CARDIOVASCULAR SAFETY OF HIGH-DOSES OF INHALED FENOTEROL AND ALBUTEROL IN ACUTE SEVERE ASTHMA

Background: It has been suggested that overuse of fenoterol metered-do se inhalers (MDIs) may increase the risk of death from asthma due to c ardiac arrhythmias. Our primary objective was to compare the cardiovas cular safety of fenoterol and albuterol MDIs when administered in maxi mal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute seve re asthma. Methods: Asthmatic patients presenting to the ED with acute severe asthma (FEV(1) less than 50% of predicted) were enrolled in a multicenter, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determ ination of serum potassium and serum theophylline levels, oximetry, 12 -lead ECG, and spirometry), each patient received 4 puffs of either fe noterol, 200 mu g per puff, or albuterol, 100 mu g per puff, 1 puff ev ery 30 s via an MDI attached to a holding chamber. Additional doses of inhaled beta(2)-agonist were administered by dose titration, 2 puffs every 10 min to a maximal cumulative dose of 16 puffs of albuterol or fenoterol, side effects were intolerable to the patient, or an FEV(1) plateau (ie, <10% improvement for 2 consecutive doses) occurred. ECG w as recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV(1) were assessed after each dose. Resul ts: 128 patients were randomized to receive fenoterol and 129 to recei ve albuterol. Overall, fenoterol increased FEV(1) 160 mL more than alb uterol. The mean (SEM) FEV(1) increase from baseline was 0.75+/-0.06 L in the fenoterol group and 0.59+/-0.06 L in the albuterol group (p<0. 03). Both beta(2)-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23+/-0.04 mmol/L) t han in the salbutamol (0.06+/-0.03 mmol/L) group (p=0.0002). There was also a greater increase in the Q-Tc interval in the fenoterol group, 0.011+/-0.003 s compared with 0.003+/-0.003 s in the albuterol group ( p<0.05). Differences in hypokalemia and Q-Tc prolongation associated w ith fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular p remature beats, 14 in the fenoterol group and 18 in the albuterol grou p. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycar dia were detected in either group. Conclusions: In adequately oxygenat ed patients, using dose titration of fenoterol, in a formulation of 20 0 mu g per puff by MDI valved holding chamber and mask, to a total dos e of 3,200 mu g and salbutamol (100 mu g per puff) to a total dose of 1,600 mu g over 90 min, showed cardiovascular safety in acute severe a sthma. This was evidenced by absence of cardiovascular mortality or cl inically significant arrhythmias in either group. The 100% greater dos e of fenoterol improved FEV(1) significantly more than salbutamol and was associated with a relatively small but significantly greater prolo ngation of the Q-Tc interval and decrease in serum potassium level. Th is study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia.