Jayne C. Carberry

Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea.

STUDY OBJECTIVES To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients. METHODS Twelve patients with OSA (apnea-hypopnea index = 41 ± 8 events/h) were studied during 2 single night sleep studies conducted approximately 1 w apart after receiving 7.5 mg of zopiclone or placebo according to a double-blind, placebo-controlled, randomized, crossover design. The respiratory arousal threshold (epiglottic pressure immediately prior to arousal during naturally occurring respiratory events), genioglossus activity and its responsiveness to pharyngeal pressure during respiratory events, and markers of OSA severity were compared between conditions. Genioglossus movement patterns and upper airway anatomy were also assessed via magnetic resonance imaging in a subset of participants (n = 7) during wakefulness. RESULTS Zopiclone increased the respiratory arousal threshold versus placebo (-31.8 ± 5.6 versus -26.4 ± 4.6 cmH2O, P = 0.02) without impairing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure during respiratory events (-0.56 ± 0.2 versus -0.44 ± 0.1 %max/-cmH2O, P = 0.48). There was substantial interindividual variability in the changes in OSA severity with zopiclone explained, at least in part, by differences in pathophysiological characteristics including body mass index, arousal threshold, and genioglossus movement patterns. CONCLUSIONS In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others. CLINICAL TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry, http://www.anzctr.org.au, trial ID: ACTRN12614000364673.

Mechanisms contributing to the response of upper-airway muscles to changes in airway pressure

This study assessed the effects of inhaled lignocaine to reduce upper airway surface mechanoreceptor activity on 1) basal genioglossus and tensor palatini EMG, 2) genioglossus reflex responses to large pulses (∼10 cmH2O) of negative airway pressure, and 3) upper airway collapsibility in 15 awake individuals. Genioglossus and tensor palatini muscle EMG and airway pressures were recorded during quiet nasal breathing and during brief pulses (250 ms) of negative upper-airway pressure. Lignocaine reduced peak inspiratory (5.6 ± 1.5 vs. 3.8 ± 1.1% maximum; mean ± SE, P < 0.01) and tonic (2.8 ± 0.8 vs. 2.1 ± 0.7% maximum; P < 0.05) genioglossus EMG during quiet breathing but had no effect on tensor palatini EMG (5.0 ± 0.8 vs. 5.0 ± 0.5% maximum; P = 0.97). Genioglossus reflex excitation to negative pressure pulses decreased after anesthesia (60.9 ± 20.7 vs. 23.6 ± 5.2 μV; P < 0.05), but not when expressed as a percentage of the immediate prestimulus baseline. Reflex excitation was closely related to the change in baseline EMG following lignocaine (r(2) = 0.98). A short-latency genioglossus reflex to rapid increases from negative to atmospheric pressure was also observed. The upper airway collapsibility index (%difference) between nadir choanal and epiglottic pressure increased after lignocaine (17.8 ± 3.7 vs. 28.8 ± 7.5%; P < 0.05). These findings indicate that surface receptors modulate genioglossus but not tensor palatini activity during quiet breathing. However, removal of input from surface mechanoreceptors has minimal effect on genioglossus reflex responses to large (∼10 cmH2O), sudden changes in airway pressure. Changes in pressure rather than negative pressure per se can elicit genioglossus reflex responses. These findings challenge previous views and have important implications for upper airway muscle control.

Personalized Management Approach for OSA

&NA; OSA is a heterogeneous disorder. If left untreated, it has major health, safety, and economic consequences. In addition to varying levels of impairment in pharyngeal anatomy (narrow/collapsible airway), nonanatomical “phenotypic traits” are also important contributors to OSA for most patients. However, the majority of existing therapies (eg, CPAP, oral appliances, weight loss, positional therapy, upper airway surgery) target only the anatomical cause. These are typically administered as monotherapy according to a trial and error management approach in which the majority of patients are first prescribed CPAP. Despite its high efficacy, CPAP adherence remains unacceptably low, and second‐line therapies have variable and unpredictable efficacies. Recent advances in knowledge regarding the multiple causes of OSA using respiratory phenotyping techniques have identified new targets or “treatable traits” to direct therapy. Identification of the traits and development of therapies that selectively target one or more of the treatable traits has the potential to personalize the management of this chronic health condition to optimize patient outcomes according to precision medicine principles. This brief review highlights the latest developments and emerging therapies for personalized management approaches for OSA.

Obstructive sleep apnea: current perspectives

The prevalence of obstructive sleep apnea (OSA) continues to rise. So too do the health, safety, and economic consequences. On an individual level, the causes and consequences of OSA can vary substantially between patients. In recent years, four key contributors to OSA pathogenesis or “phenotypes” have been characterized. These include a narrow, crowded, or collapsible upper airway “anatomical compromise” and “non-anatomical” contributors such as ineffective pharyngeal dilator muscle function during sleep, a low threshold for arousal to airway narrowing during sleep, and unstable control of breathing (high loop gain). Each of these phenotypes is a target for therapy. This review summarizes the latest knowledge on the different contributors to OSA with a focus on measurement techniques including emerging clinical tools designed to facilitate translation of new cause-driven targeted approaches to treat OSA. The potential for some of the specific pathophysiological causes of OSA to drive some of the key symptoms and consequences of OSA is also highlighted.

