Hypnotics on Obstructive Sleep Apnea Severity and Endotypes: A Systematic Review and Meta-Analysis.

RATIONALE: Low arousal threshold and poor muscle responsiveness are common determinants of obstructive sleep apnea (OSA). Hypnotics were hypothesized as an alternative OSA treatment via raising the arousal threshold and possibly genioglossus responsiveness. OBJECTIVES: Effect of common hypnotics on arousal threshold, OSA severity and genioglossus responsiveness. METHODS: We searched MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov for randomized clinical trials, and ran meta-analyses to determine the effect of oral hypnotics on arousal threshold, OSA severity and genioglossus responsiveness. GRADE was used to rate the quality of evidence (QoE). The association between post-treatment AHI and arousal threshold percent reductions was explored in individual patient data (IPD) metanalyses (overall sample and low arousal threshold subgroups). MEASUREMENTS AND MAIN RESULTS: Based on our analysis (27 studies; 25 for AHI, 11 for arousal threshold, 4 for genioglossus responsiveness), hypnotics minimally raised arousal threshold (mean difference [95% CI]: 2.7 [1.5, 3.8] cmH2O epiglottic pressure swings; moderate QoE), but did not change OSA severity (1.4 [3.5, 0.7] events/h; moderate QoE). IPD meta-analysis (N=114) showed no association between changes in arousal threshold and AHI, independent of low arousal threshold subgrouping. However, people with very-low arousal threshold or those who exhibited 0-25% arousal threshold increase from placebo experienced the greatest-yet still modest-post-treatment AHI reductions (10%). Hypnotics did not affect genioglossus responsiveness (high QoE). CONCLUSIONS: Further research testing or clinical use of hypnotics as OSA alternative treatments should be discouraged, unless in the presence of comorbid insomnia or as part of combination therapy in individuals with very-low arousal threshold.

Continuous positive airway pressure and adherence in patients with different endotypes of obstructive sleep apnea.

Determining the endotypes of obstructive sleep apnea (OSA) has potential implications for precision interventions. Here we assessed whether continuous positive airway pressure (CPAP) treatment outcomes differ across endotypic subgroups. We conducted a retrospective analysis of data obtained from 225 patients with moderate-to-severe OSA from a single sleep centre. Polysomnographic and CPAP titration study data were collected between May 2020 and January 2022. One-month CPAP treatment adherence was followed. Obstructive sleep apnea endotypes, namely arousal threshold, collapsibility, loop gain, and upper airway gain were estimated from polysomnography and dichotomised as high versus low. We examined associations between endotypic subgroups and (1) optimal CPAP titration pressure, (2) CPAP-related improvements in sleep architecture (proportions of slow-wave and rapid eye movement (REM) sleep), and (3) CPAP adherence. We observed that patients with high collapsibility required a higher CPAP pressure than those with low collapsibility (∆ = 0.4 cmH2 O, 95% confidence interval [CI] = 0.3-1.7). A larger increase in slow-wave sleep and in REM sleep proportions after CPAP treatment were observed in patients with a high arousal threshold, high collapsibility, high loop gain, or high upper airway gain than in those with low levels of endotypes. High loop gain and high collapsibility were independently associated with longer CPAP use hours per night (∆ = 0.6 h, 95% CI = 0.2-1.5 and ∆ = 0.3 h, 95% CI = 0.03-1.5, respectively). In conclusion, different endotypic subgroups of OSA exhibit a difference in outcomes of CPAP treatment. Knowledge of endotypes may help clinicians to understand which patients are expected to benefit most from CPAP therapy prior to its administration.

Low arousal threshold: a common pathophysiological trait in patients with obstructive sleep apnea syndrome and asthma.

