Sleep apnea physiological burdens and markers of white matter injury: the Multi-Ethnic Study of Atherosclerosis.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is associated with cognitive impairment; however, the underlying mechanisms remain incompletely understood. OSA is characterized by periods of interrupted ventilation ("ventilatory burden (VB)"), leading to hypoxemia ("hypoxic burden (HB)") and/or arousal ("arousal burden (AB)") from sleep. While hypoxemia is considered a key mechanism underlying white matter injury, its measurement has been limited. In our primary analysis, we assessed the association of HB, a quantitative measure of hypoxemia, with white matter hyperintensity volume (WMHv), a marker of small vessel disease, and compared with that of VB and AB (quantitative measures of ventilatory deficit and arousals). METHODS: Data from participants in the Multi-Ethnic Study of Atherosclerosis with full polysomnograms (PSG) and brain MRI were analyzed. HB was defined as the total area under the oxygen desaturation curve per hour of sleep, while VB was defined as the event-specific area under the ventilation signal and AB was defined as the normalized cumulative duration of all arousals. The primary outcome was WMHv, with other MRI measures considered secondary outcomes. RESULTS: The analysis included PSGs from 587 participants (age: 65.5±8.2 years). In the fully adjusted model, each 1 standard deviation (SD) increase in HB was associated with a 0.09 SD increase in WMHv (p=0.023), after adjusting for demographics, study site, and comorbidities. In contrast, VB, AB, and conventional OSA measures were not associated with outcomes. CONCLUSIONS: Hypoxic burden was associated with white matter hyperintensity volume in a racially/ethnically diverse cohort of older individuals with a high prevalence of OSA.

Mouth Closure and Airflow in Patients With Obstructive Sleep Apnea: A Nonrandomized Clinical Trial.

Importance: Mouth breathing is associated with increased airway resistance, pharyngeal collapsibility, and obstructive sleep apnea (OSA) severity. The common belief is that closing the mouth can mitigate the negative effects of mouth breathing during sleep. However, mouth breathing may serve as an essential route to bypassing obstruction along the nasal route (eg, the velopharynx). Objective: To investigate the role of mouth breathing as an essential route in some patients with OSA and its association with upper airway anatomical factors. Design, Setting, and Participants: This nonrandomized clinical trial included participants diagnosed with OSA who underwent drug-induced sleep endoscopy. Patients were stratified into 3 quantiles based on oral-breathing level (quantile 1: oral airflow < 0.05 L/min; quantile 2: oral airflow 0.05-2.2 L/min; quantile 3: oral airflow > 2.2 L/min). Interventions: Closing the mouth during sleep during alternating breaths by applying pressure to the mentum until teeth are in occlusion. Main Outcomes and Measures: The primary outcome was total inspiratory flow defined as the change in airflow in the transition from mouth relaxed to mouth closed, analyzed overall and by 3 oral-breathing quantiles. The association of velopharyngeal obstruction on the change in total inspiratory airflow was also investigated. Results: Of 66 enrolled patients with OSA, 12 were excluded due to insufficient baseline airflow. The analytic cohort consisted of 54 patients (39 [72%] male; median [IQR] age, 55 [46-64] years; apnea-hypopnea index, 26.9 [17.6-39.9] events/h; and body mass index calculated as weight in kilograms divided by height in meters squared, 28.9 [27.1-31.6]). Mouth closure increased total inspiratory flow by 27.8 percentage points overall (ß, 1.0 [95% CI, 0.4-1.9] L/min). However, outcomes varied based on the degree of baseline oral breathing. No association was found for 10 patients with near-zero mouth breathing (0.9 [95% CI, -0.2 to 2.1] L/min). Airflow improved with mouth closure in 32 patients with moderate levels of mouth breathing (2.0 [95% CI, 1.3-2.7] L/min), whereas it worsened in patients with high levels of mouth breathing (-1.9 [95% CI, -3.1 to -0.6] L/min). Velopharyngeal obstruction was associated with increased mouth breathing (0.6 [95% CI, 0.1-3.0] L/min) and reduced airflow with mouth closure (-1.9 [95% CI, -3.1 to -0.7] L/min). Conclusion and Relevance: Although mouth closure increased inspiratory airflow in the overall cohort of this nonrandomized clinical trial, the outcomes were heterogeneous. In patients who breathe primarily through their mouth during sleep and have velopharyngeal obstruction, airflow worsens with mouth closure. Hence, personalized approaches to treating mouth breathing should be considered. Trial Registration: ClinicalTrials.gov Identifier: NCT06547658.

