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Background: The "Baveno classification" replaced the apnoea-hypopnoea index (AHI) with symptoms and comorbidities for treatment indication in obstructive sleep apnoea (OSA). This study evaluates a modified Baveno classification which adds a validated cardiovascular disease (CVD) risk score and acknowledges severe breathing disturbances., Method: OSA patients from the European Sleep Apnoea Database (ESADA) were retrospectively allocated into CVD risk groups 1-3 based on the SCORE2 risk prediction model and European Society of Cardiology guidelines. AHI ≥30 events·h -1 conferred strong treatment indication. When AHI was <30 events·h -1 , symptoms and CVD risk dictated allocation to the weak, intermediate or strong treatment indication group. Changes in Epworth Sleepiness Scale (ESS) score and office systolic blood pressure (SBP) at follow-up (12-24 months) under positive airway pressure (PAP) were assessed., Results: 8625 patients were analysed (29% female; median (interquartile range) age 56 (49-64) years and body mass index 31.9 (28.4-36.3) kg·m -2 ). Treatment indication was weak in 501 (6%), intermediate in 2085 (24%) and strong in 6039 (70%). There was a continuous increase in age, SBP, C-reactive protein and glycosylated haemoglobin from weak to strong (p<0.001). PAP prescription increased from 52% to 64% to 93% (weak to strong; p<0.001). The change in ESS score was -2, -4 and -5, respectively (p<0.001). Reductions of ≥3 mmHg median SBP occurred when AHI was ≥30 events·h -1 and in symptomatic patients with CVD risk levels >1 when AHI was <30 events·h -1 ., Conclusion: This analysis provides supporting evidence for the key role of CVD risk assessment and severe breathing disturbances in the identification of OSA patients most likely to benefit from treatment., Competing Interests: Conflict of interest: S. Matthes reports travel grants from Chiesi and Boehringer. L. Grote has performed educational activities for AstraZeneca, Lundbeck, ResMed, Philipps and Itamar, has interests in two patents licensed to Desitin GMBH, and provides medical advice to Onera BV. J. Hedner has provided scientific advice to SomnoMed and is a part owner of two patents, outside the submitted work. J-L. Pépin is funded by the French National Research Agency in the framework of the “Investissements d'avenir” programme (ANR-15-IDEX-02) and “e-health and integrated care and trajectories medicine and MIAI artificial intelligence” (ANR-19-P3IA-0003) Chairs of excellence from the Grenoble Alpes University; and reports income related to medical education from ResMed, Bioprojet, Jazz and Zoll. W.T. McNicholas reports participation in the Horizon 2020 research and innovation programme under grant agreement number 965417: Sleep Revolution, and is a board member at ESRS. J. Verbraecken reports grants and fees from SomnoMed, AirLiquide, Atos Medical, Vivisol, Mediq Tefa, Medidis, Micromed OSG, Bioprojet, Desitin, Epilog, Idorsia, Inspire Medical Systems, Löwenstein Medical, Ectosense, Philips, ProSomnus, ResMed, Sefam, SD Worx, SOS Oxygène, Tilman, Total Care, Vlaamse Gemeenschap, Vlerick and Zoll Itamar, outside the submitted work, and consultancy for Bioprojet and Epilog. G. Parati reports honoraria for lectures from Omron, SOMNOmedics, Merck and ReCor. W.J. Randerath reports grants and personal fees from Philips Respironics, Loewenstein Medical, ResMed, Bayer Vital, Bioprojet and Vanda Pharma, outside the submitted work. The remaining authors have no potential conflicts of interest to disclose., (Copyright ©The authors 2024. For reproduction rights and permissions contact permissions@ersnet.org.)

Introduction: The Swedish Sleep Apnea Registry (SESAR) collects clinical data from individual obstructive sleep apnea (OSA) patients since 2010. SESAR has recently been integrated with additional national healthcare data. The current analysis presents the SESAR structure and representative clinical data of a national sleep apnea cohort., Methods: Clinical data from unselected patients with a diagnosis of OSA are submitted to the SESAR registry. 48 sleep centers report data from diagnosis, treatment starts with Continuous Positive Airway Pressure (CPAP), oral devices (OD), and Upper Airway Surgery (UAS). Data from follow-up are included. SESAR is linked to mandatory national healthcare data (mortality, comorbidities, procedures, prescriptions) and diagnosis-specific quality registries (e.g. stroke, heart failure, diabetes) within the DISCOVERY project., Results: 83,404 OSA patients have been reported during the diagnostic workup (age 55.4 ± 14.1 years, BMI 30.8 ± 6.5 kg/m 2 , AHI 25.8 ± 21.6n/h, respectively). At least one cardiometabolic and respiratory comorbidity is recognized in 57 % of female and 53 % of male OSA patients with a linear increase across OSA severity. In 54,468, 7,797, and 390 patients, start of CPAP, OD or UAS treatment is reported, respectively. OD patients have 4 units lower BMI and 10 units lower AHI compared to patients started on CPAP. UAS patients are characterized by 10 years lower age. The degree of daytime sleepiness is comparable between treatment groups with mean Epworth Sleepiness Scale Scores between 9 and 10., Conclusion: SESAR is introduced as a large national registry of OSA patients. SESAR provides a useful tool to highlight OSA management and to perform relevant outcome research., Competing Interests: Declaration of competing interest The authors declare participation in the steering committees for the SESAR and/or the Swedevox registries. Outside the submitted work, LG has received unrestricted institutional grants for the ESADA collaboration from RESMED; RESPIRONICS and BAYER AG. LG has lectured for Itamar, Lundbeck, Astra Zeneca, Resmed, and Respironics. LG owns shares of a company which has licensed a patent for pharmacological OSA therapy to Desitin GMBH. Outside the submitted work, ME has received a research grant from ResMed and personal fees from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche. Outside the submitted work, JH has received unrestricted institutional grants for maintenance of the ESADA collaboration from RESMED; RESPIRONICS and BAYER AG. JH has lectured for Itamar, Astra Zeneca, Resmed, and Somnomed. JH is part owner of a company which has licensed a patent for pharmacological OSA therapy to Desitin GMBH., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Obstructive sleep apnoea (OSA) and its associations with lung function., Background: OSA is highly prevalent and characterised by abnormal respiration during sleep. This large, population-based study aimed to investigate the associations between OSA and lung function in subjects aged 50-64 years., Method: The population-based Swedish CArdioPulmonary bioimage Study includes information on anthropometry, comorbidities and spirometry. The current analysis included data from three centres (Gothenburg, Umeå and Uppsala) on whole-night respiratory polygraphy as a meta-analysis examining the overall effect size of lung function on sleep apnoea severity, expressed as ß-coefficient after stratifying for sex and adjusting for age, waist circumference and smoking status., Results: Data from 9016 participants (54% women, age 58±4 years, body mass index 27±4 kg/m 2 ) with sleep recordings of good quality were included in the final analysis. Forced expiratory volume during 1 s (FEV 1 ) (ß=-0.10 (95% CI -0.16 to -0.03)), forced vital capacity (FVC) (-0.15 (-0.21 to -0.10)) and diffusion capacity for carbon monoxide (DL CO ) (-0.08 (-0.10 to -0.05)) were all negatively associated with the oxygen desaturation index (ODI) and also with per cent of registration with nocturnal oxygen saturation <90% FVC (-0.44 (-0.87 to -0.01)), FEV 1 (-0.86 (-1.36 to -0.36)) and DL CO (-0.47 (-0.60 to -0.35)). Additionally, a positive association was observed between FEV 1 (0.13 (0.05 to 0.22)) and DL CO (0.07 (0.04 to 0.09)) with the mean nocturnal saturation. There was a negative association between DL CO and apnoea-hypopnoea index, AHI, (ß=-0.04 (95% CI-0.06 to -0.03)), while no associations were found between FEV 1 or FVC and AHI., Conclusion: In OSA, lower lung function is more distinctly associated with the nocturnal hypoxic burden than AHI. Potential lung function impairment should be investigated in OSA patients with a high ODI relative to AHI., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The carbonic anhydrase inhibitor sulthiame reduces OSA severity, increases overnight oxygenation, and improves sleep quality. Insights into how sulthiame modulates OSA pathophysiologic features (endotypic traits) adds to our understanding of the breathing disorder itself, as well as the effects of carbonic anhydrases in respiratory regulation., Research Question: How does sulthiame treatment modify endotypic traits in OSA?, Study Design and Methods: Per-protocol tertiary analysis of a randomized controlled trial with the inclusion criteria as follow: BMI, ≥ 20 to ≤ 35 kg/m 2 ; age, 18-75 years; apnea-hypopnea index (AHI) ≥ 15 events/h; Epworth sleepiness scale score, ≥ 6; as well as nonacceptance or nontolerance of positive airway pressure treatment. Patients were randomized to receive placebo (n = 22), sulthiame 200 mg (n = 12), or sulthiame 400 mg (n = 24) during 4 weeks of treatment. Polysomnography was applied twice at baseline and follow-up. Endotypic traits were determined from polysomnography tracings (PUPBeta). Sulthiame plasma concentration was analyzed. Differences from baseline to follow-up (Δs) were analyzed with the analysis of covariance or Kruskal-Wallis H test and Pearson (r) or Spearman correlations (r s )., Results: Sulthiame (200-mg and 400-mg groups) consistently reduced loop gain (response to a 1-cycle/min disturbance, LG 1 ; mean, -0.16 [95% CI, -0.18 to -0.13]; P < .05) in addition to increased ventilation at lowest decile of ventilatory drive (V min ; median, +12 [95% CI, 4-20]; P < .05) and median ventilation at eupneic ventilatory drive (V passive ; median, +4 [95% CI, 0-5]; P < .05). ΔLG 1 correlated with ΔAHI percentage (200 mg: r = 0.65; P < .05). V min and V passive correlated with ΔAHI (all sulthiame: r s  = -0.59 and r s  = -0.65; P < .05 for all). The reduction of LG 1 was seen already in the lower sulthiame concentration range, whereas changes in V min peaked in the higher range., Interpretation: The effect of sulthiame in OSA may be explained by a reduction of ventilatory instability (LG 1 ) as well as upper airway collapsibility (V min and V passive )., Trial Registry: European Union Drug Regulating Authorities Clinical Trials Database; No.: EudraCT 2017-004767-13; URL: https://www.clinicaltrialsregister.eu., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: L. G. reports speakers bureau for ResMed Inc, Philips, Lundbeck, and Astra Zeneca outside the scope of the current work. J. H. participated in the DSMB for Respicardia. L. G. and J. H. received unrestricted grants on behalf of the ESADA group from ResMed, Inc., and Philips Respironics, and research grants from Bayer Pharma and Desitin GmbH. L. G., K. S., and J. H. are part owner of two patents related to sleep apnea therapy. None declared (E. H., C. S., D. Z.)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In people with OSA, excessive daytime sleepiness is a prominent symptom and can persist despite adherence to CPAP, the first-line therapy for OSA. Pitolisant was effective in reducing daytime sleepiness in two 12-week randomized controlled trials (RCTs), one in patients adherent to CPAP (BF2.649 in Patients With OSA and Treated by CPAP But Still Complaining of EDS [HAROSA 1]) and the other in patients refusing or not tolerating CPAP (BF2.649 in Patients With OSA, Still Complaining of EDS and Refusing to be Treated by CPAP [HAROSA 2])., Research Question: Does the efficacy and safety of pitolisant persist when these patients take it long-term?, Study Design and Methods: All adults included in the HAROSA 1 and HAROSA 2 RCTs (both pitolisant and placebo arms) were offered pitolisant (up to 20 mg/d) after completion of the short-term double-anonymized phase (ie, from week 13) in an open-label cohort study. The primary efficacy outcome was the change in Epworth Sleepiness Scale score between baseline and week 52. Safety outcomes were treatment-emergent adverse event(s) (TEAE[s]), serious TEAEs, and special interest TEAEs., Results: Out of 512 adults included in the two RCTs, 376 completed the 1-year follow-up. The pooled mean difference in Epworth Sleepiness Scale score from baseline to 1 year for the intention-to-treat sample was -8.0 (95% CI, -8.3 to -7.5). The overall proportions of TEAEs, serious TEAEs, and TEAEs of special interest were 35.1%, 2.0%, and 11.1%, respectively, without any significant difference between patients in the initial pitolisant and placebo arms. No cardiovascular safety issues were reported., Interpretation: Pitolisant is effective in reducing daytime sleepiness over 1 year in adults with OSA, with or without CPAP treatment. Taken for 1 year, it has a good safety profile (including cardiovascular)., Trial Registration: ClinicalTrials.gov; Nos.: NCT01071876 and NCT01072968; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J.-L. P. reports administrative support and APC from Bioprojet during the conduct of the study; research grants from Agiradom, Air Liquide Foundation, Astra Zeneca, Bioprojet, Jazz Pharmaceuticals, Philips, Resmed, Sefam, and Vitalaire, outside the reported work; and honoraria or consultation fees from Agiradom, Somnomed, Bioprojet, ITAMAR, Jazz Pharmaceuticals, Philips, Resmed, and SEFAM, outside the reported work. C. C. is an employee of Bioprojet. Outside the reported work, J. V. has received institutional fees and educational grants from AirLiquide, AstraZen, Bekaert Deslee Academy, Bioprojet, Desitin, Ectosense, Epilog, Fisher & Paykel, Heinen & Löwenstein, Idorsia, Inspire, Jazz Pharmaceutics, Medidis, Mediq Tefa, OSG, Philips, ResMed, Sefam, SomnoMed, Total Care, UCB Pharma, Vivisol, and Westfalen Medical. Outside the reported work, R. T. reports research grants paid to his institution (Resmed, Inspire, BioProjet); personal lecture fees from Périmetres, Philips, Resmed, Jazz Pharmaceutical, and Bioprojet; and participation in advisory boards of Narval (Resmed), Bioprojet, and Idorsia. I. L. is an employee and shareholder of Bioprojet. Y. D. reports grants from Bioprojet, during the conduct of the study; and grants and/or consulting fees from UCB, JAZZ, Takeda, Theranexus, Harmony bioscience, Avadel, Paladin, and Idorsia, outside the submitted work. P. Lehert was a consultant statistician for Bioprojet during the conduct of the study; and is a consultant statistician for Merck, Sanofi, and Aguettant Pharma, outside the submitted work. None declared (V. A., J. H., and P. Lévy)., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale: Positive airway pressure (PAP) is standard treatment for obstructive sleep apnea. Telemedicine has been introduced for improved PAP follow-up. Objectives: Our study aim was to evaluate the clinical utility of and patient satisfaction with PAP follow-up with an early intervention telemedical protocol. Methods: A randomized controlled trial was conducted at four sleep clinics of the same county. Treatment-naive patients with obstructive sleep apnea were randomized to standard PAP follow-up (203 patients, fixed follow-up procedures) or early intervention telemedical follow-up (AirView, ResMed; 206 patients, continuous follow-up) for 3 months. Evaluated variables included PAP adherence at 3 months, patient-reported outcome measures (Epworth Sleepiness Scale, 36-item Short Form Health Survey, Insomnia Severity Index, Hospital Anxiety and Depression Scale), and staff time. Group differences were analyzed with linear mixed regression models adjusted for age, body mass index, apnea-hypopnea index, and study center. Results: The study groups were comparable at baseline ( N  = 409; mean age, 59 ± 12 yr; body mass index, 31.9 ± 6 kg/m 2 , apnea-hypopnea index, 41.5 ± 21 events/h). PAP adherence was higher in the proactive telemedicine group than in the control group (4.3 ± 2.4 and 4.1 ± 2.6 h/night; P  = 0.01, respectively), and mean mask pressure at follow-up was significantly lower in the telemedicine group than in the control group (8.7 ± 2.1 cm H 2 O vs. 9.2 ± 2.5 cm H 2 O; P  = 0.028). In post hoc analysis, the difference in PAP adherence between groups was most pronounced in patients with depression (4.8 ± 2.6 h/night vs. 2.7 ± 2.3 h/night; P  = 0.03). Relevant mask leakage (>24 L/min) was lower in the telemedicine group (5.4% vs. 12.1%, P  = 0.024). Improvement of patient-reported outcome measures and patient satisfaction was equivalent between groups. Conclusions: Proactive telemedical management of the initial follow-up of PAP treatment compared favorably with conventional follow-up in terms of adherence, pressure level, and mask leakage. Patients with depression may particularly benefit from telemedical follow-up. Specific clinical routines are required to establish this practice in sleep clinics. Clinical trial registered with www.clinicaltrials.gov (NCT03446560).