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) and asthma are two diseases with a high epidemiological impact that may often coexist. Both diseases have underlying pathogenic mechanisms (chronic inflammation, genetic predisposition, etc.); it is still unclear whether or not their coexistence is due to a specific pathophysiological factor. In the literature, the pathogenesis of OSAS has four pathophysiological traits: one or more anatomical predisposing factors, a low arousal threshold (low AT), high loop gain, and poor muscle responsiveness. In this study, we hypothesized that a low AT is a common pathophysiological factor in OSAS and asthma. METHODS: A retrospective study of patients attending the Pulmonology Unit of the University Hospital of Trieste was carried out. Low AT was predicted on the bases of the following polysomnography features, as previously shown by Edwards et al.: an AHI of < 30 events/h, a nadir SpO2 of > 82.5%, and a hypopnea fraction of total respiratory events of > 58.3%. RESULTS: Thirty-five patients with asthma and OSAS and 36 with OSAS alone were included in the study. Low AT was present in 71% of patients affected by asthma and OSAS (25 patients out of 35) versus 31% (11 patients out of 36) of patients affected by OSAS alone with a statistically significant difference (p = 0.002) between the two groups. Stratifying for BMI and OSAS severity, the difference between groups remained statistically significant. CONCLUSIONS: This is the first study to describe specific polysomnographic characteristics of patients affected by asthma and OSAS. A low AT may well be the pathophysiological factor common to the two diseases. If confirmed by other studies, this finding could lead to the presence of asthma and OSAS in the same individual being considered a syndrome with a common pathophysiological factor.

Covert sleep-related biological processes are revealed by probabilistic analysis in Drosophila.

Sleep pressure and sleep depth are key regulators of wake and sleep. Current methods of measuring these parameters in Drosophila melanogaster have low temporal resolution and/or require disrupting sleep. Here we report analysis tools for high-resolution, noninvasive measurement of sleep pressure and depth from movement data. Probability of initiating activity, P(Wake), measures sleep depth while probability of ceasing activity, P(Doze), measures sleep pressure. In vivo and computational analyses show that P(Wake) and P(Doze) are largely independent and control the amount of total sleep. We also develop a Hidden Markov Model that allows visualization of distinct sleep/wake substates. These hidden states have a predictable relationship with P(Doze) and P(Wake), suggesting that the methods capture the same behaviors. Importantly, we demonstrate that both the Doze/Wake probabilities and the sleep/wake substates are tied to specific biological processes. These metrics provide greater mechanistic insight into behavior than measuring the amount of sleep alone.

Sleep Analysis in Adult C. elegans Reveals State-Dependent Alteration of Neural and Behavioral Responses.

Sleep, a state of quiescence associated with growth and restorative processes, is conserved across species. Invertebrates including the nematode Caenorhabditis elegans exhibit sleep-like states during development, satiety, and stress. Here, we describe behavior and neural activity during sleep and awake states in adult C. elegans hermaphrodites using new microfluidic methods. We observed effects of fluid flow, oxygen, feeding, odors, and genetic perturbations on long-term sleep behavior over 12 h. We developed a closed-loop sleep detection system to automatically deliver chemical stimuli to assess sleep-dependent changes to evoked neural responses in individual animals. Sleep increased the arousal threshold to aversive stimulation, yet the associated sensory neuron and first-layer interneuron responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the premotor interneurons, rather than afferent sensory circuits. However, sleep prolonged responses in appetitive chemosensory neurons, suggesting that sleep modulates responsiveness specifically across sensory systems rather than broadly damping global circuit activity.SIGNIFICANCE STATEMENT Much is known about molecular mechanisms that facilitate sleep control. However, it is unclear how these pathways modulate neural circuit-level sensory processing or how misregulation of neural activity contributes to sleep disorders. The nematode Caenorhabditis elegans provides the ability to study neural circuitry with single-neuron resolution, and recent studies examined sleep states between developmental stages and when stressed. Here, we examine an additional form of spontaneous sleep in adult C. elegans at the behavioral and neural activity levels. Using a closed-loop system, we show that delayed behavioral responses to aversive chemical stimulation during sleep arise from sleep-dependent sensorimotor modulation localized presynaptic to the premotor circuit, rather than early sensory circuits.

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).

