Christian Schlatzer

Effect of CPAP therapy on endothelial function in obstructive sleep apnoea: A systematic review and meta‐analysis

Obstructive sleep apnoea (OSA) is a prevalent sleep‐related breathing disorder associated with adverse cardiovascular outcome. Endothelial dysfunction is one of the proposed mechanistic links between OSA and the increased cardiovascular risk. Treatment with continuous positive airway pressure (CPAP) may reverse this detrimental pathophysiological consequence of OSA. Most studies on the effect of CPAP on endothelial function in OSA are limited by their low sample size. The objective of this systematic review was to assess the effect CPAP therapy on endothelial function in patients with OSA. We conducted a systematic review and meta‐analysis searching literature databases up to August 2013 for randomized controlled trials (RCTs) on the effect of CPAP on endothelial function in OSA, assessed by flow‐mediated dilatation (FMD) and other validated techniques. The primary outcome for the meta‐analysis (DerSimonian/Laird random‐effects method) was the treatment effect on FMD. Eight RCTs comparing the effects of therapeutic CPAP versus subtherapeutic CPAP (or no intervention) on endothelial function involving 245 OSA patients were included in the systematic review. The studies are consistent in effect direction, showing an improvement of endothelial function by CPAP. Four RCTs involving 150 patients could be used for the meta‐analysis. Compared to the control group, CPAP therapy (range 2–24 weeks) significantly increased absolute % FMD by 3.87% (95% confidence interval: 1.93–5.80, P < 0.001). In patients with OSA, CPAP therapy improves endothelial function significantly and to a clinically important extent.

Comparison of the effects of continuous positive airway pressure and mandibular advancement devices on sleepiness in patients with obstructive sleep apnoea: a network meta-analysis

BACKGROUND Excessive daytime sleepiness is the most important symptom of obstructive sleep apnoea and can affect work productivity, quality of life, and the risk of road traffic accidents. We aimed to quantify the effects of the two main treatments for obstructive sleep apnoea (continuous positive airway pressure and mandibular advancement devices) on daytime sleepiness and to establish predictors of response to continuous positive airway pressure. METHODS We searched MEDLINE and the Cochrane Library from inception to May 31, 2015, to identify randomised controlled trials comparing the effects of continuous positive airway pressure, mandibular advancement devices or an inactive control (eg, placebo or no treatment) on the Epworth Sleepiness Scale (ESS, range 0-24 points) in patients with obstructive sleep apnoea. We did a network meta-analysis using multivariate random-effects meta-regression to assess the effect of each treatment on ESS. We used meta-regression to assess the association of the reported effects of continuous positive airway pressure versus inactive controls with the characteristics of trials and their risk of bias. FINDINGS We included 67 studies comprising 6873 patients in the meta-analysis. Compared with an inactive control, continuous positive airway pressure was associated with a reduction in ESS score of 2·5 points (95% CI 2·0-2·9) and mandibular advancement devices of 1·7 points (1·1-2·3). We estimated that, on average, continuous positive airway pressure reduced the ESS score by a further 0·8 points compared with mandibular advancement devices (95% CI 0·1-1·4; p=0·015). However, there was a possibility of publication bias in favour of continuous positive airway pressure that might have resulted in this difference. We noted no evidence that studies reporting higher continuous positive airway pressure adherence also reported larger treatment effects (p=0·70). INTERPRETATION Continuous positive airway pressure and mandibular advancement devices are effective treatments for reducing daytime sleepiness in patients with obstructive sleep apnoea. Continuous positive airway pressure seemed to be a more effective treatment than mandibular advancement devices, and had an increasingly larger effect in more severe or sleepier obstructive sleep apnoea patients when compared with inactive controls. However, mandibular advancement devices are an effective alternative treatment should continuous positive airway pressure not be tolerated. FUNDING Swiss National Science Foundation and the University of Zurich Clinical Research Priority Program Sleep and Health.

