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

doi:10.1016/j.amjcard.2011.01.060

The American Journal of Cardiology

Volume 107, Issue 11, 1 June 2011, Pages 1675-1680

https://doi.org/10.1016/j.amjcard.2011.01.060 Get rights and content

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.

Section snippets

Methods

From September 2008 to February 2010, we screened 48 ambulatory patients with HF from our clinic with left ventricular systolic dysfunction (left ventricular ejection fraction <50%) and C-S respiration on ambulatory cardiorespiratory polygraphy (apnea-hypopnea index, defined as the number of apnea or hypopnea episodes per hour of recording, >15 per hour). Exclusion criteria were New York Heart Association class IV, acute coronary syndromes within the previous 6 months, glomerular filtration

Results

The study population consisted of 12 patients with HF (11 men) receiving optimal medical therapy. The mean age was 62 ± 9 years, the mean body mass index 29 ± 4 kg/m², and the mean left ventricular ejection fraction 24 ± 9%. On the whole, patients showed at baseline a moderate degree of neurohormonal activation: median N-terminal–pro-brain natriuretic peptide was 1,216 ng/L (interquartile range 863 to 1,844), median norepinephrine 509 ng/L (interquartile range 461 to 736), median plasma renin

Discussion

This study demonstrates that in patients with HF and C-S respiration, acetazolamide blunts chemosensitivity to hypoxia while increasing the chemosensitivity to hypercapnia. This action on the chemoreflex is associated with (1) significant decreases in nighttime and daytime C-S respiration and (2) improvement in oxygen saturation, with no adverse impact on sympathetic activation. However, acetazolamide was associated with a negative effect on maximal workload achieved during exercise and on

