The public health burden of obstructive sleep apnea.

Obstructive sleep apnea (OSA) is the most common respiratory disorder of sleep. The vast majority (>80%) of adults with moderate to severe OSA remain undiagnosed. The economic costs associated with OSA are substantial for both the individual and society as a whole; expenses are likely to be underestimated given that the disease remains undiagnosed in such a large percentage of individuals. The economic burden of motor vehicle collisions related to OSA alone is significant; it is estimated that 810,000 collisions and 1400 fatalities from car crashes in the United States were attributable to sleep apnea in 2000. The many health consequences of OSA include daytime sleepiness, reduced quality of life, decreased learning skills, and importantly, neurocognitive impairments that include impaired episodic memory, executive function, attention and visuospatial cognitive functions. Untreated OSA leads to numerous medical problems such as cardiovascular diseases that can potentially increase healthcare utilization. Untreated patients with sleep apnea consume a disproportionate amount of healthcare resources, expenditures that decrease after treatment. The gold-standard management of OSA remains treatment with CPAP (Continuous Positive Airway Pressure), which is effective in eliminating sleep fragmentation and preserving nocturnal oxygenation, thereby improving daytime sleepiness and quality of life. However, its impacts in reversing neurocognitive function are still uncertain. A significant impediment to CPAP effectiveness is low adherence rates (ranges from 50% to 75%). It is commonly accepted that CPAP improves excessive drowsiness; hence meliorates attention, and accumulating data suggest that CPAP improves a variety of other outcomes such as the risk of motor vehicle crashes.

Cognitive Function in a Sleep Clinic Cohort of Patients with Obstructive Sleep Apnea.

Rationale: Obstructive sleep apnea (OSA) is associated with an increased risk of mild cognitive impairment (MCI) within the general population. However, MCI risk in sleep-clinic populations of patients with OSA is poorly characterized.Objectives: To determine the prevalence of MCI in a sleep-clinic population of patients with OSA and which patients are at the greatest risk for this complication.Methods: Adults (n = 1,084) referred to three academic sleep centers for suspected OSA who had home sleep apnea testing or in-laboratory polysomnography were recruited. Patients completed sleep and medical history questionnaires, the Montreal Cognitive Assessment Test (MoCA) of global cognition, the Rey Auditory Verbal Learning Test of memory, and the Wechsler Adult Intelligence Scale-Fourth Edition Digit-Symbol Coding (DSC) subtest of information processing speed.Results: A MoCA score <26 (range 0-30) was operationally defined as MCI. MCI was present in 47.9% of our entire patient cohort, increasing to >55.3% in patients with moderate and severe OSA. Patients with a MoCA <26 were predominantly older males with more severe OSA, hypoxemia, and vascular comorbidities. Moderate and severe OSA were independently associated with >70% higher odds for MCI compared with patients with no OSA (P = 0.003). Memory and information processing speed was lower than age-matched normal values (P < 0.001), with lower MoCA and DSC scores associated with a higher oxygen desaturation index and nocturnal hypoxemia.Conclusions: Cognitive impairment is highly prevalent in patients referred to sleep clinics for suspected OSA, occurring predominantly in older males with moderate to severe OSA and concurrent vascular comorbidities. Moderate to severe OSA is an independent risk factor for MCI.

Obstructive Sleep Apnea Severity, Body Mass Index, and Circulating Levels of Cellular Adhesion Molecules.

