Do Children with Acute Asthma Benefit More from
Anticholinergics and Beta₂ Agonists than from Beta₂ Agonists Alone?

CASEY CLEARY-HAMMARSTEDT, M.P.A., and CHERYL A. FLYNN, M.D., M.S.
State University of New York Upstate Medical University, Syracuse, New York

The Cochrane Abstract below is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Casey Cleary-Hammarstedt, M.P.A., and Cheryl A. Flynn, M.D., M.S., present a clinical scenario and question based on the Cochrane Abstract, along with the evidence-based answer and a full critique of the abstract.

Clinical Scenario

A five-year-old female child presents with moderate asthma exacerbation of four hours' duration.

Clinical Question

Do children with acute asthma benefit more from combined anticholinergics and beta₂ agonists than from beta₂ agonists alone?

Evidence-Based Answer

Children with moderate to severe asthma exacerbations experience improved respiratory function and are less likely to require hospital admission when treated with multiple doses of beta₂ agonists combined with anticholinergics. The same benefit has not been proved in children with mild to moderate asthma exacerbations.

Cochrane Abstract Background. Several randomized controlled trials have examined, with conflicting results, the efficacy of adding anticholinergics to beta2 agonists in acute pediatric asthma.1 The pooling of a number of randomized controlled trials provides greater power for detecting group differences and offers insight into the influence of patient characteristics and treatment modalities on efficacy. Objectives. The aim of this study was to estimate the therapeutic and adverse effects attributable to the addition of inhaled anticholinergics to beta2 agonists in the treatment of acute pediatric asthma. Search Strategy. The authors searched MEDLINE (1966 to April 2000), EMBASE (1980 to April 2000), CINAHL (1982 to April 2000) and reference lists of studies. They also contacted drug manufacturers and researchers. Selection Criteria. Randomized controlled trials conducted in emergency department settings comparing the combination of inhaled anticholinergics and beta2 agonists with beta2 agonists alone in children 18 months to 17 years of age with acute asthma. Data Collection and Analysis. Assessments of trial quality and data extraction were done by two reviewers independently. Primary Results. Of the 40 identified trials, 13 were relevant, and eight of these were of high quality. The addition of a single dose of anticholinergic to beta2 agonist therapy did not reduce hospital admission (relative risk [RR], 0.93; 95 percent confidence interval [CI], 0.65, 1.32). However, significant group differences in lung function supporting the combination of anticholinergics and beta2 agonists were observed at 60 minutes (standardized mean difference [SMD], 0.57; 95 percent CI, 0.21, 0.93) and 120 minutes (SMD, 0.53; 95 percent CI, 0.17, 0.90) after the dose of anticholinergic. In contrast, the addition of multiple doses of anticholinergics to beta2 agonist therapy reduced the risk of hospital admission by 25 percent (RR, 0.75; 95 percent CI, 0.62, 0.89) in children with predominantly moderate and severe exacerbations. Twelve children (95 percent CI, 8, 32) would need to be treated to avoid one admission. When restricting this strategy to children with severe exacerbations, seven children (95 percent CI, 5, 20) need to be treated to avoid an admission. At 60 minutes after the last anticholinergic inhalation, a weighted mean group difference of 9.68 in change in percent predicted forced expiratory volume in one second (FEV1) (95 percent CI, 5.70, 13.68) favored anticholinergic use. In the two studies where anticholinergics were systematically added to every beta2 agonist inhalation, irrespective of asthma severity, no group differences were observed for the few available outcomes. There was no increase in the amount of nausea, vomiting, or tremor in patients treated with anticholinergics. Reviewer's Conclusions. A single dose of an anticholinergic agent is not effective in the treatment of mild and moderate asthma exacerbations and is insufficient in the treatment of severe exacerbations. Adding multiple doses of anticholinergics to beta2 agonist therapy appears safe, improves lung function, and would avoid hospital admission in one of 12 such treated patients. Although multiple doses should be preferred to single doses of anticholinergics, the available evidence supports their use only in school-aged children with severe asthma exacerbation. There is no conclusive evidence for using multiple doses of anticholinergics in children with mild or moderate exacerbations. These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in The Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (www.cochrane.org).

