Low-Dose Morphine Does Not Cause Sleepiness in COPD: A Secondary Analysis of a Randomized Trial.

RATIONALE: Regular, low-dose, sustained-release morphine is frequently prescribed for persistent breathlessness in chronic obstructive pulmonary disease (COPD). However, effects on daytime sleepiness, perceived sleep quality and daytime function have not been rigorously investigated. OBJECTIVES: Determine the effects of regular, low-dose, sustained-release morphine on sleep parameters in COPD. METHODS: Pre-specified secondary analyses of validated sleep questionnaire data from a randomized trial of daily, low-dose, sustained -release morphine versus placebo over four weeks commencing at 8mg or 16mg/day with blinded up-titration over two weeks to a maximum of 32mg/day. Primary outcomes for these analyses were week-1 Epworth Sleepiness Scale (ESS) and Karolinska Sleepiness Scale (KSS) responses on morphine versus placebo. Secondary outcomes included Leeds Sleep Evaluation Questionnaire (LSEQ) scores (end of weeks 1 and 4), KSS and ESS beyond week-1 and associations between breathlessness, morphine, and questionnaire scores. MEASUREMENTS AND MAIN RESULTS: 156 people were randomized. Week-1 sleepiness scores were not different on morphine versus placebo (∆ESS [95%CI] versus placebo: 8mg group: -0.59 [-1.99, 0.81], p=0.41; 16mg group: -0.72 [-2.33, 0.9], p=0.38; ∆KSS versus placebo: 8mg group: 0.11 [-0.7, 0.9], p=0.78; 16mg group: -0.41 [-1.31, 0.49], p=0.37). This neutral effect persisted at later timepoints. In addition, participants who reported reduced breathlessness with morphine at 4 weeks also had improvement in LSEQ domain scores including perceived sleep quality and daytime function. CONCLUSIONS: Regular, low-dose morphine does not worsen sleepiness when used for breathlessness in COPD. Individual improvements in breathlessness with morphine may be related to improvements in sleep.

A novel TASK channel antagonist nasal spray reduces sleep apnea severity in physiological responders: a randomized, blinded, trial.

Preclinical and human physiological studies indicate that topical, selective TASK 1/3 K+ channel antagonism increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and nasal breathing during sleep. The primary aim of this study was to determine the effects of BAY2586116 nasal spray on obstructive sleep apnea (OSA) severity and whether individual responses vary according to differences in physiological responses and route of breathing. Ten people (5 females) with OSA [apnea-hypopnea index (AHI) = 47 ± 26 events/h (means ± SD)] who completed previous sleep physiology studies with BAY2586116 were invited to return for three polysomnography studies to quantify OSA severity. In random order, participants received either placebo nasal spray (saline), BAY2586116 nasal spray (160 µg), or BAY2586116 nasal spray (160 µg) restricted to nasal breathing (chinstrap or mouth tape). Physiological responders were defined a priori as those who had improved upper airway collapsibility (critical closing pressure ≥2 cmH2O) with BAY2586116 nasal spray (NCT04236440). There was no systematic change in apnea-hypopnea index (AHI3) from placebo versus BAY2586116 with either unrestricted or nasal-only breathing versus placebo (47 ± 26 vs. 43 ± 27 vs. 53 ± 33 events/h, P = 0.15). However, BAY2586116 (unrestricted breathing) reduced OSA severity in physiological responders compared with placebo (e.g., AHI3 = 28 ± 11 vs. 36 ± 12 events/h, P = 0.03 and ODI3 = 18 ± 10 vs. 28 ± 12 events/h, P = 0.02). Morning blood pressure was also lower in physiological responders after BAY2586116 versus placebo (e.g., systolic blood pressure = 137 ± 24 vs. 147 ± 21 mmHg, P < 0.01). In conclusion, BAY2586116 reduces OSA severity during sleep in people who demonstrate physiological improvement in upper airway collapsibility. These findings highlight the therapeutic potential of this novel pharmacotherapy target in selected individuals.NEW & NOTEWORTHY Preclinical findings in pigs and humans indicate that blocking potassium channels in the upper airway with topical nasal application increases pharyngeal dilator muscle activity and reduces upper airway collapsibility. In this study, BAY2586116 nasal spray (potassium channel blocker) reduced sleep apnea severity in those who had physiological improvement in upper airway collapsibility. BAY2586116 lowered the next morning's blood pressure. These findings highlight the potential for this novel therapeutic approach to improve sleep apnea in certain people.

