Indira Gurubhagavatula

CPAP, Weight Loss, or Both for Obstructive Sleep Apnea

BACKGROUND Obesity and obstructive sleep apnea tend to coexist and are associated with inflammation, insulin resistance, dyslipidemia, and high blood pressure, but their causal relation to these abnormalities is unclear. METHODS We randomly assigned 181 patients with obesity, moderate-to-severe obstructive sleep apnea, and serum levels of C-reactive protein (CRP) greater than 1.0 mg per liter to receive treatment with continuous positive airway pressure (CPAP), a weight-loss intervention, or CPAP plus a weight-loss intervention for 24 weeks. We assessed the incremental effect of the combined interventions over each one alone on the CRP level (the primary end point), insulin sensitivity, lipid levels, and blood pressure. RESULTS Among the 146 participants for whom there were follow-up data, those assigned to weight loss only and those assigned to the combined interventions had reductions in CRP levels, insulin resistance, and serum triglyceride levels. None of these changes were observed in the group receiving CPAP alone. Blood pressure was reduced in all three groups. No significant incremental effect on CRP levels was found for the combined interventions as compared with either weight loss or CPAP alone. Reductions in insulin resistance and serum triglyceride levels were greater in the combined-intervention group than in the group receiving CPAP only, but there were no significant differences in these values between the combined-intervention group and the weight-loss group. In per-protocol analyses, which included 90 participants who met prespecified criteria for adherence, the combined interventions resulted in a larger reduction in systolic blood pressure and mean arterial pressure than did either CPAP or weight loss alone. CONCLUSIONS In adults with obesity and obstructive sleep apnea, CPAP combined with a weight-loss intervention did not reduce CRP levels more than either intervention alone. In secondary analyses, weight loss provided an incremental reduction in insulin resistance and serum triglyceride levels when combined with CPAP. In addition, adherence to a regimen of weight loss and CPAP may result in incremental reductions in blood pressure as compared with either intervention alone. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT0371293 .).

Noninferiority of functional outcome in ambulatory management of obstructive sleep apnea.

RATIONALE Home portable monitor testing is increasingly being used to diagnose patients with obstructive sleep apnea (OSA) and to initiate them on continuous positive airway pressure (CPAP) treatment. OBJECTIVES To compare functional outcome and treatment adherence in patients who receive ambulatory versus in-laboratory testing for OSA. METHODS Veterans with suspected OSA were randomized to either home testing or standard in-laboratory testing. Home testing consisted of a type 3 portable monitor recording followed by at least three nights using an automatically adjusting positive airway pressure apparatus. Participants diagnosed with OSA were treated with CPAP for 3 months. MEASUREMENTS AND MAIN RESULTS We measured the change in Functional Outcomes of Sleep Questionnaire score, with an a priori noninferiority delta of -1, and the mean daily hours of objectively measured CPAP adherence, with an a priori noninferiority delta of -0.75 hour/day. Of the 296 subjects enrolled, 260 (88%) were diagnosed with OSA, and 213 (75%) were initiated on CPAP. Mean ± SD functional outcome score improved 1.74 ± 2.81 in the home group (P < 0.001) and 1.85 ± 2.46 in the in-laboratory group (P < 0.0001). The lower bound of the one-sided 95% noninferiority confidence interval was -0.54. Mean ± SD hours of daily CPAP adherence were 3.5 ± 2.5 hours/day in the home group and 2.9 ± 2.3 hours/day in the in-laboratory group (P = 0.08). The lower bound of the one-sided 95% noninferiority confidence interval was 0.03. CONCLUSIONS Functional outcome and treatment adherence in patients evaluated according to a home testing algorithm is not clinically inferior to that in patients receiving standard in-laboratory polysomnography.

Continuous positive airway pressure treatment of sleepy patients with milder obstructive sleep apnea: results of the CPAP Apnea Trial North American Program (CATNAP) randomized clinical trial.

RATIONALE Twenty-eight percent of people with mild to moderate obstructive sleep apnea experience daytime sleepiness, which interferes with daily functioning. It remains unclear whether treatment with continuous positive airway pressure improves daytime function in these patients. OBJECTIVES To evaluate the efficacy of continuous positive airway pressure treatment to improve functional status in sleepy patients with mild and moderate obstructive sleep apnea. METHODS Patients with self-reported daytime sleepiness (Epworth Sleepiness Scale score >10) and an apnea-hypopnea index with 3% desaturation and from 5 to 30 events per hour were randomized to 8 weeks of active or sham continuous positive airway pressure treatment. After the 8-week intervention, participants in the sham arm received 8 weeks of active continuous positive airway pressure treatment. MEASUREMENTS AND MAIN RESULTS The Total score on the Functional Outcomes of Sleep Questionnaire was the primary outcome measure. The adjusted mean change in the Total score after the first 8-week intervention was 0.89 for the active group (n = 113) and -0.06 for the placebo group (n = 110) (P = 0.006). The group difference in mean change corresponded to an effect size of 0.41 (95% confidence interval, 0.14-0.67). The mean (SD) improvement in Functional Outcomes of Sleep Questionnaire Total score from the beginning to the end of the crossover phase (n = 91) was 1.73 ± 2.50 (t[90] = 6.59; P < 0.00001) with an effect size of 0.69. CONCLUSIONS Continuous positive airway pressure treatment improves the functional outcome of sleepy patients with mild and moderate obstructive sleep apnea.

