Sleep Deficiency and Cardiometabolic Disease.

Epidemiologic studies have demonstrated that short sleep duration is associated with an increased risk of cardio-metabolic health outcomes including cardiovascular disease mortality, coronary heart disease, type 2 diabetes mellitus, hypertension, and metabolic syndrome. Experimental sleep restriction studies have sought to explain these findings. This review describes the main evidence of these associations and possible mechanisms explaining them. Whether sleep extension reverses these now widely acknowledged adverse health effects and the feasibility of implementing such strategies on a public health level is discussed.

The Health Effects of 72 Hours of Simulated Wind Turbine Infrasound: A Double-Blind Randomized Crossover Study in Noise-Sensitive, Healthy Adults.

BACKGROUND: Large electricity-generating wind turbines emit both audible sound and inaudible infrasound at very low frequencies that are outside of the normal human range of hearing. Sufferers of wind turbine syndrome (WTS) have attributed their ill-health and particularly their sleep disturbance to the signature pattern of infrasound. Critics have argued that these symptoms are psychological in origin and are attributable to nocebo effects. OBJECTIVES: We aimed to test the effects of 72 h of infrasound (1.6-20 Hz at a sound level of ∼90 dB pk re 20µPa, simulating a wind turbine infrasound signature) exposure on human physiology, particularly sleep. METHODS: We conducted a randomized double-blind triple-arm crossover laboratory-based study of 72 h exposure with a >10-d washout conducted in a noise-insulated sleep laboratory in the style of a studio apartment. The exposures were infrasound (∼90 dB pk), sham infrasound (same speakers not generating infrasound), and traffic noise exposure [active control; at a sound pressure level of 40-50 dB LAeq,night and 70 dB LAFmax transient maxima, night (2200 to 0700 hours)]. The following physiological and psychological measures and systems were tested for their sensitivity to infrasound: wake after sleep onset (WASO; primary outcome) and other measures of sleep physiology, wake electroencephalography, WTS symptoms, cardiovascular physiology, and neurobehavioral performance. RESULTS: We randomized 37 noise-sensitive but otherwise healthy adults (18-72 years of age; 51% female) into the study before a COVID19-related public health order forced the study to close. WASO was not affected by infrasound compared with sham infrasound (-1.36 min; 95% CI: -6.60, 3.88, p=0.60) but was worsened by the active control traffic exposure compared with sham by 6.07 min (95% CI: 0.75, 11.39, p=0.02). Infrasound did not worsen any subjective or objective measures used. DISCUSSION: Our findings did not support the idea that infrasound causes WTS. High level, but inaudible, infrasound did not appear to perturb any physiological or psychological measure tested in these study participants. https://doi.org/10.1289/EHP10757.

Sleep Deficiency and Cardiometabolic Disease.

Epidemiologic studies have demonstrated that short sleep duration is associated with an increased risk of cardio-metabolic health outcomes including cardiovascular disease mortality, coronary heart disease, type 2 diabetes mellitus, hypertension, and metabolic syndrome. Experimental sleep restriction studies have sought to explain these findings. This review describes the main evidence of these associations and possible mechanisms explaining them. Whether sleep extension reverses these now widely acknowledged adverse health effects and the feasibility of implementing such strategies on a public health level is discussed.

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.

The Impact of Device Modifications and Pressure Delivery on Adherence.

This article reviews the evidence to date examining whether adherence to positive airway pressure (PAP) therapy is affected by any device modifications to pressure delivery. To date there is no robust evidence from systematic reviews and meta-analyses indicating that any modification to standard fixed-pressure PAP makes a clinically significant difference to patient adherence to therapy. The main modifications are reviewed in this article and whether improving pressure could drive adherence, in turn improving patient outcomes, is discussed.

Magnesium supplementation for the treatment of restless legs syndrome and periodic limb movement disorder: A systematic review.

