Beat-to-beat cardiac repolarization lability increases during hypoxemia and arousals in obstructive sleep apnea patients.

Obstructive sleep apnea (OSA) is associated with the progression of cardiovascular diseases, arrhythmias, and sudden cardiac death (SCD). However, the acute impacts of OSA and its consequences on heart function are not yet fully elucidated. We hypothesized that desaturation events acutely destabilize ventricular repolarization, and the presence of accompanying arousals magnifies this destabilization. Ventricular repolarization lability measures, comprising heart rate corrected QT (QTc), short-time-variability of QT (STVQT), and QT variability index (QTVI), were calculated before, during, and after 20,955 desaturations from lead II electrocardiography signals of 492 patients with suspected OSA (52% men). Variations in repolarization parameters were assessed during and after desaturations, both with and without accompanying arousals, and groupwise comparisons were performed based on desaturation duration and depth. Regression analyses were used to investigate the influence of confounding factors, comorbidities, and medications. The standard deviation (SD) of QT, mean QTc, SDQTc, and STVQT increased significantly (P < 0.01), whereas QTVI decreased (P < 0.01) during and after desaturations. The changes in SDQT, mean QTc, SDQTc, and QTVI were significantly amplified (P < 0.01) in the presence of accompanying arousals. Desaturation depth was an independent predictor of increased SDQTc (ß = 0.405, P < 0.01), STVQT (ß = 0.151, P < 0.01), and QTVI (ß = 0.009, P < 0.01) during desaturation. Desaturations cause acute changes in ventricular repolarization, with deeper desaturations and accompanying arousals independently contributing to increased ventricular repolarization lability. This may partially explain the increased risk of arrhythmias and SCD in patients with OSA, especially when the OSA phenotype includes high hypoxic load and fragmented sleep.NEW & NOTEWORTHY Nocturnal desaturations are associated with increased ventricular repolarization lability. Deeper desaturations with accompanying arousals increase the magnitude of alterations, independent of confounding factors, comorbidities, and medications. Changes associated with desaturations can partially explain the increased risk of arrhythmias and sudden cardiac death in patients with OSA, especially in patients with high hypoxic load and fragmented sleep. This highlights the importance of detailed electrocardiogram analytics for patients with OSA.

CPAP resumption after a first termination and impact on all-cause mortality in France.

BACKGROUND: Continuation of continuous positive airway pressure (CPAP) therapy after initial prescription has been shown to reduce all-cause mortality versus therapy termination. However, there is a lack of data on the rates and impact of resuming CPAP in patients with obstructive sleep apnoea (OSA). This analysis determined the prevalence of CPAP resumption in the year after termination, characterised determinants of CPAP resumption, and examined the impact of CPAP resumption on all-cause mortality. METHODS: French national health insurance reimbursement system data for adults aged ≥18 years were used. CPAP prescription was identified by specific treatment codes. Patients who resumed CPAP after first therapy termination and continued to use CPAP for 1 year were matched with those who resumed CPAP then terminated therapy for a second time. RESULTS: Out of 103 091 individuals with a first CPAP termination, 26% resumed CPAP over the next 12 months, and 65% of these were still using CPAP 1 year later. Significant predictors of CPAP continuation after resumption included male sex, hypertension and CPAP prescription by a pulmonologist. In the matched population, the risk of all-cause death was 38% lower in individuals who continued using CPAP after therapy resumption versus those who had a second therapy discontinuation (hazard ratio 0.62, 95% CI 0.48-0.79; p=0.0001). CONCLUSION: These data suggest that individuals with OSA who fail initial therapy with CPAP should be offered a second trial with the device to ensure that effective therapy is not withheld from those who might benefit.

Intermittent hypoxia increases lipid insulin resistance in healthy humans: A randomized crossover trial.

