Jessie P. Bakker

The effect of continuous positive airway pressure treatment on blood pressure: a systematic review and meta-analysis of randomized controlled trials.

STUDY OBJECTIVES We sought to provide an updated systematic review and meta-analysis of studies investigating the effect of positive airway pressure (PAP) treatment for obstructive sleep apnea (OSA) on systolic and diastolic blood pressure (SBP, DBP). METHODS Two independent investigators undertook a systematic search of the PubMed database (1980-2012) to identify randomized controlled trials comparing therapeutic PAP to sham-PAP, pill placebo, or standard care over at least one week in adult OSA patients without major comorbidities. The mean, variance, and sample size for diurnal and nocturnal SBP and DBP data were also extracted independently from each study. Random effects meta-analyses were conducted, followed by pre-specified subgroup and meta-regression analyses. RESULTS 32 studies were identified, with data available from 28 studies representing n = 1,948 patients. The weighted mean difference in diurnal SBP (-2.58 mm Hg, 95% CI -3.57 to -1.59 mm Hg) and DBP (-2.01 mm Hg, 95% CI -2.84 to -1.18 mm Hg) both significantly favored PAP treatment over control arms, with similar results seen in nocturnal readings. Statistically significant reductions in BP were seen in studies whose patients were younger, sleepier, had more severe OSA, and exhibited greater PAP adherence. Meta-regression indicated that the reductions in DBP with PAP were predicted by mean baseline BP (β = -0.22, p = 0.02) and Epworth Sleepiness Scale scores (β = -0.27, p = 0.04). CONCLUSIONS PAP treatment for OSA is associated with modest but significant reductions in diurnal and nocturnal SBP and DBP. Future research should be directed towards identifying subgroups likely to reap greater treatment benefits as well as other therapeutic benefits provided by PAP therapy.

Adaptive Servoventilation for Treatment of Sleep-Disordered Breathing in Heart Failure: A Systematic Review and Meta-analysis

BACKGROUND Adaptive servoventilation (ASV) has demonstrated efficacy in treating sleep-disordered breathing (SDB) in patients with heart failure (HF), but large randomized trials are lacking. We, therefore, sought to perform a systematic review and meta-analysis of existing data. METHODS A systematic search of the PubMed database was undertaken in March 2012. Publications were independently assessed by two investigators to identify studies of ≥ 1-week duration that compared ASV to a control condition (ie, subtherapeutic ASV, continuous or bilevel pressure ventilation, oxygen therapy, or no treatment) in adult patients with SDB and HF. Mean, variability,and sample size data were extracted independently for the following outcomes: apneahypopnea index (AHI), left ventricular ejection fraction (LVEF), quality of life (SF-36 Health Survey; Medical Outcomes Trust), 6-min walk distance, peak oxygen consumption ( VO 2 ) % predicted, and ventilatory equivalent ratio for CO 2 ( VE / Vco 2 ) slope measured during exercise. Random effects meta-analysis models were applied. RESULTS Fourteen studies were identified (N = 538). Comparing ASV to control conditions, the weighted mean difference in AHI ( -14.64 events/h; 95% CI, -21.03 to - 8.25) and LVEF (0.40;95% CI, 0.08-0.71) both significantly favored ASV. ASV also improved the 6-min walk distance,but not peak O 2 % predicted, VE / VCO 2 slope, or quality of life, compared with control conditions. CONCLUSIONS In patients with HF and SDB, ASV was more effective than control conditions in reducing the AHI and improving cardiac function and exercise capacity. These data provide a compelling rationale for large-scale randomized controlled trials to assess the clinical impact of ASV on hard outcomes in these patients.

Clinical predictors of the respiratory arousal threshold in patients with obstructive sleep apnea.

