Clinical trial NCT04720547
Conditions: Sleep-disordered Breathing
Keywords: Sleep-disordered Breathing central sleep apnea
Sponsor: Wayne State University
Start date: 2018-07-03; Completion date: 2020-02-29
Enrollment: 14 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: Participants will be administered zolpidem for the first night study, and No Treatment during the second night study. arm 2: Participants will be administered zolpidem for the second night study, and No Treatment during the first night study.
Interventions: intervention 1: Zolpidem intervention 2: No Treatment
Intervention descriptions: intervention 1: A nonbenzodiazepine hypnotic intervention 2: The Control condition in which participants do not receive medication.

Protocol documents:
Prot_SAP_000.pdf: 
Sleep and Breathing in the General Population - Chemical Stimuli 
NCT04720547 
Date – 02/06/2019 


 
 
 
Study Protocol 
Recruitment 
Participants will be recruited via flyers, recruitment letters, and word of mouth. Additionally, hospital 
databases will be searched to identify patients who completed polysomnography (PSG) studies at a 
sleep clinic and were diagnosed with CSA. Patients with no record of a previous PSG study or who 
underwent a PSG study earlier than 2 years at the screening date will have to undergo an in-laboratory 
PSG study to determine eligibility. Furthermore, patients who underwent medical procedures, surgeries, 
or had changes in health conditions or active medication that may affect sleep following the most recent 
PSG, will also undergo an in-lab PSG study irrespective of the date of the previous PSG study. Eligibility 
criteria include patients with an apnea–hypopnea index (AHI)≥15 and a central AHI (CAHI)≥5. Patients 
with OSA (AHI≥15) and narrow CO2 reserve (>−2.0 mmHg) will also be eligible due to their increased 
propensity to develop CSA [1]. Participants whose control night study does not meet the above criteria 
will be excluded. Additionally, patients with a history of severe respiratory, cardiac, renal, and 
neurologic disease and those with co-morbid sleep conditions will be excluded. 
 
Randomization and Study Procedures 
Eligible participants will sign an informed consent and complete an in-laboratory night study on 5 mg 
Zolpidem and a control night study with no medication. The dose of Zolpidem of 5 mg was selected 
according to current FDA recommendations to avoid adverse effects [2]. The order of the night studies 
(Zolpidem and control) will be randomized according to a randomized crossover study design. The 
randomization sequence for treatment order will be generated via Microsoft Excel. Participants and lab 
staff performing the night studies will not be blinded to the treatment order. Analysis of physiologic 
parameters and sleep studies scoring will be performed by lab personnel and reviewed by the principal 
investigator or a co-investigator, all of whom will be blinded to the study treatment arm at the time of 
the scoring, analysis, and review. The study statistician will also be blinded.  
Night studies will be scheduled based on participants’ availability and must be within 6 months of each 
other. Zolpidem has a short elimination half-life, and a washout period for a single 5 mg dose is 
unnecessary. When possible, consecutive night studies will be scheduled. Participants will be contacted 
by phone, and their medical records will be reviewed during each sleep study to ensure that no changes 
in medical conditions or medications occurred.  
After the participant consents to take part of the study, the participant will completed the Epworth 
Sleepiness Scale (ESS), the Fatigue Severity Scale (FSS) questionnaire, the Pittsburgh Sleep Quality Index 
(PSQI) questionnaire, and the Berlin questionnaire which help us to assess their sleep patterns and daily 
functional outcomes.  
 


