Comments
Abstract
Rationale: Acetazolamide has been used to attenuate Hunter-Cheyne-Stokes breathing with central sleep apnea (CSA) associated with heart failure. However, the mechanisms underlying this improvement remain to be fully elucidated.
Objectives: We hypothesized that acetazolamide stabilizes CSA by attenuating the ventilatory sensitivity to CO2, which is increased in patients with heart failure and is thought to be the major mechanism mediating CSA.
Methods: Six consecutive male patients with stable systolic heart failure and CSA (apnea-hypopnea index [AHI] ≥ 15 episodes/h) were randomized to a double-blind crossover protocol with acetazolamide or placebo received 1 hour before bedtime for six nights with 2 weeks of wash-out. Under both conditions, we measured the hypercapnic ventilatory response (HCVR), arterial blood Pco2, steady-state metabolic CO2 production, overnight attended polysomnography, and also assessed cardiac and pulmonary function.
Measurements and Main Results: Compared with placebo, acetazolamide significantly decreased the AHI (65 ± 32 vs. 31 ± 19 events/h, mean ± SD). Acetazolamide increased the HCVR slope by 55% (3.3 ± 1.7 vs. 5.1 ± 2.4 L/min/mm Hg; P = 0.03), an increase that far exceeded the 12% fall in arterial Pco2 (P = 0.02). The acetazolamide-induced change in the balance of these effects (ΔHCVR × Pco2) was inversely associated with the reduction in AHI (r = 0.8; P = 0.045).
Conclusions: This placebo-controlled study indicates that acetazolamide improves CSA in patients with heart failure despite an increase in the slope of the HCVR. However, because the degree of HCVR elevation inhibits the improvement in unstable breathing, an increased CO2 chemosensitivity may be a key mechanism underlying an incomplete resolution of CSA with acetazolamide.
Periodic breathing with central sleep apnea (CSA), known as Hunter–Cheyne–Stokes breathing, occurs in approximately one third of patients with heart failure and is an independent predictor of poor outcome (1–4). Although the successful resolution of CSA using continuous positive airway pressure is associated with greater transplant-free survival (4, 5) and with improvements in heart function and quality of life, it is successful in resolving unstable breathing in only approximately 50% of patients with heart failure (5, 6) and is thus a major health concern.
Acetazolamide is a promising pharmaceutical alternative that has been shown to attenuate CSA in patients with chronic heart failure (7, 8), although the mechanisms underlying the improvement remain to be fully elucidated. CSA in heart failure is broadly considered the consequence of an unstable ventilatory control system (elevated loop gain) due to a hypersensitive ventilatory chemoreflex response to hypercapnia (increased “controller gain”) in the background of increased circulatory delay (9–13). In naturally sleeping dogs, Nakayama and associates (14) have demonstrated that acetazolamide decreases the plant gain (change in Pco2 for a unit fluctuation in ventilation) without changing CO2 sensitivity below eupnea (14) by lowering eupneic Pco2. This reduction in plant gain, at least in part, should account for the effectiveness of acetazolamide in improving CSA in patients with heart failure. However, studies examining how acetazolamide alters controller gain are quite disparate, with the available evidence suggesting that it can increase (8, 15), decrease (16–18), or does not change (19, 20) the hypercapnic ventilatory response (HCVR). In the present study, we investigated the effect of acetazolamide on control of breathing by measuring the HCVR (reflecting controller gain), arterial Pco2 (reflecting plant gain), and the balance between these effects (i.e., loop gain for CO2 control = controller gain × plant gain) in patients with heart failure and CSA. We hypothesized that acetazolamide decreases CO2 chemosensitivity and lowers arterial Pco2 and thereby stabilizes breathing (i.e., lowers loop gain).
Six male patients with systolic heart failure whose initial polysomnograms demonstrated CSA with a Hunter-Cheyne-Stokes pattern and an apnea-hypopnea index (AHI) ≥ 15 events/h participated in the study. Participants were a subset of a previously published study (7) demonstrating the effect of acetazolamide on CSA and cardiorespiratory characteristics. The patients were ambulatory and had stable heart failure with reduced left ventricular ejection fraction less than 35% and were either New York Heart Association class II or III. Patients were receiving angiotensin-converting enzyme inhibitor (n = 5), digoxin (n = 5), or diuretics (n = 4). There were no changes in the medications during the study period. Exclusion criteria have been detailed previously (7, 21) and included unstable cardiovascular status; significant intrinsic pulmonary, renal, or liver disorders; and the use of morphine derivatives, benzodiazepines, or theophylline.
