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 upper airway collapsibility and genioglossus muscle activity (EMG GG) during sleep in OSA patients.
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 EMG GG activity while awake and at sleep onset (alpha-theta transition at the electroencephalogram). 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 cmH2O in order to modify upper airway pressure and measure pharyngeal critical collapsing pressure (Pcrit), ventilation at 0 cmH2O when UA muscle are passive and active as well as change in EMG GG as a function of epiglottic pressure (muscle responsiveness). Apnea-hypopnea index (AHI) will be calculated in each night from the part of the study off CPAP.
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 65 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosed OSA (moderate-to-severe; apnea hypopnea index \>15 events/hr)
Exclusion criteria
* Cardiovascular disease other than well controlled hypertension * Depression
Design outcomes
Primary
| 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Genioglossus Muscle Responsiveness to Progressively Greater Epiglottic Pressure Swings | 1 night | Electromyography (EMG) was used to analyze genioglossus (GG) \[EMG GG\] muscle activity. EMG GG activity was recorded via standard needle electrodes inserted into the genioglossus muscle (tongue). 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). 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 and measure change in EMG GG as a function of epiglottic pressure (muscle responsiveness) (%max/cmH2O). |
| Number of Apnoea-Hypopnea Index (AHI) Events During Non-Random Eye Movement (NREM) Sleep | 1 night | The AHI is the number of apneas (pauses in breathing) or hypopneas (shallow breathing) recorded during the study per hour of sleep. Data for the calculation of the AHI was collected while the participant was in NREM sleep in the supine position and off CPAP (breathing spontaneously). |
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. 1 participant was excluded due to insufficient sleep time. | 14 |
| Total | 14 |
Baseline characteristics
| Characteristic | All Analyzed Participants |
|---|---|
| Age, Continuous | 55 years |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 16 | 0 / 15 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 |
Outcome results
Primary
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. 1 participant was excluded due to insufficient sleep time.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Desipramine | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Active Pcrit | -5.2 cm H2O |
| Desipramine | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Passive Pcrit | -2.2 cm H2O |
| Placebo | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Active Pcrit | -1.9 cm H2O |
| Placebo | Change in Pharyngeal Critical Collapsing Pressure (Pcrit) as a Measure of Upper Airway Collapsibility | Passive Pcrit | -0.7 cm H2O |
Comparison: Active Pcritp-value: 0.049Wilcoxon Matched-Pairs Signed-Rank Test
Comparison: Passive Pcritp-value: 0.135Wilcoxon Matched-Pairs Signed-Rank Test
Secondary
Genioglossus Muscle Responsiveness to Progressively Greater Epiglottic Pressure Swings
Electromyography (EMG) was used to analyze genioglossus (GG) \[EMG GG\] muscle activity. EMG GG activity was recorded via standard needle electrodes inserted into the genioglossus muscle (tongue). 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). 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 and measure change in EMG GG as a function of epiglottic pressure (muscle responsiveness) (%max/cmH2O).
Time frame: 1 night
Population: All participants who were randomized, completed both study nights, and were included in the analysis. 1 participant was excluded due to insufficient sleep time.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Desipramine | Genioglossus Muscle Responsiveness to Progressively Greater Epiglottic Pressure Swings | -0.24 %max/cmH2O |
| Placebo | Genioglossus Muscle Responsiveness to Progressively Greater Epiglottic Pressure Swings | -0.25 %max/cmH2O |
Secondary
Number of Apnoea-Hypopnea Index (AHI) Events During Non-Random Eye Movement (NREM) Sleep
The AHI is the number of apneas (pauses in breathing) or hypopneas (shallow breathing) recorded during the study per hour of sleep. Data for the calculation of the AHI was collected while the participant was in NREM sleep in the supine position and off CPAP (breathing spontaneously).
Time frame: 1 night
Population: All participants who were randomized, completed both study nights, and were included in the analysis. 1 participant was excluded due to insufficient sleep time.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Desipramine | Number of Apnoea-Hypopnea Index (AHI) Events During Non-Random Eye Movement (NREM) Sleep | 34.3 events per hour |
| Placebo | Number of Apnoea-Hypopnea Index (AHI) Events During Non-Random Eye Movement (NREM) Sleep | 42.0 events per hour |