We recruited 5,970 hypertensive patients with obstructive sleep apnea (OSA) on current antihypertensive treatment from the European Sleep Apnea Database (ESADA) cohort. The group was subdivided into those receiving monotherapy (n = 3,594) and those receiving dual combined therapy (n = 2,376). We studied how major OSA confounders like age, gender, and body mass index as well as the degree of sleep apnea modified office systolic and diastolic blood pressure. Beta-blockers alone or in combination with a diuretic were compared with other antihypertensive drug classes. Monotherapy with beta-blocker was associated with lower systolic blood pressure, particularly in non-obese middle-aged males with hypertension. Conversely, the combination of a beta-blocker and a diuretic was associated with lower systolic and diastolic blood pressure in hypertensive patients with moderate-severe OSA. Systolic blood pressure was better controlled in female patients using this combined treatment. Our cross-sectional data suggest that specific clinical characteristics and type of antihypertensive medication influence the degree of blood pressure control in hypertensive OSA patients. Controlled trials are warranted., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Objective: New drug treatments are under development in obstructive sleep apnea (OSA). The placebo effect is well recognized in various conditions, but its relevance in OSA is debated. In the current study we determined the influence of a placebo effect in studies of drug therapy in OSA., Methods: A systematic review and meta-analysis (PROSPERO CRD42021229410) with searches in MEDLINE, Scopus, Web of Science and Cochrane CENTRAL from inception to 2021-01-19. Inclusion criteria were (i) RCTs of adults with OSA, (ii) drug intervention with placebo baseline and follow-up sleep study (iii) outcomes: apnea hypopnea index (AHI), mean oxygen saturation (mSaO 2 ), oxygen desaturation index (ODI) and/or Epworth Sleepiness Scale (ESS). Risk-of-bias was assessed with Cochrane RoB 2., Results: 7436 articles were identified and 29 studies included (n = 413). Studies were generally small (median n = 14), with 78% men, baseline AHI range 9-74 events/h and treatment duration range 1-120 days. Meta-analyses were conducted for main outcomes. Mean change of the primary outcome, AHI, was -0.84 (95% CI -2.98 to 1.30); mSaO 2 and ODI estimations were also non-significant. ESS showed a trend towards a reduction of -1 unit. Subgroup analysis did not show significant differences. Risk-of-bias assessment indicated mostly low risk but studies were small with wide confidence intervals., Conclusions: In this meta-analysis we did not identify systematic placebo effects on the AHI, ODI or mSaO 2 while ESS score showed a trend for a small reduction. These results have an impact on the design and interpretation of drug trials in OSA., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Emerging data suggest that determination of physiologic endotypic traits (eg, loop gain) may enable precision medicine in OSA., Research Question: Does a single-night assessment of polysomnography-derived endotypic traits provide reliable estimates in moderate to severe OSA?, Study Design and Methods: Two consecutive in-lab polysomnography tests from a clinical trial (n = 67; male, 69%; mean ± SD age, 61 ± 10 years; apnea-hypopnea index [AHI] 53 ± 22 events/h) were used for the reliability analysis. Endotypic traits, reflecting upper airway collapsibility (ventilation at eupneic drive [V passive ]), upper airway dilator muscle tone (ventilation at the arousal threshold [V active ]), loop gain (stability of ventilatory control, LG1), and arousal threshold (ArTh) were determined. Reliability was expressed as an intraclass correlation coefficient (ICC). Minimal detectable differences (MDDs) were computed to provide an estimate of maximum spontaneous variability. Further assessment across four repeated polysomnography tests was performed in a subcohort (n = 22)., Results: Reliability of endotypic traits between the two consecutive nights was moderate to good (ICC: V passive  = 0.82, V active  = 0.76, LG1 = 0.72, ArTh = 0.83). Variability in AHI, but not in body position or in sleep stages, was associated with fluctuations in V passive and V active (r = -0.49 and r = -0.41, respectively; P < .001 for both). MDDs for single-night assessments were: V passive  = 22, V active  = 34, LG1 = 0.17, and ArTh = 21. Multiple assessments (mean of two nights, n = 22) further reduced MDDs by approximately 20% to 30%., Interpretation: Endotypic trait analysis using a single standard polysomnography shows acceptable reliability and reproducibility in patients with moderate to severe OSA. The reported MDDs of endotypic traits may facilitate the quantification of relevant changes and may guide future evaluation of interventions in OSA., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Blood bicarbonate concentration plays an important role for obstructive sleep apnea (OSA) patients to maintain acid-base balance. We investigated the association between arterial standard bicarbonate ([HCO3 - ]) and nocturnal hypoxia as well as comorbid hypertension in OSA., Methods: A cross-sectional analysis of 3329 patients in the European Sleep Apnea Database (ESADA) was performed. Arterial blood gas analysis and lung function test were performed in conjunction with polysomnographic sleep studies. The 4% oxygen desaturation index (ODI), mean and minimum oxygen saturation (SpO 2 ), and percentage of time with SpO 2 below 90% (T90%) were used to reflect nocturnal hypoxic burden. Arterial hypertension was defined as a physician diagnosis of hypertension with ongoing antihypertensive medication. Hypertensive patients with SBP/DBP below or above 140/90 mmHg were classified as controlled-, uncontrolled hypertension, respectively., Results: The [HCO3 - ] level was normal in most patients (average 24.0 ± 2.5 mmol/L). ODI, T90% increased whereas mean and minimum SpO 2 decreased across [HCO3 - ] tertiles (ANOVA, p = 0.030, <0.001, <0.001, and <0.001, respectively). [HCO3 - ] was independently associated with ODI, mean SpO 2 , minimum SpO 2 , and T90% after adjusting for confounders (β value [95%CI]: 1.21 [0.88-1.54], -0.16 [-0.20 to -0.11], -0.51 [-0.64 to -0.37], 1.76 [1.48-2.04], respectively, all p < 0.001). 1 mmol/L elevation of [HCO3 - ] was associated with a 4% increased odds of uncontrolled hypertension (OR: 1.04 [1.01-1.08], p = 0.013)., Conclusion: We first demonstrated an independent association between [HCO3 - ] and nocturnal hypoxic burden as well as uncontrolled hypertension in OSA patients. Bicarbonate levels as an adjunctive measure provide insight into the pathophysiology of hypertension in OSA., Competing Interests: Declaration of competing interest DZ, OKB, JV, SS, P. Sliwinski, P. Steiropoulos, CL, HH, JLP, GP, and WTM declare no competing interests related the current work. LG reports grants from Bayer, Philips Respironics Foundation, ResMed Foundation for the ESADA network during the conduct of the study. JH reports grants from ResMed, Respironics, European Respiratory Society and Bayer, during the conduct of the study., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: This analysis characterized changes in weight in participants with obstructive sleep apnea (OSA) or narcolepsy treated with solriamfetol (Sunosi™) 37.5 (OSA only), 75, 150, or 300 mg/d., Methods: In two 12-week, randomized, placebo-controlled trials and one 1-year open-label extension study, changes in weight were evaluated from baseline to end of study (week 12 or week 40 of the open-label extension [after up to 52 weeks of solriamfetol treatment]) in participants with OSA or narcolepsy., Results: After 12 weeks of solriamfetol treatment, median percent change in weight from baseline across all solriamfetol doses was -0.84%, compared with 0.54% for placebo, in participants with OSA; and -0.07%, compared with 3.08% for placebo, in participants with narcolepsy. After up to 52 weeks of solriamfetol treatment, overall median percent change in weight from baseline was -1.76%, which showed a dose-dependent pattern (75 mg, 0.57%; 150 mg, -1.2%; 300 mg, -2.5%). Results were similar in subgroups of participants with OSA or narcolepsy, with overall median percent changes in weight of -2.2% and -1.1%, respectively. After up to 52 weeks of solriamfetol treatment, the percentage of participants with weight loss ≥5% relative to baseline was 25.7% overall and increased in a dose-dependent manner (75 mg, 4.5%; 150 mg, 17.3%; 300 mg, 32.4%). Results were similar among subgroups of participants with OSA or narcolepsy, with 26.4% and 24.2% of participants experiencing weight loss ≥5%, respectively. No weight-related treatment-emergent adverse events were serious., Conclusions: Solriamfetol treatment was associated with decreases in body weight in a dose-related manner., Competing Interests: Declaration of competing interest A Malhotra has served as a principal investigator for a Jazz study. He is funded by the NIH and reports income related to medical education from Jazz, Livanova, Equillium and Corvus. ResMed gave a philanthropic donation to the University of California, San Diego, in support of a sleep center. PJ Strollo, Jr has received consultancy fees and honoraria from Inspire Medical Systems, ResMed, Philips-Respironics, Emmi Solutions, Jazz Pharmaceuticals, and Itamar; has received research funding from the National Institutes of Health and Inspire Medical Systems; and has a provisional patent for positive airway pressure with integrated oxygen. J-L Pepin has received lecture fees or conference traveling grants from Resmed, Perimetre, Philips, Fisher and Paykel, AstraZeneca, Jazz Pharmaceuticals, Agiradom, and Teva, and has received unrestricted research funding from ResMed, Philips, GlaxoSmithKline, Bioprojet, Fondation de la Recherche Medicale (Foundation for Medical Research), Direction de la Recherche Clinique du CHU de Grenoble (Research Branch Clinic CHU de Grenoble), and fond de dotation “Agir pour les Maladies Chroniques” (endowment fund “Acting for Chronic Diseases”). P Schweitzer has received consultancy fees from Jazz Pharmaceuticals and Apnimed. Her institution has received research funding from Apnimed, Avadel, Jazz Pharmaceuticals, Inspire Medical Systems, and Suven Life Sciences. GJ Lammers has received consultancy fees and/or honoraria and has been a speakers’ bureau member and/or an advisory board participant for UCB Pharma, Bioprojet, Theranexus, and Jazz Pharmaceuticals. J Hedner has served on the speakers’ bureaus for AstraZeneca, Philips Respironics, Itamar Medical, and BresoTec, and serves as a board member for Cereus Pharma. S Redline: has received grant support and consulting fees from Jazz Pharma as well as consulting fees from Eisai Inc, Eli Lilly Inc, and Respicardia Inc. D Chen and P Chandler are employees of Jazz Pharmaceuticals who, in the course of this employment, have received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. S Bujanover is a former employee of Jazz Pharmaceuticals who, in the course of this employment, received stock options exercisable for, and other stock awards of, ordinary shares of Jazz Pharmaceuticals plc. K Strohl has served as an advisory board member and is a principal investigator for Jazz; is a site principal investigator for Inspire Medical Systems; and has received consultancy fees from Sommetrics, GSK (Galvani Bioelectronics), and Seven Dreamers., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Excessive daytime sleepiness (EDS) is a hallmark symptom in obstructive sleep apnea (OSA). It is commonly eliminated by obstructive sleep apnea therapy and constitutes a major treatment indication. This study aimed to identify determinants of excessive daytime sleepiness by the Epworth Sleepiness Scale (ESS) scores in the large, representative national obstructive sleep apnea patient cohort of the Swedish Sleep Apnea Registry (SESAR, www.sesar.se). Data from 34,684 patients with obstructive sleep apnea recruited at 23 sites (33% females, mean age 55.7 ± 13.7 years, BMI 30.2 ± 6.3 kg/m 2 , AHI 29.1 ± 22.3, and ODI 24.9 ± 21.4 events/h) had a mean ESS score in the mild to moderate excessive daytime sleepiness range (9.7 ± 4.9). The proportion of patients with excessive daytime sleepiness was 41.4% in men and 44.6% in women. Independent predictors of excessive daytime sleepiness included gender, age, and hypoxic markers (high ODI and low mean saturation). Univariate and multivariate analyses were used to identify significant predictors for the ESS score and for excessive daytime sleepiness (ESS ≥10) amongst anthropometric factors, sleep apnea frequency (apnea-hypopnea index (AHI)), markers of intermittent hypoxia (oxygen desaturation index (ODI), mean saturation (mSaO 2 )), as well as prevalent comorbidities. Depression was associated with higher ESS scores and hypertension/atrial fibrillation with lower scores. The oxygen desaturation index provided a stronger predictor of excessive daytime sleepiness than the apnea-hypopnea index. The severity of obstructive sleep apnea, captured as the apnea-hypopnea index, was only weakly associated with daytime sleepiness in this representative obstructive sleep apnea patient cohort. Age had different effects in men and women.The impact of obstructive sleep apnea in a wider patient related perspective needs to be determined after the inclusion of factors other than the apnea-hypopnea index., (© 2022 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Purpose of Review: This review provides a condensed description of pharmacological remedies explored in patients with obstructive sleep apnoea (OSA) as well as projections of what we might expect in terms of clinical performance of these drugs., Recent Findings: Conventional drug therapies explored in OSA have generally produced disappointing results and there is a shortage of pharmacological treatment alternatives in this disorder. Recent insights into pathophysiological mechanisms potentially involved in OSA suggest that the condition may be divided into distinct subgroups based on clusters or defined by means of unique functional endotypic criteria. In fact, positive outcomes in clinical trials have now resulted in several drug candidates that show a convincing reduction of sleep disordered breathing in both short and intermediate term. Such drugs may be particularly useful in certain variants of OSA but not in others. These insights have also raised the ambition to create personalized therapies in OSA. Another recent development is the insight that OSA-linked conditions such as obesity, daytime somnolence and various forms of cardiovascular/metabolic disease may provide drug-based targets. For instance, pharmacological obesity therapy may provide not only positive metabolic effects but may also be a way to eliminate the anatomic component in obese OSA patients., Summary: Recent insights into the pathophysiology of OSA have opened possibilities to develop personalized therapy. Drugs addressing fundamental aspects of the sleep and breathing disorder provide a particularly promising avenue for development of novel forms of treatment in OSA., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Despite extensive research, there is currently no approved drug for obstructive sleep apnea (OSA) treatment. OSA is a heterogeneous condition that involves multiple dominating pathophysiological traits. Drug development in this field needs to address both pathophysiological mechanisms and associated comorbid conditions in order to meet requirements for long-term therapy in OSA. Several drug candidates have been proposed and ongoing phase II trials that target various forms of sleep-disordered breathing have been initiated. The field is moving toward tailored therapeutic approaches in patients with OSA., Competing Interests: Disclosure Dr J. Hedner has received funding from Swedish Heart and Lung Foundation, Swedish State Funds for Clinical Research LUA/ALF, ResMed, Philips, Bayer, and Desitin., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Obstructive sleep apnea is linked to severe health consequences such as hypertension, daytime sleepiness, and cardiovascular disease. Nearly a billion people are estimated to have obstructive sleep apnea with a substantial economic burden. However, the current diagnostic parameter of obstructive sleep apnea, the apnea-hypopnea index, correlates poorly with related comorbidities and symptoms. Obstructive sleep apnea severity is measured by counting respiratory events, while other physiologically relevant consequences are ignored. Furthermore, as the clinical methods for analysing polysomnographic signals are outdated, laborious, and expensive, most patients with obstructive sleep apnea remain undiagnosed. Therefore, more personalised diagnostic approaches are urgently needed. The Sleep Revolution, funded by the European Union's Horizon 2020 Research and Innovation Programme, aims to tackle these shortcomings by developing machine learning tools to better estimate obstructive sleep apnea severity and phenotypes. This allows for improved personalised treatment options, including increased patient participation. Also, implementing these tools will alleviate the costs and increase the availability of sleep studies by decreasing manual scoring labour. Finally, the project aims to design a digital platform that functions as a bridge between researchers, patients, and clinicians, with an electronic sleep diary, objective cognitive tests, and questionnaires in a mobile application. These ambitious goals will be achieved through extensive collaboration between 39 centres, including expertise from sleep medicine, computer science, and industry and by utilising tens of thousands of retrospectively and prospectively collected sleep recordings. With the commitment of the European Sleep Research Society and Assembly of National Sleep Societies, the Sleep Revolution has the unique possibility to create new standardised guidelines for sleep medicine., (© 2022 European Sleep Research Society.)

