REM sleep breathing: Insights beyond conventional respiratory metrics.

Breathing and sleep state are tightly linked. The traditional approach to evaluation of breathing in rapid eye movement sleep has been to focus on apneas and hypopneas, and associated hypoxia or hypercapnia. However, rapid eye movement sleep breathing offers novel insights into sleep physiology and pathology, secondary to complex interactions of rapid eye movement state and cardiorespiratory biology. In this review, morphological analysis of clinical polysomnogram data to assess respiratory patterns and associations across a range of health and disease is presented. There are several relatively unique insights that may be evident by assessment of breathing during rapid eye movement sleep. These include the original discovery of rapid eye movement sleep and scoring of neonatal sleep, control of breathing in rapid eye movement sleep, rapid eye movement sleep homeostasis, sleep apnea endotyping and pharmacotherapy, rapid eye movement sleep stability, non-electroencephalogram sleep staging, influences on cataplexy, mimics of rapid eye movement behaviour disorder, a reflection of autonomic health, and insights into cardiac arrhythmogenesis. In summary, there is rich clinically actionable information beyond sleep apnea encoded in the respiratory patterns of rapid eye movement sleep.

Sleep apnea-related hypoxic burden as a predictor of pregnancy and neonatal outcome.

STUDY OBJECTIVES: To determine the clinical impact of sleep apnea-related hypoxic burden in pregnant women and neonates. METHODS: This is a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) study. Hypoxia burden was calculated from the home sleep apnea test (HSAT) and defined as the total area under respiratory events. Logistic regression analysis assessed the relationship between hypoxia burden and pregnancy/neonatal outcomes. RESULTS: A total of 3006 subjects in the early term, and 2326 subjects in the middle term of pregnancy, had HSAT. A hypoxic burden greater than 6.8%min was present in 1740 at early term and associated with a higher risk of preeclampsia (odds ratio 1.297, 95 % confidence interval 1.032-1.630, p: 0.026) after adjusted by obstructive sleep apnea (OSA) severity. In the middle term, 1058 subjects had a hypoxia burden more than 11.8%min, which was a predictor for higher incidence of gestational diabetes (OR 1.795, 95 % CI 1.097-2.938, p: 0.020) and an Apgar <7 at 1 min (OR 1.446, 95 % CI 1.079-1.939, p: 0.012) after adjusted by obstructive sleep apnea (OSA) severity. After adjusted by oxygenation disturbance index, HB was not related with Apgar <7 at 1 min (p:0.565). CONCLUSIONS: The hypoxic burden is an independent predictor for preeclampsia and gestational diabetes and an Apgar <7 at 1 min.

The association between the effective apnea-hypopnea index and blood pressure reduction efficacy following CPAP/oxygen treatment.

BACKGROUND: The effect of sleep apnea treatment on reducing cardiovascular disease risk remains inconclusive. This study aims to assess if the effective apnea hypopnea index (eAHI), a measure of residual sleep apnea burden post-treatment, is a factor in determining blood pressure (BP) response to continuous positive airway pressure therapy. The eAHI integrates time on therapy, residual apnea, and % of sleep time untreated. METHODS: A secondary analysis of the Heart Biomarker Evaluation in Apnea Treatment (HeartBEAT) study, a randomized, controlled, parallel group assessment of continuous positive airway pressure (CPAP), oxygen and sleep hygiene. The Delta-AHI (▲AHI) was defined as the difference between baseline AHI and effective AHI at 12 weeks. Logistic and linear regression models estimated the predictors for nocturnal systolic BP change following sleep apnea therapy. RESULTS: One hundred and sixty-nine subjects with a mean age of 62.82 ± 6.99 years were included in the final analysis. Fifty subjects had ▲AHI ≤8/hour of sleep and 119 subjects were higher. After adjustment, baseline mean nighttime systolic blood pressure (OR 1.036, 95% CI 1.015-1.058, p: 0.001) and ▲AHI ≥8/hour (OR 2.406, 95% CI 1.116-5.185, p:0.025) were independent predictors for mean nighttime systolic blood pressure change >3 mm Hg. The higher effective AHI was negatively related with BNP (ß: -2.564, SE: 1.167, p: 0.029) and positively related with troponin change (ß: 0.703, SE: 0.256, p: 0.007). CONCLUSION: The ▲AHI was an independent predictor of the blood pressure response to sleep apnea treatment. REGISTER NUMBER: NCT01086800.