Combination Tonsillectomy and Hypoglossal Nerve Stimulation for Sleep Apnea Patients With Oropharyngeal Lateral Wall Collapse.

OBJECTIVE: The efficacy of hypoglossal nerve stimulation (HGNS) therapy is limited by obstruction of the oropharyngeal lateral walls (OLWs). Our objective was to investigate the effect of palatine tonsillectomy on HGNS efficacy in obstructive sleep apnea (OSA) patients with OLW collapse. STUDY DESIGN: Case-control study of patients with moderate-to-severe OSA, complete-or-partial OLW collapse, and small tonsils (1 - 2+). Concomitant palatine tonsillectomy and HGNS (HGNS+T) were compared against a control group of patients who underwent HGNS alone. SETTING: Single academic institution. METHODS: Study outcomes were measures of HGNS efficacy defined as a %reduction in apnea-hypopnea index (AHI) (primary) and successful treatment response (50% AHI reduction to <15/h, logistic regression), respectively. Regression analyses quantified the additional effect of tonsillectomy (HGNS+T vs HGNS alone, independent variable) on HGNS efficacy. Analyses were adjusted for OLW collapse severity (complete vs partial), tonsil size, age, sex, body mass index, and baseline AHI. RESULTS: Nineteen patients underwent HGNS+T and had follow-up sleep testing for the current analysis. The control group (HGNS alone) consisted of 78 patients. Baseline demographics and OSA severity were similar between the groups, except HGNS+T group had increased prevalence of complete OLW collapse. Linear regression demonstrated that adding tonsillectomy resulted in an additional 22.9% [7.5, 35.2] reduction in AHI [95% confidence interval, CI] (P = .006), and 8.6 [1.7,43.4] (P = .010) greater odds [95% CI] of a successful treatment response with HGNS. CONCLUSION: Compared to historically poorer outcomes of HGNS in patients with OLW collapse, these early results suggest combining tonsillectomy with HGNS may represent a promising strategy to improve success rates.

Novel physiologic predictors of positive airway pressure effectiveness (NICEPAP) study: rationale, design and methods.

PURPOSE: Continuous positive airway pressure (CPAP) is the primary therapy for obstructive sleep apnea (OSA); however the effectiveness of CPAP remains suboptimal. We describe the Novel PhysIologiC prEdictors of Positive Airway Pressure Effectiveness (NICEPAP) study. Its purpose is to determine whether physiological traits of OSA contribute to CPAP effectiveness. METHODS: NICEPAP (NCT05067088) is a prospective, observational cohort study conducted at an academic sleep center. Adults newly diagnosed with OSA (n = 267) are assessed for OSA traits of loop gain, arousal threshold, pharyngeal collapsibility, and muscle compensation from baseline polysomnography. We perform a comprehensive assessment of covariates relevant to CPAP adherence, efficacy, and patient-centered outcomes. Participants are followed for 12 months. Primary outcomes include (1) CPAP adherence (hours/night), (2) CPAP efficacy (apneas-hypopneas/hour), and (3) quality of life at six months measured by objective CPAP data and Functional Outcomes of Sleep Questionnaire. Secondary outcomes include sleep quality, sleepiness, insomnia, and neurocognitive function. RESULTS: Data on covariates, including demographics, sleep symptoms, medical history, medications, sleep quality, OSA and treatment self-efficacy, decisional balance, and socio-economic and social and partner support, are collected using validated instruments. The analysis for primary outcomes includes a generalized linear mixed model for an outcome (e.g., CPAP adherence) with OSA traits as exposures followed by the addition of relevant covariates. CONCLUSION: The findings of the NICEPAP study will inform research aimed to enhance CPAP effectiveness. Understanding the role of physiological OSA traits in CPAP effectiveness is a crucial step toward a precision medicine approach to OSA.

Physiologic Consequences of Upper Airway Obstruction in Sleep Apnea.

OSA is diagnosed and managed by a metric called the apnea-hypopnea index (AHI). The AHI quantifies the number of respiratory events (apnea or hypopnea), disregarding important information on the characteristics and physiologic consequences of respiratory events, including degrees of ventilatory deficit and associated hypoxemia, cardiac autonomic response, and cortical activity. The oversimplification of the disorder by the AHI is considered one of the reasons for divergent findings on the associations of OSA and cardiovascular disease (CVD) in observational and randomized controlled trial studies. Prospective observational cohort studies have demonstrated strong associations of OSA with several cardiovascular diseases, and randomized controlled trials of CPAP intervention have not been able to detect a benefit of CPAP to reduce the risk of CVD. Over the last several years, novel methodologies have been proposed to better quantify the magnitude of OSA-related breathing disturbance and its physiologic consequences. As a result, stronger associations with cardiovascular and neurocognitive outcomes have been observed. In this review, we focus on the methods that capture polysomnographic heterogeneity of OSA.

