Rationale: Acetazolamide is a mild diuretic and a respiratory stimulant. It is used to treat periodic breathing at high altitude.
Objectives: To determine the therapeutic efficacy of acetazolamide on central sleep apnea associated with heart failure.
Methods: Twelve male patients with stable systolic heart failure whose initial polysomnograms showed more than 15 episodes per hour of apnea and hypopnea participated in the study. The patients were randomized to a double-blind cross-over protocol with acetazolamide or placebo, taken 1 h before bedtime for six nights with 2 wk of washout.
Measurements: Polysomnography, pulmonary function tests, arterial blood gases, and left ventricular ejection fraction were obtained initially along with a sleep questionnaire, history, and physical examination. Baseline measurements were repeated at the end of each arm.
Main Results: There were no significant differences between parameters at baseline and placebo. In comparing placebo with acetazolamide, the hourly number of episodes of central apnea (49 ± 28 vs. 23 ± 21 [mean ± SD]; p = 0.004) and the percentage of total sleep time spent below an arterial oxyhemoglobin saturation of 90% (19 ± 32 vs. 6 ± 13%; p = 0.01) decreased significantly. Acetazolamide improved subjective perception of overall sleep quality (p = 0.003), feeling rested on awakening (p = 0.007), daytime fatigue (p = 0.02), and falling asleep unintentionally during daytime (p = 0.002).
Conclusions: In patients with heart failure, administration of a single dose of acetazolamide before sleep improves central sleep apnea and related daytime symptoms.
Keywords: Cheyne-Stokes breathing; heart failure; metabolic acidosis
Central apnea is a temporary failure of the generation of breathing rhythm. Central apnea occurs when the level of PCO^sub 2^ falls below the apneic threshold, a PCO^sub 2^ level below which breathing ceases. Polysomnographically, central apnea is recognized by the absence of naso-oral airflow and by thoracoabdominal excursions that reflect the failure of activation of inspiratory pump muscles (1). Episodes of central sleep apnea (CSA) associated with periodic breathing (Cheyne-Stokes breathing) occur in severe heart failure with systolic dysfunction (2-5). CSA also occurs in an idiopathic form and at high altitude (1).
Few studies have reported on the use of acetazolamide to treat CSA of high altitude as well as idiopathic CSA (6-9). In six patients with idiopathic CSA, White and colleagues (6) showed significant improvement in sleep apnea after 1 wk of drug therapy. A similar finding was reported by DeBacker and coworkers (7) after chronic administration of acetazolamide.
The mechanism of therapeutic action of acetazolamide has been elucidated in a study (10) of normal subjects with induced periodic breathing during sleep. Nakayama and coworkers showed that because of metabolic acidosis induced by acetazolamide, the difference between the prevailing PCO^sub 2^ and the apneic threshold PCO^sub 2^ increased. As a result of this, acetazolamide decreased the likelihood of developing sleep apnea (10).
On the basis of the results of the above-cited studies (6-10), we hypothesized that acetazolamide will also be effective in the treatment of central apnea in heart failure, the most common cause of central sleep apnea in the general population (2-5). Although acetazolamide has been used in congestive heart failure for many years, there are no systematic studies regarding its effect on Cheyne-Stokes breathing. The present study is the first randomized, double-blind, placebo-controlled study to test the hypothesis that short-term use of acetazolamide improves central sleep apnea in heart failure. Because central apnea occurs primarily during sleep, we used single-dose acetazolamide 1 h before bedtime.
This was a double-blind, placebo-controlled, cross-over study. Only a researcher in pharmacology and a physician, both of whom were monitoring the patients, were not blind to randomization. The patients, the principal investigator, and the technicians who performed various tests were unaware of randomization. The procedures were identical for placebo and acetazolamide arms.
Patients included 14 consecutive eligible male subjects with systolic heart failure whose initial polysomnograms showed Cheyne-Stokes breathing with an apnea-hypopnea index (number of episodes/hour) of more than 15/hour. One patient refused to take part in the study (because of long travel distance) and one patient did not complete the study (see below).
The 12 remaining patients were ambulatory and had stable heart failure with left ventricular systolic dysfunction (left ventricular ejection fraction
Exclusion criteria have been detailed previously (5,11) and included unstable cardiovascular status; significant intrinsic pulmonary, renal, or liver disorders; and use of morphine derivatives, benzodiazepines, or theophylline. For uniformity only male patients were studies as female patients are seldom referred to this center (Pulmonary Service, Department of Veterans Affairs Medical Center, Cincinnati, OH).
