Andrew Vakulin

Sleep disordered breathing and chronic respiratory failure in patients with chronic pain on long term opioid therapy.

STUDY OBJECTIVES The use of opioid medication for chronic pain has been increasing. The main aim of this study was to assess how many patients on opioids for chronic pain had sleep disordered breathing (SDB) and the type of SDB. The impact of these medications on daytime arterial blood gas (ABG) measurements and psychomotor vigilance was also studied. METHODS Twenty-four patients (aged 18-75 years) on long-term opioids were prospectively recruited. Patients underwent home polysomnogram (PSG), psychomotor vigilance testing (PVT), and awake daytime ABG. Overnight PSG findings were compared to those of patients matched for age, sex, and BMI referred to our sleep service for evaluation of SDB. PVT results in the patient cohort were compared to PVT in healthy controls. RESULTS Forty-six percent of opioid patients had severe SDB as defined by an apnea hypopnea index (AHI) > 30/h. The severity of SDB was similar in opioid-treated pain clinic patients and sleep clinic patients (mean ± SD AHI: Opioid-treated patients 32.7 ± 25.6; Sleep Study comparator group 28.9 ± 24.6, p = 0.6). Opioid patients had a higher frequency of central apneas and a lower arousal index (CAI: 3.9 ± 8.3 vs. 0.3 ± 0.5 events/h; p = 0.004, AI 8.0 ± 4.1 vs. 20.1 ± 13.8, p < 0.001). Pain clinic patients had impaired gas exchange during sleep and wakefulness. Nine of 20 (45%) had daytime hypercapnia, indicating a surprising number were in chronic respiratory failure. Morphine equivalent doses correlated with the severity of SDB. PVT was impaired when compared to a healthy PVT comparator group (RT: Opioid-treated patients 0.43 ± 0.27: Healthy PVT comparator group 0.28 ± 0.03 sec; p < 0.001). CONCLUSIONS Patients on long-term opioids frequently have severe SDB, which in part is central in origin. PVT was markedly impaired. Half of the patients studied have evidence of chronic ventilatory failure. COMMENTARY A commentary on this article appears in this issue on page 853

Maintenance of Wakefulness Test scores and driving performance in sleep disorder patients and controls

OBJECTIVE Sleepiness at the wheel is a risk factor for traffic accidents. Past studies have demonstrated the validity of the Maintenance of Wakefulness Test (MWT) scores as a predictor of driving impairment in untreated patients with obstructive sleep apnea syndrome (OSAS), but there is limited information on the validity of the maintenance of wakefulness test by MWT in predicting driving impairment in patients with hypersomnias of central origin (narcolepsy or idiopathic hypersomnia). The aim of this study was to compare the MWT scores with driving performance in sleep disorder patients and controls. METHODS 19 patients suffering from hypersomnias of central origin (9 narcoleptics and 10 idiopathic hypersomnia), 17 OSAS patients and 14 healthy controls performed a MWT (4×40-minute trials) and a 40-minute driving session on a real car driving simulator. Participants were divided into 4 groups defined by their MWT sleep latency scores. The groups were pathological (sleep latency 0-19 min), intermediate (20-33 min), alert (34-40 min) and control (>34 min). The main driving performance outcome was the number of inappropriate line crossings (ILCs) during the 40 minute drive test. RESULTS Patients with pathological MWT sleep latency scores (0-19 min) displayed statistically significantly more ILC than patients from the intermediate, alert and control groups (F (3, 46)=7.47, p<0.001). INTERPRETATION Pathological sleep latencies on the MWT predicted driving impairment in patients suffering from hypersomnias of central origin as well as in OSAS patients. MWT is an objective measure of daytime sleepiness that appears to be useful in estimating the driving performance in sleepy patients.

Cybersickness provoked by head-mounted display affects cutaneous vascular tone, heart rate and reaction time.

