R. Doug McEvoy

A Randomized Controlled Trial of Nurse-led Care for Symptomatic Moderate–Severe Obstructive Sleep Apnea

RATIONALE Obstructive sleep apnea (OSA) is a prevalent disease. Often limited clinical resources result in long patient waiting lists. Simpler validated methods of care are needed. OBJECTIVES To demonstrate that a nurse-led model of care can produce health outcomes in symptomatic moderate-severe OSA not inferior to physician-led care. METHODS A randomized controlled multicenter noninferiority clinical trial was performed. Of 1,427 potentially eligible patients at 3 centers, 882 consented to the trial. Of these, 263 were excluded on the basis of clinical criteria. Of the remaining 619, 195 met home oximetry criteria for high-probability moderate-severe OSA and were randomized to 2 models of care: model A, the simplified model, using home autoadjusting positive airway pressure to set therapeutic continuous positive airway pressure (CPAP), with all care supervised by an experienced nurse; and model B, involving two laboratory polysomnograms to diagnose and treat OSA, with clinical care supervised by a sleep physician. The primary end point was change in Epworth Sleepiness Scale (ESS) score after 3 months of CPAP. Other outcome measures were collected. MEASUREMENTS AND MAIN RESULTS For the primary outcome change in ESS score, nurse-led management was no worse than physician-led management (4.02 vs. 4.15; difference, -0.13; 95% confidence interval: -1.52, 1.25) given a prespecified noninferiority margin of -2 for the lower 95% confidence interval. There were also no differences between both groups in CPAP adherence at 3 months or other outcome measures. Within-trial costs were significantly less in model A. CONCLUSIONS A simplified nurse-led model of care has demonstrated noninferior results to physician-directed care in the management of symptomatic moderate-severe OSA, while being less costly. Clinical trial registered with http://www.anzctr.org.au (ACTRN012605000064606).

Obstructive sleep apnoea syndrome

Obstructive sleep apnoea syndrome (OSAS) is a common clinical condition in which the throat narrows or collapses repeatedly during sleep, causing obstructive sleep apnoea events. The syndrome is particularly prevalent in middle-aged and older adults. The mechanism by which the upper airway collapses is not fully understood but is multifactorial and includes obesity, craniofacial changes, alteration in upper airway muscle function, pharyngeal neuropathy and fluid shift towards the neck. The direct consequences of the collapse are intermittent hypoxia and hypercapnia, recurrent arousals and increase in respiratory efforts, leading to secondary sympathetic activation, oxidative stress and systemic inflammation. Excessive daytime sleepiness is a burden for the majority of patients. OSAS is also associated with cardiovascular co-morbidities, including hypertension, arrhythmias, stroke, coronary heart disease, atherosclerosis and overall increased cardiovascular mortality, as well as metabolic dysfunction. Whether treating sleep apnoea can fully reverse its chronic consequences remains to be established in adequately designed studies. Continuous positive airway pressure (CPAP) is the primary treatment modality in patients with severe OSAS, whereas oral appliances are also widely used in mild to moderate forms. Finally, combining different treatment modalities such as CPAP and weight control is beneficial, but need to be evaluated in randomized controlled trials. For an illustrated summary of this Primer, visit: http://go.nature.com/Lwc6te

Primary care vs specialist sleep center management of obstructive sleep apnea and daytime sleepiness and quality of lIfe: a randomized trial

IMPORTANCE Due to increasing demand for sleep services, there has been growing interest in ambulatory models of care for patients with obstructive sleep apnea. With appropriate training and simplified management tools, primary care physicians are ideally positioned to take on a greater role in diagnosis and treatment. OBJECTIVE To compare the clinical efficacy and within-trial costs of a simplified model of diagnosis and care in primary care relative to that in specialist sleep centers. DESIGN, SETTING, AND PATIENTS A randomized, controlled, noninferiority study involving 155 patients with obstructive sleep apnea that was treated at primary care practices (n=81) in metropolitan Adelaide, 3 rural regions of South Australia or at a university hospital sleep medicine center in Adelaide, Australia (n = 74), between September 2008 and June 2010. INTERVENTIONS Primary care management of obstructive sleep apnea vs usual care in a specialist sleep center; both plans included continuous positive airway pressure, mandibular advancement splints, or conservative measures only. MAIN OUTCOME AND MEASURES The primary outcome was 6-month change in Epworth Sleepiness Scale (ESS) score, which ranges from 0 (no daytime sleepiness) to 24 points (high level of daytime sleepiness). The noninferiority margin was -2.0. Secondary outcomes included disease-specific and general quality of life measures, obstructive sleep apnea symptoms, adherence to using continuous positive airway pressure, patient satisfaction, and health care costs. RESULTS There were significant improvements in ESS scores from baseline to 6 months in both groups. In the primary care group, the mean baseline score of 12.8 decreased to 7.0 at 6 months (P < .001), and in the specialist group, the score decreased from a mean of 12.5 to 7.0 (P < .001). Primary care management was noninferior to specialist management with a mean change in ESS score of 5.8 vs 5.4 (adjusted difference, -0.13; lower bound of 1-sided 95% CI, -1.5; P = .43). There were no differences in secondary outcome measures between groups. Seventeen patients (21%) withdrew from the study in the primary care group vs 6 patients (8%) in the specialist group. CONCLUSIONS AND RELEVANCE Among patients with obstructive sleep apnea, treatment under a primary care model compared with a specialist model did not result in worse sleepiness scores, suggesting that the 2 treatment modes may be comparable. TRIAL REGISTRATION anzctr.org.au Identifier: ACTRN12608000514303.