PURPOSE: To investigate the relationship between obstructive sleep apnea (OSA) severity, body mass index (BMI), and circulating levels of inflammatory adhesion molecules (intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin). METHODS: A cross-sectional clinical cohort study on all consecutive adults referred to the University of British Columbia (UBC) Sleep Laboratory for a polysomnogram (PSG) for suspected OSA provided a morning blood sample. Samples were analyzed with multiplex immune assay (MilliporeSigma, CA) to assess the levels of adhesion molecules. RESULTS: 488 patients were studied; the majority were male (68%) with a mean age of 50 yrs, mean AHI of 23 events/hour, and mean BMI of 32 kg/m2. In multivariable linear regression models, all three adhesion molecules were significantly associated with BMI (E-selectin p < 0.0001; ICAM-1 p = 0.0007; VCAM-1 p = 0.0003). However, only E-selectin was independently associated with AHI (p = 0.02); there was no significant interaction between AHI and BMI for E-selectin (p = 0.33). CONCLUSIONS: Although all three adhesion molecules were associated with BMI, only E-selectin was independently associated with OSA severity. Future studies are needed to determine the clinical significance of the relationship between E-selectin and OSA.

Symptom subtypes and cognitive function in a clinic-based OSA cohort: a multi-centre Canadian study.

BACKGROUND: Distinct symptom subtypes are found in patients with OSA. The association between these subtypes and neurocognitive function is unclear. OBJECTIVE: The purposes of this study were to assess whether OSA symptom subtypes are present in a cohort of Canadian patients with suspected OSA and evaluate the relationship between subtypes and neurocognitive function. METHODS: Patients with suspected OSA who completed a symptom questionnaire and underwent testing for OSA were included. Symptom subtypes were identified using latent class analysis. Associations between subtypes and neurocognitive outcomes (Montreal Cognitive Assessment [MoCA], Rey Auditory Verbal Learning Test [RAVLT], Wechsler Adult Intelligence Scale [WAIS-IV], Digit-Symbol Coding subtest [DSC]) were assessed using analysis of covariance (ANCOVA), controlling for relevant covariates. RESULTS: Four symptom subtypes were identified in patients with OSA (oxygen desaturation index ≥5 events/hour). Three were similar to prior studies, including the Excessively Sleepy (N=405), Disturbed Sleep (N=382) and Minimally Symptomatic (N=280), and one was a novel subtype in our sample defined as Excessively Sleepy with Disturbed Sleep (N=247). After covariate adjustment, statistically significant differences among subtypes (p=0.037) and among subtypes and patients without OSA (p=0.044) were observed in DSC scores; the Minimally Symptomatic subtype had evidence of higher DSC scores than all other groups, including non-OSA patients. No differences were seen in MoCA or RAVLT. CONCLUSIONS: Results support the existence of previously identified OSA symptom subtypes of excessively sleepy, disturbed sleep and minimally symptomatic in a clinical sample from Canada. Subtypes were not consistently associated with neurocognitive function across multiple instruments.

Air Pollution and Systemic Inflammation in Patients With Suspected OSA Living in an Urban Residential Area.

BACKGROUND: Air pollution and OSA are independently associated with systemic inflammation, but it is unknown if these exposures interact to influence systemic inflammation. RESEARCH QUESTION: The study objective was to determine the relative importance of these factors and their combined potential to influence systemic inflammation in patients under assessment for sleep ailments. STUDY DESIGN AND METHODS: A total of 315 patients contributed data, including a questionnaire, polysomnogram, and morning serum IL-6 and IL-10 concentrations. For each patient, residential annual average air pollution exposure (nitrogen dioxide [NO2], black carbon [BC], and particulate matter with an aerodynamic diameter ≤ 2.5 µm [PM2.5]) was estimated with a land use regression model. Linear regression modeling was used adjusting for age, sex, apnea-hypopnea index, BMI, smoking, socioeconomic status, and comorbidities. RESULTS: In adjusted models, quartile 4 PM2.5 exposure (compared with quartiles 1-3) was associated with increased IL-6 and IL-10 concentrations (estimated adjusted, 7.1 pg/mL [95% CI, 2.5-11.7; P < .01] and 71.4 pg/mL [95% CI, 38.2-103.7; P < .0001], respectively). OSA, BC, and NO2 were not associated with IL-6 or IL-10 in similar analyses; however, moderate to severe OSA influenced the effect of BC on IL-6 (interaction term, P = .01), with no significant interaction terms observed for NO2 or PM2.5. Subsequent stratified analysis showed that in the 173 patients with moderate to severe OSA, quartile 4 BC exposure (compared with quartiles 1-3) was associated with an increased IL-6 concentration (estimated adjusted, 8.9 pg/mL; 95% CI, 1.7-16.1; P = .02). INTERPRETATION: Long-term residential PM2.5 exposure was associated with increased IL-6 and IL-10 concentrations in patients evaluated for suspected OSA. BC exposure was also associated with increased IL-6 but only in the subgroup of patients with moderate to severe OSA. These data suggest the potential for joint effects of moderate to severe OSA and air pollution on systemic inflammation.

