Sleep-disordered Breathing
Conditions
Keywords
Sleep-disordered Breathing, central sleep apnea
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.
Interventions
DRUGZolpidem
A nonbenzodiazepine hypnotic
OTHERNo Treatment
The Control condition in which participants do not receive medication.
Sponsors
Wayne State University
National Institutes of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
Personnel conducting assessment of outcomes and data analysis are blinded to treatment.
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Central Apnea-hypopnea Index | one night | The number of central apneas and hypopneas per hour of sleep was obtained from polysomnography studies. |
| Respiratory Arousal Index | one night | A measure of the frequency of respiratory-related arousals during sleep |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CO2 Reserve | one night | 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 | one night | 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. |
| Stead-State Plant Gain (mmHg | one night | 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. |
| Respiratory Arousal Threshold | one night | The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zolpidem, Then No Treatment Participants will be administered zolpidem for the first night study, and No Treatment during the second night study.
Zolpidem: A nonbenzodiazepine hypnotic
No Treatment: The Control condition in which participants do not receive medication. | 6 |
| No Treatment, Then Zolpidem Participants will be administered zolpidem for the second night study, and No Treatment during the first night study.
Zolpidem: A nonbenzodiazepine hypnotic
No Treatment: The Control condition in which participants do not receive medication. | 5 |
| Total | 11 |
Baseline characteristics
| Characteristic | No Treatment, Then Zolpidem | Total | Zolpidem, Then No Treatment |
|---|---|---|---|
| Age, Continuous | 70.4 years STANDARD_DEVIATION 4.3 | 62.9 years STANDARD_DEVIATION 11.8 | 56.7 years STANDARD_DEVIATION 12.7 |
| BMI | 32.2 kg/m^2 STANDARD_DEVIATION 4.8 | 30.8 kg/m^2 STANDARD_DEVIATION 5.3 | 29.6 kg/m^2 STANDARD_DEVIATION 5.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 11 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Neck Girth | 41.4 cm STANDARD_DEVIATION 3.5 | 40.0 cm STANDARD_DEVIATION 5.1 | 38.9 cm STANDARD_DEVIATION 6.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 7 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 4 Participants | 3 Participants |
| Region of Enrollment United States | 5 participants | 11 participants | 6 participants |
| Sex: Female, Male Female | 0 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 5 Participants | 9 Participants | 4 Participants |
| Veteran Status: Yes | 5 Participants | 10 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 14 |
| other Total, other adverse events | 0 / 14 | 0 / 14 |
| serious Total, serious adverse events | 0 / 14 | 0 / 14 |
Outcome results
Primary
Respiratory Arousal Index
A measure of the frequency of respiratory-related arousals during sleep
Time frame: one night
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem | Respiratory Arousal Index | 23.3 events per hour | Standard Error 4.4 |
| No Treatment | Respiratory Arousal Index | 39.7 events per hour | Standard Error 7.7 |
Primary
The Central Apnea-hypopnea Index
The number of central apneas and hypopneas per hour of sleep was obtained from polysomnography studies.
Time frame: one night
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem | The Central Apnea-hypopnea Index | 14.1 events per hour | Standard Error 4.4 |
| No Treatment | The Central Apnea-hypopnea Index | 29.9 events per hour | Standard Error 7.6 |
Secondary
CO2 Reserve
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.
Time frame: one night
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem | CO2 Reserve | -0.63 mmHg | Standard Error 2.42 |
| No Treatment | CO2 Reserve | -0.44 mmHg | Standard Error 4.17 |
Secondary
Controller Gain
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.
Time frame: one night
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem | Controller Gain | 2.39 L/min*mmHg | Standard Error 1.1 |
| No Treatment | Controller Gain | 3.95 L/min*mmHg | Standard Error 2.34 |
Secondary
Respiratory Arousal Threshold
The nadir pressure in the upper airway (supra-glottic pressure) prior to the occurrence of an arousal
Time frame: one night
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem | Respiratory Arousal Threshold | -8.72 cmH2O | Standard Error 4.2 |
| No Treatment | Respiratory Arousal Threshold | -8.25 cmH2O | Standard Error 5.63 |
Secondary
Stead-State Plant Gain (mmHg
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.
Time frame: one night
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zolpidem | Stead-State Plant Gain (mmHg | 4.78 mmHg*L/min | Standard Error 0.79 |
| No Treatment | Stead-State Plant Gain (mmHg | 5.27 mmHg*L/min | Standard Error 1 |