A simplified model of screening questionnaire and home monitoring for obstructive sleep apnoea in primary care

Background To address the growing burden of disease and long waiting lists for sleep services, a simplified two-stage model was developed and validated for identifying obstructive sleep apnoea (OSA) in primary care using a screening questionnaire followed by home sleep monitoring. Methods 157 patients aged 25–70 years attending their primary care physician for any reason at six primary care clinics in rural and metropolitan regions of South Australia participated. The first 79 patients formed the development group and the next 78 patients the validation group. A screening questionnaire was developed from factors identified from sleep surveys, demographic and anthropometric data to be predictive of moderate to severe OSA. Receiver operating characteristic (ROC) curve analysis was used to validate the two-channel ApneaLink device against full polysomnography. The diagnostic accuracy of the overall two-stage model was then evaluated. Results Snoring, waist circumference, witnessed apnoeas and age were predictive of OSA and incorporated into a screening questionnaire (ROC area under curve (AUC) 0.84, 95% CI 0.75 to 0.94, p<0.001). ApneaLink oximetry with a 3% dip rate was highly predictive of OSA (AUC 0.96, 95% CI 0.91 to 1.0, p<0.001). The two-stage diagnostic model showed a sensitivity of 0.97 (95% CI 0.81 to 1.00) and specificity of 0.87 (95% CI 0.74 to 0.95) in the development group, and a sensitivity of 0.88 (95% CI 0.60 to 0.98) and specificity of 0.82 (95% CI 0.70 to 0.90) in the validation group. Conclusion A two-stage model of screening questionnaire followed by home oximetry can accurately identify patients with OSA in primary care and has the potential to expedite care for patients with this common sleep disorder.

Predictors of long-term adherence to continuous positive airway pressure therapy in patients with obstructive sleep apnea and cardiovascular disease in the SAVE study

STUDY OBJECTIVES To determine the clinical variables that best predict long- term continuous positive airway pressure (CPAP) adherence among patients with cardiovascular disease who have obstructive sleep apnea (OSA). DESIGN 12-mo prospective within-trial observational study. SETTING Centers in China, Australia, and New Zealand participating in the Sleep Apnea cardioVascular Endpoints (SAVE) study. PATIENTS There were 275 patients age 45-70 y with cardiovascular disease (i.e., previously documented transient ischemic attack, stroke, or coronary artery disease) and OSA (4% oxygen desaturation index (ODI) > 12) who were randomized into the CPAP arm of the SAVE trial prior to July 1, 2010. METHODS Age, sex, country of residence, type of cardiovascular disease, baseline ODI, severity of sleepiness, and Hospital Anxiety and Depression Scale (HADS) scores plus CPAP side effects and adherence at 1 mo were entered in univariate analyses in an attempt to identify factors predictive of CPAP adherence at 12 mo. Variables with P < 0.2 were then included in a multivariate analysis using a linear mixed model with sites as a random effect and 12-mo CPAP use as the dependent outcome variable. MEASUREMENTS AND RESULTS CPAP adherence at 1, 6, and 12 mo was (mean ± standard deviation) 4.4 ± 2.0, 3.8 ± 2.3, and 3.3 ± 2.4 h/night, respectively. CPAP use at 1 mo (effect estimate ± standard error, 0.65 ± 0.07 per h increase, P < 0.001) and side effects at 1 mo (-0.24 ± 0.092 per additional side effect, P = 0.009) were the only independent predictors of 12- mo CPAP adherence. CONCLUSION Continuous positive airway pressure use in patients with coexisting cardiovascular disease and moderate to severe obstructive sleep apnea decreases significantly over 12 months. This decline can be predicted by early patient experiences with continuous positive airway pressure (i.e., adherence and side effects at 1 month), raising the possibility that intensive early interventions could improve long-term continuous positive airway pressure compliance in this patient population. CLINICAL TRIALS REGISTER Clinical Trials, http://www.clinicaltrials.gov, NCT00738179.

