapy, and cointerventions), control (agent and dose), outcomes (types of outcome measures, timing of outcomes, complications, and adverse events), whether the study used an intention-to-treat protocol, funding source, and results. Data were entered into RevMan 4.1 (The Cochrane Collaboration, Oxford, England, 2000) by one reviewer (K.R.) and checked for accuracy by a second reviewer (L.H.).

Individual patient clinical score data were extracted from graphs for 1 study.⁹ Means were extracted from graphs for 4 studies,^{6 ,10 - 12} SDs for 1,¹² and 95% confidence limits for 1.¹¹ One trial used a crossover design; therefore, only data from the first phase were used in the meta-analysis.¹³ This same study included 2 placebo groups; data from both groups were pooled. In some cases, variance was imputed from confidence intervals (CIs)^{6 ,11 ,13 - 16} and SEs.^{14 ,17} To calculate the variance of change in oximetry in 1 study, the end time-point SDs were substituted with the baseline SDs.¹⁵ Finally, for 1 study,¹⁰ the mean SDs from other studies were substituted for missing SDs for the clinical score outcomes.

Analyses were performed using RevMan 4.1 (The Cochrane Collaboration, Oxford, England, 2000) and Splus 2000 (Insightful Corporation, Seattle, Wash, 1999). Separate analyses were conducted for the 2 types of control groups (ie, placebo and nonepinephrine bronchodilators) and patient status (ie, inpatient or outpatient). Dichotomous data (eg, improvement) were expressed as Mantel-Haenszel odds ratios, and a common Mantel-Haenszel odds ratio with 95% CIs was calculated. The number needed to treat was derived for significant results to help clarify the degree of possible benefit for the averaged (inverse-variance method¹⁸ ) baseline rates. There were too few studies to check whether the relative risk was constant across different baseline rates; therefore the numbers needed to treat were not provided for a range of baseline rates. The changes in clinical score and oximetry were calculated using baseline and time-point data; a correlation of 0.5 was assumed. The clinical scores were converted to a standardized mean difference because the 14 studies used a total of 6 different clinical scores. An overall standardized mean difference with 95% CIs was calculated. A standardized mean difference is "the difference between 2 means divided by an estimate of the within-group standard deviation."¹⁹ Other continuous data (eg, oximetry, heart rate, respiratory rate, and length of stay) were converted to the mean difference, and an overall weighted mean difference (with 95% CIs) was calculated. When mean differences (difference between treatment group means) are pooled by the inverse variance method, each mean difference is weighted by the inverse of the estimate's variance, giving more weight to studies with more precise estimates. Only 1 study included results of pulmonary function tests as an outcome¹⁴ ; these results are presented separately.

Results were calculated using random-effects models, regardless of heterogeneity. In particular, all clinical scores were calculated using random effects owing to the supposition that these clinical scores measured different clinical features of bronchiolitis or weighted these differently. Fixed effects were also calculated in a sensitivity analysis. Possible sources of heterogeneity were not assessed by subgroup and sensitivity analyses because of the small numbers of studies for each outcome. Publication bias was not assessed because of the small number of trials in each outcome, comparison, and patient status group included in the review. Post hoc power calculations were assessed using independent 2-sample t tests and Pearson χ² tests in PASS 2002 (Number Cruncher Statistical Systems, Kaysville, Utah, 2002).

The results reported in this article differ slightly from those in a previously published abstract,²⁰ as 5 trials were subsequently added.

Seventy-six unique references were identified (the full list of references is available from the authors). Twenty-five studies were identified as being potentially relevant. Fourteen studies met the inclusion criteria^{6 ,9 - 17 ,21 - 24} ; there was 100% agreement between the 2 reviewers with respect to study inclusion. The included studies are described in Table 1. The studies were generally small, but ranged in sample size from 30 to 194. Most studies (n = 12) were published in English, with 2 published in Turkish.^{10 ,21} The studies were conducted in a variety of primarily high-income countries.

A wide range of outcomes was reported. Table 1 describes the primary outcomes studied in each trial. Secondary outcomes included clinical score; oxygen saturation; respiratory rate; heart rate; blood pressure; activity status; time receiving oxygen; highest oxygen flow rates; need for supplemental parenteral fluids; transcutaneous oxygen and carbon dioxide tensions; time from admission to normal oxygenation, adequate intake, and minimal respiratory distress; pulmonary mechanics; duration of hospitalization; rate of hospitalization; and improvement as defined by the individual trials.

