Sleep and Breathing in the General Population - Chemical Stimuli

Sleep and Breathing in Health and Disease (Part 2A - Chemical Stimuli, Sleep and Breathing in the General Population)

Central sleep apnea (CSA) is a common condition and its treatment remains elusive. The focus of this proposal is to identify the role of the physiologic path involving cortical arousals in CSA by decreasing arousal frequency using the pharmacological agent zolpidem. The goal is to identify the acute effects of administering zolpidem on sleep and respiratory outcomes, and subsequently, its effect on the severity of CSA and propensity to develop CSA. This study will shed light on the mechanisms underlying CSA that involve cortical arousals and will guide future therapeutic interventions for CSA.

The literature suggests that zolpidem may be effective in the treatment of central sleep apnea (CSA). However, evidence regarding the efficacy of zolpidem and the underlying mechanisms involved in its effect on CSA are not well-studied. Furthermore, respiratory-related arousals are hypothesized to contribute CSA symptoms and severity. The aim of the study is to determine the effect of decreasing respiratory-related arousals on the propensity to develop central apnea. The investigators hypothesize that administration of the nonbenzodiazepine hypnotic zolpidem will decrease the frequency of respiratory-related arousals, lower the central apnea-hypopnea index, and widen the CO2 reserve during sleep in patients with CSA compared to no treatment. Participants will complete a night study on a low dose of zolpidem and another night study without zolpidem in a crossover manner. The order of night studies is randomized. The results will help unveil the role of arousals in CSA and the acute effect of zolpidem on CSA severity and the propensity to CSA.

After an initial assessment to determine eligibility, participant complete two in-lab night studies in a randomized manner including one night with the administration of zolpidem and another without zolpidem.

Participants will be administered zolpidem for the first night study, and No Treatment during the second night study.

Participants will be administered zolpidem for the second night study, and No Treatment during the first night study.

The number of central apneas and hypopneas per hour of sleep was obtained from polysomnography studies.

CO2 reserve is the requisite change to induce central apnea is referred to as the CO2 reserve, which can be positive or negative. CO2 reserve is defined as the difference between the eupneic end-tidal CO2 pressure and the end-tidal CO2 pressure induced by the ventilation protocol that is sufficient to trigger a central apnea as defined by the American Academy of Sleep Medicine.

Controller gain is a ventilatory response to changes in end-tidal PCO2. Controller gain was calculated by dividing the difference in minute ventilation between the post-mechanical ventilation induced by the ventilation protocol and steady-state respiration by the difference in the end-tidal CO2 pressure between the mechanical ventilation and steady-state respiration.

Plant gain is a blood gas response to a change in ventilation. This measure represents the effectiveness of the "plant" in eliminating CO2. Steady-state plant gain was calculated from the ratio of end-tidal CO2 to minute ventilation during stable respiration.

The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal

Inclusion Criteria: Men and women Veterans with central sleep apnea, defined as Apnea Hypopnea Index (AHI)>15/hour with CAHI>5/hour, will be included in the experiments. Exclusion Criteria: less than 18 years old pregnant or breastfeeding female have severe respiratory disease that require to be on oxygen recent health event that may affect the ability to participate in the study, Body Mass Index (BMI) is >40 kg/m2 significant insomnia mental instability recent health event that may affect sleep if at any time the principal investigator (PI) identifies that a certain drug is not suitable, or are unable to use the device that is used to treat sleep apnea, will be not be allowed to participate in the study

Ahmad B, Sankari A, Eshraghi M, Aldwaikat A, Yarandi H, Zeineddine S, Salloum A, Badr MS. Effect of Zolpidem on nocturnal arousals and susceptibility to central sleep apnea. Sleep Breath. 2023 Mar;27(1):173-180. doi: 10.1007/s11325-022-02593-3. Epub 2022 Mar 14.