Physiological Determinants of Snore Loudness.

Rationale: The physiological factors modulating the severity of snoring have not been adequately described. Airway collapse or obstruction is generally the leading determinant of snore sound generation; however, we suspect that ventilatory drive is of equal importance. Objective: To determine the relationship between airway obstruction and ventilatory drive on snore loudness. Methods: In 40 patients with suspected or diagnosed obstructive sleep apnea (1-98 events/hr), airflow was recorded via a pneumotachometer attached to an oronasal mask, ventilatory drive was recorded using calibrated intraesophageal diaphragm electromyography, and snore loudness was recorded using a calibrated microphone attached over the trachea. "Obstruction" was taken as the ratio of ventilation to ventilatory drive and termed flow:drive, i.e., actual ventilation as a percentage of intended ventilation. Lower values reflect increased flow resistance. Using 165,063 breaths, mixed model analysis (quadratic regression) quantified snore loudness as a function of obstruction, ventilatory drive, and the presence of extreme obstruction (i.e., apneic occlusion). Results: In the presence of obstruction (flow:drive = 50%, i.e., doubled resistance), snore loudness increased markedly with increased drive (+3.4 [95% confidence interval, 3.3-3.5] dB per standard deviation [SD] change in ventilatory drive). However, the effect of drive was profoundly attenuated without obstruction (at flow:drive = 100%: +0.23 [0.08-0.39] dB per SD change in drive). Similarly, snore loudness increased with increasing obstruction exclusively in the presence of increased drive (at drive = 200% of eupnea: +2.1 [2.0-2.2] dB per SD change in obstruction; at eupneic drive: +0.14 [-0.08 to 0.28] dB per SD change). Further, snore loudness decreased substantially with extreme obstruction, defined as flow:drive <20% (-9.9 [-3.3 to -6.6] dB vs. unobstructed eupneic breathing). Conclusions: This study highlights that ventilatory drive, and not simply pharyngeal obstruction, modulates snore loudness. This new framework for characterizing the severity of snoring helps better understand the physiology of snoring and is important for the development of technologies that use snore sounds to characterize sleep-disordered breathing.

Drive versus Pressure Contributions to Genioglossus Activity in Obstructive Sleep Apnea.

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, ßdrive:ßpressure; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half (n = 22 of 42) exhibited drive-dominant responses (i.e., ßdrive:ßpressure > 2:1), and one-quarter (n = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., ßdrive:ßpressure < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] %baseline/standard deviation of ßdrive:ßpressure; P = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

Sleep Apnea Physiological Burdens and Cardiovascular Morbidity and Mortality.

Rationale: Obstructive sleep apnea is characterized by frequent reductions in ventilation, leading to oxygen desaturations and/or arousals. Objectives: In this study, association of hypoxic burden with incident cardiovascular disease (CVD) was examined and compared with that of "ventilatory burden" and "arousal burden." Finally, we assessed the extent to which the ventilatory burden, visceral obesity, and lung function explain variations in hypoxic burden. Methods: Hypoxic, ventilatory, and arousal burdens were measured from baseline polysomnograms in the Multi-Ethnic Study of Atherosclerosis (MESA) and the Osteoporotic Fractures in Men (MrOS) studies. Ventilatory burden was defined as event-specific area under ventilation signal (mean normalized, area under the mean), and arousal burden was defined as the normalized cumulative duration of all arousals. The adjusted hazard ratios for incident CVD and mortality were calculated. Exploratory analyses quantified contributions to hypoxic burden of ventilatory burden, baseline oxygen saturation as measured by pulse oximetry, visceral obesity, and spirometry parameters. Measurements and Main Results: Hypoxic and ventilatory burdens were significantly associated with incident CVD (adjusted hazard ratio [95% confidence interval] per 1 SD increase in hypoxic burden: MESA, 1.45 [1.14, 1.84]; MrOS, 1.13 [1.02, 1.26]; ventilatory burden: MESA, 1.38 [1.11, 1.72]; MrOS, 1.12 [1.01, 1.25]), whereas arousal burden was not. Similar associations with mortality were also observed. Finally, 78% of variation in hypoxic burden was explained by ventilatory burden, whereas other factors explained only <2% of variation. Conclusions: Hypoxic and ventilatory burden predicted CVD morbidity and mortality in two population-based studies. Hypoxic burden is minimally affected by measures of adiposity and captures the risk attributable to ventilatory burden of obstructive sleep apnea rather than a tendency to desaturate.

Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis.

STUDY OBJECTIVES: There is uncertainty on best approaches for defining apnea-hypopnea events. To clarify the contributions of desaturation vs arousal to defining hypopneas, we examined the associations of events with desaturation (≥ 3%) but not arousal (apnea-hypopnea index [AHI]≥3%Only) vs events with arousals but no desaturation (AHIArOnly) with obstructive sleep apnea-related comorbidities and incident cardiovascular disease across multiple cohorts. METHODS: In the Sleep Heart Health Study (n = 5,473), the Multi-Ethnic Study of Atherosclerosis (n = 1,904), and the Osteoporotic Fractures in Men Study (n = 2,685), we examined the independent associations of AHI≥3%Only and AHIArOnly with hypertension, diabetes, and daytime sleepiness, and incident cardiovascular disease. RESULTS: After adjusting for covariates and AHI based on events with electroencephalogram arousal (regardless of desaturation), AHI≥3%Only was associated with hypertension in Sleep Heart Health Study (odds ratio: 1.12; 95% confidence interval: 1.04,1.21), per 1 standard deviation increase). Similar associations were observed in the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study, as well as for associations with diabetes (odds ratio: 1.30; 1.09,1.54, and 1.25; 1.07,1.47, respectively), sleepiness (odds ratio: 1.19; 1.00,1.41; and 1.17; 1.01-1.35), and incident cardiovascular disease (hazard ratio: 1.37; 1.05,1.77 and 1.14; 1.00,1.29). In contrast, after adjusting for events with desaturation (regardless of arousal), AHIArOnly was unassociated with these outcomes. In Sleep Heart Health Study, greater baseline obstructive sleep apnea severity was associated with a reduction in arousal frequency over 5 years (P < .0001). CONCLUSIONS: In middle-aged and older individuals, addition of events with arousals does not improve the strength of associations with comorbidities or incident cardiovascular disease. Research is needed to understand generalizability to younger individuals and the mechanistic role of arousals in obstructive sleep apnea. CITATION: Azarbarzin A, Sands SA, Han S, et al. Relevance of cortical arousals for risk stratification in sleep apnea: a 3 cohort analysis. J Clin Sleep Med. 2023;19(8):1475-1484.

Hypoxic Burden in Obstructive Sleep Apnea: Present and Future

Conventional measures of obstructive sleep apnea (OSA) severity, such as the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) are commonly used to quantify OSA severity and guide therapeutical decision-making processes. However, it is widely recognized that both AHI and ODI have important limitations and novel physiologically-informed metrics are needed to better capture the severity of OSA and characterize its physiological consequences, particularly the severity of recurrent nocturnal hypoxemia, ensuing the respiratory events. According to recent studies, the sleep apnea-specific “hypoxic burden (HB)”, defined as the sum of individual areas under the oxygen desaturation curve, has shown some promise in identifying high risk individuals with OSA. In addition to the frequency of respiratory events, HB capture the depth and duration of OSA-related hypoxemia that may prove to be important disease characterizing features, not captured by the conventional “frequency-based” metrics, such as AHI and ODI. In this “perspective” paper the methods to quantify the HB, its characteristics, associations with health outcomes, and its limitations will be discussed. (AU)

Pathophysiology Underlying Demographic and Obesity Determinants of Sleep Apnea Severity.