Antibodies Against the First Ig-Like Domain of Human Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) That Inhibit PECAM-1-Dependent Homophilic Adhesion Block In Vivo Neutrophil Recruitment

Platelet endothelial cell adhesion molecule (PECAM-1), a member of the Ig superfamily, is found on endothelial cells and neutrophils and has been shown to be involved in the migration of leukocytes across the endothelium. Adhesion is mediated, at least in part, through binding interactions involving its first N-terminal Ig-like domain, but it is still unclear which sequences in this domain are required for in vivo function. Therefore, to identify functionally important regions of the first Ig-like domain of PECAM-1 that are required for the participation of PECAM-1 in in vivo neutrophil recruitment, a panel of mAbs against this region of PECAM-1 was generated and characterized in in vitro adhesion assays and in an in vivo model of cutaneous inflammation. It was observed that mAbs that disrupted PECAM-1-dependent homophilic adhesion in an L cell aggregation assay also blocked TNF-α-induced intradermal accumulation of neutrophils in a transmigration model using human skin transplanted onto SCID mice. Localization of the epitopes of these Abs indicated that these function-blocking Abs mapped to specific regions on either face of domain 1. This suggests that these regions of the first Ig-like domain may contain or be close to binding sites involved in PECAM-1-dependent homophilic adhesion, and thus may represent potential targets for the development of antiinflammatory reagents.

Habitual sleep duration associated with self-reported and objectively determined cardiometabolic risk factors

BACKGROUND Self-reported short or long sleep duration has been associated with adverse cardiometabolic health outcomes in laboratory and epidemiologic studies, but interpretation of such data has been limited by methodologic issues. METHODS Adult respondents of the 2007-2008 US National Health and Nutrition Examination Survey (NHANES) were examined in a cross-sectional analysis (N=5649). Self-reported sleep duration was categorized as very short (<5 h), short (5-6 h), normal (7-8 h), or long (≥9 h). Obesity, diabetes mellitus (DM), hypertension, and hyperlipidemia were objectively assessed by self-reported history. Statistical analyses included univariate comparisons across sleep duration categories for all variables. Binary logistic regression analyses and cardiometabolic factor as outcome, with sleep duration category as predictor, were assessed with and without covariates. Observed relationships were further assessed for dependence on race/ethnicity. RESULTS In adjusted analyses, very short sleep was associated with self-reported hypertension (odds ratio [OR], 2.02, [95% confidence interval {CI},1.45-2.81]; P<0.0001), self-reported hyperlipidemia (OR, 1.96 [95% CI, 1.43-2.69]; P<0.0001), objective hyperlipidemia (OR, 1.41 [95% CI, 1.04-1.91]; P=0.03), self-reported DM (OR, 1.76 [95% CI, 1.13-2.74]; P=0.01), and objective obesity (OR, 1.53 [95% CI, 1.03-1.43]; P=0.005). Regarding short sleep (5-6 h), in adjusted analyses, elevated risk was seen for self-reported hypertension (OR, 1.22 [95% CI, 1.02-1.45]; P=0.03) self-reported obesity (OR, 1.21 [95% CI, 1.03-1.43]; P=0.02), and objective obesity (OR, 1.17 [95% CI, 1.00-1.38]; P<0.05). Regarding long sleep (≥9 h), no elevated risk was found for any outcomes. Interactions with race/ethnicity were significant for all outcomes; race/ethnicity differences in patterns of risk varied by outcome studied. In particular, the relationship between very short sleep and obesity was strongest among blacks and the relationship between short sleep and hypertension is strongest among non-Hispanic whites, blacks, and non-Mexican Hispanics/Latinos. CONCLUSIONS Short sleep duration is associated with self-reported and objectively determined adverse cardiometabolic outcomes, even after adjustment for many covariates. Also, these patterns of risk depend on race/ethnicity.

Engagement of human PECAM-1 (CD31) on human endothelial cells increases intracellular calcium ion concentration and stimulates prostacyclin release.

