Authors' objectives

To determine whether inhaled ipratropium bromide provides additional benefits to adults with acute asthma, who are being treated with beta-agonists in an emergency department.

Searching

MEDLINE was searched from 1978 to April 1999 using the following MeSH terms: 'N-isopropylatropine' or 'ipratropium bromide', and 'adult', 'acute asthma' or status asthmaticus'. Searches of Current Contents, the Science Citation Index, and review articles were also performed. Studies were limited to those published in the English language. Details of additional published and unpublished studies were obtained by contacting experts (pulmonologists and emergency physicians) and the manufacturer of ipratropium bromide (Boehringer Ingelheim), and by searching the Medical Editors Trial Amnesty.

Study selection

Assessment of study quality

Validity was assessed and scored using the following criteria:

randomisation method, scored 1 (not specified) to 2 (specified);

demographic characteristics of the sample provided, scored from 0 (none) to 2 (detailed;

inclusion and exclusion criteria specified, scored from 0 (none) to 2 (detailed);

asthma definition, scored from 0 (no definition) to 2 (American Thoracic Society criteria used);

sample size calculation, scored from 0 (none) to 2 (detailed); and

withdrawals, scored from 0 (more than 20% of participants) to 2 (none or no more than 20% of participants, with reasons given).

Two reviewers, blinded to the authors and outcome of each study, scored each selected study. The mean score of the two evaluations was divided by the possible score of 12 points, giving values between 0.8 and 1.0. The agreement between reviewers was calculated using a weighted kappa statistic (kappa=0.86).

Data extraction

The following data were extracted: title; author; year and source of publication; the number of patients; the demographic characteristics of the patients; the dosage and route of all medications used; spirometric measure used; the mean and standard deviation of spirometric values at baseline and after treatment; the time of follow-up; statistical analysis; the admission rate; and adverse effects.

The effect of treatment in each study was computed as a standardised effect size for FEV1, if reported; otherwise, PF was used. Each effect size was adjusted for differences in the baseline spirometric measures between treatment groups.

Methods of synthesis

Results of the review

Ten RCTs (1,483 patients) were included.

Only 5 RCTs indicated the method of randomisation; 4 RCTs defined the inclusion and/or exclusion criteria in detail; and 7 RCTs included a sample size estimate. The mean methodological quality score was 0.66. There was a significant correlation (rho) between the year of publication and methodological quality (rho=0.76, p=0.02). However, there were no significant correlations between the effect size and year of publication (rho=0.29, p=0.4) or methodological quality (rho =0.42, p=0.2).

Pulmonary function at 90 minutes: the addition of ipratropium to beta-agonist therapy led to a significant benefit. The pooled effect size was 0.14 (95% CI: 0.04, 0.24, p=0.008). The fail-safe N was 36.4. There was no evidence of heterogeneity (p>0.5).

Sensitivity analyses: when the 5 lower quality studies were excluded, the findings were practically unchanged; the results were not reported. For the 4 studies of patients with FEV1 or PF less than 35% of the predicted value, the addition of ipratropium to beta-agonist therapy led to a significant benefit (pooled effect size 0.38, 95% CI: 0.09, 0.67). Systemic steroids had a moderate effect on outcome (pooled effect size 0.14, 95% CI: 0.00, 0.28).

Publication bias: the funnel plot was statistically symmetrical (p=0.58).

Admission rates (5 RCTs, 1,186 patients): the addition of ipratropium to beta-agonist therapy led to a significant reduction in the admission rates. The odds ratio was 0.62 (95% CI: 0.44, 0.88, p=0.007) and the number-needed-to-treat was 18 (95% CI: 11, 77). No evidence of heterogeneity was found (p>0.3). Most papers did not clearly describe their criteria for admission or discharge.

Side-effects (6 RCTs): there were no significant differences between the treatment groups in terms of tremor, heart rate, blood-pressure, respiratory rate, anxiety, dry mouth, or oxygen saturation.

Authors' conclusions

The addition of ipratropium to beta-agonist therapy offered a statistically-significant, albeit modest, improvement in pulmonary function, as well as a reduction in the rate of hospital admission.

CRD commentary

The aims were stated and the inclusion criteria were defined in terms of participants, study design, and interventions. Searches were conducted for published and unpublished material. By restricting studies to those published in the English language, other relevant studies may have been omitted; this possibility was acknowledged by the authors. The methods used to select the studies were described, and publication bias was assessed. The included studies were limited to RCTs. Validity was assessed and scored using defined criteria, and the methods used to assess the validity were described.

Some relevant details of the primary studies were presented in tabular format, although the method of drug delivery and the criteria used to diagnose acute asthma were not specified. Statistical heterogeneity was assessed and outcomes from the individual studies were presented graphically. A meta-analysis was appropriate given the statistical homogeneity. Sensitivity analyses were undertaken to examine the robustness of the findings.

The evidence supports the authors' conclusions.

Implications of the review for practice and research

Practice: The authors state that the addition of ipratropium to beta-agonist therapy offers a statistically-significant, albeit modest, improvement in pulmonary function, as well as a reduction in the rate of hospital admission.

Research: The authors state that future studies should examine whether greater or cumulative doses of ipratropium bromide give any additional bronchodilation over and above that achievable with beta-agonists. These studies should use standardised criteria for admission or discharge.

Bibliographic details

Rodrigo G, Rodrigo C, Burschtin O. A meta-analysis of the effects of ipratropium bromide in adults with acute asthma. American Journal of Medicine 1999; 107(4): 363-370. [PubMed: 10527039]

Other publications of related interest

1. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-48. 2. Hedges LV, Olkin I. Statistical methods for meta-analysis. San Diego (CA): Academic Press; 1985.

This additional published commentary may also be of interest. Peters J. Review: ipratropium bromide with beta-agonists improves pulmonary function and reduces admissions to hospital in acute asthma. Evid Based Med 2000;5:107.

Indexing Status

Subject indexing assigned by NLM

MeSH

Acute Disease; Administration, Inhalation; Adrenergic beta-Agonists /therapeutic use; Adult; Albuterol /therapeutic use; Asthma /drug therapy; Bronchodilator Agents /administration & dosage /therapeutic use; Drug Synergism; Fenoterol /therapeutic use; Forced Expiratory Volume /drug effects; Humans; Ipratropium /administration & dosage /therapeutic use; Middle Aged; Odds Ratio; Randomized Controlled Trials as Topic; Treatment Outcome

AccessionNumber

11999002129

Database entry date

31/05/2002

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.