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.

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.

Mechanisms relating to sleeping position to the endotypes of sleep disordered breathing.

PURPOSE: Obstructive sleep apnea (OSA) severity varies considerably depending on the body position during sleep in certain subjects. Such variability may be underpinned by specific, body position-related changes in OSA pathophysiological determinants, or endotypes. Also head position relative to trunk may influence OSA endotypes. However, no studies to our knowledge have reviewed the endotype variations according to head or body position up to now. RECENT FINDINGS: Several findings illustrate that supine OSA is mostly attributable to unfavorable upper airway anatomy compared to lateral position. However, a reduced lung volume, with consequent ventilatory instability (or elevated loop gain), may also play a role. Furthermore, preliminary findings suggest that prone and reclined positions may have a beneficial effect on collapsibility and loop gain. SUMMARY: Sleeping supine induces many unfavorable pathophysiological changes, especially in certain predisposed OSA patients. Little is known on the influence of other sleep positions on key endotypic traits.

Cardiovascular Benefit of Continuous Positive Airway Pressure in Adults with Coronary Artery Disease and Obstructive Sleep Apnea without Excessive Sleepiness.

Rationale: Randomized controlled trials of continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) have not demonstrated protection against adverse cardiovascular outcomes. Recently, observational studies revealed that OSA-related cardiovascular risk is concentrated in patients with an elevated pulse rate response to respiratory events (ΔHR). Objectives: Here, in this post hoc analysis of a prospective clinical trial, we test the hypothesis that a greater pretreatment ΔHR is associated with greater CPAP-related protection against adverse cardiovascular outcomes. Methods: ΔHR was measured from baseline polysomnography of the RICCADSA (Randomized Intervention with CPAP in CAD and OSA) randomized controlled trial (patients with coronary artery disease [CAD] and OSA [apnea-hypopnea index ⩾ 15 events/h] with Epworth Sleepiness Scale score < 10; nCPAP:ncontrol = 113:113; male, 85%; age, 66 ± 8 [mean ± SD] yr). The primary outcome was a composite of repeat revascularization, myocardial infarction, stroke, and cardiovascular mortality. Multivariable Cox regression assessed whether the effect of CPAP was moderated by ΔHR (treatment-by-ΔHR interaction). Measurements and Main Results: The CPAP-related reduction in risk increased progressively with increasing pretreatment ΔHR (interaction hazard ratio [95% confidence interval], 0.49 [0.27 to 0.90] per SD increase in ΔHR; P < 0.05). This means that in patients with a ΔHR of 1 SD above the mean (i.e., 10 beats/min), CPAP was estimated to reduce cardiovascular risk by 59% (6% to 82%) (P < 0.05), but no significant risk reduction was estimated in patients with a mean ΔHR (6 beats/min; CPAP risk reduction, 16% [-53% to 54%]; P = 0.6). Conclusions: The protective effect of CPAP in patients with CAD and OSA without excessive sleepiness was modified by the ΔHR. Specifically, patients with higher ΔHR exhibit greater cardiovascular benefit from CPAP therapy.

Ventilatory Drive Withdrawal Rather Than Reduced Genioglossus Compensation as a Mechanism of Obstructive Sleep Apnea in REM Sleep.

Rationale: REM sleep is associated with reduced ventilation and greater obstructive sleep apnea (OSA) severity than non-REM (nREM) sleep for reasons that have not been fully elucidated. Objectives: Here, we use direct physiological measurements to determine whether the pharyngeal compromise in REM sleep OSA is most consistent with 1) withdrawal of neural ventilatory drive or 2) deficits in pharyngeal pathophysiology per se (i.e., increased collapsibility and decreased muscle responsiveness). Methods: Sixty-three participants with OSA completed sleep studies with gold standard measurements of ventilatory "drive" (calibrated intraesophageal diaphragm EMG), ventilation (oronasal "ventilation"), and genioglossus EMG activity. Drive withdrawal was assessed by examining these measurements at nadir drive (first decile of drive within a stage). Pharyngeal physiology was assessed by examining collapsibility (lowered ventilation at eupneic drive) and responsiveness (ventilation-drive slope). Mixed-model analysis compared REM sleep with nREM sleep; sensitivity analysis examined phasic REM sleep. Measurements and Main Results: REM sleep (⩾10 min) was obtained in 25 patients. Compared with drive in nREM sleep, drive in REM sleep dipped to markedly lower nadir values (first decile, estimate [95% confidence interval], -21.8% [-31.2% to -12.4%] of eupnea; P < 0.0001), with an accompanying reduction in ventilation (-25.8% [-31.8% to -19.8%] of eupnea; P < 0.0001). However, there was no effect of REM sleep on collapsibility (ventilation at eupneic drive), baseline genioglossus EMG activity, or responsiveness. REM sleep was associated with increased OSA severity (+10.1 [1.8 to 19.8] events/h), but this association was not present after adjusting for nadir drive (+4.3 [-4.2 to 14.6] events/h). Drive withdrawal was exacerbated in phasic REM sleep. Conclusions: In patients with OSA, the pharyngeal compromise characteristic of REM sleep appears to be predominantly explained by ventilatory drive withdrawal rather than by preferential decrements in muscle activity or responsiveness. Preventing drive withdrawal may be the leading target for REM sleep OSA.