RATIONALE A low respiratory arousal threshold (ArTH) is one of several traits involved in obstructive sleep apnea pathogenesis and may be a therapeutic target; however, there is no simple way to identify patients without invasive measurements. OBJECTIVES To determine the physiologic determinates of the ArTH and develop a clinical tool that can identify patients with low ArTH. METHODS Anthropometric data were collected in 146 participants who underwent overnight polysomnography with an epiglottic catheter to measure the ArTH (nadir epiglottic pressure before arousal). The ArTH was measured from up to 20 non-REM and REM respiratory events selected randomly. Multiple linear regression was used to determine the independent predictors of the ArTH. Logistic regression was used to develop a clinical scoring system. MEASUREMENTS AND MAIN RESULTS Nadir oxygen saturation as measured by pulse oximetry, apnea-hypopnea index, and the fraction of events that were hypopneas (Fhypopneas) were independent predictors of the ArTH (r(2) = 0.59; P < 0.001). Using this information, we used receiver operating characteristic analysis and logistic regression to develop a clinical score to predict a low ArTH, which allocated a score of 1 to each criterion that was satisfied: (apnea-hypopnea index, <30 events per hour) + (nadir oxygen saturation as measured by pulse oximetry >82.5%) + (Fhypopneas >58.3%). A score of 2 or above correctly predicted a low arousal threshold in 84.1% of participants with a sensitivity of 80.4% and a specificity of 88.0%, a finding that was confirmed using leave-one-out cross-validation analysis. CONCLUSIONS Our results demonstrate that individuals with a low ArTH can be identified from standard, clinically available variables. This finding could facilitate larger interventional studies targeting the ArTH.

Effect of Sleep Apnea and Continuous Positive Airway Pressure on Cardiac Structure and Recurrence of Atrial Fibrillation

Background Sleep apnea (SA) is associated with an increased risk of atrial fibrillation (AF). We sought to determine the effect of SA on cardiac structure in patients with AF, whether therapy for SA was associated with beneficial cardiac structural remodelling, and whether beneficial cardiac structural remodelling translated into a reduced risk of recurrence of AF after pulmonary venous isolation (PVI). Methods and Results A consecutive group of 720 patients underwent a cardiac magnetic resonance study before PVI. Patients with SA (n=142, 20%) were more likely to be male, diabetic, and hypertensive and have an increased pulmonary artery pressure, right ventricular volume, atrial dimensions, and left ventricular mass. Treated SA was defined as duration of continuous positive airway pressure therapy of >4 hours per night. Treated SA patients (n=71, 50%) were more likely to have paroxysmal AF, a lower blood pressure, lower ventricular mass, and smaller left atrium. During a follow‐up of 42 months, AF recurred in 245 patients. The cumulative incidence of AF recurrence was 51% in patients with SA, 30% in patients without SA, 68% in patients with untreated SA, and 35% in patients with treated SA. In a multivariable model, the presence of SA (hazard ratio 2.79, CI 1.97 to 3.94, P<0.0001) and untreated SA (hazard ratio 1.61, CI 1.35 to 1.92, P<0.0001) were highly associated with AF recurrence. Conclusions Patients with SA have an increased blood pressure, pulmonary artery pressure, right ventricular volume, left atrial size, and left ventricular mass. Therapy with continuous positive airway pressure is associated with lower blood pressure, atrial size, and ventricular mass, and a lower risk of AF recurrence after PVI.

Flexible Pressure Delivery Modification of Continuous Positive Airway Pressure for Obstructive Sleep Apnea Does Not Improve Compliance With Therapy: Systematic Review and Meta-analysis

BACKGROUND Continuous positive airway pressure (CPAP) is the first-line therapy for obstructive sleep apnea (OSA), but patient compliance is a major barrier to long-term effectiveness. Flexible pressure delivery of PAP reduces pressure during early exhalation with the aim of improving comfort and, therefore, compliance, leading to subsequent symptoms improvement. METHODS We undertook a systematic literature search of PubMed (January 1, 2000, to July 11, 2010) to identify all randomized trials comparing flexible and standard CPAP in adult patients with OSA with at least 1-week follow-up. Either we or the original trial investigators extracted means, SEs, and sample sizes for all relevant outcome measures. We then performed meta-analyses quantifying improvements in objective compliance and symptoms as measured by the Epworth Sleepiness Scale (ESS), the Maintenance of Wakefulness Test (MWT), and the Psychomotor Vigilance Task (PVT). RESULTS We found 10 relevant trials (599 patients). Meta-analysis of the seven trials where we could extract compliance data (514 patients) indicated that flexible pressure did not improve compliance compared with CPAP in either the parallel (0.16 h; 95% CI, -0.09-0.42; P = .21) or the crossover trials (0.20 h; 95% CI, -0.26-0.66; P = .39). Flexible pressure caused no improvement over CPAP in any secondary outcome (ESS, MWT, PVT, and residual OSA, all P > .05). CONCLUSIONS Flexible pressure modification neither significantly improves compliance with CPAP in patients with OSA nor significantly improves patient outcomes beyond the effects of CPAP. Unfortunately, we were unable to locate compliance data in the correct format for three out of the 10 suitable trials.