Although most studies measured clinical scores, a number of different scoring systems were used, and the scores were reported in different ways (Table 1 and Table 2). The Respiratory Distress Assessment Instrument was the scoring system most commonly used. It was used in 7 studies^{6 ,11 - 13 ,22 - 24} ; however, in 2 of these studies, scores were not reported. In 1 study,²⁴ the authors reported the mean time to a Respiratory Distress Assessment Instrument score of no greater than 4, and in another study⁶ the authors reported only a P value for the mean change in score. The remaining studies used a variety of partially validated or unvalidated scales that measured different clinical features of bronchiolitis.

Most studies conducted short-term follow-up of up to 4 hours, whereas 3 studies followed up inpatients during their hospital stay (herein referred to as longer-term outcomes).^{16 - 17 ,24} In addition, 1 outpatient study evaluated 72-hour relapse rates,⁶ and 1 inpatient study asked general physicians to notify the study personnel of any deterioration in the patients' condition during the 48-hour postdischarge period (no data presented).¹⁶

The methodological quality of studies is reported in Table 3. Three studies received pharmaceutical sponsorship^{6 ,11 ,14} ; funding was received from other external sources in 6 trials^{9 ,13 - 15 ,22 ,24} ; the source of funding was not mentioned in 4 trials^{10 ,12 ,17 ,21} ; and 2 studies received no funding.^{16 ,23} Two studies conducted an intention-to-treat analysis.^{16 ,24} Four studies reported withdrawals and excluded these from the analysis.^{13 - 15 ,17} Eight studies did not report any withdrawals.^{6 ,9 - 12 ,21 - 23}

Results were stratified by inpatient vs outpatient status. Table 4 presents the results for the epinephrine vs placebo comparison. Five inpatient studies compared epinephrine and placebo.^{11 ,13 ,15 - 16 ,24} Only 1 of 10 inpatient outcomes demonstrated a significant difference between treatment groups; change in clinical score at 60 minutes favored epinephrine.

Three studies compared epinephrine and placebo among outpatients.^{9 ,12 ,21} Five of 10 outcomes were significant. Change in clinical score at 60 minutes after treatment, change in oxygen saturation at 30 minutes after treatment, respiratory rate at 30 minutes after treatment (weighted mean difference [WMD], −4.54; 95% CI, −8.89 to −0.19), and improvement favored epinephrine. In 1 study, improvement was defined as a positive change in the respiratory assessment change score of at least 4 U,⁹ and in the other study it was not defined.²¹ Heart rate at 60 minutes after treatment favored placebo. Admission rates (Figure 1), change in clinical score at 30 minutes after treatment, change in oxygen saturation at 60 minutes after treatment, and heart rate at 30 minutes after treatment were not significantly different between the treatment arms. Sensitivity analyses using fixed-effects models found 1 significant difference favoring epinephrine in change in clinical score at 30 minutes. One Turkish study¹⁰ did not indicate its inpatient/outpatient status. This study reported a significant change in clinical score at 60 minutes favoring epinephrine compared with placebo.

Table 5 presents the results of epinephrine vs albuterol. Four studies compared epinephrine with albuterol among inpatients.^{13 - 14 ,17 ,24} Only 1 of the 7 outcomes was statistically significant: respiratory rate at 30 minutes favored epinephrine compared with albuterol (WMD, −5.12; 95% CI, −6.83 to −3.41). The clinical scores, oxygen saturation, heart rate, and length of stay (Figure 2) outcomes showed no significant difference.

Four outpatient studies reported on the epinephrine-albuterol comparison.^{6 ,21 - 23} Four of 16 outcomes showed the following statistically significant differences between treatment groups: change in oxygen saturation at 60 minutes, change in heart rate at 90 minutes (WMD, −14.00; 95% CI, −22.95 to −5.05), respiratory rate at 60 minutes (WMD, −7.76; 95% CI, −11.35 to −4.17), and improvement after treatment significantly favored epinephrine. Improvement in 1 study referred to patients in whom moderate and severe distress was converted to normal or mild distress after intervention²³ ; the other study did not define improvement.²¹ One outcome, the incidence of pallor at 30 minutes after treatment, favored albuterol. Sensitivity analyses using fixed-effects models found significant differences favoring epinephrine for change in clinical score at 60 minutes and admissions. In addition, fixed-effects analyses for heart rate at 60 minutes favored albuterol.

