Night-to-night variability of respiratory events in obstructive sleep apnoea: a systematic review and meta-analysis.

BACKGROUND: It is current practice to use a single diagnostic sleep study in the diagnostic workup of obstructive sleep apnoea (OSA). However, a relevant night-to-night variability (NtNV) of respiratory events has been reported. METHODS: We evaluated the NtNV of respiratory events in adults with suspected or already diagnosed OSA who underwent more than one diagnostic sleep study. Data sources were PubMed, Cochrane and Embase up to 23 January 2019. Random-effects models were used for evidence synthesis. For moderator analysis, mixed-effects regression analysis was performed. The study was registered with PROSPERO (CRD42019135277). RESULTS: Of 2143 identified papers, 24 studies, comprising 3250 participants, were included. The mean Apnoea-Hypopnoea Index (AHI) difference between the first and second night was -1.70/hour (95% CI -3.61 to 0.02). REM time differences (first to second night) were significantly positive associated with differences in mean AHI (ß coefficient 0.262 (95% CI 0.096 to 0.428). On average, 41% (95% CI 27% to 57%) of all participants showed changes of respiratory events >10/hour from night to night. Furthermore, 49% (95% CI 32% to 65%) of participants changed OSA severity class (severity thresholds at 5/hour, 15/hour and 30/hour) at least once in sequential sleep studies. Depending on the diagnostic threshold (5/hour, 10/hour or 15/hour), on average 12% (95% CI 9% to 15%), 12% (95% CI 8% to 19%) and 10% (95% CI 8% to 13%) of patients would have been missed during the first night due to single night testing. CONCLUSION: While there was no significant difference between mean AHI in two sequential study nights on a group level, there was a remarkable intraindividual NtNV of respiratory events, leading to misdiagnosis and misclassification of patients with suspected OSA.

Effects of suboptimal adherence of CPAP therapy on symptoms of obstructive sleep apnoea: a randomised, double-blind, controlled trial.

INTRODUCTION: Continuous positive airway pressure (CPAP) is currently the treatment of choice for sleepiness in patients with obstructive sleep apnoea (OSA); however, adherence is often thought to be suboptimal. We investigated the effects of suboptimal CPAP usage on objective and subjective sleepiness parameters in patients with OSA. MATERIAL AND METHODS: In this 2-week, parallel, double-blind, randomised controlled trial we enrolled moderate-to-severe OSA patients with excessive pre-treatment daytime sleepiness (Epworth sleepiness scale (ESS) score >10 points) who had suboptimal CPAP adherence over ≥12 months (mean nightly usage time 3-4 h). Patients were allocated through minimisation to either subtherapeutic CPAP ("sham CPAP") or continuation of CPAP ("therapeutic CPAP"). A Bayesian analysis with historical priors calculated the posterior probability of superiority. RESULTS: Between May, 2016 and November, 2018, 57 patients (aged 60±8 years, 79% male, 93% Caucasian) were allocated in total, and 52 who completed the study (50% in each arm) were included in the final analysis. The unadjusted ESS score increase was 2.4 points (95% CI 0.6-4.2, p=0.01) in the sham-CPAP group when compared to continuing therapeutic CPAP. The probability of superiority of therapeutic CPAP over sham CPAP was 90.4% for ESS, 90.1% for systolic blood pressure and 80.3% for diastolic blood pressure. CONCLUSIONS: Patients with moderate-to-severe OSA and daytime sleepiness are still getting a substantial benefit from suboptimal CPAP adherence, albeit not as much as they might get if they adhered more. Whether a similar statement can be made for even lower adherence levels remains to be established in future trials.

Increased augmentation index in patients with Ehlers-Danlos syndrome.

