Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity.

BACKGROUND: Obstructive sleep apnea is characterized by disordered breathing during sleep and is associated with major cardiovascular complications; excess adiposity is an etiologic risk factor. Tirzepatide may be a potential treatment. METHODS: We conducted two phase 3, double-blind, randomized, controlled trials involving adults with moderate-to-severe obstructive sleep apnea and obesity. Participants who were not receiving treatment with positive airway pressure (PAP) at baseline were enrolled in trial 1, and those who were receiving PAP therapy at baseline were enrolled in trial 2. The participants were assigned in a 1:1 ratio to receive either the maximum tolerated dose of tirzepatide (10 mg or 15 mg) or placebo for 52 weeks. The primary end point was the change in the apnea-hypopnea index (AHI, the number of apneas and hypopneas during an hour of sleep) from baseline. Key multiplicity-controlled secondary end points included the percent change in AHI and body weight and changes in hypoxic burden, patient-reported sleep impairment and disturbance, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure. RESULTS: At baseline, the mean AHI was 51.5 events per hour in trial 1 and 49.5 events per hour in trial 2, and the mean body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) was 39.1 and 38.7, respectively. In trial 1, the mean change in AHI at week 52 was -25.3 events per hour (95% confidence interval [CI], -29.3 to -21.2) with tirzepatide and -5.3 events per hour (95% CI, -9.4 to -1.1) with placebo, for an estimated treatment difference of -20.0 events per hour (95% CI, -25.8 to -14.2) (P<0.001). In trial 2, the mean change in AHI at week 52 was -29.3 events per hour (95% CI, -33.2 to -25.4) with tirzepatide and -5.5 events per hour (95% CI, -9.9 to -1.2) with placebo, for an estimated treatment difference of -23.8 events per hour (95% CI, -29.6 to -17.9) (P<0.001). Significant improvements in the measurements for all prespecified key secondary end points were observed with tirzepatide as compared with placebo. The most frequently reported adverse events with tirzepatide were gastrointestinal in nature and mostly mild to moderate in severity. CONCLUSIONS: Among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, hsCRP concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes. (Funded by Eli Lilly; SURMOUNT-OSA ClinicalTrials.gov number, NCT05412004.).

Comparative short-term safety and efficacy of hypnotics: A quantitative risk-benefit analysis.

Several professional societies have provided recommendations for prescribing medications for insomnia. None has provided an integrative analysis that concurrently quantifies safety and efficacy (e.g., risk-benefit ratios). This represents an important gap for informing clinician decision-making. Accordingly, the aim of the present review is to provide such an analysis for five classes of sleep-promoting medications. Adverse event data values were extracted from the most recent FDA-approved package inserts and converted to an integer before being placebo-adjusted and standardized as a rate per 1000 (AEr). Efficacy data, pre-to-post self-reported data for active and placebo conditions were acquired from pivotal trials identified in "white papers" and systematic reviews/meta-analyses. Weighted effect sizes were calculated for subjective sleep latency, wake time after sleep onset and total sleep time, and then were averaged by medication class for each sleep continuity variable. Overall efficacy was represented by a single variable, SWT (sleep latency + wake time after sleep onset + total sleep time). Risk-benefit was represented using a simple ratio value. For safety, it was found that melatonin receptor agonists had the lowest adverse event rate (AEr = 43.1), and non-benzodiazepine benzodiazepine receptor agonists had the highest rate (AEr = 255.0). For efficacy, it was found that the pre-to-post placebo adjusted effect sizes were largest for benzodiazepines (effect size = 1.94) and smallest for melatonin receptor agonists (effect size = 0.109). For risk-benefit, histamine antagonist had the most favourable profile (risk-benefit = 69.5), while melatonin receptor agonist had the least favourable profile (risk-benefit = 395.7). Overall, the combined metric for risk-benefit suggests that treatment with a histamine antagonist is optimal and potentially represents the best first-line therapy for the medical management of insomnia.

Improving sleep health management in primary care: A potential role for community nurses?