Sympathetic overactivity caused by chronic intermittent hypoxia is a hallmark of obstructive sleep apnea. A high sympathetic tone elicits increases in plasma free fatty acid and insulin. Our objective was to assess the impact of 14 nights of chronic intermittent hypoxia exposure on sympathetic activity, glucose control, lipid profile and subcutaneous fat tissue remodelling in non-obese healthy humans. In this prospective, double-blinded crossover study, 12 healthy subjects were randomized, among them only nine underwent the two phases of exposures of 14 nights chronic intermittent hypoxia versus air. Sympathetic activity was measured by peroneal microneurography (muscle sympathetic nerve activity) before and after each exposure. Fasting glucose, insulin, C-peptide and free fatty acid were assessed at rest and during a multisampling oral glucose tolerance test. We assessed histological remodelling, adrenergic receptors, lipolysis and lipogenesis genes expression and functional changes of the adipose tissue. Two weeks of exposure of chronic intermittent hypoxia versus ambient air significantly increased sympathetic activity (p = 0.04). Muscle sympathetic nerve activity increased from 24.5 [18.9; 26.8] before to 21.7 [13.8; 25.7] after ambient air exposure, and from 20.6 [17.4; 23.9] before to 28.0 [24.4; 31.5] bursts per min after exposure to chronic intermittent hypoxia. After chronic intermittent hypoxia, post-oral glucose tolerance test circulating free fatty acid area under the curve increased (p = 0.05) and free fatty acid sensitivity to insulin decreased (p = 0.028). In adipocyte tissue, intermittent hypoxia increased expression of lipolysis genes (adipocyte triglyceride lipase and hormone-sensitive lipase) and lipogenesis genes (fatty acid synthase; p < 0.05). In this unique experimental setting in healthy humans, chronic intermittent hypoxia induced high sympathetic tone, lipolysis and decreased free fatty acid sensitivity to insulin. This might participate in the trajectory to systemic insulin resistance and diabetes for patients with obstructive sleep apnea.

Functional recovery after ischemic stroke: Impact of different sleep health parameters.

Sleep disturbances after ischaemic stroke include alterations of sleep architecture, obstructive sleep apnea, restless legs syndrome, daytime sleepiness and insomnia. Our aim was to explore their impacts on functional outcomes at month 3 after stroke, and to assess the benefit of continuous positive airway pressure in patients with severe obstructive sleep apnea. Ninety patients with supra-tentorial ischaemic stroke underwent clinical screening for sleep disorders and polysomnography at day 15 ± 4 after stroke in a multisite study. Patients with severe obstructive apnea (apnea-hypopnea index ≥ 30 per hr) were randomized into two groups: continuous positive airway pressure-treated and sham (1:1 ratio). Functional independence was assessed with the Barthel Index at month 3 after stroke in function of apnea-hypopnea index severity and treatment group. Secondary objectives were disability (modified Rankin score) and National Institute of Health Stroke Scale according to apnea-hypopnea index. Sixty-one patients (71.8 years, 42.6% men) completed the study: 51 (83.6%) had obstructive apnea (21.3% severe apnea), 10 (16.7%) daytime sleepiness, 13 (24.1%) insomnia, 3 (5.7%) depression, and 20 (34.5%) restless legs syndrome. Barthel Index, modified Rankin score and Stroke Scale were similar at baseline and 3 months post-stroke in the different obstructive sleep apnea groups. Changes at 3 months in those three scores were similar in continuous positive airway pressure versus sham-continuous positive airway pressure patients. In patients with worse clinical outcomes at month 3, mean nocturnal oxygen saturation was lower whereas there was no association with apnea-hypopnea index. Poorer outcomes at 3 months were also associated with insomnia, restless legs syndrome, depressive symptoms, and decreased total sleep time and rapid eye movement sleep.

Patient motivation ranked by caregivers at continuous positive airway pressure initiation is predictive of adherence and 1-year therapy termination rate.

PURPOSE: In patients diagnosed with obstructive sleep apnea (OSA), continuous positive airway pressure therapy (CPAP) is effective in reducing symptoms and improving quality of life. However, poor mid- to long-term adherence and high termination rates are a problem. We asked whether or not patient motivation at CPAP initiation was associated with 15-day and 1-year CPAP adherence and termination rates. METHODS: In this nationwide multicenter observational study, individual patient motivation for achieving CPAP adherence was subjectively evaluated at the time of CPAP set-up by the home-care provider's technician on a simple scale (low, average, good, very good). Then, adherence and CPAP termination rates were objectively monitored via the home-care provider's CPAP remote monitoring platform at 15 days and 1 year. RESULTS: A total of 10,450 adults with OSA initiating CPAP were included by 36 centers. CPAP adherence at day 15 was significantly different between the low and the very good motivation groups: 5.4 [3.2; 6.9] hours and 6.0 [4.2; 7.3] hours per night respectively. In the 72.0% of patients using CPAP at 1 year, CPAP adherence was 5.2 [3.1; 6.7] and 5.5 [4.0; 7.0] hours per night in the groups with low and very good motivation respectively. Therapy termination rates at 1 year were 14.6% in the low motivation group and 8.0% in the very good motivation group. CONCLUSION: Our study suggests that motivation of patients with OSA estimated by caregivers at CPAP initiation using a simple four-item ranking is associated with CPAP adherence and primary therapy termination rates during the first year of treatment.