Platelet-endothelial cell adhesion molecule-1 (PECAM-1) is a member of the immunoglobulin superfamily that plays a role in a number of endothelial cell (EC) functions including migration, angiogenesis, and transmigration of leukocytes across endothelium. We postulated that one way PECAM-1 might exert its effects was by regulating intracellular EC levels of calcium. Using single-cell fluorometry, we found that engagement of PECAM-1 by mAbs induced a slow but sustained increase in intracellular calcium, both in EC and in an adherent PECAM-1-transfected cell line that models endothelium. Generation of this signal was specific for certain anti-PECAM-1 antibodies, required the presence of the cytoplasmic domain, depended on extracellular calcium and on tyrosine phosphorylation, but did not require cross-linking; in fact, calcium increases were stimulated by certain Fab fragments. Activation of EC by PECAM-1 also caused a time-dependent increase in prostacyclin release. Given the importance of intracellular calcium and prostacyclin release as signaling molecules, engagement of PECAM-1 during cell-cell interactions may alter a number of EC functions including secretion of vasoactive mediators.

Sleep apnea and commercial motor vehicle operators: statement from the joint Task Force of the American College of Chest Physicians, American College of Occupational and Environmental Medicine, and the National Sleep Foundation

M edical research supports the finding that obstructive sleep apnea (OSA) is a significant cause of motor vehicle crashes (MVCs) resulting in twoto sevenfold increased risk. Recent reports indicate OSA is present in a greater prevalence in operators of commercial motor vehicle (CMV) operators than in the general population. Although U.S. commercial drivers are required by federal statute to undergo medical qualification examinations at least every 2 years, the most recent OSA recommendations for medical examiners were prepared during a 1991 conference sponsored by the Federal Highway Administration (FHWA). Since then, the clinical diagnosis, evaluation, treatment, and follow-up criteria have changed significantly. Lacking current recommendations from the U.S. Department of Transportation (DOT), commercial driver medical examiners (CDMEs) must rely on outdated guidance and are thus forced to fill in the many existing gaps when evaluating CMV operators for this safety-sensitive type of work. In addition to causing difficulties for the medical examiner, the current guidelines, or lack thereof, foster an environment in which drivers who possibly have OSA are afraid to be evaluated because it might result in their removal from work. This set of circumstances may lead to the underrecognition of this condition and an increase in MVCs. From OccuMedix, Inc. (Dr Hartenbaum), Dresher, Pennsylvania; the Department of Medicine, Division of Pulmonary/Critical Care Medicine (Dr Collop), Johns Hopkins University, Baltimore, Maryland; the Department of Medicine, Divisions of Sleep Medicine and Pulmonary, Allergy & Critical Care Medicine (Dr Rosen), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; the Division of Pulmonary Critical Care and Sleep Medicine (Dr Phillips), University of Kentucky College of Medicine, Lexington, Kentucky; the Department of Medicine, Division of Respirology (Dr George), University of Western Ontario, and the Sleep Laboratory, London Health Sciences Centre, South Street Hospital, London, Ontario, Canada; the Department of Medicine, Division of Pulmonary, Critical Care & Sleep Medicine, Department of Internal Medicine (Dr Rowley), Wayne State University School of Medicine, Harper University Hospital, Detroit, Michigan; The Sleep and Behavior Medicine Institute and Pulmonary Physicians of the North Shore (Dr Freedman), Bannockburn, Illinois; Biobehavioral and Health Sciences Division (Dr Weaver), University of Pennsylvania School of Nursing, Philadelphia, Pennsylvania; the Department of Medicine, Divisions of Sleep, Pulmonary and Critical Care Medicine (Dr Gurubhagavatula), University of Pennsylvania Medical Center, Philadelphia, Pennsylvania; the Department of Medicine, Director (Dr Strohl), Center for Sleep Disorders Research, Case Western Reserve University School of Medicine, Louis Stokes DVA Medical Center, Cleveland, Ohio; the IHC Health Services to Business (Dr Leaman), Intermountain WorkMed, Salt Lake City, Utah; and Arkansas Occupational Health (Dr Moffitt), Springdale, Arkansas; Alertness Solutions (Dr Rosekind), Cupertino, CA. Address correspondence to: Natalie Hartenbaum, MD, MPH, FACOEM, President and Chief Medical Officer, OccuMedix, Inc., P.O. Box 197, Dresher, PA 19025; E-mail: occumedix@comcast.net. Copyright

Estimated Cost of Crashes in Commercial Drivers Supports Screening and Treatment of Obstructive Sleep Apnea

Sleep apnea among commercial drivers may increase the risk of fall-asleep crashes, which incur large expenses. Drivers of passenger cars whose apnea is treated experience lower crash risk. Among community-based holders of commercial drivers licenses, we considered three methods for identifying sleep apnea syndrome: (1) in-lab polysomnography; (2) selective in-lab polysomnography for high-risk drivers, where high risk is first identified by body mass index, age and gender, followed by oximetry in a subset of drivers; (3) not screening. The costs for each of these three programs equaled the sum of the costs of testing, treatment of identified cases, and crashes. Assuming that treatment prevents apnea-related crashes, polysomnography is not cost-effective, because it was more expensive than the cost of crashes when no screening is done. Screening with BMI, age and gender, however, with confirmatory in-lab polysomnography only on high-risk drivers was cost-effective, as long as a high proportion (73.8%) of screened drivers accepts treatment. These findings indicate that strategies that reduce reliance on in-laboratory polysomnography may be more cost-effective than not screening, and that treatment acceptance may need to be a condition of employment for affected drivers.

