The stability of slow-wave sleep and EEG oscillations across two consecutive nights of laboratory polysomnography in cognitively normal older adults.

Laboratory polysomnography provides gold-standard measures of sleep physiology, but multi-night investigations are resource intensive. We assessed the night-to-night stability via reproducibility metrics for sleep macrostructure and electroencephalography oscillations in a group of cognitively normal adults attending two consecutive polysomnographies. Electroencephalographies were analysed using an automatic algorithm for detection of slow-wave activity, spindle and K-complex densities. Average differences between nights for sleep macrostructure, electroencephalography oscillations and sleep apnea severity were assessed, and test-retest reliability was determined using two-way intraclass correlations. Agreement was calculated using the smallest real differences between nights for all measures. Night 2 polysomnographies showed significantly greater time in bed, total sleep time (6.3 hr versus 6.8 hr, p < 0.001) and percentage of rapid eye movement sleep (17.5 versus 19.7, p < 0.001). Intraclass correlations were low for total sleep time, percentage of rapid eye movement sleep and sleep efficiency, moderate for percentage of slow-wave sleep and percentage of non-rapid eye movement 2 sleep, good for slow-wave activity and K-complex densities, and excellent for spindles and apnea-hypopnea index with hypopneas defined according to 4% oxygen desaturation criteria only. The smallest real difference values were proportionally high for most sleep macrostructure measures, indicating moderate agreement, and proportionally lower for most electroencephalography microstructure variables. Slow waves, K-complexes, spindles and apnea severity indices are highly reproducible across two consecutive nights of polysomnography. In contrast, sleep macrostructure measures all demonstrated poor reproducibility as indicated by low intraclass correlation values and moderate agreement. Although there were average differences in percentage of rapid eye movement sleep and total sleep time, these were numerically small and perhaps functionally or clinically less significant. One night of in-laboratory polysomnography is enough to provide stable, reproducible estimates of an individual's sleep concerning measures of slow-wave activity, spindles, K-complex densities and apnea severity.

Ventilatory Burden as a Measure of Obstructive Sleep Apnea Severity Is Predictive of Cardiovascular and All-Cause Mortality.

Rationale: The apnea-hypopnea index (AHI), used for the diagnosis of obstructive sleep apnea, captures only the frequency of respiratory events and has demonstrable limitations. Objectives: We propose a novel automated measure, termed "ventilatory burden" (VB), that represents the proportion of overnight breaths with less than 50% normalized amplitude, and we show its ability to overcome limitations of AHI. Methods: Data from two epidemiological cohorts (EPISONO [Sao Paolo Epidemiological Study] and SHHS [Sleep Heart Health Study]) and two retrospective clinical cohorts (DAYFUN; New York University Center for Brain Health) were used in this study to 1) derive the normative range of VB, 2) assess the relationship between degree of upper airway obstruction and VB, and 3) assess the relationship between VB and all-cause and cardiovascular disease (CVD) mortality with and without hypoxic burden that was derived using an in-house automated algorithm. Measurements and Main Results: The 95th percentiles of VB in asymptomatic healthy subjects across the EPISONO and the DAYFUN cohorts were 25.2% and 26.7%, respectively (median [interquartile range], VBEPISONO, 5.5 [3.5-9.7]%; VBDAYFUN, 9.8 [6.4-15.6]%). VB was associated with the degree of upper airway obstruction in a dose-response manner (VBuntreated, 31.6 [27.1]%; VBtreated, 7.2 [4.7]%; VBsuboptimally treated, 17.6 [18.7]%; VBoff-treatment, 41.6 [18.1]%) and exhibited low night-to-night variability (intraclass correlation coefficient [2,1], 0.89). VB was predictive of all-cause and CVD mortality in the SHHS cohort before and after adjusting for covariates including hypoxic burden. Although AHI was predictive of all-cause mortality, it was not associated with CVD mortality in the SHHS cohort. Conclusions: Automated VB can effectively assess obstructive sleep apnea severity, is predictive of all-cause and CVD mortality, and may be a viable alternative to the AHI.

