Sleep Apnea, Obstructive
Conditions
Brief summary
Obstructive sleep apnea (OSA) is common and has major health implications but treatment options are limited. OSA patients show a marked reduction in upper airway (UA) dilator muscle activity at sleep onset and this phenomenon leads to increased collapsibility of UA compared to normal participants. Until recently, the search for medicines to activate pharyngeal muscles in sleeping humans has been discouraging. However, exciting new animal research has shown that drugs with noradrenergic and antimuscarinic effects can restore pharyngeal muscle activity to waking levels. In this protocol the investigators will test the effect of desipramine (a tricyclic antidepressant with strong noradrenergic and antimuscarinic effects) on genioglossus muscle activity (EMG GG) during sleep in healthy control participants.
Detailed description
Two overnight sleep studies, a placebo night and a drug night, will be performed approximately one week apart in random order. The placebo or drug will be administered 2 hours before lights out. At least 15 minutes of quiet wakefulness will be recorded to quantify the participant's awake EMG GG activity. Participants will then sleep in the lateral position to minimize pharyngeal resistance similar to previous studies of this kind. The same will be done for stable non-rapid eye movement (NREM) and rapid eye movement (REM) sleep (free of arousals and other artifacts). Both NREM and REM sleep will be analyzed, recognizing that REM is less frequent on these drugs. During the second part of the night, the participants will be connected to a modified continuous positive airway pressure (CPAP) machine (Pcrit3000, Respironics) which can provide a wide range of pressures between 20 and -20 cm H2O in order to modify upper airway pressure and measure change in EMG GG as a function of epiglottic pressure (muscle responsiveness).
Interventions
DRUGDesipramine
200 mg administered 2 hours before normal sleep time
DRUGPlacebo
Placebo-matching desipramine administered 2 hours before normal sleep time
Sponsors
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Healthy control subjects
Exclusion criteria
* Cardiovascular disease other than well controlled hypertension * Depression
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Genioglossus Activity During Non-rapid Eye Movement (NREM) Sleep Measured as Percent of Wakefulness Activity | 1 night | Electromyography (EMG) was used to analyze genioglossus (GG) \[EMG GG\] muscle movement. EMG GG activity was recorded via standard needle electrodes inserted into the genioglossus (tongue) muscle. Activity of EMG GG was measured during wakefulness and sleep as % of maximum activation obtained pushing the tongue against closed teeth during wakefulness (GG%max). Sleep values were then expressed as %wakefulness value for tonic and phasic EMG GG activity. Tonic activity was defined as the lowest EMG GG value during expiration, phasic activity was calculated as the peak value during inspiration minus the tonic value. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | 1 night | Participants were connected to a modified continuous positive airway pressure (CPAP) machine (Pcrit3000, Respironics) which provided a wide range of pressures between 20 and -20 cm H2O in order to modify upper airway pressure. Following a baseline recording period of 5 minutes, the CPAP level was reduced to varying suboptimal pressures. Change in Pcrit was used to determine the collapsibility of the upper airway under both passive and active conditions, and is expressed as Passive Pcrit: ventilation at a nasal pressure of 0 cm H2O when pharyngeal muscles are passive; Active Pcrit: ventilation at a nasal pressure of 0 cm H2O when pharyngeal muscles are active. Improved=more negative Pcrit. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Analyzed Participants All participants who were randomized, completed both study nights, and were included in the analysis. 4 participants were excluded: 3 due to intermittent electromyographic amplifier malfunction; and 1 did not sleep on both study nights. | 10 |
| Total | 10 |
Baseline characteristics
| Characteristic | All Analyzed Participants |
|---|---|
| Age, Continuous | 27.5 years |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 16 |
| serious Total, serious adverse events | 0 / 15 | 0 / 16 |
Outcome results
Primary
Genioglossus Activity During Non-rapid Eye Movement (NREM) Sleep Measured as Percent of Wakefulness Activity
Electromyography (EMG) was used to analyze genioglossus (GG) \[EMG GG\] muscle movement. EMG GG activity was recorded via standard needle electrodes inserted into the genioglossus (tongue) muscle. Activity of EMG GG was measured during wakefulness and sleep as % of maximum activation obtained pushing the tongue against closed teeth during wakefulness (GG%max). Sleep values were then expressed as %wakefulness value for tonic and phasic EMG GG activity. Tonic activity was defined as the lowest EMG GG value during expiration, phasic activity was calculated as the peak value during inspiration minus the tonic value.
Time frame: 1 night
Population: All participants who were randomized, completed both study nights, and were included in the analysis. 4 participants were excluded: 3 due to intermittent electromyographic amplifier malfunction; and 1 did not sleep on both study nights.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Desipramine | Genioglossus Activity During Non-rapid Eye Movement (NREM) Sleep Measured as Percent of Wakefulness Activity | Tonic | 96 percent wakefulness |
| Desipramine | Genioglossus Activity During Non-rapid Eye Movement (NREM) Sleep Measured as Percent of Wakefulness Activity | Phasic | 84 percent wakefulness |
| Placebo | Genioglossus Activity During Non-rapid Eye Movement (NREM) Sleep Measured as Percent of Wakefulness Activity | Tonic | 75 percent wakefulness |
| Placebo | Genioglossus Activity During Non-rapid Eye Movement (NREM) Sleep Measured as Percent of Wakefulness Activity | Phasic | 93 percent wakefulness |
Comparison: Tonic analysisp-value: 0.01Wilcoxon Matched-Pairs Signed-Rank Test
Comparison: Phasic analysisp-value: 0.38Wilcoxon Matched-Pairs Signed-Rank Test
Secondary
Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility
Participants were connected to a modified continuous positive airway pressure (CPAP) machine (Pcrit3000, Respironics) which provided a wide range of pressures between 20 and -20 cm H2O in order to modify upper airway pressure. Following a baseline recording period of 5 minutes, the CPAP level was reduced to varying suboptimal pressures. Change in Pcrit was used to determine the collapsibility of the upper airway under both passive and active conditions, and is expressed as Passive Pcrit: ventilation at a nasal pressure of 0 cm H2O when pharyngeal muscles are passive; Active Pcrit: ventilation at a nasal pressure of 0 cm H2O when pharyngeal muscles are active. Improved=more negative Pcrit.
Time frame: 1 night
Population: All participants who were randomized, completed both study nights, and were included in the analysis. 4 participants were excluded: 3 due to intermittent electromyographic amplifier malfunction; and 1 did not sleep on both study nights.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Desipramine | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Passive Pcrit | -10.0 cm H2O |
| Desipramine | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Active Pcrit | -14.9 cm H2O |
| Placebo | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Passive Pcrit | -8.1 cm H2O |
| Placebo | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Active Pcrit | -10.5 cm H2O |
Comparison: Passive Pcritp-value: 0.037Wilcoxon Matched-Pairs Signed-Rank Test
Comparison: Active Pcritp-value: >0.5Wilcoxon Matched-Pairs Signed-Rank Test