Ronald R. Grunstein

Adherence to continuous positive airway pressure therapy: the challenge to effective treatment.

Despite the high efficacy of continuous positive airway pressure (CPAP) to reverse upper airway obstruction in sleep apnea, treatment effectiveness is limited by variable adherence to prescribed therapy. When adherence is defined as greater than 4 hours of nightly use, 46 to 83% of patients with obstructive sleep apnea have been reported to be nonadherent to treatment. Evidence suggests that use of CPAP for longer than 6 hours decreases sleepiness, improves daily functioning, and restores memory to normal levels. The decision to embrace CPAP occurs during the first few days of treatment. Although many strategies in patient interface with CPAP or machine modality are marketed to improve CPAP usage, there are few data to support this. No single factor has been consistently identified as predictive of adherence. Patient perception of symptoms and improvement in sleepiness and daily functioning may be more important in determining patterns of use than physiologic aspects of disease severity. Emerging data suggest that various behavioral interventions may be effective in improving CPAP adherence.

CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea

BACKGROUND Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. METHODS After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. RESULTS Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. CONCLUSIONS Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT00738179 ; Australian New Zealand Clinical Trials Registry number, ACTRN12608000409370 .).

Nocturnal non-invasive nasal ventilation in stable hypercapnic COPD: a randomised controlled trial

Background: Sleep hypoventilation has been proposed as a cause of progressive hypercapnic respiratory failure and death in patients with severe chronic obstructive pulmonary disease (COPD). A study was undertaken to determine the effects of nocturnal non-invasive bi-level pressure support ventilation (NIV) on survival, lung function and quality of life in patients with severe hypercapnic COPD. Method: A multicentre, open-label, randomised controlled trial of NIV plus long-term oxygen therapy (LTOT) versus LTOT alone was performed in four Australian University Hospital sleep/respiratory medicine departments in patients with severe stable smoking-related COPD (forced expiratory volume in 1 s (FEV1.0) <1.5 litres or <50% predicted and ratio of FEV1.0 to forced vital capacity (FVC) <60% with awake arterial carbon dioxide tension (Paco2) >46 mm Hg and on LTOT for at least 3 months) and age <80 years. Patients with sleep apnoea (apnoea-hypopnoea index >20/h) or morbid obesity (body mass index >40) were excluded. Outcome measures were survival, spirometry, arterial blood gases, polysomnography, general and disease-specific quality of life and mood. Results: 144 patients were randomised (72 to NIV + LTOT and 72 to LTOT alone). NIV improved sleep quality and sleep-related hypercapnia acutely, and patients complied well with therapy (mean (SD) nightly use 4.5 (3.2) h). Compared with LTOT alone, NIV (mean follow-up 2.21 years, range 0.01–5.59) showed an improvement in survival with the adjusted but not the unadjusted Cox model (adjusted hazard ratio (HR) 0.63, 95% CI 0.40 to 0.99, p = 0.045; unadjusted HR 0.82, 95% CI 0.53 to 1.25, p = NS). FEV1.0 and Paco2 measured at 6 and 12 months were not different between groups. Patients assigned to NIV + LTOT had reduced general and mental health and vigour. Conclusions: Nocturnal NIV in stable oxygen-dependent patients with hypercapnic COPD may improve survival, but this appears to be at the cost of worsening quality of life. Trial registration number: ACTRN12605000205639

Health Outcomes of Continuous Positive Airway Pressure versus Oral Appliance Treatment for Obstructive Sleep Apnea A Randomized Controlled Trial