Early Increase in Blood-Brain Barrier Permeability in a Murine Model Exposed to Fifteen Days of Intermittent Hypoxia.

Obstructive sleep apnea (OSA) is characterized by intermittent repeated episodes of hypoxia-reoxygenation. OSA is associated with cerebrovascular consequences. An enhanced blood-brain barrier (BBB) permeability has been proposed as a marker of those disorders. We studied in mice the effects of 1 day and 15 days intermittent hypoxia (IH) exposure on BBB function. We focused on the dorsal part of the hippocampus and attempted to identify the molecular mechanisms by combining in vivo BBB permeability (Evans blue tests) and mRNA expression of several junction proteins (zona occludens (ZO-1,2,3), VE-cadherin, claudins (1,5,12), cingulin) and of aquaporins (1,4,9) on hippocampal brain tissues. After 15 days of IH exposure we observed an increase in BBB permeability, associated with increased mRNA expressions of claudins 1 and 12, aquaporins 1 and 9. IH seemed to increase early for claudin-1 mRNA expression as it doubled with 1 day of exposure and returned near to its base level after 15 days. Claudin-1 overexpression may represent an immediate response to IH exposure. Then, after 15 days of exposure, an increase in functional BBB permeability was associated with enhanced expression of aquaporin. These BBB alterations are possibly associated with a vasogenic oedema that may affect brain functions and accelerate neurodegenerative processes.

Cost-effectiveness of outpatient versus inpatient non-invasive ventilation setup in obesity hypoventilation syndrome: the OPIP trial.

BACKGROUND: Current guidelines recommend that patients with obesity hypoventilation syndrome (OHS) are electively admitted for inpatient initiation of home non-invasive ventilation (NIV). We hypothesised that outpatient NIV setup would be more cost-effective. METHODS: Patients with stable OHS referred to six participating European centres for home NIV setup were recruited to an open-labelled clinical trial. Patients were randomised via web-based system using stratification to inpatient setup, with standard fixed level NIV and titrated during an attended overnight respiratory study or outpatient setup using an autotitrating NIV device and a set protocol, including home oximetry. The primary outcome was cost-effectiveness at 3 months with daytime carbon dioxide (PaCO2) as a non-inferiority safety outcome; non-inferiority margin 0.5 kPa. Data were analysed on an intention-to-treat basis. Health-related quality of life (HRQL) was measured using EQ-5D-5L (5 level EQ-5D tool) and costs were converted using purchasing power parities to £(GBP). RESULTS: Between May 2015 and March 2018, 82 patients were randomised. Age 59±14 years, body mass index 47±10 kg/m2 and PaCO2 6.8±0.6 kPa. Safety analysis demonstrated no difference in ∆PaCO2 (difference -0.27 kPa, 95% CI -0.70 to 0.17 kPa). Efficacy analysis showed similar total per-patient costs (inpatient £2962±£580, outpatient £3169±£525; difference £188.20, 95% CI -£61.61 to £438.01) and similar improvement in HRQL (EQ-5D-5L difference -0.006, 95% CI -0.05 to 0.04). There were no differences in secondary outcomes. DISCUSSION: There was no difference in medium-term cost-effectiveness, with similar clinical effectiveness, between outpatient and inpatient NIV setup. The home NIV setup strategy can be led by local resource demand and patient and clinician preference. TRIAL REGISTRATION NUMBERS: NCT02342899 and ISRCTN51420481.

Respiratory effort during sleep and prevalent hypertension in obstructive sleep apnoea.

