Effect of continuous positive airway pressure treatment of obstructive sleep apnea-hypopnea in multiple sclerosis: A randomized, double-blind, placebo-controlled trial (SAMS-PAP study).

OBJECTIVE: The aim of this study was to evaluate the effect of continuous positive airway pressure (CPAP) treatment on the Fatigue Severity Scale (FSS, preplanned primary outcome), another fatigue measure, sleep quality, somnolence, pain, disability, and quality of life in multiple sclerosis (MS) patients with obstructive sleep apnea-hypopnea (OSAH). METHODS: In a randomized, double-blind trial (NCT01746342), MS patients with fatigue, poor subjective sleep quality, and OSAH (apnea-hypopnea index of ⩾ 15 events per hour/sleep), but without severe OSAH (apnea-hypopnea index > 30, and 4% oxygen desaturation index > 15 events/hour or severe somnolence), were randomized to fixed CPAP or sham CPAP for 6 months. Outcome assessments were performed at 3 and 6 months. RESULTS: Of 49 randomized patients, 34 completed the protocol. Among completers, FSS did not improve with CPAP compared to sham at 6 months. FSS tended to improve (p = 0.09), and sleepiness (Epworth Sleepiness Scale) improved significantly (p = 0.03) at 3 months with CPAP compared to sham, but there were no other improvements with CPAP at either study evaluation. CONCLUSION: In non-severe OSAH patients, CPAP did not significantly improve the primary outcome of FSS change at 6 months. In secondary analyses, we found a trend to improved FSS, and a significant reduction in somnolence with CPAP at 3 months.

Sleep-disordered breathing in high-risk pregnancies is associated with elevated arterial stiffness and increased risk for preeclampsia.

BACKGROUND: Impaired vascular function is a central feature of pathologic processes preceding the onset of preeclampsia. Arterial stiffness, a composite indicator of vascular health and an important vascular biomarker, has been found to be increased throughout pregnancy in those who develop preeclampsia and at the time of preeclampsia diagnosis. Although sleep-disordered breathing in pregnancy has been associated with increased risk for preeclampsia, it is unknown if sleep-disordered breathing is associated with elevated arterial stiffness in pregnancy. OBJECTIVE: This prospective observational cohort study aimed to evaluate arterial stiffness in pregnant women, with and without sleep-disordered breathing and assess the interaction between arterial stiffness, sleep-disordered breathing, and preeclampsia risk. STUDY DESIGN: Women with high-risk singleton pregnancies were enrolled at 10 to 13 weeks' gestation and completed the Epworth Sleepiness Score, Pittsburgh Sleep Quality Index, and Restless Legs Syndrome questionnaires at each trimester. Sleep-disordered breathing was defined as loud snoring or witnessed apneas (≥3 times per week). Central arterial stiffness (carotid-femoral pulse wave velocity, the gold standard measure of arterial stiffness), peripheral arterial stiffness (carotid-radial pulse wave velocity), wave reflection (augmentation index, time to wave reflection), and hemodynamics (central blood pressures, pulse pressure amplification) were assessed noninvasively using applanation tonometry at recruitment and every 4 weeks from recruitment until delivery. RESULTS: High-risk pregnant women (n=181) were included in the study. Women with sleep-disordered breathing (n=41; 23%) had increased carotid-femoral pulse wave velocity throughout gestation independent of blood pressure and body mass index (P=.042). Differences observed in other vascular measures were not maintained after adjustment for confounders. Excessive daytime sleepiness, defined by Epworth Sleepiness Score >10, was associated with increased carotid-femoral pulse wave velocity only in women with sleep-disordered breathing (Pinteraction=.001). Midgestation (first or second trimester) sleep-disordered breathing was associated with an odds ratio of 3.4 (0.9-12.9) for preeclampsia, which increased to 5.7 (1.1-26.0) in women with sleep-disordered breathing and hypersomnolence, whereas late (third-trimester) sleep-disordered breathing was associated with an odds ratio of 8.2 (1.5-39.5) for preeclampsia. CONCLUSION: High-risk pregnant women with midgestational sleep-disordered breathing had greater arterial stiffness throughout gestation than those without. Sleep-disordered breathing at any time during pregnancy was also associated with increased preeclampsia risk, and this effect was amplified by hypersomnolence.

Scoring heart rate increases as a surrogate arousal marker on portable monitor studies for obstructive sleep apnea: Impact on diagnostic accuracy and clinical decision-making.