Rationale: Current therapies for obstructive sleep apnea (OSA) are limited by insufficient efficacy, compliance, or tolerability. An effective pharmacological treatment for OSA is warranted. Carbonic anhydrase inhibition has been shown to ameliorate OSA. Objectives: To explore safety and tolerability of the carbonic anhydrase inhibitor sulthiame (STM) in OSA. Methods: A 4-week double-blind, randomized, placebo-controlled dose-guiding trial was conducted in patients with moderate and/or severe OSA not tolerating positive airway pressure treatment. Measurements and Main Results: Intermittent paresthesia was reported by 79%, 67%, and 18% of patients receiving 400 mg STM ( n  = 34), 200 mg STM ( n  = 12), and placebo ( n  = 22), respectively. Dyspnea was reported after 400 mg STM (18%). Six patients in the higher dose group withdrew because of adverse events. There were no serious adverse events. STM reduced the apnea-hypopnea index from 55.2 to 33.0 events/h (-41.0%) in the 400-mg group and from 61.1 to 40.6 events/h (-32.1%) after 200 mg ( P  < 0.001 for both). Corresponding placebo values were 53.9 and 50.9 events/h (-5.4%). The apnea-hypopnea index reduction threshold of ⩾50% was reached in 40% of patients after 400 mg, 25% after 200 mg, and 5% after placebo. Mean overnight oxygen saturation improved by 1.1% after 400 and 200 mg ( P  < 0.001 and P  = 0.034, respectively). Patient-related outcomes were unchanged. Conclusions: STM showed a satisfactory safety profile in moderate and/or severe OSA. STM reduced OSA, on average, by more than 20 events/h, one of the strongest reductions reported in a drug trial in OSA. Larger scale clinical studies of STM in OSA are justified. Clinical trial registered with www.clinicaltrialsregister.eu (2017-004767-13).

