© 2004 American Thoracic Society
Intravenous Montelukast in Acute AsthmaTo the Editor:Camargo and colleagues (1) examined only the asthma history and the duration of symptoms before presentation, but, unfortunately, they failed to identify the prior treatments and the asthma triggers as predictors of response to treatment in patients being administered the study drug in less than an hour from their arrival in the emergency department. The period preceding their admission, when the prior treatments should have been discontinued to prevent important pharmacologic interactions with the study medicines, was precisely defined for every drug elsewhere (2). An observational study (3) showed that albuterol was used during this period by 98% of patients, followed by corticosteroids, either inhaled (69%) or oral (49%). The viral infections (74%) represented the main asthma trigger. We hypothesized that montelukast used in the emergency department setting had an additive effect to the prior corticosteroid treatment, on a background of upper respiratory infections triggered mainly by rhinoviruses, in patients who also did not respond to excessive albuterol use, so that their initial response to ß agonists after being admitted was found to be suboptimal.
Rhinoviruses enhanced both the expression (through increased nuclear factor- In these albuterol-resistant patients, a drug active on a different target, like montelukast, proved beneficial either by increasing the partially switched off effect of corticosteroids during the viral infection, consequently up-regulating the ß-adrenoceptor, or by adding up to the lower level of corticoid activity in partially compliant patients. In conclusion, the level of prior corticoid activity, as a predictor of response to treatment, had to be checked in correlation with the latest level of compliance before admission and with the specific triggers. The prior albuterol use, defined as either excessive (greater than the dose recommended in the past for regular use) or usual (less than this threshold) also needed to be included in the statistical analysis.
Division of Research Brooklyn Hospital Brooklyn, New York REFERENCES
To the Editor: We read with interest the recent article from Camargo and colleagues (1) regarding the administration of intravenous montelukast in adult patients with acute moderate to severe asthma. This multicenter, randomized, controlled study showed that intravenous administration of montelukast compared with placebo was associated with a rapid but modest benefit in FEV1 accompanied by trends toward improvements in treatment failure rates. However, this study has a critical limitation: the standard therapy used as comparison (nebulized ß2-agonists and corticosteroids). Accordingly, the authors excluded the ipratropium bromide use. In the DISCUSSION, they examined new interventions in addition to current standard treatment and recognized from high quality evidence (see References 20–23 within Camargo and colleagues' study [1]) that inhaled ipratropium bromide (IB) may provide a "modest" benefit and an improvement in hospital admission rates, particularly in patients with acute severe asthma. Surprising, the authors validated the statement that "there is no clear consensus regarding their [anticholinergics] use" on the basis of one letter to editor, one nonrandomized study, and one controlled trial that used low doses of ß2-agonists and IB (see References 24–26 within Camargo and colleagues' study [1]). It is important to clarify that in the last few years it has been demonstrated that the use of multiple doses of IB added to ß-agonists are indicated in the emergency department treatment of children and adults with acute severe asthma (2–5). The studies report a substantial reduction in hospital admissions (NNT = 5 to 11) and statistical and clinical significant differences in lung function favoring the combined treatment (PEF variation > 50 L/minute at 90 minutes of treatment). Thus, this evidence has been recently included in the latest guidelines of acute asthma management (6). In summary, this study suggests that in adult patients with moderate to severe acute asthma, intravenous montelukast produces a small benefit in pulmonary function, but it does not prove that intravenous montelukast should be added to conventional current treatment. The true question here is whether adding intravenous montelukast will produce further improvements in patients who have received conventional first-line treatment including inhaled high dose bronchodilators (ß-agonists plus IB) and systemic corticosteroids.
a Emergency Department Hospital Central de las Fuerzas Armadas Montevideo, Uruguay REFERENCES
From the Authors:
We thank Drs. Jalba, Rodrigo, and Rodrigo for their interest in our study. As Dr. Jalba suggests, prior therapy may have an impact on response to treatment for acute asthma. In our pilot study (1), we excluded patients with asthma who were being treated with corticosteroids before their asthma attack. Consistent with the data cited by Dr. Jalba (2), 92% of patients in our study had received short-acting ß2-agonists (SABA), typically albuterol, before their presentation for acute asthma. A post hoc analysis of high ( Drs. Rodrigo and Rodrigo make several reasonable comments supporting the use of ipratropium bromide in acute asthma. The purpose of our pilot study, however, was not to determine if intravenous montelukast should be added to conventional treatment for acute asthma; rather, it was to determine whether intravenous montelukast could demonstrate efficacy (in terms of FEV1 response) in acute asthma, a question that had not been previously examined. Our results clearly support this hypothesis. With regard to additive effects, it is reasonable to predict that montelukast would in fact be efficacious when given in addition to standard therapy including ipratropium because (1) montelukast was additive to ß-agonists and anticholinergics have only a modest, if any, additive effect on FEV1, especially in patients with asthma whose initial response to ß-agonists is impaired (3); (2) montelukast has a mechanism of action independent of anticholinergics; and (3) montelukast is additive to corticosteroids in chronic asthma (4, 5) and was additive when corticosteroids were given for acute asthma in our study (1). In contrast, the interaction between ipratropium and corticosteroids in acute asthma has not been rigorously evaluated (for example, in the one primary study cited by Drs. Rodrigo and Rodrigo, systemic corticosteroids were excluded [6]). Taken together, our data strongly support the role of cysteinyl leukotrienes in the pathobiology of acute asthma (7), and further suggest that montelukast may be an effective treatment for this condition. We agree that this latter hypothesis should be tested directly in the context of larger, confirmatory clinical trials.
a Massachusetts General Hospital Channing Laboratory Brigham and Women's Hospital Harvard Medical School Boston, Massachusetts REFERENCES
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–mediated transcription) and action of intercellular adhesion molecule-1, inducing proasthmatic changes in airway smooth muscle responsiveness. Through an upregulated expression of the inhibitory 
3 G protein, they impaired two related ß-adrenoceptor–mediated actions: the stimulation of cyclic AMP accumulation and the airway smooth muscle relaxation (
8 puffs/day albuterol or equivalent) versus low (< 8 puffs/day albuterol or equivalent) SABA use failed to demonstrate any interaction between prior SABA use and response to montelukast (p = 0.75 for the primary FEV1 end-point). Similar results were obtained when other thresholds for high and low SABA use were considered.