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Purpose: Noradrenergics and antimuscarinics have been proposed as future pharmacotherapy for obstructive sleep apnea (OSA). However, the available randomized controlled trials (RCTs) showed heterogeneous results regarding the safety and efficacy of the combined regimen in OSA. Therefore, we performed this meta-analysis from the published RCTs to clarify this conflicting evidence., Methods: A systematic search of four electronic databases was done till December 2023., Results: Thirteen RCTs (n = 345) were systematically reviewed and meta-analyzed. The combined regimen significantly reduced apnea-hypopnea index (AHI): AHI 3% [events/h; Mean difference (MD): - 6.30; 95% Confidence interval (CI) (- 9.74, - 2.87); P = 0.0003], AHI 4% [events/h; MD: - 6.50; 95% CI (- 8.74, - 4.26 events/h); P < 0.00001]. All gasometric measures significantly improved in the combined regimen group except mean SpO2. No difference was found in total sleep time between the treatment and placebo. However, compared to placebo, the combined regimen altered sleep architecture and decreased sleep efficiency. Regarding OSA endotypes, the combined regimen significantly improved loop gain, pharyngeal muscle compensation, pharyngeal muscle recruitment, and respiratory arousal threshold., Conclusion: The combined regimen effectively reduces AHI and OSA severity with improvement in almost all OSA endotypes. However, this regimen decreased sleep efficiency and altered sleep architecture. Short-term side effects can be confined to increased heart rate, dry mouth and urinary hesitancy. Therefore, noradrenergics and anti-muscarinics is a promising regimen for treating OSA, yet this optimism must be titrated by the lack of long-term effects of the regimen. Future RCTs with focus on the long-term efficacy of the regimen and cardiovascular outcomes is recommended., Competing Interests: Declarations. Ethical approval: This article does not contain any studies with human participants performed by any of the authors. Conflict of interest: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers' bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Chinese Herbal Medicine (CHM) may have a place in the treatment of obstructive sleep apnoea (OSA), but the evidence has not been systematically assessed. The objective of this study is to evaluate the evidence for the effectiveness of CHM for OSA., Methods: CENTRAL, EMBase, PubMed, CINAHL, CNKI, Wanfang and Chongqing VIP were searched from database inception to the 13th of August 2023. Randomised-controlled trials in which the effect of CHM on sleep variables was tested in the treatment of OSA were selected. The primary outcomes of this review and meta-analysis were the apnoea hypopnoea index (AHI) measured with polysomnography., Results: A total of 58 studies, involving 4,590 participants, were included. The meta-analysis showed that CHM reduced AHI more significantly than placebo (mean difference = -7.10 events/hour, 95% CI = -11.95, -2.25, P < 0.01, 7 studies, 583 participants) and the combination of CHM and Continuous Positive Airway Pressure (CPAP) more effective than CPAP alone (mean difference = -4.71 events/hour, 95% CI = -5.62, -3.80, P < 0.001, 28 studies, 2,267 participants). CHM improved sleepiness, quality of life, body weight, oxidative biomarkers, inflammatory biomarkers, cognitive function, blood pressure and respiratory function., Conclusion: Our results suggest that CHM, alone and as an adjunct treatment, can improve various aspects of OSA and its comorbidities and is therefore a viable therapeutic option for OSA., Competing Interests: Declarations. Ethical approval: This article does not contain any studies with human participants performed by any of the authors. Competing interests: All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Norepinephrine reuptake inhibitors such as atomoxetine (ato) can improve OSA by increasing pharyngeal muscle activity. Mineralocorticoid antagonists such as spironolactone, may potentiate the reduction of OSA severity and reduce blood pressure. We evaluated whether adding spironolactone to atomoxetine (ato-spiro) improved responses in hypertensive OSA patients., Methods: Twenty-one patients with an apnea-hypopnea index (AHI) between 10 and 50 events/h and a history of hypertension were recruited and crossed-over in random order to ato 80 mg and ato-spiro 80/50 mg for 1 week after a 3-day low dose run-in period. Two dropped out due to drug related side effects. Polysomnography and 24-hour blood pressure (BP) monitoring were performed at baseline and after each treatment period., Results: AHI decreased on both ato and ato-spiro from a baseline median(IQR) of 20.3(18.8 to 28.5) to 8.2(7 to 13.1) and 6.2(5.7 to 14.1), respectively (p < 0.001 for both). Systolic BP (mmHg) fell by mean(95%CI) -4.5(-13.8 to 4.8, p = 0.33) on ato and - 10.3(-19.2 to -1.5, p = 0.02) on ato-spiro, and diastolic BP dropped by -3.0(-8.0 to 2.0, p = 0.23) on ato and - 5.0(-9.1 to -0.9; p = 0.02) on ato-spiro. Both ato and ato-spiro led to a significant shift from apnea to hypopnea predominance (p < 0.001), and significant reductions in hypoxic burden (p ≤ 0.001) and REM sleep (p ≤ 0.001)., Conclusions: Both ato-spiro and ato alone decreased OSA severity similarly, but ato-spiro led to even greater, statistically significant and clinically meaningful falls in systolic and diastolic BP. BP reductions were likely due to ato-related improvements in upper airway patency and hypoxemia, and to spiro-related reduced fluid retention. These findings show promise for ato-spiro as an oral treatment for hypertensive OSA patients. REGISTERED AT CLINICALTRIALS.GOV: NCT04905979., Competing Interests: Declarations Ethical approval All procedures performed in studies involving human participants were in accordance with the ethical standards of the (place name of institution and/or national research committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Name of the ethic committee Advarra, 6100 Merriweather Dr. Ste 600, Columbia, MD 21044. Conflict of interest Within the past two years, AS reports sponsored research from NIH/NHLBI, Apnimed, Itamar/Zoll, and Periodic Breathing LLC. AS provided consultancy for Apnimed, Humannity Foundation, Invicta Medical, Itamar/Zoll, LivaNova, Lunair, Nyxoah, Periodic Breathing, Respicardia/Zoll, Sonosa. RB reports sponsored research for Apnimed, Avadel, Axsome, Bresotec, Bayer, Idorsia, Suven, Jazz, Balance, NLS, Vanda, Merck, Eisai, Philips, Fresca, Takeda, Liva Nova, Roche, Sanofi, Sommetrics, Noctrix, Oura. RB provided consultancy to Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, Oventus, Axsome. He provided consultancy for Jazz Pharmaceuticals, Harmony Biosciences, Avadel Pharmaceuticals, Takeda, Oventus, Axsome. Speakers Bureau for Jazz, Eisai, Harmony, Axsome, Idorsia. RB is a shareholder of WaterMark Medical, Healthy Humming, LLC and sits on the board of directors of WaterMark Medical. BC reports sponsored research from Apnimed, Avadel, Axsome, Harmony, Jazz, NLS, Takeda, Zefra Therapeutics. BC has been consultant for Avadel and speaker for Axsome and Jazz Pharmaceuticals. HP and LT-M are Apnimed employees. LH has no conflict to disclose., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: Obstructive sleep apnea (OSA) is a common clinical problem that is associated with adverse cardiovascular outcomes attributed to the oxidative stress due to sympathetic overstimulation. Treatment approaches targeting oxidative stress have been tried by multiple investigators. This systematic review and meta-analysis evaluated the efficacy and safety of such approaches., Methods: Pubmed and Embase databases were searched for human studies evaluating the utility of antioxidant therapies in patients with OSA., Results: A total of six studies (five randomized trials and one case-control study) were included, including 160 patients with OSA using N-acetyl cysteine, vitamin C, carbocysteine, superoxide dismutase, vitamin E, allopurinol, and their combinations. There was a significant improvement in flow-mediated dilatation (FMD) following antioxidants, with the pooled effect being 2.16 % (95% CI 1.65-2.67) using the random-effects model (I2 = 0% and p<0.001). It was also associated with a significant reduction in malondialdehyde levels and an increase in reduced glutathione (GSH) levels. There was also a significant improvement in the Epworth sleepiness scale, oxygen desaturation index, and minimum oxygen saturation during sleep without any significant adverse effects., Conclusion: Antioxidant therapy in patients with OSA is associated with improved endothelial function, reduced oxidative stress, and improved sleep parameters. These results call for future multicentre studies with longer follow-ups to assess the utility of antioxidant therapy in patients with OSA., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The increased incidence of hypertension associated with obstructive sleep apnea (OSA) presents significant physical, psychological, and economic challenges. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a role in both OSA and hypertension, yet the therapeutic potential of PPARγ agonists and antagonists for OSA-related hypertension remains unexplored. Therefore, we constructed a chronic intermittent hypoxia (CIH)-induced hypertension rat model that mimics the pathogenesis of OSA-related hypertension in humans. The model involved administering PPARγ agonist rosiglitazone (RSG), PPARγ antagonist GW9662, or normal saline, followed by regular monitoring of blood pressure and thoracic aorta analysis using staining and electron microscopy. Intriguingly, our results indicated that both RSG and GW9662 appeared to potently counteract CIH-induced hypertension. In silico study suggested that GW9662's antihypertensive effect might mediated through angiotensin II receptor type 1 (AGTR1). Our findings provide insights into the mechanisms of OSA-related hypertension and propose novel therapeutic targets., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Obstructive sleep apnea (OSA) is often associated with glycemic abnormalities. This study is conducted to investigate the effects of hypoglycemic therapy on OSA-related indicators., Method: We systematically searched Web of Science, PubMed, Embase, and the Cochrane Library for articles on OSA patients receiving any hypoglycemic drugs, published until December 25, 2022. Seven original studies were finally included. The proposal was registered with PROSPERO (CRD42022351206)., Results: In summary, in addition to reduced glycosylated hemoglobin A1c (HbA1c), we found that hypoglycemic treatment can lower the apnea-hypopnea index (AHI) by 7.07/h (p = 0.0001). Although long-term treatment (> 12 weeks) achieved a more significant reduction in HbA1c (- 1.57% vs. - 0.30%) compared to short-term treatment (≤ 12 weeks), there was no significant difference between the two in terms of AHI (intergroup p-value = 0.27). We also found that patients using sodium glucose cotransporter 2 inhibitors (SGLT2i) experienced a greater reduction in AHI (- 11.00/h, p < 0.00001). Additionally, hypoglycemic treatment also showed certain improvements in related indicators like Epworth Sleepiness Scale, body mass index, and blood pressure., Conclusions: Our results affirm the benefits of hypoglycemic treatment for OSA patients and highlight the notable effect of SGLT2i. Further researches are needed to help doctors gain a comprehensive understanding of the interaction between OSA and glycemic abnormalities., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: The recent discovery of new therapeutic approaches to heart failure with reduced ejection fraction (HFrEF), including sodium-glucose cotransporter-2 (SGLT-2) inhibitors, as well as improved treatment of co-morbidities has provided much needed help to HFrEF. In addition, dapagliflozin, one of the SGLT-2 inhibitors, serves as a promising candidate in treating obstructive sleep apnea (OSA) of HFrEF patients due to its likely mechanism of countering the pathophysiology of OSA of HFrEF., Methods: This 3-month multicenter, prospective, randomized controlled trial enrolled participants with left ventricular ejection fraction (LVEF) less than 40% and apnea-hypopnea index (AHI) greater than 15. Participants were randomized into two groups: the treatment group received optimized heart failure treatment and standard-dose dapagliflozin, while the control group only received optimized heart failure treatment. The primary endpoint was the difference in AHI before and after treatment between the two groups. Secondary endpoints included oxygen desaturation index (ODI), minimum oxygen saturation, longest apnea duration, inflammatory factors (CRP, IL-6), quality of life score, and LVEF., Results: A total of 107 patients were included in the final analysis. AHI, LVEF and other baseline data were similar for the dapagliflozin and control groups. After 12 weeks of dapagliflozin treatment, the dapagliflozin group showed significant improvements in sleep parameters including AHI, HI, longest pause time, ODI, time spent with SpO 2  < 90%, and average SpO 2 . Meanwhile, the control group showed no significant changes in sleep parameters, but did demonstrate significant improvements in left ventricular end-diastolic diameter, LVEF, and NT-proBNP levels at 12 weeks. In the experimental group, BMI was significantly reduced, and there were improvements in ESS score, MLHFQ score, and EQ-5D-3L score, as well as significant reductions in CRP and IL-6 levels, while the CRP and IL-6 levels were not improved in the control group. The decrease in LVEF was more significant in the experimental group compared to the control group. There were no significant differences in the magnitude of the decreases between the two groups., Conclusions: Dapagliflozin may be an effective treatment for heart failure complicated with OSA, and could be considered as a potential new treatment for OSA. (Trial registration  www.chictr.org.cn , ChiCTR2100049834. Registered 10 August 2021)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To observe the efficacy and side effects of liraglutide in the treatment of type 2 diabetes mellitus (T2DM) patients with severe obstructive sleep apnea (OSA)., Methods: The study conducted in an outpatient setting was a two-center, prospective randomized controlled study. T2DM patients with severe OSA were randomized to the control group (continuous positive airway pressure [CPAP] and drug treatment without liraglutide) or the liraglutide group (CPAP and drug treatment including liraglutide). Demographic and clinical characteristics, sleep-disordered breathing indices, cardiac function indices, and side effects were evaluated and compared between the two groups before and after 3 months., Results: Of 90 patients, 45 were randomized to the intervention arm (with liraglutide) and 45 to the control arm (without liraglutide). One patient in the liraglutide group dropped out of the study on day 8 after enrollment due to obvious gastrointestinal symptoms. No significant differences were found between the two groups in baseline demographics, clinical characteristics, cardiac function indicators, or sleep disorder respiratory indices (P > 0.05). After 3 months, the body mass index (BMI), apnea hypopnea index (AHI), and mean systolic blood pressure in the liraglutide treatment group were significantly lower than those in the control group (P < 0.05). The minimum oxygen saturation was significantly higher in the liraglutide group compared with that in the control group after 3 months of follow-up (P < 0.05). No difference was found between the two groups in the summary of side effects (P > 0.05)., Conclusions: Liraglutide combined with CPAP can effectively reduce BMI, lower mean systolic blood pressure, and improve AHI scores and hypoxia in T2DM patients with severe OSA. Liraglutide did not increase side effects., (© 2022. The Author(s).)