Cortical arousal-related hypopneas are not scored on type 3 home devices, which therefore limits their diagnostic accuracy for obstructive sleep apnea. The objective of this study was to evaluate whether scoring heart rate accelerations as surrogate markers of arousal improves type 3 portable monitor diagnostic agreement compared with polysomnography and improves therapeutic decision-making. We prospectively recruited patients evaluated for obstructive sleep apnea to undergo in-laboratory simultaneous full polysomnography + type 3 portable monitoring. Hypopnea events were scored on portable monitor studies with and without autonomic scoring, which was defined as an associated increase in pulse oximetry-derived heart rate ≥6 beats per min (autonomic hypopnea). Portable monitor diagnostic agreement compared with polysomnography with and without autonomic hypopnea scoring was assessed. We also evaluated whether reporting autonomic hypopnea scoring improves portable monitor clinical treatment decision agreement after four physicians reviewed clinical data and sleep study results (polysomnography, portable monitor with autonomic hypopnea, portable monitor without autonomic hypopnea). Eighty-two participants completed simultaneous polysomnography and in-laboratory portable monitor studies. Scoring autonomic hypopnea resulted in a decreased mean difference between in-laboratory portable monitor respiratory event index and polysomnography apnea-hypopnea index in Bland-Altman analysis (mean difference 14.6 per hr without versus 6.1 per hr with autonomic hypopnea scoring [p ˂ 0.01]), and increased intraclass correlation from 0.769 to 0.844. Inclusion of autonomic hypopnea scoring resulted in better accuracy between portable monitor and polysomnography expert's treatment decisions, and ultimately resulted in 24% fewer additional polysomnographies requested. The addition of pulse oximetry heart rate increases for autonomic hypopnea scoring during portable monitor resulted in better diagnostic agreement, improved clinical decision-making and reduced additional polysomnography testing.

Accuracy of portable devices in sleep apnea using oximetry-derived heart rate increases as a surrogate arousal marker.

PURPOSE: Type 3 home study (HS) monitors do not detect cortical arousal-related hypopneas and may therefore underestimate the polysomnography (PSG)-based apnea-hypopnea index (AHI). Our aim was to test the hypothesis that scoring hypopneas using heart rate accelerations as a surrogate marker for cortical arousal (autonomic hypopnea; AnH) improves the accuracy of HS for OSA diagnosis, using PSG AHI as the diagnostic gold standard. METHODS: We retrospectively identified patients referred for OSA who underwent complete PSG following an initial inconclusive HS. Respiratory events were scored using AASM research (Chicago) criteria with additional HS scoring for AnH, defined as hypopneas based on flow criteria associated with an increase in pulse oximetry-derived heart rate ≥ 6 beats/min. RESULTS: A total of 178 patients met inclusion criteria, with mean (±SD) HS AHI = 4.4 ± 4.2/h, which increased to 8.5 ± 5.3/h with AnH scoring. The hypopnea arousal index on subsequent PSG was 7.6 ± 7.7/h, with total AHI 15.6 ± 11.9/h. Bland-Altman analysis showed improved agreement between HS and PSG AHI (mean difference 11.2/h (95%CI 33.6, - 11.1) without vs. 7.2/h (95%CI 29.6, - 15.4) with AnH scoring). Overall diagnostic accuracy was improved with AnH scoring as reflected by an increased area under the receiver-operating characteristic curve for AHI thresholds of 10 and 15 events/h. CONCLUSIONS: In this retrospective analysis, the diagnostic accuracy of type 3 HS was improved by the inclusion of hypopnea-associated heart rate increases as a surrogate marker of arousal. Prospective studies are warranted to evaluate the impact of AnH scoring on clinical decision-making and patient outcomes.

Maternal sleep-disordered breathing and the risk of delivering small for gestational age infants: a prospective cohort study.