Rationale: Sleep apnea is the manifestation of key endotypic traits, including greater pharyngeal collapsibility, reduced dilator muscle compensation, and elevated chemoreflex loop gain. Objectives: We investigated how endotypic traits vary with obesity, age, sex, and race/ethnicity to influence sleep apnea disease severity (apnea-hypopnea index [AHI]). Methods: Endotypic traits were estimated from polysomnography in a diverse community-based cohort study (Multi-Ethnic Study of Atherosclerosis, N = 1,971; age range, 54-93 yr). Regression models assessed associations between each exposure (continuous variables per 2 standard deviations [SDs]) and endotypic traits (per SD) or AHI (events/h), independent of other exposures. Generalizability was assessed in two independent cohorts. Results: Greater AHI was associated with obesity (+19 events/h per 11 kg/m2 [2 SD]), male sex (+13 events/h vs. female), older age (+7 events/h per 20 yr), and Chinese ancestry (+5 events/h vs. White, obesity adjusted). Obesity-related increase in AHI was best explained by elevated collapsibility (+0.40 SD) and greater loop gain (+0.38 SD; percentage mediated, 26% [95% confidence interval (CI), 20-32%]). Male-related increase in AHI was explained by elevated collapsibility (+0.86 SD) and reduced compensation (-0.40 SD; percentage mediated, 57% [95% CI, 50-66%]). Age-related AHI increase was explained by elevated collapsibility (+0.37 SD) and greater loop gain (+0.15 SD; percentage mediated, 48% [95% CI, 34-63%]). Increased AHI with Chinese ancestry was explained by collapsibility (+0.57 SD; percentage mediated, 87% [95% CI, 57-100]). Black race was associated with reduced collapsibility (-0.30 SD) and elevated loop gain (+0.29 SD). Similar patterns were observed in the other cohorts. Conclusions: Different subgroups exhibit different underlying pathophysiological pathways to sleep apnea, highlighting the variability in mechanisms that could be targeted for intervention.

Hypoxic Burden in Obstructive Sleep Apnea: Present and Future.

Conventional measures of obstructive sleep apnea (OSA) severity, such as the apnea-hypopnea index (AHI) and oxygen desaturation index (ODI) are commonly used to quantify OSA severity and guide therapeutical decision-making processes. However, it is widely recognized that both AHI and ODI have important limitations and novel physiologically-informed metrics are needed to better capture the severity of OSA and characterize its physiological consequences, particularly the severity of recurrent nocturnal hypoxemia, ensuing the respiratory events. According to recent studies, the sleep apnea-specific "hypoxic burden (HB)", defined as the sum of individual areas under the oxygen desaturation curve, has shown some promise in identifying high risk individuals with OSA. In addition to the frequency of respiratory events, HB capture the depth and duration of OSA-related hypoxemia that may prove to be important disease characterizing features, not captured by the conventional "frequency-based" metrics, such as AHI and ODI. In this "perspective" paper the methods to quantify the HB, its characteristics, associations with health outcomes, and its limitations will be discussed.

WITHDRAWN: Hypoxic Burden in Obstructive Sleep Apnea: Present and Future.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.arbres.2022.08.005. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/policies/article-withdrawal

Patients with Epiglottic Collapse Are Less Adherent to Autotitrating Positive Airway Pressure Therapy for Obstructive Sleep Apnea.

Rationale: The anatomic orientation of the epiglottis is such that it points in the opposite direction to inspiratory flow, thereby potentially making positive airway pressure (PAP) treatment challenging in patients with epiglottic collapse. However, no previous studies have analyzed PAP adherence in these patients. Objectives: This study aimed to analyze adherence to autotitrating PAP (APAP) treatment in patients with epiglottic collapse. Methods: We performed an age- and sex-matched case-control study. On the basis of their overnight level-I polysomnogram, patients were prescribed APAP in a tertiary hospital between July 2018 and March 2019. The site of airway collapse was diagnosed with drug-induced sleep endoscopy. Demographic factors, sleep questionnaire, polysomnography, and APAP usage statistics were analyzed. Results: Eighteen patients with epiglottic collapse (epi-group) and 36 without epiglottic collapse (control group) were analyzed. We found that 22.8% of patients in the epi-group terminated APAP within 2 weeks, whereas only 2.8% of patients in the control group terminated APAP within 2 weeks (P = 0.048). The percentage of days with usage over 4 hours was significantly lower in the epi-group (64.6% vs. 75.6%; P = 0.008). In addition, the adherence failure rate was 66.7% in the epi-group and 33.3% in the control group (P = 0.039). Patients with epiglottic collapse were also found to have lower body mass index, which is an unfavorable predictor of APAP adherence. Conclusions: This study suggests that patients with epiglottic collapse have a higher APAP adherence failure rate than patients without epiglottic collapse. Thus, patients with epiglottic collapse should be followed closely during treatment, and alternative therapies should probably be considered for these patients.

