Effective Treatment for Idiopathic Central Sleep Apnea?

In this issue, Quadri et al.¹ explore the treatment of idiopathic central sleep apnea (ICSA) with zolpidem. The authors defined ICSA as the presence of excessive daytime sleepiness (defined as an Epworth Sleepiness Scale, [ESS] ≥ 10), a central apnea-hypopnea index (CAHI) ≥ 10 events/hour, and an obstructive apnea-hypopnea index (OAHI) ≤ 5 events/hour. The study design was observational and involved small numbers of subjects (n = 20). Subjects with medical conditions associated with other forms of central sleep apnea were excluded (CHF with EF < 40%, diastolic dysfunction, history of transient ischemic attacks or stroke). In addition, other forms of nighttime respiratory disturbances (Cheyne Stokes respiration, obesity hypoventilation, hypercarbic lung disease) and other sleep disorders were excluded. Subjects who had already initiated therapy that might treat ICSA were also excluded. Subjects were offered therapy with 10 mg of zolpidem to be taken 30 minutes prior to sleep on a nightly basis. Repeat polysomnographic testing was performed 6-10 weeks later on zolpidem therapy.

Quadri et al. found that following chronic zolpidem administration, overall apnea-hypopnea index (AHI) decreased from approximately 30 to 13.5 events/hour, mainly due to a decrease in central apneas and hypopneas. In fact, they note that 18/20 subjects had > 50% reduction in CAHI. Quadri et al. also found that arousal index, ESS, mean sleep latency, sleep efficiency, and sleep architecture improved. Despite the lack of statistically significant differences in rates of obstructive events after zolpidem therapy, 7/20 subjects had an increase in OAHI. All but 2 of these 7 subjects were noted to have an improvement in the overall AHI. However, on closer examination, all of these subjects had an OAHI > 5 events/hour, and 4/7 had persistent moderate sleep apnea (overall AHI of > 15 events/hour) while on zolpidem therapy. Additionally, although, the average oxygen saturation nadir did not change with zolpidem therapy, but it is unclear if those individuals with an increase in OAHI may have had greater hypoxia. Thus, despite improvements noted in central respiratory events, residual obstructive events persisted in a minority of subjects.

Regarding methodology, it should be noted that piezoelectric crystal thoracic and abdominal belts were used to quantify effort rather than an esophageal balloon. This method overestimates the degree of central respiratory events, but still allows for accurate classification of CSA while providing increased patient comfort.^2,3 In addition, naso-oral flow during sleep was detected with a thermistor, also potentially leading to an underestimation of obstructive respiratory events.⁴ It is important to note that, though obstructive events missed by thermistor monitoring may be “milder,” they may still generate intrathoracic pressure swings, hypercarbia, arousals, and sympathetic surges, and are not necessarily benign. These methodologic issues may bias towards an underestimation of obstructive respiratory events, leaving the subjects at increased risk of untreated residual obstructive sleep apnea (OSA).

Limitations of this study include the small numbers of subjects, the lack of a placebo control, and the lack of randomization. Larger, controlled trials will need to be performed before zolpidem for the treatment of ICSA can be recommended for routine clinical use. For now, caution is advised if it used for the treatment of ICSA. Worsening of obstructive events was not predictable from baseline OAHI; thus a repeat PSG on zolpidem therapy may be warranted to avoid the neurocognitive and cardiovascular sequelae of untreated residual OSA.

The authors are to be congratulated for their addition to the scant literature on available treatment options for ICSA.^5,6 Due to the low prevalence of this disorder, the vast majority of the data available on treatment options for CSA is in the context of heart failure or neurologic disease. The efficacy of CPAP, acetazolamide, inhaled CO₂, dead space and benzodiazepines for ICSA have been reported in only small observational trials.^7–10 The effectiveness of oxygen therapy for ICSA has been reported only in CSA subjects with CHF and strokes.¹¹ The only literature available for nonbenzodiazepine hypnotic agents to date is a recent case report demonstrating the efficacy of zolpidem therapy for ICSA.¹² Thus, the work of Quadri et al. adds to our understanding of treatment options for ICSA, and raises many important questions.

For the scientist, several questions remain unanswered: (1) What is the mechanism by which zolpidem therapy reduces central respiratory events? By elevating baseline pCO₂, changing ventilatory responsiveness, or by diminishing arousals? (2) Does zolpidem therapy lead to changes in pharyngeal collapsibility in a subset of subjects? (3) Can measurements such as the Pcrit (a measurement of upper airway collapsibility) performed after zolpidem administration be used to predict which subjects will have an increase in OAHI?

For the clinician, the remaining questions include: (1) Are there clinical characteristics that might predict an increase in OAHI with zolpidem therapy? (2) Are there clinical predictors that can identify patients that preferentially respond to zolpidem therapy in comparison to therapies such as CPAP, acetazolamide or oxygen? (3) Does the efficacy of zolpidem in treating ICSA wane as tolerance develops? (4) Are there consequences of ICSA that are not addressed by zolpidem therapy (i.e., cardiovascular consequences)? (5) How does zolpidem therapy compare to other treatment options? (6) Is zolpidem therapy useful in addition to other therapies, especially therapies that may address the increased pharyngeal collapsibility noted in patients with ICSA?¹³

DISCLOSURE STATEMENT

The author has indicated no financial conflict of interest.