Michele Ostrowski

Genioglossus activity available via non-arousal mechanisms vs. that required for opening the airway in obstructive apnea patients

It is generally believed that reflex recruitment of pharyngeal dilator muscles is insufficient to open the airway of obstructive apnea (OSA) patients once it is closed and, therefore, that arousal is required. Yet arousal promotes recurrence of obstruction. There is no information about how much dilator [genioglossus (GG)] activation is required to open the airway (GG Opening Threshold) or about the capacity of reflex mechanisms to increase dilator activity before/without arousal (Non-Arousal Activation). The relationship between these two variables is important for ventilatory stability. We measured both variables in 32 OSA patients (apnea-hypopnea index 74 ± 42 events/h). GG activity was monitored while patients were on optimal continuous positive airway pressure (CPAP). Zopiclone was administered to delay arousal. Maximum GG activity (GG(MAX)) and airway closing pressure (P(CRIT)) were measured. During stable sleep CPAP was decreased to 1 cmH(2)O to induce obstructive events and the dial-downs were maintained until the airway opened with or without arousal. GG activity at the instant of opening (GG Opening Threshold) was measured. GG Opening Threshold averaged only 10.4 ± 9.5% GG(Max) and did not correlate with P(CRIT) (r = 0.04). Twenty-six patients had >3 openings without arousal, indicating that Non-Arousal Activation can exceed GG Opening Threshold in the majority of patients. GG activity reached before arousal in Arousal-Associated Openings was only 5.4 ± 4.6% GG(MAX) below GG Opening Threshold. We conclude that in most patients GG activity required to open the airway is modest and can be reached by non-arousal mechanisms. Arousals occur in most cases just before non-arousal mechanisms manage to increase activity above GG Opening Threshold. Measures to reduce GG Opening Threshold even slightly may help stabilize breathing in many patients.

Response of genioglossus muscle to increasing chemical drive in sleeping obstructive apnea patients.

STUDY OBJECTIVES Subjects with a collapsible upper airway must activate their pharyngeal dilators sufficiently in response to increasing chemical drive if they are to maintain airway patency without arousal from sleep. Little is known about the response of pharyngeal dilators to increasing chemical drive in these subjects. We wished to determine, in obstructive apnea patients, the response of the genioglossus to increasing chemical drive and the contribution of mechanoreceptor feedback to this response. DESIGN Physiological study. SETTING University-based sleep laboratory. PATIENTS 20 patients with obstructive apnea. INTERVENTIONS Genioglossus activity was monitored during overnight polysomnography on optimal continuous positive airway pressure (CPAP). Intermittently, inspired gases were altered to produce different levels of ventilatory stimulation. CPAP was then briefly reduced to 1.0 cm H(2)O (dial-down), inducing an obstruction. MEASUREMENTS AND RESULTS Without mechanoreceptor feedback (i.e., on CPAP) the increase in genioglossus activity as ventilation increased from 6.1 ± 1.4 to 16.1 ± 4.8 L/min was modest (ΔTonic activity 0.3% ± 0.5%maximum; ΔPhasic activity 1.7% ± 3.4%maximum). Genioglossus activity increased immediately upon dial-down, reflecting mechanoreceptor feedback, but only when ventilation before dial-down exceeded a threshold value. This threshold varied among patients and, once surpassed, genioglossus activity increased briskly with further increases in chemical drive (1.1% ± 0.84%GG(MAX) per L/min increase in V(E)). CONCLUSIONS In sleeping obstructive apnea patients: (1) Mechanoreceptor feedback is responsible for most of the genioglossus response to chemical drive. (2) Mechanoreceptor feedback is effective only above a threshold chemical drive, which varies greatly among patients. These findings account in part for the highly variable relation between pharyngeal mechanical abnormalities and apnea severity.

Ventilatory and cerebrovascular responses to hypercapnia in patients with obstructive sleep apnoea: effect of CPAP therapy.

The purpose of this study was to assess whether the cerebrovascular response to hypercapnia is blunted in OSA patients and if this could alter the ventilatory response to hypercapnia before and after CPAP therapy. We measured the cerebrovascular, cardiovascular and ventilatory responses to hypercapnia in 8 patients with OSA (apnoea-hypopnoea index=101+/-10) before and after 4-6 weeks of CPAP therapy and in 10 control subjects who did not undergo CPAP therapy. The cerebrovascular and ventilatory responses to hypercapnia were not different between OSA and controls at baseline or follow-up. The cardiovascular response to hypercapnia was significantly increased in the OSA group by CPAP therapy (mean arterial pressure response: 1.30+/-0.16 vs. 2.04+/-0.36 mmHg Torr(-1); p=0.007). We conclude that in normocapnic, normotensive OSA patients without cardiovascular disease, the ventilatory, cerebrovascular, and cardiovascular responses to hypercapnia are normal, but the cardiovascular response to hypercapnia is heightened following 1 month of CPAP therapy.