AIMS: To explore community nurses sleep health practices and their perspectives on improving sleep health care provision. DESIGN: An exploratory study utilizing the qualitative description methodology. METHODS: Semi-structured interviews were conducted with community nurses from May 2019 - October 2021. Interviews were audio-recorded, transcribed, and subjected to an inductive thematic analysis using a constructivist-interpretive paradigm. RESULTS: Twenty-three Australian community nurses were interviewed. Participants frequently encountered sleep disturbances/disorders in their patients. Data analysis yielded three main themes: (1) Sleep health in the community serviced, (2) sleep health awareness and management, and (3) community nurses' A to Z of improving sleep health. The most common sleep disorder presentations were insomnia and sleep apnea. Although most community sleep apnea cases were appropriately managed, insomnia was often mismanaged. Participants described their sleep health knowledge as deficient, with the majority advocating for increased sleep-related education tailored to their profession. Other important factors needed for improving sleep health provision were standardized patient treatment/referral pathways, increased interprofessional collaboration, and sufficient time for patient consults. CONCLUSION: Community nurses service a patient population that requires increased sleep health care. However, they are currently underequipped to do so, leading to suboptimal treatment provision. Providing community nurses with the appropriate resources, such as increased sleep-related education and standardized treatment frameworks, could enable them to better manage sleep disturbance/disorder presentations, such as insomnia. IMPACT: Little is known about how community nurses care for patients with sleep disturbance/sleep disorders. This study found that contemporary sleep health care was lacking due to knowledge deficits, competing challenges, and a need for standardized care pathways. These findings can inform the development of targeted education/training and standardized guidelines for community nurses providing sleep health care to patients as well as the design of future practice models of care provision. PATIENT OR PUBLIC CONTRIBUTION: Previous research by authors has involved extensive engagement with patients and health professionals, such as community pharmacists, general practitioners, and naturopaths who play a role in sleep health in the primary health care sector. These previous research projects built a significant understanding of the patient and health practitioner experience and have provided the background to the concept and design of this study.

Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea.

It is challenging to determine which patients with obstructive sleep apnea (OSA) have impaired driving ability. Vulnerability to this neurobehavioral impairment may be explained by lower brain metabolites levels involved in mitochondrial metabolism. This study compared markers of brain energy metabolism in OSA patients identified as vulnerable vs resistant to driving impairment following extended wakefulness. 44 patients with moderate-severe OSA underwent 28hr extended wakefulness with three 90min driving simulation assessments. Using a two-step cluster analysis, objective driving data (steering deviation and crashes) from the 2nd driving assessment (22.5 h awake) was used to categorise patients into vulnerable (poor driving, n = 21) or resistant groups (good driving, n = 23). 1 H magnetic resonance spectra were acquired at baseline using two scan sequences (short echo PRESS and longer echo-time asymmetric PRESS), focusing on key metabolites, creatine, glutamate, N-acetylaspartate (NAA) in the hippocampus, anterior cingulate cortex and left orbito-frontal cortex. Based on cluster analysis, the vulnerable group had impaired driving performance compared with the resistant group and had lower levels of creatine (PRESS p = ns, APRESS p = 0.039), glutamate, (PRESS p < 0.01, APRESS p < 0.01), NAA (PRESS p = 0.038, APRESS p = 0.035) exclusively in the left orbito-frontal cortex. Adjusted analysis, higher glutamate was associated with a 21% (PRESS) and 36% (APRESS) reduced risk of vulnerable classification. Brain mitochondrial bioenergetics in the frontal brain regions are impaired in OSA patients who are vulnerable to driving impairment following sleep loss. These findings provide a potential way to identify at risk OSA phenotype when assessing fitness to drive, but this requires confirmation in larger future studies.

Safety of higher doses of melatonin in adults: A systematic review and meta-analysis.