Regional associations between inspiratory tongue dilatory movement and genioglossus activity during wakefulness in people with obstructive sleep apnoea.

Inspiratory tongue dilatory movement is believed to be mediated via changes in neural drive to genioglossus. However, this has not been studied during quiet breathing in humans. Therefore, this study investigated this relationship and its potential role in obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue dilatory movement, quantified with tagged magnetic resonance imaging, and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in nine controls [apnoea-hypopnea index (AHI) ≤5 events/h] and 37 people with untreated OSA (AHI >5 events/h). Measurements were obtained for 156 neuromuscular compartments (85%). Analysis was adjusted for nadir epiglottic pressure during inspiration. Only for 106 compartments (68%) was a larger anterior (dilatory) movement associated with a higher phasic EMG [mixed linear regression, beta = 0.089, 95% CI [0.000, 0.178], t(99) = 1.995, P = 0.049, hereafter EMG↗/mvt↗]. For the remaining 50 (32%) compartments, a larger dilatory movement was associated with a lower phasic EMG [mixed linear regression, beta = -0.123, 95% CI [-0.224, -0.022], t(43) = -2.458, P = 0.018, hereafter EMG↘/mvt↗]. OSA participants had a higher odds of having at least one decoupled EMG↘/mvt↗ compartment (binary logistic regression, odds ratio [95% CI]: 7.53 [1.19, 47.47] (P = 0.032). Dilatory tongue movement was minimal (>1 mm) in nearly all participants with only EMG↗/mvt↗ compartments (86%, 18/21). These results demonstrate that upper airway dilatory mechanics cannot be predicted from genioglossus EMG, particularly in people with OSA. Tongue movement associated with minimal genioglossus activity suggests co-activation of other airway dilator muscles. KEY POINTS: Inspiratory tongue movement is thought to be mediated through changes in genioglossus activity. However, it is unknown if this relationship is altered by obstructive sleep apnoea (OSA). During awake supine quiet nasal breathing, inspiratory tongue movement, quantified with tagged magnetic resonance imaging (MRI), and inspiratory phasic genioglossus EMG normalised to maximum EMG were measured in four tongue compartments of people with and without OSA. Larger tongue anterior (dilatory) movement was associated with higher phasic genioglossus EMG for 68% of compartments. OSA participants had an ∼7-times higher odds of having at least one compartment for which a larger anterior tongue movement was not associated with a higher phasic EMG than controls. Therefore, higher genioglossus phasic EMG does not consistently translate into tongue dilatory movement, particularly in people with OSA. Large dilatory tongue movements can occur despite minimal genioglossus inspiratory activity, suggesting co-activation of other pharyngeal muscles.

Effects of the antipsychotic quetiapine on sleep and breathing: a review of clinical findings and potential mechanisms.

Quetiapine is an antipsychotic medication indicated for schizophrenia and bipolar disorder. However, quetiapine also has hypnotic properties and as such is increasingly being prescribed at low doses 'off-label' in people with insomnia symptoms. Pharmacologically, in addition to its dopaminergic properties, quetiapine also modulates multiple other transmitter systems involved in sleep/wake modulation and potentially breathing. However, very little is known about the impact of quetiapine on obstructive sleep apnoea (OSA), OSA endotypes including chemosensitivity, and control of breathing. Given that many people with insomnia also have undiagnosed OSA, it is important to understand the effects of quetiapine on OSA and its mechanisms. Accordingly, this concise review covers the existing knowledge on the effects of quetiapine on sleep and breathing. Further, we highlight the pharmacodynamics of quetiapine and its potential to alter key OSA endotypes to provide potential mechanistic insight. Finally, an agenda for future research priorities is proposed to fill the current key knowledge gaps.

Healthy lifestyle is associated with reduced cardiovascular disease, depression and mortality in people at elevated risk of sleep apnea.