BACKGROUND: Mechanisms underlying blood pressure changes in obstructive sleep apnoea (OSA) are incompletely understood. Increased respiratory effort is one of the main features of OSA and is associated with sympathetic overactivity, leading to increased vascular wall stiffness and remodelling. This study investigated associations between a new measure of respiratory effort (percentage of total sleep time spent with increased respiratory effort based on measurement of mandibular jaw movements (MJM): REMOV, %TST) and prevalent hypertension in adults referred for evaluation of suspected OSA. METHODS: A machine learning model was built to predict hypertension from clinical data, conventional polysomnography (PSG) indices and MJM-derived parameters (including REMOV). The model was evaluated in a training subset and a test subset. RESULTS: The analysis included 1127 patients: 901 (80%) in the training subset and 226 (20%) in the test subset. The prevalence of hypertension was 31% and 30%, respectively, in the training and test subsets. A risk stratification model based on 18 input features including REMOV had good accuracy for predicting prevalent hypertension (sensitivity 0.75 and specificity 0.83). Using the Shapley additive explanation method, REMOV was the best predictor of hypertension after clinical risk factors (age, sex, body mass index and neck circumference) and time with oxygen saturation <90%, ahead of standard PSG metrics (including the apnoea-hypopnoea index and oxygen desaturation index). CONCLUSION: The proportion of sleep time spent with increased respiratory effort automatically derived from MJM was identified as a potential new reliable metric to predict prevalent hypertension in patients with OSA.

Effect of adaptive servo-ventilation for central sleep apnoea in systolic heart failure on muscle sympathetic nerve activity: a SERVE-HF randomised ancillary study.

BACKGROUND: Adaptive servo-ventilation (ASV) effectively suppresses central sleep apnoea (CSA) but has been associated with increased all-cause and cardiovascular mortality in chronic heart failure patients with reduced ventricular ejection fraction (HFrEF). All-cause and, especially, cardiovascular mortality in chronic heart failure is highly correlated with sympathetic tone. This analysis of SERVE-HF data investigated the effect of ASV on sympathetic tone in patients with HFrEF and CSA. METHODS: HFrEF patients in the SERVE-HF trial (left ventricular ejection fraction (LVEF) ≤45%, apnoea-hypopnoea index (AHI) ≥15 events·h-1 with predominant CSA) were randomly assigned to receive guideline-based heart failure treatment alone (controls) or plus ASV. For this analysis, the primary outcome was change in muscle sympathetic nerve activity (MSNA) at 3-month follow-up. The effects of baseline MSNA and change in MSNA over time on mortality in the main study were also assessed. RESULTS: 40 patients with HFrEF were included in this analysis (age 71.3±11.7 years, LVEF 34.2±7.7%, 57.5% in New York Heart Association (NYHA) Functional Class II, 42.5% in NYHA Functional Class III, AHI 35.2±11 events·h-1). Sympathetic tone evolution during follow-up did not differ between groups (controls: 47.6±8.3 bursts·min-1 at baseline to 44.6±11.2 bursts·min-1; ASV group: 43.0±9.0 bursts·min-1 at baseline to 42.74±9.45 bursts·min-1). The reduction in sympathetic tone was associated with significantly increased cardiovascular mortality in the ASV group, whereas in the control group reduced sympathetic tone appeared to be protective. CONCLUSIONS: Suppression of CSA with ASV did not seem to have a significant effect on chronic heart failure-related sympathetic activation. Simultaneous suppression of CSA and reduction in MSNA was associated with increased cardiovascular mortality.

Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the ICU: An Observational Study From the OUTCOMEREA Database, 1997-2018.

OBJECTIVES: Our aim was to describe changes in the management of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) by ICUs and patient outcomes. DESIGN: We extracted data from the OutcomeRea database concerning patients admitted for AECOPD between 1997 and 2018. We analyzed trends in the use of ventilatory support, corticosteroid therapy, antibiotic therapy, and patient survival. SETTING: ICUs at 32 French sites. PATIENTS: One thousand eight hundred sixteen patients in the database had a diagnosis of AECOPD. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Over time, there was a reduction in the prescription of corticosteroids and antibiotics. In a time-series analysis, these changes in practice were not linked with ICU mortality. The proportion of patients treated with invasive mechanical ventilation (IMV) also gradually declined (from 51% between 1997 and 2002 to 35% between 2013 and 2018) with an association between decrease in IMV use and reduction in ICU mortality in a time series analysis. Rates of noninvasive ventilation (NIV) failure decreased with an increase in NIV use to support weaning from IMV. There was a reduction in the median ICU length of stay (from 8 d in 1997-2002 to 4 d in 2013-2018) and in the median total duration of hospitalization (from 23 d in 1997-2002 to 14 d in 2013-2018). We observed an improvement in prognosis, with decreases in overall hospital mortality (from 24% between 1997 and 2002 to 15% between 2013 and 2018), ICU mortality (from 14% between 1997 and 2002 to 10% between 2013 and 2018), and 90-day mortality (from 41% between 1997 and 2002 to 22% between 2013 and 2018). CONCLUSIONS: The length of stay and mortality of patients with AECOPD admitted to ICUs has decreased over the last 20 years, with a wider use of NIV and a reduction in antibiotic and corticosteroid prescriptions.