Melatonin is commonly used for sleep and jetlag at low doses. However, there is less documentation on the safety of higher doses, which are being increasingly used for a wide variety of conditions, including more recently COVID-19 prevention and treatment. The aim of this review was to investigate the safety of higher doses of melatonin in adults. Medline, Scopus, Embase and PsycINFO databases from inception until December 2019 with convenience searches until October 2020. Randomised controlled trials investigating high-dose melatonin (≥10 mg) in human adults over 30 years of age were included. Two investigators independently abstracted articles using PRISMA guidelines. Risk of bias was assessed by a committee of three investigators. 79 studies were identified with a total of 3861 participants. Studies included a large range of medical conditions. The meta-analysis was pooled data using a random effects model. The outcomes examined were the number of adverse events (AEs), serious adverse events (SAEs) and withdrawals due to AEs. A total of 29 studies (37%) made no mention of the presence or absence of AEs. Overall, only four studies met the pre-specified low risk of bias criteria for meta-analysis. In that small subset, melatonin did not cause a detectable increase in SAEs (Rate Ratio = 0.88 [0.52, 1.50], p = .64) or withdrawals due to AEs (0.93 [0.24, 3.56], p = .92), but did appear to increase the risk of AEs such as drowsiness, headache and dizziness (1.40 [1.15, 1.69], p < .001). Overall, there has been limited AE reporting from high-dose melatonin studies. Based on this limited evidence, melatonin appears to have a good safety profile. Better safety reporting in future long-term trials is needed to confirm this as our confidence limits were very wide due to the paucity of suitable data.

Sleep-Dependent Memory in Older People With and Without MCI: The Relevance of Sleep Microarchitecture, OSA, Hippocampal Subfields, and Episodic Memory.

This study aimed to determine if, relative to cognitively healthy controls, sleep-dependent memory consolidation (SDMC) is diminished in mild cognitive impairment (MCI), a group at high risk of conversion to dementia. We also sought to determine whether SDMC is associated with sleep characteristics, daytime episodic memory, and hippocampal integrity. Participants with MCI (n = 43) and controls (n = 20) underwent clinical and neuropsychological profiling. From polysomnography, apnea hypopnea index (AHI) and non-REM sleep spindle characteristics were derived. From magnetic resonance imaging, hippocampal subfield volumes were computed. Participants learned a novel 32-item word-pair prior to sleep; morning retention of the word-pairs was used to determine SDMC. Results showed that SDMC did not differ between MCI and controls, but there was a large effect size decrement in SDMC in those with multiple domain MCI (Hedge's g = 0.85). In MCI, poorer SDMC was correlated with CA1 and CA3 hippocampal atrophy, shorter spindle duration, and worse daytime episodic memory. In controls, poorer SDMC was associated with higher AHI. Impaired daytime memory consolidation, reduced hippocampal volumes, shorter sleep spindles, and greater sleep apnea severity are indicators of diminished SDMC in older adults and should be explored in future studies.

Predictors of weight loss in obese patients with obstructive sleep apnea.

PURPOSE: Consistent predictors of weight loss outcomes with very low-energy diets (VLEDs) in obstructive sleep apnea (OSA) have not been identified. This study aimed to identify variables predictive of weight loss success in obese patients with OSA undertaking an intensive weight loss programme. METHODS: We analysed biological, psychological, and behavioural variables as potential predictors of weight loss in obese patients with OSA after a 2-month VLED followed by one of two 10-month weight loss maintenance diets. Actigraphy, in-lab polysomnography, urinary catecholamines, and various psychological and behavioural variables were measured at baseline, 2, and 12 months. Spearman's correlations analysed baseline variables with 2-month weight loss, and 2-month variables with 2-12 month-weight change. RESULTS: Forty-two patients completed the VLED and thirty-eight completed the maintenance diets. Actigraphy data revealed that late bedtime (rs = - 0.45, p = < 0.01) was correlated with 2-month weight loss. The change in the time that participants got out of bed (rise-time) from baseline to two months was also correlated with 2-month weight loss (rs = 0.36, p = 0.03). The Impact of Weight on Quality of Life-Lite questionnaire (IWQOL) Public Distress domain (rs = - 0.54, p = < 0.01) and total (rs = - 0.38, p = 0.02) scores were correlated with weight loss maintenance from 2 to 12 months. CONCLUSIONS: Results from this small patient sample reveal correlations between actigraphy characteristics and weight loss in obese patients with OSA. We suggest the IWQOL may also be a useful clinical tool to identify OSA patients at risk of weight regain after initial weight loss. CLINICAL TRIAL REGISTRATION: This clinical trial was prospectively registered on 18/02/2013 with the Australia and New Zealand Clinical Trials Registry (ACTRN12613000191796). PUBLIC REGISTRY TITLE: Sleep, Lifestyle, Energy, Eating, Exercise Program for the management of sleep apnea patients indicated for weight loss treatment: A randomised, controlled pilot study. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363680.

