Respiratory impedance response to a deep inhalation in asthmatic children with spontaneous airway obstruction

Abstract

Previous reports suggest that regular use of b-agonists does not lead to tolerance to their bronchodilator effects. However, most studies have been conducted in stable asthma. This study investigates whether bronchodilator tolerance can be demonstrated during acute bronchoconstriction.Thirty-four asthmatic subjects were treated with 6 weeks inhaled terbutaline (1 mg q.i.d.), budesonide (400 mg, b.i.d.), both drugs or placebo in a randomized, doubleblind, cross-over study. After each treatment methacholine was administered to induce a 20% fall in the forced expiratory volume in one second (FEV1). The response to inhaled salbutamol 100, 100, 200 mg at 5 min intervals) was then measured. Doseresponse curves were compared using an analysis of covariance. Pre-methacholine FEV1, the highest pre-methacholine FEV1, the fall in FEV1 induced by methacholine and the logarithm of the provocative dose of methacholine required to induce the 20% fall in FEV1 (PD20) were used as covariates.There was a significantly reduced response to salbutamol after 6 weeks terbutaline treatment: the mean (95% confidence intervals (CI)) area under the dose-response curve was reduced by 36% (24, 47) compared to placebo (p<0.0001). The reduction in bronchodilator response was not affected by concomitant treatment with budesonide.Significant tolerance to the bronchodilator effect of inhaled b-agonists may be demonstrated when tested during acute bronchoconstriction. Continuous treatment with inhaled b-agonists may lead to a reduced response to emergency b-agonist treatment during asthma exacerbations. Eur Respir J 1999; 14: 283±287. b-agonists are highly effective bronchodilators and have an important role in the treatment of asthma exacerbations. However, many of the pharmacological effects of b-agonists diminish during chronic treatment, and there has been some concern that regular use of these drugs could lead to a failure to respond to treatment during severe asthma attacks. Some recent studies have shown a small reduction in bronchodilator response during treatment with long-acting b-agonists [1±3], but in general asthmatics have been found to be surprisingly resistant to the development of bronchodilator tolerance [4,5]. The reason for this is unknown. It may be because there is a high turnover of b 2 -receptors on airway smooth muscle such that receptor down-regulation has little impact on the receptor density [6]. Alternatively, it may be because maximal bronchodilation can be achieved by stimulation of a fraction of the normal receptor number.In contrast, there is increasing evidence that continuous b-agonist treatment leads to a reduction in their bronchoprotective effect for a variety of bronchoconstricting stimuli including methacholine, histamine, adenosine, exercise and allergen [7]. However, the clinical significance of these changes is uncertain in view of the apparently preserved acute bronchodilator response.This dissociation between the tendency to develop tolerance to the bronchodilator and bronchoprotective effects...