Method of Administering Acetazolamide-KCl and Placebo
Patients received three identical capsules of either placebo or one acetazolamide and two KCl capsules. Potassium chloride (total, 30 mEq) was given to compensate for acetazolamide-induced urinary potassium loss. Acetazolamide was administered at 3.5 mg/kg. Our aim was to induce mild metabolic acidosis and to decrease total CO2 by about 5 mmol/L. Therefore, a venous blood sample was obtained on the morning of the third day of randomization, and the dose of acetazolamide was increased to 4 mg/kg to achieve the target concentration of total CO2. This was accomplished by the physician and pharmacology researcher who were monitoring the patients and were not blind to randomization. However, to maintain double-blind status, venous blood was obtained from patients in the placebo arm as well.
Capsules were taken orally 1 h before bedtime for six nights each, in a randomized, double-blind fashion. Cross-over studies were performed after a 2-wk washout period.
All patients were compliant as evidenced by the count of capsules and development of metabolic acidosis while taking acetazolamide.
Procedures and Tests
The following tests were performed initially, and at the end of each arm of the study (acetazolamide and placebo): polysomnography, radionuclide ventriculography, arterial blood gases and pH, serum electrolytes, and pulmonary function tests. A subjective sleep questionnaire was also obtained at the end of placebo and acetazolamide arms.
Polysomnography was performed by standard techniques as detailed previously (5, 11-14). All patients were adapted to the sleep laboratory; that is, during the first night, electrodes were placed without recording. Polysomnography was performed during the second night. To stage sleep, we recorded electroencephalogram (two channel), chin electromyogram (one channel), and electrooculogram (two channels). Thoracoabdominal excursions were measured qualitatively with a respiratory inductance plethysmograph (Respitrace; Ambulatory Monitoring, Inc., Ardsley, NY) placed over the rib cage and abdomen. Airflow was qualitatively monitored with an oral/nasal thermocouple (model TCT1R; Grass-Telefactor Product Group of Astro-Med, West Warwick, RI). Arterial blood oxyhemoglobin saturation was recorded with an ear oximeter (Biox IIA; Datex-Ohmeda Division of Instrumentarium, Louisville, CO). These variables were recorded on a multichannel polygraph (model 78D; Grass-Telefactor Product Group of Astro-Med). An apnea was defined as cessation of inspiratory airflow for 10 s or more. An obstructive apnea was defined as the absence of airflow in the presence of rib cage and abdominal excursions. A central apnea was defined as the absence of airflow with absence of rib cage and abdominal excursions. Hypopnea was defined as a reduction of airflow lasting 10 s or more and associated with at least a 4% drop in arterial oxyhemoglobin saturation and/or an arousal, as defined elsewhere (15). The number of apneas and hypopneas per hour of sleep is referred to as the apnea-hypopnea index. The number of arousals per hour of sleep is referred to as the arousal index (for further details see References 5, 12, and 13).
Coded polysomnograms were scored blindly page by page by the author for staging of sleep, arousals, and respiratory events. Similarly, the time below saturation of 90% was calculated manually.
Arterial blood samples were obtained (the morning after polysomnography), using strict criteria as detailed previously (16). To minimize pain, 2% lidocaine was used to anesthetize skin where the radial artery was punctured. Afterward, by touching the patient's skin with a needle, the patient was assured that the procedure was painless. Our hope was to minimize pain and anxiety and, therefore, any attendant change in arterial PCO^sub 2^. Details of pulmonary function tests (17), and of measuring left and right ventricular ejection fractions by radionuclide technique (5), have been described previously. We used a subjective questionnaire previously used in this laboratory (5, 11) to assess the effects of acetazolamide on patient perception of sleep quality and daytime symptoms. Each patient was initially instructed to compare the items of the questionnaire between the two arms (placebo vs. acetazolamide). The subjective items were as follows: overall sleep quality, waking up refreshed, daytime fatigue, daytime sleepiness, and falling asleep unintentionally. Patients were asked specifically if they felt improved in comparing the first arm versus the second arm. Patients were also asked to report any side effects while on placebo or acetazolamide.
The protocol was approved by the Institutional Review Board of the University of Cincinnati College of Medicine. All patients signed informed consent.
