Is there a threshold that triggers cortical arousals in obstructive sleep apnea.

STUDY OBJECTIVES: To determine whether there is a consistent epiglottic pressure value that predicts respiratory arousal from sleep. METHODS: Thirty-one patients with obstructive sleep apnea underwent overnight polysomnography while instrumented with an epiglottic catheter to measure airway pressures. Nadir epiglottic pressures during respiration events (obstructive apneas/hypopneas) terminated with or without arousals were compared. The events were selected by two methods, (1) 20 events with/without arousals were randomly selected, and (2) Events were sampled in pairs (one terminated with arousal and one without arousal) to minimize the effect of sleep duration/stage on the measurement. RESULTS: A total of 1,317 respiratory events were analyzed. There was substantial variability in nadir epiglottic pressure within an individual and among different individuals. The average pressure of 20 randomly selected events with arousals was (-21.2 ± 11.2, ranged -6.68 to -63.34 cm H2O). The nadir epiglottic pressure during respiratory events in NREM stage 2 sleep terminated with arousals was more negative compared with those terminated without arousals using both sampling methods (-23.5 vs. -18.5 cm H2O, p = 0.007 and -20.3 vs. -16.3 cm H2O, p < 0.001). CONCLUSIONS: There were very different levels of epiglottic pressures that preceded arousals within and among individuals. However, cortical arousals are associated with a level of more negative epiglottic pressure compared to events terminated without arousal, findings which support the concept of a respiratory arousal threshold. CLINICAL TRIAL REGISTRATION: The study used existing data to study methodology (from clinical trial "The Impact of Arousal Threshold in Obstructive Sleep Apnea" https://clinicaltrials.gov/show/NCT02264353) and it is not a clinical trial.

Identifying obstructive sleep apnoea patients responsive to supplemental oxygen therapy.

A possible precision-medicine approach to treating obstructive sleep apnoea (OSA) involves targeting ventilatory instability (elevated loop gain) using supplemental inspired oxygen in selected patients. Here we test whether elevated loop gain and three key endophenotypic traits (collapsibility, compensation and arousability), quantified using clinical polysomnography, can predict the effect of supplemental oxygen on OSA severity.36 patients (apnoea-hypopnoea index (AHI) >20 events·h-1) completed two overnight polysomnographic studies (single-blinded randomised-controlled crossover) on supplemental oxygen (40% inspired) versus sham (air). OSA traits were quantified from the air-night polysomnography. Responders were defined by a ≥50% reduction in AHI (supine non-rapid eye movement). Secondary outcomes included blood pressure and self-reported sleep quality.Nine of 36 patients (25%) responded to supplemental oxygen (ΔAHI=72±5%). Elevated loop gain was not a significant univariate predictor of responder/non-responder status (primary analysis). In post hoc analysis, a logistic regression model based on elevated loop gain and other traits (better collapsibility and compensation; cross-validated) had 83% accuracy (89% before cross-validation); predicted responders exhibited an improvement in OSA severity (ΔAHI 59±6% versus 12±7% in predicted non-responders, p=0.0001) plus lowered morning blood pressure and "better" self-reported sleep.Patients whose OSA responds to supplemental oxygen can be identified by measuring their endophenotypic traits using diagnostic polysomnography.

Upper airway dynamic imaging during tidal breathing in awake and asleep subjects with obstructive sleep apnea and healthy controls.

We used magnetic resonance imaging (MRI) to quantify change in upper airway dimension during tidal breathing in subjects with obstructive sleep apnea (OSA, N = 7) and BMI-matched healthy controls (N = 7) during both wakefulness and natural sleep. Dynamic MR images of the upper airway were obtained on a 1.5 T MR scanner in contiguous 7.5 mm-thick axial slices from the hard palate to the epiglottis along with synchronous MRI-compatible electroencephalogram and nasal/oral flow measurements. The physiologic data were retrospectively scored to identify sleep state, and synchronized with dynamic MR images. For each image, the upper airway was characterized by its area, and linear dimensions (lateral and anterior-posterior). The dynamic behavior of the upper airway was assessed by the maximum change in these parameters over the tidal breath. Mean upper airway caliber was obtained by averaging data over the tidal breath. There was no major difference in the upper airway structure between OSA and controls except for a narrower airway at the low-retropalatal/high-retroglossal level in OSA than in controls. Changes in upper airway size over the tidal breath ((maximum - minimum)/mean) were significantly larger in the OSA than in the control group in the low retropalatal/high retroglossal region during both wakefulness and sleep. In the four OSA subjects who experienced obstructive apneas during MR imaging, the site of airway collapse during sleep corresponded to the region of the upper airway where changes in caliber during awake tidal breathing were the greatest. These observations suggest a potential role for dynamic OSA imaging during wakefulness.

