Reversing acute bronchoconstriction in asthma: the effect of bronchodilator tolerance after treatment with formoterol

Continuous treatment with a short-acting beta2-agonist can lead to reduced bronchodilator responsiveness during acute bronchoconstriction. This study evaluated bronchodilator tolerance to salbutamol following regular treatment with a long-acting beta2-agonist, formoterol. The modifying effect of intravenous corticosteroid was also studied. Ten asthmatic subjects (using inhaled steroids) participated in a randomised, double-blind, placebo-controlled, cross-over study. Formoterol 12 microg b.i.d. or matching placebo was given for 10-14 days with >2 weeks washout. Following each treatment, patients underwent a methacholine challenge to induce a fall in forced expired volume in one second (FEV1) of at least 20%, then salbutamol 100 microg, 100 microg, and 200 microg was inhaled via a spacer at 5 min intervals, with a further 400 microg at 45 min. After a third single-blind formoterol treatment period, hydrocortisone 200 mg was given intravenously prior to salbutamol. Dose-response curves for change in FEV1 with salbutamol were compared using analysis of covariance to take account of methacholine-induced changes in spirometry. Regular formoterol resulted in a significantly lower FEV1 after salbutamol at each time point compared to placebo (p<0.01). The area under the curves (AUCs) for 15 (AUC0-15) and 45 (AUC0-45) min were 28.8% and 29.5% lower following formoterol treatment (p<0.001). Pretreatment with hydrocortisone had no significant modifying effect within 2 h of administration. It is concluded that significant tolerance to the bronchodilator effects of inhaled salbutamol occurs 36 h after stopping the regular administration of formoterol. This bronchodilator tolerance is evident in circumstances of acute bronchconstriction.