Analysis of variance for repeated measures with Bonferroni correction factor was used to compare baseline, placebo, and acetazolamide studies. For variables that were not normally distributed, Dunn's nonparametric test for multiple comparisons was used. When only two variables were to be compared, a two-tailed paired t test was used. Dichotomous values were compared by chi-square test. p
The mean age of patients was 66 ± 6 yr and the mean body mass index was 26 ± 4 kg/m^sup 2^. There were no significant differences in body mass index, systolic and diastolic blood pressures, heart rate and left ventricular ejection fraction when baseline, placebo and acetazolamide were compared (Table 1).
There were no significant differences in episodes of sleep apnea and hypopnea and arterial oxyhemoglobin desaturation when baseline and placebo were compared (Table 2). However, acetazolamide resulted in a considerable reduction in central apneas (Table 2). This was associated with a significant improvement in arterial oxyhemoglobin saturation during sleep as reflected in a decrease in the total time spent below saturation of 90%, and minimum saturation during sleep (Table 2).
Total sleep time, sleep efficiency, and sleep stages did not differ significantly when baseline, placebo, and acetazolamide were compared (data not shown). However, there was a trend in the reduction of total arousals (p = 0.1; Table 1) and this was primarily due to a reduction in arousals secondary to periodic breathing (p = 0.06).
There were no significant differences in spirometric measurements, lung volumes, and diffusion capacity among the three arms (data not shown). There were no significant differences in serum electrolytes and acid-base data in comparing baseline with placebo. However, acetazolamide resulted in mild metabolic acidosis (Table 3) in the morning.
In comparing the two arms of the study, it was found that more patients reported subjective improvement in sleep quality (seven vs. one; p = 0.003), daytime fatigue (seven vs. two; p = 0.02), waking up rested (eight vs. two; p = 0.007), and falling asleep unintentionally (five vs. none; p = 0.002) while talking acetazolamide compared with placebo. One patient who had severe heart failure and was first randomized to acetazolamide developed shortness of breath on the third night after taking the medication. The study was discontinued. When rechallenged later, he complained of shortness of breath. The study was terminated. This patient, however, was the only one on the cardiac transplantation list. Another patient developed nausea with diarrhea while taking acetazolamide. He was thought to have a viral infection. The study was discontinued. Later he repeated the study without any problem.
None of the patients complained of paresthesia or bad taste. On the night of polysomnography, three patients, one in each of the three arms of study, had nocturia.
From the results of this prospective, randomized, placebo-controlled, cross-over, double-blind study, we conclude that among patients with stable heart failure (NYHA class II and III), before-bedtime administration of a single dose of acetazolamide improves sleep-disordered breathing and associated arterial blood oxyhemoglobin desaturation. This is reflected in patient perception of improved sleep quality and daytime function.
Although no studies in heart failure have ever been reported, acetazolamide has been shown to alleviate idiopathic central sleep apnea (6, 7) and central apnea at high altitude (8, 9). The present study shows that acetazolamide is also effective in heart failure. Acetazolamide decreased the apnea-hypopnea index in each subject, and the reduction in the apnea-hypopnea index occurred mostly because of a reduction in central apneas (Table 2).
Another important finding of this double-blind study was the significant improvement in patient perception of improved sleep quality, waking up more refreshed, with less daytime fatigue and sleepiness while taking acetazolamide, compared with placebo. These results are in agreement with those of White and associates in patients with idiopathic central sleep apnea (6). The reduction in periodic breathing, perhaps via the combination of improved oxygen saturation and a trend toward diminished arousals, contributed to patient perception of improvement.
The mechanism of action of acetazolamide is related to metabolic acidosis, which stimulates chemoreceptors (the carotid bodies and the central chemoreceptors; Table 3). It is noteworthy that in spite of the fall in PaCO^sub 2^, central apneas improved, emphasizing that it is not the absolute value of steady state PaCO^sub 2^ that increases the likelihood of developing central apnea (18). Rather, it is the difference between the prevailing PCO^sub 2^ and apneic threshold PCO^sub 2^ that is important (10, 19, 20). As noted earlier, in the face of background increased stimulus to breathe, the apneic threshold PCO^sub 2^ decreases considerably (more than the fall in PaCO^sub 2^) such that there is a widening of the difference between the prevailing PCO^sub 2^ and the apneic threshold PCO^sub 2^ (10). This widening decreases the likelihood of developing central sleep apnea.
