Effect of Acetazolamide on Chemosensitivity, Cheyne-Stokes Respiration, and Response to Effort in Patients With Heart Failure

Abstract

Increased chemosensitivity to hypoxia and hypercapnia, together with a prolonged circulatory time, are the main determinants of Cheyne-Stokes (C-S) respiration in heart failure. To evaluate the effect of acetazolamide, a carbonic anhydrase inhibitor, on chemosensitivity and respiratory dynamics in patients with heart failure with C-S respiration, 12 patients (mean age 62 ± 9 years, mean left ventricular ejection fraction 24 ± 9%) and C-S respiration (mean apnea-hypopnea index 23 ± 13) who underwent 4 consecutive days of oral acetazolamide treatment (250 mg twice daily) were enrolled in this study. Assessment of chemosensitivity to hypoxia and hypercapnia, cardiopulmonary stress testing, 24-hour cardiorespiratory polygraphy, and neurohormonal characterization were performed at baseline and at the end of treatment. Acetazolamide improved central apneas (apnea-hypopnea index 23 ± 13 to 15 ± 9, p = 0.012) and the percentage of time spent below an arterial oxyhemoglobin saturation of 90% (16 ± 23% to 10 ± 18%, p = 0.005). Chemosensitivity to hypoxia was blunted (1.03 ± 0.69 to 0.78 ± 0.55 L/min/mm Hg, p = 0.032), while chemosensitivity to hypercapnia increased after acetazolamide (1.27 ± 0.71 to 1.54 ± 0.78 L/min/% arterial oxygen saturation, p = 0.023); patients achieved a lower workload (90 ± 30 to 81 ± 30 W, p <0.001), with no differences in peak oxygen consumption, while there was an increment in the regression slope relating minute ventilation to carbon dioxide output (39 ± 10 to 43 ± 9, p = 0.010). In conclusion, in patients with heart failure, acetazolamide diminishes C-S respiration and improves oxyhemoglobin saturation, likely by decreasing chemosensitivity to hypoxia. However, it is associated with reduced maximal workload achieved during effort and increased chemosensitivity to hypercapnia, inducing a reduction in the ventilatory efficiency.

Exercising in Hypoxia and Other Stimuli: Heart Rate Variability and Ventilatory Oscillations

“…A stimulation of central chemoreceptors by CO 2 or acetazolamide (ACZ) elevates ventilation level and arterial O 2 saturation at high altitude and considerably reduces occurrence and length of apnea episodes. Likewise, a similar effect on ventilatory oscillations was observed in awake CHF patients at rest and during exercise [23,40]. In normal subjects, we found a similar effect of ACZ on .…”

Exercising in Hypoxia and Other Stimuli: Heart Rate Variability and Ventilatory Oscillations

“…A stimulation of central chemoreceptors by CO 2 or acetazolamide (ACZ) elevates ventilation level and arterial O 2 saturation at high altitude and considerably reduces occurrence and length of apnea episodes. Likewise, a similar effect on ventilatory oscillations was observed in awake CHF patients at rest and during exercise [23,40]. In normal subjects, we found a similar effect of ACZ on .…”

Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial

“…The present study should be interpreted as a proof of concept considering the single-centre nature and the sample size (similar to previous studies based on theophylline, n = 15, or acetazolamide, n = 12), 6,7 suggesting caution when interpreting negative findings (i.e. exercise performance, neurohormonal status and side effects).…”

“…Administration of buspirone does not require monitoring of plasma concentrations, as opposed to theophylline, 6 and has an overall safer profile, especially on arrhythmias. Compared to acetazolamide, which reduces exercise capacity and ventilatory efficiency during cardiopulmonary stress testing, 7 buspirone shows neutral effects on exercise performance.…”

Acetazolamide and Inhaled Carbon Dioxide Reduce Periodic Breathing During Exercise in Patients With Chronic Heart Failure

“…29 Slowing of these responses may be sufficient enough that in the event of a random increase or decrease in V E causing a change in PaCO 2 and PaO 2 , the tendency of the respiratory controller to overreact and then underreact in response will be dampened or abolished, such as is the case in high-altitude PB. 30,31 Our results showing PB suppression in exercise with acetazolamide differ somewhat from those of Fontana et al, 14 who failed to find any effect, despite showing, as we did, reduction in PB and central apneas during sleep in these patients (see also Javaheri 13 ) and reduction in maximal exercise capacity. They used a lower dose of prolonged acetazolamide (250 mg every 12 hours for 4 days) in contrast to our higher dosing of 500 mg every 8 hours over 24 hours.…”