BACKGROUND: Ehlers-Danlos Syndrome (EDS) comprises a heterogeneous group of diseases characterized by joint hypermobility, connective tissue friability, and vascular fragility. Reliable prognostic factors predicting vascular disease progression (e.g. arterial aneurysms, dissections, and ruptures) in EDS patients are still missing. Recently, applanation tonometry derived augmentation index (AIx), an indirect marker of arterial stiffness, has shown to be positively associated with progression of aortic disease in Marfan syndrome. In this study, we assessed aortic AIx in patients with EDS and matched healthy controls. METHODS: We performed noninvasive applanation tonometry in 61 adults with EDS (43 women and 18 men aged 39.3 ± 14.6 years) and 61 age-, gender-, height-, and weight-matched healthy controls. Radial artery pulse waveforms were recorded and analyzed using the SphygmoCor System (AtCor Medical, Sydney, NSW, Australia). Calculated AIx was adjusted to a heart rate of 75/min. Groups were compared and association between AIx and EDS was determined by univariate and multivariate regression analysis. RESULTS: EDS patients were categorized in classical type EDS (34%), hypermobile type EDS (43%), vascular type EDS (5%), or remained unassignable (18%) due to overlapping features. EDS patients showed a significantly increased aortic AIx compared to healthy controls (22.8% ± 10.1 vs 14.8% ± 14.0, p < 0.001). EDS showed a positive association with AIx; independent of age, sex, height, blood pressure, medication, and pack years of smoking. CONCLUSIONS: Patients with EDS showed elevated AIx, indicating increased arterial stiffness when compared to healthy controls. Further investigations are needed in order to assess the prognostic value of increased AIx for cardiovascular outcomes in patients with EDS.

Prevalence of Obstructive Sleep Apnea in Patients with Thoracic Aortic Aneurysm: A Prospective, Parallel Cohort Study.

BACKGROUND: The pathogenesis and etiology of thoracic aortic aneurysms (TAA) are largely unknown. Preliminary data from patients with aortic dissection and abdominal aneurysms suggest a causal link of obstructive sleep apnea (OSA) on aortic disease. OBJECTIVES: The aim of the study was to assess the prevalence of OSA in patients with TAA compared to a matched control group. METHOD: In this prospective parallel-cohort study, we 2-to-1 matched 208 patients with verified TAA (at the aortic sinus and/or ascending aorta) to 104 controls without TAA according to sex, age, height, weight, and left ventricular ejection fraction. All participants underwent an ultrasound of the thoracic aorta and a level III respiratory polygraphy. OSA was defined as apnea-hypopnea index ≥5/h. The prevalence of OSA was compared with conditional logistic regression and controlling for the matching variables. RESULTS: A total of 312 patients (mean age 65 ± 11 years, 82% male, mean body mass index 27 ± 4 kg/m2) were successfully 2-to-1 matched in the final model. Prevalence of OSA was significantly higher in the TAA-group when compared to the matched control group (63 vs. 47%; odds ratio 1.87 [95% CI 1.05-3.34]; p = 0.03). When applying a higher apnea-hypopnea index threshold (≥15/h), the odds ratio increased to 3.25 (95% CI 1.65-6.42; p < 0.001). The median apnea-hypopnea index was higher in patients with TAA (9.2/h [3.3-20.0] vs. 4.5/h [2.2-11.1], p < 0.001). CONCLUSIONS: Patients with TAA have a higher prevalence of OSA when compared to the general population. Since OSA is effectively treatable and might contribute to the pathogenesis of TAA, further longitudinal trials are needed to assess the association between OSA and TAA.

Endocrine responses during CPAP withdrawal in obstructive sleep apnoea: data from two randomised controlled trials.

The aim of this investigation was to elucidate the effect of CPAP withdrawal on neurometabolic and cardiometabolic markers in patients with obstructive sleep apnoea. We evaluated 70 patients (mean age 61±10 years, 82% men) treated with CPAP in two 2-week, parallel, randomised controlled trials. CPAP withdrawal resulted in elevated 3,4-dihydroxyphenylglycol, norepinephrine and cortisol after 2 weeks of CPAP withdrawal; however, no statistically significant changes of the renin-angiotensin-aldosterone system (RAAS) determinants were documented. In summary, CPAP withdrawal may be more prominently linked to short-term increases in sympathetic activation than hypothalamic-pituitary-adrenal axis or RAAS activation. ClinicalTrials.gov Identifier: NCT02493673 and NCT02050425.

Effects of short-term continuous positive airway pressure withdrawal on cerebral vascular reactivity measured by blood oxygen level-dependent magnetic resonance imaging in obstructive sleep apnoea: a randomised controlled trial.