Acute and long-term effects of acetazolamide in presumed high loop gain sleep apnea.

BACKGROUND: The acute effect during positive pressure titration and long term efficacy of acetazolamide (AZT) in high loop gain sleep apnea (HLGSA) is inadequately assessed. We predicted that AZT may improve HLGSA in both conditions. METHODS: A retrospective analysis of polysomnograms from patients with presumed HLGSA and residual respiratory instability administered AZT (125 or 250 mg) about 3 h into an initially drug-free positive pressure titration. A responder was defined as ≥ 50% reduction of the apnea hypopnea index(AHI 3% or arousal) before and after AZT. A multivariable logistic regression model estimated responder predictors. Long term efficacy of AZT was assessed by comparing both auto-machine (aREIFLOW) and manually scored respiratory events (sREIFLOW) extracted from the ventilator, prior to and after 3 months of AZT, in a subset. RESULTS: Of the 231 participants (median age of 61[51-68] years) and 184 (80%) males in the acute effect testing: 77 and 154 patients were given 125 mg and 250 mg AZT. Compared to PAP alone, PAP plus AZT was associated with a lower breathing related arousal index (8 [3-16] vs. 5 [2-10], p < 0.001), and AHI3% (19 [7-37] vs. 11 [5-21], p < 0.001); 98 patients were responders. The non-rapid eye movement sleep (NREM) AHI3% (OR 1.031, 95%CI [1.016-1.046], p < 0.001) was a strong predictor for responder status with AZT exposure. In the 109 participants with 3-month data, both aREIFLOW and sREIFLOWwere significantly reduced after AZT. CONCLUSIONS: AZT acutely and chronically reduced residual sleep apnea in presumed HLGSA; NREM AHI3% is a response predictor. AZT was well tolerated and beneficial for at least 3 months.

Predictors and consequences of residual apnea during positive airway pressure therapy.

STUDY OBJECTIVES: Determine the risk factors for, and consequences of, residual apnea during long-term positive airway pressure (PAP) therapy for obstructive sleep apnea (OSA). METHODS: A prospective cohort study of 195 subjects after a split-night polysomnogram. Estimation of residual respiratory events on PAP were done by both automated and manual scoring of data in EncoreAnywhere™. Clinical and polysomnographic predictors of residual apnea were estimated. RESULTS: There were 166 and 101 patients still on PAP at the 3 and 12 months, respectively. Seventy four (44.6%) and 46 (45.5%) had a residual scored respiratory event index-flow (sREIFLOW) ≥ 15/hour of use and 46 (45.5%) at the 3rd and 12th month, respectively. Treatment phase central apnea hypopnea index (TCAHI), a surrogate of high loop gain, was the main predictor for residual sREIFLOW (ß = 0.345, p: 0.025) at the 3rd and 12th month (ß = 0.147, p: 0.020). TCAHI also predicted unstable breathing (U) %. The body mass index (hazard ratio [HR] 1.034, 95% CI 1.008-1.062, p: 0.012) and effective sREIFLOW>15/hour in the first month (HR 2.477, 95% CI 1.510-4.065, p < 0.001) were the key predictors for drop out of PAP use at the 12th month. Effective sREIFLOW>15/hour in the first month was also a predictor for median usage duration >4 h for 70% of the night at both the 3rd month (odds ratio [OR] 0.947, 95% CI 0.909-0.986, p: 0.008) and 12th month (OR 0.973, 95% CI 0.951-0.994, p: 0.014). CONCLUSIONS: Treatment-phase CAHI predicts long-term residual apnea on PAP. High residual disease adversely impacts adherence.

Automated deep neural network analysis of lateral cephalogram data can aid in detecting obstructive sleep apnea.