We used a double-blind, randomized, placebo-controlled crossover study design. Details have been described previously (7). In brief, patients received three identical capsules that were received orally 1 hour before bedtime for six nights; the three capsules consisted of three placebos or one acetazolamide (3.5 mg/kg) and two potassium chloride capsules (total 30 mEq) to compensate for acetazolamide-induced urinary potassium loss. Crossover studies were performed after a 2-week washout period. All patients were compliant as evidenced by the count of capsules and development of metabolic acidosis while on acetazolamide. The protocol was approved by the Institutional Review Board of the University of Cincinnati College of Medicine. All patients signed informed consent.
The following tests were performed at baseline, and again at the end of each arm of the study (acetazolamide and placebo): polysomnography (PSG), arterial blood gases, pulmonary function tests, and HCVR measurement.
Participants spent two consecutive nights in our sleep laboratory for their baseline diagnostic PSG. The first night was an adaptation night where electrodes were placed without recording. On the second night, PSG was performed as detailed previously (21–23). Full-night attended PSG was also performed on the last night of each arm of the study.
For staging sleep, we recorded electroencephalogram, chin electromyogram, and electrooculogram. Thoracoabdominal excursions were measured by respiratory inductance plethysmography (Respitrace; Ambulatory Monitoring Inc., Ardsley, NY). Airflow was monitored using an oral/nasal thermocouple (model TCT1R; Grass Instrument Co., Quincy, MA). Arterial blood oxyhemoglobin saturation was recorded using an ear oximeter (Biox IIA; BT Inc., Boulder, CO). These variables were recorded on a multichannel polygraph (model 78D; Grass Instrument Co.). Coded PSGs were scored blindly for staging of sleep, arousals, and respiratory events. Standard criteria were applied for scoring apneas (≥10 s). Hypopneas were defined as a discernible reduction in thoracoabdominal excursions or airflow (30%) lasting 10 seconds or more and were associated with at least a 4% drop in arterial oxyhemoglobin saturation and/or an arousal (24). The number of apneas and hypopneas per hour of sleep is referred to as the AHI. The number of arousals per hour of sleep is referred to as the “arousal index.”
Arterial blood samples were obtained in the morning using strict criteria as detailed previously (25). To minimize discomfort, 2% lidocaine was used to anesthetize skin where the radial artery was punctured. With the patient in sitting position and breathing comfortably for several minutes, an arterial blood sample was obtained painlessly as attested by the patient. Participants underwent pulmonary function tests as detailed elsewhere (25).
To establish the mechanism responsible for the improvement in CSA with acetazolamide, steady-state controller gains were obtained by measuring the slope of the HCVR performed under hyperoxic conditions. HCVR tests were conducted carefully by one investigator to ensure uniformity in technique. Tests were performed more than 2 hours after a meal. Patients withheld caffeine and emptied their bladders before the tests. Seated HCVR was measured during monitored wakefulness with the subject wearing a nose clip and breathing through a mouthpiece connected to a low-resistance two-way valve. Measurements were started after a period of familiarization and after a stable baseline had been achieved (i.e., after ventilation and end-tidal Pco2 had not changed for several minutes). During the baseline period, ventilation (e), O2 consumption, and CO2 production were measured. Respiratory quotient, dead space, and alveolar ventilation were calculated.
The hyperoxic HCVR was determined by Read’s rebreathing method (26). Linear regression was used to determine the slope according to the following equation:
| (1) |
In theory, an increased HCVR slope exerts a destabilizing effect that is modulated by three other variables that contribute to the loop gain of the ventilatory feedback system controlling Pco2 (11, 13, 27):
| (2) |
ANOVA with repeated measures and Bonferroni correction factor was used to compare baseline, placebo, and acetazolamide variables. When only two variables were available for comparison, paired Student's t test was used. P < 0.05 was considered significant. Values are presented as mean ± SD.
