Effect of theophylline on sleep-disordered breathing in heart failure

N Engl J Med. 1996 Aug 22;335(8):562-7. doi: 10.1056/NEJM199608223350805.


Background: Theophylline has been used to treat central apnea associated with Cheyne-Stokes respiration (periodic breathing). We studied the effect of short-term oral theophylline therapy on periodic breathing associated with stable heart failure due to systolic dysfunction.

Methods: Fifteen men with compensated heart failure (left ventricular ejection fraction, 45 percent or less) participated in the study. Their base-line polysomnograms showed periodic breathing, with more than 10 episodes of apnea and hypopnea per hour. In a double-blind crossover study, the patients received theophylline or placebo orally twice daily for five days, with one week of washout between the two periods.

Results: After five days of treatment, the mean (+/-SD) plasma theophylline concentration was 11 +/- 2 microgram per milliliter. Theophylline therapy resulted in significant decreases in the number of episodes of apnea and hypopnea per hour (18 +/- 17, vs. 37 +/- 23 with placebo and 47 +/- 21 at base line; P<0.001), the number of episodes of central apnea per hour (6 +/- 14, vs. 26 +/- 21 and 26 +/- 20, respectively; P<0.001), and the percentage of total sleep time during which the arterial oxyhemoglobin saturation was less than 90 percent (6 +/- 11 percent, vs., 23 +/- 37 and 14 +/- 14 percent, respectively; P<0.04). There were no significant differences in the characteristics of sleep, the frequency of ventricular arrhythmias, daytime arterial-blood gas values, or the left ventricular ejection fraction during the base-line, placebo, and theophylline phases of the study.

Conclusions: In patients with stable heart failure, oral theophylline therapy reduced the number of episodes of apnea and hypopnea and the duration of arterial oxyhemoglobin desaturation during sleep.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cardiac Output / drug effects
  • Cross-Over Studies
  • Double-Blind Method
  • Heart Failure / complications*
  • Heart Failure / physiopathology
  • Humans
  • Male
  • Oxygen / blood
  • Respiratory Mechanics / drug effects
  • Sleep / drug effects
  • Sleep Apnea Syndromes / drug therapy*
  • Sleep Apnea Syndromes / etiology
  • Sleep Apnea Syndromes / physiopathology
  • Theophylline / pharmacology
  • Theophylline / therapeutic use*
  • Ventricular Dysfunction, Left / complications


  • Theophylline
  • Oxygen