RATIONALE Continuous positive airway pressure (CPAP) and mandibular advancement device (MAD) therapy are commonly used to treat obstructive sleep apnea (OSA). Differences in efficacy and compliance of these treatments are likely to influence improvements in health outcomes. OBJECTIVES To compare health effects after 1 month of optimal CPAP and MAD therapy in OSA. METHODS In this randomized crossover trial, we compared the effects of 1 month each of CPAP and MAD treatment on cardiovascular and neurobehavioral outcomes. MEASUREMENTS AND MAIN RESULTS Cardiovascular (24-h blood pressure, arterial stiffness), neurobehavioral (subjective sleepiness, driving simulator performance), and quality of life (Functional Outcomes of Sleep Questionnaire, Short Form-36) were compared between treatments. Our primary outcome was 24-hour mean arterial pressure. A total of 126 patients with moderate-severe OSA (apnea hypopnea index [AHI], 25.6 [SD 12.3]) were randomly assigned to a treatment order and 108 completed the trial with both devices. CPAP was more efficacious than MAD in reducing AHI (CPAP AHI, 4.5 ± 6.6/h; MAD AHI, 11.1 ± 12.1/h; P < 0.01) but reported compliance was higher on MAD (MAD, 6.50 ± 1.3 h per night vs. CPAP, 5.20 ± 2 h per night; P < 0.00001). The 24-hour mean arterial pressure was not inferior on treatment with MAD compared with CPAP (CPAP-MAD difference, 0.2 mm Hg [95% confidence interval, -0.7 to 1.1]); however, overall, neither treatment improved blood pressure. In contrast, sleepiness, driving simulator performance, and disease-specific quality of life improved on both treatments by similar amounts, although MAD was superior to CPAP for improving four general quality-of-life domains. CONCLUSIONS Important health outcomes were similar after 1 month of optimal MAD and CPAP treatment in patients with moderate-severe OSA. The results may be explained by greater efficacy of CPAP being offset by inferior compliance relative to MAD, resulting in similar effectiveness. Clinical trial registered with https://www.anzctr.org.au (ACTRN 12607000289415).

Prevention Conference VII Obesity, a Worldwide Epidemic Related to Heart Disease and Stroke: Group III: Worldwide Comorbidities of Obesity

Current concerns about the increased risk of cardiovascular and other diseases induced by excessive weight gain in children and adults have been highlighted by the Surgeon General’s report on the problem of obesity in the United States.1 This call to action followed a global analysis of the problem of excess weight and how to define and combat it that was undertaken by the World Health Organization (WHO) in 19972 and an analogous National Institutes of Health (NIH) assessment and reclassification of US rates of overweight and obesity in 1998.3 It is generally accepted that body mass index (BMI), or weight in kilograms per square meter of height, is a convenient measure of an approximate height-independent index of both children and adults’ weight for height and provides a crude indication of the body’s fat content. It is becoming clear that different ethnic groups have different proportions of fat-to-lean tissues at equivalent BMIs4,5 and that the magnitude of the multiple comorbidities associated with higher BMIs also may differ among different ethnic groups for reasons that may reflect the impact of environmental–genetic interactions. Nevertheless, current international comparisons use a standard format and classification system. In all societies a spectrum of BMIs exists for children and adults of all ages. Individual positions within the percentile range tend to remain the same as children grow and adults steadily gain weight. As the average weight of children and adults increases, so does the spread of BMIs, with a marked progressive increase in the numbers with very high BMIs (see Figure 1). Thus, the escalation in obesity rates reflects the upward shift in body weights of the whole population in response to environmental changes. Adults with a BMI of 18.5 to 24.9 are categorized as being of normal weight, on the basis of …

Ropinirole is effective in the treatment of restless legs syndrome. TREAT RLS 2 : A 12-week, double-blind, randomized, parallel-group, placebo-controlled study