Cochrane Critique

Did the authors address a focused clinical question? Yes.

Were the criteria used to select articles for inclusion appropriate? Yes. In addition to those outlined in the abstract, no language restrictions were applied.

Is it likely that important relevant articles were missed? No. In addition to using three databases, the authors searched appropriately for unpublished data.

Was the validity of the individual articles appraised? Yes. Most studies were of high quality.

Were the assessments of studies reproducible? Yes.

Were the results similar from study to study? Yes. The included studies were statistically homogeneous.

How precise were the results? For summed results, confidence intervals were reasonably narrow.

Can the results be applied to patient care? Yes.

Do the conclusions make biologic and clinical sense? Yes.

Are the benefits worth the harms and cost? Yes. There was a clinically significant decrease in hospitalization rates that would more than offset the expense of the medication. There was no increase in the occurrence of adverse effects.

Practice Pointers

In addition to beta₂ agonists, current regimens for treating children with acute asthma exacerbations routinely include the use of glucocorticoids. Systemically administered steroids have been shown to decrease hospital admission rates (number needed to treat [NNT], 3)² and prevent asthma relapses.³ Cochrane reviewers also have demonstrated benefit from inhaled steroids in emergency department treatment of asthma flares in children.⁴ Based on the findings of this Cochrane review, standard treatment of asthma exacerbations in children also should include inhaled anticholinergics. Adding ipratropium bromide (Atrovent) to beta₂-agonist inhalation improved lung function and decreased hospital admission rates (NNT, 12) without any increase in side effects such as nausea, vomiting, or tremor. This benefit seemed to be independent of systemic steroid use.

The benefit of anticholinergics was greatest in patients with severe exacerbations (NNT, 7 for prevention of hospitalization). The subset of children with moderate or moderate to severe asthma flares had similar relative improvements, but because of the limited number of studies addressing this subgroup, these results did not reach statistical significance. Those with only mild asthma exacerbations are unlikely to benefit from the addition of anticholinergics.

The improvements were found only in the group receiving multiple doses of anticholinergics in the initial phase of treatment (usually in the first one to two hours following presentation to the emergency department). One-time use of ipratropium did not improve outcomes. Because only two small trials considered the efficacy of continuing the combined treatments, it is unclear whether adding anticholinergics during hospitalization or following discharge from the emergency department will further improve outcomes.

Returning to our clinical scenario, we would recommend that our five-year-old patient with a moderate asthma exacerbation receive anticholinergics in addition to the beta₂ agonists and oral steroid therapy. While the timing and quantity of dosing varied across studies, general recommendations would include two to four doses of 250 to 500 mcg of ipratropium in the first two hours of acute care.

REFERENCES

1. Plotnick LH, Ducharme FM. Combined inhaled anticholinergics and beta₂-agonists for initial treatment of acute asthma in children. Cochrane Database Syst Rev 2000;4:CD000060.
2. Rowe BH, Spooner C, Ducharme FM, Bretzlaff JA, Bota GW. Early emergency department treatment of acute asthma with systemic corticosteroids. Cochrane Database Syst Rev 2001;1:CD002178.
3. Rowe BH, Spooner CH, Ducharme FM, Bretzlaff JA, Bota GW. Corticosteroids for preventing relapse following acute exacerbations of asthma. Cochrane Database Syst Rev 2001;1:CD000195.
4. Edmonds ML, Camargo CA, Pollack CV, Rowe BH. Early use of inhaled corticosteroids in the emergency department treatment of acute asthma. Cochrane Database Syst Rev 2000;3: CD002308.

Casey Cleary-Hammarstedt, M.P.A. is an education specialist in the family medicine department at the State University of New York Upstate Medical University, Syracuse, N.Y., and has been involved with teaching evidence-based medicine to medical students.

Cheryl A. Flynn, M.D., M.S., is assistant professor of family medicine and researcher in the Center for Evidence-Based Practice at SUNY Upstate Medical University, Syracuse.

Address correspondence to Cheryl A. Flynn, M.D., M.S., Department of Family Medicine, 475 Irving Ave. #200, Syracuse, NY 13210. Reprints are not available from the authors.