Evidence from studies of provocative motion indicates that motion sickness is tightly linked to the disturbances of thermoregulation. The major aim of the current study was to determine whether provocative visual stimuli (immersion into the virtual reality simulating rides on a rollercoaster) affect skin temperature that reflects thermoregulatory cutaneous responses, and to test whether such stimuli alter cognitive functions. In 26 healthy young volunteers wearing head-mounted display (Oculus Rift), simulated rides consistently provoked vection and nausea, with a significant difference between the two versions of simulation software (Parrot Coaster and Helix). Basal finger temperature had bimodal distribution, with low-temperature group (n=8) having values of 23-29 °C, and high-temperature group (n=18) having values of 32-36 °C. Effects of cybersickness on finger temperature depended on the basal level of this variable: in subjects from former group it raised by 3-4 °C, while in most subjects from the latter group it either did not change or transiently reduced by 1.5-2 °C. There was no correlation between the magnitude of changes in the finger temperature and nausea score at the end of simulated ride. Provocative visual stimulation caused prolongation of simple reaction time by 20-50 ms; this increase closely correlated with the subjective rating of nausea. Lastly, in subjects who experienced pronounced nausea, heart rate was elevated. We conclude that cybersickness is associated with changes in cutaneous thermoregulatory vascular tone; this further supports the idea of a tight link between motion sickness and thermoregulation. Cybersickness-induced prolongation of reaction time raises obvious concerns regarding the safety of this technology.

The Relationship between Functional Health Literacy and Obstructive Sleep Apnea and its Related Risk Factors and Comorbidities in a Population Cohort of Men

STUDY OBJECTIVES To examine the relationship between functional health literacy (FHL) and obstructive sleep apnea (OSA), its diagnosis, related risk factors, and comorbidities. DESIGN Population cohort study. SETTING Adelaide, South Australia, 2011-12. PARTICIPANTS 1,021 Men Androgen Inflammation Lifestyle Environment and Stress Study participants aged ≥ 40 years, of whom 627 were identified with OSA by self-report (n = 184 previously diagnosed) or with in-home polysomnography in 837 randomly selected participants without self-reported OSA (n = 443 previously undiagnosed). INTERVENTIONS The Newest Vital Sign assessed FHL in 88% of participants. Full in-home unattended polysomnography (Embletta X100) was scored by 2007 AASM (alternative) criteria. MEASUREMENTS AND RESULTS FHL was adequate in 75.3% (n = 122) of previously diagnosed and 68.3% (n = 261) of previously undiagnosed OSA. Not having a previous diagnosis was independently associated with inadequate FHL (odds ratio [OR]:2.84, 95% confidence interval [CI]:1.25-6.45) and workforce participation (OR = 2.04, 95% CI = 1.01-4.00), and inversely associated with previous snoring (OR = 0.48, 95% CI = 0.29-0.81), obesity (OR = 0.35, 95% CI = 0.15-0.81), and cardiovascular disease (OR = 0.45, 95% CI = 0.24-0.85). In polysomnography participants, inadequate FHL was independently associated with previously undiagnosed OSA (OR = 2.43, 95% CI = 1.40-4.20). In undiagnosed men, less than adequate FHL was independently associated with sedentary lifestyle (OR = 2.42, 95% CI = 1.36-4.29), and depression (OR = 2.50, 95% CI = 1.23-5.09) and inadequate FHL was associated with current smoking (OR = 2.87, 95% CI = 1.21-6.84). The depression association was attenuated after additional adjustment for comorbidities and general health (OR = 2.04, 95% CI = 0.93-4.49, P = 0.076). In previously diagnosed OSA, less than adequate FHL was independently associated with cardiovascular disease (OR = 2.76, 95% CI = 1.09-7.01). CONCLUSIONS Limited functional health literacy was independently associated with obstructive sleep apnea (OSA), OSA diagnosis, lifestyle factors and comorbidities, highlighting the importance of developing and promoting national disease-specific health literacy policies.