Within-night repeatability and long-term consistency of sleep apnea endotypes: the Multi-Ethnic Study of Atherosclerosis and Osteoporotic Fractures in Men Study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is characterized by multiple "endotypic traits," including pharyngeal collapsibility, muscle compensation, loop gain, and arousal threshold. Here, we examined (1) within-night repeatability, (2) long-term consistency, and (3) influences of body position and sleep state, of endotypic traits estimated from in-home polysomnography in mild-to-severe OSA (apnea-hypopnea index, AHI > 5 events/h). METHODS: Within-night repeatability was assessed using Multi-Ethnic Study of Atherosclerosis (MESA): Traits derived separately from "odd" and "even" 30-min periods were correlated and regression (error vs. N windows available) provided a recommended amount of data for acceptable repeatability (Rthreshold = 0.7). Long-term consistency was assessed using the Osteoporotic Fractures in Men Study (MrOS) at two time points 6.5 ± 0.7 years apart, before and after accounting for across-year body position and sleep state differences. Within-night dependence of traits on position and state (MESA plus MrOS data) was estimated using bootstrapping. RESULTS: Within-night repeatability for traits ranged from R = 0.62-0.79 and improved to R = 0.69-0.83 when recommended amounts of data were available (20-35 7-min windows, available in 94%-98% of participants); repeatability was similar for collapsibility, loop gain, and arousal threshold (R = 0.79-0.83), but lower for compensation (R = 0.69). Long-term consistency was modest (R = 0.30-0.61) and improved (R = 0.36-0.63) after accounting for position and state differences. Position/state analysis revealed reduced loop gain in REM and reduced collapsibility in N3. CONCLUSIONS: Endotypic traits can be obtained with acceptable repeatability. Long-term consistency was modest but improved after accounting for position and state changes. These data support the use of endotypic assessments in large-scale epidemiological studies. CLINICAL TRIAL INFORMATION: The data used in the manuscript are from observational cohort studies and are not a part of the clinical trial.

Head rotation improves airway obstruction, especially in patients with less severe obstructive sleep apnea without oropharyngeal collapse.

PURPOSE: Head rotation is thought to have an effect on obstructive sleep apnea (OSA) severity. However, keeping the head rotated fully during sleep is difficult to maintain, and the effect of head rotation is not the same in all OSA patients. Thus, this study aimed to identify whether less head rotation has an effect on airway patency and determine the responder characteristics to the head rotation maneuver (HRM). METHODS: We recruited 221 patients who underwent overnight polysomnography and drug-induced sleep endoscopy (DISE) in a tertiary hospital from June 2019 to July 2020. Airway patency and the site of airway collapse were determined in the supine position with the head at 0, 30, and 60 degrees of rotation (HRM0°, HRM30°, and HRM60°, respectively) during DISE. The site of collapse was determined using the VOTE classification system: the velum (palate), oropharyngeal lateral walls, tongue base, and epiglottis. Each structure was labeled as 0, 1, or 2 (patent, partially obstructed, and completely obstructed, respectively). Airway response to the HRM30° and 60° and the clinical characteristics associated with airway opening were analyzed. RESULTS: The study population had a median age of 52 (25-61) years, a body mass index of 26.7(24.6-29.4) kg/m2, and the apnea-hypopnea index (AHI) of 28.2(13.7-71.9) events/h. HRM influenced airway patency positively not only with HRM60° (p<0.001) but also following limited rotation (HRM30°, p<0.001). Patients with tongue base (40.0% with HRM 60°) and epiglottic (52.6% with HRM 60°) collapse responded particularly well to HRM. Multivariate analysis revealed that lower AHI (p<0.001) and an absence of oropharyngeal lateral walls collapse (p = 0.011) were significant predictors of responders to HRM. CONCLUSION: Head rotation improved airway obstruction in OSA patients, even with a small degree of rotation, and should be further explored as a potential form of therapy in appropriately selected patients.