Purpose: The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA., Methods: In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term "sleep apnea syndrome." A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA., Results: Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m 2 ; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28-0.96; P = 0.04)., Conclusions: In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA., Clinicaltrials: gov identifier: NCT01986881., (© 2022. Pfizer Inc. and The Author(s).)

Objective: This study aimed to evaluate the effect of sacubitril-valsartan (SV) on central apneas (CA) and obstructive apneas (OA) in patients with heart failure with reduced ejection fraction (HFrEF)., Methods: In patients with HFrEF, SV initiation was titrated to the highest tolerable dosage. Patients were evaluated with portable apnea monitoring, echocardiography, and cardiopulmonary exercise testing at baseline and 3 months later., Results: Of a total of 18 patients, 9 (50%) had OA, 7 (39%) had CA, and 2 (11%) had normal breathing. SV therapy was related to a reduction in NT-pro BNP and an improvement in LV function after 3 months. Portable apnea monitoring revealed a significant decrease of the respiratory event index (REI) after treatment with SV (20 ± 23 events/h to 7 ± 7 events/h, p = 0.003). When subgrouping according to type of apneas, REI, and time spent below 90% saturation (T90) decreased in patients with CA and OA (all p < 0.05)., Conclusion: In this prospective study, SV treatment for 3 months in patients with CA and OA is associated with a significant decrease in REI., (© 2022. The Author(s).)