Blood pressure improvement with continuous positive airway pressure is independent of obstructive sleep apnea severity

STUDY OBJECTIVES We sought to perform a patient-level meta-analysis using the individual patient data of the trials identified in our previous study-level meta-analysis investigating the effect of positive airway pressure (PAP) treatment for obstructive sleep apnea (OSA) on blood pressure (BP). DESIGN Patient-level meta-analysis. SETTING N/A. PARTICIPANTS 968 adult OSA subjects without major comorbidities drawn from eight randomized controlled trials. INTERVENTIONS Therapeutic PAP versus non-therapeutic control conditions (sham-PAP, pill placebo or standard care) over at least one week. MEASUREMENTS AND RESULTS The mean reductions in BP between PAP and non-therapeutic control arms were -2.27 mm Hg (95% CI -4.01 to -0.54) for systolic BP and -1.78 mm Hg (95% CI -2.99 to -0.58) for diastolic BP. The presence of uncontrolled hypertension at baseline was significantly associated with a reduction in systolic BP of 7.1 mm Hg and diastolic BP of 4.3 mm Hg after controlling for OSA severity (apnea-hypopnea index, Epworth Sleepiness Scale score, PAP level), patient demographics (age, gender, body mass index, use of antihypertensive medication/s), and measures of PAP efficacy (PAP adherence and treatment duration). CONCLUSIONS OSA patients with uncontrolled hypertension are likely to gain the largest benefit from PAP in terms of a substantial reduction in BP, even after controlling for disease severity.

Molecular Biomarkers of Vascular Dysfunction in Obstructive Sleep Apnea

Untreated and long-lasting obstructive sleep apnea (OSA) may lead to important vascular abnormalities, including endothelial cell (EC) dysfunction, hypertension, and atherosclerosis. We observed a correlation between microcirculatory reactivity and endothelium-dependent release of nitric oxide in OSA patients. Therefore, we hypothesized that OSA affects (micro)vasculature and we aimed to identify vascular gene targets of OSA that could possibly serve as reliable biomarkers of severity of the disease and possibly of vascular risk. Using quantitative RT-PCR, we evaluated gene expression in skin biopsies of OSA patients, mouse aortas from animals exposed to 4-week intermittent hypoxia (IH; rapid oscillations in oxygen desaturation and reoxygenation), and human dermal microvascular (HMVEC) and coronary artery endothelial cells (HCAEC) cultured under IH. We demonstrate a significant upregulation of endothelial nitric oxide synthase (eNOS), tumor necrosis factor-alpha-induced protein 3 (TNFAIP3; A20), hypoxia-inducible factor 1 alpha (HIF-1α?? and vascular endothelial growth factor (VEGF) expression in skin biopsies obtained from OSA patients with severe nocturnal hypoxemia (nadir saturated oxygen levels [SaO2]<75%) compared to mildly hypoxemic OSA patients (SaO2 75%–90%) and a significant upregulation of vascular cell adhesion molecule 1 (VCAM-1) expression compared to control subjects. Gene expression profile in aortas of mice exposed to IH demonstrated a significant upregulation of eNOS and VEGF. In an in vitro model of OSA, IH increased expression of A20 and decreased eNOS and HIF-1α expression in HMVEC, while increased A20, VCAM-1 and HIF-1αexpression in HCAEC, indicating that EC in culture originating from distinct vascular beds respond differently to IH stress. We conclude that gene expression profiles in skin of OSA patients may correlate with disease severity and, if validated by further studies, could possibly predict vascular risk in OSA patients.

Ethnic Disparities in CPAP Adherence in New Zealand: Effects of Socioeconomic Status, Health Literacy and Self-Efficacy