Cardiovascular Benefit of Continuous Positive Airway Pressure in Adults with Coronary Artery Disease and Obstructive Sleep Apnea without Excessive Sleepiness.

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Objectives: Here, in this post hoc analysis of a prospective clinical trial, we test the hypothesis that a greater pretreatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes. Methods: ΔHR was measured from baseline polysomnography of the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) randomized controlled trial (patients with coronary artery disease [CAD] and OSA [apnea-hypopnea index ⩾ 15 events/h] with Epworth Sleepiness Scale score < 10; nCPAP:ncontrol = 113:113; male, 85%; age, 66 ± 8 [mean ± SD] yr). The primary outcome was a composite of repeat revascularization, myocardial infarction, stroke, and cardiovascular mortality. Multivariable Cox regression assessed whether the effect of CPAP was moderated by ΔHR (treatment-by-ΔHR interaction). Measurements and Main Results: The CPAP-related reduction in risk increased progressively with increasing pretreatment ΔHR (interaction hazard ratio [95% confidence interval], 0.49 [0.27 to 0.90] per SD increase in ΔHR; P < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) (P < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P = 0.6). Conclusions: The protective effect of CPAP in patients with CAD and OSA without excessive sleepiness was modified by the ΔHR. Specifically, patients with higher ΔHR exhibit greater cardiovascular benefit from CPAP therapy.

Mouth Closing to Improve the Efficacy of Mandibular Advancement Devices in Sleep Apnea.

Rationale: Mouth breathing increases upper airway collapsibility, leading to decreased efficacy of obstructive sleep apnea (OSA) treatments. We hypothesized that the use of mandibular advancement devices (MAD) increases mouth breathing, and thus, using an adhesive mouthpiece (AMT) to prevent mouth breathing in combination with MAD can improve the treatment efficacy. Objectives: To evaluate the efficacy of MAD + AMT in comparison with MAD alone. Methods: A prospective crossover pilot study was designed to test this hypothesis. Briefly, adult participants with an apnea-hypopnea index (AHI) between 10 and 50 events/h at the screening visit were randomized to no treatment (baseline), MAD treatment, AMT treatment, and MAD + AMT treatment. As a primary analysis, absolute AHI was compared between MAD and MAD + AMT arms. Secondary analyses included quantifying the percent change in AHI, percentage of complete (AHI < 5 events/h) and incomplete (5-10 events/h) responders, and the efficacy of AMT alone in comparison with other treatment arms. Results: A total of 21 participants were included (baseline AHI = 24.3 ± 9.9 events/h). The median AHI (interquartile range) in the MAD and MAD + AMT arms were 10.5 (5.4-19.6) events/h and 5.6 (2.2-11.7) events/h (P = 0.02), respectively. A total of 76% of individuals achieved an AHI of <10 events/h in the MAD + AMT arm versus 43% in the MAD arm (P < 0.01). Finally, the observed effect was similar in moderate to severe OSA (AHI ⩾ 15 events/h) in terms of absolute reduction and treatment responders, and AMT alone did not significantly reduce the AHI compared with baseline. Conclusions: A combination of an adhesive mouthpiece and MAD is a more effective therapy than MAD alone. These findings may help improve clinical decision making in sleep apnea.

Clinical polysomnographic methods for estimating pharyngeal collapsibility in obstructive sleep apnea.