OBJECTIVE: It is unclear whether objectively measured maternal sleep-disordered breathing (SDB) leads to poor fetal outcomes. In this study, we prospectively assessed whether polysomnography-based diagnosis of SDB in the third trimester is associated with the delivery of small for gestational age (SGA) infants. STUDY DESIGN: Participants were recruited from a multicentre pregnancy cohort study. Eligible participants were evaluated for SDB based on symptoms (snoring and/or witnessed apnoeas assessed using the Pittsburgh Sleep Quality Index questionnaire) and in-home complete polysomnography in the third trimester. SGA was defined as <10th centile using customised birthweight centiles adjusted for maternal parity, prepregnancy body mass index (BMI), ethnicity, gestational age and infant sex. RESULTS: Of the 234 pregnant participants who completed a sleep study, 82% were Caucasian, with mean (SD) age of 31 (4.3) years and a prepregnancy BMI of 23 (4) kg/m(2). The delivery of SGA infants occurred in 27 (12%) of the study participants. The symptoms of SDB had poor overall sensitivity and specificity for diagnosing SDB identified by polysomnography. Symptoms of SDB in the third trimester demonstrated a potential association with delivering an SGA infant, however this did not reach statistical significance (OR 2.36 (95% CI 0.85 to 6.54, p=0.10)). However, the odds of delivering an SGA infant were significantly increased with polysomnography-based diagnosis of maternal SDB (using apnoea-hypopnoea index cut-off of 10, OR 2.65 (95% CI 1.15 to 6.10, p=0.02)). CONCLUSIONS: Objectively measured SDB in the third trimester is significantly associated with the delivery of SGA infants.

Obstructive sleep apnea in Parkinson's disease patients: effect of Sinemet CR taken at bedtime.

PURPOSE: Obstructive sleep apnea (OSA) results from upper airway (UA) obstruction. In Parkinson's disease (PD), levodopa improves UA obstruction during wakefulness. We hypothesized that bedtime controlled-release levodopa (Sinemet CR) is associated with less severe OSA (lower apnea-hypopnea index [AHI]) in PD patients. METHODS: Idiopathic PD subjects underwent nocturnal polysomnography (PSG) and were divided into those taking bedtime Sinemet CR (SinCR+) and those not taking Sinemet CR (SinCR-). Outcomes were compared between groups for PSG recordings analyzed in whole and split at their mid-point with each half analyzed separately, using linear regression. RESULTS: Fifty-seven subjects were studied, eight SinCR+, and 49 SinCR-. They were 65 % male, aged 64.4 ± 10.3 years (mean ± SD), with body mass index 27.26 ± 3.98 kg/m(2). The whole night AHI was 15.6 ± 13.3 and 29.1 ± 20.8 in SinCR+ and SinCR-, respectively (p = 0.07 unadjusted, p = 0.11 adjusted for confounders). A similar trend was observed in the first half of the night. In the second half, the SinCR+ group had significantly lower AHI (beta = -18.8; p = 0.01 adjusted) and respiratory arousal index (beta = -14.2; p = 0.02 adjusted) than the SinCR- group. CONCLUSIONS: Bedtime Sinemet CR appears to reduce OSA in PD patients. There were no significant differences between groups in the first half of the night likely because of residual effects of short-acting levodopa in both groups, while Sinemet CR had residual effect in the second half. These results possibly provide an alternative to help manage OSA and improve sleep quality in PD patients.

Maternal sleep-disordered breathing and adverse pregnancy outcomes: a systematic review and metaanalysis.

OBJECTIVE: Symptoms of sleep-disordered breathing (SDB) are increased in pregnancy compared to the nongravid state. Maternal SDB may be associated with adverse pregnancy outcomes, but this is still under investigation. We performed a systematic literature review, and where feasible, a metaanalysis, to evaluate whether women with SDB in pregnancy have a higher risk of specific adverse pregnancy outcomes compared with women without SDB. STUDY DESIGN: Original studies published until June 2012 evaluating the association between gestational hypertension/preeclampsia, gestational diabetes, low birthweight infants, and maternal SDB, defined either by symptoms or the reference standard polysomnography, were identified from PubMed, EMBASE, and Web of Science. Data were extracted on study design and outcome estimates. When appropriate, effect estimates from each study were pooled using a random-effects model. RESULTS: Of the 4386 studies identified, 31 met the defined criteria. Twenty-one studies, all observational in design, reported dichotomous outcomes; 9 of these adjusted for potential confounders. Maternal SDB was significantly associated with gestational hypertension/preeclampsia (pooled adjusted odds ratio [aOR], 2.34; 95% confidence interval [CI], 1.60-3.09; 5 studies), and gestational diabetes (pooled aOR, 1.86; 95% CI, 1.30-2.42; 5 studies). CONCLUSION: Based on published observational studies to date, maternal SDB is associated with an increased risk of gestational hypertension and gestational diabetes after adjusting for potential confounders. However, large-scale, prospective cohort, and interventional studies are needed to further elucidate the relationship between maternal SDB and adverse pregnancy outcomes.