Genioglossus reflex inhibition to upper-airway negative-pressure stimuli during wakefulness and sleep in healthy males

During wakefulness, obstructive sleep apnoea patients appear to compensate for an anatomically narrow upper airway by increasing upper airway dilator muscle activity, e.g. genioglossus, at least partly via a negative‐pressure reflex that may be diminished in sleep. Previous studies have assessed the negative‐pressure reflex using multi‐unit, rectified, moving‐time‐average EMG recordings during brief pulses of negative upper‐airway pressure. However, moving‐time averaging probably obscures the true time‐related reflex morphology, potentially masking transient excitatory and inhibitory components. This study aimed to re‐examine the genioglossus negative‐pressure reflex in detail, without moving‐time averaging. Bipolar fine‐wire electrodes were inserted per orally into the genioglossus muscle in 17 healthy subjects. Two upper airway pressure catheters were inserted per nasally. Genioglossus EMG reflex responses were generated via negative‐pressure stimuli (∼−10 cmH2O at the choanae, 250 ms duration) delivered during wakefulness and sleep. Ensemble‐averaged, rectified, genioglossus EMG recordings demonstrated reflex activation (onset latency 26 ± 1 ms; peak amplitude 231 ± 29% of baseline) followed by a previously unreported suppression (peak latency 71 ± 4 ms; 67 ± 8% of baseline). Single‐motor‐unit activity, clearly identifiable in ∼10% of trials in six subjects, showed a concomitant increase in the interspike interval from baseline (26 ± 9 ms, P= 0.01). Genioglossus negative‐pressure reflex morphology and amplitude of the initial peak were maintained in non‐rapid eye movement (NREM) sleep but suppression amplitude was more pronounced during NREM and declined further during REM sleep compared to wakefulness. These data indicate there are both excitatory and inhibitory components to the genioglossus negative‐pressure reflex which are differentially affected by state.

Factors affecting sleep quality of patients in intensive care unit

INTRODUCTION Sleep disturbance is a frequently overlooked complication of intensive care unit (ICU) stay. AIM To evaluate sleep quality among patients admitted to ICU and investigate environmental and non-environmental factors that affect sleep quality in ICU. METHODS Over a 22-month period, we consecutively recruited patients who spent ≥ 2 nights post-endotracheal extubation in ICU and who were orientated to time, place, and person on the day of discharge. Self-reported sleep quality, according to a modified Freedman questionnaire, which provided data on self-reported ICU sleep quality in ICU and environmental factors affecting sleep quality in the ICU, were collected. We also investigated non-environmental factors, such as severity of illness, ICU interventions, and medications that can affect sleep quality. RESULTS Fifty males and 50 females were recruited with a mean (± SD) age of 65.1 ± 15.2 years. APACHE II score at admission to ICU was 18.1 ± 7.5 with duration of stay 6.7 ± 6.5days. Self-reported sleep quality score at home (1 = worst; 10 = best) was 7.0 ± 2.2; this decreased to 4.0 ± 1.7 during their stay in ICU (p < 0.001). In multivariate analysis with APACHE III as severity of illness (R(2) = 0.25), factors [exp(b)(95% CI), p value] which significantly affected sleep in ICU were sex [0.37(0.19-0.72), p < 0.01], age and sex interaction [1.02(1.01-1.03), p < 0.01], bedside phone [0.92(0.87-0.97), p < 0.01], prior quality of sleep at home [1.30(1.05-1.62), p = 0.02], and use of steroids [0.82(0.69-0.98), p = 0.03] during the stay in ICU. CONCLUSION Reduced sleep quality is a common problem in ICU with a multifactorial etiology.

The influence of gender and upper airway resistance on the ventilatory response to arousal in obstructive sleep apnoea in humans