Australian Consultant Pharmacists' Potential Roles in Sleep Health Care: Exploring a New Avenue for Improving the Management of Insomnia.

BACKGROUND: The first-line treatment for insomnia is cognitive-behavioral therapy. However, there is persistent use of pharmacotherapy, particularly, sedative-hypnotics. Consultant pharmacists can provide medication review services for people using multiple medications. Therefore, they are well placed to provide sleep health/insomnia care with regard to sedative-hypnotic use and behavioral treatment recommendations/sleep health education. However, this avenue is, as yet, unexplored. OBJECTIVES: To explore consultant pharmacists' current sleep health-related provisions and what their perspectives are around developing/implementing a consultant pharmacist-led behavioral service for insomnia. METHODS: Qualitative semi-structured interviews were conducted with a convenience-based sample of consultant pharmacists. Interviews were audio-recorded, transcribed, and inductively analyzed. RESULTS: Twenty-four consultant pharmacists were interviewed. Three themes were gauged: 1) Trivializing insomnia and sleep health, 2) Providing patient-centered care, 3) Service implementation - What do we need to consider? Participants commonly dealt with older patients and frequently encountered patients with sleep complaints/taking sleep medications. Generally, it was believed that sleep health was given minimal priority, with other comorbidities taking precedence in health provisions. Patients' attitudes toward management approaches were regarded critical to future treatment developments. While interested in expanding their sleep health/insomnia practice, participants expressed the need for appropriate education/training, funding, and collaborative treatment frameworks. CONCLUSION: Insomnia/sleep health concerns are growing. Primary health professionals need to scale up their sleep health-care provisions to accommodate for this health demand. Consultant pharmacists are interested/willing to expand their sleep-related practice and provide evidence-based insomnia therapies; however, factors such as education/training, service configuration support, and patient attitudes should be addressed.

The Effectiveness of Digital Insomnia Treatment with Adjunctive Wearable Technology: A Pilot Randomized Controlled Trial.

OBJECTIVE: This pilot trial aimed to provide evidence for whether the integration of a wearable device with digital behavioral therapy for insomnia (dBTi) improves treatment outcomes and engagement. PARTICIPANTS AND METHODS: One hundred and twenty-eight participants with insomnia symptoms were randomized to a 3-week dBTi program (SleepFix®) with a wearable device enabling sleep data synchronization (dBTi+wearable group; n = 62) or dBTi alone (n = 66). Participants completed the Insomnia Severity Index (ISI) and modified Pittsburgh Sleep Quality Index (PSQI) parameters: wake-after-sleep-onset (WASO), sleep-onset-latency (SOL), and total sleep time (TST) at baseline and weeks 1, 2, 3, and primary endpoint of week 6 and follow-up at 12 weeks. Engagement was measured by the number of daily sleep diaries logged in the app. RESULTS: There was no difference in ISI change scores between the groups from pre- to post-treatment (Cohen's d= 0.7, p= .061). The dBTi+wearable group showed greater improvements in WASO (d= 0.8, p = .005) and TST (d= 0.3, p= .049) compared to the dBTi group. Significantly greater engagement (sleep diary entries) was observed in the dBTi+wearable group (mean = 22.4, SD = 10.0) compared to the dBTi group (mean = 14.1, SD = 14.2) (p = .010). CONCLUSIONS: This pilot trial found that integration of wearable device with a digital insomnia therapy enhanced user engagement and led to improvements in sleep parameters compared to dBTi alone. These findings suggest that adjunctive wearable technologies may improve digital insomnia therapy effectiveness.

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.