STUDY OBJECTIVES We aimed to investigate the influence of ethnicity on adherence with continuous positive airway pressure (CPAP) in a sample of New Zealand patients. DESIGN Observational study over one month. SETTING A university-based sleep laboratory. PATIENTS 126 consecutively consenting CPAP-naïve patients (19.8% Māori, mean±SD apnea-hypopnea index 57.9 ± 38.9 events/h, CPAP 11.1 ± 3.1 cm H2O). INTERVENTIONS Patients underwent a 4-week supervised home trial of CPAP following pressure titration. MEASUREMENTS AND RESULTS Self-identified ethnicity (Māori/non-Māori), Epworth Sleepiness Scale, Self-Efficacy Measure for Sleep Apnea, Rapid Estimate of Adult Literacy in Medicine, New Zealand Deprivation Index (calculated from residential address), New Zealand Individual Deprivation Index (validated 8-item questionnaire), educational history, income, and employment assessed at baseline were compared to objective CPAP adherence after one month. Māori demonstrated significantly lower usage than non-Māori (median 5.11, interquartile range 2.24 h/night compared with median 5.71, interquartile range 2.61 h/night, P = 0.05). There were no significant relationships between adherence and subjective sleepiness, health literacy, or self-efficacy. In a multivariate logistic regression model incorporating 5 variables (ethnicity, eligibility for government-subsidized healthcare, individual deprivation scores, income, and education), non-completion of tertiary education, and high individual socioeconomic deprivation remained significant independent predictors of average CPAP adherence not reaching ≥ 4 h (odds ratio 0.25, 95% CI 0.08-0.83, P = 0.02; odds ratio 0.10, 95% CI 0.02-0.86, P = 0.04, respectively). The overall model explained approximately 23% of the variance in adherence. CONCLUSIONS The disparity in CPAP adherence demonstrated between Māori and non-Māori can be explained in part by lower education levels and socioeconomic status.

Effect of mild, asymptomatic obstructive sleep apnea on daytime heart rate variability and impedance cardiography measurements.

Dysregulation of autonomic nervous system dynamics is important in the pathophysiology of cardiovascular risk in obstructive sleep apnea (OSA). Heart rate variability (HRV) and impedance cardiography measures can estimate autonomic activity but have not gained traction clinically. The hypothesis of this study was that even in a cohort of patients with mild, asymptomatic OSA without overt cardiovascular disease, daytime HRV metrics and impedance cardiography measurements of preejection period would demonstrate increased sympathetic and decreased parasympathetic modulation compared to matched controls. Obese subjects (body mass index ≥30 kg/m(2)) without any known cardiovascular or inflammatory co-morbidities were recruited from the community. Subjects underwent standard in-laboratory polysomnography followed by simultaneous electrocardiographic and impedance cardiographic recordings while supine, supine with paced breathing, and after standing. Seventy-four subjects were studied, and 59% had OSA (apnea-hypopnea index ≥10 events/hour), with a median apnea-hypopnea index of 25.8 events/hour. Subjects with OSA had significantly decreased daytime time- and frequency-domain HRV indexes, but not significantly different preejection periods, compared to controls. Apnea-hypopnea index was a significant independent predictor of time-domain HRV measures in all awake conditions, after controlling for age, gender, blood pressure, fasting cholesterol levels and glycosylated hemoglobin. In conclusion, these results demonstrate reductions in cardiac vagal modulation, as measured by multiple daytime time-domain markers of HRV, in patients with asymptomatic OSA compared to controls. Further prospective outcomes-based studies are needed to evaluate the applicability of these metrics for noninvasive screening of obese patients with asymptomatic OSA, before the onset of overt cardiovascular disease.

Evaluation of Right Ventricular Remodeling Using Cardiac Magnetic Resonance Imaging in Co-Existent Chronic Obstructive Pulmonary Disease and Obstructive Sleep Apnea

Abstract Untreated chronic obstructive pulmonary disease (COPD) co-existing with obstructive sleep apnea (OSA), also known as overlap syndrome, has higher cardiovascular mortality than COPD alone but its underlying mechanism remains unclear. We hypothesize that the presence of overlap syndrome is associated with more extensive right ventricular (RV) remodeling compared to patients with COPD alone. Adult COPD patients (GOLD stage 2 or higher) with at least 10 pack-years of smoking history were included. Overnight laboratory-based polysomnography was performed to test for OSA. Subjects with an apnea-hypopnea index (AHI) >10/h were classified as having overlap syndrome (n = 7), else classified as having COPD-only (n = 11). A cardiac MRI was performed to assess right and left cardiac chambers sizes, ventricular masses, and cine function. RV mass index (RVMI) was markedly higher in the overlap group than the COPD-only group (19 ± 6 versus 11 ± 6; p = 0.02). Overlap syndrome subjects had a reduced RV remodeling index (defined as the ratio between RVMI and RV end-diastolic volume index) compared to the COPD-only group (0.27 ± 0.06 versus 0.18 ± 0.08; p = 0.02). In the overlap syndrome subjects, the extent of RV remodeling was associated with severity of oxygen desaturation (R2 = 0.65, p = 0.03). Our pilot results suggest that untreated overlap syndrome may cause more extensive RV remodeling than COPD alone.