STUDY OBJECTIVES: Obstructive sleep apnea has major health consequences but is challenging to treat. For many therapies, efficacy is determined by the severity of underlying pharyngeal collapsibility, yet there is no accepted clinical means to measure it. Here, we provide insight into which polysomnographic surrogate measures of collapsibility are valid, applicable across the population, and predictive of therapeutic outcomes. METHODS: Seven promising polysomnography-derived surrogate collapsibility candidates were evaluated: Vpassive (flow at eupneic ventilatory drive), Vmin (ventilation at nadir drive), event depth (depth of the average respiratory event), oxygen desaturation slope and mean oxygen desaturation (events-related averages), Fhypopneas (fraction of events scored as hypopneas), and apnea index. Evaluation included (1) validation by comparison to physiological gold-standard collapsibility values (critical closing pressure, Pcrit), (2) capacity to detect increased collapsibility with older age, male sex, and obesity in a large community-based cohort (Multi-Ethnic Study of Atherosclerosis, MESA), and (3) prediction of treatment efficacy (oral appliances and pharmacological pharyngeal muscle stimulation using atomoxetine-plus-oxybutynin). RESULTS: Pcrit was significantly correlated with Vmin (r = -0.54), event depth (r = 0.49), Vpassive (r = -0.38), Fhypopneas (r = -0.46), and apnea index (r = -0.46; all p < .01) but not others. All measures detected greater collapsibility with male sex, age, and obesity, except Fhypopneas and apnea index which were not associated with obesity. Fhypopneas and apnea index were associated with oral appliance and atomoxetine-plus-oxybutynin efficacy (both p < .05). CONCLUSIONS: Among several candidates, event depth, Fhypopneas, and apnea index were identified as preferred pharyngeal collapsibility surrogates for use in the clinical arena.

Neural ventilatory drive decline as a predominant mechanism of obstructive sleep apnoea events.

BACKGROUND: In the classic model of obstructive sleep apnoea (OSA), respiratory events occur with sleep-related dilator muscle hypotonia, precipitating increased neural ventilatory 'drive'. By contrast, a drive-dependent model has been proposed, whereby falling drive promotes dilator muscle hypotonia to precipitate respiratory events. Here we determine the extent to which the classic versus drive-dependent models of OSA are best supported by direct physiological measurements. METHODS: In 50 OSA patients (5-91 events/hour), we recorded ventilation ('flow', oronasal mask and pneumotach) and ventilatory drive (calibrated intraoesophageal diaphragm electromyography, EMG) overnight. Flow and drive during events were ensemble averaged; patients were classified as drive dependent if flow fell/rose simultaneously with drive. Overnight effects of lower drive on flow, genioglossus muscle activity (EMGgg) and event risk were quantified (mixed models). RESULTS: On average, ventilatory drive fell (rather than rose) during events (-20 (-42 to 3)%baseline, median (IQR)) and was strongly correlated with flow (R=0.78 (0.24 to 0.94)). Most patients (30/50, 60%) were classified as exhibiting drive-dependent event pathophysiology. Lower drive during sleep was associated with lower flow (-17 (-20 to -14)%/drive) and EMGgg (-3.5 (-3.8 to -3.3)%max/drive) and greater event risk (OR: 2.2 (1.8 to 2.5) per drive reduction of 100%eupnoea); associations were concentrated in patients with drive-dependent OSA (ie, flow: -37 (-40 to -34)%/drive, OR: 6.8 (5.3 to 8.7)). Oesophageal pressure-without tidal volume correction-falsely suggested rising drive during events (classic model). CONCLUSIONS: In contrast to the prevailing view, patients with OSA predominantly exhibit drive-dependent event pathophysiology, whereby flow is lowest at nadir drive, and lower drive raises event risk. Preventing ventilatory drive decline is therefore considered a target for OSA intervention.

The Effectiveness of Digital Insomnia Treatment with Adjunctive Wearable Technology: A Pilot Randomized Controlled Trial.