The average age of our patients was 66 ± 6 years. Body mass index was unchanged between acetazolamide and placebo (26.6 ± 5.3 vs. 26.6 ± 5.2 kg/m2). There were no significant effects of acetazolamide on systolic and diastolic blood pressures, heart rate, and left ventricular ejection fraction (Table 1). Similarly, the spirometric data, lung volumes, and diffusion capacity did not differ between the placebo and acetazolamide conditions.
| Parameters | Placebo | Acetazolamide |
|---|---|---|
| Cardiorespiratory characteristics* | ||
| Systolic blood pressure, mm Hg | 113 ± 18† | 112 ± 16 |
| Diastolic blood pressure, mm Hg | 65 ± 10 | 61 ± 13 |
| Heart rate, beats/min | 70 ± 10 | 65 ± 9 |
| Left ventricular ejection fraction, % | 23 ± 10 | 24 ± 9 |
| Right ventricular ejection fraction, % | 47 ± 12 | 47 ± 12 |
| FEV1, L/s | 2.4 ± 0.4 | 2.3 ± 0.3 |
| FVC, liters | 3.5 ± 0.5 | 3.3 ± 0.5 |
| FRC, liters | 3.4 ± 0.7 | 3.2 ± 0.7 |
| DlCO, ml/min/mmHg | 15.2 ± 2.3 | 15.4 ± 2.4 |
| Sleep characteristics | ||
| Total time in bed, min | 407 ± 45 | 403 ± 16 |
| Total sleep time, min | 251 ± 59 | 293 ± 66 |
| Sleep efficiency, % | 62 ± 14 | 73 ± 16‡ |
| AHI, events/hr | 65 ± 32 | 31 ± 19‡ |
| CAI, events/hr | 54 ± 36 | 18 ± 22 |
| OAI, events/hr | 1 ± 2 | 4 ± 7 |
| HI, events/hr | 10 ± 5 | 8 ± 4 |
| Arl, events/hr | 29 ± 24 | 17 ± 3 |
| DBArl, events/hr | 26 ± 25 | 13 ± 3 |
| Resting awake SaO2, % | 95 ± 10 | 97 ± 2‡ |
| Lowest SaO2, % | 83 ± 8 | 88 ± 3 |
| SaO2 < 90%, %TST | 23 ± 42 | 6 ± 14 |
Patients exhibited severe CSA with a mean AHI of 65 events/h, predominantly driven by the number of central apneas (central apnea index = 54 events/h). Acetazolamide resulted in a considerable reduction in overall AHI and central apnea index (Table 1). This improvement was accompanied by a significant improvement in arterial oxyhemoglobin saturation during sleep (i.e., decreased time spent below saturation of 90% and higher nadir saturation) and increased sleep efficiency. There was a trend toward a reduction of total arousals (P = 0.1) accompanying a near-significant reduction in arousals secondary to respiratory events (P = 0.07).
Acetazolamide resulted in a mild metabolic acidosis (Table 2), which was associated with a 12% decrease in PaCO2 and a significant increase in Vt. There were no changes in metabolic rate. Most notably, acetazolamide increased the HCVR by 55% (3.3 ± 1.7 vs. 5.1 ± 2.4 L/min/mm Hg; P = 0.03) (Figure 1). This increase remained evident after normalizing the slope of the HCVR for body surface area (P = 0.009), FVC (P = 0.03), and maximum voluntary ventilation (P = 0.04). Figure 1C demonstrates that acetazolamide did not significantly alter the product of the HCVR slope and Pco2 (S × Pco2; a variable encapsulating the net balance between the rise in HCVR slope and the fall in Pco2 provided by acetazolamide).
| Placebo | Acetazolamide | P Value | |
|---|---|---|---|
| Ventilatory characteristics | |||
| Vt, ml† | 727 ± 92* | 839 ± 139 | 0.03 |
| Breathing rate, breaths/min | 16 ± 4 | 15 ± 3 | 0.4 |
| e, L/min | 11.5 ± 2.7 | 12.8 ± 3.8 | 0.4 |
| Maximum voluntary ventilation, L/min | 90 ± 13 | 94 ± 23 | 0.7 |
| CO2 production, ml/min‡ | 217 ± 40 | 226 ± 59 | 0.7 |
| O2 consumption, ml/min‡ | 268 ± 51 | 269 ± 70 | 0.9 |
| S, L/min/mm Hg | 3.3 ± 1.7 | 5.1 ± 2.4 | 0.01 |
| Arterial blood gas characteristics | |||
| PaCO2, mm Hg | 38.7 ± 3.0 | 34.2 ± 0.8 | 0.01 |
| PaO2, mm Hg | 83.6 ± 9.5 | 92.5 ± 11.7 | 0.007 |
| pH | 7.43 ± 0.04 | 7.36 ± 0.05 | 0.0001 |
| [HCO3−], mmol/l | 27 ± 5 | 19 ± 2 | 0.002 |
| [Na+], mmol/l | 140 ± 1 | 139 ± 3 | 0.2 |
| [K+], mmol/l | 4.3 ± 0.4 | 4.1 ± 0.4 | 0.4 |
| [Cl−], mmol/l | 103 ± 2 | 106 ± 5 | 0.1 |
Figure 1. The effect of acetazolamide on the hypercapnic ventilatory response (HCVR) slope and Pco2. Acetazolamide administration significantly increased the slope of the hyperoxic HCVR (increased CO2 controller gain) (A) while decreasing Pco2 (lowering plant gain) (B). (C) The product of the HCVR slope and Pco2 was not reduced (a variable encapsulating the net balance between the rise in HCVR slope and the fall in Pco2 provided by acetazolamide), demonstrating that the CO2 feedback loop was not stabilized by acetazolamide.