Magnesium supplementation is often suggested for restless legs syndrome (RLS) or period limb movement disorder (PLMD) based on anecdotal evidence that it relieves symptoms and because it is also commonly recommended for leg cramps. We aimed to review all articles reporting the effects of magnesium supplementation on changes in RLS and/or PLMD. We conducted a systematic search looking for all relevant articles and then two reviewers read all article titles and abstracts to identify relevant studies. Eligible studies were scored for their quality as interventional trials. We found 855 abstracts and 16 of these could not be definitively excluded for not addressing all aspects of our research question. Seven full-text articles were unlocatable and one was ineligible which left eight studies with relevant data. One was a randomised placebo-controlled trial, three were case series and four were case studies. The RCT did not find a significant treatment effect of magnesium but may have been underpowered. After quality appraisal and synthesis of the evidence we were unable to make a conclusion as to the effectiveness of magnesium for RLS/PLMD. It is not clear whether magnesium helps relieve RLS or PLMD or in which patient groups any benefit might be seen.

Dose-dependent effects of continuous positive airway pressure for sleep apnea on weight or metabolic function: Individual patient-level clinical trial meta-analysis.

Therapeutic-continuous positive airway pressure seems to increase weight compared with placebo-continuous positive airway pressure. It is not known whether weight gain with therapeutic-continuous positive airway pressure dose is dependent or whether it causes metabolic dysfunction. Data synthesis of three randomised placebo-continuous positive airway pressure-controlled trials (2-3 months) was performed to test whether there is a dose-dependent effect of continuous positive airway pressure on weight. Fasting glucose, insulin, insulin resistance (homeostatic model assessment), lipids and visceral abdominal fat were also tested to determine any effect on metabolic function. Mixed-model analysis of variance was used to quantify these effects. One-hundred and twenty-eight patients were analysed. Overall there was a small increase in weight with therapeutic-continuous positive airway pressure use compared with placebo-continuous positive airway pressure (difference: 1.17 kg; 0.37-1.97, p = 0.005), which was greater with high-use therapeutic-continuous positive airway pressure compared with high-use placebo-continuous positive airway pressure (1.45 kg; 0.10-2.80, p = 0.04). Continuous positive airway pressure use as a continuous variable was also significantly associated with weight change in continuous positive airway pressure users (0.30 kg hr-1  night-1 ; 0.04-0.56, p = 0.001), but not in placebo users (0.04 kg hr-1  night-1 ; -0.22 to 0.26, p = 0.76). Neither therapeutic-continuous positive airway pressure nor the dose of therapeutic-continuous positive airway pressure caused any changes to metabolic outcomes. The weight gain effects of medium-term therapeutic-continuous positive airway pressure appear modest and are not accompanied by any adverse metabolic effects.

Metabolic and hormonal effects of 'catch-up' sleep in men with chronic, repetitive, lifestyle-driven sleep restriction.

OBJECTIVE: Acutely restricting sleep worsens insulin sensitivity in healthy individuals whose usual sleep is normal in duration and pattern. The effect of recovery or weekend 'catch-up' sleep on insulin sensitivity and metabolically active hormones in individuals with chronic sleep restriction who regularly 'catch-up' on sleep at weekends is as yet unstudied. DESIGN: 19 men (mean ± SEM age 28·6 ± 2·0 years, BMI 26·0 ± 0·8 kg/m(2) ) with at least 6 months' history (5·1 ± 0·9 years) of lifestyle-driven, restricted sleep during the working week (373 ± 6·6 min/night) with regular weekend 'catch-up' sleep (weekend sleep extension 37·4 ± 2·3%) completed an in-laboratory, randomized, crossover study comprising two of three conditions, stratified by age. Conditions were 3 weekend nights of 10 hours, 6 hours or 10 hours time-in-bed with slow wave sleep (SWS) suppression using targeted acoustic stimuli. MEASUREMENTS: Insulin sensitivity was measured in the morning following the 3rd intervention night by minimal modelling of 19 samples collected during a 2-h oral glucose tolerance test. Glucose, insulin, c-peptide, leptin, peptide YY (PYY), ghrelin, cortisol, testosterone and luteinizing hormone (LH) were measured from daily fasting blood samples; HOMA-IR, HOMA-ß and QUICKI were calculated. RESULTS: Insulin sensitivity was higher following three nights of sleep extension compared to sustained sleep restriction. Fasting insulin, c-peptide, HOMA-IR, HOMA-ß, leptin and PYY decreased with 'catch-up' sleep, QUICKI and testosterone increased, while morning cortisol and LH did not change. Targeted acoustic stimuli reduced SWS by 23%, but did not alter insulin sensitivity. CONCLUSIONS: Three nights of 'catch-up' sleep improved insulin sensitivity in men with chronic, repetitive sleep restriction. Methods to improve metabolic health by optimizing sleep are plausible.