OBJECTIVE: This pilot trial aimed to provide evidence for whether the integration of a wearable device with digital behavioral therapy for insomnia (dBTi) improves treatment outcomes and engagement. PARTICIPANTS AND METHODS: One hundred and twenty-eight participants with insomnia symptoms were randomized to a 3-week dBTi program (SleepFix®) with a wearable device enabling sleep data synchronization (dBTi+wearable group; n = 62) or dBTi alone (n = 66). Participants completed the Insomnia Severity Index (ISI) and modified Pittsburgh Sleep Quality Index (PSQI) parameters: wake-after-sleep-onset (WASO), sleep-onset-latency (SOL), and total sleep time (TST) at baseline and weeks 1, 2, 3, and primary endpoint of week 6 and follow-up at 12 weeks. Engagement was measured by the number of daily sleep diaries logged in the app. RESULTS: There was no difference in ISI change scores between the groups from pre- to post-treatment (Cohen's d= 0.7, p= .061). The dBTi+wearable group showed greater improvements in WASO (d= 0.8, p = .005) and TST (d= 0.3, p= .049) compared to the dBTi group. Significantly greater engagement (sleep diary entries) was observed in the dBTi+wearable group (mean = 22.4, SD = 10.0) compared to the dBTi group (mean = 14.1, SD = 14.2) (p = .010). CONCLUSIONS: This pilot trial found that integration of wearable device with a digital insomnia therapy enhanced user engagement and led to improvements in sleep parameters compared to dBTi alone. These findings suggest that adjunctive wearable technologies may improve digital insomnia therapy effectiveness.

Ventilatory Drive Withdrawal Rather Than Reduced Genioglossus Compensation as a Mechanism of Obstructive Sleep Apnea in REM Sleep.

Rationale: REM sleep is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity than non-REM (nREM) sleep for reasons that have not been fully elucidated. Objectives: Here, we use direct physiological measurements to determine whether the pharyngeal compromise in REM sleep OSA is most consistent with 1) withdrawal of neural ventilatory drive or 2) deficits in pharyngeal pathophysiology per se (i.e., increased collapsibility and decreased muscle responsiveness). Methods: Sixty-three participants with OSA completed sleep studies with gold standard measurements of ventilatory "drive" (calibrated intraesophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG activity. Drive withdrawal was assessed by examining these measurements at nadir drive (first decile of drive within a stage). Pharyngeal physiology was assessed by examining collapsibility (lowered ventilation at eupneic drive) and responsiveness (ventilation-drive slope). Mixed-model analysis compared REM sleep with nREM sleep; sensitivity analysis examined phasic REM sleep. Measurements and Main Results: REM sleep (⩾10 min) was obtained in 25 patients. Compared with drive in nREM sleep, drive in REM sleep dipped to markedly lower nadir values (first decile, estimate [95% confidence interval], -21.8% [-31.2% to -12.4%] of eupnea; P < 0.0001), with an accompanying reduction in ventilation (-25.8% [-31.8% to -19.8%] of eupnea; P < 0.0001). However, there was no effect of REM sleep on collapsibility (ventilation at eupneic drive), baseline genioglossus EMG activity, or responsiveness. REM sleep was associated with increased OSA severity (+10.1 [1.8 to 19.8] events/h), but this association was not present after adjusting for nadir drive (+4.3 [-4.2 to 14.6] events/h). Drive withdrawal was exacerbated in phasic REM sleep. Conclusions: In patients with OSA, the pharyngeal compromise characteristic of REM sleep appears to be predominantly explained by ventilatory drive withdrawal rather than by preferential decrements in muscle activity or responsiveness. Preventing drive withdrawal may be the leading target for REM sleep OSA.

Metrics of sleep apnea severity: beyond the apnea-hypopnea index.

Obstructive sleep apnea (OSA) is thought to affect almost 1 billion people worldwide. OSA has well established cardiovascular and neurocognitive sequelae, although the optimal metric to assess its severity and/or potential response to therapy remains unclear. The apnea-hypopnea index (AHI) is well established; thus, we review its history and predictive value in various different clinical contexts. Although the AHI is often criticized for its limitations, it remains the best studied metric of OSA severity, albeit imperfect. We further review the potential value of alternative metrics including hypoxic burden, arousal intensity, odds ratio product, and cardiopulmonary coupling. We conclude with possible future directions to capture clinically meaningful OSA endophenotypes including the use of genetics, blood biomarkers, machine/deep learning and wearable technologies. Further research in OSA should be directed towards providing diagnostic and prognostic information to make the OSA diagnosis more accessible and to improving prognostic information regarding OSA consequences, in order to guide patient care and to help in the design of future clinical trials.