Impaired cerebral vascular reactivity (CVR) increases long-term stroke risk. Obstructive sleep apnoea (OSA) is associated with peripheral vascular dysfunction and vascular events. The aim of this trial was to evaluate the effect of continuous positive airway pressure (CPAP) withdrawal on CVR.41 OSA patients (88% male, mean age 57±10 years) were randomised to either subtherapeutic or continuation of therapeutic CPAP. At baseline and after 2 weeks, patients underwent a sleep study and magnetic resonance imaging (MRI). CVR was estimated by quantifying the blood oxygen level-dependent (BOLD) MRI response to breathing stimuli.OSA did recur in the subtherapeutic CPAP group (mean treatment effect apnoea-hypopnoea index +38.0 events·h-1, 95% CI 24.2-52.0; p<0.001) but remained controlled in the therapeutic group. Although there was a significant increase in blood pressure upon CPAP withdrawal (mean treatment effect +9.37 mmHg, 95% CI 1.36-17.39; p=0.023), there was no significant effect of CPAP withdrawal on CVR assessed via BOLD MRI under either hyperoxic or hypercapnic conditions.Short-term CPAP withdrawal did not result in statistically significant changes in CVR as assessed by functional MRI, despite the recurrence of OSA. We thus conclude that, unlike peripheral endothelial function, CVR is not affected by short-term CPAP withdrawal.

Impact of hypertension on cerebral microvascular structure in CPAP-treated obstructive sleep apnoea patients: a diffusion magnetic resonance imaging study.

PURPOSE: Obstructive sleep apnoea (OSA) is a highly prevalent sleep-related breathing disorder associated with hypertension, impaired peripheral vascular function and an increased risk of stroke. Evidence suggests that abnormalities of the cerebral microcirculation, such as capillary rarefication, may be present in these patients. We evaluated whether the presence of hypertension may affect the cerebral capillary architecture and function assessed by Intravoxel Incoherent Motion (IVIM) magnetic resonance imaging (MRI) in patients with continuous positive airway pressure (CPAP)-treated OSA. METHODS: Forty-one patients (88% male, mean age 57 ± 10 years) with moderate-to-severe OSA were selected and divided into two groups (normotensive vs. hypertensive). All hypertensive OSA patients were adherent with their antihypertensive medication. Cerebral microvascular structure was assessed in grey (GM) and white matter (WM) using an echo-planar diffusion imaging sequence with 14 different b values. A step-wise IVIM analysis algorithm was applied to compute true diffusion (D), perfusion fraction (f) and pseudo-diffusion (D*) values. Group comparisons were performed with the Wilcoxon-Mann-Whitney-Test. Regression analysis was adjusted for age. RESULTS: Diffusion- and perfusion-related indexes in middle-aged OSA normotensive patients were quantified in both tissue types (D [10-3 mm2/s]: GM = 0.83 ± 0.03; WM = 0.72 ± 0.03; f (%) GM = 0.09 ± 0.01; WM = 0.06 ± 0.01; D* [10-3 mm2/s]: GM = 7.72 ± 0.89; WM = 7.38 ± 0.98). In the examined tissue types, hypertension did not result in changes on the estimated MRI IVIM index values. CONCLUSION: Based on IVIM analysis, cerebral microvascular structure and function showed no difference between hypertensive and normotensive patients with moderate-to-severe OSA treated with CPAP. Treatment adherence with antihypertensive drug regime and, in turn, controlled hypertension seems not to affect microvascular structure and perfusion of the brain. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02493673.

[Asthma, COPD or overlap? Symptoms and diagnostic procedures]. / Asthma, COPD oder Overlap? Symptomatik und Diagnostik.

Asthma, COPD or overlap? Symptoms and diagnostic procedures Abstract. Medical history combined with spirometry before and after bronchodilation provides important information, and allows distinguishing between asthma and Chronic obstructive pulmonary disease (COPD) in most of the cases. COPD and asthma are sometimes difficult to discriminate, mainly in older patients with a smoking history and /or history of atopia. Symptoms and the results of diagnostic tests are the basis on which therapeutic decisions are made. Differentiation between asthma and COPD is of great importance because management approaches and goals for these conditions differ. Asthma-COPD-overlap has to be considered if a significant interleave of clinical features of both conditions is identified. If it is not possible to differentiate between the two conditions, ways of additional diagnostic testing are described in this article.

Validation of breath biomarkers for obstructive sleep apnea.