Modafinil/armodafinil in obstructive sleep apnoea: a systematic review and meta-analysis

Modafinil is used internationally to treat residual sleepiness despite continuous positive airway pressure in obstructive sleep apnoea (res-OSA). In 2011, the European Medicines Agency removed the indication based on an unfavourable risk–benefit profile in two trials for efficacy and all accumulated safety data. We performed a meta-analysis of all randomised controlled trials of modafinil (or armodafinil) in res-OSA to quantify efficacy and safety. We systematically searched and assessed studies from major databases, conferences and trials registries to find randomised, placebo-controlled trials of modafinil/armodafinil for ≥2 weeks in adult res-OSA treating sleepiness. We analysed 10 of the 232 articles identified that met inclusion criteria (1466 patients). Modafinil/armodafinil improved the Epworth Sleepiness Scale score (2.2 points, 95% CI 1.5–2.9) and the Maintenance of Wakefulness Test over placebo (3 min, 95% CI 2.1–3.8 min). Modafinil/armodafinil tripled adverse events and doubled adverse events leading to withdrawal but did not increase serious adverse events (hospitalisations or death). Modafinil and armodafinil improve subjective and objective daytime sleepiness in res-OSA. We believe our analysis is a fairer analysis of the risk–benefit profile of this indication. Clinicians may want to use this data to balance the risks and benefits on a case-by-case basis with their patients. An EMA risk–benefit analysis of modafinil in OSA was negative. Does analysing extra trials change the conclusion? http://ow.ly/VYvO8

Quantitative sleep EEG and polysomnographic predictors of driving simulator performance in obstructive sleep apnea

OBJECTIVES To improve identification of obstructive sleep apnea (OSA) patients at risk of driving impairment, this study explored predictors of driving performance impairment in untreated OSA patients using clinical PSG metrics, sleepiness questionnaires and quantitative EEG markers from routine sleep studies. METHODS Seventy-six OSA patients completed sleepiness questionnaires and driving simulator tests in the evening of their diagnostic sleep study. All sleep EEGs were subjected to quantitative power spectral analysis. Correlation and multivariate linear regression were used to identify the strongest predictors of driving simulator performance. RESULTS Absolute EEG spectral power across all frequencies (0.5-32 Hz) throughout the entire sleep period and separately in REM and NREM sleep, (r range 0.239-0.473, all p<0.05), as well as sleep onset latency (r=0.273, p<0.017) positively correlated with driving simulator steering deviation. Regression models revealed that amongst clinical and qEEG variables, the significant predictors of worse steering deviation were greater total EEG power during NREM and REM sleep, greater beta EEG power in NREM and greater delta EEG power in REM (range of variance explained 5-17%, t range 2.29-4.0, all p<0.05) and sleep onset latency (range of variance explained 4-9%, t range 2.15-2.5, all p<0.05). CONCLUSIONS In OSA patients, increased EEG power, especially in the faster frequency (beta) range during NREM sleep and slower frequency (delta) range in REM sleep were associated with worse driving performance, while no relationships were observed with clinical metrics e.g. apnea, arousal or oxygen indices. SIGNIFICANCE Quantitative EEG analysis in OSA may provide useful markers of driving impairment risk. Future studies are necessary to confirm these findings and assess the clinical significance of quantitative EEG as predictors of driving impairment in OSA.

Obstructive sleep apnea and schizophrenia: A systematic review to inform clinical practice.

BACKGROUND Risk factors for obstructive sleep apnea (OSA) are common in people with schizophrenia. Identification and treatment of OSA may improve physical health in this population; however there are no guidelines to inform screening and management. OBJECTIVES Systematic review to determine, in people with schizophrenia and related disorders: the prevalence of OSA; the prevalence of OSA compared to general population controls; the physical and psychiatric correlates of OSA, associations between antipsychotic medications and OSA; the impact of treatment of OSA on psychiatric and physical health; and the diagnostic validity of OSA screening tools. DATA SOURCES Medline, EMBASE, ISI Web of Science and PsycINFO electronic databases. Cohort, case-control and cross-sectional studies and RCTs reporting on prevalence of OSA in subjects with schizophrenia and related disorders were reviewed. RESULTS The prevalence of OSA varied between 1.6% and 52%. The prevalence of OSA was similar between people with schizophrenia and population controls in two studies. Diagnosis of OSA was associated with larger neck circumference, BMI>25, male sex and age>50years. There were no data on physical or psychiatric outcomes following treatment of OSA. The diagnostic utility of OSA screening tools had not been investigated. CONCLUSION OSA may be prevalent and potentially under-recognized in people with schizophrenia. Further research is required to determine utility of OSA screening tools, the relationships between antipsychotic medications and OSA and any benefits of treating OSA. We propose a strategy for the identification of OSA in people with schizophrenia and related disorders.

