Prevalence, characteristics, and respiratory arousal threshold of positional obstructive sleep apnea in China: a large scale study from Shanghai Sleep Health Study cohort.

PURPOSE: To evaluate the prevalence, characteristics, and respiratory arousal threshold (ArTH) of Chinese patients with positional obstructive sleep apnea (POSA) according to the Cartwright Classification (CC) and Amsterdam Positional Obstructive Sleep Apnea Classification (APOC). METHODS: A large-scale cross-sectional study was conducted in our sleep center from 2007 to 2018 to analyze the clinical and polysomnography (PSG) data of Chinese POSA patients. Low ArTH was defined based on PSG indices. RESULTS: Of 5,748 OSA patients, 36.80% met the CC criteria, and 42.88% the APOC criteria, for POSA. The prevalence of POSA was significantly higher in women than men (40.21% and 46.52% vs. 36.13% and 42.18% for CC and APOC, respectively). Chinese POSA patients had a lower apnea hypopnea index (AHI) and lower oxygen desaturation index, shorter duration of oxygen saturation (SaO2) < 90%, and a higher mean SaO2 and higher lowest SaO2 value compared to subjects with non-positional OSA (NPOSA). More than 40% of the POSA patients had a low ArTH; the proportion was extremely high in the supine-isolated-POSA (si-POSA) group and APOC I group. In multivariate logistic regression analyses, higher mean SaO2 and lower AHI during sleep were positive predictors of POSA. CONCLUSIONS: According to the CC and APOC criteria, more than 1/3 of our Chinese subjects with OSA had POSA. Chinese POSA patients had less severe OSA and nocturnal hypoxia. Compared to NPOSA patients, significantly more patients with POSA had a low ArTH. A low ArTH may be an important endotype in the pathogenesis of POSA, especially in patients with si-POSA and APOC I. Further studies are necessary to develop personalized management strategies for POSA patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry; URL: http://www.chictr.org.cn ; No. ChiCTR1900025714 (retrospectively registered).

Estimated respiratory arousal threshold in patients with rapid eye movement obstructive sleep apnea.

PURPOSE: Rapid eye movement (REM) obstructive sleep apnea (OSA) is a prevalent clinical phenotype. However, the literature focusing on the pathophysiology of REM OSA is limited. This study compared the proportion of individuals with a low respiratory arousal threshold between patients with REM and non-REM OSA. METHODS: REM OSA was defined as having an apnea-hypopnea index (AHI) ≥ 5 and AHI during REM (AHI-REM)/AHI during NREM (AHI-NREM) ≥ 2. REM OSA was sub-divided into REM-predominant OSA and REM-isolated OSA. REM-predominant OSA was defined as satisfying the definition of REM OSA and having an AHI-NREM ≥ 5. REM-isolated OSA was defined as satisfying the definition of REM OSA and having an AHI-NREM < 5. Patients with an AHI-REM/AHI-NREM < 2 were defined as having non-REM OSA. A low respiratory arousal threshold was defined as having 2 or more of the following conditions: AHI < 30 events/h, proportion of hypopnea > 58.3%, and nadir SpO2 > 82.5%. RESULTS: The proportions of individuals with low respiratory arousal thresholds among individuals with REM-predominant OSA and REM-isolated OSA were significantly higher (77.2% and 93.7%, respectively) than that of patients with non-REM OSA (48.6%). This was also true when the analysis was performed according to sex. CONCLUSION: These results indicate that a low respiratory arousal threshold might be an important endotype that contributes to the pathogenesis of REM OSA, especially in REM-isolated OSA.

Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial.

BACKGROUND AND OBJECTIVE: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). METHODS: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. RESULTS: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. CONCLUSION: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

Differences in respiratory arousal threshold in Caucasian and Chinese patients with obstructive sleep apnoea.

BACKGROUND AND OBJECTIVE: Ethnic differences in obstructive sleep apnoea (OSA) phenotype may not be limited to obesity and craniofacial factors. The aims of the study were to (i) compare the proportion of Caucasians and Chinese patients with a low respiratory arousal threshold (ArTH) and (ii) explore the influence of anatomical compromise on ArTH. METHODS: Interethnic comparison was conducted between cohorts of Caucasian and Chinese patients from specialist sleep disorder clinics. Polysomnography and craniofacial photography were performed. A low respiratory ArTH was determined by an ArTH score of 2 or above (one point for each: apnoea-hypopnoea index (AHI) < 30/h, nadir oxygen saturation (SaO2 ) > 82.5%, fractions of hypopnoeas > 58.3%). Anatomical compromise was stratified according to the photographic face width measurement. RESULTS: A total of 348 subjects (163 Caucasians and 185 Chinese) were analysed. There was a significantly lower proportion of Chinese patients with moderate-severe OSA (AHI ≥ 15) who had a low ArTH (28.4% vs 48.8%, P = 0.004). This difference remained significant among those with severe OSA (AHI ≥ 30) (2.6% vs 17.1%, P = 0.02). The proportion of moderate-severe OSA Caucasians with a low ArTH was significantly less in those with severe anatomical compromise (36.6% vs 61.0%, P = 0.03), whereas there was no difference in Chinese patients (25.5% vs 31.5%, P = 0.49). CONCLUSION: Compared to Caucasians with severe OSA, a low respiratory ArTh appears to be a less common pathophysiological mechanism in Chinese patients. Caucasians with less severe anatomical compromise exhibit evidence of a lower ArTh, an association which is absent in Chinese patients. Our data suggest that OSA mechanisms may vary across racial groups.