We assessed: (1) the independent and joint association of obstructive sleep apnea risk and healthy lifestyle with common consequences (excessive daytime sleepiness, depression, cardiovascular disease and stroke) of obstructive sleep apnea; and (2) the effect of healthy lifestyle on survival in people with increased obstructive sleep apnea risk. Data from 13,694 adults (median age 46 years; 50% men) were used for cross-sectional and survival analyses (mortality over 15 years). A healthy lifestyle score with values from 0 (most unhealthy) to 5 (most healthy) was determined based on diet, alcohol intake, physical activity, smoking and body mass index. In the cross-sectional analysis, obstructive sleep apnea risk was positively associated with all chronic conditions and excessive daytime sleepiness in a dose-response manner (p for trend < 0.001). The healthy lifestyle was inversely associated with all chronic conditions (p for trend < 0.001) but not with excessive daytime sleepiness (p for trend = 0.379). Higher healthy lifestyle score was also associated with reduced odds of depression and cardiovascular disease. We found an inverse relationship between healthy lifestyle score with depression (p for trend < 0.001), cardiovascular disease (p for trend = 0.003) and stroke (p for trend = 0.025) among those who had high obstructive sleep apnea risk. In the survival analysis, we found an inverse association between healthy lifestyle and all-cause mortality for all categories of obstructive sleep apnea risk (moderate/high- and high-risk groups [p for trend < 0.001]). This study emphasises the crucial role of a healthy lifestyle in mitigating the effects of obstructive sleep apnea risk in individuals with an elevated obstructive sleep apnea risk.

Opioid Use Disorder, Sleep Deficiency, and Ventilatory Control: Bidirectional Mechanisms and Therapeutic Targets.

Opioid use continues to rise globally. So too do the associated adverse consequences. Opioid use disorder (OUD) is a chronic and relapsing brain disease characterized by loss of control over opioid use and impairments in cognitive function, mood, pain perception, and autonomic activity. Sleep deficiency, a term that encompasses insufficient or disrupted sleep due to multiple potential causes, including sleep disorders, circadian disruption, and poor sleep quality or structure due to other medical conditions and pain, is present in 75% of patients with OUD. Sleep deficiency accompanies OUD across the spectrum of this addiction. The focus of this concise clinical review is to highlight the bidirectional mechanisms between OUD and sleep deficiency and the potential to target sleep deficiency with therapeutic interventions to promote long-term, healthy recovery among patients in OUD treatment. In addition, current knowledge on the effects of opioids on sleep quality, sleep architecture, sleep-disordered breathing, sleep apnea endotypes, ventilatory control, and implications for therapy and clinical practice are highlighted. Finally, an actionable research agenda is provided to evaluate the basic mechanisms of the relationship between sleep deficiency and OUD and the potential for behavioral, pharmacologic, and positive airway pressure treatments targeting sleep deficiency to improve OUD treatment outcomes.

Multinight Prevalence, Variability, and Diagnostic Misclassification of Obstructive Sleep Apnea.

Rationale: Recent studies suggest that obstructive sleep apnea (OSA) severity can vary markedly from night to night, which may have important implications for diagnosis and management. Objectives: This study aimed to assess OSA prevalence from multinight in-home recordings and the impact of night-to-night variability in OSA severity on diagnostic classification in a large, global, nonrandomly selected community sample from a consumer database of people that purchased a novel, validated, under-mattress sleep analyzer. Methods: A total of 67,278 individuals aged between 18 and 90 years underwent in-home nightly monitoring over an average of approximately 170 nights per participant between July 2020 and March 2021. OSA was defined as a nightly mean apnea-hypopnea index (AHI) of more than 15 events/h. Outcomes were multinight global prevalence and likelihood of OSA misclassification from a single night's AHI value. Measurements and Main Results: More than 11.6 million nights of data were collected and analyzed. OSA global prevalence was 22.6% (95% confidence interval, 20.9-24.3%). The likelihood of misdiagnosis in people with OSA based on a single night ranged between approximately 20% and 50%. Misdiagnosis error rates decreased with increased monitoring nights (e.g., 1-night F1-score = 0.77 vs. 0.94 for 14 nights) and remained stable after 14 nights of monitoring. Conclusions: Multinight in-home monitoring using novel, noninvasive under-mattress sensor technology indicates a global prevalence of moderate to severe OSA of approximately 20%, and that approximately 20% of people diagnosed with a single-night study may be misclassified. These findings highlight the need to consider night-to-night variation in OSA diagnosis and management.

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.

Novel avenues to approach non-CPAP therapy and implement comprehensive obstructive sleep apnoea care.