An automated algorithm to identify and reject artefacts for quantitative EEG analysis during sleep in patients with sleep-disordered breathing.

PURPOSE: Large quantities of neurophysiological electroencephalogram (EEG) data are routinely collected in the sleep laboratory. These are underutilised due to the burden of managing artefact contamination. The aim of this study was to develop a new tool for automated artefact rejection that facilitates subsequent quantitative analysis of sleep EEG data collected during routine overnight polysomnography (PSG) in subjects with and without sleep-disordered breathing (SDB). METHODS: We evaluated the accuracy of an automated algorithm to detect sleep EEG artefacts against artefacts manually scored by three experienced technologists (reference standard) in 40 PSGs. Spectral power was computed using artefact-free EEG data derived from (1) the reference standard, (2) the algorithm and (3) raw EEG without any prior artefact rejection. RESULTS: The algorithm showed a high level of accuracy of 94.3, 94.7 and 95.8% for detecting artefacts during the entire PSG, NREM sleep and REM sleep, respectively. There was good to moderate sensitivity and excellent specificity of the algorithm detection capabilities during sleep. The EEG spectral power for the reference standard and algorithm was significantly lower than that of the raw, unprocessed EEG signal. CONCLUSIONS: These preliminary findings support an automated way to process EEG artefacts during sleep, providing the opportunity to investigate EEG-based markers of neurobehavioural impairment in sleep disorders in future studies.

Continuous positive airway pressure increases pulsatile growth hormone secretion and circulating insulin-like growth factor-1 in a time-dependent manner in men with obstructive sleep apnea: a randomized sham-controlled study.

STUDY OBJECTIVES: To assess the time-dependent effect of continuous positive airway pressure (CPAP), on insulin-like growth factor-1 (IGF-1), IGF binding proteins (IGFBPs) and pulsatile growth hormone (GH) secretion. DESIGN: A randomized, double-blind, sham-controlled, parallel group study. PARTICIPANTS: Sixty-five middle-aged men with moderate to severe obstructive sleep apnea. INTERVENTION: Active (n = 34) or sham (n = 31) CPAP for 12 weeks, followed by 12 weeks of active CPAP (n = 65). MEASUREMENTS AND RESULTS: Fasting morning IGF-1, IGFBP-3, and IGFBP-1 blood levels at 0, 6, 12, and 24 weeks. Overnight GH secretion was calculated by mathematical deconvolution of serial GH measurements from serum samples collected every 10 min (22:00-06:00) during simultaneous polysomnography in a subset of 18 men (active n = 11, sham n = 7) at week 12. Active, compared with sham, CPAP increased IGF-1 at 12 weeks (P = 0.006), but not at 6 weeks (P = 0.44). Changes in IGFBP-3 and IGFBP-1 were not different between groups at 6 or 12 weeks (all P ≥ 0.15). At week 24, there was a further increase in IGF-1 and a decrease in IGFBP-1 in the pooled group (P = 0.0001 and 0.046, respectively). In the subset, total (P = 0.001) and pulsatile (P = 0.002) GH secretion, mean GH concentration (P = 0.002), mass of GH secreted per pulse (P = 0.01) and pulse frequency (P = 0.04) were all higher after 12 weeks of CPAP compared with sham. Basal secretion, interpulse regularity, and GH regularity were not different between groups (all P > 0.11). CONCLUSIONS: Twelve weeks, but not 6 weeks, of CPAP increases IGF-1, with a further increase after 24 weeks. Total and pulsatile GH secretion, secretory burst mass and pulse frequency are also increased by 12 weeks. CPAP improves specific elements of the GH/IGF-1 axis in a time-dependent manner. CLINICAL TRIALS REGISTRATION: Australia New Zealand Clinical Trials Network, www.anzctr.org.au, number ACTRN12608000301369.