Purpose: Obstructive sleep apnoea (OSA) is a common condition with a range of short- and long-term health implications. Providing patient-centred care is a key principle to ensure patients are well informed and empowered to participate in clinical decision making. This study aimed to develop a patient-centred sleep study report for patients with obstructive sleep apnoea and to determine whether or not its implementation led to improved patient understanding of their disease., Methods: The study was performed in two phases. The first phase utilised the Delphi-survey technique to develop and critically appraise a patient-centred sleep study report (PCSR) for patients with OSA, to accurately and simply convey key components of the patient's diagnosis and management. The second phase was a prospective, randomised controlled trial to assess the effect of the PCSR on patient knowledge, self-efficacy, and understanding as measured through validated patient questionnaires., Results: The PCSR was developed on key concepts deemed to be important by the surveyed physicians, senior sleep scientists and patients. This included ensuring the results were customised, highlighting the patient's apnoea-hypopnea index, oxygen desaturation index and arousal index and limiting technical information to a few key pieces. Patients randomised to receive the PCSR had improved understanding and perceived patient-physician interaction compared to those randomised to standard care., Conclusion: The development and implementation of the PCSR was feasible and improved patient understanding and perceived patient-physician interaction in patients with moderate to severe OSA. Whether or not use of the PCSR will translate to improved compliance with therapy will require further evaluation., (© 2022. The Author(s).)

Purpose: This systematic review sought to answer the following focused question: "What are the effects of respiratory training devices on obstructive sleep apnea (OSA) outcomes in adults?" METHODS : The acronym "PICOS" was used to determine eligibility criteria, which consists of (P population) = adults with mild to moderate OSA, (I intervention) = spirometry devices or breathing exercises, (C comparison) = compared to no breathing exercises in adults (> 18 years) with mild to moderate OSA, (O outcomes) = improved sleep quality (sleep quality indexes) and improved apnea-hypopnea indexes (AHI), (S study types) = randomized, pseudo-randomized, and non-randomized clinical trials. The search was performed in the following databases: PubMed/Medline, LILACS, Scopus, Web of Science, Scopus, and Cochrane Library, in addition to gray literature through Google Scholar, Proquest, and Open Grey. The risk of bias was assessed using the Cochrane Collaboration tool. The certainty of the evidence was assessed using the GRADE tool. Meta-analyses of random effects were performed for the outcomes of interest., Results: A total of 1171 references were found. Applying the eligibility criteria, six studies were included in qualitative synthesis. Expiratory exercises showed a decrease in the apnea-hypopnea index (AHI) when compared to baseline (MD =  - 8.4; 95% CI =  - 12.4 to - 4.4; I 2  = 19%). There was a decrease in values compared to baseline (MD =  - 4.4; 95% CI =  - 8.2 to - 0.6; I 2  = 0%) for the Epworth Sleepiness Scale (ESS), when considering the inspiratory exercises. Both groups of breathing exercises showed a significant decrease in the mean index assessed by the Pittsburgh Sleep Quality Index (PSQI)., Conclusion: Results of this meta-analysis suggests that breathing exercises lead to a measurable improvement in AHI for patients with mild to moderate OSA, as well as an improvement in sleep quality and daytime sleepiness., Systematic Review Registration: CRD42020148513 (PROSPERO)., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background and Objective: Obstructive sleep apnea (OSA) is associated with hypertension, psychological impairment, neurocognitive dysfunction, and poor quality of sleep. Continuous positive airway pressure (CPAP) has been confirmed to effectively improve OSA, while the effects of supplemental oxygen therapy on OSA have still remained controversial. This meta-analysis aimed to compare the effects of supplemental oxygen therapy and CPAP on patients with OSA., Methods: PubMed, Cochrane library, EMBASE, and Web of Science databases were systematically searched from inception until April 2020. Randomized controlled trials (RCTs) that compared the effects of supplemental oxygen therapy and CPAP on patients with OSA were selected without language restriction., Results: In this meta-analysis, 8 RCTs that involved 887 patients were found eligible for further analyses. Pooled data showed that there was no significant difference in improving nocturnal oxygen saturation (SpO 2 ) level (95% confidence interval (CI) = - 1.17 to 1.53) or symptoms of depression (95%CI = - 0.69 to 1.19) between supplemental oxygen therapy and CPAP. Supplemental oxygen therapy was found less effective in reducing apnea-hypopnea index (AHI), time of SpO 2 < 90%, blood pressure, and improving quality of sleep compared with CPAP. A subgroup analysis based on flow rate of oxygen indicated that the effects of supplemental oxygen therapy on blood pressure significantly differed. Furthermore, an improvement in overall time of SpO 2 < 90% was correlated to duration of supplemental oxygen therapy., Conclusions: CPAP is clinically effective for the treatment of patients with OSA. However, supplemental oxygen therapy can be cautiously used for improving nocturnal hypoxia and symptoms of depression when CPAP is not acceptable or not tolerated. Supplemental oxygen therapy is a promising option to alleviate partial disorders of OSA. Further studies need to focus on flow rate of oxygen and duration of supplemental oxygen therapy., (© 2021. Springer Nature Switzerland AG.)

Purpose: This study estimated thresholds for clinically important responses and minimally important differences for two indicators of improvement for the 10-item version of the functional outcomes of sleep questionnaire (FOSQ-10)., Methods: Participants with excessive daytime sleepiness with narcolepsy or obstructive sleep apnea received 12 weeks of solriamfetol treatment. Participants completed the FOSQ-10 and other patient-reported outcome measures, including the single-item patient global impression of change (PGI-C) assessment. Clinicians completed the single-item clinician global impression of change (CGI-C) for each participant. Data from the two studies were analyzed separately, both without regard to treatment assignment. In total, 690 participants (47% female, mean age 48 years, 77% Caucasian, 91% from North America) were enrolled. Two clinically important changes, defined as a minimally important difference and a clinically important response, were determined using distribution and anchor-based analyses. A receiver operating characteristic analysis was used to determine the optimal FOSQ-10 change threshold., Results: Spearman correlations between change in FOSQ-10 scores and PGI-C and CGI-C were - 0.57 and - 0.49 for participants with narcolepsy and - 0.42 and - 0.37 for participants with obstructive sleep apnea. Receiver operating characteristic analysis suggested minimally important difference and clinically important response estimates of 1.7 and 2.5 and 1.8 and 2.2 points in narcolepsy and obstructive sleep apnea, respectively., Conclusions: Minimally important difference and clinically important response estimates for the FOSQ-10 for adults with excessive daytime sleepiness in narcolepsy or obstructive sleep apnea will be helpful for interpreting changes over time and defining a clinical responder. CLINICALTRIALS., Gov Identifiers: NCT02348593 (first submitted January 15, 2015) and NCT02348606 (first submitted January 15, 2015)., (© 2021. The Author(s).)

Purpose: Obstructive sleep apnea (OSA) is a disorder characterized by recurrent episodes of obstruction of the upper respiratory tract during sleep often accompanied by oxygen desaturations. Antioxidant defense mechanisms are important to prevent OSA-associated diseases and decrease mortality. We aimed to determine the levels of selenium and vitamins A, C, and E in patients with OSA but without any comorbidities and compare the results with a control group, theorizing that the findings may be helpful to understand the antioxidant mechanisms in the pathogenesis of OSA and associated diseases., Methods: We designed a case-control study with 146 subjects. Subjects were categorized into four groups by apnea-hypopnea index (AHI) scores: control (n = 32; AHI < 5), mild OSA (n = 32; 5 ≤ AHI < 15), moderate OSA (n = 34; 15 ≤ AHI < 30), and severe OSA (n = 48; AHI ≥ 30) groups. Serum levels of selenium were measured by atomic absorption spectrometer. Vitamin A, C, and E levels were measured by high-performance liquid chromatography and ultraviolet (HPLC-UV) detector., Results: After adjusting for age, BMI, and gender, serum selenium and vitamin A levels were found to be higher in patients with OSA compared with controls (ANCOVA, p < 0.008, and p = 0.014 respectively), and levels of these markers increased with the severity of the disease. AHI was positively correlated with selenium (r = 0.289; p < 0.001), and vitamin A levels (r = 0.276; p < 0.001)., Conclusion: These results demonstrated that antioxidant response with increased vitamin A, and selenium concentrations, may be important defense mechanisms in patients with OSA patients who do not have other comorbidities. Antioxidant nutrients or supplements may be implemented as a complementary treatment of OSA to support antioxidant defense.