Recent advances in obstructive sleep apnoea (OSA) pathophysiology and translational research have opened new lines of investigation for OSA treatment and management. Key goals of such investigations are to provide efficacious, alternative treatment and management pathways that are better tailored to individual risk profiles to move beyond the traditional continuous positive airway pressure (CPAP)-focused, "one size fits all" trial-and-error approach, which is too frequently inadequate for many patients. Identification of different clinical manifestations of OSA (clinical phenotypes) and underlying pathophysiological phenotypes (endotypes) that contribute to OSA have provided novel insights into underlying mechanisms and have underpinned these efforts. Indeed, this new knowledge has provided the framework for precision medicine for OSA to improve treatment success rates with existing non-CPAP therapies such as mandibular advancement devices and upper airway surgery, and newly developed therapies such as hypoglossal nerve stimulation and emerging therapies such as pharmacotherapies and combination therapy. Additionally, these concepts have provided insight into potential physiological barriers to CPAP adherence for certain patients. This review summarises the recent advances in OSA pathogenesis, non-CPAP treatment, clinical management approaches and highlights knowledge gaps for future research. OSA endotyping and clinical phenotyping, risk stratification and personalised treatment allocation approaches are rapidly evolving and will further benefit from the support of recent advances in e-health and artificial intelligence.

Comorbid insomnia and sleep apnoea is associated with all-cause mortality.

BACKGROUND: Increased mortality has been reported in people with insomnia and in those with obstructive sleep apnoea (OSA). However, these conditions commonly co-occur and the combined effect of comorbid insomnia and sleep apnoea (COMISA) on mortality risk is unknown. This study used Sleep Heart Health Study (SHHS) data to assess associations between COMISA and all-cause mortality risk. METHODS: Insomnia was defined as difficulties falling asleep, maintaining sleep and/or early morning awakenings from sleep ≥16 times per month, and daytime impairments. OSA was defined as an apnoea-hypopnoea index ≥15 events·h-1. COMISA was defined if both conditions were present. Multivariable adjusted Cox proportional hazards models were used to determine the association between COMISA and all-cause mortality (n=1210) over 15 years of follow-up. RESULTS: 5236 participants were included. 2708 (52%) did not have insomnia/OSA (reference group), 170 (3%) had insomnia-alone, 2221 (42%) had OSA-alone and 137 (3%) had COMISA. COMISA participants had a higher prevalence of hypertension (OR 2.00, 95% CI 1.39-2.90) and cardiovascular disease (CVD) (OR 1.70, 95% CI 1.11-2.61) compared with the reference group. Insomnia-alone and OSA-alone were associated with higher risk of hypertension but not CVD compared with the reference group. Compared with the reference group, COMISA was associated with a 47% (hazard ratio 1.47, 95% CI 1.06-2.07) increased risk of mortality. The association between COMISA and mortality was consistent across multiple definitions of OSA and insomnia. CONCLUSIONS: COMISA was associated with higher rates of hypertension and CVD at baseline, and an increased risk of all-cause mortality compared with no insomnia/OSA.

The association of co-morbid insomnia and sleep apnea with prevalent cardiovascular disease and incident cardiovascular events.

Insomnia and obstructive sleep apnea commonly co-occur (co-morbid insomnia and sleep apnea), and their co-occurrence has been associated with worse cardiometabolic and mental health. However, it remains unknown if people with co-morbid insomnia and sleep apnea are at a heightened risk of incident cardiovascular events. This study used longitudinal data from the Sleep Heart Health Study (N = 5803) to investigate potential associations between co-morbid insomnia and sleep apnea and cardiovascular disease prevalence at baseline and cardiovascular event incidence over ~11 years follow-up. Insomnia was defined as self-reported difficulties initiating and/or maintaining sleep AND daytime impairment. Obstructive sleep apnea was defined as an apnea-hypopnea index ≥ 15 events per hr sleep. Co-morbid insomnia and sleep apnea was defined if both conditions were present. Data from 4160 participants were used for this analysis. The prevalence of no insomnia/obstructive sleep apnea, insomnia only, obstructive sleep apnea only and co-morbid insomnia and sleep apnea was 53.2%, 3.1%, 39.9% and 1.9%, respectively. Co-morbid insomnia and sleep apnea was associated with a 75% (odd ratios [95% confidence interval]; 1.75 [1.14, 2.67]) increase in likelihood of having cardiovascular disease at baseline after adjusting for pre-specified confounders. In the unadjusted model, co-morbid insomnia and sleep apnea was associated with a twofold increase (hazard ratio, 95% confidence interval: 2.00 [1.33, 2.99]) in risk of cardiovascular event incidence. However, after adjusting for pre-specified covariates, co-morbid insomnia and sleep apnea was not significantly associated with incident cardiovascular events (hazard ratio 1.38 [0.92, 2.07]). Comparable findings were obtained when an alternative definition of insomnia (difficulties initiating and/or maintaining sleep without daytime impairment) was used.