Odds Ratio Product of Sleep EEG as a Continuous Measure of Sleep State

STUDY OBJECTIVES To develop and validate an algorithm that provides a continuous estimate of sleep depth from the electroencephalogram (EEG). DESIGN Retrospective analysis of polysomnograms. SETTING Research laboratory. PARTICIPANTS 114 patients who underwent clinical polysomnography in sleep centers at the University of Manitoba (n = 58) and the University of Calgary (n = 56). INTERVENTIONS None. MEASUREMENTS AND RESULTS Power spectrum of EEG was determined in 3-second epochs and divided into delta, theta, alpha-sigma, and beta frequency bands. The range of powers in each band was divided into 10 aliquots. EEG patterns were assigned a 4-digit number that reflects the relative power in the 4 frequency ranges (10,000 possible patterns). Probability of each pattern occurring in 30-s epochs staged awake was determined, resulting in a continuous probability value from 0% to 100%. This was divided by 40 (% of epochs staged awake) producing the odds ratio product (ORP), with a range of 0-2.5. In validation testing, average ORP decreased progressively as EEG progressed from wakefulness (2.19 ± 0.29) to stage N3 (0.13 ± 0.05). ORP < 1.0 predicted sleep and ORP > 2.0 predicted wakefulness in > 95% of 30-s epochs. Epochs with intermediate ORP occurred in unstable sleep with a high arousal index (> 70/h) and were subject to much interrater scoring variability. There was an excellent correlation (r(2) = 0.98) between ORP in current 30-s epochs and the likelihood of arousal or awakening occurring in the next 30-s epoch. CONCLUSIONS Our results support the use of the odds ratio product (ORP) as a continuous measure of sleep depth.

Contribution of Arousal from Sleep to Postevent Tachycardia in Patients with Obstructive Sleep Apnea

STUDY OBJECTIVES Heart rate increases after obstructive events in patients with obstructive sleep apnea (OSA). This response is generally attributed to arousal from sleep. Opening of the obstructed airway, however, is associated with ventilatory and hemodynamic changes that could result in physiologic responses unrelated to arousal. Our objective was to determine the contribution of these physiologic responses to postevent tachycardia. DESIGN Analysis of data obtained during previous research protocols. SETTING Academic sleep laboratory. PARTICIPANTS Twenty patients with severe OSA. INTERVENTIONS Patients were placed on a continuous positive airway pressure (CPAP) device. CPAP was reduced during sleep to different levels (dial-downs), producing obstructive events of varying severity. Some dial-downs with severe obstruction were maintained until spontaneous airway opening. In others, CPAP was increased after three obstructed breaths, terminating the events approximately 10 sec before spontaneous termination in long dial-downs. MEASUREMENT AND RESULTS Beat-by-beat heart rate (HR) was measured for 20 sec following airway opening. Spontaneous opening during sustained dial-downs occurred 21.9 ± 8.4 sec after dial-down, was associated with arousal, and resulted in the greatest postevent tachycardia (7.8 ± 4.0 min(-1)). However, deliberate termination of events (12.2 ± 2.6 sec after dial-down) was also followed by tachycardia that, in the absence of cortical arousal, showed a dose-response behavior, increasing with severity of obstruction and without apparent threshold. ΔHR following deliberately brief, severe obstruction (3.8 ± 3.0 min(-1)) was approximately half the ΔHR that followed spontaneous opening of equally severe obstructions despite the shorter duration and absence of cortical arousal. CONCLUSIONS Postevent tachycardia is due in large part to physiologic (arousal-unrelated) responses that occur upon relief of obstruction.

Heritability of Heart Rate Response to Arousals in Twins

Objectives To determine if the large and highly reproducible interindividual differences in arousal intensity and heart rate response to arousal (ΔHR) during non-REM sleep are heritable. Methods Polysomnograms of 55 monozygotic (14 male and 41 female pairs) and 36 dizygotic (15 male and 21 female pairs) same-sex twin pairs were analyzed. Arousals were scored using the 2012 American Academy of Sleep Medicine criteria. Arousal intensity was scaled (between 0 and 9) using an automatic algorithm based on the change in electroencephalogram time and frequency characteristics. The ΔHR was determined at each arousal. We calculated average arousal duration, average arousal intensity, average overall ΔHR, average ΔHR at a given arousal intensity, slope of ΔHR per arousal intensity, and arousal intensity threshold of ΔHR. Results The intraclass correlations among monozygotic and dizygotic twin pairs were 0.663 and 0.146, respectively, for average arousal intensity, and 0.449 and 0, respectively, for arousal intensity threshold of ΔHR controlling for age, sex, and race. These values imply large broad sense heritability (H2) for these traits. This evidence was confirmed by a robust maximum likelihood-based variance components estimation approach, with an additive genetic heritability of 0.64 (95% confidence interval: 0.48 to 0.80) for average arousal intensity and a combined additive and dominance genetic heritability and of 0.46 (0.25 to 0.68) for arousal intensity threshold of ΔHR. Results also suggested significant additive genetic effects for average arousal duration, ΔHR at arousal intensity scale 4 and the overall average ΔHR. Conclusion Genetic factors explain a significant fraction of the phenotypic variability for average arousal intensity and arousal intensity threshold of ΔHR. Results suggest that the duration of arousals and specific average ΔHR values may also be heritable traits. Clinical trial registration NCT02827461.