The effect of acute morphine on sleep in male patients suffering from sleep apnea: Is there a genetic effect? An RCT Study.

Questionnaire-based studies have suggested genetic differences in sleep symptoms in chronic opioid users. The present study aims to investigate if there is a genetic effect on sleep architecture and quantitative electroencephalogram (EEG) in response to acute morphine. Under a randomized, double-blind, placebo-controlled, crossover design, 68 men with obstructive sleep apnea undertook two overnight polysomnographic studies conducted at least 1 week apart. Each night they received either 40 mg of controlled-release morphine or placebo. Sleep architecture and quantitative EEG were compared between conditions. Blood was sampled before sleep and on the next morning for genotyping and pharmacokinetic analyses. We analysed three candidate genes (OPRM1 [rs1799971, 118 A > G], ABCB1[rs1045642, 3435 C > T] and HTR3B [rs7103572 C > T]). We found that morphine decreased slow wave sleep and rapid eye movement sleep and increased stage 2 sleep. Those effects were less in subjects with HTR3B CT/TT than in those with CC genotype. Similarly, sleep onset latency was shortened in the ABCB1 CC subgroup compared with the CT/TT subgroup. Total sleep time was significantly increased in ABCB1 CC but not in CT/TT subjects. Sleep apnea and plasma morphine and metabolite concentration were not confounding factors for these genetic differences in sleep. With morphine, patients had significantly more active/unstable EEG (lower delta/alpha ratio) during sleep. No genetic effects on quantitative EEG were detected. In summary, we identified two genes (HTR3B and ABCB1) with significant variation in the sleep architecture response to morphine. Morphine caused a more active/unstable EEG during sleep. Our findings may have relevance for a personalized medicine approach to targeted morphine therapy.

Chronic Opioid Use and Central Sleep Apnea, Where Are We Now and Where To Go? A State of the Art Review.

Opioids are commonly used for pain management, perioperative procedures, and addiction treatment. There is a current opioid epidemic in North America that is paralleled by a marked increase in related deaths. Since 2000, chronic opioid users have been recognized to have significant central sleep apnea (CSA). After heart failure-related Cheyne-Stokes breathing (CSB), opioid-induced CSA is now the second most commonly seen CSA. It occurs in around 24% of chronic opioid users, typically after opioids have been used for more than 2 months, and usually corresponds in magnitude to opioid dose/plasma concentration. Opioid-induced CSA events often mix with episodes of ataxic breathing. The pathophysiology of opioid-induced CSA is based on dysfunction in respiratory rhythm generation and ventilatory chemoreflexes. Opioids have a paradoxical effect on different brain regions, which result in irregular respiratory rhythm. Regarding ventilatory chemoreflexes, chronic opioid use induces hypoxia that appears to stimulate an augmented hypoxic ventilatory response (high loop gain) and cause a narrow CO2 reserve, a combination that promotes respiratory instability. To date, no direct evidence has shown any major clinical consequence from CSA in chronic opioid users. A line of evidence suggested increased morbidity and mortality in overall chronic opioid users. CSA in chronic opioid users is likely to be a compensatory mechanism to avoid opioid injury and is potentially beneficial. The current treatments of CSA in chronic opioid users mainly focus on continuous positive airway pressure (CPAP) and adaptive servo-ventilation (ASV) or adding oxygen. ASV is more effective in reducing CSA events than CPAP. However, a recent ASV trial suggested an increased all-cause and cardiovascular mortality with the removal of CSA/CSB in cardiac failure patients. A major reason could be counteracting of a compensatory mechanism. No similar trial has been conducted for chronic opioid-related CSA. Future studies should focus on (1) investigating the phenotypes and genotypes of opioid-induced CSA that may have different clinical outcomes; (2) determining if CSA in chronic opioid users is beneficial or detrimental; and (3) assessing clinical consequences on different treatment options on opioid-induced CSA.

Development and validation of a model for diagnosis of obstructive sleep apnoea in primary care.