Healthcare resource utilisation and costs in patients with treated obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a highly prevalent yet underdiagnosed disease that creates a large economic burden on the United States healthcare system. In this retrospective study, we tested the hypothesis that adherence to positive airway pressure (PAP) therapy, the 'gold standard' treatment for OSA, is associated with reduced healthcare resource utilisation and costs. We linked de-identified payer-sourced medical claims and objective PAP usage data for patients newly diagnosed with OSA. Inverse probability of treatment weighting was used to create balanced groups of patients who were either adherent, intermediately adherent, or non-adherent to PAP therapy. From a sample of 179,542 patients (average age 52.5 years, 61% male), 37% were adherent, 40% intermediate, and 23% non-adherent. During the first year, PAP adherence was significantly associated with fewer emergency room visits (mean [SD] adherent: 0.39 [1.20] versus intermediate: 0.47 [1.30], p < 0.001; versus non-adherent: 0.54 [1.44], p < 0.001), all-cause hospitalisations (mean [SD] adherent: 0.09 [0.43] versus intermediate: 0.12 [0.51], p < 0.001; versus non-adherent: 0.13 [0.55], p < 0.001), and lower total costs (mean [SD] adherent $5874 [8045] versus intermediate $6523 [9759], p < 0.001; versus non-adherent $6355 [10,517], p < 0.001). Results were similar in the second year of PAP use. These results provide additional evidence from a large, diverse sample to support the diagnosis and treatment of OSA and encourage long-term adherence to PAP therapy.

Respiratory effort during sleep and the rate of prevalent type 2 diabetes in obstructive sleep apnoea.

AIM: To determine the association between total sleep time (TST) spent in increased respiratory effort (RE) and the prevalence of type 2 diabetes in a large cohort of individuals with suspected obstructive sleep apnoea (OSA) referred for in-laboratory polysomnography (PSG). MATERIALS AND METHODS: We conducted a retrospective cross-sectional study using the clinical data of 1128 patients. Non-invasive measurements of RE were derived from the sleep mandibular jaw movements (MJM) bio-signal. An explainable machine-learning model was built to predict prevalent type 2 diabetes from clinical data, standard PSG indices, and MJM-derived parameters (including the proportion of TST spent with increased respiratory effort [REMOV [%TST]). RESULTS: Original data were randomly assigned to training (n = 853) and validation (n = 275) subsets. The classification model based on 18 input features including REMOV showed good performance for predicting prevalent type 2 diabetes (sensitivity = 0.81, specificity = 0.89). Post hoc interpretation using the Shapley additive explanation method found that a high value of REMOV was the most important risk factor associated with type 2 diabetes after traditional clinical variables (age, sex, body mass index), and ahead of standard PSG metrics including the apnoea-hypopnea and oxygen desaturation indices. CONCLUSIONS: These findings show for the first time that the proportion of sleep time spent in increased RE (assessed through MJM measurements) is an important predictor of the association with type 2 diabetes in individuals with OSA.

Prevalence of sleep apnoea in patients with type 1 diabetes and its association with comorbidities and diabetic complications: A French nationwide prospective study.

