Adverse Pregnancy Outcomes and Pharyngeal Flow Limitation during Sleep: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

RATIONALE: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. OBJECTIVE: To determine whether a novel objective measure of flow limitation identifies an increased risk of preeclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be. METHODS: Flow limitation severity scores (0%=fully obstructed, 100%=open airway)- quantified from breath-by-breath airflow shape-were obtained from home sleep tests during early (6-15 weeks) and mid (22-31 weeks) pregnancy. Multivariable logistic regression quantified associations between flow limitation (median overnight severity, both time-points averaged) and preeclampsia, adjusting for maternal age, body mass index (BMI), race, ethnicity, chronic hypertension, and flow limitation during wakefulness. Secondary outcomes were hypertensive disorders of pregnancy (HDP), gestational diabetes mellitus (GDM), and infant birthweight. RESULTS: Of 1939 participants with flow limitation data at both time-points (age: 27.0±5.4 yr [mean±sd], BMI: 27.7±6.1 kg·m-2), 5.8% developed preeclampsia, 12.7% developed HDP, and 4.5% developed GDM. Greater flow limitation was associated with increased preeclampsia risk: adjusted Odds Ratio (OR) 2.49, 95% Confidence Interval [1.69, 3.69], per 2SD increase in severity. Findings persisted in women without sleep apnea (apnea-hypopnea index <5 events·hr-1). Flow limitation was associated with HDP (OR: 1.77 [1.33, 2.38]) and reduced infant birthweight (83.7 [31.8, 135.6] g), but not GDM. CONCLUSIONS: Greater flow limitation is associated with increased risk of preeclampsia, HDP, and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy.

Polysomnographic airflow shapes and site of collapse during drug-induced sleep endoscopy.

RATIONALE: Differences in the pharyngeal site-of-collapse influences efficacy of non-CPAP therapies for obstructive sleep apnoea (OSA). Notably, complete concentric collapse at the palate (CCCp) during drug-induced sleep endoscopy (DISE) is associated with reduced efficacy of hypoglossal nerve stimulation, but CCCp is currently not recognisable using polysomnography. Here we develop a means to estimate DISE-based site-of-collapse using overnight polysomnography. METHODS: 182 OSA patients provided DISE and polysomnography data. Six polysomnographic flow-shape characteristics (mean during hypopnoeas) were identified as candidate predictors of CCCp (primary outcome variable, N=44/182), including inspiratory skewness and inspiratory scoopiness. Multivariable logistic regression combined the six characteristics to predict clear presence (N=22) versus absence (N=128) of CCCp (partial collapse and concurrent tongue-base collapse excluded). Odds ratios for actual CCCp between predicted subgroups were quantified after cross-validation. Secondary analyses examined complete lateral wall, tongue-base, or epiglottis collapse. External validation was performed on a separate dataset (Ntotal=466). RESULTS: CCCp was characterised by greater scoopiness (ß=1.5±0.6 per 2SD, multivariable estimate±se) and skewness (ß=11.4±2.4) compared to non-CCCp. Odds ratio [95%CI] for CCCp in predicted positive versus negative subgroups was 5.0[1.9-13.1]. The same characteristics provided significant cross-validated prediction of lateral wall (OR=6.3[2.4-16.5]), tongue-base (3.2[1.4-7.3]), and epiglottis (4.4[1.5-12.4]) collapse. CCCp and lateral wall collapse shared similar characteristics (skewed, scoopy), diametrically opposed to tongue-base and epiglottis collapse characteristics. External validation confirmed model prediction. CONCLUSIONS: The current study provides a means to recognise patients with likely CCCp or other DISE-based site-of-collapse categories using routine polysomnography. Since site-of-collapse influences therapeutic responses, polysomnographic airflow shape analysis could facilitate precision site-specific OSA interventions.

Treatment of Sleep Apnea and Reduction in Blood Pressure: The Role of Heart Rate Response and Hypoxic Burden.