One Turkish study¹⁰ did not indicate its patient status (inpatients vs outpatients); neither of its 2 change-in-clinical-score outcomes was significant.

Only 1 study evaluated pulmonary mechanics among 24 patients randomized to receive epinephrine or albuterol.¹⁴ Significant differences between pretreatment and posttreatment values were noted in inspiratory, expiratory, and total pulmonary resistance in the epinephrine group, but not the albuterol group. There were no significant differences compared with baseline values in either group with respect to tidal volume, minute ventilation, dynamic compliance, or duration of inspiration as a fraction of total breath duration.

Because of the small number of studies that evaluated longer-term outcomes, some of these outcomes were not included in the meta-analysis. The largest trial, conducted by Wainwright et al,¹⁶ randomized 194 inpatients to epinephrine or placebo and found no differences between groups in length of stay or time ready for discharge. The second largest trial involved 149 inpatients randomized to epinephrine, albuterol, or placebo and found no significant difference between groups in length of stay or any secondary outcomes.²⁴ Bertrand et al¹⁷ followed up 30 inpatients randomized to epinephrine or albuterol and found no statistically significant differences in length of stay or duration of oxygen therapy, although the trend favored epinephrine. Mull et al⁶ assessed the relapse rate at 72 hours after treatment among 66 outpatients randomized to epinephrine or albuterol and found no significant difference.

Three studies reported on patient return to the hospital or emergency department after the study. Sanchez et al¹⁴ found that only 3 of 24 patients (treatment group not specified) were readmitted to the hospital for acute wheezing during a 6- to 10-month follow-up period; Bertrand et al¹⁷ found that no patients were readmitted in the 2 weeks after discharge from the hospital; and Patel et al²⁴ reported that 93 of 149 infants (21 receiving epinephrine; 21, albuterol; and 25, placebo) had a medical visit in the week after discharge, that 8 of these visits (1 patient receiving epinephrine; 3, albuterol; and 4, placebo) were to the emergency department, and that 3 patients (receiving placebo) were readmitted. One study noted that children were sent home receiving oral medication but did not specify the type.²³

The objective of this study was to provide some resolution to the uncertainty in the literature regarding the use of epinephrine in the treatment of bronchiolitis. Some evidence supports the use of epinephrine among outpatients. The combined results of the outpatient studies favored epinephrine compared with albuterol in terms of oxygen saturation at 60 minutes, heart rate at 90 minutes, respiratory rate at 60 minutes, and improvement. These results are based on a small number of studies of varying quality. Some evidence also suggests that epinephrine is favorable compared with placebo among outpatients in terms of clinical score at 60 minutes after treatment, oxygen saturation at 30 minutes after treatment, heart rate at 60 minutes after treatment, and overall improvement. None of the studies reported any significant adverse effects resulting from the administration of epinephrine, although 1 study reported significantly less pallor at 30 minutes after treatment in the albuterol group.

Because of the small number of studies for each comparison, we did not have the ability to examine the relative efficacy of epinephrine among other potentially important subgroups such as first-time vs recurrent wheezers, severity of illness, specific viral etiology, age, and stage of the disease.³ We also did not have the ability to assess different forms of delivery such as type of epinephrine, route of delivery, number of administrations, and dosage. We used a more liberal definition of bronchiolitis, as is common in North America and parts of Europe.² The results should be interpreted in light of this.

Several factors may contribute to the lack of consistency in the findings. First, there may be no difference between treatment with epinephrine vs treatment with albuterol or placebo, and any significant findings may have been spurious associations resulting from multiple comparisons.

The efficacy of the drug may be different for various subgroups (eg, outpatients vs inpatients). The subgrouping of outpatients vs inpatients may be a proxy for severity of illness, as those admitted may be more severely affected, later in the course of the disease, or more resistant to treatment. Continued focused evaluation within these subgroups is warranted.

Six different scoring systems were used across the component studies, which resulted in statistically significant heterogeneity between studies. Multiple comparisons between clinical scores at different time points, among different subgroups (outpatients and inpatients), and for the different controls (albuterol and placebo) were performed, and only 3 of 14 comparisons resulted in statistically significant results. It is possible that these were spurious findings. Alternatively, the scoring systems may not be sensitive to clinically important differences. They may not measure, or may measure differentially, the clinical improvement in bronchiolitis. There is clearly a need to evaluate the clinical scores currently in use. Validation and checking sensitivity of the scores used in individual trials would facilitate comparisons between studies.