Endotypic Mechanisms of Successful Hypoglossal Nerve Stimulation for Obstructive Sleep Apnea.

Rationale: Approximately one-third of patients with obstructive sleep apnea (OSA) treated with hypoglossal nerve stimulation (HGNS) therapy are incomplete responders, despite careful patient selection based on baseline characteristics and drug-induced sleep endoscopy.Objectives: Here we use polysomnographic endotyping to assess the pathophysiological mechanisms underlying favorable versus incomplete responses to HGNS therapy.Methods: Baseline polysomnography data of the STAR (Stimulation Therapy for Apnea Reduction) trial were included. Raw baseline polysomnographic data from 91/126 patients were available for analysis. Traits-loop gain, arousal threshold, collapsibility, and muscle compensation-were calculated from the baseline polysomnography data according to Sands and colleagues (AJRCCM 2018, SLEEP 2018). Logistic regression assessed apnea-hypopnea index (AHI)-adjusted associations between HGNS response (>50% reduction in AHI to <10/h at 1 yr) and OSA traits.Measurements and Main Results: Overall, HGNS treatment reduced AHI from 30.7 (24.9-39.9) to 8.5 (4.0-19.5) events/h (P < 0.0001; median [quartiles 1-3]); N = 53/91 were responders. In adjusted analysis, a favorable response to therapy was independently associated with higher arousal threshold (odds ratio [95% confidence interval]: 6.76 [2.44-23.3], P = 0.001), greater compensation (odds ratio: 4.22 [1.70-12.55] per SD, P = 0.004), and lower loop gain (in milder collapsibility, per significant interaction, P = 0.003). The higher arousal threshold was evident in responders before adjusted analysis. Predicted responders had an approximately fourfold lower treatment AHI versus predicted nonresponders (4.9 [2.7-8.5] vs. 20.7 [10.9-29.7], P < 0.0001; median [quartiles 1-3]); differences remained significant after cross-validation.Conclusions: Favorable responses to HGNS therapy are associated with the pathophysiological traits causing OSA, particularly a higher arousal threshold. Along with established criteria, individuals with favorable traits could potentially be prioritized for precision HGNS therapy.This analysis was a secondary analysis of the STAR trial registered with clinicaltrials.gov (NCT01161420).

Physiological Traits and Adherence to Sleep Apnea Therapy in Individuals with Coronary Artery Disease.

Rationale: Untreated obstructive sleep apnea (OSA) is associated with adverse outcomes in patients with coronary artery disease (CAD). Continuous positive airway pressure (CPAP) is the most common treatment, but despite interventions addressing established adherence determinants, CPAP use remains poor. Objectives: To determine whether physiological traits that cause OSA are associated with long-term CPAP adherence in patients with CAD. Methods: Participants in the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) trial with objective CPAP adherence (h/night) over 2 years and analyzable raw polysomnography data were included (N = 249). The physiological traits-loop gain, arousal threshold (ArTH), pharyngeal collapsibility (Vpassive), and pharyngeal muscle compensation (Vcomp)-were measured by using polysomnography. Linear mixed models were used to assess the relationship between the traits and adherence. We also compared actual CPAP adherence between those with physiologically predicted "poor" adherence (lowest quartile of predicted adherence) and those with physiologically predicted "good" adherence (all others). Measurements and Main Results: The median (interquartile range) CPAP use declined from 3.2 (1.0-5.8) h/night to 3.0 (0.0-5.6) h/night over 24 months (P < 0.001). In analyses adjusted for demographics, anthropometrics, OSA characteristics, and clinical comorbidities, a lower ArTH was associated with worse CPAP adherence (0.7 h/SD of the ArTH; P = 0.021). Both high and low Vcomp were associated with lower adherence (P = 0.008). Those with predicted poor adherence exhibited markedly lower CPAP use than those with predicted good adherence for up to 2 years of follow-up (group differences of 2.0-3.2 h/night; P < 0.003 for all). Conclusions: A low ArTH, as well as a very low and high Vcomp, are associated with worse long-term CPAP adherence in patients with CAD and OSA. Physiological traits-alongside established determinants-may help predict and improve CPAP adherence. Clinical trial registered with www.clinicaltrials.gov (NCT00519597).