BACKGROUND AND OBJECTIVES: Obstructive sleep apnea (OSA) is an underdiagnosed respiratory disease with negative metabolic and cardiovascular effects. The current gold standard for diagnosing OSA is in-hospital polysomnography, a time-consuming and costly procedure, often inconvenient for the patient. Recent studies revealed evidence for the potential of breath analysis for the diagnosis of OSA based on a disease-specific metabolic pattern. However, none of these findings were validated in a larger and broader cohort, an essential step for its application in clinics. METHODS: In the present study, we validated a panel of breath biomarkers in a cohort of patients with possible OSA (N = 149). These markers were previously identified in our group by secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS). RESULTS: Here, we could confirm significant differences between metabolic patterns in exhaled breath from OSA patients compared to control subjects without OSA as well as the association of breath biomarker levels with disease severity. Our prediction of the diagnosis for the patients from this completely independent validation study using a classification model trained on the data from the previous study resulted in an area under the receiver operating characteristic curve of 0.66, which is comparable to questionnaire-based OSA screenings. CONCLUSIONS: Thus, our results suggest that breath analysis by SESI-HRMS might be useful to screen for OSA as an objective measure. However, its true predictive power should be tested in combination with OSA screening questionnaires. CLINICAL TRIAL: "Mass Spectral Fingerprinting in Obstructive Sleep Apnoea", NCT02810158, www.ClinicalTrials.gov.

A few more steps lead to improvements in endothelial function in severe and very severe COPD.

INTRODUCTION: Cardiovascular disease is among the most prevalent concomitant chronic diseases in COPD. Physical activity (PA) modifies endothelial function and is commonly impaired in COPD. However, studies directly investigating the effects of increased PA on endothelial function in COPD are lacking. We investigated the effect of changes in PA on endothelial function in patients with severe to very severe COPD. Furthermore, we determined which variables modify this effect. MATERIALS AND METHODS: This is a secondary outcome analysis from a randomised controlled trial investigating the effects of combined PA counselling and pedometer-based feedback in COPD. We analysed the change in PA based on three visits during one year. We measured PA using a validated triaxial accelerometer, and endothelial function using flow-mediated dilation. RESULTS: Data was analysed from 54 patients, which provided 101 change scores. Multiple regression modelling, including adjustment for baseline step count, showed strong evidence for an association between changes in flow-mediated dilation and changes in PA (p < 0.001). The analysis of several effect modificators showed no evidence of any influence on the interaction between PA and endothelial function: smoking status (p = 0.766), severity of airflow obstruction (p = 0.838), exacerbation frequency (p = 0.227), lung diffusion capacity of carbon monoxide % pred. (p = 0.735). CONCLUSION: We found strong evidence that increasing steps per day ameliorates the heavily impaired endothelial function in patients with severe and very severe COPD. Further studies should examine which factors influence this relationship in a positive or negative manner.

[CME: Obstructive Sleep Apnea: A Common Disease]. / CME: Volkskrankheit obstruktive Schlafapnoe.

CME: Obstructive Sleep Apnea: A Common Disease Abstract. Obstructive sleep apnea is a common sleep related breathing disorder with a collapse of the upper respiratory tract, leading to repetitive oxygen desaturations and 'micro arousals'. If the physiological sleep architecture is impaired, patients are at risk for an increased daytime sleepiness and an increased blood pressure. Main risk factors are central obesity, age, male sex, (and snoring). By means of weight loss, alcohol restriction, and continuous nocturnal positive pressure ventilation (CPAP), the obstructive sleep apnea syndrome can be treated, with mandibular advancement devices representing a second-choice therapy.

Patterns of nightly CPAP usage in OSA patients with suboptimal treatment adherence.

BACKGROUND AND OBJECTIVES: Low adherence impairs the effectiveness of continuous positive airway pressure (CPAP) therapy in patients with obstructive sleep apnoea (OSA), but knowledge on CPAP usage micro-patterns is mostly lacking. Thus, the aim of this study was to analyse usage micro-patterns among patients with suboptimal CPAP adherence. METHODS: We analysed CPAP usage datasets comprising the initial 31 nights of therapy. By employing a threshold of 4 h usage in at least 70% of nights, we subdivided the patients into suboptimal and optimal users. We investigated single CPAP start- and stop-points, and introduced the parameter "interruption-rate", by dividing the amount of therapy interruptions per night by the usage duration per night. This parameter represents the amount of interruptions per 1 h of CPAP usage. Group comparison analysis was performed via t-test, Wilcoxon rank sum-test, and via Chi2-test. RESULTS: We included datasets of 48 suboptimal and 48 optimal users (55.9 ± 11.3 years, 83.3% men) in the analysis. Interruption-rate was significantly higher among suboptimal users, when compared with optimal users (median (quartiles) 0.24 (0.14/0.45) versus 0.15 (0.05/0.28), p < 0.001∗). Suboptimal users were more likely to report that CPAP reduced their sleep quality, waked them up at night, and that CPAP side effects or problems with the device impaired their adherence. CONCLUSIONS: CPAP usage micro-patterns are more fragmented among OSA patients with lower overall adherence. These patterns might result from impaired sleep quality, due to CPAP side effects, and device-associated problems.