Purpose: Intermittent hypoxia is a characteristic pathological change in obstructive sleep apnoea (OSA) that can initiate oxidative stress reaction and pro-inflammatory cytokine release. The purpose of this study was to assess the effect and protective mechanism of Astragaloside IV (AS-IV) in intermittent hypoxia-induced human lung epithelial Beas-2B cells., Methods: Human lung epithelial Beas-2B cells were exposed to intermittent hypoxia or normoxia in the absence or presence of AS-IV. MTT assay was performed to determine the cell viability. The levels of reactive oxygen species (ROS), lactate dehydrogenase (LDH), malonaldehyde (MDA), and superoxide dismutase (SOD) were measured to evaluate oxidative stress. The levels of cytokines interleukin (IL)-8, IL-1β, and IL-6 were evaluated by enzyme-linked immunosorbent assay and real-time PCR. The expression of Toll-like receptor 4 (TLR4), mitogen-activated protein kinase (MAPK), and nuclear transcription factor-kappa B (NF-κB) signalling pathways was analysed by western blot., Results: The results showed that AS-IV significantly reduced the levels of ROS, LDH, MDA, IL-8, IL-1β, and IL-6, and increased the level of SOD in intermittent hypoxia-induced Beas-2B cells. It also suppressed the phosphorylation of MAPKs, including P38, c-Jun N-terminal kinase and extracellular signal-regulated kinase, and inhibited the activation of the NF-κB signalling pathway by reducing the phosphorylation of IκBα and p65., Conclusions: AS-IV attenuates inflammation and oxidative stress by inhibiting TLR4-mediated MAPK/NF-κB signalling pathways in intermittent hypoxia-induced Beas-2B cells.

Purpose: To establish the efficacy of oral antidepressants compared to placebo in improving obstructive sleep apnea (OSA) as measured on a polysomnography study. Secondary outcomes included self-reported sleepiness., Methods: Authors identified prospective randomized placebo-controlled studies from MEDLINE through PubMed, Web of Science, the Cochrane Library and EMBASE up to February 2019 in English language. Antidepressants included tricyclic antidepressants (TCA), tetracyclic antidepressants (TeCA), selective serotonin reuptake inhibitors (SSRI), and serotonin receptor modulators (SRM). Studies were assessed for inclusion and exclusion criteria, as well as risk of bias based on the Cochrane handbook., Results: The initial search yielded 254 unduplicated references ultimately reduced to 8 relevant studies, in which 198 OSA participants were included. Patients with an average baseline AHI of 26.7 events/hour taking 15-45mg mirtazapine had a statistically significant reduction in apnea-hypopnea index compared to placebo by -10.5 events/hour (p<0.001), apnea index by -3.6 events/hour (p=0.001) and hypopnea index by -5.9 events/hour (p=0.037). In one study, patients taking 100mg trazodone 1 night improved significantly in AHI compared to placebo group (p<0.001). Arousal index, sleepiness, and sleep efficiency were not statistically significantly reduced with any antidepressant medication compared to placebo (p>0.05)., Conclusions: Of the five antidepressant medications studied, only mirtazapine and trazadone showed a statistically significant reduction in AHI in the treated groups but not in sleepiness scale nor an increase in sleep efficiency. In this review, the total sample sizes were small, adverse side effects of some of the antidepressant medications were clinically significant, overall risk of bias of the studies was high or unclear, and overall quality of the evidence was low. Based on the evidence available at this time, we cannot recommend the antidepressants studied in the treatment of OSA.

Epidemiological studies showing the higher frequency of obstructive sleep apnea hypopnea syndrome in men, polycystic ovary syndrome (PCOS), and in post-menopausal women suggest the beneficial role of estrogen. These findings are well supported by the pre-clinical studies (ten research studies described in this review) showing that estrogen and phytoestrogens attenuate the deleterious effects of chronic intermittent hypoxia (obstructive apnea in animals) on the genioglossal muscles and on other organs (co-morbidities) in ovariectomized rodents. Moreover, clinical studies (four research studies described in this review) have also shown the beneficial role of estrogen therapy on the parameters of obstructive apnea in post-menopausal women. The beneficial effects of estrogen and phytoestrogens on obstructive sleep apnea and its co morbidities have been attributed to increase in thioredoxin, Nrf-2, activation of p38 MAP kinases, inhibition of vagal C fibers, and attenuation of HIF-1α. It is possible that estrogen-mediated activation of p38 MAP kinase may inhibit HIF-1α to attenuate lung inflammation, which may inhibit the activation of vagal C fibers to attenuate bronchoconstriction and prevent obstruction during sleep. Moreover, estrogen-mediated increase in thioredoxin and Nrf-2 may also contribute in increasing antioxidant defense and attenuating inflammation.

Purpose: β-Blocker use has been controversial for a long time in the management of hypertensive patients with obstructive sleep apnea (OSA). The aim of present study was to compare the effects of metoprolol on BP lowering with amlodipine in hypertensive OSA patients., Methods: Hypertensive subjects with OSA were randomly assigned to metoprolol and amlodipine groups, receiving 12 weeks of oral either metoprolol (47.5 mg once daily) or amlodipine (5 mg once daily) treatment. At baseline and after the 12-week treatment period, 24-h ambulatory blood pressure monitoring was performed in both groups., Results: Both of metoprolol and amlodipine treatments significantly lowered 24-h blood pressure (BP) (from 143/88 to 132.3/81.6 mmHg; from 141.3/84.5 to 133.7/80.8 mmHg), daytime BP (from 146/90.2 to 136.4/84.6 mmHg; from 145.1/87.6 to 138.2/84.1 mmHg), and nighttime BP (from 139.1/83.9 to 125.7/76.2 mmHg; from 134.5/78.5 to 125.8/74.1 mmHg) (all P < 0.05). But there were no significant differences between the groups in BP variability (P > 0.05). Besides, metoprolol significantly reduced daytime heart rate (HR) (P < 0.05), while 24-h and nighttime HR values had no remarkable changes compared with baseline (P > 0.05)., Conclusions: Metoprolol had similar therapeutic effects on BP lowering as amlodipine and could not decrease HR during the nighttime in hypertensive patients with OSA.

Purpose: During drug-induced sleep endoscopy (DISE) in patients with obstructive sleep apnea, the increased depth of propofol anesthesia is related to the increased collapsibility of the upper airway with dose-dependent. We examined the effect of remifentanil on propofol concentration during DISE., Methods: In a prospective randomized trial, 56 adult patients were divided into remifentanil-propofol (n = 28) and propofol alone (n = 28) groups. Anesthesia was administered using a target-controlled infusion system. In the remifentanil-propofol group, 0.5 ng/ml remifentanil was administered prior to propofol infusion and its concentration maintained; thereafter, in the propofol alone group, normal saline was injected instead of remifentanil. Propofol was infused at a concentration of 1.5 μg/ml after the target concentration of remifentanil was reached. In both groups, the concentration of propofol was increased by 0.5 μg/ml if the degree of sedation was not sufficient. The sedation level was targeted at observer's assessment of alertness/sedation (OAA/S) scale 3., Results: The mean propofol concentration was 2.87 ± 0.60 μg/ml in the remifentanil-propofol group, which was lower than that in the propofol alone group (3.38 ± 0.72 μg/ml, P < 0.001). The time until sufficient sedation to perform DISE was shorter in the remifentanil-propofol group (P < 0.001). Apnea-hypopnea index and the lowest peripheral capillary oxygen saturation (SpO 2 ) during polysomnography showed no statistical difference between groups (P > 0.05). The lowest SpO 2 and VOTE classification during DISE were also not statistically different (P > 0.05)., Conclusions: Use of remifentanil during DISE reduces the target concentration of propofol required for patient sedation to perform DISE without respiratory depression.