BACKGROUND AND OBJECTIVE: Use of in-laboratory polysomnography (PSG) to diagnose obstructive sleep apnoea (OSA) is cost and resource intensive. Questionnaires, physical measurements and home monitors have been studied as potential simpler alternatives. This study aimed to develop a diagnostic model for OSA for use in primary care. METHODS: Primary care practitioners were trained to recognize symptoms of sleep apnoea and recruited patients based on the clinical need to investigate OSA. Assessment was by symptom questionnaires, anthropomorphic measurements, digital facial photography, and a single-channel nasal flow monitor (Flow Wizard©, DiagnoseIT, Sydney, Australia) worn at home for 3 nights. The in-laboratory PSG was the reference test, with OSA defined as apnoea-hypopnoea index (AHI) ≥10 events/h. RESULTS: In the model development phase, 25 primary care practitioners studied 315 patients in whom they suspected OSA, of which 57% had AHI≥10 and 22% had AHI≥30. Published OSA questionnaires provided low to moderate prediction of OSA (area under the curve [AUC] 0.53-0.73). The nasal flow monitor alone yielded high accuracy for predicting OSA with AUC of 0.87. Sensitivity was 0.87 and specificity 0.77 at a threshold respiratory event index (REI) of 18 events/h. A model adding age, gender, symptoms and BMI to the nasal flow monitor REI only modestly improved OSA prediction (AUC 0.89), with similar AUC (0.88) confirmed in the validation population of 114 patients. CONCLUSION: Sleep apnoea can be diagnosed in the primary care setting with a combination of clinical judgement and portable monitor test outcomes.

Sleep EEG microstructure is associated with neurobehavioural impairment after extended wakefulness in obstructive sleep apnea.

PURPOSE: Using quantitative EEG (qEEG) analysis, we investigated sleep EEG microstructure as correlates of neurobehavioural performance after 24 h of extended wakefulness in untreated OSA. METHODS: Eight male OSA patients underwent overnight polysomnography (PSG) at baseline followed by 40 h awake with repeated performance testing (psychomotor vigilance task [PVT] and AusEd driving simulator). EEG slowing during REM and spindle density during NREM sleep were calculated using power spectral analysis and a spindle detection algorithm at frontal and central electrode sites. Correlations between sleep EEG microstructure measures and performance after 24-h awake were assessed. RESULTS: Greater EEG slowing during REM sleep was associated with slower PVT reaction times (rho = - 0.79, p = 0.02), more PVT lapses (rho = 0.87, p = 0.005) and more AusEd crashes (rho = 0.73, p = 0.04). Decreased spindle density in NREM sleep was also associated with slower PVT reaction times (rho = 0.89, p = 0.007). Traditional PSG measures of disease severity were not consistent correlates of neurobehavioural performance in OSA. CONCLUSIONS: Sleep EEG microstructure measures recorded during routine PSG are associated with impaired vigilance in OSA patients after sleep deprivation. SIGNIFICANCE: Quantitative brain oscillatory (or EEG)-based measures of sleep may better reflect the deleterious effects of untreated OSA than traditional PSG metrics in at-risk individuals. Trial Registration ACTRN12606000066583.

Assessment, referral and management of obstructive sleep apnea by Australian general practitioners: a qualitative analysis.

BACKGROUND: The high and increasing demand for obstructive sleep apnea (OSA) care has exceeded the capacity of specialist sleep services prompting consideration of whether general practitioners could have an enhanced role in service delivery. However, little is known about the current involvement, experiences and attitudes of Australian general practitioners towards OSA. The purpose of this study was to provide an in-depth analysis of Australian general practitioners' experiences and opinions regarding their care of patients with OSA to inform the design and implementation of new general practice models of care. METHODS: Purposive sampling was used to recruit participants with maximum variation in age, experience and location. Semi-structured interviews were conducted and were analysed using Thematic Analysis. RESULTS: Three major themes were identified: (1) General practitioners are important in recognising symptoms of OSA and facilitating a diagnosis by others; (2) Inequities in access to the assessment and management of OSA; and (3) General practitioners currently have a limited role in the management of OSA. CONCLUSIONS: When consulting with patients with symptoms of OSA, general practitioners see their primary responsibility as providing a referral for diagnosis by others. General practitioners working with patients in areas of greater need, such as rural/remote areas and those of socio-economic disadvantage, demonstrated interest in being more involved in OSA management. Inequities in access to assessment and management are potential drivers for change in future models of care for OSA in general practice.