The Effect of Donepezil on Arousal Threshold and Apnea-Hypopnea Index. A Randomized, Double-Blind, Cross-Over Study.

RATIONALE: Obstructive sleep apnea (OSA) has multiple pathophysiological causes. A low respiratory arousal threshold (ArTh) and a high loop gain (unstable ventilatory control) can contribute to recurrent respiratory events in patients with OSA. Prior studies have shown that donepezil, an acetylcholinesterase inhibitor, might improve OSA, but the mechanism is unknown. OBJECTIVES: To determine whether a single dose of donepezil lowers the apnea-hypopnea index by modulating the ArTh or loop gain. METHODS: In this randomized, double-blind, crossover trial, 41 subjects with OSA underwent two polysomnograms with ArTh and loop gain evaluated, during which 10 mg of donepezil or placebo was administered. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, sleep efficiency (77.2 vs. 71.9%; P = 0.015) and total sleep time decreased with donepezil (372 vs. 351 min; P = 0.004). No differences were found in apnea-hypopnea index (51.8 vs. 50.0 events/h; P = 0.576) or nadir oxygen saturation as determined by pulse oximetry (80.3 vs. 81.1%; P = 0.241) between placebo and donepezil, respectively. ArTh was not significantly changed (-18.9 vs. -18.0 cm H2O; P = 0.394) with donepezil. As a whole group, loop gain (ventilatory response to a 1-cycle/min disturbance) did not change significantly (P = 0.089). CONCLUSIONS: A single dose of donepezil did not appear to affect the overall severity of OSA in this patient group, and no consistent effects on ArTh or loop gain were observed. Donepezil may have minor effects on sleep architecture. Clinical trial registered with www.clinicaltrials.gov (NCT02264353).

Trazodone Effects on Obstructive Sleep Apnea and Non-REM Arousal Threshold.

RATIONALE: A low respiratory arousal threshold is a physiological trait involved in obstructive sleep apnea (OSA) pathogenesis. Trazodone may increase arousal threshold without compromising upper airway muscles, which should improve OSA. OBJECTIVES: We aimed to examine how trazodone alters OSA severity and arousal threshold. We hypothesized that trazodone would increase the arousal threshold and improve the apnea/hypopnea index (AHI) in selected patients with OSA. METHODS: Subjects were studied on two separate nights in a randomized crossover design. Fifteen unselected subjects with OSA (AHI ≥ 10/h) underwent a standard polysomnogram plus an epiglottic catheter to measure the arousal threshold. Subjects were studied after receiving trazodone (100 mg) and placebo, with 1 week between conditions. The arousal threshold was calculated as the nadir pressure before electrocortical arousal from approximately 20 spontaneous respiratory events selected randomly. MEASUREMENTS AND MAIN RESULTS: Compared with placebo, trazodone resulted in a significant reduction in AHI (38.7 vs. 28.5 events/h, P = 0.041), without worsening oxygen saturation or respiratory event duration. Trazodone was not associated with a significant change in the non-REM arousal threshold (-20.3 vs. -19.3 cm H2O, P = 0.51) compared with placebo. In subgroup analysis, responders to trazodone spent less time in N1 sleep (20.1% placebo vs. 9.0% trazodone, P = 0.052) and had an accompanying reduction in arousal index, whereas nonresponders were not observed to have a change in sleep parameters. CONCLUSIONS: These findings suggest that trazodone could be effective therapy for patients with OSA without worsening hypoxemia. Future studies should focus on underlying mechanisms and combination therapies to eliminate OSA. Clinical trial registered with www.clinicaltrials.gov (NCT 01817907).

Physiological mechanisms of upper airway hypotonia during REM sleep.