Treatment of obstructive sleep apnoea (OSA) in adults is evolving, as new therapies have been explored and introduced in clinical practice, while other approaches have been refined or reconsidered. In this European Respiratory Society (ERS) guideline on non-continuous positive airway pressure (CPAP) therapies for OSA, we present recommendations determined by a systematic review of the literature. It is an update of the 2011 ERS statement on non-CPAP therapies, advanced into a clinical guideline. A multidisciplinary group of experts, including pulmonary, surgical, dentistry and ear-nose-throat specialists, methodologists and patient representatives considered the most relevant clinical questions (for both clinicians and patients) relating to the management of OSA. Eight key clinical questions were generated and a systematic review was conducted to identify published randomised clinical trials that answered these questions. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the quality of the evidence and the strength of recommendations. The resulting guideline addresses gastric bypass surgery, custom-made dual-block mandibular advancement devices, hypoglossal nerve stimulation, myofunctional therapy, maxillo-mandibular osteotomy, carbonic anhydrase inhibitors and positional therapy. These recommendations can be used to benchmark quality of care for people with OSA across Europe and to improve outcomes., Competing Interests: Conflicts of Interest: W. Randerath reports personal fees received from Weinmann, Heinen & Löwenstein, Resmed, Inspire, Philips Respironics, and Bioprojet, outside the submitted work. Conflicts of interest: J. Verbraecken reports receiving payments to institution for lectures, presentations, speakers bureaus, manuscript writing or educational events from SomnoMed and Inspire Medical Systems, outside the submitted work. Participation on a Data Safety Monitoring Board or Advisory Board for ResMed Narval, payments to institution, outside the submitted work. Conflicts of interest: C.A.L. de Raaff has nothing to disclose. Conflicts of interest: J. Heder reports grants received from ResMed, outside the submitted work. Lecture fees from Bayer Pharma and Jazz Pharmaceuticals outside the submitted work. Patent filed and granted for Pharmacological therapy in OSA. Participation on a data safety monitoring board or advisory board for DSMB. Conflicts of interest: S. Herkenrath has nothing to disclose. Conflicts of interest: W. Hohenhorst has nothing to disclose. Conflicts of interest: T. Jakob has nothing to disclose. Conflicts of interest: O. Marrone has nothing to disclose. Conflicts of interest: M. Marklund has nothing to disclose. Conflicts of interest: W.T. McNicholas has nothing to disclose. Conflicts of interest: R.L. Morgan has nothing to disclose. Conflicts of interest: J-L. Pépin reports grants and research funds from (payments made to the institutions) Air Liquide Foundation, Agiradom, AstraZeneca, Fisher and Paykel, Mutualia, Philips, Resmed and Vitalaire, outside the submitted work. Consulting fees from: Agiradom, AstraZeneca, Boehringer Ingelheim, Jazz pharmaceutical, Night Balance, Philips, Resmed, and Sefam, outside the submitted work. Conflicts of interest: S. Schiza has nothing to disclose. Conflicts of interest: N. Skoetz reports support for the present manuscript from the European Respiratory Society. Personal payments received from Cochrane outside the submitted work. Conflicts of interest: D. Smyth has nothing to disclose. Conflicts of interest: J. Steier reports receiving grants from the British Lung Foundation, outside the submitted work. Payments of honoraria received from Jazz Pharmaceuticals and Sanofi. Named inventor on pending patent WO2016124739A1. President of the British Sleep Society. Conflicts of interest: T. Tonia acts as an ERS methodologist. Conflicts of interest: W. Trzepizur has nothing to disclose. Conflicts of interest: P-H. van Mechelen has nothing to disclose. Conflicts of interest: P. Wijkstra has nothing to disclose., (Copyright ©The authors 2021.)

Patients with obstructive sleep apnea (OSA) are at increased risk of developing metabolic disease such as diabetes. The effects of positive airway pressure on glycemic control are contradictory. We therefore evaluated the change in glycated hemoglobin (HbA1c) in a large cohort of OSA patients after long-term treatment with positive airway pressure. HbA1c levels were assessed in a subsample of the European Sleep Apnea Database [n=1608] at baseline and at long-term follow up with positive airway pressure therapy (mean 378.9±423.0 days). In a regression analysis, treatment response was controlled for important confounders. Overall, HbA1c decreased from 5.98±1.01% to 5.93±0.98% (p=0.001). Patient subgroups with a more pronounced HbA1c response included patients with diabetes (-0.15±1.02, p=0.019), those with severe OSA baseline (-0.10±0.68, p=0.005), those with morbid obesity (-0.20±0.81, p<0.001). The strongest HbA1c reduction was observed in patients with a concomitant weight reduction >5 kilos (-0.38±0.99, p<0.001). In robust regression analysis, severe OSA (p=0.038) and morbid obesity (p=0.005) at baseline, and weight reduction >5 kilos (p<0.001) during follow up were independently associated with a reduction of HbA1c following PAP treatment. In contrast, PAP treatment alone without weight reduction was not associated with significant Hb1Ac reduction. In conclusion, positive airway pressure therapy is associated with HbA1c reduction in patients with severe OSA, in morbidly obese patients. and most obviously in those with significant weight lost during the follow-up. Our study underlines the importance to combine positive airway pressure use with adjustments in lifestyle to substantially modify metabolic complications in OSA., (© 2021 European Sleep Research Society.)

Study Objectives: Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved in the United States and European Union for excessive daytime sleepiness in adults with narcolepsy (75-150 mg/day) or obstructive sleep apnea (OSA; 37.5-150 mg/day). In 12-week studies, solriamfetol was associated with improvements in quality of life in participants with narcolepsy or OSA. These analyses evaluated the long-term effects of solriamfetol on quality of life., Methods: Participants with narcolepsy or OSA who completed previous solriamfetol studies were eligible. A 2-week titration was followed by a maintenance phase ≤ 50 weeks (stable doses: 75, 150, or 300 mg/day). Quality of life assessments included Functional Outcomes of Sleep Questionnaire short version, Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, and 36-Item Short Form Health Survey version 2. Mean (standard deviation) changes from baseline to end of study were evaluated. Data were summarized descriptively. Adverse events were assessed., Results: Safety population comprised 643 participants (417 OSA, 226 narcolepsy). Solriamfetol improved Functional Outcomes of Sleep Questionnaire short version Total scores (mean change [standard deviation], 3.7 [3.0]) and 36-Item Short Form Health Survey version 2 Physical and Mental Component Summary scores (3.1 [6.9] and 4.3 [8.4], respectively); improvements were sustained throughout treatment. On Work Productivity and Activity Impairment Questionnaire: Specific Health Problem, solriamfetol reduced (improved) % presenteeism, % overall work impairment, and % activity impairment by a minimum of 25%. Common adverse events (≥ 5%): headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection., Conclusions: Long-term solriamfetol treatment was associated with clinically meaningful, sustained improvements in functional status, work productivity, and quality of life for up to 52 weeks. Adverse events were similar between narcolepsy and OSA., Clinical Trial Registration: Registry: ClinicalTrials.gov; Name: A Long-Term Safety Study of JZP-110 in the Treatment of Excessive Sleepiness in Subjects with Narcolepsy or OSA; Identifier: NCT02348632; URL: https://clinicaltrials.gov/ct2/show/NCT02348632., Citation: Weaver TE, Pepin J-L, Schwab R, et al. Long-term effects of solriamfetol on quality of life and work productivity in participants with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. J Clin Sleep Med . 2021;17(10):1995-2007., (© 2021 American Academy of Sleep Medicine.)

Recent studies indicate that ambient temperature may modulate obstructive sleep apnoea (OSA) severity. However, study results are contradictory warranting more investigation in this field. We analysed 19,293 patients of the European Sleep Apnoea Database (ESADA) cohort with restriction to the three predominant climate zones according to the Köppen-Geiger climate classification: Cfb (warm temperature, fully humid, warm summer), Csa (warm temperature, summer dry, hot summer), and Dfb (snow, fully humid, warm summer). Average outside temperature values were obtained and several hierarchical regression analyses were performed to investigate the impact of temperature on the apnea-hypopnea index (AHI), oxygen desaturation index (ODI), time of oxygen saturation <90% (T90) and minimum oxygen saturation (MinSpO 2 ) after controlling for confounders including age, body mass index, gender, and air conditioning (A/C) use. AHI and ODI increased with higher temperatures with a standardised coefficient beta (β) of 0.28 for AHI and 0.25 for ODI, while MinSpO 2 decreased with a β of -0.13 (all results p < .001). When adjusting for climate zones, the temperature effect was only significant in Cfb (AHI: β = 0.11) and Dfb (AHI: β = 0.08) (Model 1: p < .001). The presence of A/C (3.9% and 69.3% in Cfab and Csa, respectively) demonstrated only a minor increase in the prediction of the variation (Cfb: AHI, R 2 +0.003; and Csa: AHI, R 2 +0.007; both p < .001). Our present study indicates a limited but consistent influence of environmental temperature on OSA severity and this effect is modulated by climate zones., (© 2021 European Sleep Research Society.)