Framework for the Design Engineering and Clinical Implementation and Evaluation of mHealth Apps for Sleep Disturbance: Systematic Review.

BACKGROUND: Mobile health (mHealth) apps offer a scalable option for treating sleep disturbances at a population level. However, there is a lack of clarity about the development and evaluation of evidence-based mHealth apps. OBJECTIVE: The aim of this systematic review was to provide evidence for the design engineering and clinical implementation and evaluation of mHealth apps for sleep disturbance. METHODS: A systematic search of studies published from the inception of databases through February 2020 was conducted using 5 databases (MEDLINE, Embase, Cochrane Library, PsycINFO, and CINAHL). RESULTS: A total of 6015 papers were identified using the search strategy. After screening, 15 papers were identified that examined the design engineering and clinical implementation and evaluation of 8 different mHealth apps for sleep disturbance. Most of these apps delivered cognitive behavioral therapy for insomnia (CBT-I, n=4) or modified CBT-I (n=2). Half of the apps (n=4) identified adopting user-centered design or multidisciplinary teams in their design approach. Only 3 papers described user and data privacy. End-user acceptability and engagement were the most frequently assessed implementation metrics. Only 1 app had available evidence assessing all 4 implementation metrics (ie, acceptability, engagement, usability, and adherence). Most apps were prototype versions (n=5), with few matured apps. A total of 6 apps had supporting papers that provided a quantitative evaluation of clinical outcomes, but only 1 app had a supporting, adequately powered randomized controlled trial. CONCLUSIONS: This is the first systematic review to synthesize and examine evidence for the design engineering and clinical implementation and evaluation of mHealth apps for sleep disturbance. The minimal number of apps with published evidence for design engineering and clinical implementation and evaluation contrasts starkly with the number of commercial sleep apps available. Moreover, there appears to be no standardization and consistency in the use of best practice design approaches and implementation assessments, along with very few rigorous efficacy evaluations. To facilitate the development of successful and evidence-based apps for sleep disturbance, we developed a high-level framework to guide researchers and app developers in the end-to-end process of app development and evaluation.

Morphine alters respiratory control but not other key obstructive sleep apnoea phenotypes: a randomised trial.

Accidental opioid-related deaths are increasing. These often occur during sleep. Opioids such as morphine may worsen obstructive sleep apnoea (OSA). Thus, people with OSA may be at greater risk of harm from morphine. Possible mechanisms include respiratory depression and reductions in drive to the pharyngeal muscles to increase upper airway collapsibility. However, the effects of morphine on the four key phenotypic causes of OSA (upper airway collapsibility (pharyngeal critical closure pressure; P crit), pharyngeal muscle responsiveness, respiratory arousal threshold and ventilatory control (loop gain) during sleep) are unknown.21 males with OSA (apnoea-hypopnoea index range 7-67 events·h-1) were studied on two nights (1-week washout) according to a double-blind, randomised, cross-over design (ACTRN12613000858796). Participants received 40 mg of MS-Contin on one visit and placebo on the other. Brief reductions in continuous positive airway pressure (CPAP) from the therapeutic level were delivered to induce airflow limitation during non-rapid eye movement (REM) sleep to quantify the four phenotypic traits. Carbon dioxide was delivered via nasal mask on therapeutic CPAP to quantify hypercapnic ventilatory responses during non-REM sleep.Compared to placebo, 40 mg of morphine did not change P crit (-0.1±2.4 versus -0.4±2.2 cmH2O, p=0.58), genioglossus muscle responsiveness (-2.2 (-0.87 to -5.4) versus -1.2 (-0.3 to -3.5) µV·cmH2O-1, p=0.22) or arousal threshold (-16.7±6.8 versus -15.4±6.0 cmH2O, p=0.41), but did reduce loop gain (-10.1±2.6 versus -4.4±2.1, p=0.04) and hypercapnic ventilatory responses (7.3±1.2 versus 6.1±1.5 L·min-1, p=0.006).Concordant with recent clinical findings, 40 mg of MS-Contin does not systematically impair airway collapsibility, pharyngeal muscle responsiveness or the arousal threshold in moderately severe OSA patients. However, consistent with blunted chemosensitivity, ventilatory control is altered.