Estimating sleep stages using cardiorespiratory signals: validation of a novel algorithm across a wide range of sleep-disordered breathing severity.

STUDY OBJECTIVES: We have developed the CardioRespiratory Sleep Staging (CReSS) algorithm for estimating sleep stages using heart rate variability and respiration, allowing for estimation of sleep staging during home sleep apnea tests. Our objective was to undertake an epoch-by-epoch validation of algorithm performance against the gold standard of manual polysomnography sleep staging. METHODS: Using 296 polysomnographs, we created a limited montage of airflow and heart rate and deployed CReSS to identify each 30-second epoch as wake, light sleep (N1 + N2), deep sleep (N3), or rapid eye movement (REM) sleep. We calculated Cohen's kappa and the percentage of accurately identified epochs. We repeated our analyses after stratification by sleep-disordered breathing (SDB) severity, and after adding thoracic respiratory effort as a backup signal for periods of invalid airflow. RESULTS: CReSS discriminated wake/light sleep/deep sleep/REM sleep with 78% accuracy; the kappa value was 0.643 (95% confidence interval, 0.641-0.645). Discrimination of wake/sleep demonstrated a kappa value of 0.711 and accuracy of 89%, non-REM sleep/REM sleep demonstrated a kappa of 0.790 and accuracy of 94%, and light sleep/deep sleep demonstrated a kappa of 0.469 and accuracy of 87%. Kappa values did not vary by more than 0.07 across subgroups of no SDB, mild SDB, moderate SDB, and severe SDB. Accuracy increased to 80%, with a kappa value of 0.680 (95% confidence interval, 0.678-0.682), when CReSS additionally utilized the thoracic respiratory effort signal. CONCLUSIONS: We observed substantial agreement between CReSS and the gold-standard comparator of manual sleep staging of polysomnographic signals, which was consistent across the full range of SDB severity. Future research should focus on the extent to which CReSS reduces the discrepancy between the apnea-hypopnea index and the respiratory event index, and the ability of CReSS to identify REM sleep-related obstructive sleep apnea.

Impact of cold and flu medication on obstructive sleep apnoea and its underlying traits: A pilot randomized controlled trial.

BACKGROUND AND OBJECTIVE: Animal studies indicate that alpha-1 adrenergic receptor agonists and antimuscarinic agents improve genioglossus muscle activity during sleep and may be candidates for the pharmacological treatment of OSA. On the other hand, noradrenergic stimulants may be wake-promoting or cause insomnia symptoms if taken before bedtime, and the addition of a medication with sedative properties, such as an antihistaminic, may reduce these side effects. In this study, we aimed to determine the effects of the combination of an alpha-1 adrenergic agonist (pseudoephedrine) and an antihistaminic-antimuscarinic (diphenhydramine) on OSA severity (AHI), genioglossus responsiveness and other endotypic traits (Vpassive , muscle compensation, LG and arousal threshold). METHODS: Ten OSA patients performed a randomized, placebo-controlled, double-blind, crossover trial comparing one night of pseudoephedrine 120 mg plus diphenhydramine 50 mg (DAW1033D) to placebo administered prior to sleep. The AHI, genioglossus muscle responsiveness to negative oesophageal pressure and the endotypic traits were measured via PSG. RESULTS: The participants' median (interquartile range) age was 50 (46-53) years and body mass index (BMI) was 34.3 (30.6-39.2) kg/m2 . The drug combination had no effect on AHI (21.6 (9.1-49.8) on placebo vs 37.9 (5.1-55.4) events/h on DAW1033D, P > 0.5) or genioglossus responsiveness (6.0 (2.6-9.2) on placebo vs 4.0 (3.5-7.3) %/cm H2 O). Amongst the phenotypic traits, only Vpassive was improved by 29 (3-55) % eupnoea, P = 0.03 (mean (95% CI)). CONCLUSION: The combination of pseudoephedrine and diphenhydramine did not improve OSA severity or genioglossus responsiveness but induced a small improvement in upper airway collapsibility, possibly due to the decongestant effect of the medications. The results of this study do not support the use of these medications for OSA treatment.