The worldwide COVID-19 pandemic has affected the operation of health care systems. The direct impact of obstructive sleep apnea (OSA) on COVID-19 infection outcome remains to be elucidated. However, the coincidence of common risk factors for OSA and severe COVID-19 suggests that patients with OSA receiving positive airway pressure therapy may have an advantage relative to those untreated when confronted with a COVID-19 infection. The ongoing COVID-19 pandemic has led to a substantial reduction of sleep medicine services, and the long-term consequences may be considerable. New strategies for the management of sleep disorders are needed to overcome the current underdiagnosis and delay of treatment., Competing Interests: Disclosure The authors have no conflict of interest to declare for the content of the submitted manuscript. Outside the submitted work, Dr L. Grote reports grants from Bayer, Philips Respironics Foundation, Resmed Foundation, European Respiratory Society, Itamar Medical, Resmed, and Philips. Dr L. Grote received personal fees for lectures from Respironics, Resmed, Itamar, Fisher &Paykel and Astra Zeneca. In addition. Dr L. Grote has two patents on sleep apnea therapy licensed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Arterial hypertension is highly prevalent and difficult to control in patients with obstructive sleep apnea (OSA). High sympathoadrenergic activity is a hallmark physiological phenomenon in OSA. We hypothesized that an antihypertensive drug with inhibitory properties on this activity, such as beta blockers (BBs), may be particularly efficacious in OSA patients., Methods: Hypertensive OSA patients receiving blood pressure-lowing treatment in the European Sleep Apnea Database (ESADA) (n = 5818, 69% men, age 58 ± 11 years, body mass index 33 ± 7 kg/m2, apnea hypopnea index 34 ± 26 events/h) were analyzed. Reported medications [BB, diuretic, renin-angiotensin blocker (RAB), calcium channel blocker (CCB), and centrally acting antihypertensive (CAH)] were classified according to ATC code. Office blood pressure was compared in patients with monotherapy or combination therapy controlling for confounders., Results: Poorly controlled SBP according to the ESC/ESH guidelines was found in 66% of patients. Patients receiving monotherapy with RAB, CCB or CAH had 2.2 (95% CI 1.4-3.0), 3.0 (1.9-4.1) and 3.0 (1.7-4.7) mmHg higher SBP compared with those on BB (adjusted model, P = 0.007, 0.008 and 0.017, respectively). In those with a combination of two antihypertensive drugs, SBP was 5.5 (4.0-7.1), 5.1 (3.7-6.6), 4.3 (2.5-6.1) and 3.1 (1.6-4.6) mmHg higher in those on CCB/RAB, BB/RAB, BB/CCB or diuretic/RAB compared with those on BB/diuretic (adjusted model, P < 0.001, <0.001, 0.018 and 0.036, respectively)., Conclusion: Poorly controlled blood pressure was common in OSA patients with antihypertensive medication. Treatment with BB alone or BB in combination with a diuretic was associated with the lowest systolic pressure in this large clinical cohort., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The impact of removing the upper airway lymphoid tissue and in particular, tonsillectomy, in adults with OSA has not been demonstrated in large populations., Aims: To compare the severity of OSA and the prevalence of cardiovascular, metabolic and respiratory co-morbidities between patients with OSA who had undergone previous tonsillectomy and those who had not., Methods: The 19,711 participants in this study came from the European sleep apnea database (ESADA) which comprises data from unselected adult patients aged 18-80 years with a history of symptoms suggestive of OSA referred to sleep centers throughout Europe., Results: There were no differences between the two groups in terms of sex ratio and age (146 patients with previous tonsillectomy vs. 19565 patients without). Patients who had undergone tonsillectomy had a lower body mass index (29.3 ± 5.2 kg/m 2 vs 32.2 ± 6.6 kg/m 2 , p < 0.001), lower subjective sleep latency (17.1 ± 17.8 min vs 25.5 ± 30.4 min, p = 0.001), lower ODI (15.7 ± 18.3 events/hour vs 30.7 ± 26.1 events/hour, p < 0.001), and SpO 2 <90% time during sleep (21.8 ± 47.5 min vs 52.6 ± 80.8 min, p < 0.001). OSA patients with tonsillectomy had a lower prevalence of Type II diabetes mellitus (p = 0.001), hypertension (p < 0.001) and a higher prevalence of hyperlipidemia (p < 0.001) and were less likely to be commenced on CPAP (p < 0.001)., Conclusion: In a large population of almost 20,000 OSA patients from across Europe, patients who had undergone tonsillectomy presented with less severe OSA at time of diagnosis, and had a lower prevalence of Type II diabetes mellitus and cardiovascular co-morbidities., (Copyright © 2020. Published by Elsevier B.V.)

Background and Aim: Obstructive sleep apnea (OSA) is an independent risk factor for dyslipidemia. The current study examined the effects of positive airway pressure (PAP) treatment on lipid status in the European Sleep Apnea Database (ESADA)., Methods: The prospective cohort study enrolled 1564 OSA subjects (74% male, mean age 54 ± 11y, body mass index (BMI) 32.7 ± 6.6 kg/m 2 and apnea-hypopnea index (AHI) 40.3 ± 24.4 n/h) undergoing PAP therapy for at least three months (mean 377.6 ± 419.5 days). Baseline and follow-up total cholesterol (TC) from nine centers were analyzed. Repeated measures and logistic regression tests (adjusted for age, sex, weight changes, lipid lowering medication, PAP compliance, and treatment duration) were used to compare changes in TC concentration. Incident risk for a coronary heart disease event (CHD) was used to compute a Framingham CHD risk score (estimated from age, BMI, blood pressure, and TC)., Results: Adjusted means of TC decreased from 194.2 mg/dl to 189.3 mg/dl during follow-up (p = 0.019). A clinically significant (10%) reduction of TC at PAP follow-up was observed in 422 patients (27%). Duration of PAP therapy was identified as independent predictor for TC reduction, which implies an approximately 10% risk reduction for incident CHD events (from 26.7% to 24.1% in men and from 11.2% to 10.1% in women, p < 0.001 respectively)., Conclusion: This observational study demonstrates a reduction of TC after long-term PAP treatment. The close association between TC concentration and cardiovascular (CV) mortality suggests that identification and treatment of OSA may have a beneficial effect on overall CV risk due to this mechanism. This possibility needs to be evaluated in prospective randomized studies., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Study Objectives: Patients with chronic kidney disease (CKD) often report poor sleep quality, but they commonly exhibit OSA. The aim of this study was to evaluate the influence of OSA severity and of estimated glomerular filtration rate impairment on objective sleep quality in nondialyzed patients with CKD, defined as an estimated glomerular filtration rate <60 mL/min/1.73m²., Methods: Polysomnographic sleep characteristics were compared between patients with (n = 430) and without CKD (n = 6,639) in the European Sleep Apnea Database cohort. Comparisons were repeated in 375 patients with CKD and 375 control patients without CKD matched for sleep center, age, sex, and AHI, and in 310 matched CKD and non-CKD patients without psychiatric disturbances., Results: Among all patients with and without CKD, total sleep time was similar but sleep stage N1 (median 8.7% [IQR 4.8-18.0] vs 6.7% [3.6-12.7], respectively) and sleep stage R (12.6% [6.8-17.7] vs 14.2% [8.8-19.8], respectively) significantly differed (P < .0001). No difference in sleep characteristics was observed between matched patients either with or without psychiatric disturbances. After subdividing the matched patients according to AHI tertile (<25, ≥25 to <49, and ≥49 events/h) and estimated glomerular filtration rate (≥60, 45 to <60, <45 mL/min/1.73m²), we found a significant effect of AHI on sleep stages N2, N3, and R (P < .001), but there was no effect of CKD., Conclusions: In nondialyzed patients with CKD, objective sleep quality is influenced similarly by AHI as in patients without CKD but is not affected by CKD severity. Previously reported poor sleep quality in CKD may partly result from the high prevalence of OSA in CKD., (© 2020 American Academy of Sleep Medicine.)

Study Objectives: The association of mild obstructive sleep apnea (OSA) with important clinical outcomes remains unclear. We aimed to investigate the association between mild OSA and systemic arterial hypertension (SAH) in the European Sleep Apnea Database cohort., Methods: In a multicenter sample of 4,732 participants, we analyzed the risk of mild OSA (subclassified into 2 groups: mild AHI 5-<11/h (apnea-hypopnea index [AHI], 5 to <11 events/h) and mild AHI 11-<15/h (AHI, ≥11 to <15 events/h) compared with nonapneic snorers for prevalent SAH after adjustment for relevant confounding factors including sex, age, smoking, obesity, daytime sleepiness, dyslipidemia, chronic obstructive pulmonary disease, type 2 diabetes, and sleep test methodology (polygraphy or polysomnography)., Results: SAH prevalence was higher in the mild AHI 11-<15/h OSA group compared with the mild AHI 5-<11/h group and nonapneic snorers (52% vs 45% vs 30%; P < .001). Corresponding adjusted odds ratios for SAH were 1.789 (mild AHI 11-<15/h ; 95% confidence interval [CI], 1.49-2.15) and 1.558 (mild AHI 5-<11/h ; 95%, CI, 1.34-1.82), respectively (P < .001). In sensitivity analysis, mild AHI 11-<15/h OSA remained a significant predictor for SAH both in the polygraphy (odds ratio, 1.779; 95% CI, 1.403-2.256; P < .001) and polysomnography groups (odds ratio, 1.424; 95% CI, 1.047-1.939; P = .025)., Conclusions: Our data suggest a dose-response relationship between mild OSA and SAH risk, starting from 5 events/h in polygraphy recordings and continuing with a further risk increase in the 11- to <150-events/h range. These findings potentially introduce a challenge to traditional thresholds of OSA severity and may help to stratify participants with OSA according to cardiovascular risk., (© 2020 American Academy of Sleep Medicine.)

Rationale: Excessive daytime sleepiness is a common disabling symptom in obstructive sleep apnea syndrome. Objectives: To evaluate the efficacy and safety of pitolisant, a selective histamine H3 receptor antagonist with wake-promoting effects, for the treatment of daytime sleepiness in patients with moderate to severe obstructive sleep apnea refusing continuous positive airway pressure treatment. Methods: In an international, multicenter, double-blind, randomized (3:1), placebo-controlled, parallel-design trial, pitolisant was individually titrated at up to 20 mg/d over 12 weeks. The primary endpoint was the change in the Epworth Sleepiness Scale score. Key secondary endpoints were maintenance of wakefulness assessed on the basis of the Oxford Sleep Resistance test, safety, Clinical Global Impression of severity, patient's global opinion, EuroQol quality-of-life questionnaire, and Pichot fatigue questionnaire. Measurements and Main Results: A total of 268 patients with obstructive sleep apnea (75% male; mean age, 52 yr; apnea-hypopnea index, 49/h; baseline sleepiness score, 15.7) were randomized (200 to pitolisant and 68 to placebo) and analyzed on an intention-to-treat basis. The Epworth Sleepiness Scale score was reduced more with pitolisant than with placebo (-2.8; 95% confidence interval, -4.0 to -1.5; P  < 0.001). Wake maintenance tests were not improved. The Pichot fatigue score was reduced with pitolisant. The overall impact of pitolisant was confirmed by both physicians' and patients' questionnaires. Adverse event incidence, mainly headache, insomnia, nausea, and vertigo, was similar in the pitolisant and placebo groups (29.5% and 25.4%, respectively), with no cardiovascular or other significant safety concerns. Conclusions: Pitolisant significantly reduced self-reported daytime sleepiness and fatigue and improved patient-reported outcomes and physician disease severity assessment in sleepy patients with obstructive sleep apnea refusing or nonadherent to continuous positive airway pressure.Clinical trial registered with www.clinicaltrials.gov (NCT01072968) and EU Clinical Trials Register (EudraCT 2009-017251-94).

Whole blood carbonic anhydrase activity (CAa) is increased in patients with obstructive sleep apnea (OSA). Our study investigated the influence of positive airway pressure (PAP) or CA inhibitor acetazolamide (ACT) therapy on CAa, OSA and blood pressure. Thirty-three OSA patients (21 hypertensive, body mass index (BMI) 37 ± 7 kg/m 2 and apnea-hypopnea index (AHI) of 47 ± 31 events/hr) were followed-up after PAP treatment (compliance, 4.7 ± 1.5 hr/day; duration, median 6 [IQR 6,6] months) (Cohort A). A second OSA Cohort (B) contained nine hypertensive patients (BMI, 29 ± 4 kg/m 2 ; AHI, 39 ± 20 events/hr) with 2-week treatment of ACT, PAP or ACT + PAP in an open crossover study. CAa was assessed at baseline and at the end of each treatment period. In Cohort A, baseline CAa was higher in hypertensive, compared with normotensive, patients (1,033 ± 204 versus 861 ± 201 units, p = .028). PAP treatment reduced systolic/diastolic blood pressure but not CAa (-9 ± 11/-5 ± 7 mmHg and -20 ± 289 units, p < .001, <.001 and .70). In Cohort B, blood pressure was reduced in both ACT-treated groups (-10 ± 10/-5 ± 7 mmHg, p = .043 and .019; and -5 ± 5/-13 ± 13 mmHg, p < .001 and .009). AHI was reduced in both groups: ACT only, -17 ± 9 events/hr p = .001; and ACT + PAP, -39 ± 19 events/hr, p < .001. PAP did not change CAa (p = .98) but activity tended to decrease after ACT with or without PAP (p = .081 and .056). CAa is elevated in hypertensive OSA patients. Long-term PAP reduced blood pressure without affecting CAa. ACT reduced blood pressure and CAa. Increased CAa may constitute a physiological characteristic in OSA, contributing to comorbid hypertension., (© 2019 European Sleep Research Society.)