Background: Obstructive sleep apnea is a common disorder characterized by multiple pathogenetic roots. Continuous positive airway pressure (CPAP) is almost always prescribed as the first-line treatment to all patients regardless of the heterogeneous pathophysiology, because it mechanically splints the airways open and reduces the collapsibility of the upper airway. Despite its high efficacy, CPAP is burdened by poor adherence and compliance rates. In this pilot study, we treated OSA patients with composite approaches different than CPAP, tailoring the therapeutic choice on OSA phenotypic traits., Methods: We used the CPAP dial down technique to assess phenotypic traits in eight OSA patients with BMI<35. According to these traits, patients received personalized therapies for 2-week period, after which we ran a second polygraphy to compare apnea-hypopnea index (AHI) before and after therapy., Results: Two weeks of combined behavioral and pharmacological therapy induced a significant reduction in mean AHI, which dropped from 26 ± 15 at baseline to 9 ± 7 post-treatment (p = 0.01). Furthermore, there was a significant reduction in mean ODI (p = 0.03) and subjective sleepiness (p = 0.01) documented by Epworth Sleepiness Scale (ESS) from baseline to post-treatment recordings., Conclusions: Treating OSA patients with a personalized combination of pharmacological and behavioral therapies according to phenotypic traits leads to a significant improvement in AHI, ODI, and subjective sleepiness.

Purpose: The hypoxia and reoxygenation cycles in obstructive sleep apnea syndrome (OSAS) cause a change in the oxidative balance, leading to the formation of reactive oxygen species capable of reacting with other organic molecules impairing their functions. This study aimed to determine the best markers of oxidative stress in OSAS and what better antioxidant agent to be used to treat the disease., Methods: Searches were conducted in three different databases (PubMed, LILACS, SCIELO), using as descriptors the terms obstructive sleep apnea, oxidative stress, and antioxidant therapy. A total of 120 articles were found but only those considered of interest to the research were selected. Thus, 10 articles were included for further analysis regarding the biomarkers of oxidative stress in OSAS, and 6 articles to evaluate the antioxidant most often used for demonstration of efficacy., Results: The thioredoxin, malondialdehyde, superoxide dysmutase, and reduced iron were the most commonly used biomarkers and showed a more consistent relationship between increased oxidative stress and OSAS. As antioxidant therapy, vitamin C and N-acetylcysteine (NAC) presented interesting results as a reduction of oxidative stress, which may become an alternative to the complementary treatment of OSAS., Conclusions: This review's findings agree mostly to measure that the markers of oxidative stress in OSAS may be a contributing aspect to assessment and monitoring of patient, and the antioxidant therapy appears to be beneficial in the treatment of OSAS.

Purpose: Obstructive sleep apnea (OSA) results from upper airway (UA) obstruction. In Parkinson's disease (PD), levodopa improves UA obstruction during wakefulness. We hypothesized that bedtime controlled-release levodopa (Sinemet CR) is associated with less severe OSA (lower apnea-hypopnea index [AHI]) in PD patients., Methods: Idiopathic PD subjects underwent nocturnal polysomnography (PSG) and were divided into those taking bedtime Sinemet CR (SinCR+) and those not taking Sinemet CR (SinCR-). Outcomes were compared between groups for PSG recordings analyzed in whole and split at their mid-point with each half analyzed separately, using linear regression., Results: Fifty-seven subjects were studied, eight SinCR+, and 49 SinCR-. They were 65 % male, aged 64.4 ± 10.3 years (mean ± SD), with body mass index 27.26 ± 3.98 kg/m(2). The whole night AHI was 15.6 ± 13.3 and 29.1 ± 20.8 in SinCR+ and SinCR-, respectively (p = 0.07 unadjusted, p = 0.11 adjusted for confounders). A similar trend was observed in the first half of the night. In the second half, the SinCR+ group had significantly lower AHI (beta = -18.8; p = 0.01 adjusted) and respiratory arousal index (beta = -14.2; p = 0.02 adjusted) than the SinCR- group., Conclusions: Bedtime Sinemet CR appears to reduce OSA in PD patients. There were no significant differences between groups in the first half of the night likely because of residual effects of short-acting levodopa in both groups, while Sinemet CR had residual effect in the second half. These results possibly provide an alternative to help manage OSA and improve sleep quality in PD patients.

Background: Previous studies have reported that selective serotonin reuptake inhibitors (SSRIs) might improve sleep-related breathing disorders (SRBDs). However, the effects of SSRIs on breathing are not evaluated in subjects without moderate-to-severe SRBDs. Further, many symptoms of depression and SRBDs overlap, and so, it is interesting whether there are interactions between breathing and psychopathologic symptoms during SSRI treatment for depression., Methods: Data were taken from an open-label 8-week trial of sertraline in depressed patients with insomnia (n = 31). The depressed patients were administered 50 mg sertraline at 8 AM on the first day, and the dosage was subsequently titrated up to a maximum of 200 mg/day during the 8-week trial. All the patients were tested by repeated polysomnography (PSG) (baseline, 1st day, 14th day, 28th day, and 56th day). Sleep-disordered breathing events were categorized as apneas, hypopneas, and respiratory event-related arousals (RERAs)., Results: The clinical responses and PSG characteristics improved continuously during the 8-week trial. From the 14th day on, the RERA index during all-night and non-rapid eye movement (NREM) sleep became stable and significantly higher than baseline and the first day (RERA index 7.3 ± 2.2 at baseline, 7.3 ± 2.5 on the 1st day, 4.4 ± 1.9 on the 14th day, 3.9 ± 1.3 on the 28th day, 4.2 ± 2.0 on the 56th day, F = 5.71, P = 0.02; NREM-RERA index 6.2 ± 2.0 at baseline, 6.3 ± 2.3 on the 1st day, 3.2 ± 1.5 on the 14th day, 3.5 ± 0.9 on the 28th day, 3.2 ± 1.7 on the 56th day, F = 4.92, P = 0.03). Additionally, the NREM-apnea index showed a similar pattern to that of the RERA index and reached a significant difference between baseline (1.0 ± 0.5) and the 14th day (0.5 ± 0.4) (KW = 4.28, P = 0.047). Compared to the no-improvement group, the improvement group with a decreasing score rate of the respiratory disturbance index (RDI) greater than or equal to -50 % had a more positive decreasing score rate of slow wave sleep (SWS) (439.0 ± 78.2 vs 373.2 ± 77.9 %, T = 3.46, P = 0.04) and a more negative decreasing score rate on the arousal index (-43.7 ± 16.7 vs -26.6 ± 9.7 %, T = 9.16, P = 0.01), Pittsburgh Sleep Quality Index (PSQI) scores (-65.1 ± 33.7 vs -49.6 ± 21.4 %, T = 4.74, P = 0.05), and Epworth Sleepiness Scale (ESS) scores (-55.7 ± 21.3 vs -36.4 ± 17.5 %, T = 6.44, P = 0.02)., Discussion: This research indicates that SRBDs could be improved to some extent by sertraline treatment, which might be more common in patients with relatively more severe sleep-disordered breathing (e.g., RDI ≥ 10 in the current study). Although the sertraline-induced SRBD improvement seems not to have a significant clinical effect, the SRBD improvement group with decreasing score rate of RDI greater than or equal to -50 % has better subjective and objective sleep aspects than the no-improvement group. Thus, the fact that the SRBDs' improvement was related to SSRIs might have a potential clinical benefit in the antidepressant treatment.

Background: Snoring is the sound produced by the vibration of the soft tissues caused by the air passing through a narrow upper airway during sleep. It is usually associated with the conditions that increase upper airway resistance, but can occur in their absence too (primary snoring). Considering its sheer prevalence, the associated comorbidities, like carotid atherosclerosis and the social disorder that it can represent, treatment for snoring must be considered even in the absence of any other medical condition. Treatment options include conservative approaches like weight reduction, smoking and alcohol cessation, sleep positioning, mechanical nasal dilators, and continuous positive airway pressure (CPAP) to more radical approaches like surgery. Till date, we have no drugs for treating the primary pathology of snoring., Methods: A systematic literature search was carried out in PUBMED and EMBASE, and we found only nine randomized control trial's and one interventional study focusing on the pharmacotherapy of snoring per se, even as the literature is replete with studies evaluating drug therapy for obstructive sleep apnea., Result: Drugs evaluated include protriptyline, pseudoephedrine and domperidone, mometasone, nasal surfactant, Botulinum toxin type A, and some homeopathic and oil-based nasal sprays. The selected studies showed no strength in data and had a great methodological heterogeneity, so it is impossible to compare the analyzed studies., Discussion: Even though there are no consistent data to support pharmacologic treatment for primary snoring, through the critical analysis of these studies, we have discussed about the future directions for clinical trials in this area to arrive at a clinically meaningful decision.