In-laboratory Night Studies  
As part of standard care, a polysomnography (PSG) is a test conducted record an individual’s sleep study 
along with audio and video recording. A PSG is a test conducted to study sleep and to diagnose a variety 
of sleep disorders. A PSG is used not only to help diagnose a variety of sleep disorders, but also to learn 
whether adjustments to treatment plans are needed or if current treatment plan is effective. An 
enhanced PSG will be performed during both nights including electrooculography, surface 
electromyography, electrocardiography, and pulse oximetry (Carefusion, SomnoStar z4 Sleep System, 
San Diego, CA, USA) consistent with the technical criteria of the American Academy of Sleep Medicine 
(AASM) [3]. Additionally, a nasal mask will be connected to an in-line pneumotachometer (Hans 
Rudolph; model 3700A, Shawnee, KS, USA). An RSS 100HR Research Pneumotach System will acquire 
data (Hans Rudolph) to achieve airflow, pressure, and volume measurements. The end-tidal partial 
pressure of carbon dioxide (PETCO2) will be measured by connecting a tube placed in the nasal vestibule 
to a respiratory gas analyzer (CWE, Inc., GEMINI Respiratory Monitor, Ardmore, PA, USA). Airflow and 
PETCO2 will be recorded by a PowerLab data acquisition system (AD Instruments, Inc., model 16SP, 
Colorado Springs, CO, USA). Tidal volume (VT) is derived by integrating the airflow channel, and minute 
ventilation (VE) is calculated by multiplying VT by breathing frequency (FB). Arterial oxygen saturation 
will be monitored by an ear clip oximeter (Ohmeda Medical Inc., Biox 3740, Laurel, MD, USA). PSG 
variables, including apnea, arousal, and desaturation indices, will all be calculated during both nights. 
Sleep staging and arousals will be measured and scored according to standard criteria using oximetry, 
EEG, EOG, and EMG and standard PSG methods. 
 
Physiologic parameters  
In addition to PSG, a noninvasive positive air pressure ventilation protocol will be used to calculate the 
CO2 reserve and the controller gain. The CO2 reserve is defined as the difference between the eupneic 
end-tidal CO2 pressure and the end-tidal CO2 pressure (PETCO2) induced by the ventilation protocol 
that is sufficient to trigger a central apnea as defined by the AASM. If we are not able to acquire a period 
of stable eupneic breathing due to the persistence of spontaneous central events, we will administer a 
40% CO2 gas mixture balanced with nitrogen to stabilize breathing. The combination will be 
administered at 5-min intervals in 0.5 L/min increments. The volume per unit time of the mixture gas 
required to resolve central events will be determined, and PETCO2 allowed to return to baseline. We 
will perform three 5-min trials at the therapeutic volume per unit of the mixture gas separated by 
sufficient time to return to baseline PETCO2. Here, the CO2 reserve is defined as the difference between 
baseline PETCO2 and the PETCO2 during the administration of the gas mixture at which central events 
were resolved. Controller gain is 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. In participants administered the gas mixture as described above, the controller gain will not 
be calculated due to the absence of mechanical ventilation in that protocol. Steady-state plant gain is 
calculated from the ratio of end-tidal CO2 to minute ventilation during stable respiration. All physiologic 
parameters will be calculated during non-rapid eye movement (non-REM) sleep in both the control and 
the zolpidem night studies.  


During both nights, a supraglottic catheter will be inserted in the patient’s nostril to measure epiglottic 
pressure throughout the PSG portion of the night study. The epiglottic nadir pressure occurring 
immediately before cortical arousal and during an obstructive respiratory event is defined by the AASM 
mark one instance of effort sufficient to trigger the arousal. These instances will be measured for all 
obstructive events followed by arousals during the PSG portion and averaged to produce the respiratory 
arousal threshold during REM and non-REM sleep.  
 
Outcomes  
The primary endpoint is the frequency of respiratory-related arousals, or the respiratory arousal index 
(R-ArI). R-ArI represents the number per hour of arousals resulting from respiratory events. Clinical 
outcomes will also compared between the two-night studies and included the total respiratory arousal 
index (ArI), AHI, and CAHI. The total ArI represents the number per hour of all arousals, whether 
spontaneous or due to a respiratory event. Lastly, physiologic outcomes, including the CO2 reserve, 
plant gain, controller gain, and arousal threshold, will be calculated and sleep and desaturation 
parameters will be reported as well.  
 
Statistical analysis  
A crossover design is used to investigate the potential influence of sequence (the order of medication 
administration) and period (the time of medication administration) on the effects of the two treatments 
(control and Zolpidem) on the clinical outcomes. The significance level will be set at a p-value equal to or 
less than 0.05. For the primary endpoint and clinical outcomes, the difference between the control night 
and the intervention night will be calculated for each participant, and Grubb’s test may be utilized to 
identify outliers (alpha=0.05). Statistical analyses were carried out using SPSS, SAS, and R.