Exploring obstructive sleep apnea and sleep architecture in Parkinson's disease motor subtypes.

INTRODUCTION: Parkinson's disease (PD) can be divided into motor subtypes: postural instability/gait difficulty (PIGD), tremor dominant, and indeterminate. This study aimed to assess differences in sleep structure and obstructive sleep apnea (OSA) between the PIGD and non-PIGD subtypes. METHODS: PD participants with or without OSA (defined as apnea-hypopnea index (AHI) ≥ 15 events/hour on overnight polysomnography) were included. Patients were separated into two groups: PIGD and non-PIGD. Linear regression was used to explore differences in sleep, AHI, and other respiratory parameters between groups (adjusted for variables determined a priori). Logistic regression adjusted for the same variables was used to determine if the proportion of patients with OSA differed across groups. Subset analyses were performed: subset 1 excluding patients on psychoactive medication; subset 2 excluding patients taking levodopa or dopaminergic agonists (DAs) at nighttime and subset 3 excluding patients on either of the abovementioned drugs. RESULTS: 146 participants were studied. The non-PIGD group had less N3 sleep compared to the PIGD group (12.4% vs 16.9% p = 0.06), reaching significance in subsets 1 and 3. The AHI was significantly lower in the PIGD group (p = 0.047), including when medication effects were removed (p < 0.05). OSA was more frequent in the non-PIGD group, but only significantly in subset 3 (adjusted OR 0.3, p = 0.04). CONCLUSION: OSA may be more severe in non-PIGD subtypes, and more frequent, in a subset free of psychoactive medication, and of levodopa and DAs, possibly owing to motor complications and dyskinesia. Future studies are required to confirm this.

Long-term health outcomes for patients with obstructive sleep apnea: placing the Agency for Healthcare Research and Quality report in context-a multisociety commentary.

This multisociety commentary critically examines the Agency for Healthcare Research and Quality (AHRQ) final report and systematic review on long-term health outcomes in obstructive sleep apnea. The AHRQ report was commissioned by the Centers for Medicare & Medicaid Services and particularly focused on the long-term patient-centered outcomes of continuous positive airway pressure, the variability of sleep-disordered breathing metrics, and the validity of these metrics as surrogate outcomes. This commentary raises concerns regarding the AHRQ report conclusions and their potential implications for policy decisions. A major concern expressed in this commentary is that the AHRQ report inadequately acknowledges the benefits of continuous positive airway pressure for several established, long-term clinically important outcomes including excessive sleepiness, motor vehicle accidents, and blood pressure. While acknowledging the limited evidence for the long-term benefits of continuous positive airway pressure treatment, especially cardiovascular outcomes, as summarized by the AHRQ report, this commentary reviews the limitations of recent randomized controlled trials and nonrandomized controlled studies and the challenges of conducting future randomized controlled trials. A research agenda to address these challenges is proposed including study designs that may include both high quality randomized controlled trials and nonrandomized controlled studies. This commentary concludes by highlighting implications for the safety and quality of life for the millions of people living with obstructive sleep apnea if the AHRQ report alone was used by payers to limit coverage for the treatment of obstructive sleep apnea while not considering the totality of available evidence. CITATION: Patil SP, Billings ME, Bourjeily G, et al. Long-term health outcomes for patients with obstructive sleep apnea: placing the Agency for Healthcare Research and Quality report in context-a multisociety commentary. J Clin Sleep Med. 2024;20(1):135-149.

Positive Airway Pressure Treatment of Obstructive Sleep Apnea-Hypopnea in Hypertensive Disorders of Pregnancy: A Pilot Randomized Proof-of-Concept Clinical Trial.

