Exercise-induced asthma (EIA) is a very frequent clinical problem. Often asthmatic patients avoid exercise, sometimes on mistaken advice of a physician. In fact, it is usually possible to completely prevent exercise-induced asthma, or to minimize its severity, by prophylactic administration of certain drugs.
The most effective preventive measure is inhalation of an aerosolized beta-adrenergic agent, a few minutes before the exercise. Up to 75 percent to 87 percent of patients can be completely protected from EIA by inhaled albuterol or metaproterenol. Apart from the fact that some patients are not protected, the duration of the EIA-preventive effect is for some drugs much shorter than the duration of the same drugs bron-chodilating effect. Thus, metaproterenol given by metered dose inhaler has a bronchodilating effect of four to six hours, whereas its protective effect from EIA lasts only slightly over one hour.
The newer p2 selective sympathomimetic bronchodilators that have been introduced in the last few years are credited with a longer duration of action. Fenoterol has a reported duration of action of six to eight hours, but Anderson and associates, using a dose of 0.4 mg (two whiffs), found that its EIA-preventive effect lasted less than four hours. The effect of dose on duration of action has not so far been investigated.
The present investigation was undertaken to determine the length of time for which fenoterol suppresses EIA, and how the dose level is related both to the degree of the initial protection provided and to the duration of the protective effect.
Subjects and Methods
Twelve young male subjects with a mean age of 21.7 years (range 17 to 29 years) participated in the study. All had asthma as defined by the American Thoracic Society and responded to exercise with a fall in FEV1 (forced expiratory volume in one second) of at least 20 percent within 20 minutes.
The exercise tests, performed on three separate test days, consisted of running on a treadmill at a speed and slope that would raise the heart rate to 90 percent of the predicted age-related maximum. Mean room temperature and levels of relative humidity were essentially identical on the three days of the study; there were no statistically significant differences. On each day, three exercise tests were performed 10,120, and 240 minutes after administration of a single drug or placebo dose (Fig 1). Three regimens were thus tested on separate days in a double-blind, randomized manner: A: placebo inhaler, four whiffs; B: placebo inhaler, two whiffs, plus fenoterol inhaler, two whiffs (0.4 mg); C: fenoterol inhaler, four whiffs (0.8 mg). All short-acting bronchodilators (theophylline and beta-agonists) were excluded for 12 hours prior to testing. None of the patients was taking long-acting bronchodilators. Cromolyn was withheld for eight hours before testing. Inhaled steroids were permitted if the dose was stabilized for one month prior to the study, but no steroid doses were given for at least eight hours before any study day.
The FEV1 and FEF1 (mean forced expiratory flow during the middle half of FVC) were measured with a Collins-Stead-Wells water-sealed spirometer according to accepted standards. The pulmonary function measurements were made just before administration of fenoterol or placebo, immediately before exercise (ten minutes, and two and four hours after drug administration), and at 1, 5, 10, 15, and 20 minutes after each of the three exercise periods.
A complete history was taken, and a physical examination was made before the study. Pulse rate and blood pressure were measured just before treatment, just before exercise, and 5 to 20 minutes after completion of the exercise. The ECG (what is it?) was monitored during the treadmill runs.
Bronchodilation was determined by calculating the percent changes in FEV, and FEV from baseline to the pre-exercise values obtained at intervals of ten minutes and two and four hours after administration. The changes caused by exercise were calculated by the following formula:
Protection was considered complete if the decrease in FEV1 or FEF25±75 was 10 percent or less, which is within the normal limits of variation. The postbronchodilator and postexercise FEF1, values were obtained at the same volumes after peak inspiration as at baseline (iso-volume). The paired Students f-test was used for statistical analysis of the results, p values of less than 0.05 being considered significant.
Figure 1. Mean changes in FEV1 (liters) before treatment and after exercise runs (six minutes each) ten min and two and four hours after treatment with 0.4 mg and 0.8 mg of fenoterol and placebo.