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.

Chemoreceptor mechanisms regulating CO2 -induced arousal from sleep.

Arousal from sleep in response to CO2 is a life-preserving reflex that enhances ventilatory drive and facilitates behavioural adaptations to restore eupnoeic breathing. Recurrent activation of the CO2 -arousal reflex is associated with sleep disruption in obstructive sleep apnoea. In this review we examine the role of chemoreceptors in the carotid bodies, the retrotrapezoid nucleus and serotonergic neurons in the dorsal raphe in the CO2 -arousal reflex. We also provide an overview of the supra-medullary structures that mediate CO2 -induced arousal. We propose a framework for the CO2 -arousal reflex in which the activity of the chemoreceptors converges in the parabrachial nucleus to trigger cortical arousal.

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.

Low arousal threshold is associated with unfavorable shift of PAP compliance over time in patients with OSA.

PURPOSE: To determine the predictive factors of initial and long-term adherence to positive airway pressure (PAP) therapy and factors leading to an unfavorable shift of PAP compliance. METHODS: This follow-up study was comprised of newly diagnosed patients with obstructive sleep apnea (OSA) amenable to PAP therapy from January 2017 to April 2019. Information on basic demographics, comorbidities, and sleep-related symptoms were collected. PAP adherence data were collected at the end of the first week and the third month. RESULTS: Of 166 patients enrolled, data from 142 (86%) were in the final analysis. Overall PAP usage was worse at 3 months declining from the first week. After adjusting for age and gender, multinomial logistic regression analysis showed that a small number of sleep-related symptoms (OR, 0.69; 95% CI, 0.52-0.91) and low arousal threshold (ArTH) (OR, 4.44; 95% CI, 1.52-12.98) were associated with higher odds of noncompliance. Low ArTH (OR, 2.87; 95% CI, 1.09-7.57) and lower body mass index (BMI) (OR, 0.88; 95% CI, 0.78-0.99) increased the risk of compliance-to-noncompliance shift. Sixty-two patients with polysomnography were analyzed separately. After adjustment for age and gender, poor sleep efficiency (OR, 0.80; 95% CI, 0.68-0.94) was associated with higher odds of consistent noncompliance. Low ArTH (OR, 15.36; 95% CI, 1.44-164.24) increased the risk of compliance-to-noncompliance shift in this subgroup. CONCLUSIONS: Lower BMI and low ArTH were associated with an unfavorable shift of PAP compliance over time in patients with OSA, which was different from the predictors of consistent PAP noncompliance of patients with OSA.

Impact of low arousal threshold on treatment of obstructive sleep apnea in patients with post-traumatic stress disorder.

PURPOSE: We sought to determine the prevalence of low arousal threshold (LAT) in veterans with post-traumatic stress disorder (PTSD) and whether or not LAT is associated with decreased use of continuous positive airway pressure (CPAP). METHODS: We conducted a retrospective study of all veterans with documented PTSD who had an apnea hypopnea index > 5/h over a 27-month period. Demographic, clinical characteristics, and CPAP usage were extracted from the medical records. A multivariate analysis was conducted to assess predictors of CPAP use at 3 months in patients with LAT after adjusting for severity of PTSD. RESULTS: LAT was identified in 55% of 119 patients with PTSD and newly diagnosed OSA. LAT was associated with younger age (odds ratio [OR] 0.91; 95% confidence interval [CI] 0.86-0.95), lower BMI (OR 0.82; 95% CI 0.73-0.91), presence of insomnia (OR 1.34; 95% CI 1.19-1.81), and use of antidepressant (OR 1.14; 95% CI 1.09-2.01). PTSD severity, REM rebound, and the presence of baseline comorbid insomnia were each associated with CPAP use at 3 months. Neither daytime sleepiness, body mass index (BMI), nor LAT endotype was correlated with CPAP utilization. Insomnia was the only factor associated with decreased CPAP use in patients with PTSD and LAT (P = 0.04). CONCLUSION: The LAT endotype is common among veterans with PTSD. An improved understanding of how insomnia in this population affects CPAP utilization would be instrumental in designing targeted therapy to improve sleep quality.