Breath-holding physiology, radiological severity and adverse outcomes in COVID-19 patients: A prospective validation study.

BACKGROUND AND OBJECTIVE: COVID-19 remains a major cause of respiratory failure, and means to identify future deterioration is needed. We recently developed a prediction score based on breath-holding manoeuvres (desaturation and maximal duration) to predict incident adverse COVID-19 outcomes. Here we prospectively validated our breath-holding prediction score in COVID-19 patients, and assessed associations with radiological scores of pulmonary involvement. METHODS: Hospitalized COVID-19 patients (N = 110, three recruitment centres) performed breath-holds at admission to provide a prediction score (Messineo et al.) based on mean desaturation (20-s breath-holds) and maximal breath-hold duration, plus baseline saturation, body mass index and cardiovascular disease. Odds ratios for incident adverse outcomes (composite of bi-level ventilatory support, ICU admission and death) were described for patients with versus without elevated scores (>0). Regression examined associations with chest x-ray (Brixia score) and computed tomography (CT; 3D-software quantification). Additional comparisons were made with the previously-validated '4C-score'. RESULTS: Elevated prediction score was associated with adverse COVID-19 outcomes (N = 12/110), OR[95%CI] = 4.54[1.17-17.83], p = 0.030 (positive predictive value = 9/48, negative predictive value = 59/62). Results were diminished with removal of mean desaturation from the prediction score (OR = 3.30[0.93-11.72]). The prediction score rose linearly with Brixia score (ß[95%CI] = 0.13[0.02-0.23], p = 0.026, N = 103) and CT-based quantification (ß = 1.02[0.39-1.65], p = 0.002, N = 45). Mean desaturation was also associated with both radiological assessment. Elevated 4C-scores (≥high-risk category) had a weaker association with adverse outcomes (OR = 2.44[0.62-9.56]). CONCLUSION: An elevated breath-holding prediction score is associated with almost five-fold increased adverse COVID-19 outcome risk, and with pulmonary deficits observed in chest imaging. Breath-holding may identify COVID-19 patients at risk of future respiratory failure.

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

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

The noradrenergic agent reboxetine plus the antimuscarinic hyoscine butylbromide reduces sleep apnoea severity: a double-blind, placebo-controlled, randomised crossover trial.