Biomarkers of oxidative stress following continuous positive airway pressure withdrawal: data from two randomised trials

There is conflicting evidence whether intermittent hypoxia in obstructive sleep apnoea (OSA) influences oxidative stress. We hypothesised that withdrawal of continuous positive airway pressure (CPAP) from patients with OSA would raise markers of oxidative stress. 59 patients with CPAP-treated moderate-to-severe OSA (oxygen desaturation index (ODI) >20 events·h−1) were randomised 1:1 to either stay on CPAP (n=30) or change to sham CPAP (n=29) for 2 weeks. Using samples from two similar studies at two sites, we measured early morning blood malondialdehyde (MDA, a primary outcome in one study and a secondary outcome in the other), lipid hydroperoxides, total antioxidant capacity, superoxide generation from mononuclear cells and urinary F2-isoprostane. We also measured superoxide dismutase as a marker of hypoxic preconditioning. “Treatment” effects (sham CPAP versus CPAP) were calculated via linear regression. Sham CPAP provoked moderate-to-severe OSA (mean ODI 46 events·h−1), but blood markers of oxidative stress did not change significantly (MDA “treatment” effect (95% CI) −0.02 (−0.23 to +0.19) μmol·L−1). Urinary F2-isoprostane fell significantly by ∼30% (−0.26 (−0.42 to −0.10) ng·mL−1) and superoxide dismutase increased similarly (+0.17 (+0.02 to +0.30) ng·mL−1). We found no direct evidence of increased oxidative stress in patients experiencing a return of their moderate-to-severe OSA. The fall in urinary F2-isoprostane and rise in superoxide dismutase implies that hypoxic preconditioning may have reduced oxidative stress. Obstructive sleep apnoea may induce hypoxic preconditioning and reduce, rather than increase, oxidative stress http://ow.ly/MaUoN

Effect of CPAP Withdrawal on myocardial perfusion in OSA: A randomized controlled trial.

Obstructive sleep apnoea (OSA) is highly prevalent and associated with an increased incidence of cardiovascular events. Endothelial dysfunction is the proposed causative mechanism. Continuous positive airway pressure (CPAP) is presumed to improve cardiovascular outcome in OSA. CPAP withdrawal was recently shown to lead to peripheral endothelial dysfunction. However, it is not known whether short‐term CPAP withdrawal reduces myocardial perfusion in OSA.

Coronary artery calcification, epicardial fat burden, and cardiovascular events in chronic obstructive pulmonary disease.

Rationale Patients with chronic obstructive pulmonary disease (COPD) suffer from significantly more cardiovascular comorbidity and mortality than would be anticipated from conventional risk factors. The aim of this study was to determine whether COPD patients have a higher coronary artery calcium score (CACS) and epicardial fat burden, compared to control subjects, and their association with cardiovascular events. Methods From a registry of 1906 patients 81 patients with clinically diagnosed COPD were one-to-one matched to 81 non-COPD control subjects with a smoking history, according to their age, sex, and the number of classic cardiovascular risk factors (arterial hypertension, diabetes mellitus, dyslipidemia, family history of premature coronary artery disease). CACS, epicardial fat, and subsequent major adverse cardiovascular events (MACE) during follow-up were compared between groups. Results Patients with COPD (Global Initiative for Chronic Obstructive Lung Disease-classification I: 5%, II: 23%, III: 16% and IV: 56%) showed no difference in CACS (median difference 68 Agatston Units [95% confidence interval -176.5 to 192.5], p=0.899) or epicardial fat volume (mean difference -0.5 cm3 [95% confidence interval -20.9 to 21.9], p=0.961) compared with controls. After a median follow-up of 42.6 months a higher incidence of MACE was observed in COPD patients (RR=2.80, p=0.016) compared with controls. Cox proportional hazard regression identified cardiac ischemias and CACS as independent predictors for MACE. Conclusion COPD patients experienced a higher MACE incidence compared to controls despite no baseline differences in coronary calcification and epicardial fat burden. Other mechanisms such as undersupply of medication seem to account for an excess cardiovascular comorbidity in COPD patients.