Rationale: Maternal obstructive sleep apnea-hypopnea (OSAH) is associated with hypertensive disorders of pregnancy (HDP). OSAH treatment with positive airway pressure (PAP) in the general population lowers blood pressure (BP). However, there are limited data on the effects of PAP therapy in maternal OSAH. Objectives: Our primary objective was to assess the feasibility of recruitment to a pilot randomized trial and adherence to PAP therapy for OSAH in women with HDP. Secondary objectives included assessment of PAP effects on 24-h BP, arterial stiffness, and maternal and fetal outcomes. Methods: Women with singleton pregnancies at ⩾12 weeks' gestation and hypertension underwent home level 2 polysomnography; those with mild to moderate OSAH (apnea-hypopnea index ⩾ 5 events/h; women with severe OSAH with apnea-hypopnea index > 30 events/h and oxygen desaturation index > 30 were excluded) were randomized to either PAP or nasal dilator strip (NDS; control) therapy. After PAP education, adherence was monitored online with episodic phone or in-person support by research personnel. Twenty-four-hour BP and arterial stiffness were assessed at baseline and before delivery. Maternal and fetal outcomes were also recorded. Results: Of 105 potentially eligible participants, 67 agreed to undergo screening for OSAH over 38 months; 48 women meeting OSAH inclusion criteria were randomized to PAP (n = 27) or NDS (n = 21) therapy. Of these, 14 PAP (52%) and 13 NDS (62%) participants completed all predelivery measurements, with lack of completion due to urgent delivery (19% in the PAP group, 14% in the NDS group), PAP intolerance at initiation (19%), or other factors. Mean PAP use was 3.1 ± 2.5 h/night, with use ⩾4 h/night on 38.4 ± 33.7% of nights during 9.6 ± 4.0 weeks of treatment. BP was controlled within the target range in most participants. There were no differences in mean change in 24-hour BP or arterial stiffness measurements or in adverse maternal and fetal outcomes between the PAP and NDS groups in either intention-to-treat or per-protocol analyses. Conclusions: PAP adherence was suboptimal in this HDP cohort despite education and troubleshooting. Further work is required to identify optimal OSAH treatment strategies during pregnancy. Clinical trial registered with www.clinicaltrials.gov (NCT03309826).

Long term effects of continuous positive airway pressure treatment of obstructive sleep apnea-hypopnea syndrome in multiple sclerosis patients.

BACKGROUND: Obstructive sleep apnea-hypopnea (OSAH) is common in MS patients and is associated with fatigue. We recently published a randomized, controlled trial (RCT) of active vs sham continuous positive airway pressure (CPAP) treatment in MS patients with fatigue, poor sleep quality, and (OSAH) (Mult Scl J 2022;28:82-92). Our aim was to evaluate the long-term effects of CPAP treatment on fatigue (Fatigue Severity Scale, FSS, primary outcome) and other clinical outcomes in MS patients with OSAH. METHODS: Following the RCT, participants were offered treatment with CPAP and participation in an open label study. Patients were re-evaluated with RCT outcome measures at least 6 months after completion of the RCT. RESULTS: Twenty-eight of 34 (82 %) RCT-completers participated in this study a mean of 2.7 years after the RCT. Sixteen (57 %) patients were treated with CPAP (mean use 5.4 ± 1.0 h/night during the 6 months prior to follow-up visit), while the other 12 patients declined CPAP use and received no other OSAH treatments. Baseline clinical characteristics, including MS related disability and sleep outcomes, were not significantly different between CPAP-treated vs non-CPAP treated patients. Patients using CPAP at follow-up (n = 16) demonstrated significant improvements from RCT baseline in FSS (p = 0.005), Fatigue Scale for Motor and Cognitive Functions (p = 0.008, p = 0.012), Pittsburgh Sleep Quality Index (p = 0.016), Center of Epidemiological Studies-Depression Scale (p = 0.05), and Multiple Sclerosis Quality of Life-54 (MSQOL-54) physical and mental component scores (p = 0.012, p = 0.023), but no improvements in Epworth Sleepiness Scale, Pain Visual Analog Scale, or Expanded Disability Status Scale. Patients not using CPAP (n = 12) had no significant improvements in outcome measures. Using a linear mixed model, FSS (p = 0.03), morning fatigue (p = 0.048), and MSQOL-54 physical component score (p = 0.02) improved significantly in CPAP treated patients compared with non-CPAP treated patients from RCT baseline. CONCLUSION: In this post-RCT open label study, long-term CPAP use was associated with improved fatigue (FSS, our primary outcome) and physical quality of life in MS patients with OSAH.

Adaptive servo-ventilation for sleep-disordered breathing in patients with heart failure with reduced ejection fraction (ADVENT-HF): a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial.