Endotyping Sleep Apnea One Breath at a Time: An Automated Approach for Separating Obstructive from Central Sleep-disordered Breathing.

Rationale: Determining whether an individual has obstructive or central sleep apnea is fundamental to selecting the appropriate treatment. Objectives: Here we derive an automated breath-by-breath probability of obstruction, as a surrogate of gold-standard upper airway resistance, using hallmarks of upper airway obstruction visible on clinical sleep studies. Methods: From five nocturnal polysomnography signals (airflow, thoracic and abdominal effort, oxygen saturation, and snore), nine features were extracted and weighted to derive the breath-by-breath probability of obstruction (Pobs). A development and initial test set of 29 subjects (development = 6, test = 23) (New York, NY) and a second test set of 39 subjects (Solingen, Germany), both with esophageal manometry, were used to develop Pobs and validate it against gold-standard upper airway resistance. A separate dataset of 114 subjects with 2 consecutive nocturnal polysomnographies (New York, NY) without esophageal manometry was used to assess the night-to-night variability of Pobs. Measurements and Main Results: A total of 1,962,229 breaths were analyzed. On a breath-by-breath level, Pobs was strongly correlated with normalized upper airway resistance in both test sets (set 1: cubic adjusted [adj.] R2 = 0.87, P < 0.001, area under the receiver operating characteristic curve = 0.74; set 2: cubic adj. R2 = 0.83, P < 0.001, area under the receiver operating characteristic curve = 0.7). On a subject level, median Pobs was associated with the median normalized upper airway resistance (set 1: linear adj. R2 = 0.59, P < 0.001; set 2: linear adj. R2 = 0.45, P < 0.001). Median Pobs exhibited low night-to-night variability [intraclass correlation(2, 1) = 0.93]. Conclusions: Using nearly 2 million breaths from 182 subjects, we show that breath-by-breath probability of obstruction can reliably predict the overall burden of obstructed breaths in individual subjects and can aid in determining the type of sleep apnea.

Tenecteplase With Concomitant Anticoagulation for Acute Respiratory Failure in Patients With COVID-19: A Randomized Controlled Trial.

Background Pulmonary thrombosis and thromboembolism play a significant role in the physiologic derangements seen in COVID-19 acute respiratory failure. The effect of thrombolysis with tenecteplase on patient outcomes is unknown. Methods We conducted a randomized, controlled, double-blind, phase II trial comparing tenecteplase versus placebo in patients with COVID-19 acute respiratory failure (NCT04505592). Patients with COVID-19 acute respiratory failure were randomized to tenecteplase 0.25 mg/kg or placebo in a 2:1 proportion. Both groups received therapeutic heparin for at least 72 hours. Results Thirteen patients were included in the trial. Eight patients were randomized to tenecteplase and five were randomized to placebo. At 28 days, 63% (n = 5) of patients assigned to the treatment group were alive and free from respiratory failure compared to 40% (n = 2) in the placebo arm (p = 0.43). Mortality at 28 days was 25% (n = 2) in the treatment arm and 20% (n = 1) in the control arm (p = 1.0). No patients in the treatment arm developed renal failure by 28 days compared to 60% (n = 3) in the placebo arm (p = 0.07). Major bleeding occurred in 25% (n = 2) of the treatment arm and 20% (n = 1) in the placebo arm; however, no patients in either arm experienced intracranial hemorrhage. Conclusions Tenecteplase with concomitant heparin may improve patient outcomes in patients with COVID-19 respiratory failure. As this study was limited by a small sample size, larger confirmatory studies are needed.

Night-to-night reliability and agreement of obstructive sleep apnea pathophysiologic mechanisms estimated with phenotyping using polysomnography in cognitively normal elderly participants.

