Circuit-dependent carbon dioxide rebreathing during continuous positive airway pressure.

BACKGROUND: The current standard treatment for obstructive sleep apnea (OSA), continuous positive airway pressure (CPAP), is characterized by a low adherence rate due to various factors including circuit-dependent carbon dioxide (CO2) rebreathing, which can exacerbated by disparate factors, such as low PAP, use of auto-titrating PAP or ramps. However, risk factors for rebreathing are often overlooked or poorly understood in clinical practice. Therefore, our objective was to evaluate the extent of rebreathing occurring with commonly used CPAP masks across varying PAPs, tidal volumes, and respiratory rates. METHODS: In a bench study, we assessed the rebreathing rate of nine masks interfacing a CPAP with a lung simulator providing different breathing respiratory rates (15 or 20 breaths/min) and tidal volumes (400, 500, 600, 700 and 750 mL). Additionally, a theoretical model was developed to describe the likelihood of CO2 rebreathing from four different masks at various breathing settings. RESULTS: Overall, all masks performed worse in situations characterized by low PAPs, high tidal volumes, and high respiratory rates. However, Dreamwear, Nuance, Siesta, Vitera, and particularly V2 masks exhibited greater susceptibility to rebreathing compared to F20, P10, Brevida, and Rio masks for the same variations of PAPs or ventilatory parameters. The mathematical model suggested that the risk of rebreathing for Rio, P10 and Nuance mask is negligible for respiratory rates of 10 breaths/min or below. CONCLUSIONS: Circuit-dependent CO2 rebreathing can be a common occurrence and warrants careful mask selection upon CPAP therapy initiation for optimal clinical outcomes.

Treatment of Sleep Apnea and Reduction in Blood Pressure: The Role of Heart Rate Response and Hypoxic Burden.

BACKGROUND: Obstructive sleep apnea is associated with increased blood pressure (BP). Obstructive sleep apnea treatment reduces BP with substantial variability, not explained by the apnea-hypopnea index, partly due to inadequate characterization of obstructive sleep apnea's physiological consequences, such as oxygen desaturation, cardiac autonomic response, and suboptimal treatment efficacy. We sought to examine whether a high baseline heart rate response (ΔHR), a marker of high cardiovascular risk in obstructive sleep apnea, predicts a larger reduction in post-treatment systolic BP (SBP). Furthermore, we aimed to assess the extent to which a reduction in SBP is explained by a treatment-related reduction in hypoxic burden (HB). METHODS: ΔHR and HB were measured from pretreatment and posttreatment polygraphy, followed by a 24-hour BP assessment in 168 participants treated with continuous positive airway pressure or nocturnal supplemental oxygen from the HeartBEAT study (Heart Biomarker Evaluation in Apnea Treatment). Multiple linear regression models assessed whether high versus mid (reference) ΔHR predicted a larger reduction in SBP (primary outcome) and whether there was an association between treatment-related reductions in SBP and HB. RESULTS: A high versus mid ΔHR predicted improvement in SBP (adjusted estimate, 5.8 [95% CI, 1.0-10.5] mm Hg). Independently, a greater treatment-related reduction in HB was significantly associated with larger reductions in SBP (4.2 [95% CI, 0.9-7.5] mm Hg per 2 SD treatment-related reduction in HB). Participants with substantial versus minimal treatment-related reductions in HB had a 6.5 (95% CI, 2.5-10.4) mm Hg drop in SBP. CONCLUSIONS: A high ΔHR predicted a more favorable BP response to therapy. Furthermore, the magnitude of the reduction in BP was partly explained by a greater reduction in HB.

Physiological Determinants of Snore Loudness.