Another possible therapeutic action of acetazolamide could have been diuresis and improvement in pulmonary congestion, which could result in an improvement in periodic breathing. However, reduction in pulmonary capillary pressure is thought to alleviate Cheyne-Stokes breathing by normalization of PCO^sub 2^ (21), and probably increases the difference between the PCO^sub 2^ and the apneic threshold. However, in this study PCO^sub 2^ fell, making it difficult to assess any contribution of diminished lung water to improvement in Cheyne-Stokes breathing. Finally, hypoxic ventilatory response is increased in heart failure (22). If treatment with acetazolamide improved heart failure and the heightened ventilatory response in our patients, it could have contributed to stabilization of periodic breathing.
One important feature of this study was to administer acetazolamide as a single dose at night. In this way, the long-term side effects of frequent administration of acetazolamide could perhaps be minimized. In the present study, none of the patients complained of paresthesias, which occur with large doses of acetazolamide (23). One patient developed shortness of breath, which was probably mediated by acetazolamide-induced increased ventilation. However, in clinical practice, when the initiating dose could be less than in the present study and dose titration could be done gradually, such side effects may be further minimized, and gradually the maximum dose resulting in the least periodic breathing could be achieved.
Meanwhile, we were happily surprised that in spite of the short duration of the study and modest reduction in periodic breathing, patient perception improved. We hypothesize that with long-term therapy, as sleep-related breathing disorders improve, it may be reflected in an improvement in cardiac function that will further improve periodic breathing, resulting in a positive feedback cycle. Improvement in sleep apnea may improve cardiac function by a variety of mechanisms such as improved oxygenation (24). Use of acetazolamide in patients with heart failure may have the additional benefit of mild diuresis and the combating of metabolic alkalosis (induced by use of other diuretics), which may promote periodic breathing (10). Meanwhile, potential long-term deleterious effects of acetazolamide in heart failure are not known. It is conceivable that metabolic acidosis and chemoreceptor stimulation by acetazolamide increase sympathetic activity, and studies investigating this important issue are needed. However, studies by Teppema and Dahan (25) show that a clinical dose of acetazolamide does not significantly change chemosensitivity. Furthermore, with single-dose nocturnal use of acetazolamide, metabolic acidosis is mild (Table 3) and mostly overnight. On the other hand, by decreasing sleep apneas and improving oxyhemoglobin saturation, acetazolamide should decrease sympathetic activity. The second potential deleterious effect of acetazolamide relates to respiratory muscle stimulation and hyperventilation, which could result in respiratory muscle fatigue in patients with heart failure (26). In this context, because acetazolamide was administered as a single dose before bedtime, its respiratory muscle stimulation should be diminished by daytime. Furthermore, it is also conceivable that the overall ventilation during sleep at night could have been similar in comparing acetazolamide with placebo because of reduction in the hyperpneic episodes of Cheyne-Stokes breathing by acetazolamide. Further studies monitoring nocturnal ventilation should shed light on this issue.
In summary, results of the present double-blind, placebo-controlled study show that before-bedtime administration of acetazolamide, which induces mild metabolic acidosis, results in improvement in sleep apnea, desaturation, and daytime symptoms of patients with systolic heart failure.
Now that the short-term efficacy of acetazolamide in improving periodic breathing in heart failure has been established, more long-term studies with measurements of cardiac function, quality of life, and plasma and urinary norepinephrine are needed. We hope that with long-term improvement in periodic breathing, left ventricular ejection fraction will eventually improve. Furthermore, a single dose at night should, it is hoped, be associated with fewer side effects than multiple dosing. Importantly, in the study by DeBacker and coworkers (7), who administered singledose acetazolamide before bedtime for 1 mo to treat idiopathic central sleep apnea, patients did not report side effects.
Conflict of Interest Statement: S.J. has no relationship with a commercial entity that has an interest in the subject of this manuscript.
Acknowledgment: The author thanks Candice Brown for help in data entry and for performing statistical analysis, and Judy Harrer for assistance in randomization and medication titration.
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Pulmonary Service, Department of Veterans Affairs Medical Center, and Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio
(Received in original form July 5, 2005; accepted in final form October 14, 2005)
Supported by Merit Review grants from the Department of Veterans Affairs.
Correspondence and requests for reprints should be addressed to S. Javaheri, M.D., Pulmonary Section (111F), VA Medical Center, 3200 Vine Street, Cincinnati, OH 45220. E-mail: firstname.lastname@example.org
Am J Respir Crit Care Med Vol 173. pp 234-237, 2006
Originally Published in Press as DOI: 10.1164/rccm.200507-1035OC on October 20, 2005
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