Study Objectives: To evaluate long-term safety and maintenance of efficacy of solriamfetol treatment for excessive daytime sleepiness in narcolepsy and obstructive sleep apnea (OSA)., Methods: Participants with narcolepsy or OSA who completed a prior solriamfetol study were eligible. A 2-week titration period was followed by a maintenance phase (up to 50 weeks). Efficacy was assessed by Epworth Sleepiness Scale (ESS) and Patient and Clinical Global Impression of Change (PGI-C and CGI-C, respectively). After approximately 6 months of treatment, a subgroup entered a 2-week placebo-controlled randomized withdrawal (RW) phase. Change in ESS from beginning to end of the RW phase was the primary endpoint; PGI-C and CGI-C were secondary endpoints. Safety was assessed throughout the study., Results: In the maintenance phase, solriamfetol-treated participants demonstrated clinically meaningful improvements on ESS, PGI-C, and CGI-C. In the RW phase, least squares mean change on ESS was 1.6 in participants continuing solriamfetol versus 5.3 in participants switched to placebo (p < .0001). For both secondary endpoints, higher percentages of participants receiving placebo were reported as worse at the end of the RW phase versus solriamfetol (p < .0001). Common treatment-emergent adverse events (TEAEs) with solriamfetol were headache, nausea, nasopharyngitis, insomnia, dry mouth, anxiety, decreased appetite, and upper respiratory tract infection; 27 (4.2%) participants experienced at least one serious TEAE, and 61 (9.5%) withdrew because of TEAEs., Conclusions: This study demonstrated long-term maintenance of efficacy of solriamfetol under open-label and double-blind, placebo-controlled conditions. Safety profile of solriamfetol was consistent with previous 12-week studies; no new safety concerns were identified., Trial Registration: NCT02348632., (© Sleep Research Society 2019. Published by Oxford University Press [on behalf of the Sleep Research Society].)

Objective/background: The Clinical Global Impression scale (CGI) reflects the clinician's assessment of the disease impact on patient's global functioning. We assessed predictors of CGI scale rating in patients with obstructive sleep apnea (OSA)., Patients/methods: Consecutive patients with suspected OSA (n = 7581) were identified in the European Sleep Apnea Database (ESADA). Anthropometrics, comorbidities, apnea severity obtained by polygraphy or polysomnography, and daytime sleepiness [Epworth Sleepiness Scale (ESS)] were assessed. The CGI 7-point scale was completed at the end of the diagnostic process (CGI-severity, ie, CGI-S) and, in a subpopulation, at treatment follow-up (CGI-Improvement)., Results: CGI-S was rated mild to moderate in 44% of patients. CGI rating at any given apnea intensity was worse in women than in men (p < 0.01). Patients undergoing polygraphy (n = 5075) were more frequently rated as severely ill compared to those studied with polysomnography (19.0% vs 13.0%, p < 0.001). In patients aged ≤65 years, CGI scoring was generally better than in the elderly despite a similar degree of OSA (eg, 'normal, not ill' 24.2% vs 15.3%, p < 0.01, respectively). Independent predictors of CGI rating included age, BMI, AHI, ESS, cardio-metabolic comorbidities, and diagnosis based on polygraphy. CGI-improvement rating (Beta = -0.406, p < 0.01) was superior to sleep apnea severity or ESS-score (Beta = 0.052 and -0.021, p = 0.154 and 0.538 respectively) at baseline for prediction of good CPAP compliance at follow-up., Conclusions: CGI rating is confounded by gender, age class and the type of sleep diagnostic method. As OSA phenotypes differ, CGI may contribute as a clinical tool to reflect the significance of clinical disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Excessive sleepiness (ES) is a common symptom of OSA, which often persists despite primary OSA therapy. This phase III randomized withdrawal trial evaluated solriamfetol (JZP-110) for the treatment of ES in adults with OSA., Methods: After 2 weeks of clinical titration (n = 174) and 2 weeks of stable dose administration (n = 148), participants who reported improvement on the Patient Global Impression of Change (PGI-C) and had numerical improvements on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) were randomly assigned to placebo (n = 62) or solriamfetol (n = 62) for 2 additional weeks. Coprimary end points were change from weeks 4 to 6 in MWT and ESS., Results: In the modified intention-to-treat population (n = 122), MWT mean sleep latencies and ESS scores improved from baseline to week 4 (from 12.3-13.1 to 29.0-31.7 minutes and from 15.3-16.0 to 5.9-6.4, respectively). From weeks 4 to 6, participants treated with solriamfetol maintained improvements (least squares [LS] mean [SE] changes of -1.0 [1.4] minutes on MWT and -0.1 [0.7] on ESS), whereas participants treated with placebo worsened (LS mean [SE] change of -12.1 [1.3] minutes on MWT and 4.5 [0.7] on ESS); LS mean differences between treatments were 11.2 minutes (95% CI, 7.8-14.6) and -4.6 (95% CI, -6.4 to -2.8) on MWT and ESS, respectively. Fewer participants treated with solriamfetol reported worsening on the PGI-C from weeks 4 to 6 (20% vs 50%; P = .0005). Common adverse events included headache, dry mouth, nausea, dizziness, and insomnia., Conclusions: This study demonstrated maintenance of solriamfetol efficacy and safety over 6 weeks., Trial Registry: ClinicalTrials.gov; No.: NCT02348619; URL: www.clinicaltrials.gov; EudraCT No.: 2014-005515-16., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objective: Obstructive sleep apnoea (OSA) and dyslipidaemia are independent risk factors for cardiovascular disease. This study investigates the association between OSA and plasma lipid concentrations in patients enrolled in the European Sleep Apnea Database (ESADA) cohort., Methods: The cross-sectional analysis included 8592 patients without physician-diagnosed hyperlipidaemia or reported intake of a lipid-lowering drug (age 50.1 ± 12.7 years, 69.1% male, BMI: 30.8 ± 6.6 kg/m 2 , mean apnoea-hypopnoea index (AHI): 25.7 ± 25.9 events/h). The independent relationship between measures of OSA (AHI, oxygen desaturation index (ODI), mean and lowest oxygen saturation) and lipid profile (total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and fasting triglycerides (TG)) was determined by means of general linear model analysis., Results: There was a dose response relationship between TC and ODI (mean ± SE (mg/dL): 180.33 ± 2.46, 184.59 ± 2.42, 185.44 ± 2.42 and 185.73 ± 2.44; P < 0.001 across ODI quartiles I-IV). TG and LDL concentrations were better predicted by AHI than by ODI. HDL-C was significantly reduced in the highest AHI quartile (mean ± SE (mg/dL): 48.8 ± 1.49 vs 46.50 ± 1.48; P = 0.002, AHI quartile I vs IV). Morbid obesity was associated with lower TC and higher HDL-C values. Lipid status was influenced by geographical location with the highest TC concentration recorded in Northern Europe., Conclusion: OSA severity was independently associated with cholesterol and TG concentrations., (© 2018 Asian Pacific Society of Respirology.)

Obstructive sleep apnea (OSA) and asthma are often associated and several studies suggest a bidirectional relationship between asthma and OSA. This study analyzed the characteristics of patients with suspected OSA from the European Sleep Apnea Database according to presence/absence of physician-diagnosed asthma. Cross-sectional data in 16,236 patients (29.1% female) referred for suspected OSA were analyzed according to occurrence of physician-diagnosed asthma for anthropometrics, OSA severity and sleepiness. Sleep structure was assessed in patients studied by polysomnography (i.e. 48% of the sample). The prevalence of physician-diagnosed asthma in the entire cohort was 4.8% (7.9% in women, 3.7% in men, p < 0.0001), and decreased from subjects without OSA to patients with mild-moderate and severe OSA (p = 0.02). Obesity was highly prevalent in asthmatic women, whereas BMI distribution was similar in men with and without physician-diagnosed asthma. Distribution of OSA severity was similar in patients with and without physician-diagnosed asthma, and unaffected by treatment for asthma or gastroesophageal reflux. Asthma was associated with poor sleep quality and sleepiness. Physician-diagnosed asthma was less common in a sleep clinic population than expected from the results of studies in the general population. Obesity appears as the major factor raising suspicion of OSA in asthmatic women, whereas complaints of poor sleep quality were the likely reason for referral in asthmatic men., (© 2018 European Sleep Research Society.)

The effect of positive airway pressure treatment on weight and markers of central obesity in patients with obstructive sleep apnea remains unclear. We studied the change in body weight and anthropometric measures following positive airway pressure treatment in a large clinical cohort. Patients with obstructive sleep apnea with positive airway pressure treatment from the European Sleep Apnea Database registry (n = 1,415, 77% male, age 54 ± 11 [mean ± SD] years, body mass index 31.7 ± 6.4 kg/m 2 , apnea-hypopnea index 37 ± 24 n per hr, Epworth Sleepiness Scale 10.2 ± 5.0) were selected. Changes in body mass index and neck/waist/hip circumferences at baseline and at follow-up visit were analysed. Overall, body mass index (0.0 [95% confidence interval, -0.1 to 0.2] kg/m 2 ) and neck circumference (0.0 (95% confidence interval, -0.1 to 0.1] cm) were unchanged after positive airway pressure treatment compared with baseline (follow-up duration 1.1 ± 1.0 years and compliance 5.2 ± 2.1 hr per day). However, in non-obese (body mass index <30 kg/m 2 ) patients, positive airway pressure treatment was associated with an increased body mass index and waist circumference (0.4 [0.3-0.5] kg/m 2 and 0.8 [0.4-1.2] cm, respectively, all p < 0.05), and weight gain was significantly associated with higher positive airway pressure compliance and longer positive airway pressure treatment duration. In the obese subgroup, body mass index was reduced after positive airway pressure treatment (-0.3 [-0.5 to -0.1] kg/m 2 , p < 0.05) mainly in patients with a strong reduction in Epworth Sleepiness Scale. In conclusion, positive airway pressure therapy was not found to systematically change body mass index in the European Sleep Apnea Database cohort, but the response was heterogeneous. Our findings suggest that weight gain may be restricted to an obstructive sleep apnea phenotype without established obesity. Lifestyle intervention needs to be considered in both lean and obese patients with obstructive sleep apnea receiving positive airway pressure treatment., (© 2018 European Sleep Research Society.)