STUDY OBJECTIVES: Phenotyping using polysomnography (PUP) is an algorithmic method to quantify physiologic mechanisms underlying obstructive sleep apnea (OSA): loop gain (LG1), arousal threshold (ArTH), and upper airway collapsibility (Vpassive) and muscular compensation (Vcomp). The consecutive-night test-retest reliability and agreement of PUP-derived estimates are unknown. From a cohort of elderly (age ≥55 years), largely non-sleepy, community-dwelling volunteers who underwent in-lab polysomnography (PSG) on 2 consecutive nights, we determined the test-retest reliability and agreement of PUP-estimated physiologic factors. METHODS: Participants who had an apnea-hypopnea index (AHI3A) of at least 15 events per hour on the first night were included. PUP analyses were performed on each of the two PSGs from each participant. Physiologic factor estimates were derived from NREM sleep and compared across nights using intraclass correlation coefficients for reliability and smallest real differences (SRD) for agreement. RESULTS: Two PSGs from each of 43 participants (86 total) were analyzed. A first-night effect was evident with increased sleep time and stability and decreased OSA severity on the second night. LG1, ArTH, and Vpassive demonstrated good reliability (ICC > 0.80). Vcomp had modest reliability (ICC = 0.67). For all physiologic factors, SRD values were approximately 20% or more of the observed ranges, suggesting limited agreement of longitudinal measurements for a given individual. CONCLUSIONS: For NREM sleep in cognitively normal elderly individuals with OSA, PUP-estimated LG1, ArTH, and Vpassive demonstrated consistent relative ranking of individuals (good reliability) on short-term repeat measurement. For all physiologic factors, longitudinal measurements demonstrated substantial intraindividual variability across nights (limited agreement).

Night-to-Night Variability of Polysomnography-Derived Physiologic Endotypic Traits in Patients With Moderate to Severe OSA.

BACKGROUND: Emerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA. RESEARCH QUESTION: Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in moderate to severe OSA? STUDY DESIGN AND METHODS: Two consecutive in-lab polysomnography tests from a clinical trial (n = 67; male, 69%; mean ± SD age, 61 ± 10 years; apnea-hypopnea index [AHI] 53 ± 22 events/h) were used for the reliability analysis. Endotypic traits, reflecting upper airway collapsibility (ventilation at eupneic drive [Vpassive]), upper airway dilator muscle tone (ventilation at the arousal threshold [Vactive]), loop gain (stability of ventilatory control, LG1), and arousal threshold (ArTh) were determined. Reliability was expressed as an intraclass correlation coefficient (ICC). Minimal detectable differences (MDDs) were computed to provide an estimate of maximum spontaneous variability. Further assessment across four repeated polysomnography tests was performed in a subcohort (n = 22). RESULTS: Reliability of endotypic traits between the two consecutive nights was moderate to good (ICC: Vpassive = 0.82, Vactive = 0.76, LG1 = 0.72, ArTh = 0.83). Variability in AHI, but not in body position or in sleep stages, was associated with fluctuations in Vpassive and Vactive (r = -0.49 and r = -0.41, respectively; P < .001 for both). MDDs for single-night assessments were: Vpassive = 22, Vactive = 34, LG1 = 0.17, and ArTh = 21. Multiple assessments (mean of two nights, n = 22) further reduced MDDs by approximately 20% to 30%. INTERPRETATION: Endotypic trait analysis using a single standard polysomnography shows acceptable reliability and reproducibility in patients with moderate to severe OSA. The reported MDDs of endotypic traits may facilitate the quantification of relevant changes and may guide future evaluation of interventions in OSA.

Quantification of airway conductance from noninvasive ventilatory drive in patients with sleep apnea.