Different antimuscarinics when combined with atomoxetine have differential effects on obstructive sleep apnea severity.

The combination of the noradrenergic agent atomoxetine plus the antimuscarinic oxybutynin has recently been shown to improve upper airway physiology and reduce obstructive sleep apnea (OSA) severity. However, the effects of different antimuscarinics when combined with atomoxetine is limited. This study aimed to determine the effects of atomoxetine combined with two different antimuscarinics with varying M-subtype receptor selectivity on OSA severity and upper airway physiology. Ten people with predominantly severe OSA completed a double-blind, randomized, placebo-controlled, cross-over trial. Participants completed three overnight in-laboratory sleep studies after either 80 mg atomoxetine + 5 mg solifenacin succinate (ato-sol) or 80 mg atomoxetine + 2 mg biperiden hydrochloride (ato-bip) or placebo. OSA severity, ventilatory stability (loop gain), respiratory-arousal threshold (via epiglottic manometry), next-day subjective sleepiness [Karolinska Sleepiness Scale (KSS)], and alertness were compared between conditions. Neither drug combination altered the apnea/hypopnea index versus placebo (P = 0.63). Ato-sol caused a shift toward milder respiratory events with reduced frequency of obstructive apneas (13 ± 14 vs. 22 ± 17 events/h; means ± SD, P = 0.04) and increased hypopneas during nonrapid eye movement (NREM) (38 ± 21 vs. 24 ± 18 events/h, P = 0.006) with improved nadir oxygenation versus placebo (83 ± 4 vs. 80 ± 8%, P = 0.03). Both combinations reduced loop gain by ∼10% versus placebo; sleep efficiency and arousal threshold were unaltered. Ato-bip reduced next-day sleepiness versus placebo (KSS = 4.3 ± 2.2 vs. 5.6 ± 1.6, P = 0.03). Atomoxetine + biperiden hydrochloride reduces perceived sleepiness, and atomoxetine + solifenacin modestly improves upper airway function in people with OSA but to a lesser extent versus recently published atomoxetine + oxybutynin (broad M-subtype receptor selectivity) findings. These results provide novel mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.NEW & NOTEWORTHY In contrast to recent findings of major reductions in OSA severity when atomoxetine is combined with a nonspecific antimuscarinic, oxybutynin (broad M-subtype receptor selectivity), addition of solifenacin succinate (M2 and M3 muscarinic receptor selectivity) or biperiden (M1 muscarinic receptor selectivity) with atomoxetine had modest effects on upper airway function during sleep, which provide mechanistic insight into the role of noradrenergic and antimuscarinic agents on sleep and breathing and are important for pharmacotherapy development for OSA.

Low Arousal Threshold: A Potential Bridge Between OSA and Periodic Limb Movements of Sleep.

OBJECTIVE: Periodic Limb Movements of Sleep (PLMS) is a poorly understood comorbidity with close association to Obstructive Sleep Apnea (OSA). The mechanistic link between the two is unclear. Recent studies on the latter have uncovered low respiratory arousal threshold as an important non-anatomical cause of the disorder. This study sought to investigate whether periodic limb movements are associated with the low respiratory arousal threshold (ArTH) in OSA. METHODS: Retrospective data on 720 OSA patients (mean age = 47.0) who underwent Polysomnography (PSG) were collected. Using PLMS diagnostic criteria of PLMS index ≥ 15, patients were divided into the OSA-PLMS group (n=95) and the OSA-only group (n=625). Binary logistic regression analysis was used to examine the correlation between PLMS and the presence of low ArTH, classified using a predicted tool (developed by Edward et al) requiring meeting at least two of the three criteria: apnea-hypopnea index (AHI) < 30/h, nadir oxygen saturation (SaO2) > 82.5%, and fraction of hypopneas > 58.3%. The resulting model was validated in the external MrOS database. RESULTS: The patients in the OSA-PLMS group tend to be older, with a higher prevalence of hypertension, diabetes, and stroke. PLMS was associated with age, diabetes, oxygen desaturation index, and low respiratory arousal threshold (OR=8.78 (4.73-16.30), p<0.001). When validated against the MrOS database, low ArTH remained a significant predictor of PLMS with an odds ratio of 1.33 (1.08-1.64, p = 0.009). CONCLUSION: This is the first study that demonstrated a strong correlation between PLMS and low respiratory arousal threshold. This suggests a possible mechanistic link between the physical manifestation of PLMS and the non-anatomical low arousal threshold phenotype in OSA.