Obstructive Sleep Apnea and Circulating Biomarkers of Oxidative Stress: A Cross-Sectional Study.

Oxidative stress (OS) drives cardiometabolic diseases. Intermittent hypoxia consistently increases oxidative stress markers. Obstructive sleep apnea (OSA) patients experience intermittent hypoxia and an increased rate of cardiovascular disease, however, the impact of OSA on OS markers is not clear. The objective was to assess relationships between OSA severity and biomarker levels. Patients with suspected OSA referred for a polysomnogram (PSG) provided fasting blood sample. Plasma levels of 8-isoprostane, 8-hydroxydeoxyguanosine (8-OHdG), and superoxide dismutase (SOD) were measured. The relationship between OSA and OS was assessed both before and after controlling for confounders (age, sex, smoking history, history of cardiovascular disease, ethnicity, diabetes, statin usage, body mass index (BMI)). 402 patients were studied (68% male, mean age ± SD = 50.8 ± 11.8 years, apnea-hypopnea index (AHI) = 22.2 ± 21.6 events/hour, BMI = 31.62 ± 6.49 kg/m2). In a multivariable regression, the AHI significantly predicted 8-isoprostane levels (p = 0.0008) together with age and statin usage; AHI was not a predictor of 8-OHdG or SOD. Female sex (p < 0.0001) and no previous history of cardiovascular disease (p = 0.002) were associated with increased antioxidant capacity. Circulating 8-isoprostane levels may be a promising biomarker of the severity of oxidative stress in OSA patients. Prospective studies are needed to determine whether this biomarker is associated with long-term cardiometabolic complications in OSA.

Circulating biomarkers to identify cardiometabolic complications in patients with Obstructive Sleep Apnea: A systematic review.

Untreated Obstructive sleep apnea (OSA) is associated with an increased risk of cardiometabolic diseases such as diabetes and myocardial infarction. However, it is difficult to predict which patients are at particularly high risk. This systematic review aimed to identify potentially useful circulating biomarkers that could predict cardiometabolic complications in OSA. We searched Cochrane (EBM), EMBASE, Medline, PubMed, and Web of Science databases. Search concepts included: "Obstructive Sleep Apnea", "Biomarkers" and "Risk-Stratification". Manuscripts were included if they studied adults with OSA, circulating (blood) markers, and relationships with clinical outcomes. After screening, 10 were included. Studies addressed cardiovascular disease, type 2 diabetes, end-stage renal disease and metabolic syndrome. In general, levels of inflammatory markers, adhesion molecules, and vascular proteins were associated with the presence of cardiometabolic disease in OSA patients. Although studies regarding prognostic circulating biomarkers in OSA are limited, a number of potentially promising biomarkers were identified in our review. However, more research is needed using prospective cohorts to determine which biomarkers are most robustly associated with and useful in predicting future cardiovascular and metabolic sequelae in OSA patients. Identification of such biomarkers could guide more selective and targeted therapy for OSA in an emerging era of precision-based medicine.

Adhesion molecule gene variants and plasma protein levels in patients with suspected obstructive sleep apnea.