BACKGROUND: Obstructive sleep apnea is associated with increased blood pressure (BP). Obstructive sleep apnea treatment reduces BP with substantial variability, not explained by the apnea-hypopnea index, partly due to inadequate characterization of obstructive sleep apnea's physiological consequences, such as oxygen desaturation, cardiac autonomic response, and suboptimal treatment efficacy. We sought to examine whether a high baseline heart rate response (ΔHR), a marker of high cardiovascular risk in obstructive sleep apnea, predicts a larger reduction in post-treatment systolic BP (SBP). Furthermore, we aimed to assess the extent to which a reduction in SBP is explained by a treatment-related reduction in hypoxic burden (HB). METHODS: ΔHR and HB were measured from pretreatment and posttreatment polygraphy, followed by a 24-hour BP assessment in 168 participants treated with continuous positive airway pressure or nocturnal supplemental oxygen from the HeartBEAT study (Heart Biomarker Evaluation in Apnea Treatment). Multiple linear regression models assessed whether high versus mid (reference) ΔHR predicted a larger reduction in SBP (primary outcome) and whether there was an association between treatment-related reductions in SBP and HB. RESULTS: A high versus mid ΔHR predicted improvement in SBP (adjusted estimate, 5.8 [95% CI, 1.0-10.5] mm Hg). Independently, a greater treatment-related reduction in HB was significantly associated with larger reductions in SBP (4.2 [95% CI, 0.9-7.5] mm Hg per 2 SD treatment-related reduction in HB). Participants with substantial versus minimal treatment-related reductions in HB had a 6.5 (95% CI, 2.5-10.4) mm Hg drop in SBP. CONCLUSIONS: A high ΔHR predicted a more favorable BP response to therapy. Furthermore, the magnitude of the reduction in BP was partly explained by a greater reduction in HB.

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.

Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial.

BACKGROUND: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP). METHODS: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h-1) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h-1). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level. RESULTS: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship. CONCLUSION: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis.

Central sleep apnea treated by a constant low-dose CO2 supplied by a novel device.

CO2 inhalation has been previously reported as a treatment for central sleep apnea both when associated with heart failure or where the cause is unknown. Here, we evaluated a novel CO2 supply system using a novel open mask capable of comfortably delivering a constantly inspired fraction of CO2 ([Formula: see text]) during sleep. We recruited 18 patients with central sleep apnea (13 patients with cardiac disease, and 5 patients idiopathic) diagnosed by diaphragm electromyogram (EMG) recordings made during overnight full polysomnography (PSG) (night 1). In each case, the optimal [Formula: see text] was determined by an overnight manual titration with PSG (night 2). Titration commenced at 1% CO2 and increased by 0.2% increments until central sleep apnea (CSA) disappeared. Patients were then treated on the third night (night 3) with the lowest therapeutically effective concentration of CO2 derived from night 2. Comparing night 1 and night 3, both apnea-hypopnea index (AHI; 31 ± 14 vs. 6 ± 3 events/h, P < 0.01) and arousal index (22 ± 8 vs. 15 ± 8 events/h, P < 0.01) were significantly improved during CO2 treatment. Sleep efficiency improved from 71 ± 18 to 80 ± 11%, P < 0.05, and sleep latency was shorter (23 ± 18 vs. 10 ± 10 min, P < 0.01). Heart rate was not different between night 1 and night 3. Our data confirm the feasibility of our CO2 delivery system and indicate that individually titrated CO2 supplementation with a novel device including a special open mask can reduce sleep disordered breathing severity and improve sleep quality. Randomized controlled studies should now be undertaken to assess therapeutic benefit for patients with CSA.NEW & NOTEWORTHY A novel device using a special mask was developed and proved that CO2 therapy using the device could eliminate central sleep apnea (CSA) events and improve sleep quality including reducing arousal index in patients with heart failure. The device would become a useful clinical treatment for heart failure patients with CSA.