STUDY OBJECTIVES: Information on obstructive sleep apnea (OSA) is often latently detected in diagnostic tests conducted for other purposes, providing opportunities for maximizing value. This study aimed to develop a convolutional neural network (CNN) to identify the risk of OSA using lateral cephalograms. METHODS: The lateral cephalograms of 5,648 individuals (mean age, 49.0 ± 15.8 years; men, 62.3%) with or without OSA were collected and divided into training, validation, and internal test datasets in a 5:2:3 ratio. A separate external test dataset (n = 378) was used. A densely connected CNN was trained to diagnose OSA using a cephalogram. Model performance was evaluated using the area under the receiver operating characteristic curve (AUROC). Gradient-weighted class activation mapping (Grad-CAM) was used to evaluate the region of focus, and the relationships between the model outputs, anthropometric characteristics, and OSA severity were evaluated. RESULTS: The AUROC of the model for the presence of OSA was 0.82 (95% confidence interval, 0.80-0.84) and 0.73 (95% confidence interval, 0.65-0.81) in the internal and external test datasets, respectively. Grad-CAM demonstrated that the model focused on the area of the tongue base and oropharynx in the cephalogram. Sigmoid output values were positively correlated with OSA severity, body mass index, and neck and waist circumference. CONCLUSIONS: Deep learning may help develop a model that classifies OSA using a cephalogram, which may be clinically useful in the appropriate context. The definition of ground truth was the main limitation of this study. CITATION: Jeong H-G, Kim T, Hong JE, et al. Automated deep neural network analysis of lateral cephalogram data can aid in detecting obstructive sleep apnea. J Clin Sleep Med. 2023;19(2):327-337.

Sleep Duration, Sleep Apnea, and Gray Matter Volume.

This study aimed to evaluate the effect of sleep duration on brain structures in the presence versus absence of sleep apnea in middle-aged and older individuals. The study investigated a population-based sample of 2,560 individuals, aged 49-80 years. The presence of sleep apnea and self-reported sleep duration were examined in relation to gray matter volume (GMV) in total and lobar brain regions. We identified ranges of sleep duration associated with maximal GMV using quadratic regression and bootstrap sampling. A significant quadratic association between sleep duration and GMV was observed in total and lobar brain regions of men with sleep apnea. In the fully adjusted model, optimal sleep durations associated with peak GMV between brain regions ranged from 6.7 to 7.0 hours. Shorter and longer sleep durations were associated with lower GMV in total and 4 sub-regions of the brain in men with sleep apnea.

A longitudinal study of the accuracy of positive airway pressure therapy machine-detected apnea-hypopnea events.

STUDY OBJECTIVES: During positive airway pressure (PAP) therapy for sleep apnea syndromes, the machine-detected respiratory event index (REIFLOW) is an important method for clinicians to evaluate the beneficial effects of PAP. There are concerns about the accuracy of this detection, which also confounds a related question, How common and severe are residual events on PAP? METHODS: Patients with obstructive sleep apnea who underwent a split-night polysomnography were recruited prospectively. Those treated with PAP and tracked by the EncoreAnywhere system (Philips Respironics, Murrysville, PA) were analyzed. Those who stopped PAP within 1 month were excluded from this analysis. Compliance, therapy data, and waveform data were analyzed. Machine-detected vs manually scored events were compared at the first, third, sixth, and 12th month from PAP initiation. Logistic regression was used to determine factors associated with a high REIFLOW difference. RESULTS: One hundred and seventy-nine patients with a mean age 59.06 ± 13.97 years, median body mass index of 33.60 (29.75-38.75) kg/m2, and median baseline apnea-hypopnea index of 46.30 (31.50-65.90) events/h were included. The difference between the machine-detected REIFLOW and manually scored REIFLOW was 10.72 ± 8.43 events/h in the first month and remained stable for up to 12 months. Male sex and large leak ≥ 1.5% were more frequent in patients who had an REIFLOW difference of ≥ 5 events/h of use. A titration arousal index ≥ 15 events/h of sleep, and higher ratio of unstable to stable breathing were also associated with an REIFLOW difference ≥ 5 events/h of use. CONCLUSIONS: There is a substantial and sustained difference between manual and automated event estimates during PAP therapy, and some associated factors were identified. CITATION: Ni Y-N, Thomas RJ. A longitudinal study of the accuracy of positive airway pressure therapy machine-detected apnea-hypopnea events. J Clin Sleep Med. 2022;18(4):1121-1134.

Digital sleep measures and white matter health in the Framingham Heart Study.