Assessing the role of nocturnal core body temperature dysregulation as a biomarker of neurodegeneration.

The vast majority of patients with idiopathic rapid eye movement sleep behaviour disorder will develop a neurodegenerative α-synuclein-related condition, such as Parkinson's disease or dementia with Lewy bodies. The pathology underlying dream enactment overlaps anatomically with the brainstem regions that regulate circadian core body temperature. Previously, nocturnal core body temperature regulation has been shown to be impaired in Parkinson's disease. However, no study to date has investigated nocturnal core body temperature changes in patients with idiopathic rapid eye movement sleep behaviour disorder, which may prove to be an early objective biomarker for α-synucleinopathies. Ten healthy controls, 15 patients with idiopathic rapid eye movement sleep behaviour disorder, 31 patients with Parkinson's disease and six patients with dementia with Lewy bodies underwent clinical assessment and nocturnal polysomnography with core body temperature monitoring. A validated cosinor method was utilised for core body temperature analysis. No differences in mesor, nadir or time of nadir were observed between groups. However, when compared with healthy controls, the amplitude of the nocturnal core body temperature (mesor minus nadir) was significantly reduced in patients with idiopathic rapid eye movement sleep behaviour disorder, Parkinson's disease with concurrent rapid eye movement sleep behaviour disorder and dementia with Lewy bodies (p < 0.001, p = 0.043 and p = 0.017, respectively). Importantly, this relationship was not seen in those patients with Parkinson's disease without rapid eye movement sleep behaviour disorder. In addition, there was a significant negative correlation between amplitude of the core body temperature and self-reported rapid eye movement sleep behaviour disorder symptoms. Changes in thermoregulatory circadian rhythm may be specifically associated with the pathology underlying rapid eye movement sleep behaviour disorder rather than simply that of α-synucleinopathy. These findings implicate thermoregulatory dysfunction as a potential early biomarker for development of rapid eye movement sleep behaviour disorder-associated neurodegeneration, and suggest that subpopulations with differing pathological underpinnings might exist in Parkinson's disease.

The effect of acute exposure to morphine on breathing variability and cardiopulmonary coupling in men with obstructive sleep apnea: A randomized controlled trial.

Opioid-related deaths from respiratory depression are increasing but there is only limited information on the effect of morphine on breathing during sleep. This study aimed to detect and quantify opioid-induced cardiorespiratory pattern changes during sleep in obstructive sleep apnea (OSA) patients using novel automated methods and correlate these with conventional polysomnography (PSG) measures. Under a randomized double-blind placebo-controlled crossover design, 60 male OSA patients attended two one-night visits to the sleep laboratory, at least a week apart. Either a 40-mg controlled-release oral morphine dose or placebo was administered. Breathing during sleep was measured by standard in-laboratory PSG. We analysed the inter-breath interval (IBI) from the PSG flow channel to quantify breathing irregularity. Cardiopulmonary coupling (CPC) was analysed using the PSG electrocardiogram (ECG) channel. Following the consumption of morphine, the 60 OSA patients had fewer breaths (p = .0006), a longer inter-breath interval (p < .0001) and more irregular breathing with increased IBI coefficient of variation (CV) (p = .0015) compared to the placebo night. A higher CPC sleep quality index was found with morphine use. The change of key IBI and CPC parameters was significantly correlated with the change of key PSG sleep-disordered breathing parameters. In conclusion, 40 mg controlled-release morphine resulted in a longer breathing cycle and increased breathing irregularity but generally more stable sleep in OSA patients. The significant links between the IBI and CPC techniques and a range of PSG sleep-disordered breathing parameters may suggest a practical value as surrogate overnight cardiorespiratory measurements, because both respiratory flow and ECG can be detected by small portable devices.