Intrathoracic pressure swings induced by simulated obstructive sleep apnoea promote arrhythmias in paroxysmal atrial fibrillation

AIMS There is preliminary evidence for a link between obstructive sleep apnoea (OSA) and arrhythmias such as paroxysmal atrial fibrillation (PAF) and sudden cardiac death but underlying mechanisms remain largely unknown. METHODS AND RESULTS In this interventional crossover study, we evaluated whether intrathoracic pressure changes, induced by simulated OSA, trigger premature cardiac beats, and alter measures of ventricular repolarization [QTc and Tpeak-to-Tend (TpTec) intervals] in patients with PAF. 12-Lead-electrocardiograms were recorded continuously in 44 patients, while simulating obstructive apnoea (Mueller manoeuvre, MM), obstructive hypopnoea (inspiration through a threshold load, ITH), end-expiratory central apnoea (AP), and during normal breathing (NB) in randomized order. The prevalence of OSA in these 44 patients was assessed by a sleep study. Atrial premature beats (APBs) occurred more frequently during MM (55% of patients) and ITH (32%), but not during AP (14%), compared with NB (9%) (P < 0.001, P = 0.006 and P = 0.688, respectively). Mueller manoeuvre led to a significant prolongation of QTc and TpTec intervals (+17.3 ms, P < 0.001 and +4.3 ms, P = 0.005). Inspiration through a threshold load significantly increased QTc (+9.6 ms, P < 0.001) but not TpTec. End-expiratory central apnoea did not alter QTc and TpTec intervals. According to the sleep study, 56% of patients had OSA (apnoea hypopnoea index ≥5). CONCLUSION Simulated OSA induces APBs which may be important in patients with PAF, because the majority of episodes of PAF has been shown to be triggered by APBs. Simulated OSA leads to a significant prolongation of ventricular repolarization.

The effect of continuous positive airway pressure on metabolic variables in patients with obstructive sleep apnoea

Obstructive sleep apnoea (OSA) is increasingly considered as a risk factor for metabolic disturbances, such as diabetes mellitus or dyslipidaemia. Continuous positive airway pressure (CPAP) therapy, the standard treatment for patients with OSA, may improve various metabolic variables, such as insulin sensitivity, glucose metabolism, lipids, fat distribution and adipokines. Several observational and uncontrolled clinical studies claim an improvement of these metabolic variables through the use of CPAP. However, there is only a limited number of clinical randomised controlled trials (RCTs) evaluating the effect of CPAP on metabolic variables. In this review, we summarise and discuss non-randomised studies and RCTs evaluating the effect of CPAP on metabolic variables in patients with OSA. In summary, the currently available body of evidence does not support a clinically important effect of CPAP treatment on any of the investigated metabolic variables. However, some investigators found small, but statistically significant changes in some metabolic variables, thus beneficial effects of CPAP treatment in selected patient cohorts cannot be excluded. To answer this question, more data from RCTs with well-defined study populations are warranted.

Simulated Obstructive Sleep Apnea Increases P-Wave Duration and P-Wave Dispersion.

Background A high P-wave duration and dispersion (Pd) have been reported to be a prognostic factor for the occurrence of paroxysmal atrial fibrillation (PAF), a condition linked to obstructive sleep apnea (OSA). We tested the hypothesis of whether a short-term increase of P-wave duration and Pd can be induced by respiratory manoeuvres simulating OSA in healthy subjects and in patients with PAF. Methods 12-lead-electrocardiography (ECG) was recorded continuously in 24 healthy subjects and 33 patients with PAF, while simulating obstructive apnea (Mueller manoeuvre, MM), obstructive hypopnea (inspiration through a threshold load, ITH), central apnea (AP), and during normal breathing (BL) in randomized order. The P-wave duration and Pd was calculated by using dedicated software for ECG-analysis. Results P-wave duration and Pd significantly increased during MM and ITH compared to BL in all subjects (+13.1ms and +13.8ms during MM; +11.7ms and +12.9ms during ITH; p<0.001 for all comparisons). In MM, the increase was larger in healthy subjects when compared to patients with PAF (p<0.05). Conclusion Intrathoracic pressure swings through simulated obstructive sleep apnea increase P-wave duration and Pd in healthy subjects and in patients with PAF. Our findings imply that intrathoracic pressure swings prolong the intra-atrial and inter-atrial conduction time and therefore may represent an independent trigger factor for the development for PAF.