KEY POINTS: Recent animal and human physiology studies indicate that noradrenergic and muscarinic processes are key mechanisms that mediate pharyngeal muscle control during sleep. The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, whether these findings translate to the clinically relevant patient population of people with obstructive sleep apnoea (OSA), and the effects of the agents on OSA severity, are unknown. We found that reboxetine plus hyoscine butylbromide reduced OSA severity, including overnight hypoxaemia, via increases in pharyngeal muscle responsiveness, improvements in respiratory control and airway collapsibility without changing the respiratory arousal threshold. These findings provide mechanistic insight into the role of noradrenergic and anti-muscarinic agents on upper airway stability and breathing during sleep and are important for pharmacotherapy development for OSA. ABSTRACT: The noradrenergic agent reboxetine combined with the anti-muscarinic hyoscine butylbromide has recently been shown to improve upper airway function during sleep in healthy individuals. However, the effects of this drug combination on obstructive sleep apnoea (OSA) severity are unknown. Accordingly, this study aimed to determine if reboxetine plus hyoscine butylbromide reduces OSA severity. Secondary aims were to investigate the effects on key upper airway physiology and endotypic traits. Twelve people with OSA aged 52 ± 13 years, BMI = 30 ± 5 kg/m2 , completed a double-blind, randomised, placebo-controlled, crossover trial (ACTRN12617001326381). Two in-laboratory sleep studies with nasal mask, pneumotachograph, epiglottic pressure sensor and bipolar fine-wire electrodes into genioglossus and tensor palatini muscles were performed separated by approximately 1 week. Each participant received either reboxetine (4 mg) plus hyoscine butylbromide (20 mg), or placebo immediately prior to sleep. Polysomnography, upper airway physiology and endotypic estimates of OSA were compared between conditions. Reboxetine plus hyoscine butylbromide reduced the apnoea/hypopnoea index by (mean ± SD) 17 ± 17 events/h from 51 ± 30 to 33 ± 22 events/h (P = 0.005) and nadir oxygen saturation increased by 6 ± 5% from 82 ± 5 to 88 ± 2% (P = 0.002). The drug combination increased tonic genioglossus muscle responsiveness during non-REM sleep (median [25th, 75th centiles]: -0.007 [-0.0004, -0.07] vs. -0.12 [-0.02, -0.40] %maxEMG/cmH2 O, P = 0.02), lowered loop gain (0.43 ± 0.06 vs. 0.39 ± 0.07, P = 0.01), and improved airway collapsibility (90 [69, 95] vs. 93 [88, 96] %eupnoea, P = 0.02), without changing the arousal threshold (P = 0.39). These findings highlight the important role that noradrenergic and muscarinic processes have on upper airway function during sleep and the potential for pharmacotherapy to target these mechanisms to treat OSA.

Breath-holding as a novel approach to risk stratification in COVID-19.

BACKGROUND: Despite considerable progress, it remains unclear why some patients admitted for COVID-19 develop adverse outcomes while others recover spontaneously. Clues may lie with the predisposition to hypoxemia or unexpected absence of dyspnea ('silent hypoxemia') in some patients who later develop respiratory failure. Using a recently-validated breath-holding technique, we sought to test the hypothesis that gas exchange and ventilatory control deficits observed at admission are associated with subsequent adverse COVID-19 outcomes (composite primary outcome: non-invasive ventilatory support, intensive care admission, or death). METHODS: Patients with COVID-19 (N = 50) performed breath-holds to obtain measurements reflecting the predisposition to oxygen desaturation (mean desaturation after 20-s) and reduced chemosensitivity to hypoxic-hypercapnia (including maximal breath-hold duration). Associations with the primary composite outcome were modeled adjusting for baseline oxygen saturation, obesity, sex, age, and prior cardiovascular disease. Healthy controls (N = 23) provided a normative comparison. RESULTS: The adverse composite outcome (observed in N = 11/50) was associated with breath-holding measures at admission (likelihood ratio test, p = 0.020); specifically, greater mean desaturation (12-fold greater odds of adverse composite outcome with 4% compared with 2% desaturation, p = 0.002) and greater maximal breath-holding duration (2.7-fold greater odds per 10-s increase, p = 0.036). COVID-19 patients who did not develop the adverse composite outcome had similar mean desaturation to healthy controls. CONCLUSIONS: Breath-holding offers a novel method to identify patients with high risk of respiratory failure in COVID-19. Greater breath-hold induced desaturation (gas exchange deficit) and greater breath-holding tolerance (ventilatory control deficit) may be independent harbingers of progression to severe disease.

Addition of zolpidem to combination therapy with atomoxetine-oxybutynin increases sleep efficiency and the respiratory arousal threshold in obstructive sleep apnoea: A randomized trial.