The relationship between anxiety, depression, daytime sleepiness in the REM-related mild OSAS and the NREM-related mild OSAS.

INTRODUCTION: Obstructive sleep apnea syndrome (OSAS) is a common form of sleep-related respiratory disease characterized by recurrent blockages in the upper airway. Rapid eye movement (REM)-related OSAS is a condition in which apneas and hypopneas are more common during REM sleep. We investigated whether there was any difference between REM-related mild OSAS group and NREM-related mild OSAS group in terms of anxiety, depression, and daytime sleepiness. METHODS: A total of 166 patients with mild OSAS (72 patients with REM-related and 94 NREM-related OSAS) participated in the study. Hospital Anxiety-Depression Scale (HADS) and Epworth Sleepiness Scale (ESS) questionnaires were completed by both groups. RESULTS: Anxiety and depression scores were significantly higher in patients with REM-related OSAS in comparison to the NREM-related OSAS group (p = 0.01, p = 0.02 respectively). There was no statistically significant difference between the two groups in terms of ESS scores (p = 0.60). CONCLUSION: The results of our study suggest that patients with REM-related OSAS have higher rates of depression and anxiety compared to non-REM-related OSAS patients and this may adversely affect quality of life. It may be possible to prevent psychiatric complications, such as depression and anxiety, by administering treatments that reduce REM sleep duration and intensity in patients with REM-related OSAS.

Exposure to mild intermittent hypoxia increases loop gain and the arousal threshold in participants with obstructive sleep apnoea.

KEY POINTS: Repeated daily mild intermittent hypoxia has been endorsed as a therapy to promote the recovery of respiratory and limb motor dysfunction. One possible side-effect of this therapy is an increase in apnoeic event number and duration, which is particularly relevant to participants with motor disorders coupled with an increased incidence of sleep apnoea. In this study, we report that increases in apnoeic event number and duration, following exposure to daily intermittent hypoxia, are the result of an increase in respiratory loop gain and the arousal threshold, in participants with obstructive sleep apnoea. Daily exposure to mild intermittent hypoxia also led to an increase in the ventilatory response to arousal. Accordingly, individuals with motor disorders receiving mild intermittent hypoxia as a therapy should be screened for the presence of sleep apnoea, and if present, administration of intermittent hypoxia during hours of wakefulness should be combined with continuous positive airway pressure treatment during sleep. ABSTRACT: We determined if exposure to mild intermittent hypoxia (MIH) causes an increase in loop gain (LG) and the arousal threshold (AT) during non-rapid eye movement (NREM) sleep. Male participants with obstructive sleep apnoea (apnoea-hypopnoea index > 5 events/h), matched for age, body mass index and race were divided into two groups (n = 13 in each group). Following a baseline sleep study, one group was exposed to twelve 4-min episodes of hypoxia each day for 10 days and the other group to a sham protocol (SP). On Days 1 and 10, a sleep study was completed following exposure to MIH or the SP. For each sleep study, LG and the AT were measured during NREM sleep, using a model-based approach, and expressed as a fraction of baseline measures. LG increased after exposure to MIH (Day 1: 1.11 ± 0.03, P = 0.002, Day 10: 1.17 ± 0.05, P = 0.001), but not after the SP (Day 1: 1.03 ± 0.04, P = 1.0, Day 10: 1.0 ± 0.02, P = 1.0). AT also increased after exposure to MIH (Day 1: 1.13 ± 0.05, P = 0.01, Day 10: 1.19 ± 0.08, P = 0.05) but not after the SP (Day 1: 1.04 ± 0.05, P = 0.6, Day 10: 0.96 ± 0.04, P = 1.0). Our results might account for increases in apnoea frequency and duration previously observed during NREM sleep following exposure to MIH. Our results also have implications for the use of MIH as a therapeutic modality.