Research Priorities for Patients with Heart Failure and Central Sleep Apnea. An Official American Thoracic Society Research Statement.

Background: Central sleep apnea (CSA) is common among patients with heart failure and has been strongly linked to adverse outcomes. However, progress toward improving outcomes for such patients has been limited. The purpose of this official statement from the American Thoracic Society is to identify key areas to prioritize for future research regarding CSA in heart failure.Methods: An international multidisciplinary group with expertise in sleep medicine, pulmonary medicine, heart failure, clinical research, and health outcomes was convened. The group met at the American Thoracic Society 2019 International Conference to determine research priority areas. A statement summarizing the findings of the group was subsequently authored using input from all members.Results: The workgroup identified 11 specific research priorities in several key areas: 1) control of breathing and pathophysiology leading to CSA, 2) variability across individuals and over time, 3) techniques to examine CSA pathogenesis and outcomes, 4) impact of device and pharmacological treatment, and 5) implementing CSA treatment for all individualsConclusions: Advancing care for patients with CSA in the context of heart failure will require progress in the arenas of translational (basic through clinical), epidemiological, and patient-centered outcome research. Given the increasing prevalence of heart failure and its associated substantial burden to individuals, society, and the healthcare system, targeted research to improve knowledge of CSA pathogenesis and treatment is a priority.

Knowledge, attitudes, and practice patterns of obstructive sleep apnea among speech-language pathologists.

INTRODUCTION: Obstructive sleep apnea (OSA) is a common sleep-related breathing disorder characterised by repeated narrowing and closure of the upper airway during sleep. Despite growing evidence that dysphagia is a frequent sequela of OSA, the role of speech-language pathologists (SLPs) in managing OSA remains unclear. The aim of this international study was to evaluate SLPs knowledge, attitudes, and experience of OSA. METHODS: A validated questionnaire, OSA Knowledge and Attitudes (OSAKA), was distributed to SLPs internationally via an online survey. Additional information on demographics, educational history, and clinical practices was ascertained. RESULTS: From a total of 1647 respondents, 822 clinicians from twenty-four countries were included in the final analysis. Knowledge of OSA among SLPs was limited; the mean (SD) rate of correct answers was 55% (22%). Over half of SLPs reported patients with OSA on their caseload, with the majority of patients referred for dysphagia services. Yet, only half of SLPs reported confidence in their ability to assess or manage dysphagia in patients with OSA. SLPs' experience of OSA had an effect on their knowledge and attitudes [F (2, 817) = 17.279, p < 0.001]. CONCLUSIONS: SLPs are involved in the management of patients with OSA but are practising with limited knowledge and confidence. The findings highlight the need to increase OSA education and training for SLPs. In addition, there is a need for targeted research to increase the evidence base for development of clinical practice guidelines for dysphagia management in patients with OSA.

Effect of Regular, Low-Dose, Extended-release Morphine on Chronic Breathlessness in Chronic Obstructive Pulmonary Disease: The BEAMS Randomized Clinical Trial.