BACKGROUND AND OBJECTIVE: Atomoxetine combined with oxybutynin (Ato-Oxy) has recently been shown to reduce obstructive sleep apnoea (OSA) severity by >60%. However, Ato-Oxy also modestly reduced the respiratory arousal threshold, which may decrease sleep quality/efficiency. We sought to investigate the additional effect of zolpidem with Ato-Oxy on sleep efficiency (primary outcome), the arousal threshold, OSA severity, other standard polysomnography (PSG) parameters, next-day sleepiness and alertness (secondary outcomes). METHODS: Twelve participants with OSA received 10 mg zolpidem plus Ato-Oxy (80-5 mg, respectively) or Ato-Oxy plus placebo prior to overnight in-laboratory PSG according to a double-blind, randomized, crossover design (1-week washout). Participants were fitted with an epiglottic catheter, a nasal mask and pneumotachograph to quantify arousal threshold and airflow. Next-day sleepiness and alertness were assessed via the Karolinska Sleepiness Scale and a driving simulation task. RESULTS: The addition of zolpidem increased sleep efficiency by 9% ± 13% (80.9% ± 16.9% vs. 88.2% ± 8.2%, p = 0.037) and the respiratory arousal threshold by 17% ± 18% (-26.6 ± 14.5 vs. -33.8 ± 20.3 cm H2 O, p = 0.004) versus Ato-Oxy + placebo. Zolpidem did not systematically change OSA severity. Combination therapy was well tolerated, and zolpidem did not worsen next-day sleepiness. However, median steering deviation during the driving simulator task increased following the zolpidem combination. CONCLUSION: Zolpidem improves sleep efficiency via an increase in the respiratory arousal threshold to counteract potential wake-promoting properties of atomoxetine in OSA. These changes occur without altering the rate of respiratory events or overnight hypoxaemia. However, while the addition of zolpidem does not increase next-day perceived sleepiness, caution is warranted given the potential impact on next-morning objective alertness.

Zolpidem increases sleep efficiency and the respiratory arousal threshold without changing sleep apnoea severity and pharyngeal muscle activity.

KEY POINTS: A decreased respiratory arousal threshold is one of the main contributors to obstructive sleep apnoea (OSA) pathogenesis. Several recent studies have sought to find a drug capable of increasing the respiratory arousal threshold without impairing pharyngeal muscle activity to reduce OSA severity, with variable success. Here we show that zolpidem increases the respiratory arousal threshold by ∼15%, an effect size which was insufficient to systematically decrease OSA severity as measured by the apnoea-hypopnoea index. Unlike recent physiological findings that showed paradoxical increases in pharyngeal muscle responsiveness during transient manipulations of airway pressure, zolpidem did not alter pharyngeal muscle responsiveness during natural sleep. It did, however, increase sleep efficiency without changing apnoea length, oxygen desaturation, next-day perceived sleepiness and alertness. These novel findings indicate that zolpidem was well tolerated and effective in promoting sleep in people with OSA, which may be therapeutically useful for people with OSA and comorbid insomnia. ABSTRACT: A recent physiology study performed using continuous positive airway pressure (CPAP) manipulations indicated that the hypnotic zolpidem increases the arousal threshold and genioglossus responsiveness in people with and without obstructive sleep apnoea (OSA). Thus, zolpidem may stabilise breathing and reduce OSA severity without CPAP. Accordingly, we sought to determine the effects of zolpidem on OSA severity, upper airway physiology and next-day sleepiness and alertness. Nineteen people with OSA with low-to-moderate arousal threshold received 10 mg zolpidem or placebo according to a double-blind, randomised, cross-over design. Participants completed two overnight in-laboratory polysomnographies (1-week washout), with an epiglottic catheter, intramuscular genioglossus electromyography, nasal mask and pneumotachograph to measure OSA severity, arousal threshold and upper airway muscle responsiveness. Next-morning sleepiness and alertness were also assessed. Zolpidem did not change the apnoea-hypopnoea index versus placebo (40.6 ± 12.3 vs. 40.3 ± 16.4 events/h (means ± SD), p = 0.938) or nadir oxyhaemoglobin saturation (79.6 ± 6.6 vs. 79.7 ± 7.4%, p = 0.932), but was well tolerated. Zolpidem increased sleep efficiency by 9 ± 14% (83 ± 11 vs. 73 ± 17%, p = 0.010). Arousal threshold increased by 15 ± 5% with zolpidem throughout all sleep stages (p = 0.010), whereas genioglossus muscle responsiveness did not change. Next-morning sleepiness and alertness were not different between nights. In summary, a single night of 10 mg zolpidem is well tolerated and does not cause next-day impairment in alertness or sleepiness, or overnight hypoxaemia in OSA. However, despite increases in arousal threshold without any change in pharyngeal muscle responsiveness, zolpidem does not alter OSA severity. It does, however, increase sleep efficiency by ∼10%, which may be beneficial in people with OSA and insomnia.