The transformation of Cure4Kids: Expanding knowledge transfer capacity.

Global survival disparities among children with cancer and other catastrophic diseases are the driving force behind Cure4Kids' sustained outreach to healthcare professionals. Congruent with this need, Cure4Kids was redesigned to meet the emergent demands of diverse healthcare professionals seeking free, web-based pediatric hematology/oncology education. Herein, we present an overview of each phase of the design and development process for the transformation and describe key features of the new Cure4Kids and future opportunities for expansion.

Sleep apnea patients with epiglottic collapse elevate their larynx more with swallowing; videofluoroscopic swallowing study of 80 patients.

OBJECTIVE: The epiglottis plays an integral role in the swallowing mechanism and is also implicated as an obstruction site in obstructive sleep apnea (OSA). The underlying causes of epiglottic collapse during sleep remain unclear. This study aimed to investigate the cognitive functions using the Loewenstein Occupational Therapy Cognitive Assessment (LOTCA) and the neurophysiological and anatomical factors using videofluoroscopic swallowing studies (VFSS). We compared patients with OSA exhibiting epiglottic collapse to those without, assessing differences in anatomical or neurophysiological characteristics. METHODS: The study included 12 patients with epiglottic collapse (Epi-group) and 68 without (non-Epi group), all undergoing overnight polysomnography (PSG), drug-induced sleep endoscopy (DISE), LOTCA, and VFSS. Oral transit time (OTT), pharyngeal delay time (PDT), and pharyngeal transit time (PTT) were considered as neurophysiological traits, and laryngeal elevation length (LE) as anatomical trait, and were measured across various test diets (10 ml of liquid, soft, or solid). RESULTS: The study comprised 80 individuals, 57 men and 23 women, with no significant age, sex, body mass index or PSG parameters between groups, or DISE findings, with the exception of epiglottic collapse. Swallowing metrics from VFSS were normal, with no differences in OTT, PDT, PTT, or LOTCA scores. Notably, patients with epiglottic collapse showed a greater laryngeal elevation when swallowing soft and solid foods (p = 0.025 and p = 0.048, respectively). CONCLUSIONS: Patients with epiglottic collapse do not exhibit neurophysiological or cognitive impairments when compared to non-Epi group. However, the Epi-group displayed a significantly increased laryngeal elevation length. This suggests that anatomical factors may have a more substantial role in the development of epiglottic collapse than neurophysiological factors.

Adverse pregnancy outcomes and pharyngeal flow limitation during sleep: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b).

BACKGROUND: Pharyngeal flow limitation during pregnancy may be a risk factor for adverse pregnancy outcomes but was previously challenging to quantify. Our objective was to determine whether a novel objective measure of flow limitation identifies an increased risk of pre-eclampsia (primary outcome) and other adverse outcomes in a prospective cohort: Nulliparous Pregnancy Outcomes Study Monitoring Mothers-to-be (nuMoM2b). 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 pre-eclampsia, 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 (mean±sd age 27.0±5.4 years and BMI 27.7±6.1 kg·m-2), 5.8% developed pre-eclampsia, 12.7% developed HDP and 4.5% developed GDM. Greater flow limitation was associated with increased pre-eclampsia risk: adjusted OR 2.49 (95% CI 1.69-3.69) per 2sd increase in severity. Findings persisted in women without sleep apnoea (apnoea-hypopnoea index <5 events·h-1). Flow limitation was associated with HDP (OR 1.77 (95% CI 1.33-2.38)) and reduced infant birthweight (83.7 (95% CI 31.8-135.6) g), but not GDM. CONCLUSIONS: Greater flow limitation is associated with increased risk of pre-eclampsia, HDP and lower infant birthweight. Flow limitation may provide an early target for mitigating the consequences of sleep disordered breathing during pregnancy.

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.

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

BACKGROUND: Differences in the pharyngeal site of collapse influence efficacy of non-continuous positive airway pressure therapies for obstructive sleep apnoea (OSA). Notably, complete concentric collapse at the level of 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 with non-CCCp. The odds ratio for CCCp in predicted positive versus negative subgroups was 5.0 (95% CI 1.9-13.1). The same characteristics provided significant cross-validated prediction of lateral wall (OR 6.3, 95% CI 2.4-16.5), tongue base (OR 3.2, 95% CI 1.4-7.3) and epiglottis (OR 4.4, 95% CI 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.

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.

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.

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.

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.