Restless legs syndrome (RLS) is a neurological condition with significant impact on sleep and quality of life (QoL). This double‐blind, randomized, 12‐week, multinational study compared the efficacy and safety of ropinirole and placebo in RLS. In total, 267 outpatients with moderate‐to‐severe RLS were randomly assigned to ropinirole (0.25–4.0 mg/day) or placebo, 1 to 3 hours before bedtime. The primary endpoint was the change in International Restless Legs Scale (IRLS) score at week 12. Key secondary endpoints were the percentage of patients showing significant improvement on the Clinical Global Impression‐Improvement (CGI‐I) scale at week 12 and changes in IRLS and CGI‐I scale scores at week 1. Other measures included the Medical Outcomes Study sleep scale and Restless Legs Syndrome Quality of Life questionnaire. Improvements were significantly greater for ropinirole than placebo for change in IRLS score at week 12 (−11.2 [SE 0.76] vs. −8.7 [0.75], respectively; adjusted treatment difference −2.5 [95% confidence interval [CI], −4.6, −0.4], P = 0.0197); all key secondary endpoints; sleep and QoL parameters. Adverse events were typical for dopamine agonists; disease augmentation, although not directly assessed, was not reported during treatment. Ropinirole improves symptoms, associated sleep disturbance, and QoL of RLS patients and is generally well tolerated.

Association of serum leptin with hypoventilation in human obesity

Background: Leptin is a protein hormone produced by fat cells of mammals. It acts within the hypothalamus via a specific receptor to reduce appetite and increase energy expenditure. Plasma leptin levels correlate closely with total body fat mass operating via a central feedback mechanism. In human obesity serum leptin levels are up to four times higher than in lean subjects, indicating a failure of the feedback loop and central leptin resistance. In leptin deficient obese mice (ob/ob mice) leptin infusion reverses hypoventilation. It was hypothesised that a relative deficiency in CNS leptin, indicated by high circulating leptin levels, may be implicated in the pathogenesis of obesity hypoventilation syndrome (OHS). Methods: Fasting morning leptin levels were measured in obese and non-obese patients with and without daytime hypercapnia (n=56). Sleep studies, anthropometric data, spirometric parameters, and awake arterial blood gas tensions were measured in each patient. Results: In the whole group serum leptin levels correlated closely with % body fat (r=0.77). Obese hypercapnic patients (mean (SD) % body fat 43.8 (6.0)%) had higher fasting serum leptin levels than eucapnic patients (mean % body fat 40.8 (6.2)%), with mean (SD) leptin levels of 39.1 (17.9) and 21.4 (11.4) ng/ml, respectively (p<0.005). Serum leptin (odds ratio (OR) 1.12, 95% CI 1.03 to 1.22) was a better predictor than % body fat (OR 0.92, 95% CI 0.76 to 1.1) for the presence of hypercapnia. Conclusions: Hyperleptinaemia is associated with hypercapnic respiratory failure in obesity. Treatment with leptin or its analogues may have a role in OHS provided central leptin resistance can be overcome.

Randomised trial of CPAP vs bilevel support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation

Background: Untreated, obesity hypoventilation is associated with significant use of health care resources and high mortality. It remains unclear whether continuous positive airway pressure (CPAP) or bilevel ventilatory support (BVS) should be used as initial management. The aim of this study was to determine if one form of positive pressure is superior to the other in improving daytime respiratory failure. Methods: A prospective randomised study was performed in patients with obesity hypoventilation referred with respiratory failure. After exclusion of patients with persisting severe nocturnal hypoxaemia (Spo2 <80% for >10 min) or carbon dioxide retention (>10 mm Hg) despite optimal CPAP, the remaining patients were randomly assigned to receive either CPAP or BVS over a 3-month period. The primary outcome was change in daytime carbon dioxide level. Secondary outcome measures included daytime sleepiness, quality of life, compliance with treatment and psychomotor vigilance testing. Results: Thirty-six patients were randomised to either home CPAP (n = 18) or BVS (n = 18). The two groups did not differ significantly at baseline with regard to physiological or clinical characteristics. Following 3 months of treatment, daytime carbon dioxide levels decreased in both groups (CPAP 6 (8) mm Hg; BVS 7 (7) mm Hg) with no between-group differences. There was no difference in compliance between the two treatment groups (5.8 (2.4) h/night CPAP vs 6.1 (2.1) h/night BVS). Although both groups reported an improvement in daytime sleepiness, subjective sleep quality and psychomotor vigilance performance were better with BVS. Conclusions: Both CPAP and BVS appear to be equally effective in improving daytime hypercapnia in a subgroup of patients with obesity hypoventilation syndrome without severe nocturnal hypoxaemia. Trial registration number: Australian Clinical Trials Registry ACTRN01205000096651.