The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-controlled, Double-Blind Crossover Trial.

Rationale: There is currently no effective pharmacological treatment for obstructive sleep apnea (OSA). Recent investigations indicate that drugs with noradrenergic and antimuscarinic effects improve genioglossus muscle activity and upper airway patency during sleep. Objectives: We aimed to determine the effects of the combination of a norepinephrine reuptake inhibitor (atomoxetine) and an antimuscarinic (oxybutynin) on OSA severity (apnea-hypopnea index [AHI]; primary outcome) and genioglossus responsiveness (secondary outcome) in people with OSA. Methods: A total of 20 people completed a randomized, placebo-controlled, double-blind, crossover trial comparing 1 night of 80 mg atomoxetine plus 5 mg oxybutynin (ato-oxy) to placebo administered before sleep. The AHI and genioglossus muscle responsiveness to negative esophageal pressure swings were measured via in-laboratory polysomnography. In a subgroup of nine patients, the AHI was also measured when the drugs were administered separately. Measurements and Main Results: The participants' median (interquartile range) age was 53 (46-58) years and body mass index was 34.8 (30.0-40.2) kg/m2. ato-oxy lowered AHI by 63% (34-86%), from 28.5 (10.9-51.6) events/h to 7.5 (2.4-18.6) events/h (P < 0.001). Of the 15/20 patients with OSA on placebo (AHI > 10 events/hr), AHI was lowered by 74% (62-88%) (P < 0.001) and all 15 patients exhibited a ≥50% reduction. Genioglossus responsiveness increased approximately threefold, from 2.2 (1.1-4.7)%/cm H2O on placebo to 6.3 (3.0 to 18.3)%/cm H2O on ato-oxy (P < 0.001). Neither atomoxetine nor oxybutynin reduced the AHI when administered separately. Conclusions: A combination of noradrenergic and antimuscarinic agents administered orally before bedtime on 1 night greatly reduced OSA severity. These findings open new possibilities for the pharmacologic treatment of OSA. Clinical trial registered with www.clinicaltrials.gov (NCT02908529).

The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study.

AIMS: Apnoea-hypopnoea index (AHI), the universal clinical metric of sleep apnoea severity, poorly predicts the adverse outcomes of sleep apnoea, potentially because the AHI, a frequency measure, does not adequately capture disease burden. Therefore, we sought to evaluate whether quantifying the severity of sleep apnoea by the 'hypoxic burden' would predict mortality among adults aged 40 and older. METHODS AND RESULTS: The samples were derived from two cohort studies: The Outcomes of Sleep Disorders in Older Men (MrOS), which included 2743 men, age 76.3 ± 5.5 years; and the Sleep Heart Health Study (SHHS), which included 5111 middle-aged and older adults (52.8% women), age: 63.7 ± 10.9 years. The outcomes were all-cause and Cardiovascular disease (CVD)-related mortality. The hypoxic burden was determined by measuring the respiratory event-associated area under the desaturation curve from pre-event baseline. Cox models were used to calculate the adjusted hazard ratios for hypoxic burden. Unlike the AHI, the hypoxic burden strongly predicted CVD mortality and all-cause mortality (only in MrOS). Individuals in the MrOS study with hypoxic burden in the highest two quintiles had hazard ratios of 1.81 [95% confidence interval (CI) 1.25-2.62] and 2.73 (95% CI 1.71-4.36), respectively. Similarly, the group in the SHHS with hypoxic burden in the highest quintile had a hazard ratio of 1.96 (95% CI 1.11-3.43). CONCLUSION: The 'hypoxic burden', an easily derived signal from overnight sleep study, predicts CVD mortality across populations. The findings suggest that not only the frequency but the depth and duration of sleep related upper airway obstructions, are important disease characterizing features.

Structure and severity of pharyngeal obstruction determine oral appliance efficacy in sleep apnoea.