AIM: To investigate sleep apnoea prevalence, factors influencing severity, and associations between sleep apnoea severity and micro-/macrovascular complications in a large population of patients with type 1 diabetes. MATERIALS AND METHODS: This French multicentre prospective cohort study was conducted between July 2016 and June 2020. Adults with type 1 diabetes using an insulin pump were eligible. Home care provider nurses collected demographic and clinical data and set up oximetry to determine the oxygen desaturation index (ODI). No, mild-moderate and severe sleep apnoea were defined as ODI <15 events/h, 15 to <30 events/h and ≥30 events/h, respectively. Univariate and multivariate analyses were performed to identify factors associated with sleep apnoea, and associations between sleep apnoea severity and micro-/macrovascular complications were determined using logistic regression. RESULTS: Of 769 participants, 12.4% and 3.4% had mild-to-moderate or severe sleep apnoea, respectively. Factors significantly associated with sleep apnoea on multivariate analysis were age, sex, body mass index (BMI) and hypertension. After adjustment for age, sex and BMI, presence of severe sleep apnoea was significantly associated with macrovascular complications (odds ratio vs. no sleep apnoea: 3.96 [95% confidence interval 1.43-11.11]; P < 0.01), while mild-to-moderate sleep apnoea was significantly associated with presence of diabetic retinopathy (odds ratio 2.09 [95% confidence interval 1.10-3.74]; P < 0.01). CONCLUSION: Sleep apnoea is a significant comorbidity in patients with type 1 diabetes, especially with respect to diabetic complications. This highlights the need for sleep apnoea screening and management in these individuals.

Obstructive sleep apnea: a major risk factor for COVID-19 encephalopathy?

BACKGROUND: This study evaluates the impact of high risk of obstructive sleep apnea (OSA) on coronavirus disease 2019 (COVID-19) acute encephalopathy (AE). METHODS: Between 3/1/2020 and 11/1/2021, 97 consecutive patients were evaluated at the Geneva University Hospitals with a neurological diagnosis of COVID-19 AE. They were divided in two groups depending on the presence or absence of high risk for OSA based on the modified NOSAS score (mNOSAS, respectively ≥ 8 and < 8). We compared patients' characteristics (clinical, biological, brain MRI, EEG, pulmonary CT). The severity of COVID-19 AE relied on the RASS and CAM scores. RESULTS: Most COVID-19 AE patients presented with a high mNOSAS, suggesting high risk of OSA (> 80%). Patients with a high mNOSAS had a more severe form of COVID-19 AE (84.8% versus 27.8%), longer mean duration of COVID-19 AE (27.9 versus 16.9 days), higher mRS at discharge (≥ 3 in 58.2% versus 16.7%), and increased prevalence of brain vessels enhancement (98.1% versus 20.0%). High risk of OSA was associated with a 14 fold increased risk of developing a severe COVID-19 AE (OR = 14.52). DISCUSSION: These observations suggest an association between high risk of OSA and COVID-19 AE severity. High risk of OSA could be a predisposing factor leading to severe COVID-19 AE and consecutive long-term sequalae.

Non-ventilator-associated ICU-acquired pneumonia (NV-ICU-AP) in patients with acute exacerbation of COPD: From the French OUTCOMEREA cohort.

BACKGROUND: Non-ventilator-associated ICU-acquired pneumonia (NV-ICU-AP), a nosocomial pneumonia that is not related to invasive mechanical ventilation (IMV), has been less studied than ventilator-associated pneumonia, and never in the context of patients in an ICU for severe acute exacerbation of chronic obstructive pulmonary disease (AECOPD), a common cause of ICU admission. This study aimed to determine the factors associated with NV-ICU-AP occurrence and assess the association between NV-ICU-AP and the outcomes of these patients. METHODS: Data were extracted from the French ICU database, OutcomeRea™. Using survival analyses with competing risk management, we sought the factors associated with the occurrence of NV-ICU-AP. Then we assessed the association between NV-ICU-AP and mortality, intubation rates, and length of stay in the ICU. RESULTS: Of the 844 COPD exacerbations managed in ICUs without immediate IMV, NV-ICU-AP occurred in 42 patients (5%) with an incidence density of 10.8 per 1,000 patient-days. In multivariate analysis, prescription of antibiotics at ICU admission (sHR, 0.45 [0.23; 0.86], p = 0.02) and no decrease in consciousness (sHR, 0.35 [0.16; 0.76]; p < 0.01) were associated with a lower risk of NV-ICU-AP. After adjusting for confounders, NV-ICU-AP was associated with increased 28-day mortality (HR = 3.03 [1.36; 6.73]; p < 0.01), an increased risk of intubation (csHR, 5.00 [2.54; 9.85]; p < 0.01) and with a 10-day increase in ICU length of stay (p < 0.01). CONCLUSION: We found that NV-ICU-AP incidence reached 10.8/1000 patient-days and was associated with increased risks of intubation, 28-day mortality, and longer stay for patients admitted with AECOPD.

