Cardiovascular Safety of High Doses of Inhaled Fenoterol and Albuterol in Acute Severe Asthma

¹ From McMaster University, and Barnett Medical Aerosol Research Laboratory, St. Joseph's Hospital, Hamilton, Ontario
² From the University of Toronto, The Toronto Hospital, Toronto, Ontario
³ From the University of Toronto, Faculty of Medicine, Sunnybrook Health Science Centre, North York, Ontario
⁴ From the Department of Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, BC
⁵ From the University Faculty of Medicine, Dalhousie University, Victoria General Hospital, Halifax, Nova Scotia
⁶ From the Department of Medicine, University of Ottawa, Ottawa Civic Hospital, Ottawa, Ontario
⁷ From the University of British Columbia, St. Paul's Hospital, Vancouver, BC
⁸ From the Boehringer Ingelheim (Canada) Ltd
⁹ From the Department of Medicine, University of Toronto, Ontario

Background: It has been suggested that overuse of fenoterol metered-dose inhalers (MDIs) may increase the risk of death from asthma due to cardiac arrhythmias. Our primary objective was to compare the cardiovascular safety of fenoterol and albuterol MDIs when administered in maximal bronchodilating or maximal tolerated doses to an absolute maximum of 16 puffs, for the emergency department (ED) treatment of acute severe asthma.

Methods: Asthmatic patients presenting to the ED with acute severe asthma (FEV₁ less than 50% of predicted) were enrolled in a multicenter, randomized, double-blind, parallel-group study. Following baseline measurements, (medical history, physical examination, determination of serum potassium and serum theophylline levels, oximetry, 12-lead ECG, and spirometry), each patient received 4 puffs of either fenoterol, 200 µg per puff, or albuterol, 100 µg per puff, 1 puff every 30 s via an MDI attached to a holding chamber. Additional doses of inhaled β₂-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 FEV₁ plateau (ie, <10% improvement for 2 consecutive doses) occurred. ECG was recorded continuously via Holter monitor, and respiratory rate, BP, dyspnea (Borg scale), and FEV₁ were assessed after each dose.

Results: 128 patients were randomized to receive fenoterol and 129 to receive albuterol. Overall, fenoterol increased FEV₁ 160 mL more than albuterol. The mean (SEM) FEV₁ 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 β₂-agonists caused a decrease in serum potassium level that was significantly greater in the fenoterol (0.23±0.04 mmol/L) than 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 with fenoterol and albuterol were significantly different only after 8 puffs of fenoterol had been given. 32 patients exhibited ventricular premature beats, 14 in the fenoterol group and 18 in the albuterol group. There were 34 patients with episodes of supraventricular premature beats, 17 in each group. No episodes of sustained ventricular tachycardia were detected in either group.

Conclusions: In adequately oxygenated patients, using dose titration of fenoterol, in a formulation of 200 µg per puff by MDI valved holding chamber and mask, to a total dose of 3,200 µg and salbutamol (100 µg per puff) to a total dose of 1,600 µg over 90 min, showed cardiovascular safety in acute severe asthma. This was evidenced by absence of cardiovascular mortality or clinically significant arrhythmias in either group. The 100% greater dose of fenoterol improved FEV₁ significantly more than salbutamol and was associated with a relatively small but significantly greater prolongation of the Q-Tc interval and decrease in serum potassium level. This study does not exclude the possibility that adverse cardiac events could occur with severe hypoxemia.

Key Words: bronchodilators • emergency room • metered-dose inhaler • severe asthma

Submitted on February 21, 1996
Accepted on April 23, 2007

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