Differentiation Model for Insomnia Disorder and the Respiratory Arousal Threshold Phenotype in Obstructive Sleep Apnea in the Taiwanese Population Based on Oximetry and Anthropometric Features.

Insomnia disorder (ID) and obstructive sleep apnea (OSA) with respiratory arousal threshold (ArTH) phenotypes often coexist in patients, presenting similar symptoms. However, the typical diagnosis examinations (in-laboratory polysomnography (lab-PSG) and other alternatives methods may therefore have limited differentiation capacities. Hence, this study established novel models to assist in the classification of ID and low- and high-ArTH OSA. Participants reporting insomnia as their chief complaint were enrolled. Their sleep parameters and body profile were accessed from the lab-PSG database. Based on the definition of low-ArTH OSA and ID, patients were divided into three groups, namely, the ID, low- and high-ArTH OSA groups. Various machine learning approaches, including logistic regression, k-nearest neighbors, naive Bayes, random forest (RF), and support vector machine, were trained using two types of features (Oximetry model, trained with oximetry parameters only; Combined model, trained with oximetry and anthropometric parameters). In the training stage, RF presented the highest cross-validation accuracy in both models compared with the other approaches. In the testing stage, the RF accuracy was 77.53% and 80.06% for the oximetry and combined models, respectively. The established models can be used to differentiate ID, low- and high-ArTH OSA in the population of Taiwan and those with similar craniofacial features.

Randomized Trial on the Effects of High-Dose Zopiclone on OSA Severity, Upper Airway Physiology, and Alertness.

BACKGROUND: Studies indicate that standard doses of hypnotics reduce or do not change the apnea-hypopnea index (AHI) or pharyngeal muscle activity. A 1-month trial of nightly zopiclone (7.5 mg) modestly reduced the AHI vs baseline without changing other sleep parameters or next-day sleepiness. RESEARCH QUESTION: This study aimed to determine the effects of high-dose zopiclone (15 mg) on AHI, arousal threshold, genioglossus muscle responsiveness, and next-day alertness in selected people with OSA (low to moderate arousal thresholds without major overnight hypoxemia). We hypothesized that high-dose zopiclone would yield greater increases in arousal threshold and therefore larger reductions in AHI but may come at the expense of increased hypoxemia and next-day impairment. STUDY DESIGN AND METHODS: Twenty-eight participants (AHI = 29 ± 20 events/h) suspected to have low to moderate arousal thresholds were studied during two in-laboratory polysomnographies, separated by 1 week, with an epiglottic pressure catheter and genioglossus intramuscular electrodes. Participants received 15 mg of zopiclone or placebo at each visit according to a double-blind, randomized, crossover design. Each morning, subjective sleepiness and alertness via a driving simulator task were assessed. RESULTS: The AHI did not change from placebo to zopiclone (-1.5 events/h; 95% CI, -6.6 to 3.5 events/h; P = .54). Arousal threshold, genioglossus muscle responsiveness, and most other sleep parameters and measures of next-day sleepiness and alertness also did not change with zopiclone. INTERPRETATION: A single night of treatment with high-dose zopiclone does not systematically reduce the AHI or increase the arousal threshold in selected people with OSA. The mechanisms for these unexpected findings require further investigation. TRIAL REGISTRY: Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000988358; URL: https://www.anzctr.org.au.

Reduced cortical arousability to nocturnal apneic episodes in patients with wake-up ischemic stroke.

STUDY OBJECTIVES: Sleep breathing disorders (SBD) have been linked to wake-up stroke (WUS). Respiratory arousals have an important role in responding to danger during sleep, yet currently no studies have investigated respiratory arousability in WUS. In this study, we used a clinical tool to predict low respiratory arousal threshold (ArTH), and then compared respiratory arousability in patients with WUS and non-WUS. METHODS: We enrolled 119 patients with acute ischemic stroke and assigned them into WUS (n = 34) and non-WUS (n = 85) groups. All participants underwent polysomnography (PSG) during the acute phase of stroke. The respiratory ArTH predictive tool assigns one point for each of the following: apnea-hypopnea index (AHI) < 30/h, nadir oxygen saturation (SaO2) > 82.5%, and fraction of hypopneas > 58.3%. An ArTH score ≥2 represents low respiratory ArTH. RESULTS: Our results reconfirmed the association between moderate-to-severe sleep apnea syndrome and WUS (OR 2.879, 95% CI 1.17-7.089, p = 0.021). Significantly fewer participants with obstructive sleep apnea (AHI ≥ 5/h) had low respiratory ArTH in the WUS group than in the non-WUS group (34.8% vs. 68.1%, respectively, p = 0.008). High respiratory ArTH was independently associated with WUS (OR 5.556, 95% CI 1.959-15.761, p = 0.001). CONCLUSIONS: The correlation between SBD and WUS suggests that sleep apnea might induce acute physiological changes that trigger the onset of stroke. We show that reduced respiratory arousability is associated with WUS, and hypothesize that reduced cortical capability to generate respiratory arousal may have a role in triggering stroke during sleep.

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.