STUDY OBJECTIVES: Rapid eye movement (REM)-induced hypotonia of the major upper airway dilating muscle (genioglossus) potentially contributes to the worsening of obstructive sleep apnea that occurs during this stage. No prior human single motor unit (SMU) study of genioglossus has examined this possibility to our knowledge. We hypothesized that genioglossus SMUs would reduce their activity during stable breathing in both tonic and phasic REM compared to stage N2 sleep. Further, we hypothesized that hypopneas occurring in REM would be associated with coincident reductions in genioglossus SMU activity. DESIGN: The activity of genioglossus SMUs was studied in (1) neighboring epochs of stage N2, and tonic and phasic REM; and (2) during hypopneas occurring in REM. SETTING: Sleep laboratory. PARTICIPANTS: 29 subjects (38 ± 13 y) (17 male). INTERVENTION: Natural sleep, including REM sleep and REM hypopneas. MEASUREMENT AND RESULTS: Subjects slept overnight with genioglossus fine-wire intramuscular electrodes and full polysomnography. Forty-two SMUs firing during one or more of stage N2, tonic REM, or phasic REM were sorted. Twenty inspiratory phasic (IP), 17 inspiratory tonic (IT), and five expiratory tonic (ET) SMUs were characterized. Fewer units were active during phasic REM (23) compared to tonic REM (30) and stage N2 (33). During phasic REM sleep, genioglossus IP and IT SMUs discharged at slower rates and for shorter durations than during stage N2. For example, the SMU peak frequency during phasic REM 5.7 ± 6.6 Hz (mean ± standard deviation) was less than both tonic REM 12.3 ± 9.7 Hz and stage N2 16.1 ± 10.0 Hz (P < 0.001). The peak firing frequencies of IP/IT SMUs decreased from the last breath before to the first breath of a REM hypopnea (11.8 ± 10.9 Hz versus 5.7 ± 9.4 Hz; P = 0.001). CONCLUSION: Genioglossus single motor unit activity is significantly reduced in REM sleep, particularly phasic REM. Single motor unit activity decreases abruptly at the onset of REM hypopneas.

A pilot study investigating the effects of continuous positive airway pressure treatment and weight-loss surgery on autonomic activity in obese obstructive sleep apnea patients.

BACKGROUND: We have previously demonstrated that severity of obstructive sleep apnea (OSA) as measured by the apnea-hypopnea index (AHI) is a significant independent predictor of readily-computed time-domain metrics of short-term heart rate variability (HRV). METHODS: We aimed to assess time-domain HRV measured over 5-min while awake in a trial of obese subjects undergoing one of two OSA therapies: weight-loss surgery (n=12, 2 males, median and interquartile range (IQR) for BMI 43.7 [42.0, 51.4] kg/m2, and AHI 18.1 [16.3, 67.5] events/h) or continuous positive airway pressure (CPAP) (n=15, 11 males, median BMI 33.8 [31.3, 37.9] kg/m2, and AHI 36.5 [24.7, 77.3] events/h). Polysomnography was followed by electrocardiography during wakefulness; measurements were repeated at 6 and 12-18 months post-intervention. RESULTS: Despite similar measurements at baseline, subjects who underwent surgery exhibited greater improvement in short-term HRV than those who underwent CPAP (p=0.04). CONCLUSIONS: Our data suggest a possible divergence in autonomic function between the effects of weight loss resulting from bariatric surgery, and the amelioration of obstructive respiratory events resulting from CPAP treatment. Randomized studies are necessary before clinical recommendations can be made.

A mechanism for upper airway stability during slow wave sleep.

STUDY OBJECTIVES: The severity of obstructive sleep apnea is diminished (sometimes markedly) during slow wave sleep (SWS). We sought to understand why SWS stabilizes the upper airway. Increased single motor unit (SMU) activity of the major upper airway dilating muscle (genioglossus) should improve upper airway stability. Therefore, we hypothesized that genioglossus SMUs would increase their activity during SWS in comparison with Stage N2 sleep. DESIGN: The activity of genioglossus SMUs was studied on both sides of the transition between Stage N2 sleep and SWS. SETTING: Sleep laboratory. PARTICIPANTS: Twenty-nine subjects (age 38 ± 13 yr, 17 males) were studied. INTERVENTION: SWS. MEASUREMENT AND RESULTS: Subjects slept overnight with fine-wire electrodes in their genioglossus muscles and with full polysomnographic and end tidal carbon dioxide monitors. Fifteen inspiratory phasic (IP) and 11 inspiratory tonic (IT) units were identified from seven subjects and these units exhibited significantly increased inspiratory discharge frequencies during SWS compared with Stage N2 sleep. The peak discharge frequency of the inspiratory units (IP and IT) was 22.7 ± 4.1 Hz in SWS versus 20.3 ± 4.5 Hz in Stage N2 (P < 0.001). The IP units also fired for a longer duration (expressed as a percentage of inspiratory time) during SWS (104.6 ± 39.5 %TI) versus Stage N2 sleep (82.6 ± 39.5 %TI, P < 0.001). The IT units fired faster during expiration in SWS (14.2 ± 1.8 Hz) versus Stage N2 sleep (12.6 ± 3.1 Hz, P = 0.035). There was minimal recruitment or derecruitment of units between SWS and Stage N2 sleep. CONCLUSION: Increased genioglossus SMU activity likely makes the airway more stable and resistant to collapse throughout the respiratory cycle during SWS.