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 ±â€…14 versus 23 ±â€…13 events per hr, p = 0.71). Key sleep parameters were also not different compared between conditions, including sleep efficiency (79 ±â€…13 versus 81 ±â€…11%, p = 0.31) and the arousal index (26 ±â€…11 versus 27 ±â€…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 ±â€…15 versus 48 ±â€…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.

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.

The importance of obstructive sleep apnoea and hypopnea pathophysiology for customized therapy.

The objective of this study is to highlight the importance of anatomical and not-anatomical factors' identification for customized therapy in OSAHS patients. The data sources are: MEDLINE, The Cochrane Library and EMBASE. A systematic review was performed to identify studies that analyze the role of multiple interacting factors involved in the OSAHS pathophysiology. 85 out of 1242 abstracts were selected for full-text review. A variable combinations pathophysiological factors contribute to realize differentiated OSAHS phenotypes: a small pharyngeal airway with a low resistance to collapse (increased critical closing pressure), an inadequate responses of pharyngeal dilator muscles (wakefulness drive to breathe), an unstable ventilator responsiveness to hypercapnia (high loop gain), and an increased propensity to wake related to upper airway obstruction (low arousal threshold). Identifying if the anatomical or not-anatomical factors are predominant in each OSAHS patient represents the current challenge in clinical practice, moreover for the treatment decision-making. In the future, if a reliable and accurate pathophysiological pattern for each OSAHS patient can be identified, a customized therapy will be feasible, with a significant improvement of surgical success in sleep surgery and a better understanding of surgical failure.

Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea.

RATIONALE: A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements. OBJECTIVES: To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH. METHODS: Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system. MEASUREMENTS AND MAIN RESULTS: Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (Fhypopneas) were independent predictors of the ArTH (r(2) = 0.59; P < 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, <30 events per hour) + (nadir oxygen saturation as measured by pulse oximetry >82.5%) + (Fhypopneas >58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leave-one-out cross-validation analysis. CONCLUSIONS: Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH.

The effects of atomoxetine and trazodone combination on obstructive sleep apnea and sleep microstructure: A double-blind randomized clinical trial study.

STUDY OBJECTIVES: we aimed to compare the effects of atomoxetine and trazodone (A-T) in combination with placebo in patients with obstructive sleep apnea (OSA). METHODS: This randomized, placebo-controlled, double-blind, crossover trial study was conducted in adults with OSA referred to a Sleep Clinic. Participants with eligibility criteria were recruited. Patients were studied on two separate nights with one-week intervals, once treated with trazodone (50 mg) and atomoxetine (80 mg) combination and then with a placebo and the following polysomnography tests. RESULTS: A total of 18 patients with OSA completed the study protocol, 9(50%) were male, the mean age was 47.5 years (SD = 9.8) and the mean Body mass index of participants was 28.4 kg/m2 (SD = 3.4). Compared with the placebo, the A-T combination resulted in significant differences in AHI (28.3(A-T) vs. 42.7 (placebo), p = 0.025), duration of the REM stage (1.3%TST (A-T) vs. 13.1%TST (placebo), p = 0.001), and the number of REM cycles (0.8 (A-T) vs. 4.7 (placebo), p = 0.001), number of apneas (38.3 (A-T) vs. 79.3 (placebo), p = 0.011), number of obstructive apneas (37.2 (A-T) vs. 75.2 (placebo), p = 0.011), oxygen desaturation index (29.5 (A-T) vs. 42.3 (placebo), p = 0.022) and number of respiratory arousals (43.2 (A-T) vs. 68.5 (placebo), p = 0.048). This decrement effect did not change among those with a low-arousal phenotype of OSA. CONCLUSIONS: The A-T combination significantly improved respiratory events' indices compared with placebo in patients with OSA. This combination is recommended to be assessed in a large trial. It could be an alternative for those who do not adhere to the standard available treatments for OSA.