Importance: Chronic breathlessness is common in people with chronic obstructive pulmonary disease (COPD). Regular, low-dose, extended-release morphine may relieve breathlessness, but evidence about its efficacy and dosing is needed. Objective: To determine the effect of different doses of extended-release morphine on worst breathlessness in people with COPD after 1 week of treatment. Design, Setting, and Participants: Multicenter, double-blind, placebo-controlled randomized clinical trial including people with COPD and chronic breathlessness (defined as a modified Medical Research Council score of 3 to 4) conducted at 20 centers in Australia. People were enrolled between September 1, 2016, and November 20, 2019, and followed up through December 26, 2019. Interventions: People were randomized 1:1:1 to 8 mg/d or 16 mg/d of oral extended-release morphine or placebo during week 1. At the start of weeks 2 and 3, people were randomized 1:1 to 8 mg/d of extended-release morphine, which was added to the prior week's dose, or placebo. Main Outcomes and Measures: The primary outcome was change in the intensity of worst breathlessness on a numerical rating scale (score range, 0 [none] to 10 [being worst or most intense]) using the mean score at baseline (from days -3 to -1) to the mean score after week 1 of treatment (from days 5 to 7) in the 8 mg/d and 16 mg/d of extended-release morphine groups vs the placebo group. Secondary outcomes included change in daily step count measured using an actigraphy device from baseline (day -1) to the mean step count from week 3 (from days 19 to 21). Results: Among the 160 people randomized, 156 were included in the primary analyses (median age, 72 years [IQR, 67 to 78 years]; 48% were women) and 138 (88%) completed treatment at week 1 (48 in the 8 mg/d of morphine group, 43 in the 16 mg/d of morphine group, and 47 in the placebo group). The change in the intensity of worst breathlessness at week 1 was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -0.3 [95% CI, -0.9 to 0.4]) or between the 16 mg/d of morphine group and the placebo group (mean difference, -0.3 [95%, CI, -1.0 to 0.4]). At week 3, the secondary outcome of change in mean daily step count was not significantly different between the 8 mg/d of morphine group and the placebo group (mean difference, -1453 [95% CI, -3310 to 405]), between the 16 mg/d of morphine group and the placebo group (mean difference, -1312 [95% CI, -3220 to 596]), between the 24 mg/d of morphine group and the placebo group (mean difference, -692 [95% CI, -2553 to 1170]), or between the 32 mg/d of morphine group and the placebo group (mean difference, -1924 [95% CI, -47 699 to 921]). Conclusions and Relevance: Among people with COPD and severe chronic breathlessness, daily low-dose, extended-release morphine did not significantly reduce the intensity of worst breathlessness after 1 week of treatment. These findings do not support the use of these doses of extended-release morphine to relieve breathlessness. Trial Registration: ClinicalTrials.gov Identifier: NCT02720822.

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.

Vulnerability to Postoperative Complications in Obstructive Sleep Apnea: Importance of Phenotypes.

Obstructive sleep apnea (OSA) is a common comorbidity in patients undergoing surgical procedures. Patients with OSA are at heightened risk of postoperative complications. Current treatments for OSA focus on alleviating upper airway collapse due to impaired upper airway anatomy. Although impaired upper airway anatomy is the primary cause of OSA, the pathogenesis of OSA is highly variable from person to person. In many patients, nonanatomical traits play a critical role in the development of OSA. There are 4 key traits or "phenotypes" that contribute to OSA pathogenesis. In addition to (1) impaired upper airway anatomy, nonanatomical contributors include: (2) impaired upper airway dilator muscle responsiveness; (3) low respiratory arousal threshold (waking up too easily to minor airway narrowing); and (4) unstable control of breathing (high loop gain). Each of these phenotypes respond differently to postoperative factors, such as opioid medications. An understanding of these phenotypes and their highly varied interactions with postoperative risk factors is key to providing safer personalized care for postoperative patients with OSA. Accordingly, this review describes the 4 OSA phenotypes, highlights how the impact on OSA severity from postoperative risk factors, such as opioids and other sedatives, is influenced by OSA phenotypes, and outlines how this knowledge can be applied to provide individualized care to minimize postoperative risk in surgical patients with OSA.

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.

Changes in pharyngeal collapsibility and genioglossus reflex responses to negative pressure during the respiratory cycle in obstructive sleep apnoea.