[More] [Minimize]Given that an increase in HCVR is expected to be destabilizing, it appears counterintuitive that the group data demonstrated a fall in AHI accompanying an increase in HCVR. Therefore, we further tested the hypothesis that a greater rise in HCVR was seen in individuals who did not exhibit an effective CSA response to acetazolamide. Such analysis revealed a trend toward an inverse association between an augmentation of the HCVR and the reduction in AHI (r = 0.8; P = 0.057) (Figure 2A). Further analysis revealed that the reduction in AHI was significantly associated with the change in S × Pco2 (r = 0.8; P = 0.045) (Figure 2B). That is, the magnitude of rise in HCVR due to acetazolamide (after correcting for the fall in Pco2) is associated with a less effective treatment response.
Figure 2. Relationship between the reduction in the apnea-hypopnea index (AHI) with acetazolamide and the change in hypercapnic ventilatory response (HCVR) slope and HCVR slope × Pco2. (A) There was a near-significant inverse association between the reduction in AHI and the increase in the slope of the HCVR after acetazolamide administration. (B) The reduction in AHI was significantly inversely associated with the change in the product of the HCVR slope and eupneic Pco2 (the balance between the rise in HCVR slope and the fall in Pco2) between baseline and acetazolamide conditions. Thus, an increased HCVR slope (once correcting for the change in Pco2) is associated with a smaller acetazolamide-induced improvement in AHI. Gray lines indicate 95% confidence intervals.
[More] [Minimize]The major finding of our prospective, randomized, placebo-controlled, double-blind crossover study was that, in patients with stable heart failure and severe Hunter-Cheyne-Stokes breathing, administration of acetazolamide increases the slope of the HCVR (55% increase in hyperoxic CO2 chemosensitivity) despite a considerable improvement in sleep apnea severity (61% reduction in AHI). We had hypothesized the opposite because an augmented ventilatory response is considered to destabilize ventilatory control. Our data firmly suggest that the effect on the HCVR counteracts other stabilizing effects of acetazolamide on overall ventilatory control, as evidenced by the improvement to CSA. Specifically, participants whose CO2 chemosensitivity rises the most with a fall in Pco2 exhibit a smaller reduction in AHI. Thus, a greater increase in HCVR in acetazolamide “nonresponders” may be a key mechanism underlying the failure of acetazolamide to halve CSA severity in ∼60% of participants with heart failure studied (7). If confirmed in a larger study, these findings have two key implications: (1) acetazolamide should not be expected to work for patients in whom it greatly augments the HCVR, and (2) acetazolamide’s effectiveness may be greatly improved by a pharmaceutical modification that prevents an increase in the HCVR.
Studies of patients with heart failure have shown that those with CSA have a greater sensitivity to CO2 than those without CSA (9, 10, 28), and there is a significant positive correlation between CO2 chemosensitivity and the severity of CSA (9). Indeed, control theory predicts that increased CO2 chemosensitivity promotes instability, which is why we had hypothesized that acetazolamide should attenuate the augmented responsiveness. Therefore, the present finding that acetazolamide improved CSA severity in spite of an increase in CO2 chemosensitivity requires explanation. To address this paradox, we examined the other factors likely to influence instability, specifically those affecting plant gain (defined as the change in Pco2 for a given change in ventilation). If plant gain is sufficiently high, even a small increase in ventilation will lower Pco2 enough to provide a later fall in ventilatory drive and resultant central apnea/hypopnea. Factors well known to elevate plant gain include an increase in Pco2 and a reduction in functional residual capacity (13). In the present study, there were no significant changes in seated functional residual capacity, suggesting that lung gas stores were unlikely to have been altered with acetazolamide. Likewise, studies in animals have indicated that acetazolamide does not alter the end-expiratory lung volume or the end-expiratory position of the diaphragm (29). However, acetazolamide resulted in a 12% decrease in PaCO2, which is expected to decrease plant gain by a similar 12%. Such a reduction in plant gain would be inadequate to counteract the more powerful 55% increase in the slope of the HCVR.