BACKGROUND: In patients with heart failure and reduced ejection fraction, sleep-disordered breathing, comprising obstructive sleep apnoea (OSA) and central sleep apnoea (CSA), is associated with increased morbidity, mortality, and sleep disruption. We hypothesised that treating sleep-disordered breathing with a peak-flow triggered adaptive servo-ventilation (ASV) device would improve cardiovascular outcomes in patients with heart failure and reduced ejection fraction. METHODS: We conducted a multicentre, multinational, parallel-group, open-label, phase 3 randomised controlled trial of peak-flow triggered ASV in patients aged 18 years or older with heart failure and reduced ejection fraction (left ventricular ejection fraction ≤45%) who were stabilised on optimal medical therapy with co-existing sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥15 events/h of sleep), with concealed allocation and blinded outcome assessments. The trial was carried out at 49 hospitals in nine countries. Sleep-disordered breathing was stratified into predominantly OSA with an Epworth Sleepiness Scale score of 10 or lower or predominantly CSA. Participants were randomly assigned to standard optimal treatment alone or standard optimal treatment with the addition of ASV (1:1), stratified by study site and sleep apnoea type (ie, CSA or OSA), with permuted blocks of sizes 4 and 6 in random order. Clinical evaluations were performed and Minnesota Living with Heart Failure Questionnaire, Epworth Sleepiness Scale, and New York Heart Association class were assessed at months 1, 3, and 6 following randomisation and every 6 months thereafter to a maximum of 5 years. The primary endpoint was the cumulative incidence of the composite of all-cause mortality, first admission to hospital for a cardiovascular reason, new onset atrial fibrillation or flutter, and delivery of an appropriate cardioverter-defibrillator shock. All-cause mortality was a secondary endpoint. Analysis for the primary outcome was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01128816) and the International Standard Randomised Controlled Trial Number Register (ISRCTN67500535), and the trial is complete. FINDINGS: The first and last enrolments were Sept 22, 2010, and March 20, 2021. Enrolments terminated prematurely due to COVID-19-related restrictions. 1127 patients were screened, of whom 731 (65%) patients were randomly assigned to receive standard care (n=375; mean AHI 42·8 events per h of sleep [SD 20·9]) or standard care plus ASV (n=356; 43·3 events per h of sleep [20·5]). Follow-up of all patients ended at the latest on June 15, 2021, when the trial was terminated prematurely due to a recall of the ASV device due to potential disintegration of the motor sound-abatement material. Over the course of the trial, 41 (6%) of participants withdrew consent and 34 (5%) were lost to follow-up. In the ASV group, the mean AHI decreased to 2·8-3·7 events per h over the course of the trial, with associated improvements in sleep quality assessed 1 month following randomisation. Over a mean follow-up period of 3·6 years (SD 1·6), ASV had no effect on the primary composite outcome (180 events in the control group vs 166 in the ASV group; hazard ratio [HR] 0·95, 95% CI 0·77-1·18; p=0·67) or the secondary endpoint of all-cause mortality (88 deaths in the control group vs. 76 in the ASV group; 0·89, 0·66-1·21; p=0·47). For patients with OSA, the HR for all-cause mortality was 1·00 (0·68-1·46; p=0·98) and for CSA was 0·74 (0·44-1·23; p=0·25). No safety issue related to ASV use was identified. INTERPRETATION: In patients with heart failure and reduced ejection fraction and sleep-disordered breathing, ASV had no effect on the primary composite outcome or mortality but eliminated sleep-disordered breathing safely. FUNDING: Canadian Institutes of Health Research and Philips RS North America.

All Obstructive Sleep Apnea Events Are Not Created Equal: The Relationship between Event-related Hypoxemia and Physiologic Response.

Rationale: Obstructive sleep apnea (OSA) severity is typically assessed by the apnea-hypopnea index (AHI), a frequency-based metric that allocates equal weight to all respiratory events. However, more severe events may have a greater physiologic impact. Objectives: The purpose of this study was to determine whether the degree of event-related hypoxemia would be associated with the postevent physiologic response. Methods: Patients with OSA (AHI, ⩾5/h) from the multicenter Canadian Sleep and Circadian Network cohort were studied. Using mixed-effect linear regression, we examined associations between event-related hypoxic burden (HBev) assessed by the area under the event-related oxygen saturation recording with heart rate changes (ΔHRev), vasoconstriction (vasoconstriction burden [VCBev] assessed with photoplethysmography), and electroencephalographic responses (power ratio before and after events). Results: Polysomnographic recordings from 658 patients (median [interquartile range] age, 55.00 [45.00, 64.00] yr; AHI, 27.15 [14.90, 64.05] events/h; 42% female) were included in the analyses. HBev was associated with an increase in all physiologic responses after controlling for age, sex, body mass index, sleep stage, total sleep time, and study centers; for example, 1 standard deviation increase in HBev was associated with 0.21 [95% confidence interval, 0.2, 0.22], 0.08 [0.08, 0.09], and 0.22 [0.21, 0.23] standard deviation increases in ΔHRev, VCBev, and ß-power ratio, respectively. Conclusions: Increased event-related hypoxic burden was associated with greater responses across a broad range of physiologic signals. Future metrics that incorporate information about the variability of these physiologic responses may have promise in providing a more nuanced assessment of OSA severity.

