Hancox RJ, Subbarao P, Kamada D, Watson RM, Hargreave FE, Inman MD. Am J Respir Crit Care Med. 2002;165:1068–1070
Purpose of the Study.
Tolerance to the bronchoprotective effects of β2-agonists after regular use has been demonstrated by a number of groups. These authors asked whether patients receiving scheduled β2-agonist had a decrease in response to rescue use of β2-agonist when bronchospasm is induced by a “natural” stimulus, exercise. Thus, they were looking for loss of the bronchodilator response rather than loss of protection to bronchoconstriction.
Adults aged 18 to 50 years with a history of exercise-induced wheezing and a drop of forced expiratory volume in 1 second (FEV1) by at least 15% after exercise challenge. Subjects could have no interfering disease and could not be receiving >1500 μg/day beclomethasone or equivalent.
Subjects withheld β2-agonist s for 8 hours before testing (36 hours for long-acting β2-agonists). The qualifying bicycle ergometer challenge used an incremental increase in workload till the subject could not continue. A 15% fall in FEV1 was required for study entry. Before and after 1 week of study treatment, subjects performed dry-air exercise challenge at 80% of the demonstrated maximum workload for 7 minutes with an additional 1-minute dry air inhalation. Spirometry was repeated at 1, 3, and 5 minutes after exercise, then inhaled albuterol rescue was given and spirometry repeated at 10, 15, 20, and 25 minutes. The study treatments were albuterol via metered-dose inhaler (MDI) 2 puffs four times a day (QID) for 1 week, or matching placebo, given in double-blind crossover fashion with no washout between treatment weeks. During the treatment week, rescue for symptoms was limited to ipratropium.
Of 22 patients screened, 9 were randomized (8 female, age: 18–44). The mean standard deviation (SD) forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) ratio was 83%. Compared with the placebo week, after the week of albuterol treatment, the onset of bronchoconstriction was sooner, with a 90% greater fall in FEV1 at 5 minutes, although the baseline FEV1 for the groups was similar. The final FEV1 after albuterol rescue was significantly lower in the treated than placebo group, but the change in FEV1 from its nadir was similar for the 2 groups, ie, the response curves were parallel.
Scheduled short-acting bronchodilator use leads to increased bronchoconstriction after exercise and suboptimal response to rescue albuterol after exercise.
Although the subjects are young adults, the results are probably applicable to children with asthma. The question of tachyphylaxis to β2-agonists has been argued for 2 decades, at least. Large clinical trials generally have not suggested significant risk to frequent β2-agonist use, but numerous studies show at least partial loss of bronchoprotective effects with routine use of β2-agonists. Such studies have supported the recent tendency to reserve short-acting β2-agonists for symptom relief. This study further justifies this restrictive approach to short-acting β2-agonists. However, the mechanism by which the increased exercise response is generated is still unclear. The authors suggest that the effect is attributable to β2-receptor downregulation, because the earlier onset of bronchoconstriction in the albuterol group would be consistent with lack of bronchoprotection from endogenous catecholamines. The alternative explanation of increased airway inflammation associated with routine β2-agonist is not thought likely by the authors because the FEV1 was similar at baseline. An interesting study to help tease out the mechanism would add levalbuterol as a study treatment, because studies suggest it, unlike racemic albuterol, is not associated with increased methacholine sensitivity after scheduled treatment.