Our observations that acetazolamide increases the HCVR slope and does not reduce the S × Pco2 product demonstrate that the powerful improvement in CSA cannot be the result of an effect on the HCVR slope, which is considered the primary mechanism of CSA in patients with heart failure (10, 11). There are two major implications from these results: (1) this observation questions the dominance of the elevated HCVR slope (and its feedback loop) as the main mechanism of CSA, and (2) acetazolamide must therefore improve stability by other mechanisms. We note that overall stability (i.e., overall loop gain) is made up of loop gains for central CO2 and peripheral CO2 and O2 (13). Thus, we speculate that acetazolamide’s main stabilizing effect is via a reduction in the sensitivity of peripheral (carotid-body) feedback loops controlling O2 and CO2. This concept was recently supported by animal studies demonstrating that acetazolamide reduces the dynamic response to CO2 (16, 18, 30–32) and directly suppresses carotid body sensitivity (16, 18, 30, 33). The exact mechanism for such depression is unclear but has been attributed to its ability to inhibit membrane-bound carbonic anhydrase isozymes within the peripheral chemoreceptor (34). Furthermore, a recent nonrandomized observational study in patients with heart failure showed that acetazolamide attenuated the hypoxic ventilatory response (reducing loop gain for peripheral O2), whereas the steady-state HCVR was augmented (8). It is possible that acetazolamide reduces the dynamic/peripheral chemoreceptor response by attenuating the central chemoreceptors; local inhibition of medullary carbonic anhydrase in cats has demonstrated a reduced phrenic nerve response to rapid-step CO2 increases despite unchanged steady-state responses (31). Therefore, before any firm conclusions can be reached, a randomized, placebo-controlled study, similar to the present study protocol, is needed to confirm if acetazolamide attenuates the dynamic ventilatory response to O2 and CO2 (in order to assess peripheral chemosensitivity to O2 and CO2) and determine whether this effect is associated with a reduction in AHI.
There are several putative mechanisms by which acetazolamide may have stabilized breathing. First, the diuretic action of acetazolamide may have improved pulmonary edema/congestion (and its worsening via rostral fluid shift), which is thought to contribute to ventilatory instability (35–37). However, consistent with the results of the parent study (n = 12) (7), because diffusion capacity and body mass index were similar between conditions, these mechanisms seem unlikely to have contributed to the improvement in instability. Second, cardiac function was also not improved with acetazolamide (Table 1), suggesting that an improvement in circulatory delay was unlikely to have occurred. Finally, control system “damping” factors might have been altered: raising ventilation per se (independent of lowering Pco2) tends to reduce the buffering capacity of the lung (reduced lung time constant), which would be slightly destabilizing and therefore cannot explain improved stability. It is possible that acetazolamide slows the time course of the ventilatory response to CO2, making the control system more damped (16, 31, 32, 38); such a factor would not be encapsulated by the rebreathing measurement of the HCVR. However, available evidence in healthy adults without heart failure suggests that acetazolamide may not alter the time constants of the CO2 response (19) or the control system overall (39).
Increased ventilatory chemosensitivity to CO2 is thought to be a major mechanism underlying CSA in heart failure. The results of this double-blind, placebo-controlled study demonstrate that acetazolamide improves CSA in patients with systolic heart failure in spite of augmentation in HCVR. The adverse effect of an increased HCVR may be a key mechanism opposing the effective resolution of CSA with acetazolamide.
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This work was supported by Merit Review Grants from the Department of Veterans Affairs, by American Heart Association fellowship 11POST7360012 (S.A.S.), and by National Health and Medical Research Council of Australia’s CJ Martin Overseas Biomedical Fellowship no. 1035115 (B.A.E.).
Author Contributions: Conception and design: S.J. Analysis and interpretation: S.J., S.A.S., and B.A.E. Drafting the manuscript for important intellectual content: S.J., S.A.S., and B.A.E.
Author disclosures are available with the text of this article at www.atsjournals.org.