Impact of Positive Airway Pressure Therapy Adherence on Outcomes in Patients with Obstructive Sleep Apnea and Chronic Obstructive Pulmonary Disease.

Rationale: The co-occurrence of obstructive sleep apnea and chronic obstructive pulmonary disease, termed overlap syndrome, has a poor prognosis. However, data on positive airway pressure (PAP) treatments and their impact on outcomes and costs are lacking. Objectives: This retrospective observational study investigated the effects of PAP on health outcomes, resource usage, and costs in patients with overlap syndrome. Methods: Deidentified adjudicated claims data for patients with overlap syndrome in the United States were linked to objectively measured PAP user data. Patients were considered adherent to PAP therapy if they met Centers for Medicare and Medicaid Services criteria for eight 90-day timeframes from device setup through 2-year follow-up. Propensity score matching was used to create comparable groups of adherent and nonadherent patients. Healthcare resource usage was based on the number of doctor visits, all-cause emergency room visits, all-cause hospitalizations, and PAP equipment and supplies, and proxy costs were obtained. Measurements and Main Results: A total of 6,810 patients were included (mean age, 60.8 yr; 56% female); 2,328 were nonadherent. Compared with the year before therapy, there were significant reductions in the number of emergency room visits, hospitalizations, and severe acute exacerbations during 2 years of PAP therapy in patients who were versus were not adherent (all P < 0.001). This improvement in health status was paralleled by a significant reduction in the associated healthcare costs. Conclusions: PAP usage by patients with overlap syndrome was associated with reduced all-cause hospitalizations and emergency room visits, severe acute exacerbations, and healthcare costs.

Loss of Blood-Brain Barrier Integrity in an In Vitro Model Subjected to Intermittent Hypoxia: Is Reversion Possible with a HIF-1α Pathway Inhibitor?

Several sleep-related breathing disorders provoke repeated hypoxia stresses, which potentially lead to neurological diseases, such as cognitive impairment. Nevertheless, consequences of repeated intermittent hypoxia on the blood-brain barrier (BBB) are less recognized. This study compared two methods of intermittent hypoxia induction on the cerebral endothelium of the BBB: one using hydralazine and the other using a hypoxia chamber. These cycles were performed on an endothelial cell and astrocyte coculture model. Na-Fl permeability, tight junction protein, and ABC transporters (P-gp and MRP-1) content were evaluated with or without HIF-1 inhibitors YC-1. Our results demonstrated that hydralazine as well as intermittent physical hypoxia progressively altered BBB integrity, as shown by an increase in Na-Fl permeability. This alteration was accompanied by a decrease in concentration of tight junction proteins ZO-1 and claudin-5. In turn, microvascular endothelial cells up-regulated the expression of P-gp and MRP-1. An alteration was also found under hydralazine after the third cycle. On the other hand, the third intermittent hypoxia exposure showed a preservation of BBB characteristics. Furthermore, inhibition of HIF-1α with YC-1 prevented BBB dysfunction after hydralazine treatment. In the case of physical intermittent hypoxia, we observed an incomplete reversion suggesting that other biological mechanisms may be involved in BBB dysfunction. In conclusion, intermittent hypoxia led to an alteration of the BBB model with an adaptation observed after the third cycle.

Differential Impact of Intermittent vs. Sustained Hypoxia on HIF-1, VEGF and Proliferation of HepG2 Cells.