Economic Implications of the Diagnosis of Obstructive Sleep Apnea

TO THE EDITOR: Lipoprotein(a) is a genetically regulated atherogenic lipoprotein (1). Acromegaly is characterized by premature cardiovascular mortality and morbidity, but the precise pathways by which it occurs are unknown (2, 3). Although growth hormone greatly influences lipid metabolism (4), hypertriglyceridemia has been observed in some studies but not in others (2). Moreover, elevated as well as reduced cholesterol concentrations have been observed, whereas little is known about lipoprotein(a) levels (5). We assessed lipid measures in patients with acromegaly. Forty-two acromegalic patients (21 men and 21 women; mean age SD, 48 12 years), and 57 controls (24 men and 33 women; mean age, 43 16 years) were studied. Fifty-seven percent of acromegalic patients showed abnormal lipid measures compared with 51% of controls. Lipoprotein(a) was the sole lipid measure significantly altered in 31% of acromegalic patients and 7% of controls, followed by a nonsignificant elevation of triglyceride levels (21% and 21%) and total cholesterol levels (19% and 26%). Lipoprotein(a) levels were higher (39.44 50.77 mg/dL compared with 11.56 9.42 mg/dL; P =0.0013) and high-density lipoprotein cholesterol levels were lower (1.30 0.37 mmol/L compared with 1.49 0.41 mmol/L; P=0.0154) in patients than in age- and sex-matched controls. Previous surgical or radiation treatment was associated with significantly lower growth hormone and insulin-like growth factor-I levels in treated but not cured patients (11 men and 9 women) compared with untreated patients with acromegaly (10 men and 12 women): growth hormone levels, 24.58 55.54 ng/mL compared with 34.26 31.31 ng/mL (P=0.0105); insulin-like growth factor-I level, 576 367 ng/mL compared with 833 254 ng/mL (P =0.0115). The subgroup of untreated patients showed a fivefold increase in lipoprotein(a) plasma levels (51.05 58.79 mg/dL) compared with controls (11.56 9.42 mg/dL; P<0.001) and a twofold increase compared with treated acromegalic patients (26.67 37.60 mg/dL; P<0.05). Acromegalic patients exhibit increased plasma lipoprotein(a) levels that are related to disease activity. Although treated acromegalic patients did not have normal growth hormone or insulin-like growth factor-I values, they did have lipoprotein(a) levels below the risk threshold (30 mg/dL).In this issue, Chervin and colleagues present a cost–utility analysis that evaluates the relative effectiveness of three diagnostic strategies for the obstructive sleep apnea syndrome. This analysi...

Reliability of a Single Objective Measure in Assessing Sleepiness

STUDY OBJECTIVES To evaluate reliability of single objective tests in assessing sleepiness. DESIGN Subjects who completed polysomnography underwent a 4-nap multiple sleep latency test (MSLT) the following day. Prior to each nap opportunity on MSLT, subjects performed the psychomotor vigilance test (PVT) and divided attention driving task (DADT). Results of single versus multiple test administrations were compared using the intraclass correlation coefficient (ICC) and adjusted for test administration order effects to explore time of day effects. Measures were explored as continuous and binary (i.e., impaired or not impaired). SETTING Community-based sample evaluated at a tertiary, university-based sleep center. PARTICIPANTS 372 adult commercial vehicle operators oversampled for increased obstructive sleep apnea risk. INTERVENTIONS N/A. MEASUREMENTS AND RESULTS AS CONTINUOUS MEASURES, ICC WERE AS FOLLOWS: MSLT 0.45, PVT median response time 0.69, PVT number of lapses 0.51, 10-min DADT tracking error 0.87, 20-min DADT tracking error 0.90. Based on binary outcomes, ICC were: MSLT 0.63, PVT number of lapses 0.85, 10-min DADT 0.95, 20-min DADT 0.96. Statistically significant time of day effects were seen in both the MSLT and PVT but not the DADT. Correlation between ESS and different objective tests was strongest for MSLT, range [-0.270 to -0.195] and persisted across all time points. CONCLUSIONS Single DADT and PVT administrations are reliable measures of sleepiness. A single MSLT administration can reasonably discriminate individuals with MSL < 8 minutes. These results support the use of a single administration of some objective tests of sleepiness when performed under controlled conditions in routine clinical care.