Hypoxic Burden Based on Automatically Identified Desaturations Is Associated with Adverse Health Outcomes.

Rationale: Recent studies have shown that sleep apnea-specific intermittent hypoxemia quantified by the hypoxic burden (HB) predicted cardiovascular disease (CVD)-related mortality in community-based and clinical cohorts. Calculation of HB is based on manual scoring of hypopneas and apneas, which is time-consuming and prone to interscorer variability. Objective: To validate a novel method to quantify the HB that is based on automatically scored desaturations. Methods: The sample included 5,655 middle-aged or older adults from the Sleep Heart Health Study (52.8% women; age, 63.2 ± 11.3 yr). The original HB method was based on a subject-specific search window obtained from an ensemble average of oxygen saturation signals (as measured by pulse oximetry) and synchronized with respect to the termination of scored respiratory events. In this study, however, the search window was obtained from ensemble average of oxygen saturation signals that synchronized with respect to the minimum of all automatically identified desaturations (⩾2% and other thresholds, including 3% and 4%, in sensitivity analyses). The time interval between the two maxima around the minimum saturation was defined as the search window. The oximetry-derived HB (HBOxi) was defined as the total area under all desaturation curves (restricted by the search window) divided by the total sleep time. Logistic and Cox regression models assessed the adjusted odds ratio (aOR)/hazard ratio of excessive daytime sleepiness (EDS), hypertension (HTN), and CVD mortality per 1-standard deviation increase in HBOxi after adjusting for several covariates and confounders. Results: The Spearman's rank correlation between HB (median [interquartile range], 34.4 [18.4-59.8] % min/h) and HBOxi (median [interquartile range], 34.5 [21.6-53.8] % min/h) was 0.81 (P < 0.001). Similar to HB, HBOxi was significantly associated with EDS (aOR [95% confidence interval (CI)], 1.17 [1.09-1.26] per standard deviation), HTN (aOR [95% CI], 1.13 [1.05-1.21]), and CVD mortality (adjusted hazard ratio [95% CI], 1.15 [1.01-1.30]) in fully adjusted models. Conclusions: The HBOxi was highly correlated with the HB based on manually scored apneas and hypopneas and was associated with EDS, HTN, and CVD mortality with similar effect sizes as previously reported. This method could be incorporated into wearable technology that accurately records oxygen saturation signals.

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.

Association of cortical arousals with sleep-disordered breathing events.

STUDY OBJECTIVES: The American Academy of Sleep Medicine recommends scoring hypopneas in adults when there is a ≥ 3% oxygen desaturation or when the event is associated with an arousal. However, there is no rule regarding the duration of the interval between the event termination and the associated arousal. The purpose of this study is to explore the timing between arousals and sleep-disordered breathing (SDB) events. METHODS: We analyzed cortical arousals (> 1.6 million) and SDB events (> 350,000 apneas and > 1.9 million hypopneas) from 11,400 manually scored polysomnography recordings. Only arousals that started within ±30 seconds from the end of SDB events were included. We used the 2 local minimums on either side of the arousal distribution as the start/end times for the distribution and to define which arousals are associated with SDB events. Finally, we calculated arousal probability near the end of SDB events. RESULTS: Cortical arousals with start times that fell within the 2 minimums were considered to be associated with SDB events. Using this definition, we found that 90% of apnea-associated arousals started no earlier than 4 seconds before and no later than 9 seconds after the end of apneas. Similarly, 90% of hypopnea-associated arousals started no earlier than 6 seconds before and no later than 14 seconds after the end of hypopneas, with the peak of the distribution coinciding with event end time. Arousal probability was highest during the first 10 seconds after the end of the event and was higher for longer events. CONCLUSIONS: Our results suggest that 90% of SDB-associated arousals start no earlier than 6 seconds before and no later than 14 seconds after the end of the respiratory events. CITATION: Zitting K-M, Lockyer BJ, Azarbarzin A, et al. Association of cortical arousals with sleep-disordered breathing events. J Clin Sleep Med. 2023;19(5):899-912.