AIM: Impaired sleep quality and sleep oxygenation are common sleep pathologies. This study assessed the impact of these abnormalities on white matter (WM) integrity in an epidemiological cohort. METHODS: The target population was the Framingham Heart Study Generation-2/Omni-1 Cohorts. Magnetic resonance imaging (diffusion tensor imaging) was used to assess WM integrity. Wearable digital devices were used to assess sleep quality: the (M1-SleepImage™ system) and the Nonin WristOx for nocturnal oxygenation. The M1 device collects trunk actigraphy and the electrocardiogram (ECG); sleep stability indices were computed using cardiopulmonary coupling using the ECG. Two nights of recording were averaged. RESULTS: Stable sleep was positively associated with WM health. Actigraphic periods of wake during the sleep period were associated with increased mean diffusivity. One marker of sleep fragmentation which covaries with respiratory chemoreflex activation was associated with reduced fractional anisotropy and increased mean diffusivity. Both oxygen desaturation index and oxygen saturation time under 90% were associated with pathological directions of diffusion tensor imaging signals. Gender differences were noted across most variables, with female sex showing the larger and significant impact. CONCLUSIONS: Sleep quality assessed by a novel digital analysis and sleep hypoxia was associated with WM injury, especially in women.

Can improvements in sleep quality positively affect serum adiponectin-levels in patients with obstructive sleep apnea?

BACKGROUND: Assess if changes in sleep quality (Sleep Quality Index, SQI) based on cardiopulmonary coupling-analysis (CPC) impacts serum adiponectin-levels in patients with cardiovascular disease (CVD). METHODS: Secondary analysis of electrocardiogram (ECG) data from the Heart Biomarker Evaluation in Apnea Treatment study (HeartBEAT), a multicenter, controlled trial in patients with CVD and moderate-severe sleep apnea, randomly assigned to intervention of Continuous Positive Airway Pressure (CPAP), Nocturnal Supplemental Oxygen (NSO) or Healthy Lifestyle and Sleep Hygiene Education (HLSE; control group). Participants with good-quality ECG-signal (n = 241) were included. RESULTS: Improving CPC-sleep quality was associated with net average improvements in serum adiponectin-levels 2.69 µg/ml (p = 0.005) irrespective of therapy initiated. After controlling for confounders, a unit increase in SQI was associated with increase in serum adiponectin-levels 0.071 µg/ml (p = 0.012) and decrease in insulin-levels 0.197 µIU/ml (p = 0.0018). Similarly, a percentage point increase in sleep apnea indicator (SAI) was associated with decrease in serum adiponectin-levels of 0.071 µg/ml (p = 0.017) and increase in insulin-levels of 0.218 µIU/ml (p = 0.020). A percentage point increase in CPC-sleep fragmentation (eLFCBB) had a predicted increase in glucose-levels 0.371 mg/dl (p = 0.009) and insulin-levels 0.284 µIU/ml (p = 0.010). In patients receiving CPAP-therapy, a difference in serum adiponictin levels of 3.82 µg/ml (p = 0.025) is observed comparing patients in which SQI-improved to patients that SQI-declined during the study period. The difference is mostly due to a decrease in serum adiponectin levels in patients that decline in SQI (-3.20 µg/ml). CONCLUSION: Improvements in sleep quality were associated with higher serum adiponectin-levels, and improved measures of glycemic metabolism which may have beneficial effects on metabolic syndrome and cardiovascular health. CLINICAL TRIAL REGISTRATION NAME AND NUMBER: The Heart Biomarker Evaluation in Apnea Treatment (HeartBEAT) study is registered at https://clinicaltrials.gov/ct2/show/NCT01086800.

The role of acetazolamide in sleep apnea at sea level: a systematic review and meta-analysis.