New European Union (EU) regulations state that untreated moderate to severe obstructive sleep apnea (OSA) coincident with excessive daytime sleepiness (EDS) constitutes a medical disorder leading to unfitness to drive. However, fitness to drive can be re-established by successful treatment of OSA and EDS. The aim of the current study was to compare patients undergoing the certification process with those of an unselected OSA patient cohort. The study compared consecutive patients in the certification group (n = 132) with a representative group of OSA patients with a current driving license and an Apnea Hypopnea Index (AHI) ≥ 15 n/h (n = 790). The adherence to positive airway pressure (PAP) therapy and the change in EDS (Epworth Sleepiness Scale [ESS] score) with treatment were analysed. Patient characteristics and severity of sleep apnea did not differ significantly between groups (certification/reference group: BMI 30 ± 5/31 ± 5 kg/m 2 , AHI 33 ± 20/36 ± 20 n/hr, ESS 12 ± 6/11 ± 5). However, the certification group was oversampled with elderly drivers (70-85 years: 22% vs. 9%, p = 0.001). PAP compliance was higher in the certification group than in the reference group (PAP use ≥ 4 hr/night in 96% vs. 53%, p = 0.001) and mean ESS reduction was -8.0 (-8.9 - -7.1) versus -4.0 (-4.4 - -3.5), respectively (p < 0.001). Patients attending the fitness to drive evaluation reported almost complete adherence to continuous positive airway pressure (CPAP) and elimination of EDS symptoms. Besides possible baseline differences, this strong response may be explained by factors such as a selection process of elderly patients, a self-rating component in the assessment of the treatment response and the threat of a driving license suspension. Our data suggest that an improved certification process with objective rather than subjective components, along with a reduced selection bias, is warranted., (© 2018 European Sleep Research Society.)

Obstructive sleep apnoea (OSA) is a major challenge for physicians and healthcare systems throughout the world. The high prevalence and the impact on daily life of OSA oblige clinicians to offer effective and acceptable treatment options. However, recent evidence has raised questions about the benefits of positive airway pressure therapy in ameliorating comorbidities.An international expert group considered the current state of knowledge based on the most relevant publications in the previous 5 years, discussed the current challenges in the field, and proposed topics for future research on epidemiology, phenotyping, underlying mechanisms, prognostic implications and optimal treatment of patients with OSA.The group concluded that a revision to the diagnostic criteria for OSA is required to include factors that reflect different clinical and pathophysiological phenotypes and relevant comorbidities ( e.g. nondipping nocturnal blood pressure). Furthermore, current severity thresholds require revision to reflect factors such as the disparity in the apnoea-hypopnoea index (AHI) between polysomnography and sleep studies that do not include sleep stage measurements, in addition to the poor correlation between AHI and daytime symptoms such as sleepiness. Management decisions should be linked to the underlying phenotype and consider outcomes beyond AHI., Competing Interests: Conflict of interest: W. Randerath reports grants and personal fees (travel grants and speaking fees) from Heinen & Löwenstein, Weinmann, ResMed, Inspire and Philips Respironics, outside the submitted work. L. Ferini-Strambi reports personal fees from Philips Respironics (honoraria for a lecture and for chairing a scientific meeting in 2015–2016, none of which involved promotion of company products and there was no influence on lecture content) and ResMed (honoraria for participating in an advisory board), outside the submitted work. R. Farre reports other fees from ResMed (a contract between the company and the University of Barcelona (Fundació Bosch Gimpera) for assessing automatic CPAP devices in a bench test) and other fees from ANTADIR (a contract between the company and the University of Barcelona (Fundació Bosch Gimpera) for assessing automatic CPAP devices in a bench test), outside the submitted work. L. Grote reports grants and personal fees (speakers’ bureau) from ResMed and Philips, personal fees from Breas Mecical (consultancy), personal fees and nonfinancial support from Heinen & Löwenstein (consultancy), and grants from the ERS, during the conduct of the study; and personal fees (speakers’ bureau) from AstraZeneca, outside the submitted work. In addition, L. Grote has a patent on pharmacological treatment of OSA pending. J. Hedner has together with the ESADA study group received grants from ResMed and Philips Respironics to enable the ESADA database. He has also received personal speaker bureau fees from AstraZeneca, Takeda and Bayer. M. Kohler reports personal fees from Bayer (advisor fees), outside the submitted work. J-L. Pepin reports unrestricted research grants from Philips, ResMed, Fisher & Paykel, Fondation de la recherche medicale, Direction de la recherche Clinique du CHU de Grenoble and Fond de dotation “Agir pour les maladies chroniques”, and personal fees (travel grants and lecture fees) from Perimetre, Philips, Fisher & Paykel, ResMed, AstraZeneka, SEFAM, Agiradom and Teva, during the conduct of the study. J. Verbraecken reports other fees (sponsoring courses) from Koninklijke Philips Respironics, ResMed, Fisher & Paykel, NightBalance, Heinen & Löwenstein, AirLiquide, Accuramed, OSG, Medidis, MediqTefa, Wave Medical, Vivisol, TotalCare, SomnoMed, UCB Pharma, Olympus Belgium, Takeda, Masimo and Linde Healthcare, outside the submitted work. W.T. McNicholas reports personal fees from Philips Respironics (honoraria for lectures, but none of these lectures related to promotion of company products and the lecture content was not in any way influenced by the company), outside the submitted work., (Copyright ©ERS 2018.)

Background: The impact of treating OSA on renal function decline is controversial. Previous studies usually included small samples and did not consider specific effects of different CPAP modalities. The aim of this study was to evaluate the respective influence of fixed and autoadjusting CPAP modes on estimated glomerular filtration rate (eGFR) in a large sample of patients derived from the prospective European Sleep Apnea Database cohort., Methods: In patients of the European Sleep Apnea Database, eGFR prior to and after follow-up was calculated by using the Chronic Kidney Disease-Epidemiology Collaboration equation. Three study groups were investigated: untreated patients (n = 144), patients receiving fixed CPAP (fCPAP) (n = 1,178), and patients on autoadjusting CPAP (APAP) (n = 485)., Results: In the whole sample, eGFR decreased over time. The rate of eGFR decline was significantly higher in the subgroup with eGFR above median (91.42 mL/min/1.73 m 2 ) at baseline (P < .0001 for effect of baseline eGFR). This decline was attenuated or absent (P < .0001 for effect of treatment) in the subgroup of patients with OSA treated by using fCPAP. A follow-up duration exceeding the median (541 days) was associated with eGFR decline in the untreated and APAP groups but not in the fCPAP group (P < .0001 by two-way ANOVA for interaction between treatment and follow-up length). In multiple regression analysis, eGFR decline was accentuated by advanced age, female sex, cardiac failure, higher baseline eGFR, and longer follow-up duration, whereas there was a protective effect of fCPAP., Conclusions: fCPAP but not APAP may prevent eGFR decline in OSA., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

There are several reasons to develop a pharmacologic remedy in obstructive sleep apnea (OSA); but so far, there is no generally effective drug available. Previous attempts to find a drug in OSA therapy were serendipity driven in small pilot trials. There is growing literature on phenotyping pathophysiologic mechanisms of OSA that may be exploited in strategic drug development programs. The current review addresses potential pitfalls encountered in previous studies and highlights several drug candidates under development in the field., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Study Objectives: The carbonic anhydrase inhibitor acetazolamide (AZT) modulates blood pressure at high altitude and reduces sleep-disordered breathing in patients with obstructive sleep apnea (OSA). We aimed to investigate the treatment effect of AZT and in combination with continuous positive airway pressure (CPAP) on blood pressure in patients with hypertension and OSA., Methods: In a prospective, randomized, three-way crossover study, 13 male patients with hypertension and moderate to severe OSA (age 64 ± 7 years, body mass index 29 ± 4 kg/m 2 , and mean apnea-hypopnea index 37 ± 23 events/h) received AZT, CPAP, or AZT plus CPAP for 2-week periods. Antihypertensive medication was washed out. Office and 24-hour blood pressure, arterial stiffness, polygraphic sleep study data, and blood chemistry were compared., Results: AZT alone and AZT plus CPAP, but not CPAP alone, reduced office mean arterial pressure compared to baseline (-7 [95% CI -11 to -4], -7 [95% CI -11 to -4] and -1 [95% CI -5 to 4] mmHg, respectively; repeated- measures analysis of variance (RM-ANOVA; P = .015). Aortic systolic pressure and augmentation index, assessed by radial artery oscillatory tonometry, were unaffected by CPAP but decreased after AZT and AZT plus CPAP (RM-ANOVA P = .030 and .031, respectively). The apnea-hypopnea index was significantly reduced in all three treatment arms, most prominently by AZT plus CPAP (RM-ANOVA P = .003). The reduction of venous bicarbonate concentration following AZT was correlated with the change of apnea-hypopnea index ( r = 0.66, P = .013)., Conclusions: AZT reduced blood pressure, vascular stiffness, and sleep-disordered breathing in patients with OSA and comorbid hypertension. Carbonic anhydrase inhibition may constitute a potential target for drug therapy in patients with sleep apnea and comorbid hypertension., Clinical Trial Registration: Registry: ClinicalTrials.gov; Identifier: NCT02220803; Title: A Short Term Open, Randomized Cross-over Trial Exploring the Effect of Carbonic Anhydrase Inhibition by Acetazolamide on Sleep Apnea Associated Hypertension and Vascular Dysfunction; URL: https://clinicaltrials.gov/ct2/show/NCT02220803 and Registry: EU Clinical Trials Register; EudraCT Number: 2013-004866-33; Title: A short term open, randomized cross over trial exploring the effect of carbonic anhydrase inhibition by acetazolamide on sleep apnea associated hypertension; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2013-004866-33., (© 2018 American Academy of Sleep Medicine.)

Arterial stiffness, a marker for cardiovascular risk, is increased in patients with Chronic Obstructive Pulmonary Disease (COPD) and Obstructive Sleep Apnea (OSA). The specific influence of both on arterial stiffness during sleep is unknown. Nocturnal arterial stiffness (Pulse Propagation Time (PPT) of the finger pulse wave) was calculated in 142 individuals evaluated for sleep apnea: 27 COPD patients (64.7 ± 11y, 31.2 ± 8 kg/m 2 ), 72 patients with cardiovascular disease (CVD group, 58.7 ± 13y, 33.6 ± 6 kg/m 2 ) and 43 healthy controls (HC group 49.3 ± 12y, 27.6 ± 3 kg/m 2 ). Sleep stage related PPT changes were assessed in a subsample of COPD patients and matched controls (n = 12/12). Arterial stiffness during sleep was increased in COPD patients (i.e. shortened PPT) compared to healthy controls (158.2 ± 31 vs. 173.2 ± 38 ms, p = 0.075) and to patients with CVD (161.4 ± 41 ms). Arterial stiffening was particular strong during REM sleep (145.9 ± 28 vs. 172.4 ± 43 ms, COPD vs. HC, p = 0.003). In COPD, time SaO 2 < 90% was associated with reduced arterial stiffness (Beta +1.7 ms (1.1-2.3)/10 min, p < 0.001). Sleep apnea did not affect PPT. In COPD, but not in matched controls, arterial stiffness increased from wakefulness to REM-sleep (ΔPPT-8.9 ± 10% in COPD and 3.7 ± 12% in matched controls, p = 0.021). Moreover, REM-sleep related arterial stiffening was correlated with elevated daytime blood pressure (r = -0.92, p < 0.001) and increased myocardial oxygen consumption (r = -0.88, p < 0.01). Hypoxia and REM sleep modulate arterial stiffness. In contrast to healthy controls, REM sleep imposes a vascular load in COPD patients independent of sleep apnea indices, intermittent and sustained hypoxia. The link between REM-sleep, vascular stiffness and daytime cardiovascular function suggests that REM-sleep plays a role for increased cardiovascular morbidity of COPD patients.