Exercising in Hypoxia and Other Stimuli: Heart Rate Variability and Ventilatory Oscillations

“…A stimulation of central chemoreceptors by CO 2 or acetazolamide (ACZ) elevates ventilation level and arterial O 2 saturation at high altitude and considerably reduces occurrence and length of apnea episodes. Likewise, a similar effect on ventilatory oscillations was observed in awake CHF patients at rest and during exercise [23,40]. In normal subjects, we found a similar effect of ACZ on .…”

Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial

“…The present study should be interpreted as a proof of concept considering the single-centre nature and the sample size (similar to previous studies based on theophylline, n = 15, or acetazolamide, n = 12), 6,7 suggesting caution when interpreting negative findings (i.e. exercise performance, neurohormonal status and side effects).…”

“…Administration of buspirone does not require monitoring of plasma concentrations, as opposed to theophylline, 6 and has an overall safer profile, especially on arrhythmias. Compared to acetazolamide, which reduces exercise capacity and ventilatory efficiency during cardiopulmonary stress testing, 7 buspirone shows neutral effects on exercise performance.…”

Acetazolamide and Inhaled Carbon Dioxide Reduce Periodic Breathing During Exercise in Patients With Chronic Heart Failure

“…29 Slowing of these responses may be sufficient enough that in the event of a random increase or decrease in V E causing a change in PaCO 2 and PaO 2 , the tendency of the respiratory controller to overreact and then underreact in response will be dampened or abolished, such as is the case in high-altitude PB. 30,31 Our results showing PB suppression in exercise with acetazolamide differ somewhat from those of Fontana et al, 14 who failed to find any effect, despite showing, as we did, reduction in PB and central apneas during sleep in these patients (see also Javaheri 13 ) and reduction in maximal exercise capacity. They used a lower dose of prolonged acetazolamide (250 mg every 12 hours for 4 days) in contrast to our higher dosing of 500 mg every 8 hours over 24 hours.…”

Exercising in Hypoxia and Other Stimuli: Heart Rate Variability and Ventilatory Oscillations

“…A stimulation of central chemoreceptors by CO 2 or acetazolamide (ACZ) elevates ventilation level and arterial O 2 saturation at high altitude and considerably reduces occurrence and length of apnea episodes. Likewise, a similar effect on ventilatory oscillations was observed in awake CHF patients at rest and during exercise [23,40]. In normal subjects, we found a similar effect of ACZ on .…”

Benefit of buspirone on chemoreflex and central apnoeas in heart failure: a randomized controlled crossover trial

“…The present study should be interpreted as a proof of concept considering the single-centre nature and the sample size (similar to previous studies based on theophylline, n = 15, or acetazolamide, n = 12), 6,7 suggesting caution when interpreting negative findings (i.e. exercise performance, neurohormonal status and side effects).…”

“…Administration of buspirone does not require monitoring of plasma concentrations, as opposed to theophylline, 6 and has an overall safer profile, especially on arrhythmias. Compared to acetazolamide, which reduces exercise capacity and ventilatory efficiency during cardiopulmonary stress testing, 7 buspirone shows neutral effects on exercise performance.…”

Acetazolamide and Inhaled Carbon Dioxide Reduce Periodic Breathing During Exercise in Patients With Chronic Heart Failure

“…29 Slowing of these responses may be sufficient enough that in the event of a random increase or decrease in V E causing a change in PaCO 2 and PaO 2 , the tendency of the respiratory controller to overreact and then underreact in response will be dampened or abolished, such as is the case in high-altitude PB. 30,31 Our results showing PB suppression in exercise with acetazolamide differ somewhat from those of Fontana et al, 14 who failed to find any effect, despite showing, as we did, reduction in PB and central apneas during sleep in these patients (see also Javaheri 13 ) and reduction in maximal exercise capacity. They used a lower dose of prolonged acetazolamide (250 mg every 12 hours for 4 days) in contrast to our higher dosing of 500 mg every 8 hours over 24 hours.…”