STUDY OBJECTIVES: The recognition of specific endotypes as drivers of sleep apnea suggests the need of therapies targeting individual mechanisms. Acetazolamide is known to stabilize respiration at high altitude but benefits at sea level are less well understood. METHODS: All controlled studies of acetazolamide in obstructive sleep apnea and/or central sleep apnea (CSA) were evaluated. The primary outcome was the apnea-hypopnea index. RESULTS: Fifteen trials with a total of 256 patients were pooled in our systematic review. Acetazolamide reduced the overall apnea-hypopnea index (mean difference [MD] -15.82, 95% CI: -21.91 to -9.74, P < .00001) in central sleep apnea (MD -22.60, 95% CI: -29.11 to -16.09, P < .00001), but not in obstructive sleep apnea (MD -10.29, 95% CI: -33.34 to 12.77, P = .38). Acetazolamide reduced the respiratory related arousal index (MD -0.82, 95% CI: -1.56 to -0.08, P = .03), improved partial arterial of oxygen (MD 11.62, 95% CI: 9.13-14.11, P < .00001), mean oxygen saturation (MD 1.78, 95% CI: 0.53-3.04, P = .005), total sleep time (MD 25.74, 95% CI: 4.10-47.38, P = .02), N2 sleep (MD 3.34, 95% CI: 0.12-6.56, P = .04) and sleep efficiency (MD 4.83, 95% CI: 0.53-9.13, P = .03). CONCLUSIONS: Acetazolamide improves the apnea-hypopnea index and several sleep metrics in central sleep apnea. The drug may be of clinical benefit in patients with high loop gain apnea of various etiologies and patterns. The existence of high heterogeneity is an important limitation in applicability of our analysis. SYSTEMATIC REVIEW REGISTRATION: Registry: PROSPERO; Name: The effect of acetazolamide in patients with sleep apnea at sea level: a systematic review and meta analysis; URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020163316; Identifier: CRD42020163316.

Multicomponent Analysis of Sleep Using Electrocortical, Respiratory, Autonomic and Hemodynamic Signals Reveals Distinct Features of Stable and Unstable NREM and REM Sleep.

A new concept of non-rapid eye movement (NREM) and rapid eye movement (REM) sleep is proposed, that of multi-component integrative states that define stable and unstable sleep, respectively, NREMS, NREMUS REMS, and REMUS. Three complementary data sets are used: obstructive sleep apnea (20), healthy subjects (11), and high loop gain sleep apnea (50). We use polysomnography (PSG) with beat-to-beat blood pressure monitoring, and electrocardiogram (ECG)-derived cardiopulmonary coupling (CPC) analysis to demonstrate a bimodal, rather than graded, characteristic of NREM sleep. Stable NREM (NREMS) is characterized by high probability of occurrence of the <1 Hz slow oscillation, high delta power, stable breathing, blood pressure dipping, strong sinus arrhythmia and vagal dominance, and high frequency CPC. Conversely, unstable NREM (NREMUS) has the opposite features: a fragmented and discontinuous <1 Hz slow oscillation, non-dipping of blood pressure, unstable respiration, cyclic variation in heart rate, and low frequency CPC. The dimension of NREM stability raises the possibility of a comprehensive integrated multicomponent network model of NREM sleep which captures sleep onset (e.g., ventrolateral preoptic area-based sleep switch) processes, synaptic homeostatic delta power kinetics, and the interaction of global and local sleep processes as reflected in the spatiotemporal evolution of cortical "UP" and "DOWN" states, while incorporating the complex dynamics of autonomic-respiratory-hemodynamic systems during sleep. Bimodality of REM sleep is harder to discern in health. However, individuals with combined obstructive and central sleep apnea allows ready recognition of REMS and REMUS (stable and unstable REM sleep, respectively), especially when there is a discordance of respiratory patterns in relation to conventional stage of sleep.

Cardiovascular and somatic comorbidities and sleep measures using three hypopnea criteria in mild obstructive sleep-disordered breathing: sex, age, and body mass index differences in a retrospective sleep clinic cohort.

