© 2006 American Thoracic Society
Long-term Efficacy of Acetazolamide on Cheyne-Stokes Respiration in Congestive Heart FailureFrom the Author:I thank Dr. Yasuma and his colleagues for their comments on my recent article (1). As Dr. Yasuma has indicated, periodic breathing with central sleep apnea (CSA) is common in patients with systolic heart failure. In the largest prospective study of 100 patients with heart failure (2), a large number suffered from CSA, which may adversely affect survival in these patients (3). Therapeutic options are evolving (3). In spite of the initial enthusiasm for continuous positive airway pressure (CPAP), a multicenter study showed that the use of CPAP was associated with an increase in mortality early on (4). Other modalities of therapy are therefore needed (1, 3). My study was an attempt to determine the efficacy of short-term use of acetazolamide. Regarding the mechanisms by which acetazolamide improves CSA, the most likely explanation is an increase in the difference between the prevailing PaCO2 and the apneic threshold, PCO2, and a change in the slope of the ventilatory response below eupnea (5). The contribution of hemodynamic factors, such as changes in cardiac output and circulation time, was not assessed, except that left ventricular ejection fraction and heart rate did not change significantly. It is unlikely that a single dose of acetazolamide, a mild diuretic, should increase stroke volume or decrease arterial circulation time within 5 d of administration. Effects of acetazolamide on hypercapnic ventilatory response were briefly discussed. However, there is no study on this topic in patients with heart failure. Acetazolamide resulted in improvement in CSA in spite of a reduction in PaCO2. The notion that a lowered PaCO2 could worsen Cheyne-Stokes breathing is not consistent with present understanding of the mechanisms underlying the genesis of CSA (3, 5, 6). What is critical is not the absolute value of steady-state PaCO2. In this regard, in a recent study of patients with cirrhosis of the liver, we observed virtually no CSA in spite of very low steady-state PaCO2 levels (6). The critical factor in the genesis of CSA is the difference between the eucapnic minus the apneic threshold PCO2, and the latter is a moving target. It must be emphasized that because of the hyperbolic nature of the isometabolic curve relating PaCO2 to alveolar ventilation, the lower the prevailing PaCO2, the less likely the development of central apneas. At low PaCO2 levels, a large change in ventilation is necessary to decrease PaCO2 below the apneic threshold. This is an important and commonly forgotten physiological fact. Regarding side effects with long-term acetazolamide, the drug was given as a single dose just before bedtime. With such dosing, the hope is that the side effects of multiple dosing may be minimized. Regarding "physiological adaptation," this should not limit the efficacy of acetazolamide in treating CSA. Physiological adaptation to diuresis occurs after a certain level of metabolic acidosis has occurred. However, metabolic acidosis is maintained as long as the drug is administered. I should also add that in patients with heart failure there is usually alkalemia. In our patients, the pH decreased from 7.43 to 7.36 (1). Now that this randomized clinical trial shows efficacy, I hope it stimulates further long-term research studies to determine side effects and efficacy of acetazolamide in treating CSA in heart failure.
Professor Emeritus, University of Cincinnati, Cincinnati, Ohio FOOTNOTES Conflict of Interest Statement: S.J. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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