The effects of testosterone on ventilatory responses in men with obstructive sleep apnea: a randomised, placebo-controlled trial.

We recently showed that testosterone therapy worsens sleep-disordered breathing at 6-7 weeks, but not after 18 weeks, in men with obstructive sleep apnea. Changes in ventilatory chemoreflexes may be responsible. The effect of testosterone on ventilatory chemoreflexes in men with obstructive sleep apnea has not been systematically studied before. Twenty-one obese men with obstructive sleep apnea, a subgroup of our recent report, were randomised in an 18-week, randomised, double-blind, placebo-controlled, parallel group trial to three intramuscular injections (0, 6, 12 weeks) of either 1000 mg testosterone undecanoate (n = 10) or placebo (n = 11). Awake ventilatory chemoreflex testing was performed before (week 0), during (week 6) and at the end of treatment (week 18) to determine the ventilatory carbon dioxide recruitment threshold and chemosensitivity. Sleep and breathing was assessed by overnight polysomnography at 0, 7 and 18 weeks. Serum hormones levels were measured at every visit. A significant increase in blood testosterone levels (5.65 nmol L(-1) , 0.51-10.8 nmol L(-1) , P = 0.03) and lean muscle mass (2.36 kg, 0.8-3.9 kg, P = 0.007) between the two groups was observed as expected. No significant differences were seen in ventilatory chemoreflexes between the two groups at 6 weeks or at 18 weeks. However, positive correlations were observed between changes in serum testosterone and hyperoxic ventilatory recruitment threshold (r = 0.55, P = 0.03), and between changes in hyperoxic ventilatory recruitment threshold and time spent with oxygen saturations during sleep <90% (r = 0.57, P = 0.03) at 6-7 weeks, but not at 18 weeks. Time-dependent alterations in ventilatory recruitment threshold may therefore mediate the time-dependent changes in sleep breathing observed with testosterone.

Implications of sleep restriction and recovery on metabolic outcomes.

CONTEXT: Alongside the growing epidemics of obesity and diabetes mellitus, chronic partial sleep restriction is also increasingly common in modern society, and the metabolic implications of this have not been fully illustrated as yet. Whether recovery sleep is sufficient to offset these detriments is an area of ongoing research. OBJECTIVE: This review seeks to summarize the relevant epidemiological and experimental data in the areas of altered metabolic consequences of both shortened sleep and subsequent recovery sleep. DATA ACQUISITION: The medical literature from 1970 to March 2012 was reviewed for key articles. DATA SYNTHESIS: Epidemiological studies suggest associations between shortened sleep and future obesity and diabetes. Experimental data thus far show a probable link between shortened sleep and altered glucose metabolism as well as appetite dysregulation. CONCLUSION: Sleep often seems undervalued in modern society, but this may have widespread metabolic consequences as described in this review. Acute sleep loss is often unavoidable, but chronic sleep restriction ideally should not be. Understanding the implications of both sleep restriction and recovery on metabolic outcomes will guide public health policy and allow clinical recommendations to be prescribed.

Cardiometabolic changes after continuous positive airway pressure for obstructive sleep apnoea: a randomised sham-controlled study.

