Criteria abstracted from The Users' Guide to Medical Literature, from the Health Information Research Unit and Clinical Epidemiology and Biostatistics, McMaster University

Highlighted lines and questions below provide links to the pertinent description of criteria in The EBM User's Guide, now available at the Canadian Centres for Health Evidence

Article Reviewed:

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Effect of nebulized ipratropium bromide on the hospitalization rates of children with asthma.

Qureshi F, Pestian, J, Davis P, Zaritsky A.

N Engl J Med 1998;339:1030-1035. [abstract]

Reviewed by Al Torres, MD, MS and G. Kris Bysani, MD

Review posted January 21, 1999

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I. What is being studied?:

The study objective:

To determine whether the addition of ipratropium bromide to standard emergency department therapy for asthma in children would reduce hospitalization rates

The study design:

A randomized, double-blind, placebo-controlled study

The patients included:

434 patients, 2 to 18 years old, with acute exacerbations of moderate to severe asthma treated in the emergency department of a large, tertiary care children's hospital. Severity of clinical condition was assessed as either percent reduction in peak flow from predicted or by a modified asthma score.

The patients excluded:

Parents of 17 children declined to give permission for participation and 46 children were excluded because wheezing resolved before the second dose of study medication had been given. Other reasons for exclusion included treatment with ipratropium within six hours before the visit to the emergency department, a disease known to have a chronic effect on respiratory function (e.g., cystic fibrosis or cardiac disease), concurrent stridor, possible presence of an intrathoracic foreign body, a medical condition that would contraindicate the use of a beta-adrenergic or anticholinergic medications, or the need for immediate resuscitation or airway intervention.

The interventions compared:

Children in the treatment group received 500 micrograms of ipratropium bromide with the second and third doses of albuterol and children in the control group received 2.5 mL of normal saline at these times.

The outcomes evaluated:

The primary outcome measure was rate of hospitalization between the two groups. The secondary outcome measures were the number of nebulizer treatments, disposition, the time to disposition, the need for any visits to a medical facility within 72 hours after discharge, and any changes in peak expiratory rate, asthma score, heart rate, respiratory rate, or oxygen saturation from entry into the study until disposition.

II. Are the results of the study valid?

Primary questions:

1. Was the assignment of patients to treatments randomized?

Yes. The pharmacy staff used a table of random numbers to assign children by block randomization to the treatment and control groups.

2. Were all patients who entered the trial properly accounted for and attributed at its conclusion?

Was followup complete?

Unsure. A total of 480 children were enrolled and randomly assigned to the two groups. Forty-six children were excluded from the original analysis (although they were followed) because their wheezing resolved before the second dose of the study medication had been given. Eighteen of the 46 children received one dose of albuterol, 15 received saline one time, and 13 received ipratropium one time.

Although the investigators state there was no difference in number of patients seeking medical care within 72 hr after discharge (confirmed by telephone call), they do not state what percentage of subjects they were not capable of reaching.

Were patients analyzed in the groups to which they were randomized?

Yes. Of the 46 children whose condition improved before completion of the study, only two presented with severe asthma. An intention-to-treat analysis including these two patients was performed and had similar results to the original analysis (i.e., significantly less patients with severe asthma treated with ipratropium were admitted to the hospital compared to the saline group). The authors did not do an intention-to-treat analysis including all 46 children that did not receive the second dose of the study medication.

Secondary questions:

3. Were patients, health workers, and study personnel "blind" to treatment?

Yes. The investigators and the patients were unaware of the group assignments and the albuterol/ipratropium vials were indistinguishable from the albuterol/placebo in appearance and aroma.

4. Were the groups similar at the start of the trial?

Yes. The only significant difference between the two groups was the ipratropium group had a greater proportion of females than in the control group (p = 0.04). This difference in gender distribution should not have had any influence on the outcome. The groups were similar in race, age, clinical asthma score, percent predicted peak expiratory flow rate, and severity of asthma.