Sleep Apnea in Acromegaly

OBJECTIVE To provide information on the nature, prevalence, and severity of sleep apnea in patients with acromegaly. DESIGN Consecutive case series. SETTING Tertiary referral hospital. PATIENTS Fifty-three patients with acromegaly were consecutively referred: 33 patients were referred because of clinical suspicion of sleep apnea and 20 patients were referred without suspected apnea. MEASUREMENTS Sleep studies as well as growth hormone and insulin-like growth factor 1 (IGF-1) measurements were done. MAIN RESULTS Thirty-one patients (93%; 95% Cl, 85% to 100%) referred because of suspicion of sleep apnea had sleep apnea compared with 12 patients (60%; Cl, 37% to 83%) referred without suspected sleep apnea. Patients with sleep apnea did not have biochemical evidence of increased disease activity (random growth hormone, 12.7 +/- 4.4 micrograms/L; mean growth hormone at 24-hour sampling, 10.8 +/- 8.4 micrograms/L; IGF-1, 90.0 +/- 7.5 nmol/L) compared with patients without sleep apnea (random growth hormone, 14.2 +/- 4.9 micrograms/L, P greater than 0.2; mean growth hormone, 12.4 +/- 3.5 micrograms/L, P greater than 0.2; IGF-1, 90.0 +/- 10.0 nmol/L, P greater than 0.2). Central sleep apnea was the predominant type of apnea in 33% (Cl, 18% to 47%) of patients and was associated with higher random growth hormone and IGF-1 levels than was obstructive apnea (random growth hormone, 23.4 +/- 3.9 compared with 8.8 +/- 3.1 micrograms/L, P less than 0.001; IGF-1, 126 +/- 17.5 compared with 72.5 +/- 7.5 nmol/L, P less than 0.01). CONCLUSIONS Sleep apnea is common in acromegaly. The rate of central sleep apnea was unexpectedly high in patients with acromegaly, and biochemical evidence of increased disease activity was associated with the presence of central apnea rather than with the degree of sleep apnea. Altered respiratory control is a possible mechanism producing sleep apnea in acromegaly.

“Syndrome Z”: the interaction of sleep apnoea, vascular risk factors and heart disease

Obstructive sleep apnoea (OSA) has been linked to increased cardiovascular morbidity and mortality from both coronary heart disease and stroke,1-3 but whether this risk is due to coexistent known cardiovascular risk factors or specific effects of OSA remains to be established. In populations at risk of vascular disease, many patients who experience a cardiovascular event either do not have identifiable risk factors or have disease severity which appears to be out of proportion to their known risk factors. A lot of the variance in the incidence of vascular disease is therefore not explained by known risk factors. It is possible that OSA is a cardiovascular risk factor, previously largely unrecognised, which may account for some of the apparently unexplained variance in vascular risk. Data from the Framingham and other studies have clearly shown that at any level of systolic blood pressure there is a substantial increase in cardiovascular risk with increasing levels of plasma cholesterol, and the presence of glucose intolerance (insulin resistance) further increases this risk.4 Although obesity is a well recognised cardiovascular risk factor, the distribution of body fat is an independent risk factor with central or visceral obesity increasing cardiovascular risk. In the study by Larsen and co-workers5 increasing waist circumference (an index of central obesity) increased the risk of both coronary heart disease and stroke at all tertiles of body mass index. Since these risk factors have been shown to be independent predictors of adverse events, they will show at least additive effects in combination and possibly potentiate each other. Epidemiological and other studies have identified clustering of multiple vascular risk factors. One such cluster is a quartet of risk factors which includes systemic hypertension, insulin resistance, hyperlipidaemia, and central obesity which been defined as “syndrome X”.6 In this cluster there are …