Rationale: The physiological factors modulating the severity of snoring have not been adequately described. Airway collapse or obstruction is generally the leading determinant of snore sound generation; however, we suspect that ventilatory drive is of equal importance. Objective: To determine the relationship between airway obstruction and ventilatory drive on snore loudness. Methods: In 40 patients with suspected or diagnosed obstructive sleep apnea (1-98 events/hr), airflow was recorded via a pneumotachometer attached to an oronasal mask, ventilatory drive was recorded using calibrated intraesophageal diaphragm electromyography, and snore loudness was recorded using a calibrated microphone attached over the trachea. "Obstruction" was taken as the ratio of ventilation to ventilatory drive and termed flow:drive, i.e., actual ventilation as a percentage of intended ventilation. Lower values reflect increased flow resistance. Using 165,063 breaths, mixed model analysis (quadratic regression) quantified snore loudness as a function of obstruction, ventilatory drive, and the presence of extreme obstruction (i.e., apneic occlusion). Results: In the presence of obstruction (flow:drive = 50%, i.e., doubled resistance), snore loudness increased markedly with increased drive (+3.4 [95% confidence interval, 3.3-3.5] dB per standard deviation [SD] change in ventilatory drive). However, the effect of drive was profoundly attenuated without obstruction (at flow:drive = 100%: +0.23 [0.08-0.39] dB per SD change in drive). Similarly, snore loudness increased with increasing obstruction exclusively in the presence of increased drive (at drive = 200% of eupnea: +2.1 [2.0-2.2] dB per SD change in obstruction; at eupneic drive: +0.14 [-0.08 to 0.28] dB per SD change). Further, snore loudness decreased substantially with extreme obstruction, defined as flow:drive <20% (-9.9 [-3.3 to -6.6] dB vs. unobstructed eupneic breathing). Conclusions: This study highlights that ventilatory drive, and not simply pharyngeal obstruction, modulates snore loudness. This new framework for characterizing the severity of snoring helps better understand the physiology of snoring and is important for the development of technologies that use snore sounds to characterize sleep-disordered breathing.

Hypoxic burden to guide CPAP treatment allocation in patients with obstructive sleep apnoea: a post hoc study of the ISAACC trial.

BACKGROUND: Hypoxic burden (HB) has emerged as a strong predictor of cardiovascular risk in obstructive sleep apnoea (OSA). We aimed to assess the potential of HB to predict the cardiovascular benefit of treating OSA with continuous positive airway pressure (CPAP). METHODS: This was a post hoc analysis of the ISAACC trial (ClinicalTrials.gov: NCT01335087) including non-sleepy patients with acute coronary syndrome (ACS) diagnosed with OSA (apnoea-hypopnoea index ≥15 events·h-1) by respiratory polygraphy. Patients were randomised to CPAP or usual care and followed for a minimum of 1 year. HB was calculated as the total area under all automatically identified desaturations divided by total sleep time. Patients were categorised as having high or low baseline HB according to the median value (73.1%min·h-1). Multivariable Cox regression models were used to assess whether the effect of CPAP on the incidence of cardiovascular outcomes was dependent on the baseline HB level. RESULTS: The population (362 patients assigned to CPAP and 365 patients assigned to usual care) was middle-aged (mean age 59.7 years), overweight/obese and mostly male (84.5%). A significant interaction was found between the treatment arm and the HB categories. In the high HB group, CPAP treatment was associated with a significant reduction in the incidence of cardiovascular events (HR 0.57, 95% CI 0.34-0.96). In the low HB group, CPAP-treated patients exhibited a trend toward a higher risk of cardiovascular outcomes than those receiving usual care (HR 1.33, 95% CI 0.79-2.25). The differential effect of the treatment depending on the baseline HB level followed a dose-response relationship. CONCLUSION: In non-sleepy ACS patients with OSA, high HB levels were associated with a long-term protective effect of CPAP on cardiovascular prognosis.

Hypoxic Burden Based on Automatically Identified Desaturations Is Associated with Adverse Health Outcomes.