KEY POINTS: •Some patients with obstructive sleep apnoea (OSA) respond well to oral appliance therapy, whereas others do not for reasons that are unclear. •In the present study, we used gold-standard measurements to demonstrate that patients with a posteriorly-located tongue (natural sleep endoscopy) exhibit a preferential improvement in collapsibility (lowered critical closing pressure) with oral appliances. •We also show that patients with both posteriorly-located tongue and less severe collapsibility (predicted responder phenotype) exhibit greater improvements in severity of obstructive sleep apnoea (i.e. reduction in event frequency by 83%, in contrast to 48% in predicted non-responders). •The present study suggests that the structure and severity of pharyngeal obstruction determine the phenotype of sleep apnoea patients who benefit maximally from oral appliance efficacy. ABSTRACT: A major limitation to the administration of oral appliance therapy for obstructive sleep apnoea (OSA) is that therapeutic responses remain unpredictable. In the present study, we tested the hypotheses that oral appliance therapy (i) reduces pharyngeal collapsibility preferentially in patients with posteriorly-located tongue and (ii) is most efficacious (reduction in apnoea-hypopnea index; AHI) in patients with a posteriorly-located tongue and less-severe baseline pharyngeal collapsibility. Twenty-five OSA patients underwent upper airway endoscopy during natural sleep to assess tongue position (type I: vallecula entirely visible; type II: vallecula obscured; type III: vallecula and glottis obscured), as well as obstruction as a result of other pharyngeal structures (e.g. epiglottis). Additional sleep studies with and without oral appliance were performed to measure collapsibility (critical closing pressure; Pcrit) and assess treatment efficacy. Overall, oral appliance therapy reduced Pcrit by 3.9 ± 2.4 cmH2 O (mean ± SD) and AHI by 69 ± 19%. Therapy lowered Pcrit by an additional 2.7 ± 0.9 cmH2 O in patients with posteriorly-located tongue (types II and III) compared to those without (type I) (P < 0.008). Posteriorly-located tongue (p = 0.03) and lower collapsibility (p = 0.04) at baseline were significant determinants of (greater-than-average) treatment efficacy. Predicted responders (type II and III and Pcrit < 1 cmH2 O) exhibited a greater reduction in the AHI (83 ± 9 vs. 48 ± 8% baseline, P < 0.001) and a lower treatment AHI (9 ± 6 vs. 32 ± 15 events h-1 , P < 0.001) than predicted non-responders. The site and severity of pharyngeal collapse combine to determine oral appliance efficacy. Specifically, patients with a posteriorly-located tongue plus less-severe collapsibility are the strongest candidates for oral appliance therapy.

Quantifying the magnitude of pharyngeal obstruction during sleep using airflow shape.

RATIONALE AND OBJECTIVES: Non-invasive quantification of the severity of pharyngeal airflow obstruction would enable recognition of obstructive versus central manifestation of sleep apnoea, and identification of symptomatic individuals with severe airflow obstruction despite a low apnoea-hypopnoea index (AHI). Here we provide a novel method that uses simple airflow-versus-time ("shape") features from individual breaths on an overnight sleep study to automatically and non-invasively quantify the severity of airflow obstruction without oesophageal catheterisation. METHODS: 41 individuals with suspected/diagnosed obstructive sleep apnoea (AHI range 0-91 events·h-1) underwent overnight polysomnography with gold-standard measures of airflow (oronasal pneumotach: "flow") and ventilatory drive (calibrated intraoesophageal diaphragm electromyogram: "drive"). Obstruction severity was defined as a continuous variable (flow:drive ratio). Multivariable regression used airflow shape features (inspiratory/expiratory timing, flatness, scooping, fluttering) to estimate flow:drive ratio in 136 264 breaths (performance based on leave-one-patient-out cross-validation). Analysis was repeated using simultaneous nasal pressure recordings in a subset (n=17). RESULTS: Gold-standard obstruction severity (flow:drive ratio) varied widely across individuals independently of AHI. A multivariable model (25 features) estimated obstruction severity breath-by-breath (R2=0.58 versus gold-standard, p<0.00001; mean absolute error 22%) and the median obstruction severity across individual patients (R2=0.69, p<0.00001; error 10%). Similar performance was achieved using nasal pressure. CONCLUSIONS: The severity of pharyngeal obstruction can be quantified non-invasively using readily available airflow shape information. Our work overcomes a major hurdle necessary for the recognition and phenotyping of patients with obstructive sleep disordered breathing.

Internal Mammary Lymph Node Visualization as a Sentinel Sonographic Sign of Tuberculous Pleurisy.