RATIONALE AND OBJECTIVES: Impaired insulin sensitivity (ISx), increased visceral abdominal fat (VAF) and liver fat are all central components of the metabolic syndrome and characteristics of men with obstructive sleep apnoea (OSA). The reversibility of these observed changes with continuous positive airway pressure (CPAP) treatment in men with OSA has not been systematically studied in a randomised sham-controlled fashion. METHODS: 65 men without diabetes who were CPAP naïve and had moderate to severe OSA (age=49±12 years, apnoea hypopnoea index (AHI)=39.9±17.7 events/h, body mass index=31.3±5.2 kg/m(2)) were randomised to receive either real (n=34) or sham (n=31) CPAP for 12 weeks. At 12 weeks, all subjects received real CPAP for an additional 12 weeks. MEASUREMENTS AND MAIN RESULTS: Main outcomes were the change at week 12 from baseline in VAF, ISx and liver fat. Other metabolic outcomes were changes in the disposition index, total fat, and blood leptin and adiponectin concentrations. The AHI was lower on CPAP compared with sham by 33 events/h (95% CI-43.9 to -22.2, p<0.0001) after 12 weeks. There were no between-group differences at 12 weeks in VAF (-13.0 cm(3), -42.4 to 16.2, p=0.37), ISx (-0.13 (min(-1))(µU/ml))(-1), -0.40 to 0.14, p=0.33), liver fat (-0.5 cm(3), -3.8 to 2.7, p=0.74) or any other cardiometabolic parameter. At 24 weeks, ISx (3.2×10(4) (min(-1))(µU/ml))(-1), 0.9×10(4) to 6.0×10(4), p=0.009), but not VAF (-1.4 cm(3), -19.2 to 16.4, p=0.87) or liver fat (-0.2 Hounsfield units, -2.4 to 2.0, p=0.83) were improved compared with baseline in the whole study group. CONCLUSION: Reducing visceral adiposity in men with OSA cannot be achieved with CPAP alone and is likely to require weight-loss interventions. Longer-term effects of CPAP on other cardiometabolic markers such as ISx require further investigation to fully examine time dependencies. TRIAL REGISTRATION NUMBER: ACTRN12608000301369.

Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial.

STUDY OBJECTIVES: High doses of short-term testosterone have been shown to acutely worsen sleep-disordered breathing in men with obstructive sleep apnoea (OSA). The effects of lower, near-conventional doses of testosterone in obese men with OSA may differ over the longer term but have not been systematically studied. We assessed sleep and breathing effects of near-conventional testosterone treatment as an adjunct to weight loss in obese men with severe OSA. DESIGN: An 18-week randomized, double-blind, placebo-controlled, parallel group trial in 67 men. INTERVENTIONS: All subjects were placed on a hypocaloric diet and then received intramuscular injections of 1000 mg testosterone undecanoate or placebo at 0, 6 and 12 weeks. MEASUREMENTS AND RESULTS: Sleep and breathing were measured by nocturnal polysomnography at 0, 7 and 18 weeks. Testosterone, compared to placebo, worsened the oxygen desaturation index (ODI) by 10·3 events/h (95%CI, 0·8-19·8 events/h; P = 0·03) and nocturnal hypoxaemia (sleep time with oxygen saturation <90%, SpO(2) T90%) by 6·1% (95%CI, 1·5-10·6; P = 0·01) at 7 weeks. Testosterone therapy did not alter ODI (4·5, -5·4 to 14·4 events/h; P = 0·36) or SpO(2) T90% at 18 weeks (2·9, -1·9-7·7%; P = 0·23) compared to placebo. The testosterone treatment effects on ODI and SpO(2) T90% were not influenced by baseline testosterone concentrations (testosterone by treatment interactions, all P > 0·35). Blood testosterone concentrations did not correlate with ODI or SpO(2) T90% (all P > 0·19). CONCLUSIONS: Testosterone therapy in obese men with severe OSA mildly worsens sleep-disordered breathing in a time-limited manner, irrespective of initial testosterone concentrations. This time-dependency was not related to testosterone concentrations. TRIAL REGISTRATION: www.anzctr.org.au Identifier: ACTRN1260-6000404527.

Restless legs syndrome.

BACKGROUND: Restless legs syndrome (RLS) is a common, but frequently undiagnosed, chronic, sensorimotor disorder. In western countries, it is seen in approximately 10% of the general population, with a higher prevalence in women and the elderly (10-20%). OBJECTIVE: This article outlines the epidemiology, aetiology, diagnosis and management of RLS. Information that is most relevant to general practice is presented, with an emphasis on practical management. DISCUSSION: Restless legs syndrome is divided into primary and secondary forms. There is a strong genetic influence in primary RLS. Secondary forms are associated with iron deficiency, pregnancy, and renal failure. Diagnosis is essentially by clinical history using simple diagnostic criteria. Management depends on severity, and ranges from nonpharmacologic to pharmacologic measures. Recent research has provided insights into the pathophysiology of RLS and provided an evidence base for some of the newer treatments.