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.

Cure4Kids: Two decades of knowledge transfer.

Cure4Kids is a free web-based knowledge platform for professionals providing care for children with cancer and hematologic diseases, offering its users a comprehensive suite of learning opportunities. It has been a resource for the pediatric oncology community across the world for the past two decades, with 60,107 users having logged in 1,412,514 times with 22,045,553 content hits. A transformation of Cure4Kids is being planned and will include an improved user interface, increased interactivity, and more content.

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.

Effect of Pimavanserin on the Respiratory Arousal Threshold from Sleep: A Randomized Trial.

Rationale: A low respiratory arousal threshold is a key endotype responsible for obstructive sleep apnea (OSA) pathogenesis. Pimavanserin is an antiserotoninergic capable of suppressing CO2-mediated arousals without affecting the respiratory motor response in animal models, and thus it holds potential for increasing the arousal threshold in OSA and subsequently reducing OSA severity. Objectives: We measured the effect of pimavanserin on arousal threshold (primary outcome), OSA severity, arousal index, and other OSA endotypes (secondary outcomes). Methods: A total of 18 OSA participants were studied in a randomized, double-blind, crossover study. Patients received a single dose of placebo or pimavanserin 34 mg 4 hours before in-lab polysomnography. Airflow was measured with an oronasal mask attached to a pneumotachograph, and ventilatory drive was recorded with an intraesophageal electromyography catheter. Results are presented as mean or median changes (Δ) and 95% confidence intervals (CIs). Results: Pimavanserin did not increase the arousal threshold, nor did it decrease OSA severity or arousal index. It, however, prolonged total sleep time (Δ[confidence interval (CI)], 39.5 [95%CI, -1.2 to 80.1] min). In an exploratory analysis, a subgroup of seven patients who had a 10% or more increase in arousal threshold on pimavanserin exhibited a decrease in AHI4 (hypopneas associated with 4% desaturation) (Δ[CI], 5.6 [95%CI, 3.6-11.1] events/h) and hypoxic burden (Δ[CI], 22.3 [95%CI, 6.6-32.3] %min/h). Conclusions: A single dose of pimavanserin did not have a significant effect on arousal threshold or OSA severity. However, in a post hoc analysis, a subset of patients who exhibited an increase in arousal threshold on pimavanserin showed a small decrease in OSA severity. Thus, if the arousal threshold could be increased with pimavanserin, perhaps with longer dosing to reach higher drug blood concentrations, then the desired effect on OSA severity might be achievable. Clinical trial registered with ClinicalTrials.gov (NCT04538755).

Atomoxetine and fesoterodine combination improves obstructive sleep apnoea severity in patients with milder upper airway collapsibility.

BACKGROUND AND OBJECTIVE: The combination of the noradrenergic atomoxetine plus the anti-muscarinic oxybutynin acutely increased genioglossus activity and reduced obstructive sleep apnoea (OSA) severity. However, oxybutynin has shorter half-life than atomoxetine and side effects that might discourage long-term usage. Accordingly, we aimed to test the combination of atomoxetine and fesoterodine (Ato-Feso), a newer anti-muscarinic with extended release formulation, on OSA severity and endotypes. METHODS: Twelve subjects with OSA underwent a randomized, double-blind, crossover trial comparing one night of atomoxetine plus fesoterodine (80-4 mg) to placebo. Parameters of OSA severity (e.g., apnoea-hypopnoea index [AHI], nadir oxygen desaturation and hypoxic burden) were calculated from two clinical, in-lab polysomnographic studies. OSA endotypes (including collapsibility per VMIN and arousal threshold) were derived from validated algorithms. RESULTS: Compared to placebo, Ato-Feso did not reduce the AHI (34.2 ± 19.1 vs. 30.1 ± 28.2 events/h, p = 0.493), but reduced the apnoea index (12.9 [28.8] vs. 1.8 [9.1] events/h, median [interquartile range], p = 0.027) and increased nadir desaturation (76.8 [8.0] vs. 82.2 [8.8] %, p = 0.003); a non-significant trend for improved hypoxic burden was observed (52.4 [50.5] vs. 29.7 [78.9] %min/h, p = 0.093). Ato-Feso lowered collapsibility (raised VMIN ; 43.7 [29.8-55.7] vs. 56.8 [43.8-69.8] %VEUPNOEA , mean [CI], p = 0.002), but reduced the arousal threshold (129.3 [120.1-138.6] vs. 116.7 [107.5-126] %VEUPNOEA , p = 0.038). In post hoc analysis, 6/6 patients with milder collapsibility (VMIN > 43%) exhibited OSA resolution (drop in AHI > 50% and residual AHI < 10 events/h) and improved hypoxaemia. CONCLUSION: While inefficacious in unselected patients, Ato-Feso administered for one night suppressed OSA in patients with milder collapsibility. Ato-Feso may hold some promise as an alternative OSA treatment in certain subgroups of individuals.