Atrial fibrillation and obstructive sleep apnea are responsible for significant morbidity and mortality in the industrialized world. There is a high medical need for novel drugs against both diseases, and here, Kv1.5 channels have emerged as promising drug targets. In humans, TASK-1 has an atrium-specific expression and TASK-1 is also abundantly expressed in the hypoglossal motor nucleus. We asked whether known Kv1.5 channel blockers, effective against atrial fibrillation and/or obstructive sleep apnea, modulate TASK-1 channels. Therefore, we tested Kv1.5 blockers with different chemical structures for their TASK-1 affinity, utilizing two-electrode voltage clamp (TEVC) recordings in Xenopus oocytes. Despite the low structural conservation of Kv1.5 and TASK-1 channels, we found all Kv1.5 blockers analyzed to be even more effective on TASK-1 than on Kv1.5. For instance, the half-maximal inhibitory concentration (IC50) values of AVE0118 and AVE1231 (A293) were 10- and 43-fold lower on TASK-1. Also for MSD-D, ICAGEN-4, S20951 (A1899), and S9947, the IC50 values were 1.4- to 70-fold lower than for Kv1.5. To describe this phenomenon on a molecular level, we used in silico models and identified unexpected structural similarities between the two drug binding sites. Kv1.5 blockers, like AVE0118 and AVE1231, which are promising drugs against atrial fibrillation or obstructive sleep apnea, are in fact potent TASK-1 blockers. Accordingly, block of TASK-1 channels by these compounds might contribute to the clinical effectiveness of these drugs. The higher affinity of these blockers for TASK-1 channels suggests that TASK-1 might be an unrecognized molecular target of Kv1.5 blockers effective in atrial fibrillation or obstructive sleep apnea.

Purpose: Assessment of stroke risk and implementation of appropriate antithrombotic therapy is an important issue in atrial fibrillation patients. Current risk scores do not take into consideration the comorbidities associated with elevated thromboembolic like obstructive sleep apnea (OSA). The aim of the study was to establish whether atrial fibrillation patients with coexisting OSA have higher stroke risk according to CHADS2 and CHA2DS2-VASc scores., Methods: Two hundred fifty-four consecutive patients hospitalized with a primary diagnosis of atrial fibrillation participated in the study. All patients underwent whole night polygraphy and were scored in both CHADS2 and CHA2DS2-VASc according to their medical records or de novo diagnosis., Results: The study population was predominantly male (65.4%; mean age, 57.5 ± 10.0 years) with a high prevalence of hypertension (73.6%), dyslipidemia (63.4%), and obesity (42.9%). OSA was present in 47.6% of patients, who more often had history of stroke (p = 0.0007). Stroke risk profile assessed by both CHADS2 and CHA2DS2-VASc scores was higher in patients with OSA (1.2 ± 0.9 vs. 0.8 ± 0.6; p < 0.0001 and 2.2 ± 1.7 vs. 1.5 ± 1.1; p = 0.001) than without it. Differences in the stroke risk remained significant across different age strata, and the trend for point values in CHADS2 and CHA2DS2-VASc scores rose along with OSA severity according to the apnea-hypopnea index (AHI; p for trend <0.001)., Conclusions: OSA was highly prevalent in atrial fibrillation patients. Patients with OSA have higher CHADS2 and CHA2DS2-VASc scores. Mean CHADS2 and CHA2DS2-VASc scores rise with OSA severity. Future studies should prospectively research on potential inclusion of OSA to stroke prediction models.

Sleep and wakefulness are regulated by complex brain circuits located in the brain stem, thalamus, subthalamus, hypothalamus, basal forebrain, and cerebral cortex. Wakefulness and NREM and REM sleep are modulated by the interactions between neurotransmitters that promote arousal and neurotransmitters that promote sleep. Various lines of evidence suggest that sleep disorders may negatively affect neuronal plasticity and cognitive function. Pharmacological treatments may alleviate these effects but may also have adverse side effects by themselves. This chapter discusses the relationship between sleep disorders, pharmacological treatments, and brain plasticity, including the treatment of insomnia, hypersomnias such as narcolepsy, restless legs syndrome (RLS), obstructive sleep apnea (OSA), and parasomnias.

Purpose: Although there is a high co-occurrence of insomnia and obstructive sleep apnea (OSA), the administration of sedative hypnotics in patients with OSA is still inconsistent. The aim is to study the effect of non-benzodiazepine hypnotics (non-BZDs) on sleep quality and severity in patients with OSA., Methods: We conducted a systemic search for controlled clinical trials in multiple databases and pooled analysis of the impact of non-BZDs on objective sleep quality and the severity of OSA, including the apnea-hypopnea index (AHI) and mean and nadir arterial oxygen saturation (SaO2) in patients with OSA. Sensitivity analysis was carried out to explore the robustness of results., Results: Eight relevant placebo-controlled clinical trials involving 448 patients were included. Objective sleep quality, including sleep latency, sleep efficiency, and wake time after sleep onset, was significantly improved in patients taking non-BZDs compared with those taking placebo (p<0.01). The weighted estimate indicated that the administration of non-BZDs prior to bedtime had no significant effect on AHI or SaO2 in OSA patients (p>0.05)., Conclusions: The administration of non-BZDs at the commonly recommended dose has been shown to improve objective sleep quality in OSA patients without worsening sleep apnea. It suggests that OSA patients with a complaint of insomnia symptoms may benefit from taking non-BZDs.

Purpose: The multi-organ involvement of mitochondrial diseases means that patients are likely to be more vulnerable to sleep disturbances. We aimed to assess if early recognition and treatment of obstructive sleep apnea (OSA) in patients with Leigh disease may influence primary disease outcome., Methods: We describe a case of adult-onset Leigh disease presenting as severe brainstem encephalopathy of subacute onset. Based on the clinical symptoms that developed after the appearance of the neurological disease, an attended overnight polysomnography examination was performed., Results: A marked clinical recovery was seen after administration of high doses of thiamine, coenzyme Q, L-carnitine, and vitamins C and E, combined with effective treatment with continuous positive airway pressure for the underlying severe obstructive sleep apnea (OSA). The latter condition was diagnosed on the basis of suggestive symptoms that appeared a few weeks before the establishment of the neurological disease. The improvement in the neurological disease (based on clinical and brain MRI features) with the appropriate medical treatment also resulted in a significant improvement in the OSA., Conclusions: Early recognition and treatment of sleep apnea may not only improve sleep and overall quality of life but also ameliorate the deleterious effects of nocturnal desaturations on the neurological features. This may be crucial for disease outcome when added to the generally advised pharmacological therapy.

Purpose: The influence of short-term severe thyroid hormone deficiency on sleep is currently still unknown. Several studies have demonstrated an effect of long-term hypothyroidism on sleep disorders due to anatomical changes of the pharynx or body mass. The aim of this preliminary study, however, is to evaluate the changes in sleep patterns of patients with short-term hypothyroidism to elucidate the isolated effect of thyroid hormone withdrawal before anatomical changes can potentially occur., Methods: Ten patients with differentiated thyroid carcinoma were enrolled in this study. Two patients discontinued the study and one patient was finally excluded due to obesity, so that the datasets of seven patients were available for study analysis. During the course of carcinoma treatment, each patient had previously undergone total thyroidectomy and I-131 remnant ablation. Polysomnographic measurements were performed twice: (1) over the course of two consecutive nights during severe thyroid hormone deficiency after levothyroxine withdrawal and prior to further diagnostics and therapy and (2) during euthyroidism after substitution with levothyroxine., Results: Comparison of the Epworth Sleepiness Scale during hypo- and euthyroidism for each patient revealed no statistically significant difference. Furthermore, the comparison of polysomnographic parameters like (1) apnea-hypopnea index, (2) the duration of various sleep stages, (3) duration of rapid eye movement sleep, (4) latency until rapid eye movement sleep, (5) total sleep time, (6) periodic leg movements, and (7) arousal index showed no statistically significant differences between the hypothyroid or euthyroid state., Conclusions: We conclude that, in this preliminary experimental setting, short-term severe thyroid hormone deficiency per se does not cause sleep disturbances and a feeling of fatigue as described in other studies may be due to changes in perception or brain metabolism during hypothyroidism.