STUDY OBJECTIVES: To describe sex, age, and body mass index (BMI) differences in comorbidities and polysomnography measures, categorized using 3 different apnea-hypopnea index (AHI) criteria in sleep clinic patients with mild obstructive sleep-disordered breathing. METHODS: A retrospective cohort of 305 (64% female) adult sleep clinic patients who underwent full-night in-laboratory polysomnography having been diagnosed with mild sleep-disordered breathing and prescribed positive airway pressure. Effects of sex, age, and BMI on comorbidities and polysomnography measures, including rates of AHI defined by ≥ 3% desaturations (AHI3%), with arousals (AHI3%A), by ≥ 4% desaturations (AHI4%), and by respiratory disturbance index, were evaluated. RESULTS: Sixty-nine (23%), 116 (38%), 258 (85%), and 267 (88%) patients had AHI4%, AHI3%, AHI3%A, and respiratory disturbance index ≥ 5 events/h, respectively. Ninety-day positive airway pressure adherence rates were 45.9% overall and higher in women > 50-years-old (51.2%, P = 0.013) and men (54.5%, P = 0.024) with no difference whether AHI4% or AHI3%A was < 5 or ≥ 5 events/h. Men and women had similar rates of daytime sleepiness (43.3%), anxiety (44.9%), and hypertension (44.9%). Women were more likely to have obesity, anemia, asthma, depression, diabetes, fibromyalgia, hypothyroidism, migraine, and lower rates of coronary artery disease. More patients with AHI4% < 5 events/h had depression, migraines, and anemia, and more patients with AHI4% ≥ 5 events/h had congestive heart failure. Women were more likely to have higher sleep maintenance and efficiency, shorter average obstructive apnea and hypopnea durations, and less supine-dominant pattern. Average obstructive apnea and hypopnea duration decreased with increasing BMI, and average hypopnea duration increased with age. Obstructive apnea duration and obstructive hypopnea with arousal duration decreased with increasing BMI. More women had AHI4% < 5 (81.5% vs 69.1%), AHI3% < 5 (68.7% vs 49.1%), and AHI3%A < 5 events/h (18.5% vs 10.0%). Greater age and higher BMI were associated with higher AHI. CONCLUSIONS: Current AHI criteria do not predict comorbidities or adherence in mild sleep-disordered breathing patients. In this hypothesis-generating descriptive analysis, sex, BMI, and age may all be factors that should be accounted for in future research of mild sleep-disordered breathing patients. Different sleep study measures may weigh differently in calculations of risk for cardiovascular versus somatic comorbidities.

Flow limitation/obstruction with recovery breath (FLOW) event for improved scoring of mild obstructive sleep apnea without electroencephalography.

OBJECTIVE: Apnea/hypopnea index (AHI), especially without arousal criteria, does not adequately risk stratify patients with mild obstructive sleep apnea (OSA). We describe and test scoring reliability of an event, Flow Limitation/Obstruction With recovery breath (FLOW), representing obstructive airflow disruptions using only pressure transducer and snore signals available without electroencephalography. METHODS: The following process was used (i) Development of FLOW event definition, (ii) Training period and definition refinement, and (iii) Reliability testing on 10 100-epoch polysomnography (PSG) samples and two 100-sample tests. Twenty full-night in-laboratory baseline PSGs in OSA patients with AHI with ≥4% desaturations <15 were rescored for FLOW events, traditional hypopneas with desaturations, respiratory-related arousal (RRA) events (hypopneas with arousals and respiratory-effort related arousals) and non-respiratory arousals (NRA). RESULTS: Scoring of FLOW events in 100-epoch samples had good reliability with intraclass correlation (ICC) of 0.91. The overall kappa for presence of events on two sets of 100 sample events was 0.84 and 0.87 demonstrating good agreement. Moreover, 80% of RRA and 8% of NRA were concurrent with FLOW events. Furthermore, 56% of FLOW events were independent of RRA events. FLOW stratifies patients in traditional AHI categories with 50%/8% of AHI with ≥3% desaturations (AHI3) <5 and 12%/63% of AHI3 >5 in lowest/highest tertiles of AHI3 plus FLOW index. CONCLUSIONS: Scoring of FLOW after training is reliable. FLOW scores a high proportion of RRA and many currently unrepresented obstructive airflow disruptions. FLOW allows for stratification within the current normal-mild OSA category, which may better identify patients who will benefit from treatment.

Challenging Circadian Rhythm Disorder Cases.

The complex interplay of the sleep and circadian systems, which are substantially differentially regulated, provides for plasticity that is expressed in health and disease. The classic circadian rhythm disorders are readily recognizable, but atypical forms can be identified by actigraphy and melatonin profilometry. Although the dim-light melatonin onset test maps the start of the biological night, 24-hour mapping can define the limits of the biological night, whereas other forms of strategic testing can identify conditions such as iatrogenic hypermelatoninemia. Routine testing in clinical practice can expand the range of identifiable circadian rhythm disorders.