STUDY OBJECTIVES: Untreated obstructive sleep apnea (OSA) patients have an increased risk of cardiovascular disease (CVD). Adhesion molecules, including soluble E-selectin (sE-selectin), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1), are associated with incident CVD. We hypothesized that specific genetic variants will be associated with plasma levels of adhesion molecules in suspected OSA patients. We also hypothesized that there may be an interaction between these variants and OSA. METHODS: We measured levels of sE-selectin, sICAM-1 and sVCAM-1 in 491 patients with suspected OSA and genotyped them for 20 polymorphisms. RESULTS: The most significant association was between the ABO rs579459 polymorphism and sE-selectin levels (P = 7×10-21), with the major allele T associated with higher levels. The direction of effect and proportion of the variance in sE-selectin levels accounted for by rs579459 (16%) was consistent with estimates from non-OSA cohorts. In a multivariate regression analysis, addition of rs579459 improved the model performance in predicting sE-selectin levels. Three polymorphisms were nominally associated with sICAM-1 levels but none with sVCAM-1 levels. The combination of severe OSA and two rs579459 T alleles identified a group of patients with high sE-selectin levels; however, the increase in sE-selectin levels associated with severe OSA was greater in patients without two T alleles (P = 0.05 test for interaction). CONCLUSIONS: These genetic polymorphisms may help to identify patients at greatest risk of incident CVD and may help in developing a more precision-based approach to OSA care.

Epidemiology of Sleep Disturbances and Cardiovascular Consequences.

It is increasingly recognized that disruption of sleep and reduced amounts of sleep can have significant adverse cardiovascular consequences. For example, obstructive sleep apnea (OSA) is a common underdiagnosed disorder characterized by recurrent nocturnal asphyxia resulting from repetitive collapse of the upper airway; this leads to repetitive episodes of nocturnal hypoxemia and arousal from sleep. Risk factors for disease include obesity, increased age, male sex, and family history. In epidemiologic studies, OSA appears to be an independent risk factor for cardiovascular disease (CVD), and treatment is associated with better outcomes. Habitual short sleep duration is common in today's society. In epidemiologic studies, short sleep duration is associated with a number of adverse health effects, including all-cause mortality, weight gain, and incident CVD. Given the links between sleep disorders and adverse health outcomes, obtaining adequate quality and amounts of sleep should be considered a component of a healthy lifestyle, similar to good diet and exercise.

Carotid intima media thickness in patients with obstructive sleep apnea: comparison with a community-based cohort.

BACKGROUND: The impact of obstructive sleep apnea (OSA) on the development of atherosclerotic cardiovascular disease (CVD) in the absence of overt CVD or risk factors is unclear. Our purpose was to assess whether patients with OSA without overt CVD or risk factors have subclinical atherosclerosis as evaluated by carotid intima medial thickness (CIMT) compared to matched controls. METHODS: We measured CIMT in patients >40 years old, who underwent polysomnography for suspected OSA and did not have a history of CVD or risk factors (smoking, hypertension, diabetes, hyperlipidemia). OSA severity was classified according to apnea-hypopnea index. Serum levels of high-sensitivity C-reactive protein, fibrinogen, and lipids were assessed and relationships with OSA severity explored. CIMT measurements from patients with OSA were compared those of to age-, gender-, and BMI-matched controls from a community-based cohort without known CVD or OSA. RESULTS: Fifty-one patients were studied. Of these, patients with severe OSA had an increased CIMT compared to patients without OSA, but the relationship was not significant after controlling for age (p = 0.10). However, 37 patients had OSA and were matched to 105 controls. CIMT was significantly increased in OSA patients versus controls (0.77 vs. 0.68 mm, p = 0.03). The difference between patients and controls was greater for patients with severe OSA (0.83 vs. 0.71 mm) than for patients with mild-to-moderate OSA (0.71 vs. 0.67 mm). CONCLUSIONS: Patients with OSA but without a history of or risk factors for CVD have increased CIMT compared to a BMI-, age-, and gender-matched cohort. This provides evidence that OSA is an independent risk factor for the development of CVD.

Mandibular advancement splint as short-term alternative treatment in patients with obstructive sleep apnea already effectively treated with continuous positive airway pressure.