Background: Obstructive sleep apnea is characterized by intermittent hypoxia and hypercapnia. CO 2 production, transport and elimination are influenced by the carbonic anhydrase enzyme. We hypothesized that elevated standard bicarbonate, a proxy for increased carbonic anhydrase activity, is associated with apnea severity and higher blood pressure in patients with obstructive sleep apnea., Methods: A retrospective analysis of a sleep apnea cohort (n = 830) studied by ambulatory polygraphy. Office systolic/diastolic blood pressure, lung function, and arterial blood gases were assessed during daytime., Results: Arterial standard bicarbonate was increased with apnea severity (mild/moderate/severe 24.1 ± 1.8, 24.4 ± 1.7 and 24.9 ± 2.9 mmol/l, respectively, Kruskal-Wallis test p < 0.001). Standard bicarbonate was independently associated with apnea hypopnea index after adjustment for sex, age, body mass index, smoking, alcohol, hypertension, pO 2 and pCO 2 (standard bicarbonate quartile 1 vs. quartile 4, β = 10.6, p < 0.001). Log-transformed standard bicarbonate was associated with a diagnosis of hypertension or diastolic blood pressure but not systolic blood pressure adjusting for cofounders (p = 0.007, 0.048 and 0.45, respectively)., Conclusions: There was an independent association between sleep apnea severity and arterial standard bicarbonate. The link between high standard bicarbonate and daytime hypertension suggests that carbonic anhydrase activity may constitute a novel mechanism for blood pressure regulation in sleep apnea.

Sleep disordered breathing, especially obstructive sleep apnoea (OSA), has a high and increasing prevalence. Depending on the apnoea and hypopnoea scoring criteria used, and depending on the sex and age of the subjects investigated, prevalence varies between 3% and 49% of the general population. These varying prevalences need to be reflected when considering screening for OSA. OSA is a cardiovascular risk factor and patients are at risk when undergoing medical interventions such as surgery. Screening for OSA before anaesthesia and surgical interventions is increasingly considered. Therefore, methods for screening and the rationale for screening for OSA are reviewed in this study., (Copyright ©ERS 2017.)

The cross-sectional relationship of obstructive sleep apnea with moderate to severe chronic kidney disease, defined as an estimated glomerular filtration rate <60 mL min -1 ∙1.73 m -2 , was investigated in a large cohort of patients with suspected obstructive sleep apnea studied by nocturnal polysomnography or cardiorespiratory polygraphy. Data were obtained from the European Sleep Apnea Database, where information from unselected adult patients with suspected obstructive sleep apnea afferent to 26 European sleep centres had been prospectively collected. Both the Modification of Diet in Renal Disease and the Chronic Kidney Disease-Epidemiology Collaboration equations were used for the assessment of estimated glomerular filtration rate. The analysed sample included 7700 subjects, 71% male, aged 51.9 ± 12.5 years. Severe obstructive sleep apnea (apnea-hypopnea index ≥30) was found in 34% of subjects. The lowest nocturnal oxygen saturation was 81 ± 10.2%. Chronic kidney disease prevalence in the whole sample was 8.7% or 6.1%, according to the Modification of Diet in Renal Disease or the Chronic Kidney Disease-Epidemiology Collaboration equations, respectively. Subjects with lower estimated glomerular filtration rate were older, more obese, more often female, had worse obstructive sleep apnea and more co-morbidities (P < 0.001, each). With both equations, independent predictors of estimated glomerular filtration rate <60 were: chronic heart failure; female gender; systemic hypertension; older age; higher body mass index; and worse lowest nocturnal oxygen saturation. It was concluded that in obstructive sleep apnea, chronic kidney disease is largely predicted by co-morbidities and anthropometric characteristics. In addition, severe nocturnal hypoxaemia, even for only a small part of the night, may play an important role as a risk factor for kidney dysfunction., (© 2016 European Sleep Research Society.)

Modafinil is used internationally to treat residual sleepiness despite continuous positive airway pressure in obstructive sleep apnoea (res-OSA). In 2011, the European Medicines Agency removed the indication based on an unfavourable risk-benefit profile in two trials for efficacy and all accumulated safety data. We performed a meta-analysis of all randomised controlled trials of modafinil (or armodafinil) in res-OSA to quantify efficacy and safety.We systematically searched and assessed studies from major databases, conferences and trials registries to find randomised, placebo-controlled trials of modafinil/armodafinil for ≥2 weeks in adult res-OSA treating sleepiness.We analysed 10 of the 232 articles identified that met inclusion criteria (1466 patients). Modafinil/armodafinil improved the Epworth Sleepiness Scale score (2.2 points, 95% CI 1.5-2.9) and the Maintenance of Wakefulness Test over placebo (3 min, 95% CI 2.1-3.8 min). Modafinil/armodafinil tripled adverse events and doubled adverse events leading to withdrawal but did not increase serious adverse events (hospitalisations or death).Modafinil and armodafinil improve subjective and objective daytime sleepiness in res-OSA. We believe our analysis is a fairer analysis of the risk-benefit profile of this indication. Clinicians may want to use this data to balance the risks and benefits on a case-by-case basis with their patients., (Copyright ©ERS 2016.)

Background: Sleep-related breathing disorders may promote cardiovascular (CV) diseases. A novel and differentiated approach to overnight photoplethysmographic pulse wave analysis, which includes risk assessment and measurement of various pulse wave characteristics, has been evaluated in obstructive sleep apnea (OSA)., Objectives: The purpose of this study was to assess if and which of the differentiated pulse wave characteristics might be influenced by OSA treatment with positive airway pressure (PAP)., Methods: The study included two protocols. In the case-control study (group A), pulse wave-derived CV risk indices recorded during PAP therapy were compared with those obtained in age, body mass index, and CV risk class-matched patients with untreated OSA (n = 67/67). In the prospective PAP treatment study (group B), 17 unselected patients undergoing a full-night sleep test at baseline and after 23 ± 19 weeks of treatment were analyzed., Results: In untreated OSA patients (group A), the overnight hypoxic load was increased (SpO2 index 38.7 ± 17.5 vs. 24.0 ± 11.1, p < 0.001) and the pulse wave attenuation index (PWA-I) was lower (29.4 ± 9.2 vs. 33.5 ± 11.8, p = 0.022) than in treated patients. In group B, PAP therapy reduced the hypoxic load and increased the PWA-I significantly. The composite CV risk index was slightly but not significantly reduced., Conclusions: PAP therapy modified the hypoxic load and pulse wave-derived markers. The PWA-I - associated with sympathetic vascular tone - was most prominently modified by PAP. This novel approach to markers of CV function should be further evaluated in prospective studies., (© 2016 S. Karger AG, Basel.)

Polygraphy (PG) and polysomnography (PSG) are used in clinical settings in Europe for diagnosing obstructive sleep apnea (OSA), but their equivalence in unselected clinical cohorts is unknown. We hypothesized that the method would affect both diagnostic outcomes and disease severity stratification. Data from 11 049 patients in the multi-centre European Sleep Apnea Cohort (ESADA) with suspected OSA (male and female, aged 18-80 years) were used in two groups of patients to compare PG (n = 5745) and PSG (n = 5304). Respiratory events were scored using the 2007 American Association of Sleep Medicine (AASM) criteria. In subjects who underwent PSG, mean apnea-hypopnea index (AHI) using sleep time (AHIPSG 31.0 ± 26.1 h(-1) ) and total analysed time (TAT) (AHITAT 24.7 ± 22.0 h(-1) ) were higher than in subjects who underwent PG (AHIPG 22.0 ± 23.5 h(-1) ) (P < 0.0001). The oxygen desaturation index (ODI) was lower in subjects investigated with PG (ODIPG 18.4 ± 21.7 h(-1) ) compared to subjects investigated with PSG (ODIPSG 23.0 ± 25.3 h(-1) ) but not different when the PSG was indexed by TAT (ODITAT 18.6 ± 21.4 h(-1) , P < 0.65). The proportion of patients with an AHI ≥ 15 was 64% in the subjects who underwent PSG and 47% in the subjects who underwent PG (P < 0.001). Overall, patients investigated using PG are likely to have a 30% lower AHI on average, compared to patients investigated by PSG. This study suggests that PG interpreted using standard guidelines results in underdiagnosis and misclassification of OSA. We advocate the development of PG-specific guidelines for the management of OSA patients., (© 2015 European Sleep Research Society.)

Study Objectives: The catalytic function of the enzyme carbonic anhydrase (CA) plays a fundamental role in carbon dioxide (CO2), proton (H(+)), and bicarbonate (HCO3(-)) homeostasis. Hypoxia and tissue acidosis have been proposed to increase physiological CA activity in various compartments of the body. We hypothesized that CA activity in blood is upregulated in patients with obstructive sleep apnea (OSA)., Design: Cross-sectional analysis of a sleep clinic cohort., Settings: Sleep laboratory at a university hospital., Participants: Seventy referred patients with suspected OSA (48 males, age 54 ± 13 y, apnea-hypopnea index (AHI) median [interquartile range] 21 [8-41] n/h)., Interventions: N/A., Measurements and Results: In-laboratory cardiorespiratory polygraphy was used to assess OSA. CA activity was determined by an in vitro assay that quantifies the pH change reflecting the conversion of CO2 and H2O to HCO3(-) and H(+). CA activity was positively associated with AHI and 4% oxygen desaturation index (ODI4) (Spearman correlation r = 0.44 and 0.47, both P < 0.001). The associations (CA activity versus logAHI and CA versus logODI4) were independent of sex, age, body mass index, presleep oxygen saturation, nocturnal oxygen saturation, hypertension status, and use of diuretic medication in two generalized linear models (P = 0.007 and 0.011, respectively). Sitting diastolic blood pressure was associated with CA activity after adjustment of sex, age, body mass index, mean oxygen saturation, and AHI (P = 0.046)., Conclusions: Carbonic anhydrase (CA) activity increased with apnea-hypopnea index and related nocturnal hypoxemia measures in patients with obstructive sleep apnea (OSA). Altered CA activity may constitute a component that modulates respiratory control and hemodynamic regulation in patients with OSA., (© 2015 Associated Professional Sleep Societies, LLC.)

Study Objectives: Obstructive sleep apnea (OSA) is associated with an increased risk of motor vehicle accidents (MVAs). The rate of MVAs in patients suspected of having OSA was determined and the effect of continuous positive airway pressure (CPAP) was investigated., Design: MVA rate in patients referred for OSA was compared to the rate in the general population using data from the Swedish Traffic Accident Registry (STRADA), stratified for age and calendar year. The risk factors for MVAs, using demographic and polygraphy data, and MVA rate before and after CPAP were evaluated in the patient group., Setting: Clinical sleep laboratory and population based control (n = 635,786)., Patients: There were 1,478 patients, male sex 70.4%, mean age 53.6 (12.8) y., Interventions: CPAP., Measurements and Results: The number of accidents (n = 74) among patients was compared with the expected number (n = 30) from a control population (STRADA). An increased MVA risk ratio of 2.45 was found among patients compared with controls (P < 0.001). Estimated excess accident risk was most prominent in the elderly patients (65-80 y, seven versus two MVAs). In patients, driving distance (km/y), EDS (Epworth Sleepiness score ≥ 16), short habitual sleep time (≤5 h/night), and use of hypnotics were associated with increased MVA risk (odds ratios 1.2, 2.1, 2.7 and 2.1, all P ≤ 0.03). CPAP use ≥ 4 h/night was associated with a reduction of MVA incidence (7.6 to 2.5 accidents/1,000 drivers/y)., Conclusions: The MVA risk in this large cohort of unselected patients with OSA suggests a need for accurate tools to identify individuals at risk. Sleep apnea severity (e.g., apnea-hypopnea index) failed to identify patients at risk., (© 2015 Associated Professional Sleep Societies, LLC.)