Purpose: This study aims to report on catathrenia occurring in narcolepsy with cataplexy (NC) patients under sodium oxybate (SO) treatment. Catathrenia is a parasomnia characterized by groaning and an abnormal respiratory pattern during sleep., Methods: Fifty-one patients with NC and starting SO therapy underwent a baseline overnight polysomnography (PSG) to detect any sleep-related breathing disorders (SRBD). To avoid risks due to a possible central respiratory control depression by SO, all patients with concomitant obstructive sleep apnea (OSA) were treated with a nasal continuous positive airway pressure (nCPAP) device. After 2 months of treatment with SO, all patients underwent a follow-up overnight PSG to investigate possible newly occurring SRBD. They also underwent a semi-structured clinical interview to monitor other potential SO side effects., Results: At baseline, four out of 51 patients showed simple snoring, and eight, mild to severe OSA. After a titration PSG night, patients with OSA received a nCPAP device. After 2 months of SO treatment, 28 patients (54.9%) showed SO-related side effects, including SRBD in 11 (21.6%). The follow-up PSG showed a respiratory pattern characteristic of catathrenia in seven patients (13.7%) as a newly observed and possibly benign SO side effect, and ruled out a worsening of OSA., Conclusions: Catathrenia should be considered a possible side effect in NC patients under SO treatment and should be accurately identified to prevent unnecessary SO withdrawal.

Objectives: To measure apnea-hypopnea indices and snoring in children diagnosed with attention-deficit hyperactivity disorder (ADHD) in a case-control design. Additionally, the study design allowed us to investigate whether or not methylphenidate had any effect on breathing variables., Methods: Twenty-eight children (22 boys) aged 6-12 years meeting diagnostic criteria for Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV ADHD were studied together with matched controls. Two nights of polysomnography (PSG) were conducted that included recordings of snoring waveforms. A randomly assigned 48-h on-off medication protocol was used for ADHD children. Control children's recordings were matched for PSG night, but medication was not used. A low apnea-hypopnea index (AHI) threshold of >1 event per hour was used to define sleep-disordered breathing (SDB) because of a clinical relevance in ADHD., Results: Categorical analyses for paired binary data showed no significant differences between control and ADHD children for presence of an AHI >1 or snoring. Variables were extracted from a significantly shorter total sleep time (67 min) on the medication night in children with ADHD. Eight (28%) control and 11 (40%) ADHD children snored >60 dB some time during the night. Methylphenidate had no effect on central apneas, AHI, desaturation events, or any snoring data., Conclusions: Our PSG findings show no strong link between ADHD and SDB although our findings could be limited by a small sample size. Findings from PSG studies in the literature argue both for and against an association between ADHD and SDB. Our results suggest medication is not a factor in the debate.

Purpose: Sodium oxybate (SXB) is approved for cataplexy and excessive daytime sleepiness in narcolepsy. Obstructive sleep apnea syndrome (OSAS) affects ∼9-50% of narcoleptics. Effects of 2-week SXB administration on apnea-hypopnea index (AHI), oxygen saturation (SaO(2)), and sleep architecture were investigated in OSAS patients., Methods: OSAS patients (n = 48) received 2-week SXB or placebo (PBO) treatment with polysomnography at baseline and day 14. The primary outcome measure was change from baseline in mean AHI. Secondary outcomes included changes from baseline in SaO(2), and sleep architecture., Results: Compared with PBO, SXB significantly increased reduction in mean AHI and obstructive apnea index with SXB (-0.8 ± 13.3 vs. -8.2 ± 10.0; p = 0.0327 and 3.54 ± 11.1 vs. -4.72 ± 7.7; p = 0.0054, respectively) and significantly increased change in slow wave sleep duration (5.2 ± 25.0 min vs. 29.4 ± 37.0 min; p = 0.0038). There were no differences between treatments in SaO2, central apneic events, or other measures. Adverse events, most commonly headache, were noted in nine of 27 (33%) and six of 23 (26%) patients receiving SXB and PBO, respectively., Conclusions: Short-term use of 4.5 g/night SXB did not generate respiratory depressant effects in OSAS patients as measured by AHI, obstructive apnea events, central apneas, and SaO2. Extended use of SXB in higher therapeutic doses in OSAS has not been studied, and merits caution.

Introduction: Obstructive sleep apnea (OSA) is characterized by intermittent hypoxemia, arousals from sleep, and daytime sleepiness. Accumulating evidence indicates that hypoxemia and sleep disruption contribute to the development of cardiovascular abnormalities in OSA. OSA is effectively treated with continuous positive airway pressure (CPAP) therapy that splints open the airway during sleep. Studies have shown that CPAP therapy improves daytime sleepiness and attenuates cardiovascular abnormalities in patients with OSA. However, not all patients with OSA tolerate or adhere to CPAP therapy. Even patients who regularly use CPAP therapy may have a few hours each night exposed to the negative effects of untreated OSA. As a result, complementary pharmacologic therapies that can be used with CPAP therapy have the potential to reduce symptoms and consequences of OSA., Discussion: The wake-promoting medications modafinil and armodafinil effectively improve residual sleepiness in patients treated with CPAP therapy. Although results are equivocal so far, modafinil and armodafinil may also improve quality of life and global clinical condition in patients with OSA and residual sleepiness treated with CPAP therapy. Pharmacologic therapies also have the potential to be used with CPAP therapy to minimize cardiovascular perturbations and risk of cardiovascular disease. Preliminary studies suggest that inhibition of the enzyme xanthine oxidase and inhibition of sympathetic nervous system overactivity may have therapeutic potential to reduce cardiovascular harm in patients with OSA., Conclusion: Future studies of pharmacologic therapies to reduce symptoms and cardiovascular consequences of OSA should be increasingly performed as our understanding of the mechanisms mediating the adverse effects of OSA continues to evolve.

Statement of the Problem: When conducting a treatment intervention study, it is assumed that a level of reliability can be obtained from the measurement tool such that the outcome can be reasonably assessed., Purpose of Study: Investigate the reliability of laboratory polysomnography, the gold standard for assessment of treatment outcomes for obstructive sleep apnea, at a 1-month interval., Materials and Methods: In a clinical trial of 118 patients recruited to assess the effects of a pharmaceutical treatment intervention, a subset of 20 patients designated as placebo controls completed two polysomnography studies, one at baseline and one at least one month later., Results: The correlation between the overall Apnea/Hypopnea indices from the two polysomnography (PSG) studies was poor (r = 0.44) and the results were biased, with a mean increase of seven events per hour on night 2. Twenty-five percent of the subjects had an increase greater than 20 events/hour on night 2 and only 45% of participants had a night-to-night difference of < or =5 events/hour. The correlation between overall apnea indexes for nights 1 and 2 (r = 0.61) was improved, compared to the overall apnea/hypopnea indexes. The correlation in sleep efficiency across the two nights was relatively week (r = 0.52) but significant. The correlations between nights 1 and 2 for the percentage of time supine (r = 0.70) and the supine apnea-hypopnea index (AHI) (r = 0.69) were similar and highly significant. The correlation for the non-supine AHI was only 0.25, Conclusions: In this study, the reliability of a single-night PSG in measuring treatment outcome was compromised as a result of the large night-to-night variability of subjects' obstructive sleep apnea (OSA). Studies employing the AHI as an outcome need to be adequately powered with respect to the inherent night-to-night variability in the measurement. When assessing treatment intervention outcomes, there may be benefit from the acquisition and averaging of multiple nights of data in order to mitigate the inherent night-to-night variability of OSA and improve the accuracy of the outcome assessment.