Obstructive sleep apnea (OSA) is an emerging risk factor for cancer occurrence and progression, mainly mediated by intermittent hypoxia (IH). Systemic IH, a main landmark of OSA, and local sustained hypoxia (SH), a classical feature at the core of tumors, may act separately or synergistically on tumor cells. Our aim was to compare the respective consequences of intermittent and sustained hypoxia on HIF-1, endothelin-1 and VEGF expression and on cell proliferation and migration in HepG2 liver tumor cells. Wound healing, spheroid expansion, proliferation and migration were evaluated in HepG2 cells following IH or SH exposure. The HIF-1α, endothelin-1 and VEGF protein levels and/or mRNA expression were assessed, as were the effects of HIF-1 (acriflavine), endothelin-1 (macitentan) and VEGF (pazopanib) inhibition. Both SH and IH stimulated wound healing, spheroid expansion and proliferation of HepG2 cells. HIF-1 and VEGF, but not endothelin-1, expression increased with IH exposure but not with SH exposure. Acriflavine prevented the effects of both IH and SH, and pazopanib blocked those of IH but not those of SH. Macitentan had no impact. Thus, IH and SH stimulate hepatic cancer cell proliferation via distinct signaling pathways that may act synergistically in OSA patients with cancer, leading to enhanced tumor progression.

Sleep-disordered breathing and ventilatory chemosensitivity in first ischaemic stroke patients: a prospective cohort study.

RATIONALE: Sleep-disordered breathing (SDB) is highly prevalent after stroke. The clinical and ventilatory chemosensitivity characteristics of SDB, namely obstructive, central and coexisting obstructive and central sleep apnoea (coexisting sleep apnoea) following stroke are poorly described. OBJECTIVE: To determine the respective clinical and ventilatory chemosensitivity characteristics of SDB at least 3 months after a first ischaemic stroke. METHODS: Cross-sectional analysis of a prospective, monocentric cohort conducted in a university hospital. 380 consecutive stroke or transient ischaemic attack patients were screened between December 2016 and December 2019. MEASUREMENTS AND MAIN RESULTS: Full-night polysomnography, and hypercapnic ventilatory response were performed at a median (Q1; Q3) time from stroke onset of 134.5 (97.0; 227.3) days. 185 first-time stroke patients were included in the analysis. 94 (50.8%) patients presented no or mild SDB (Apnoea-Hypopnoea Index <15 events/hour of sleep) and 91 (49.2%) moderate to severe SDB, of which 52 (57.1%) presented obstructive sleep apnoea and 39 (42.9%) coexisting or central sleep apnoea. Obstructive sleep apnoea patients significantly differed regarding their clinical presentation from patients with no or mild SDB, whereas there was no difference with coexisting and central sleep apnoea patients. The latter presented a higher frequency of cerebellar lesions along with a heightened hypercapnic ventilatory response compared with no or mild SDB patients. CONCLUSION: SDB in first-time stroke patients differ in their presentation by their respective clinical traits and ventilatory chemosensitivity characteristics. The heightened hypercapnic ventilatory response in coexisting and central sleep apnoea stroke patients may orientate them to specific ventilatory support.

Adaptive servo ventilation for sleep apnoea in heart failure: the FACE study 3-month data.

RATIONALE: Adaptive servo ventilation (ASV) is contraindicated in patients with systolic heart failure (HF) who have a left ventricular ejection fraction (LVEF) below 45% and predominant central sleep apnoea (CSA). However, the effects of ASV in other HF subgroups have not been clearly defined. OBJECTIVE: The European, multicentre, prospective, observational cohort trial, FACE, evaluated the effects of ASV therapy on morbidity and mortality in patients with HF with sleep-disordered breathing (SDB); 3-month outcomes in patient subgroups defined using latent class analysis (LCA) are presented. METHODS: Consecutive patients with HF with predominant CSA (±obstructive sleep apnoea) indicated for ASV were included from 2009 to 2018; the non-ASV group included patients who refused/were noncompliant with ASV. The primary endpoint was time to composite first event (all-cause death, lifesaving cardiovascular intervention or unplanned hospitalisation for worsening of chronic HF). MEASUREMENTS AND MAIN RESULTS: Baseline assessments were performed in 503 patients, and 482 underwent 3-month follow-up. LCA identified six discrete patient clusters characterised by variations in LVEF, SDB type, age, comorbidities and ASV acceptance. The 3- month rate of primary outcome events was significantly higher in cluster 1 patients (predominantly men, low LVEF, severe HF, CSA; 13.9% vs 1.5%-5% in other clusters, p<0.01). CONCLUSION: For the first time, our data identified homogeneous patient clusters representing clinically relevant subgroups relating to SDB management in patients with HF with different ASV usage, each with a different prognosis. This may improve patient phenotyping in clinical practice and allow individualisation of therapy.