STUDY OBJECTIVES: CPAP is used as the first-line treatment for patients with severe OSA, but this machine is not always feasible to use on the long term. We performed a clinical trial to determine whether patients with OSA could use a mandibular advancement splint (MAS) as a short-term treatment alternative to CPAP. METHODS: Twenty-two patients adherent with CPAP therapy were recruited to the study. Each patient used the MAS for approximately 4 months. The transition between CPAP to MAS was gradual, and patients were asked to start using MAS together with CPAP during the MAS titration until subjective improvement or maximum mandibular advancement was achieved. Sleepiness (ESS), quality of life (SAQLI), and polysomnography were recorded prior to and after MAS titration. Patients recorded CPAP or MAS usage for the following 3 months. RESULTS: Seven women and 12 men with a mean age of 53.8 (± 12.1) years and mean body mass index of 28.1 (± 4.8) kg/m² completed the clinical trial. Prior to MAS, CPAP adherence was 5.8 h/night. AHI decreased significantly with MAS use compared to baseline (30.7 ± 23.1 vs 13.2 ± 11; p < 0.01). Fourteen patients (74%) had > 50% decrease in their AHI, while 2 patients had an increase in their AHI. There were no significant differences in SAQLI between MAS and CPAP treatment, while ESS decreased significantly on MAS. MAS self-reported usage was correlated with treatment efficacy (r = 0.52; p < 0.05). Seventy-five percent of the patients reported being sufficiently satisfied with MAS to continue to use it as an alternative short-term therapy. CONCLUSIONS: MAS partially or completely reduced sleep disordered breathing in the majority of selected, successfully CPAP-treated severe OSA patients. Many patients can probably effectively use MAS as a short-term treatment alternative to CPAP.

The impact of a telemedicine monitoring system on positive airway pressure adherence in patients with obstructive sleep apnea: a randomized controlled trial.

STUDY OBJECTIVES: First-line therapy for patients with moderate to severe obstructive sleep apnea (OSA) is positive airway pressure (PAP). Although PAP is a highly efficacious treatment, adherence to PAP is still a substantial clinical problem. The objective of this study was to determine whether PAP adherence can be improved with a telemedicine monitoring system. DESIGN: A nonblinded, single-center, randomized controlled trial that compared standard PAP treatment versus PAP treatment and a telemedicine monitoring system SETTING: University sleep disorders program in British Columbia, Canada PATIENTS: Adult patients (≥ 19 yr of age) with moderate to severe OSA (apnea hypopnea index (AHI) ≥ 15 events/hr determined by polysomnography) prescribed PAP INTERVENTIONS: Patients were randomized to either standard care with an autotitrating PAP machine or an autotitrating PAP machine that transmitted physiologic information (i.e., adherence, air leak, residual AHI) daily to a website that could be reviewed. If problems were identified from information from the website, the patient was contacted by telephone as necessary. MEASUREMENTS: PAP adherence after 3 mo, subjective sleep quality, and side effects RESULTS: Seventy-five patients were enrolled; 39 were randomized to telemedicine and 36 to standard care. The mean age ± standard deviation (SD) was 53.5 ± 11.2 yr, mean AHI was 41.6 ± 22.1 events/hr, and 80% of patients were male. After 3 mo, mean PAP adherence was significantly greater in the telemedicine arm (191 min per day) versus the standard arm (105 min per day; mean difference = 87 min, 95% confidence interval (CI): 25-148 min, P = 0.006, unpaired t test). On days when PAP was used, mean adherence was 321 min in the telemedicine arm and 207 min in the standard arm (difference = 113 min, 95% CI: 62-164 min, P < 0.0001). Significant independent predictors of adherence included age, baseline Epworth Sleepiness Scale score, and use of telemedicine. On average, an additional 67 min of technician time was spent on patients in the telemedicine arm compared with the standard arm (P = 0.0001). CONCLUSIONS: PAP adherence can be improved with the use of a web-based telemedicine system at the initiation of treatment.