Role of common hypnotics on the phenotypic causes of obstructive sleep apnoea: paradoxical effects of zolpidem

Hypnotics are contraindicated in obstructive sleep apnoea (OSA) because of concerns of pharyngeal muscle relaxation and delayed arousal worsening hypoxaemia. However, human data are lacking. This study aimed to determine the effects of three common hypnotics on the respiratory arousal threshold, genioglossus muscle responsiveness and upper airway collapsibility during sleep. 21 individuals with and without OSA (18–65 years) completed 84 detailed sleep studies after receiving temazepam (10 mg), zolpidem (10 mg), zopiclone (7.5 mg) and placebo on four occasions in a randomised, double-blind, placebo-controlled, crossover trial (ACTRN12612001004853). The arousal threshold increased with zolpidem and zopiclone versus placebo (mean±sd −18.3±10 and −19.1±9 versus −14.6±7 cmH2O; p=0.02 and p<0.001) but not with temazepam (−16.8±9 cmH2O; p=0.17). Genioglossus muscle activity during stable non-REM sleep and responsiveness during airway narrowing was not different with temazepam and zopiclone versus placebo but, paradoxically, zolpidem increased median muscle responsiveness three-fold during airway narrowing (median −0.15 (interquartile range −1.01 to −0.04) versus −0.05 (−0.29 to −0.03)% maximum EMG per cmH2O epiglottic pressure; p=0.03). The upper airway critical closing pressure did not change with any of the hypnotics. These doses of common hypnotics have differential effects on the respiratory arousal threshold but do not reduce upper airway muscle activity or alter airway collapsibility during sleep. Rather, muscle activity increases during airway narrowing with zolpidem. Contrary to previous beliefs, common sleeping pills do not reduce pharyngeal muscle activity in humans http://ow.ly/f69H30gKIot

Genioglossus reflex responses to negative upper airway pressure are altered in people with tetraplegia and obstructive sleep apnoea

Protective reflexes in the throat area (upper airway) are crucial for breathing. Impairment of these reflexes can cause breathing problems during sleep such as obstructive sleep apnoea (OSA). OSA is very common in people with spinal cord injury for unknown reasons. This study shows major changes in protective reflexes that serve to keep the upper airway open in response to suction pressures in people with tetraplegia and OSA. These results help us understand why OSA is so common in people with tetraplegia and provide new insight into how protective upper airway reflexes work more broadly.

Effects of morphine on respiratory load detection, load magnitude perception, and tactile sensation in obstructive sleep apnea

Pharyngeal and respiratory sensation is impaired in obstructive sleep apnea (OSA). Opioids may further diminish respiratory sensation. Thus protective pharyngeal neuromuscular and arousal responses to airway occlusion that rely on respiratory sensation could be impaired with opioids to worsen OSA severity. However, little is known about the effects of opioids on upper airway and respiratory sensation in people with OSA. This study was designed to determine the effects of 40 mg of MS-Contin on tactile sensation, respiratory load detection, and respiratory magnitude perception in people with OSA during wakefulness. A double-blind, randomized, crossover design (1 wk washout) was used. Twenty-one men with untreated OSA (apnea/hypopnea index = 26 ± 17 events/h) recruited from a larger clinical study completed the protocol. Tactile sensation using von Frey filaments on the back of the hand, internal mucosa of the cheek, uvula, and posterior pharyngeal wall were not different between placebo and morphine [e.g., median (interquartile range) posterior wall = 0.16 (0.16, 0.4) vs. 0.4 (0.14, 1.8) g, P = 0.261]. Similarly, compared with placebo, morphine did not alter respiratory load detection thresholds for nadir mask pressure detected = -2.05 (-3.37, -1.55) vs. -2.19 (-3.36, -1.41) cmH2O, P = 0.767], or respiratory load magnitude perception [mean ± SD Borg scores during a 5 resistive load (range: 5-126 cmH2O·l-1·s-1) protocol = 4.5 ± 1.6 vs. 4.2 ± 1.2, P = 0.347] but did reduce minute ventilation during quiet breathing (11.4 ± 3.3 vs. 10.7 ± 2.6 l/min, P < 0.01). These findings indicate that 40 mg of MS-Contin does not systematically impair tactile or respiratory sensation in men with mild to moderate, untreated OSA. This suggests that altered respiratory sensation to acute mechanical stimuli is not likely to be a mechanism that contributes to worsening of OSA with a moderate dose of morphine. NEW & NOTEWORTHY Forty milligrams of MS-Contin does not alter upper airway tactile sensation, respiratory load detection thresholds, or respiratory load magnitude perception in people with obstructive sleep apnea but does decrease breathing compared with placebo during wakefulness. Despite increasing concerns of harm with opioids, the current findings suggest that impaired respiratory sensation to acute mechanical stimuli with this dose of MS-Contin is unlikely to be a direct mechanism contributing to worsening sleep apnea severity in people with mild-to-moderate disease.