The termination of obstructive respiratory events is typically associated with arousal from sleep. The ventilatory response to arousal may be an important determinant of subsequent respiratory stability/instability and therefore may be involved in perpetuating obstructive respiratory events. In healthy subjects arousal is associated with brief hyperventilation followed by more prolonged hypoventilation on return to sleep. This study was designed to assess whether elevated sleeping upper airway resistance (RUA) alters the ventilatory response to arousal and subsequent breathing on return to sleep in patients with obstructive sleep apnoea (OSA). Inspired minute ventilation (VI), RUA and end‐tidal CO2 pressure (PET,CO2) were measured in 22 patients (11 men, 11 women) with OSA (mean ±s.e.m., apnoea–hypopnoea index (AHI) 48.9 ± 5.9 events h−1) during non‐rapid eye movement (NREM) sleep with low RUA (2.8 ± 0.3 cmH2O l−1 s; optimal continuous positive airway pressure (CPAP) = 11.3 ± 0.7 cmH2O) and with elevated RUA (17.6 ± 2.8 cmH2O l−1 s; sub‐optimal CPAP = 8.4 ± 0.8 cmH2O). A single observer, unaware of respiratory data, identified spontaneous and tone‐induced arousals of 3–15 s duration preceded and followed by stable NREM sleep. VI was compared between CPAP levels before and after spontaneous arousal in 16 subjects with tone‐induced arousals in both conditions. During stable NREM sleep at sub‐optimal CPAP, PET,CO2 was mildly elevated (43.5 ± 0.8 versus 42.5 ± 0.8 Torr). However, baseline VI (7.8 ± 0.3 versus 8.0 ± 0.3 l min−1) was unchanged between CPAP conditions. For the first three breaths following arousal, VI was higher for sub‐optimal than optimal CPAP (first breath: 11.2 ± 0.9 versus 9.3 ± 0.6 l min−1). The magnitude of hypoventilation on return to sleep was not affected by the level of CPAP and both obstructive and central respiratory events were rare following arousal. Similar results occurred after tone‐induced arousals which led to larger responses than spontaneous arousals. VI for the first breath following arousal under optimal CPAP was greater in men than women (11.0 ± 0.4 versus 7.6 ± 0.6 l min−1). These results demonstrate that the ventilatory response to arousal is influenced by pre‐arousal airway resistance and gender. Whether this contributes to the perpetuation of respiratory events and the pathogenesis of OSA is unclear.

Association of Positive Airway Pressure With Cardiovascular Events and Death in Adults With Sleep Apnea: A Systematic Review and Meta-analysis

Importance Sleep apnea (obstructive and central) is associated with adverse cardiovascular risk factors and increased risks of cardiovascular disease. Positive airway pressure (PAP) provides symptomatic relief, whether delivered continuously (CPAP) or as adaptive servo-ventilation (ASV), but the associations with cardiovascular outcomes and death are unclear. Objective To assess the association of PAP vs control with cardiovascular events and death in patients with sleep apnea. Data Sources and Study Selection MEDLINE, EMBASE, and the Cochrane Library were systematically searched from inception date to March 2017 for randomized clinical trials that included reporting of major adverse cardiovascular events or deaths. Data Extraction and Synthesis Two authors independently extracted data using standardized forms. Summary relative risks (RRs), risk differences (RDs) and 95% CIs were obtained using random-effects meta-analysis. Main Outcomes and Measures The main outcomes were a composite of acute coronary syndrome (ACS) events, stroke, or vascular death (major adverse cardiovascular events); cause-specific vascular events; and death. Results The analyses included data from 10 trials (9 CPAP; 1 ASV) of patients with sleep apnea (N = 7266; mean age, 60.9 [range, 51.5 to 71.1] years; 5847 [80.5%] men; mean [SD] body mass index, 30.0 [5.2]. Among 356 major adverse cardiovascular events and 613 deaths recorded, there was no significant association of PAP with major adverse cardiovascular events (RR, 0.77 [95% CI, 0.53 to 1.13]; P = .19 and RD, −0.01 [95% CI, −0.03 to 0.01]; P = .23), cardiovascular death (RR, 1.15 [95% CI, 0.88 to 1.50]; P = .30 and RD −0.00 [95% CI, −0.02 to 0.02]; P = .87), or all-cause death (RR, 1.13 [95% CI, 0.99 to 1.29]; P = .08 and RD, 0.00 [95% CI, −0.01 to 0.01]; P = .51). The same was true for ACS, stroke, and heart failure. There was no evidence of different associations for CPAP vs ASV (all P value homogeneity >.24), and meta-regressions identified no associations of PAP with outcomes for different levels of apnea severity, follow-up duration, or adherence to PAP (all P values > .13). Conclusions and Relevance The use of PAP, compared with no treatment or sham, was not associated with reduced risks of cardiovascular outcomes or death for patients with sleep apnea. Although there are other benefits of treatment with PAP for sleep apnea, these findings do not support treatment with PAP with a goal of prevention of these outcomes.

Prader Willi Syndrome and excessive daytime sleepiness

Prader Willi Syndrome (PWS) is a rare genetic disorder characterized by a range of physical, psychological and physiological abnormalities. PWS patients may also demonstrate a range of abnormalities of sleep architecture and of breathing during sleep, and excessive daytime sleepiness (EDS). In the general population EDS is associated with Obstructive Sleep Apnea Syndrome (OSAS). In PWS, by contrast, OSAS is unlikely to fully explain EDS and other factors, including hypothalamic dysfunction are likely to contribute. The present review examines OSAS and hypothalamic dysfunction and other contributing factors to EDS in PWS.