Accuracy of the Hospital Anxiety and Depression Scale for Identifying Depression in Chronic Obstructive Pulmonary Disease Patients

Psychological morbidity is common in chronic respiratory diseases. The diagnostic accuracy of the Hospital Anxiety and Depression Scale (HADS) and risk factors for comorbid depression in chronic obstructive pulmonary disease (COPD) are addressed. Consecutive COPD patients (GOLD stage I–IV, 40–75 years old) were enrolled in a multicentre, cross-sectional cohort study. Diagnosis of depression was ascertained through clinical records. Lung function, HADS score, 6-minute walking test (6-MWT), MRC dyspnoea score, and COPD Assessment Test (CAT) were evaluated. Two hundred fifty-nine COPD patients (mean age 62.5 years; 32% female; mean FEV1 48% predicted) were included. Patients diagnosed with depression (29/259; 11.2%) had significantly higher HADS-D and HADS-Total scores than nondepressed patients (median (quartiles) HADS-D 6 [4; 9] versus 4 [2; 7], median HADS-Total 14 [10; 20] versus 8 [5; 14]). Receiver-operating characteristic plots showed moderate accuracy for HADS-D, AUC 0.662 (95%CI 0.601–0.719), and HADS-Total, AUC 0.681 (95%CI 0.620–0.737), with optimal cut-off scores of >5 and >9, respectively. Sensitivity and specificity were 62.1% and 62.6% for HADS-D compared to 75.9% and 55.2% for HADS-Total. Age, comorbidities, sex, and lower airflow limitation predicted depression. The HADS exhibits low diagnostic accuracy for depression in COPD patients. Younger men with comorbidities are at increased risk for depression.

ECG risk markers for atrial fibrillation and sudden cardiac death in minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised trial

Objective Obstructive sleep apnoea (OSA), atrial fibrillation (AF) and sudden cardiac death (SCD) may occur concomitantly, and are of considerable epidemiological interest, potentially leading to morbidity and mortality. Effective treatment of OSA with continuous positive airway pressure (CPAP) could prevent progression and/or recurrence of AF and factors leading to SCD. Recently, a randomised controlled trial showed a statistically and clinically significant prolongation of measures of cardiac repolarisation after CPAP withdrawal in symptomatic patients with moderate to severe OSA. Whether or not CPAP therapy improves ECG risk markers of AF and SCD in patients with minimally symptomatic OSA as well, is unknown. Methods 3 centres taking part in the MOSAIC (Multicentre Obstructive Sleep Apnoea Interventional Cardiovascular) trial randomisd 303 patients with minimally symptomatic OSA to receive either CPAP or standard care for 6 months. Treatment effects of CPAP on P-wave duration, P-wave dispersion, QT interval, QT dispersion, Tpeak-to-Tend (TpTe) and TpTe/QT ratio were analysed. Results Participants were primarily men (83%). Mean age was 57.8 (7.2) and mean ODI (Oxygen Desaturation Index) at baseline was 13.1/h (12.3). Full 12-lead ECG data was available in 250 patients. Mean (SD) baseline intervals of P-wave duration, P-wave dispersion, QTc interval, QT dispersion, TpTe and TpTe/QT ratio in ms were 87.4 (8.3), 42.3 (11.9), 397.8 (22.7), 43.1 (16.7), 73.5 (13.7) and 0.19 (0.0), respectively. No treatment effect of CPAP on risk markers for AF and SCD was found. Conclusions There seems to be no effect of CPAP on ECG measures of arrhythmia risk in patients with minimally symptomatic OSA. Trial registration number ISRCTN34164388; Post-results.