Altitude-Induced Sleep Apnea Is Highly Dependent on Ethnic Background (Sherpa Vs. Tamang).

Heiniger, Grégory, Simon Walbaum, Claudio Sartori, Alban Lovis, Marco Sazzini, Andrew Wellman, and Raphael Heinzer. Altitude-Induced Sleep Apnea Is Highly Dependent on Ethnic Background (Sherpa Vs. Tamang). High Alt Med Biol. 23:165-172, 2022. Rationale: High altitude-induced hypocapnic alkalosis generates central sleep apnea (CSA). In Nepal, two ethnic groups live at medium-to-high altitude: Tamangs originate from low-altitude Tibeto-Burman populations, whereas Sherpas descend from high-altitude Tibetans. Objective: To compare apnea severity at low and high altitude between Sherpas and Tamangs. Methods: Polygraphy recordings, including airflow and oxygen saturation, were performed in Nepal at "low" (2,030 m) and "high" (4,380 m) altitudes. Resting ventilation (V̇E) and mixed-exhaled CO2 (FECO2) were also measured at the same altitudes. Differences in apnea-hypopnea index (AHI), oxygen desaturation index (ODI), and % of nocturnal periodic breathing (NPB) at the two altitudes were compared between ethnicities. Measurements and Main Results: Twenty Sherpas and 20 Tamangs were included (males, median [interquartile range] age: 24.5 [21.5-27.8] years vs. 26.0 [21.5-39.8] years, body mass index: 23.9 [22.1-26.1] kg/m2 vs. 25.21 [20.6-27.6] kg/m2). Compared with Tamangs, Sherpas showed a lower increase in AHI (+7.5 [2.6-17.2]/h vs. +31.5 [18.2-57.3]/h, p < 0.001), ODI (+13.8 [5.5-28.2]/h vs. +42.0 [22.6-77.6]/h, p < 0.001), and NPB proportion (+0.9 [0-3.5]% vs. +12.8 [3.1-27.4]%, p < 0.001) from low to high altitude. Resting V̇E was higher in Sherpas versus Tamangs at both low (8.45 [6.89-10.70] l/min vs. 6.3 [4.9-8.3] l/min, p = 0.005) and high (9.7 [8.5-11] l/min vs. 8.74 [7.39-9.73] l/min, p = 0.020) altitudes, whereas the mean ± standard deviation FECO2 decrease between low and high altitude was greater in Tamangs versus Sherpas (-0.50% ± 0.44% vs. -0.80% ± 0.33%, p < 0.023). Conclusion: Overall, altitude-adapted Sherpas showed a 3.2-times smaller increase in sleep-disordered breathing between low and high altitude compared with Tamangs, and higher ventilation and a smaller drop in FECO2 at high altitude. These data suggest that genetic differences in breathing control can be protective against CSA.

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.

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.