5. Aside from the experimental intervention, were the groups treated equally?

Yes. All children received 0.5% albuterol solution at a dose of 2.5 mg (for children weighing < 20 kg) or 5 mg (for those children weighing > 20 kg) every 20 minutes for 3 doses. A corticosteroid (prednisone or prednisolone 2 mg per kg of body weight to a maximum of 60 mg) was given orally with the second dose of nebulized albuterol. There was no difference in number of nebulized treatments before disposition (additional doses administered after the first 3 doses was at the discretion of the attending physician) or time to disposition.

III. What were the results?

1. How large was the treatment effect?

The overall rate of hospitalization was lower in the ipratropium group (27.4%, 59/215 subjects), as compared with 36.5% (80/219) in the control group (p = 0.05); relative risk reduction (RRR) = 26%, absolute risk reduction (ARR) = 9.5%. There was no significant difference in the rates of hospitalization (10.1%, 8/79 in the treatment group vs. 10.7%, 9/84 in the control group) for patients with moderate asthma. However, for patients with severe asthma the administration of ipratropium significantly reduced the hospitalization rate to 37.5% (51/136) compared to 52.6% (71/135) (p = 0.02); RRR = 28.7, ARR = 15.1%.

2. How precise was the estimate of the treatment effect?

Overall, the 95% confidence intervals for the relative risk reduction are 2% to 50%; for the absolute risk reduction, they are 0.8% to 18.2%. Although these to not cross zero, the true effect (with 95% certainty) could be quite small.

In children with severe asthma, The absolute reduction in hospitalization rate was 15.1% (95% CI 3.4, 26.8); the RRR was 28.7% (95% CI 5, 50). Once again, these confidence intervals do not cross zero. The number of children with severe asthma who would need to be treated (NNT = 1/ARR) with ipratropium to prevent one hospitalization was 6.6 (95 CI 3.7, 29.4). We can then state, with 95% confidence, that between 4 and 30 children with severe asthma would need to be treated with ipratropium to prevent one hospitalization.

IV. Will the results help me in caring for my patients?

1. Can the results be applied to my patient care?

Maybe. Despite the study demonstrating a reduction in hospitalization rate in children with severe asthma, the investigators did not evaluate the impact of ipratropium on children with severe asthma admitted to the pediatric intensive care unit. Indeed, there was no difference in the overall rates of admission to the PICU between groups.

One study of ipratropium plus albuterol administered to 23 children with severe asthma (< 50 % predicted peak expiratory flow rate) demonstrated a better response to albuterol alone (p = 0.007) (1). A review of 6 randomized, double-blind, placebo-controlled trials found none of the studies showed a statistically significant difference between ipratropium and placebo groups with respect to vital signs, clinical rating score, number of repeat nebulizations, admission rate, length of admission or side effects (2).

2. Were all clinically important outcomes considered?

Yes. Besides the rate of hospitalization, the authors examined change in clinical asthma score, change in predicted peak expiratory flow rate, oxygen saturation, and number of patients seeking medical care within 72 hr of discharge. It would have been helpful if the investigators had analyzed the response to ipratropium stratified by age. It is possible that a particular age group may have responded better than another.

3. Are the likely treatment benefits worth the potential harms and costs?

Yes. There were no adverse effects reported in any of the children receiving ipratropium and the investigators estimate the additional cost of adding a 500 microgram dose of ipratropium to a dose of albuterol is $3. The average cost of hospitalization per child with asthma at the study institution was $3,267. This is the first well designed study to suggest that the potential benefit of 2 doses of ipratroprium to the initial management of the patient with severe asthma is beneficial and has little risk or cost.

References

1. Storr J, Lenney W. Nebulized ipratropium and salbutamol in asthma. Arch Dis Child 1986;61:602-603. [abstract]
2. Osmond MH, Klassen TP. Efficacy of ipratropium bromide in acute childhood asthma: a meta-analysis. Acad Emerg Med. 1995;2:651-656. [abstract]

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Related Reviews

Osmond MH, Klassen TP. Efficacy of ipratropium bromide in acute childhood asthma: a meta-analysis. Acad Emerg Med 1995; 2:651-656. [abstract]

• Review, by A. Torres

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