KEY POINTS: Impaired pharyngeal anatomy and increased airway collapsibility is a major cause of obstructive sleep apnoea (OSA) and a mediator of its severity. Upper airway reflexes to changes in airway pressure provide important protection against airway closure. This study shows increased pharyngeal collapsibility and attenuated genioglossus reflex responses during expiration in people with OSA. ABSTRACT: Upper airway collapse contributes to obstructive sleep apnoea (OSA) pathogenesis. Pharyngeal dilator muscle activity varies throughout the respiratory cycle and may contribute to dynamic changes in pharyngeal collapsibility. However, whether upper airway collapsibility and reflex responses to changes in airway pressure vary throughout the respiratory cycle in OSA is unclear. Thus, this study quantified differences in upper airway collapsibility and genioglossus electromyographic (EMG) activity and reflex responses during different phases of the respiratory cycle. Twelve middle-aged people with OSA (2 female) were fitted with standard polysomnography equipment: a nasal mask, pneumotachograph, two fine-wire intramuscular electrodes into the genioglossus, and a pressure catheter positioned at the epiglottis and a second at the choanae (the collapsible portion of the upper airway). At least 20 brief (∼250 ms) pressure pulses (∼-11 cmH2 O at the mask) were delivered every 2-10 breaths during four conditions: (1) early inspiration, (2) mid-inspiration, (3) early expiration, and (4) mid-expiration. Mean baseline genioglossus EMG activity 100 ms prior to pulse delivery and genioglossus reflex responses were quantified for each condition. The upper airway collapsibility index (UACI), quantified as 100 × (nadir choanal - epiglottic pressure)/nadir choanal pressure during negative pressure pulses, varied throughout the respiratory cycle (early inspiration = 43 ± 25%, mid-inspiration = 29 ± 19%, early expiration = 83 ± 19% and mid-expiration = 95 ± 11% (mean ± SD) P < 0.01). Genioglossus EMG activity was lower during expiration (e.g. mid-expiration vs. mid-inspiration = 76 ± 23 vs. 127 ± 41% of early-inspiration, P < 0.001). Similarly, genioglossus reflex excitation was delayed (39 ± 11 vs. 23 ± 7 ms, P < 0.001) and reflex excitation amplitude attenuated during mid-expiration versus early inspiration (209 ± 36 vs. 286 ± 80%, P = 0.009). These findings may provide insight into the physiological mechanisms of pharyngeal collapse in OSA.

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.

Regional respiratory movement of the tongue is coordinated during wakefulness and is larger in severe obstructive sleep apnoea.

KEY POINTS: Coordination of the neuromuscular compartments of the tongue is critical to maintain airway patency. Currently, little is known about the extent to which regional tongue dilatory motion is coordinated in heathy people and if this coordination is altered in people with obstructive sleep apnoea (OSA). We show that regional tongue muscle coordination in people with and without OSA during wakefulness is associated with effective airway dilatation during inspiration, using dynamic tagged magnetic resonance imaging. The maximal movement of four compartments of the tongue were correlated and occurred concurrently towards the end of inspiration. If tongue movement was observed, people with more severe OSA had larger movement and moved more compartments (up to four) to maintain airway patency, while people without OSA moved only one compartment. These results suggest that airway patency is preserved during wakefulness in people with OSA via active dilatory movement of the genioglossus. ABSTRACT: Maintaining airway patency when supine requires neural drive to the genioglossus horizontal and oblique neuromuscular compartments (superior fan-like and inferior horizontal genioglossus, regions that are innervated by different branches of the hypoglossal nerve) to be coordinated during breathing, but it is unknown if this coordination is altered in obstructive sleep apnoea (OSA). This study aimed to assess coordination of airway dilatory motion across four mid-sagittal tongue compartments during inspiration (i.e. anterior and posterior of the horizontal and oblique compartments), and compare it in controls and OSA patients. Fifty-four participants (12 women, aged 20-73 years) underwent dynamic 'tagged' magnetic resonance imaging during wakefulness. Ten participants had no OSA [apnoea hypopnoea index (AHI) < 5 events h-1 ], 14 had mild OSA (5 < AHI ≤ 15 events h-1 ), 12 had moderate OSA (15 < AHI ≤ 30 events h-1 ) and 18 had severe OSA (AHI > 30 events h-1 ). A higher AHI was associated with a greater anterior movement of the anterior and posterior horizontal compartments (Spearman, r = -0.32, P = 0.02 for both), but not in the oblique compartments. If movement was observed, higher OSA severity was associated with an anterior movement of a greater number of compartments. Controls only moved the posterior horizontal compartment while the anterior horizontal compartment also moved in OSA participants. Oblique compartments moved only in people with severe OSA. The maximal anterior inspiratory movement of the four compartments was highly correlated (Spearman, P < 0.001) and occurred concurrently. The posterior horizontal compartment had the greatest anterior motion. These results suggest that airway patency is preserved during wakefulness in people with OSA via active dilatory movement of the genioglossus.