Rationale: Recent studies have shown that sleep apnea-specific intermittent hypoxemia quantified by the hypoxic burden (HB) predicted cardiovascular disease (CVD)-related mortality in community-based and clinical cohorts. Calculation of HB is based on manual scoring of hypopneas and apneas, which is time-consuming and prone to interscorer variability. Objective: To validate a novel method to quantify the HB that is based on automatically scored desaturations. Methods: The sample included 5,655 middle-aged or older adults from the Sleep Heart Health Study (52.8% women; age, 63.2 ± 11.3 yr). The original HB method was based on a subject-specific search window obtained from an ensemble average of oxygen saturation signals (as measured by pulse oximetry) and synchronized with respect to the termination of scored respiratory events. In this study, however, the search window was obtained from ensemble average of oxygen saturation signals that synchronized with respect to the minimum of all automatically identified desaturations (⩾2% and other thresholds, including 3% and 4%, in sensitivity analyses). The time interval between the two maxima around the minimum saturation was defined as the search window. The oximetry-derived HB (HBOxi) was defined as the total area under all desaturation curves (restricted by the search window) divided by the total sleep time. Logistic and Cox regression models assessed the adjusted odds ratio (aOR)/hazard ratio of excessive daytime sleepiness (EDS), hypertension (HTN), and CVD mortality per 1-standard deviation increase in HBOxi after adjusting for several covariates and confounders. Results: The Spearman's rank correlation between HB (median [interquartile range], 34.4 [18.4-59.8] % min/h) and HBOxi (median [interquartile range], 34.5 [21.6-53.8] % min/h) was 0.81 (P < 0.001). Similar to HB, HBOxi was significantly associated with EDS (aOR [95% confidence interval (CI)], 1.17 [1.09-1.26] per standard deviation), HTN (aOR [95% CI], 1.13 [1.05-1.21]), and CVD mortality (adjusted hazard ratio [95% CI], 1.15 [1.01-1.30]) in fully adjusted models. Conclusions: The HBOxi was highly correlated with the HB based on manually scored apneas and hypopneas and was associated with EDS, HTN, and CVD mortality with similar effect sizes as previously reported. This method could be incorporated into wearable technology that accurately records oxygen saturation signals.

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.

Drive versus Pressure Contributions to Genioglossus Activity in Obstructive Sleep Apnea.

Rationale: Loss of pharyngeal dilator muscle activity is a key determinant of respiratory events in obstructive sleep apnea (OSA). After the withdrawal of wakefulness stimuli to the genioglossus at sleep onset, mechanoreceptor negative pressure and chemoreceptor ventilatory drive feedback govern genioglossus activation during sleep, but the relative contributions of drive and pressure stimuli to genioglossus activity across progressive obstructive events remain unclear. We recently showed that drive typically falls during events, whereas negative pressures increase, providing a means to assess their individual contributions to the time course of genioglossus activity. Objectives: For the first time, we critically test whether the loss of drive could explain the loss of genioglossus activity observed within events in OSA. Methods: We examined the time course of genioglossus activity (EMGgg; intramuscular electromyography), ventilatory drive (intraesophageal diaphragm electromyography), and esophageal pressure during spontaneous respiratory events (using the ensemble-average method) in 42 patients with OSA (apnea-hypopnea index 5-91 events/h). Results: Multivariable regression demonstrated that the falling-then-rising time course of EMGgg may be well explained by falling-then-rising drive and rising negative pressure stimuli (model R = 0.91 [0.88-0.98] [95% confidence interval]). Overall, EMGgg was 2.9-fold (0.47-∞) more closely associated with drive than pressure stimuli (ratio of standardized coefficients, ßdrive:ßpressure; ∞ denotes absent pressure contribution). However, individual patient results were heterogeneous: approximately one-half (n = 22 of 42) exhibited drive-dominant responses (i.e., ßdrive:ßpressure > 2:1), and one-quarter (n = 11 of 42) exhibited pressure-dominant EMGgg responses (i.e., ßdrive:ßpressure < 1:2). Patients exhibiting more drive-dominant EMGgg responses experienced greater event-related EMGgg declines (12.9 [4.8-21.0] %baseline/standard deviation of ßdrive:ßpressure; P = 0.004, adjusted analysis). Conclusions: Loss of genioglossus activity precipitating events in patients with OSA is strongly associated with a contemporaneous loss of drive and is greatest in those whose activity tracks drive rather than pressure stimuli. These findings were upheld for events without prior arousal. Responding to falling drive rather than rising negative pressure during events may be deleterious; future therapeutic strategies whose aim is to sustain genioglossus activity by preferentially enhancing responses to rising pressure rather than falling drive are of interest.

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.

The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial.

