Life-Threatening Asthma during Treatment with Salmeterol

Abstract

Although the addition of a long-acting β2-agonist such as salmeterol to an inhaled corticosteroid has been demonstrated to provide greater control of asthma than does a substantially increased dose of the inhaled corticosteroid,1 this medication was associated with an increased risk of asthma-related death in a large population study.2 We have identified two adolescent boys with poorly controlled asthma and a history consistent with sudden asphyxial episodes during modest exertion while receiving inhaled corticosteroids and salmeterol. In addition to reporting an inadequate response to their rescue inhaler when symptomatic, they had no apparent bronchoprotective effect from shorter-acting β2-agonists administered before exercise. Because of the life-threatening nature of their acute episodes (which were associated with cyanosis, a loss of consciousness, and repeated calls for emergency care), they were admitted to the Children's Hospital of Iowa for evaluation. We found that both boys had profound bronchospasm within a few minutes after treadmill exercise despite pretreatment with albuterol or pirbuterol while they were receiving high doses of inhaled corticosteroid and salmeterol. Moreover, their recovery from the severe bronchospasm induced by relatively brief exertion required repeated inhalations of albuterol, with what appeared to be a blunted response to this agent. Once salmeterol was replaced for two days with slow-release theophylline, which has also been demonstrated to have an additive effect with inhaled corticosteroids,3 there was adequate blocking of exercise-induced bronchospasm with a β2-agonist (Table 1TABLE 1 Results of Four Exercise Studies in Two Patients Receiving Inhaled Corticosteroids, with and without Concurrent Administration of Salmeterol. ). Moreover, both patients subsequently had improved control of their asthma, tolerated exercise after pretreatment with albuterol or pirbuterol, and had virtually no acute symptoms during 10 days of inpatient observation (in the case of the first patient) or during several months of outpatient follow-up (in the case of the second patient). More than a decade ago, Grove and Lipworth reported that continuous exposure to salmeterol resulted in subsensitivity of the acute bronchodilator response to albuterol.4 Consistent with that report, our two patients reported having had previous poor responses to bronchodilators, which resulted in repeated trips for emergency care. Although our two patients had particularly severe asthma, they may represent a subgroup at risk for life-threatening episodes or death in association with the use of salmeterol.2 Although uncommon, such reactions provide support for the recent recommendation of Martinez for close medical monitoring of patients with sufficiently severe asthma to justify the addition of a long-acting β2-agonist to maintenance inhaled corticosteroids.