Background: Individuals with moderate to severe chronic obstructive pulmonary disease (COPD) have poor sleep quality. This study evaluated the effects of ramelteon, an MT(1)/MT(2) melatonin receptor agonist indicated for insomnia treatment on respiration in this population., Materials and Methods: This double-blind, crossover study enrolled 25 subjects (>or=40 years) with moderate to severe COPD (FEV(1)/FVC <70% and FEV(1) between 50 and 80% of predicted value [moderate], or FEV(1)/FVC <70% and FEV(1) <50% of predicted value [severe]). Subjects received ramelteon 8 mg or placebo for one night 30 min before polysomnographic monitoring, including measurement of oxygen saturation (SaO(2)) and respiratory effort and flow. Subjects crossed to alternate treatment after a 5- to 10-day washout. The primary endpoint was mean SaO(2) for the entire night., Results: No significant difference in SaO(2) for the entire night was observed with ramelteon vs placebo (92.2% vs 92.5%, P = 0.576). Mean SaO(2) was similar between ramelteon and placebo for each hour of the night, each sleep stage, the number of minutes that SaO(2) was <80% and <90%, and mean apnea-hypopnea index. There was a significant difference in total sleep time (389.0 vs 348.4 min, P = 0.019) and sleep efficiency (81.0 vs 72.6%, P = 0.019), and latency to persistent sleep was shorter (23.1 vs 56.9 min, P = 0.051), with ramelteon vs placebo. All adverse events were mild to moderate; none led to study discontinuation., Conclusion: Ramelteon did not produce respiratory depressant effects as measured by oxygenation or abnormal breathing events in subjects with moderate to severe COPD. Ramelteon was well tolerated in this population.

Daytime symptoms resulting from obstructive sleep apnea (OSA) include impaired neurobehavioural performance and increased sleepiness. Continuous positive airway pressure (CPAP) reduces these symptoms. However, even compliant users may temporarily withdraw from CPAP treatment resulting in an immediate return of OSA. It has been hypothesised that these treatment "holidays" may be associated with neurobehavioural decline. Acute administration of a wakefulness promoter during such treatment "holidays" may help maintain neurobehavioural functioning. We examined the effects of 200 mg modafinil on neurobehavioural performance in a placebo-controlled crossover trial including N = 12 OSA patients acutely removed from CPAP. Sleep-wake activity was assessed for four consecutive days on CPAP and one night off CPAP using actigraphy. During the night off, CPAP patients wore a single channel nasal airflow diagnostic device. On the morning after CPAP withdrawal, patients reported to the laboratory and were administered either modafinil (200 mg) or placebo. At 2 h post-administration, patients completed a single simulated drive of approximately 30 min with simultaneous administration of a divided attention task (STISIMtrade mark), critical flicker fusion (CFF) test and subjective sleepiness scales. After a 14-day washout, participants repeated the protocol. CPAP withdrawal was associated with a worsening of sleep efficiency and the movement and fragmentation index (MFI), compared to the on-CPAP nights (all p < or = 0.02). Modafinil did not result in a superior driving simulator performance or CFF responses the morning after CPAP withdrawal but did result in better subjective sleepiness (both p < or = 0.04) compared to placebo. These data do not support the use of modafinil for the maintenance of daytime functioning in patients with OSA who are acutely withdrawn from CPAP.

Residual excessive sleepiness (ES) and impaired cognition can occur despite effective and regular nasal continuous positive airway pressure (nCPAP) therapy in some patients with obstructive sleep apnea (OSA). A pooled analysis of two 12-week, randomized, double-blind studies in nCPAP-adherent patients with ES associated with OSA evaluated the effect of armodafinil on wakefulness and cognition. Three hundred and ninety-one patients received armodafinil (150 or 250 mg) and 260 patients received placebo once daily for 12 weeks. Efficacy assessments included the Maintenance of Wakefulness Test (MWT), Cognitive Drug Research cognitive performance battery, Epworth Sleepiness Scale, and Brief Fatigue Inventory. Adverse events were monitored. Armodafinil increased mean MWT sleep latency from baseline to final visit by 2.0 min vs a decrease of 1.5 min with placebo (P < 0.0001). Compared with placebo, armodafinil significantly improved quality of episodic secondary memory (P < 0.05) and patients' ability to engage in activities of daily living (P < 0.0001) and reduced fatigue (P < 0.01). The most common adverse events were headache, nausea, and insomnia. Armodafinil did not adversely affect desired nighttime sleep, and nCPAP use remained high (approximately 7 h/night). Adjunct treatment with armodafinil significantly improved wakefulness, long-term memory, and patients' ability to engage in activities of daily living in nCPAP-adherent individuals with ES associated with OSA. Armodafinil also reduced patient-reported fatigue and was well tolerated.

Clinical trials in obstructive sleep apnea syndrome patients reported moderate effects of serotoninergic drugs on oropharyngeal apneas, although numerous specific 5-HT ligands highly modulate the genioglossus muscle (GG) activity in experiments performed in anesthetized animals. The purpose of this study was to investigate time- and dose-related effects of central and systemic injections of 8-OHDPAT (5-HT1A agonist), SB224289 (5-HT1B antagonist), and DOI (5-HT2A/2C agonist) on the GG activity in anesthetized and conscious rats. Electromyographic recordings of the GG activity (GGemg) were analyzed after central and systemic injections of each drug in ketamine-xylazine anesthetized rats. Electroencephalograms (EEG), as well as neck and GG muscle activities (Nemg and GGemg), were recorded in 15 additional rats to analyze changes in sleep-wake states before and after systemic injection of the drugs. Central injections of 8-OHDPAT and DOI in anesthetized rats induced clear dose-related increases in phasic and tonic GGemg activities, respectively. The time-responses were inferior to 30 min with 8-OHDPAT and over 50 min with DOI. Moderate increases in phasic GGemg activity were also observed after central, but not peripheral injection of SB and DOI. The total sleep time measured in conscious rats significantly decreased after systemic injections of DOI and 8-OHDPAT, although no change was observed in phasic or tonic GGemg activity. The dose- and time-responses of the DOI in anesthetized rat partly explain the lack of GGemg tonic change in conscious rat. The moderate effect on the GGemg phasic activity of peripheral 5-HT1A ligand injection easily explains the lack of change in conscious rat. The serotonergic modulation of the respiratory component of the GGemg remains complex, but is highly sensitive to 5-HT1A receptors after central injection in rats under anesthesia. Forthcoming therapy in OSAS should be made of mixed profiled neurotransmitters and different routes of administration.

Sleep-disordered breathing (SDB) is associated with nitric oxide-mediated endothelial dysfunction and increased risk and prevalence of cardiovascular disease, namely, arterial hypertension. A substantial number of patients do not comply with nasal continuous positive airway pressure (nCPAP) treatment. These individuals have a persisting increased cardiovascular risk. Antihypertensive drugs have shown to improve nitric oxide-mediated endothelial dysfunction. We therefore designed a study to test the hypothesis that antihypertensive drug treatment in hypertensive patients with SDB can have beneficial effects on nitric oxide-mediated endothelial function in the absence of treatment with nCPAP. Six patients with SDB and treated arterial hypertension, six normotensive patients with SDB, and six healthy controls received sleep studies and an assessment of venodilation using the dorsal hand vein technique. Polygraphic measures using standard overnight sleep studies and dose-response curves to the endothelium-dependent vasodilator bradykinin were obtained. Maximum nitric-oxide-mediated dilation to bradykinin was significantly higher in patients with SDB who had received antihypertensive drug treatment compared to normotensive SDB patients. Nitric oxide-mediated dilation in hypertensive patients with SDB was similar to nitric oxide-mediated dilation in healthy controls. After treatment of normotensive patients with SDB using nCPAP, nitric oxide-mediated dilation in normotensive SDB patients was comparable to nitric oxide-mediated dilation in SDB patients with antihypertensive drug treatment and normal controls. Hypertensive patients with SDB present a normal nitric oxide-mediated endothelial function under antihypertensive treatment.