Auditory evoked potentials remain abnormal after CPAP treatment in patients with severe obstructive sleep apnoea.

OBJECTIVE To assess the effects of 3 months of optimal CPAP treatment on auditory event related potentials (AERP) in patients with severe obstructive sleep apnoea (OSA) compared with healthy controls. METHODS Auditory odd-ball related N1, P2, N2 and P3 AERP components were assessed in 9 severe OSA subjects and 9 healthy controls at baseline evaluation and at ∼3 months follow-up in both groups, with OSA subjects treated with continuous positive air-way pressure (CPAP) during this period. RESULTS Severe OSA subjects showed significantly delayed, P2, N2 and P3 latencies, and significantly different P2 and P3 amplitudes compared to controls at baseline (group effect, all p<0.05). At follow-up evaluation P3 latency shortened in treated OSA patients but remained prolonged compared to controls (group by treatment interaction, p<0.05) despite high CPAP compliance (6h/night). The earlier AERP (P2 and N2) components did not change in either controls or OSA patients at follow-up and remained different in patients versus controls. CONCLUSIONS This study demonstrates that in severe OSA patients AERP responses show minimal or no improvement and remain abnormal following 3 months of optimal CPAP treatment. SIGNIFICANCE Persistent cortical sensory processing abnormalities despite treatment in severe OSA may have implications for daytime neurobehavioral performance and safety in OSA patients. AERP responses may help identify residual performance deficits and risks.

Quantitative electroencephalogram measures in adult obstructive sleep apnea – Potential biomarkers of neurobehavioural functioning

Obstructive sleep apnea (OSA) results in significantly impaired cognitive functioning and increased daytime sleepiness in some patients leading to increased risk of motor vehicle and workplace accidents and reduced productivity. Clinicians often face difficulty in identifying which patients are at risk of neurobehavioural dysfunction due to wide inter-individual variability, and disparity between symptoms and conventional metrics of disease severity such as the apnea hypopnea index. Quantitative electroencephalogram (EEG) measures are determinants of awake neurobehavioural function in healthy subjects. However, the potential value of quantitative EEG (qEEG) measurements as biomarkers of neurobehavioural function in patients with OSA has not been examined. This review summarises the existing literature examining qEEG in OSA patients including changes in brain activity during wake and sleep states, in relation to daytime sleepiness, cognitive impairment and OSA treatment. It will speculate on the mechanisms which may underlie changes in EEG activity and discuss the potential utility of qEEG as a clinically useful predictor of neurobehavioural function in OSA.

Chronic Kidney Disease and Sleep Apnea Association of Kidney Disease With Obstructive Sleep Apnea in a Population Study of Men.

Study Objectives To determine the relationship between obstructive sleep apnea (OSA) and chronic kidney disease (CKD). Previous population studies of the association are sparse, conflicting and confined largely to studies of administrative data. Methods Cross-sectional analysis in unselected participants of the Men Androgens Inflammation Lifestyle Environment and Stress (MAILES) study, aged >40 years. Renal data were available for 812 men without a prior OSA diagnosis who underwent full in-home polysomnography (Embletta X100) in 2010-2011. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 or eGFR≥60 and albuminuria (albumin-creatinine ratio ≥3.0 mg/mmol). Results CKD (10.5%, n = 85 [Stage 1-3, 9.7%; Stage 4-5, 0.7%]) of predominantly mild severity showed significant associations with OSA (apnea-hypoapnea index [AHI] ≥ 10): odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.02-3.5; severe OSA (AHI ≥ 30/h): OR = 2.6, 95% CI: 1.1-6.2; and respiratory-related arousal index: ≥7.6/h, OR = 2.3, 95%CI: 1.1-4.7; but not measures of hypoxemia after adjustment for age, hypertension, diabetes, smoking, obesity, and NSAID use. There was no association of CKD with daytime sleepiness. In men with CKD, those with OSA were not significantly more likely to report symptoms (sleepiness, snoring, and apneas) or be identified with the STOP OSA screening questionnaire, compared to men without OSA. Conclusions Predominantly mild CKD is associated with severe OSA and arousals. Further population studies examining the longitudinal relationship between CKD and OSA are warranted. Better methods are needed to identify OSA in CKD which may have few symptoms.