STUDY OBJECTIVES: The potential sedative effect of dronabinol and the high expression of cannabinoid receptors on the hypoglossal motor nuclei makes this agent a good candidate for obstructive sleep apnea (OSA) pharmacotherapy to be tested with atomoxetine, a noradrenergic reuptake inhibitor that reduced OSA severity in combination with oxybutynin. Here we tested the effect of atomoxetine 80 mg plus dronabinol (Ato-Dro) at 2 different doses (5 and 10 mg) vs. baseline and atomoxetine alone in a 2-center, open-label, dose-escalating trial. The primary outcome was the effect of Ato-Dro vs. baseline on OSA severity (apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation). Safety of the combination and self-reported outcomes were also assessed. METHODS: Fifteen patients with OSA received progressively increasing Ato-Dro doses (dose escalation was performed every week, starting from Ato-Dro 40-2.5 mg, then 80-5 mg and finally 80-10 mg). A clinical, in-lab polysomnography was performed at baseline, on Ato-Dro 80-5 and Ato-Dro 80-10 mg. RESULTS: Ato-Dro 80-10 mg did not significantly reduce apnea-hypopnea index, hypopneas associated with 4% oxygen desaturation, and hypoxic burden and yielded limited clinical benefit vs. baseline and atomoxetine alone. However, Ato-Dro 80-5 mg did improve OSA severity (Δapnea-hypopnea index = 8.3[0.3, 16.3] events/h; mean [confidence interval]; Δhypoxic burden = 37.7[12.5, 62.7] %min/h) and multiple self-reported outcomes vs. baseline and/or atomoxetine alone. Ato-Dro administration was characterized by several potentially harmful side effects and treatment discontinuation in 1/3 of cases. CONCLUSIONS: Ato-Dro 80-5 mg might be useful to reduce OSA severity and lead to self-reported improvement in those who could tolerate the combination. However, given the numerous side effects and the exploratory nature of this open-label study, our results warrant further validation in larger trials. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Study for Efficacy and Dose Escalation of AD313 + Atomoxetine (SEED) (SEED); URL: https://clinicaltrials.gov/ct2/show/NCT05101122; Identifier: NCT05101122. CITATION: Messineo L, Norman D, Ojile J. The combination of atomoxetine and dronabinol for the treatment of obstructive sleep apnea: a dose-escalating, open-label trial. J Clin Sleep Med. 2023;19(7):1183-1190.

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.

Effect of Pimavanserin on the Respiratory Arousal Threshold from Sleep: A Randomized Trial.

Rationale: A low respiratory arousal threshold is a key endotype responsible for obstructive sleep apnea (OSA) pathogenesis. Pimavanserin is an antiserotoninergic capable of suppressing CO2-mediated arousals without affecting the respiratory motor response in animal models, and thus it holds potential for increasing the arousal threshold in OSA and subsequently reducing OSA severity. Objectives: We measured the effect of pimavanserin on arousal threshold (primary outcome), OSA severity, arousal index, and other OSA endotypes (secondary outcomes). Methods: A total of 18 OSA participants were studied in a randomized, double-blind, crossover study. Patients received a single dose of placebo or pimavanserin 34 mg 4 hours before in-lab polysomnography. Airflow was measured with an oronasal mask attached to a pneumotachograph, and ventilatory drive was recorded with an intraesophageal electromyography catheter. Results are presented as mean or median changes (Δ) and 95% confidence intervals (CIs). Results: Pimavanserin did not increase the arousal threshold, nor did it decrease OSA severity or arousal index. It, however, prolonged total sleep time (Δ[confidence interval (CI)], 39.5 [95%CI, -1.2 to 80.1] min). In an exploratory analysis, a subgroup of seven patients who had a 10% or more increase in arousal threshold on pimavanserin exhibited a decrease in AHI4 (hypopneas associated with 4% desaturation) (Δ[CI], 5.6 [95%CI, 3.6-11.1] events/h) and hypoxic burden (Δ[CI], 22.3 [95%CI, 6.6-32.3] %min/h). Conclusions: A single dose of pimavanserin did not have a significant effect on arousal threshold or OSA severity. However, in a post hoc analysis, a subset of patients who exhibited an increase in arousal threshold on pimavanserin showed a small decrease in OSA severity. Thus, if the arousal threshold could be increased with pimavanserin, perhaps with longer dosing to reach higher drug blood concentrations, then the desired effect on OSA severity might be achievable. Clinical trial registered with ClinicalTrials.gov (NCT04538755).

