Effect of acetazolamide on susceptibility to central sleep apnea in chronic spinal cord injury

Abstract

Spinal cord injury (SCI) is an established risk factor for central sleep apnea. Acetazolamide (ACZ), a carbonic anhydrase inhibitor, has been shown to decrease the frequency of central apnea by inducing mild metabolic acidosis. We hypothesized that ACZ would decrease the propensity to develop hypocapnic central apnea and decrease the apneic threshold. We randomized 16 participants with sleep-disordered breathing (8 SCI and 8 able-bodied controls) to receive ACZ (500 mg twice a day for 3 days) or placebo with a 1-wk washout before crossing over to the other drug arm. Study nights included polysomnography and determination of the hypocapnic apneic threshold and CO₂ reserve using noninvasive ventilation. For participants with spontaneous central apnea, CO₂ was administered until central apnea was abolished, and CO₂ reserve was measured as the difference in end-tidal Pco₂ ($\text{P}E{\text{T}}_{\text{C}{\text{O}}_2}$) before and after. Steady-state plant gain, the response of end-tidal Pco₂ to changes in ventilation, was calculated from $\text{P}\text{E}{\text{T}}_{\text{C}{\text{O}}_2}$ and V̇e ratio during stable sleep. Controller gain, the response of ventilatory drive to changes in end-tidal Pco₂, was defined as the ratio of change in V̇e between control and hypopnea to the ΔCO₂ during stable non-rapid eye movement sleep. Treatment with ACZ for three days resulted in widening of the CO₂ reserve (-4.0 ± 1.2 vs. -3.0 ± 0.7 mmHg for able-bodied, -3.4 ± 1.9 vs. -2.2 ± 2.2 mmHg for SCI, P < 0.0001), and a corresponding decrease in the hypocapnic apnea threshold (28.3 ± 5.2 vs. 37.1 ± 5.6 mmHg for able-bodied, 29.9 ± 5.4 vs. 34.8 ± 6.9 mmHg for SCI, P < 0.0001), respectively. ACZ significantly reduced plant gain when compared with placebo (4.1 ± 1.7 vs. 5.4 ± 1.8 mmHg/L min for able-bodied, 4.1 ± 2.0 vs. 5.1 ± 1.7 mmHg·L^-1·min for SCI, P < 0.01). Acetazolamide decreased apnea-hypopnea index (28.8 ± 22.9 vs. 39.3 ± 24.1 events/h; P = 0.05), central apnea index (0.6 ± 1.5 vs. 6.3 ± 13.1 events/h; P = 0.05), and oxyhemoglobin desaturation index (7.5 ± 8.3 vs. 19.2 ± 15.2 events/h; P = 0.01) compared with placebo. Our results suggest that treatment with ACZ decreases susceptibility to hypocapnic central apnea due to decreased plant gain. Acetazolamide may attenuate central sleep apnea and improve nocturnal oxygen saturation, but its clinical utility requires further investigation in a larger sample of patients.NEW & NOTEWORTHY Tetraplegia is a risk factor for central sleep-disordered breathing (SDB) and is associated with narrow CO₂ reserve (a marker of susceptibility to central apnea). Treatment with high-dose acetazolamide for 3 days decreased susceptibility to hypocapnic central apnea and reduced the frequency of central respiratory events during sleep. Acetazolamide may play a therapeutic role in alleviating central SDB in patients with cervical spinal cord injury, but larger clinical trials are needed.

Keywords: acetazolamide; central sleep apnea; loop gain; spinal cord injury.

Fig. 1.

Representative polygraphs from the noninvasive ventilation protocol depicting the difference in apneic threshold (AT) in a single spinal cord injury subject between the placebo-treated (A) and acetazolamide-treated (B) arms. Eupneic $\text{P}\mathrm{\text{E}}{\mathrm{\text{T}}}_{\text{C}{\mathrm{\text{O}}}_2}$ is represented by the upper dashed line of the bracket, and the AT $\text{P}\mathrm{\text{E}}{\mathrm{\text{T}}}_{\text{C}{\mathrm{\text{O}}}_2}$ is represented by the lower dashed line of the bracket. V_T, tidal volume; $\text{P}\mathrm{\text{E}}{\mathrm{\text{T}}}_{\text{C}{\mathrm{\text{O}}}_2}$, end-tidal CO₂ partial pressure; P_mask, mask pressure.

Fig. 2.

Effect of acetazolamide on CO₂ reserve (n = 16) (A), hypocapnic apnea threshold (n = 16) (B), plant gain (n = 16) (C), and controller gain (D) (n = 15; one subject excluded as described in methods). *P < 0.05 vs. placebo using repeated-measures ANOVA. AT $\text{P}\mathrm{\text{E}}{\mathrm{\text{T}}}_{\text{C}{\mathrm{\text{O}}}_2}$, end-tidal partial pressure of CO₂ at the hypocapnic apnea threshold.

Fig. 3.

Hyperoxic ventilatory response (HOV) in the able-bodied and SCI groups on placebo (A) and acetazolamide (B) (n = 16). *P < 0.05 for nadir versus baseline using repeated measures ANOVA. V̇e, minute ventilation.