Effect of 1 month of zopiclone on obstructive sleep apnoea severity and symptoms: a randomised controlled trial

Hypnotic use in obstructive sleep apnoea (OSA) is contraindicated due to safety concerns. Recent studies indicate that single-night hypnotic use worsens hypoxaemia in some and reduces OSA severity in others depending on differences in pathophysiology. However, longer clinical trial data are lacking. This study aimed to determine the effects of 1 month of zopiclone on OSA severity, sleepiness and alertness in patients with low–moderate respiratory arousal thresholds without major overnight hypoxaemia. 69 participants completed a physiology screening night with an epiglottic catheter to quantify arousal threshold. 30 eligible patients (apnoea–hypopnoea index (AHI) 22±11 events·h−1) then completed standard in-laboratory polysomnography (baseline) and returned for two additional overnight sleep studies (nights 1 and 30) after receiving either nightly zopiclone (7.5 mg) or placebo during a 1-month, double-blind, randomised, parallel trial (ANZCTR identifier ANZCTRN12613001106729). The change in AHI from baseline to night 30 was not different between zopiclone versus placebo groups (−5.9±10.2 versus −2.4±5.5 events·h−1; p=0.24). Similarly, hypoxaemia, next-day sleepiness and driving simulator performance were not different. 1 month of zopiclone does not worsen OSA severity, sleepiness or alertness in selected patients without major overnight hypoxaemia. As the first study to assess the effect of a hypnotic on OSA severity and sleepiness beyond single-night studies, these findings provide important safety data and insight into OSA pathophysiology. 1 month of nightly zopiclone does not worsen OSA severity or symptoms in individuals with low–moderate arousal thresholds http://ow.ly/9JD230khJpl

An automated and reliable method for breath detection during variable mask pressures in awake and sleeping humans

Accurate breath detection is crucial in sleep and respiratory physiology research and in several clinical settings. However, this process is technically challenging due to measurement and physiological artifacts and other factors such as variable leaks in the breathing circuit. Recently developed techniques to quantify the multiple causes of obstructive sleep apnea, require intermittent changes in airway pressure applied to a breathing mask. This presents an additional unique challenge for breath detection. Traditional algorithms often require drift correction. However, this is an empirical operation potentially prone to human error. This paper presents a new algorithm for breath detection during variable mask pressures in awake and sleeping humans based on physiological landmarks detected in the airflow or epiglottic pressure signal (Pepi). The algorithms were validated using simulated data from a mathematical model and against the standard visual detection approach in 4 healthy individuals and 6 patients with sleep apnea during variable mask pressure conditions. Using the flow signal, the algorithm correctly identified 97.6% of breaths with a mean difference±SD in the onsets of respiratory phase compared to expert visual detection of 23±89ms for inspiration and 6±56ms for expiration during wakefulness and 10±74ms for inspiration and 3±28 ms for expiration with variable mask pressures during sleep. Using the Pepi signal, the algorithm correctly identified 89% of the breaths with accuracy of 31±156ms for inspiration and 9±147ms for expiration compared to expert visual detection during variable mask pressures asleep. The algorithm had excellent performance in response to baseline drifts and noise during variable mask pressure conditions. This new algorithm can be used for accurate breath detection including during variable mask pressure conditions which represents a major advance over existing time-consuming manual approaches.

Polysomnography with an epiglottic pressure catheter does not alter obstructive sleep apnea severity or sleep efficiency

Pharyngeal and oesophageal manometry is used clinically and in research to quantify respiratory effort, upper‐airway mechanics and the pathophysiological contributors to obstructive sleep apnea. However, the effects of this equipment on respiratory events and sleep in obstructive sleep apnea are unclear. As part of a clinical trial (ANZCTRN12613001106729), data from 28 participants who successfully completed a physiology night with an epiglottic catheter and nasal mask followed by a standard in‐laboratory polysomnography were compared. The apnea–hypopnea index was not different during the physiology night versus standard polysomnography (22 ± 14 versus 23 ± 13 events per hr, p = 0.71). Key sleep parameters were also not different compared between conditions, including sleep efficiency (79 ± 13 versus 81 ± 11%, p = 0.31) and the arousal index (26 ± 11 versus 27 ± 11 arousals per hr, p = 0.83). There were, however, sleep stage distribution changes between nights with less N3 and rapid eye movement sleep and more N1 on the physiology night, with no difference in N2 (53 ± 15 versus 48 ± 9, p = 0.08). However, these changes did not increase next‐day sleepiness. These findings indicate that while minor sleep stage distribution changes do occur towards lighter sleep, epiglottic manometry does not alter obstructive sleep apnea severity or sleep efficiency. Thus, epiglottic manometry can be used clinically and to collect detailed physiological information for research without major sleep disruption.