Low repeatability of Epworth Sleepiness Scale after short intervals in a sleep clinic population.

STUDY OBJECTIVES: The purpose of this study was to evaluate the short-term repeatability of the Epworth Sleepiness Scale (ESS) in patients with suspected obstructive sleep apnea and to determine whether transitory sleepiness of the patient influenced ESS results. METHODS: Adult participants with suspected obstructive sleep apnea taking part in a study on the diagnostic accuracy of repeated sleep studies were eligible. For assessment of repeatability, the agreement between 2 sequential ESS scores obtained within 1 day (same-day group) or on different days within 1 week (same-week group) was evaluated. By analyzing the within-day repeatability, a possible influence of situational sleepiness on ESS results was assessed. By comparing correlations of sequential scores between both groups, a potential influence of test day-specific sleepiness on ESS results was evaluated. Data were analyzed using Bland-Altman plots, intraclass correlation coefficients, standard error of measurement analysis, and relative amounts of ESS discrepancies beyond 2, 3, 5, and 7 points. RESULTS: Forty participants (mean age, 47.7 ± 15.4 years; 67.5% men) were included in this study, with 20 in each group. Bland-Altman analysis demonstrated considerable variability of repeated scores (mean ± 1.96 × SD = 1.93 [-3.81 to 7.66]). Discrepancies of at least 3 points between sequential ESS scores were found in 48% of all participants. Comparison of ESS repeatability between both groups showed no evidence for a difference. CONCLUSIONS: A clinically relevant variability in ESS scores was found, even when repeated on the same day, possibly because of situational sleepiness influencing ESS results. Changes in ESS in response to interventions should be interpreted with caution because of its low test-retest reliability.

Efficacy of pharmacotherapy for OSA in adults: A systematic review and network meta-analysis.

Pharmacotherapy represents a desirable potential therapeutic alternative for patients with obstructive sleep apnoea (OSA). We aimed to summarize evidence on the efficacy of pharmacotherapy in adults with OSA and delineate the underlying mechanisms. Seven databases were systematically screened for randomised controlled trials (RCTs) from their inception to September 2018. According to a pre-registered study protocol (PROSPERO-ID-CRD42018086446) network meta-analysis was performed to obtain intervention effects on the apnoea-hypopnoea-index (AHI) based on data extracted from published reports. We identified 58 RCTs (n = 1710 patients) investigating 44 different drugs or drug-combinations. Interventions were classified into seven pathomechanism-groups and summarized narratively. A meta-analysis of 17 trials for seven drugs (acetazolamide, donepezil, mirtazapine, ondansetron, paroxetine, protriptyline, theophylline) indicated a small effect for acetazolamide (mean difference in AHI -9.6/h [-17.7; -1.4]; p = 0.02). In the network meta-analysis (I2 = 50%) nine drugs (tramazoline, liraglutide, spironolactone/furosemide, acetazolamide, dronabinol, zonisamide, phentermine, spironolactone, and ondansetron/fluoxetine) significantly lowered the AHI compared to placebo. Although some trials indicate favorable outcomes, these results are only valid for distinctive OSA-phenotypes or were not clinically significant. The effect sizes were small, the majority of trials were not adequately powered. There is currently insufficient evidence to recommend any pharmacotherapy for OSA and no phase-III trials are available.

Highlights from the 2018 European Respiratory Society International Congress: sleep and clinical physiology.

The 2018 European Respiratory Society (ERS) International Congress held in Paris, France, served as a platform to discover the latest research on respiratory diseases, the improvement in their treatments and patient care. Specifically, the scientific sessions organised by ERS Assembly 4 provided novel insights into sleep disordered breathing and fresh knowledge in respiratory physiology, stressing its importance to understanding and treating respiratory diseases. This article, divided by session, will summarise the most relevant studies presented at the ERS International Congress. Each session has been written by early career members specialised in the different fields of this interdisciplinary assembly.