BACKGROUND: Tuberculous pleurisy is one of the primary sites of extrapulmonary tuberculosis, but clinicians currently lack the diagnostic tools necessary for early recognition in the absence of typical signs and symptoms. With this study, we aimed to test the association between internal mammary adenopathies and tuberculous pleurisy (TP). METHODS: 60 patients with a post-thoracoscopic histological diagnosis of granulomatosis or acute infective pleurisy were retrospectively enrolled. All of them had chest sonography and/or CT scan data available. At least two expert chest sonography physicians re-analyzed the sonography images to look for any internal mammary adenopathy. Such findings were compared to the CT data. RESULTS: Chest sonography showed internal mammary adenopathy ipsilateral to the pleural effusion in 97 % of 29 patients who had a diagnosis of TP, and in 13 % of those with an acute infective pleurisy (p < 0.001). Receiver operator characteristic analysis revealed 97 % sensitivity and 87 % specificity for this technique in predicting TP (area under curve 0.92 ± 0.04, p < 0.001). CT detection power and node measures were significantly similar (p < 0.001). CONCLUSION: Sonographic internal mammary node visualization ipsilateral to the pleural effusion may become a sentinel sign for TP, contributing to early diagnosis or orienting the diagnostic management towards invasive procedures in uncertain cases.

Neural memory of the genioglossus muscle during sleep is stage-dependent in healthy subjects and obstructive sleep apnoea patients.

KEY POINTS: In most patients with obstructive sleep apnoea (OSA), there is a spontaneous resolution of the breathing disorders during slow wave sleep (SWS) for yet unknown reasons related to non-anatomical factors. Some recently identified forms of neural memory specific of upper airway muscles may play a role in this phenomenon. In the present study, we show for the first time that a form of memory of the genioglossus (tongue) muscle is greatly enhanced during SWS compared to non-rapid eye movement stage 2 sleep. The present study represents a step forward in understanding the mechanisms responsible for the spontaneous development of stable breathing during SWS in OSA patients and may help the discovery of novel therapeutic strategies for this disease. ABSTRACT: Several studies have shown that obstructive sleep apnoea (OSA) improves during slow wave sleep (SWS) for reasons that remain unclear. Recent studies have identified forms of neural memory such as short-term potentiation or after-discharge that can occur in response to upper airway obstruction. Neural memory may play a role in the development of stable breathing during SWS by increasing upper airway muscles activity in this sleep stage. We hypothesize that the after-discharge of the genioglossus muscle following upper airway obstruction is enhanced during SWS compared to non-rapid eye movement stage 2 (N2). During sleep, we performed five-breath drops in continuous positive airway pressure (CPAP-drop) to simulate obstructive events and reflexively activate the genioglossus. Immediately afterwards, CPAP was returned to an optimal level. Once the post-drop ventilation returned to eupnoea, the genioglossus after-discharge was measured as the time it took for genioglossus activity to return to baseline levels. In total, 171 CPAP-drops were analysed from a group of 16 healthy subjects and 19 OSA patients. A mixed-model analysis showed that after-discharge duration during SWS was 208% (95% confidence interval = 112% to 387%, P = 0.022) greater than during N2 after adjusting for covariates (ventilatory drive, CPAP levels). There was also a non-significant trend for a -35% reduction in after-discharge duration following an arousal vs. no-arousal from sleep (95% confidence interval = -59.5% to 5%, P = 0.08). Genioglossus after-discharge is two-fold greater in SWS vs. N2, which could partly explain the breathing stabilization described in OSA patients during this sleep stage.

Breath-holding as a means to estimate the loop gain contribution to obstructive sleep apnoea.

