Approximately 14 million persons in the United States have asthma. Of note, the prevalence of self-reported disease doubled from 1980 to 1994. Current treatment guidelines for patients with asthma recommend the regular use of anti-inflammatory agents, including inhaled steroids, mast cell stabilizers and leukotriene modifiers, to prevent chronic airway inflammation. In patients with acute asthma exacerbations, the treatment guidelines advocate nebulized therapy with a beta2-adrenergic receptor agonist combined with ipratropium. This treatment plan makes sense in theory because these two agents have different mechanisms of action by which they produce more bronchodilation in combination than beta-agonist monotherapy. However, the use of ipratropium in the treatment of patients with acute asthma remains controversial. Herner and colleagues reviewed data from several clinical trials to assess the safety, tolerability, effectiveness and price of the combined use of ipratropium with a beta-agonist in the treatment of patients with acute asthma.
Adverse effects reported by the manufacturer of ipratropium bromide solution for inhalation are from 12-week active-controlled clinical trials. The most common adverse events included tremor, agitation, vomiting, increase in pulse, dry mouth, palpitations, chest pain, back pain, nervousness, headache, nausea and dizziness. However, many of the reported side effects were minor and occurred during administration of ipratropium for more than 12 weeks; thus, these side effects may not correlate with acute asthma exacerbations. In the trials reviewed for this article, patient dropout resulting from the side effects of combined therapy did not differ from the dropout rate in the control group that received only beta-agonist therapy. In a pooled analysis including 10 trials investigating ipratropium as adjunctive therapy with beta-agonist in adults with acute asthma, no serious adverse effects were associated with any therapy, and patients who took ipratropium did not experience more side effects compared with those who took placebo. Most trials did not report adverse effect rates. The safety and efficacy of ipratropium in children younger than 12 years have not been established. Ipratropium solution for inhalation is rated as a pregnancy category B drug, and none of the other asthma medications for pregnancy has a higher safety rating.
The authors reviewed a number of clinical trials that used a variety of combined and monotherapy approaches using ipratropium and albuterol (e.g., nebulized treatments of albuterol-placebo compared with albuterolipratropium, ipratropium-albuterol compared with albuterol alone), in the treatment of adults with acute asthma. Primary and secondary end points varied among these studies and included hospital admission rates, admission-discharge ratios, length of stay in the emergency department, and changes in forced expiratory volume (FEV1) and peak expiratory flow rate (PEFR). One study evaluated the efficacy of a single nebulizer treatment of ipratropium and albuterol compared with albuterol alone. The results revealed a trend toward fewer hospitalizations in the ipratropium-albuterol group, but the difference was not statistically significant. One pooled analysis of three of the trials that evaluated the efficacy of combined ipratropium and albuterol revealed a 20 percent decrease in hospitalization rate, a 16 percent decrease in the risk of asthma exacerbation and an 8 percent decrease in the need for further asthma therapy. However, only the last outcome was statistically significant.
The authors reference the 1998 Drug Topics Red Book in evaluating cost. A single adult dose of ipratropium (2.5 mL of the 0.02 percent solution) has an average wholesale price of $1.75. In addition, mixing ipratropium solution with albuterol solution does not add to the cost of administration.
The authors conclude that, based on evidence from the reviewed clinical trials, the benefit of adding nebulized ipratropium to a beta-agonist in the treatment of adults with acute asthma remains unclear. Further studies are needed to assess subjective parameters (e.g., symptom improvement, the patient's perception of clinical benefit). In addition, further trials are needed that include patients with a PEFR/FEV1 of less than 50 percent because most cases of adult asthma that have been studied in clinical trials to date were not defined as severe.
editor's note: Despite the inconclusive evidence of the benefit of ipratropium therapy in patients with acute asthma, the current Guidelines for the Diagnosis and Management of Asthma state that if ipratropium is used, it should be given in combination with albuterol by nebulizer. Adults with severe exacerbations of asthma should be given 0.5 mg of ipratropium with 2.5 to 5 mg albuterol every 20 minutes for three doses. This should be followed by 0.5 mg of ipratropium every two to four hours and 2.5 to 10 mg of albuterol every one to four hours, as needed. The ipratropium should be discontinued when the patient attains 70 percent or more of predicted PEFR/FEV1. Systemic corticosteroids should also be administered to patients presenting to the emergency department with acute asthma.—j.t.k.