Residual sleep apnea on polysomnography after 3 months of CPAP therapy: clinical implications, predictors and patterns.

OBJECTIVE: We sought to determine the clinical implications, predictors and patterns of residual sleep apnea on continuous positive airway pressure (CPAP) treatment in patients with moderate-to-severe obstructive sleep apnea (OSA). METHODS: We performed a post hoc secondary analysis of data from a previously reported randomized trial. Sleepy patients with a high risk of moderate-to-severe OSA identified by a diagnostic algorithm were randomly assigned to standard CPAP titration during polysomnography (PSG) or ambulatory titration using auto-CPAP and home sleep testing. We observed them for 3 months and measured apnea-hypopnea index (AHI) on CPAP, Epworth sleepiness scale (ESS), sleep apnea quality of life index (SAQLI), CPAP pressure and objective CPAP compliance. RESULTS: Sixty-one patients were randomized, 30 to the PSG group and 31 to the ambulatory group. Fifteen patients (25%) had residual sleep apnea (AHI > 10/h on CPAP) with similar proportions in the PSG (7/30) and ambulatory (8/31) groups. Baseline variables including age, body mass index (BMI), ESS, SAQLI, respiratory disturbance index (RDI) and CPAP pressure did not differ between the groups. Outcomes including compliance were worse in patients with residual sleep apnea. Periodic breathing was prevalent among patients with residual sleep apnea. CONCLUSIONS: Residual sleep apnea is common in patients with moderate-to-severe OSA, despite careful CPAP titration, and is associated with worse outcomes.

Diagnosis and initial management of obstructive sleep apnea without polysomnography: a randomized validation study.

BACKGROUND: Polysomnography (PSG), despite limited availability and high cost, is currently recommended for diagnosis of obstructive sleep apnea and titration of effective continuous positive airway pressure (CPAP). OBJECTIVE: To test the utility of a diagnostic algorithm in conjunction with ambulatory CPAP titration in initial management of obstructive sleep apnea. DESIGN: A randomized, controlled, open-label trial that compared standard PSG with ambulatory CPAP titration in high-risk patients identified by a diagnostic algorithm. SETTING: A tertiary referral sleep disorders program in Vancouver, British Columbia, Canada. PATIENTS: 68 patients with a high pretest probability of moderate to severe obstructive sleep apnea (apnea-hypopnea index [AHI] >15 episodes/h) identified by sequential application of the Epworth Sleepiness Scale (ESS) score, Sleep Apnea Clinical Score, and overnight oximetry. INTERVENTION: Patients were randomly assigned to PSG or ambulatory titration by using a combination of auto-CPAP and overnight oximetry. They were observed for 3 months. MEASUREMENTS: Apnea-hypopnea index on CPAP, ESS score, quality of life, and CPAP adherence. RESULTS: The PSG and ambulatory groups had similar median BMI (38 kg/m2), age (55 years), ESS score (14 points), and respiratory disturbance index (31 episodes of respiratory disturbance/h). Each episode is determined by a computer algorithm based on analysis of oxygen saturation measured by pulse oximetry. After 3 months, there were no differences in the primary outcome, AHI on CPAP (median, 3.2 vs. 2.5; difference, 0.8/h [95% CI, -0.9 to 2.3]) (P = 0.31), between the PSG and ambulatory groups, or in the secondary outcomes, ESS score, Sleep Apnea Quality of Life Index, and CPAP. Adherence to CPAP therapy was better in the ambulatory group than in the PSG group (median, 5.4 vs. 6.0; difference, -1.12 h/night [CI, -2.0 to 0.2]) (P = 0.021). CONCLUSIONS: In the initial management of patients with a high probability of obstructive sleep apnea, PSG confers no advantage over the ambulatory approach in terms of diagnosis and CPAP titration. The ambulatory approach may improve adherence to treatment. When access to PSG is inadequate, the ambulatory approach can be used to expedite management of patients most in need of treatment.