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 Combination of Betahistine and Oxybutynin Increases Respiratory Control Sensitivity (Loop Gain) in People with Obstructive Sleep Apnea: A Randomized, Placebo-Controlled Trial.

Rationale: There are widespread histaminergic projections throughout the brain, including hypoglossal nuclei, that modulate pharyngeal muscle tone and respiratory control. Hence, histaminergic stimulation pharmacologically may increase pharyngeal muscle tone and stabilize respiratory control (loop gain) to reduce obstructive sleep apnea (OSA) severity. Antimuscarinics also increase REM pharyngeal muscle tone in rats. Thus, a combination of histaminergic and anti-muscarinic drugs may be a novel target for OSA pharmacotherapy. However, this has not been investigated. Accordingly, we aimed to test the effects of betahistine (Beta), an H3-autoreceptor antagonist which thereby increases histamine levels, in combination with the antimuscarinic oxybutynin (Oxy), on OSA severity, OSA endotypes, polysomnography parameters and next-day sleepiness and alertness. Methods: Thirteen adults with OSA received either Beta-Oxy (96-5mg) or placebo according to a randomized, crossover, double-blind design, prior to polysomnography. Participants completed the Karolinska Sleep Scale and Leeds Sleep Evaluation Questionnaire and a driving simulation task to quantify next-day sleepiness and alertness. OSA endotypes were estimated through validated algorithms using polysomnography. Results: Compared to placebo, Beta-Oxy increased respiratory control sensitivity (loop gain) (0.52[0.24] vs 0.60[0.34], median [IQR], P = 0.021) without systematically changing OSA severity (34.4±17.2 vs 40.3±27.3 events/h, mean±SD, P = 0.124), sleep efficiency, arousal index or markers of hypoxemia. Beta-Oxy was well tolerated and did not worsen next-day sleepiness/alertness. Conclusion: Rather than stabilize breathing during sleep, Beta-Oxy increases loop gain, which is likely to be deleterious for most people with OSA. However, in certain conditions characterized by blunted respiratory control (eg, obesity hypoventilation syndrome), interventions to increase loop gain may be beneficial.

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.

Mouth Closing to Improve the Efficacy of Mandibular Advancement Devices in Sleep Apnea.

Rationale: Mouth breathing increases upper airway collapsibility, leading to decreased efficacy of obstructive sleep apnea (OSA) treatments. We hypothesized that the use of mandibular advancement devices (MAD) increases mouth breathing, and thus, using an adhesive mouthpiece (AMT) to prevent mouth breathing in combination with MAD can improve the treatment efficacy. Objectives: To evaluate the efficacy of MAD + AMT in comparison with MAD alone. Methods: A prospective crossover pilot study was designed to test this hypothesis. Briefly, adult participants with an apnea-hypopnea index (AHI) between 10 and 50 events/h at the screening visit were randomized to no treatment (baseline), MAD treatment, AMT treatment, and MAD + AMT treatment. As a primary analysis, absolute AHI was compared between MAD and MAD + AMT arms. Secondary analyses included quantifying the percent change in AHI, percentage of complete (AHI < 5 events/h) and incomplete (5-10 events/h) responders, and the efficacy of AMT alone in comparison with other treatment arms. Results: A total of 21 participants were included (baseline AHI = 24.3 ± 9.9 events/h). The median AHI (interquartile range) in the MAD and MAD + AMT arms were 10.5 (5.4-19.6) events/h and 5.6 (2.2-11.7) events/h (P = 0.02), respectively. A total of 76% of individuals achieved an AHI of <10 events/h in the MAD + AMT arm versus 43% in the MAD arm (P < 0.01). Finally, the observed effect was similar in moderate to severe OSA (AHI ⩾ 15 events/h) in terms of absolute reduction and treatment responders, and AMT alone did not significantly reduce the AHI compared with baseline. Conclusions: A combination of an adhesive mouthpiece and MAD is a more effective therapy than MAD alone. These findings may help improve clinical decision making in sleep apnea.

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 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.

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.