Associations between sleep-related symptoms, obesity, cardiometabolic conditions, brain structural alterations and cognition in the UK biobank.

OBJECTIVES: Sleep disturbances are increasingly recognized as adversely affecting brain health in aging. Our aim was to investigate interrelations between subjective sleep-related symptoms, obesity, cardiometabolic disorders, brain structure and cognitive decline in a population-based aging sample. METHODS: Data were extracted from the UK Biobank for anthropometric and demographic information, self-reported sleep behaviours, cardiometabolic measures, structural brain magnetic resonance imaging and cognitive test scores. "Sleep-related symptoms" (SRS) were measured using four questionnaire items: loud snoring, daytime sleepiness, likelihood to nap and difficulty getting up in the morning. Associations were tested using a structural equation model (SEM), adjusted for confounders. Further, multiple regression analysis was used to test for direct relationships between SRS and specific cognitive domains. RESULTS: Among 36,468 participants with an average age of 63.6 (SD 7.5) years and 46.7% male, we found that SRS were associated with obesity and several pre-existing cardiometabolic disturbances. In turn, cardiometabolic disorders were associated with increased white matter hyperintensities and cortical thinning, which were related to cognitive dysfunction. SRS were also directly related to several structural brain changes and to cognitive dysfunction. Regression analyses showed that SRS were directly associated with slower reaction times, and lower scores in fluid intelligence, working memory and executive function. CONCLUSIONS: Self-reported sleep-related symptoms were associated with cognitive dysfunction directly and through pre-existing cardiometabolic disorders and brain structural alterations. These findings provide evidence that symptoms of sleep disturbances, here defined primarily by hypersomnolence and snoring, are important risk factors or markers for cognitive dysfunction in an aging population.

Strategies to Assess the Effect of Continuous Positive Airway Pressure on Long-Term Clinically Important Outcomes among Patients with Symptomatic Obstructive Sleep Apnea: An Official American Thoracic Society Workshop Report.

Continuous positive airway pressure (CPAP) is the first-line treatment for obstructive sleep apnea (OSA). Although CPAP improves symptoms (e.g., daytime sleepiness), there is a lack of high-quality evidence that CPAP prevents many long-term outcomes, including cognitive impairment, myocardial infarction, and stroke. Observational studies suggest that patients with symptoms may be particularly likely to experience these preventive benefits with CPAP, but ethical and practical concerns limited the participation of such patients in prior long-term randomized trials. As a result, there is uncertainty about the full benefits of CPAP, and resolving this uncertainty is a key priority for the field. This workshop assembled clinicians, researchers, ethicists, and patients to identify strategies to understand the causal effects of CPAP on long-term clinically important outcomes among patients with symptomatic OSA. Quasi-experimental designs can provide valuable information and are less time and resource intensive than trials. Under specific conditions and assumptions, quasi-experimental studies may be able to provide causal estimates of CPAP's effectiveness from generalizable observational cohorts. However, randomized trials represent the most reliable approach to understanding the causal effects of CPAP among patients with symptoms. Randomized trials of CPAP can ethically include patients with symptomatic OSA, as long as there is outcome-specific equipoise, adequate informed consent, and a plan to maximize safety while minimizing harm (e.g., monitoring for pathologic sleepiness). Furthermore, multiple strategies exist to ensure the generalizability and practicality of future randomized trials of CPAP. These strategies include reducing the burden of trial procedures, improving patient-centeredness, and engaging historically excluded and underserved populations.

Evaluation of upper airway patency during Cheyne-Stokes breathing in heart failure patients.