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The acute effect during positive pressure titration and long term efficacy of acetazolamide (AZT) in high loop gain sleep apnea (HLGSA) is inadequately assessed. We predicted that AZT may improve HLGSA in both conditions.
A retrospective analysis of polysomnograms from patients with presumed HLGSA and residual respiratory instability administered AZT (125 or 250 mg) about 3 h into an initially drug-free positive pressure titration. A responder was defined as ≥ 50% reduction of the apnea hypopnea index(AHI 3% or arousal) before and after AZT. A multivariable logistic regression model estimated responder predictors. Long term efficacy of AZT was assessed by comparing both auto-machine (aREI_FLOW) and manually scored respiratory events (sREI_FLOW) extracted from the ventilator, prior to and after 3 months of AZT, in a subset.
Of the 231 participants (median age of 61[51–68] years) and 184 (80%) males in the acute effect testing: 77 and 154 patients were given 125 mg and 250 mg AZT. Compared to PAP alone, PAP plus AZT was associated with a lower breathing related arousal index (8 [3-16] vs. 5 [2-10], p < 0.001), and AHI3% (19 [7-37] vs. 11 [5-21], p < 0.001); 98 patients were responders. The non-rapid eye movement sleep (NREM) AHI3% (OR 1.031, 95%CI [1.016–1.046], p < 0.001) was a strong predictor for responder status with AZT exposure. In the 109 participants with 3-month data, both aREI_FLOW and sREI_FLOWwere significantly reduced after AZT.
AZT acutely and chronically reduced residual sleep apnea in presumed HLGSA; NREM AHI3% is a response predictor. AZT was well tolerated and beneficial for at least 3 months.
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Sleep disordered breathing causes repetitive episodes of nocturnal hypoxemia, sympathetic nervous activation, and cortical arousal, often associated with excessive daytime sleepiness. Sleep disordered breathing is common in people with, or at risk of, cardiovascular (CV) disease including those who are obese or have hypertension, coronary disease, heart failure, or atrial fibrillation. Current therapy of obstructive sleep apnea includes weight loss (if obese), exercise, and positive airway pressure (PAP) therapy. This improves daytime sleepiness. Obstructive sleep apnea is associated with increased CV risk, but treatment with PAP in randomized trials has not been shown to improve CV outcome. Central sleep apnea (CSA) is not usually associated with daytime sleepiness in heart failure or atrial fibrillation and is a marker of increased CV risk, but PAP has been shown to be harmful in 1 randomized trial. The benefits of better phenotyping, targeting of higher-risk patients, and a more personalized approach to therapy are being explored in ongoing trials.
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Citation Excerpt :
Hypocapnia, increased chemosensitivity, a higher apnea threshold and circulatory delay all contribute to ventilatory instability and Central Sleep Apnea (CSA) or Cheyne Stokes Respiration (CSR) in patients with heart failure [3]. Several treatment options, ranging from pharmacological treatment with acetazolamide [4] to nocturnal oxygen therapy, positive airway pressure therapies as continuous positive airway pressure (CPAP) [5], bi-level positive airway pressure (BiPAP) [6] or adaptive servo ventilation (ASV) have been investigated [7]. However, interpretation of the results of the studies is difficult as these studies were small, short-term and/or showed conflicting results in terms of improvement in clinical outcomes.
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Acetazolamide for OSA and Central Sleep Apnea: A Comprehensive Systematic Review and Meta-Analysis
2020, Chest
Citation Excerpt :
Thus, we explored variability of acetazolamide’s effect across individuals and estimated the number needed to treat (NNT) for one patient with sleep apnea to have an AHI reduction of at least 50% (±AHIAcetazolamide<10/h), as well as the NNT for one patient with sleep apnea to experience an increase in AHI by at least 50%. We identified 28 eligible studies (subjects: NAcetazolamide = 542; NControl = 553)14,29-55 including two Japanese-language articles43,49 (Fig 1). We received clarifications and/or additional information from authors of nine studies.29,30,32,38,42,46-48,53,56
Therapy options for OSA and central sleep apnea (CSA) are limited, thus many patients remain untreated. Clinically, acetazolamide is sometimes used for CSA; however, given overlapping pathophysiologic properties of OSA and CSA, we hypothesized that acetazolamide is equally effective for both types. Prior reviews focused on specific subtypes of sleep apnea, study designs, and languages, thus including few studies (typically ≤3) limiting insights.
How efficacious is acetazolamide for sleep apnea, and is its effect modified by sleep apnea type or acetazolamide dose?
We queried MEDLINE, EMBASE, and ClinicalTrials.gov from inception until March 11, 2019. Any study in which adults with OSA/CSA received oral acetazolamide vs no acetazolamide (control) that reported sleep apnea-related outcomes was eligible, independent of study design or language. Two reviewers independently assessed eligibility and abstracted data. Primary outcomes were apnea-hypopnea index (AHI) and oxygen saturation nadir. Quality of evidence (QoE) was rated with the use of Grades of Recommendation Assessment, Development and Evaluation methods.
We included 28 studies (13 OSA/15 CSA; N_{Subjects,Acetazolamide} = 542; N_{Subjects,Control} = 553) that enabled meta-analyses for 24 outcomes. Acetazolamide doses ranged from 36 to 1000 mg/d and treatment duration from 1 to 90 d (median, 6 d). Overall, acetazolamide vs control lowered the AHI by −0.7 effect sizes (95% CI, −0.83 to −0.58; I² = 0%; moderate QoE) that corresponded to a reduction of 37.7% (95% CI, −44.7 to −31.3) or 13.8/h (95% CI, −16.3 to −11.4; AHI_Control = 36.5/h). The AHI reduction was similar in OSA vs CSA, but significantly greater with higher doses (at least up to 500 mg/d). Furthermore, acetazolamide improved oxygen saturation nadir by +4.4% (95% CI, 2.3 to 6.5; I² = 63%; no evidence of effect modification; very low QoE) and several secondary outcomes that included sleep quality measures and BP (mostly low QoE).
Short-term acetazolamide improved both OSA and CSA. Rigorous studies with long-term follow up are warranted to assess Acetazolamide’s value for the chronic treatment of patients with sleep apnea.
PROSPERO (CRD42019147504)
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Heart failureEffect of Acetazolamide on Chemosensitivity, Cheyne-Stokes Respiration, and Response to Effort in Patients With Heart Failure

Section snippets

Methods

Results

Discussion

J Am Coll Cardiol

J Am Coll Cardiol

Pulm Pharmacol Ther

Effect of acetazolamide on hypoxemia during sleep at high altitude

N Engl J Med

Respiratory stimulants and sleep periodic breathing a high altitude: almitrine versus acetazolamide

Am Rev Respir Dis

Central sleep apnea improvement with acetazolamide therapy

Arch Intern Med

Central apnea index decreases after prolonged treatment with acetazolamide

Am J Respir Crit Care Med

Acetazolamide improves central sleep apnea in heart failure: a double-blind, prospective study

Am J Respir Crit Care Med

A mechanism of central sleep apnea in patients with heart failure

N Engl J Med

Oscillatory breathing patterns during wakefulness in patients with chronic heart failure: clinical implications and role of augmented peripheral chemosensitivity

Circulation

Peripheral and central ventilatory responses in central sleep apnea with and without congestive heart failure

Am J Respir Crit Care Med

Quantitative general theory for periodic breathing in chronic heart failure and its clinical implications

Circulation

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