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Acute asthma is a common medical emergency that is often poorly managed (1) despite well-defined recommendations for its assessment and treatment (2). First line therapy usually consists of inhaled short-acting ß agonists, oxygen and systemic corticosteroids. In this issue of AJRCCM (pp. 528–533), Camargo and coworkers (3) present data from a pilot study that shows the additive benefit from the addition of either 7 mg or 14 mg of intravenous montelukast as compared with placebo in patients who were treated with nebulized albuterol alone.
Leukotriene receptor antagonists have been available for a number of years. These agents have generally been recommended for the treatment of mild asthma, especially in patients who are reluctant to take inhaled corticosteroids, or as add-on therapy for patients who remain symptomatic despite inhaled corticosteroids (4).
In the study by Camargo and coworkers (3), patients with acute asthma were screened and pretreated with a single dose of nebulized albuterol 2.5 mg. If they fulfilled predefined entry criteria, patients were then enrolled, and a further dose of albuterol by nebulization was given. Study subjects were then randomized to receive the active drug or a placebo. Further treatment was at the discretion of the local investigators. The primary end-point was the FEV1 at 20 minutes. At this time there was no significant difference between the two active treatment arms. There was, however, a statistically and clinically relevant difference between both groups, with a mean FEV1 increase of 14.8% in the active treatment groups compared with 3.6% (p = 0.007) in the placebo arm of the study. This benefit continued for the 2 hours of the study during which spirometry was measured. The distribution of response was unimodal suggesting there was no phenomenon of "responders" versus "non responders."
Studies have shown that urinary leukotrienes (leukotriene E4, a stable metabolite of leuoktriene metabolism) are elevated in acute asthma and decline during the recovery phase (5). These results were replicated in this study, baseline values being 102.4 versus 69.5 pg/mg creatinine 2 weeks later. Although there was a tendency for patients with higher levels of leukotriene E4 to have a greater response, this did not reach statistical significance.
This study shows clear benefit from the early use of montelukast in acute asthma. Important questions, however, remain unanswered. The authors underestimate the current practice of using ipratropium bromide in acute asthma as well as the evolving role of adjunct therapy with intravenous magnesium. Although ipratropium bromide, when used in acute asthma, has a marginal effect on FEV1 (6), systematic overviews, both in adult (7) and pediatric asthma (8), have shown a significant reduction in hospitalization rates when ipratropium bromide compared with placebo is added to short acting ß-agonists. This effect on hospitalizations has subsequently been shown in a prospective randomized controlled trial (9). In patients with more severe airflow obstruction, the addition of intravenous magnesium has also been shown to have a marginal effect on airflow obstruction, but a significant effect on admission rates (10).
In contrast to these predominantly bronchodilator therapies, a potential additive effect of montelukast is its well-documented antiinflammatory effects. In a recent study of patients with chronic asthma who were challenged with an allergen, both oral montelukast and inhaled budesonide (11) had antiinflammatory effects. Budesonide, however, showed greater protection against allergen-induced airway hyper-responsiveness. Both interventions had a similar effect on sputum eosinophilia. In contrast to other studies of leukotriene receptor antagonists (4), each intervention had an effect on the late-asthmatic response, but the combination had no additive effect. Montelukast alone had an effect on the early response.
In another study of patients with chronic asthma, montelukast has been shown to reduce eosinophils in induced sputum (12). Minoguchi and colleagues (12) randomized 29 patients to treatment for 4 weeks with 10 mg/day of montelukast versus a placebo. At the end of the study period, there was a significant reduction in sputum eosinphilia from 24.6 ± 12.3% at baseline to 15.1 ± 11.8%, as compared with placebo, 21.3 ± 12.1% at baseline to 21.0 ± 11.5% (p < 0.005). Similar effects were seen on peripheral blood eosinophilia, but there was no effect on asthma symptoms or airway hyper-responsiveness.
We traditionally consider corticosteroids to have a delayed effect in acute asthma, but studies now suggest that both oral and inhaled corticosteroids have an effect in the early phase of acute asthma (2, 13). A recent study from India has shown that the early use of oral prednisone versus placebo significantly reduced hospitalization (14).
Before we can define what role, if any, montelukast will have in the routine management of acute asthma, a number of key questions need to be answered. The rapid onset of action, shown in the study of Camargo and coworkers (3), suggests that the primary mechanism of action is one of bronchodilation. It is tempting to speculate that montelukast has an additional antiinflammatory effect in acute asthma. Of interest was the fact that the physicians, who were blinded to treatment allocation, were less likely to prescribe oral corticosteroids to the patients treated with montelukast. Thus, further careful prospective studies need to be performed with larger numbers of patients where the effect on hospitalizations and inflammatory indices, such as induced sputum, need to be assessed (15). These studies should also provide a more valid baseline bronchodilator intervention including both albuterol and ipratropium bromide. The studies should also assess the incremental cost of an expensive intravenous therapy when given in addition to the current standard treatment. In patients discharged from the emergency department, the addition of inhaled corticosteroids to oral prednisone has an additional benefit in reducing relapse when compared with systemic corticosteroids alone (2). It will be of interest to see, given its known antiinflammatory effect, whether intravenous montelukast will have an equivalent beneficial effect after discharge.
In conclusion, I believe montelukast has the potential to be a new adjunct in the therapy of acute asthma. This potential needs to be confirmed in larger carefully conducted studies in which subjects are prescribed a currently recommended initial bronchodilator in addition to adjunct therapy.
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