Upper airway conductance, the ratio of inspiratory airflow to inspiratory effort, quantifies the degree of airway obstruction in hypopneas observed in sleep apnea. We evaluated the ratio of ventilation to noninvasive ventilatory drive as a surrogate of conductance. Furthermore, we developed and tested a refinement of noninvasive drive to incorporate the interactions of inspiratory flow, pressure, and drive to better estimate conductance. Hypopneas were compiled from existing polysomnography studies with esophageal catheterization in 18 patients with known or suspected sleep apnea, totaling 1,517 hypopneas during NREM sleep. For each hypopnea, reference standard conductance was calculated as the ratio of peak inspiratory flow to esophageal pressure change during inspiration. Ventilatory drive was calculated using the algorithm developed by Terrill et al. and then mathematically modified according to the presence or absence of flow limitation to noninvasively estimate esophageal pressure. The ratio of ventilation to ventilatory drive and the ratio of peak inspiratory flow to estimated esophageal pressure were each compared with the reference standard for all hypopneas and for median values from individual patients. Hypopnea ventilation to drive ratios were of limited correlation with the reference standard (R2 = 0.17, individual hypopneas; R2 = 0.03, median patient values). Modification of drive to estimated pressure yielded estimated conductance, which strongly correlated with reference standard conductance (R2 = 0.49, individual hypopneas; R2 = 0.77, median patient values). We conclude that the severity of airway obstruction during hypopneas may be estimated from noninvasive drive by accounting for mechanical effects of flow on pressure. NEW & NOTEWORTHY Classification of hypopneas as obstructive (decreased upper airway conductance) or central (decreased inspiratory flow commensurate with decreased effort) is complicated by the requirement of invasive methods, such as esophageal manometry. Here, we demonstrate that using a few esophageal pressure measurements to account for the interactions between inspiratory flow, pressure, and noninvasive ventilatory drive allows estimation of upper airway conductance. Further studies may use these findings to quantify airway obstruction completely noninvasively.

Selective Continuous Positive Airway Pressure Withdrawal With Supplemental Oxygen During Slow-Wave Sleep as a Method of Dissociating Sleep Fragmentation and Intermittent Hypoxemia-Related Sleep Disruption in Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is considered to impair memory processing and increase the expression of amyloid-ß (Aß) and risk for Alzheimer's disease (AD). Given the evidence that slow-wave sleep (SWS) is important in both memory and Aß metabolism, a better understanding of the mechanisms by which OSA impacts memory and risk for AD can stem from evaluating the role of disruption of SWS specifically and, when such disruption occurs through OSA, from evaluating the individual contributions of sleep fragmentation (SF) and intermittent hypoxemia (IH). In this study, we used continuous positive airway pressure (CPAP) withdrawal to recapitulate SWS-specific OSA during polysomnography (PSG), creating conditions of both SF and IH in SWS only. During separate PSGs, we created the conditions of SWS fragmentation but used oxygen to attenuate IH. We studied 24 patients (average age of 55 years, 29% female) with moderate-to-severe OSA [Apnea-Hypopnea Index (AHI); AHI4% > 20/h], who were treated and adherent to CPAP. Participants spent three separate nights in the laboratory under three conditions as follows: (1) consolidated sleep with CPAP held at therapeutic pressure (CPAP); (2) CPAP withdrawn exclusively in SWS (OSA SWS ) breathing room air; and (3) CPAP withdrawn exclusively in SWS with the addition of oxygen during pressure withdrawal (OSA SWS + O 2). Multiple measures of SF (e.g., arousal index) and IH (e.g., hypoxic burden), during SWS, were compared according to condition. Arousal index in SWS during CPAP withdrawal was significantly greater compared to CPAP but not significantly different with and without oxygen (CPAP = 1.1/h, OSA SWS + O2 = 10.7/h, OSA SWS = 10.6/h). However, hypoxic burden during SWS was significantly reduced with oxygen compared to without oxygen [OSA SWS + O 2 = 23 (%min)/h, OSA SWS = 37 (%min)/h]. No significant OSA was observed in non-rapid eye movement (REM) stage 1 (NREM 1), non-REM stage 2 (NREM 2), or REM sleep (e.g., non-SWS) in any condition. The SWS-specific CPAP withdrawal induces OSA with SF and IH. The addition of oxygen during CPAP withdrawal results in SF with significantly less severe hypoxemia during the induced respiratory events in SWS. This model of SWS-specific CPAP withdrawal disrupts SWS with a physiologically relevant stimulus and facilitates the differentiation of SF and IH in OSA.