More than a dozen different outcome measures were evaluated within the component trials. Because of the lack of consistency in the outcomes reported, there were few studies within each comparison. In primary studies, as in meta-analyses, care needs to be taken to specify the outcomes a priori to avoid bias that can arise if only those outcomes with significant results are reported.

The quality of the trials was moderate, with a median Jadad score of 3. All studies were described as random, but only 4 studies described an appropriate method of randomization. Twelve of the 14 studies were described as double-blind, but only 5 studies described an appropriate method of double blinding. Inadequate blinding can overestimate the effect,²⁸ which could skew the results in favor of either treatment, depending on the biases of the investigators. Investigators should be aware that adequate blinding is of particular concern in a study of epinephrine for 2 reasons. First, some investigators have noted reddish nasal discharge after administration of epinephrine. However, in a large trial by Patel et al,²⁴ no instances of red nasal discharge were reported; the investigators suggested that this may be related to the age of the medication. Second, perioral pallor results with nebulized epinephrine. This is a concern in studies where a postmask assessment does not allow sufficient time for the pallor to dissipate (eg, 30 minutes). This issue is of most importance in studies that compare epinephrine with placebo vs those that compare epinephrine with albuterol, since many of the short-term adverse effects of albuterol are similar to those of epinephrine. Only 4 studies provided an adequate description of withdrawals and dropouts. Six studies reported adequate allocation concealment. Studies that do not properly conceal treatment allocation can overestimate treatment effects by as much as 40%.⁸

Finally, the meta-analysis may not have sufficient power to detect statistically significant differences between treatment groups. We calculated the power that the combined studies had to detect a simply pooled difference in the outcomes with largest combined sample size per comparison and patient status group. In a single trial with the same number of patients, there would have been only 7% to 57% power to detect a difference in these various comparisons. There would be less power for the other clinical score outcomes for which there were fewer studies and patients. The implication of this finding is that a number of large trials is needed to substantiate the relative efficacy of epinephrine in the treatment of bronchiolitis.

Some evidence suggests that epinephrine may be favorable compared with albuterol and placebo among outpatients. There is insufficient evidence to support the use of epinephrine for the treatment of bronchiolitis among inpatients. A validated, reliable scoring system is needed that is sensitive to important clinical changes in patients. The appropriateness of a scoring system may vary depending on the context in which it is used; eg, for acute changes, a clinical scoring system may be adequate, but for longer-term changes, inclusion of quality-of-life measures may be more appropriate (impact on feeding, family life, anxiety, difficulty breathing, etc). The use of a validated, reliable, and responsive scoring system would facilitate comparison of results across studies. A number of large, multicentered trials are required to examine the effectiveness of epinephrine compared with placebo and albuterol for infants presenting to the emergency department.

Corresponding author: Terry P. Klassen, MD, MSc, FRCPC, Department of Pediatrics, University of Alberta, 2C3.67 Walter C. Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada T6G 2R7 (e-mail: terry.klassen@ualberta.ca).

Accepted for publication March 6, 2003.

The Alberta Research Centre for Child Health Evidence, Edmonton, is supported by an establishment grant from the Alberta Heritage Foundation for Medical Research, Edmonton.

We thank Marlene Dorgan, MLIS, and Ellen Crumley, MLIS, for their assistance with searching, and Metin Gulmezoglum, MD, for his assistance with translation and data extraction of the Turkish studies.

This review has been registered with the Cochrane Collaboration. Regular updates will be available in the Cochrane Library.

Much controversy has surrounded the use of bronchodilators for bronchiolitis. Recent evidence has suggested that epinephrine hydrochloride may offer some clinical benefit. Epinephrine is being used with increasing frequency in this group; however, its efficacy has not been systematically reviewed.

There is insufficient evidence to support the use of epinephrine for the treatment of bronchiolitis among inpatients. Some evidence suggests that epinephrine may be favorable compared with albuterol sulfate and placebo among outpatients. Further research needs include (1) a number of large, multicentered trials to examine the effectiveness of epinephrine compared with placebo and albuterol for infants presenting to the emergency department; and (2) development and validation of a reliable scoring system that is sensitive to important clinical changes in patients with bronchiolitis.