Little is known about the changes in upper airway calibre in Cheyne-Stokes respiration (CSR) during sleep in patients with congestive heart failure. This study aimed to test the hypothesis that upper airway closure occurs during central CSR events, by assessing upper airway calibre during sleep using the forced oscillation technique (FOT). Nine males with compensated heart failure (left ventricular ejection fraction mean ± sem 27.9 ± 5.1%) and predominant central CSR (apnoea/hypopnoea index 43.9 ± 4.2 events · h(-1)) were studied during overnight polysomnography, which included pneumotachography, inductance plethysmography or oesophageal pressure and FOT-derived impedance signal (|Z|). Baseline |Z| values during stable breathing in stage 2 sleep were 11.0 ± 1.3 cmH(2)O · s · L(-1). Mean |Z| increased to 31.9 ± 6.7 cmH(2)O · s · L(-1) during obstructive apnoeas (7% of events, n = 46). Increases in |Z| consistent with upper airway narrowing (more than two-fold baseline) were common during central apnoeas (50 ± 12% of events) occurring in the middle or end of apnoeas and occurred during some central hypopnoeas (16 ± 10% of events), typically in the expiratory phase. These findings indicate that in heart failure patients, reductions in upper airway calibre are common during CSR apnoeas, and may also occur during central hypopnoeas.

Alveolar Ventilation-Targeted Versus Spontaneous/Timed Mode for Home Noninvasive Ventilation in Amyotrophic Lateral Sclerosis.

BACKGROUND: Home noninvasive ventilation (NIV) is increasingly used in amyotrophic lateral sclerosis (ALS) to improve symptoms and survival. Our primary objective was to compare intelligent volume-assured pressure support (iVAPS) versus spontaneous/timed (S/T) modes regarding time to first change in ventilator parameters and the number of interventions over 6 months in subjects with ALS in a respiratory therapist (RT)-led program. METHODS: In this study, 30 subjects with ALS meeting criteria for NIV initiation were randomized to iVAPS or S/T. NIV was initiated using standardized protocols targeting optimal tidal volume and comfort in a daytime session. Download data were recorded at 1 week and 1 and 6 months. Any changes in ventilator parameters were recorded. RESULTS: Of the 30 subjects, 56.7% had bulbar onset ALS, 8 died, and 11 in each group completed the study. Median time to first parameter change was 33.5 (interquartile range [IQR] 7.7-96.0) d versus 41.0 (IQR 12.5-216.5) d for iVAPS versus S/T groups, respectively, (P = .48). The average number of RT interventions was similar between groups (1.1 ± 1.1 vs 0.9 ± 0.9 at 1 month, P = .72; 2.4 ± 2.1 vs 2.4 ± 2.3 at 6 months, P = .95, for iVAPS vs S/T, respectively). Adherence was significantly lower with iVAPS than S/T at 1 week but not at 1 or 6 months. Download parameters were similar between groups at 1 week and 6 months except for higher residual apnea-hypopnea index (AHI) and less spontaneously triggered breaths with iVAPS at 6 months. CONCLUSIONS: The time to first change of parameters and the number of interventions at 6 months from NIV initiation were similar for the iVAPS and S/T modes in subjects with ALS. With iVAPS, adherence was lower transiently at NIV initiation, and the residual AHI was higher at 6 months. Alveolar ventilation-targeted NIV may require a longer adaptation period and result in greater upper-airway instability predominantly in patients with bulbar ALS.

Multiple Sclerosis and related disorders.

Multiple Sclerosis (MS) is a common neuroinflammatory disorder which is associated with disabling clinical consequences. The MS disease process may involve neural centers implicated in the control of breathing, leading to ventilatory disturbances during both wakefulness and sleep. In this chapter, a brief overview of MS disease mechanisms and clinical sequelae including sleep disorders is provided. The chapter then focuses on obstructive sleep apnea-hypopnea (OSAH) which is the most prevalent respiratory control abnormality encountered in ambulatory MS patients. The diagnosis, prevalence, and clinical consequences as well as data on effects of OSAH treatment in MS patients are discussed, including the impact on the disabling symptom of fatigue and other clinical sequelae. We also review pathophysiologic mechanisms contributing to OSAH in MS, and in turn mechanisms by which OSAH may impact on the MS disease process, resulting in a bidirectional relationship between these two conditions. We then discuss central sleep apnea, other respiratory control disturbances, and the pathogenesis and management of respiratory muscle weakness and chronic hypoventilation in MS. We also provide a brief overview of Neuromyelitis Optica Spectrum Disorders and review current data on respiratory control disturbances and sleep-disordered breathing in that condition.