KEY POINTS: A hypersensitive ventilatory control system or elevated "loop gain" during sleep is a primary phenotypic trait causing obstructive sleep apnoea (OSA). Despite the multitude of methods available to assess the anatomical contributions to OSA during wakefulness in the clinical setting (e.g. neck circumference, pharyngometry, Mallampati score), it is currently not possible to recognize elevated loop gain in patients in this context. Loop gain during sleep can now be recognized using simplified testing during wakefulness, specifically in the form of a reduced maximal breath-hold duration, or a larger ventilatory response to voluntary 20-second breath-holds. We consider that easy breath-holding manoeuvres will enable daytime recognition of a high loop gain in OSA for more personalized intervention. ABSTRACT: Increased "loop gain" of the ventilatory control system promotes obstructive sleep apnoea (OSA) in some patients and offers an avenue for more personalized treatment, yet diagnostic tools for directly measuring loop gain in the clinical setting are lacking. Here we test the hypothesis that elevated loop gain during sleep can be recognized using voluntary breath-hold manoeuvres during wakefulness. Twenty individuals (10 OSA, 10 controls) participated in a single overnight study with voluntary breath-holding manoeuvres performed during wakefulness. We assessed (1) maximal breath-hold duration, and (2) the ventilatory response to 20 s breath-holds. For comparison, gold standard loop gain values were obtained during non-rapid eye movement (non-REM) sleep using the ventilatory response to 20 s pulses of hypoxic-hypercapnic gas (6% CO2 -14% O2 , mimicking apnoea). Continuous positive airway pressure (CPAP) was used to maintain airway patency during sleep. Additional measurements included gold standard loop gain measurement during wakefulness and steady-state loop gain measurement during sleep using CPAP dial-ups. Higher loop gain during sleep was associated with (1) a shorter maximal breath-hold duration (r2  = 0.49, P < 0.001), and (2) a larger ventilatory response to 20 s breath-holds during wakefulness (second breath; r2  = 0.50, P < 0.001); together these factors combine to predict high loop gain (receiver operating characteristic area-under-curve: 92%). Gold standard loop gain values were remarkably similar during wake and non-REM sleep. The results show that elevated loop gain during sleep can be identified using simple breath-holding manoeuvres performed during wakefulness. This may have implications for personalizing OSA treatment.

Palatal prolapse as a signature of expiratory flow limitation and inspiratory palatal collapse in patients with obstructive sleep apnoea.

In some individuals with obstructive sleep apnoea (OSA), the palate prolapses into the velopharynx during expiration, limiting airflow through the nose or shunting it out of the mouth. We hypothesised that this phenomenon causes expiratory flow limitation (EFL) and is associated with inspiratory "isolated" palatal collapse. We also wanted to provide a robust noninvasive means to identify this mechanism of obstruction.Using natural sleep endoscopy, 1211 breaths from 22 OSA patients were scored as having or not having palatal prolapse. The patient-level site of collapse (tongue-related, isolated palate, pharyngeal lateral walls and epiglottis) was also characterised. EFL was quantified using expiratory resistance at maximal epiglottic pressure. A noninvasive EFL index (EFLI) was developed to detect the presence of palatal prolapse and EFL using the flow signal alone. In addition, the validity of using nasal pressure was assessed.A cut-off value of EFLI >0.8 detected the presence of palatal prolapse and EFL with an accuracy of >95% and 82%, respectively. The proportion of breaths with palatal prolapse predicted isolated inspiratory palatal collapse with 90% accuracy.This study demonstrates that expiratory palatal prolapse can be quantified noninvasively, is associated with EFL and predicts the presence of inspiratory isolated palatal collapse.

Predicting epiglottic collapse in patients with obstructive sleep apnoea.

Obstructive sleep apnoea (OSA) is characterised by pharyngeal obstruction occurring at different sites. Endoscopic studies reveal that epiglottic collapse renders patients at higher risk of failed oral appliance therapy or accentuated collapse on continuous positive airway pressure. Diagnosing epiglottic collapse currently requires invasive studies (imaging and endoscopy). As an alternative, we propose that epiglottic collapse can be detected from the distinct airflow patterns it produces during sleep.23 OSA patients underwent natural sleep endoscopy. 1232 breaths were scored as epiglottic/nonepiglottic collapse. Several flow characteristics were determined from the flow signal (recorded simultaneously with endoscopy) and used to build a predictive model to distinguish epiglottic from nonepiglottic collapse. Additionally, 10 OSA patients were studied to validate the pneumotachograph flow features using nasal pressure signals.Epiglottic collapse was characterised by a rapid fall(s) in the inspiratory flow, more variable inspiratory and expiratory flow and reduced tidal volume. The cross-validated accuracy was 84%. Predictive features obtained from pneumotachograph flow and nasal pressure were strongly correlated.This study demonstrates that epiglottic collapse can be identified from the airflow signal measured during a sleep study. This method may enable clinicians to use clinically collected data to characterise underlying physiology and improve treatment decisions.