Obstructive Sleep Apnea Treatment: Peripheral and Central Effects on Plasma Renin Activity and Aldosterone

Exercise capacity is impaired in obstructive sleep apnea (OSA). There are conflicting reports on the effect of continuous positive airway pressure (CPAP) on maximal exercise capacity. The objective of this review was to determine if there is a change in exercise capacity and anaerobic threshold following CPAP treatment in OSA patients. We conducted a systematic review and meta-analyses to summarize the changes in peak rate of oxygen uptake (V̇O₂ peak) or maximum rate of oxygen uptake (V̇O2 max) and anaerobic threshold (AT) during cardiopulmonary exercise testing following CPAP intervention in patients with OSA. A systematic literature review was conducted to identify published literature on markers of V̇O₂ peak, V̇O₂ max, and AT pre- vs post-CPAP using a web-based literature search of PubMed/MEDLINE, Embase, CINAHL, and Cochrane review (CENTRAL) databases. Two independent reviewers screened the articles for data extraction and analysis. The total search of all the databases returned 470 relevant citations. Following application of eligibility criteria, 6 studies were included in the final meta-analysis for V̇O₂ peak, 2 studies for V̇O₂ max, and five studies for AT. The meta-analysis showed a mean net difference in V̇O₂ peak between pre- and post-CPAP of 2.69 mL·kg-1·min-1, P = .02, favoring treatment with CPAP. There was no difference in V̇O₂ max or AT with CPAP treatment (mean net difference 0.66 mL·kg-1·min-1 [P = .78] and -144.98 mL·min-1 [P = .20] respectively). There is a paucity of high-quality studies investigating the effect of CPAP on exercise capacity. Our meta-analysis shows that V̇O₂ peak increases following CPAP treatment in patients with OSA, but we did not observe any change in V̇O₂ max or AT. Our findings should be considered preliminary and we recommend further randomized controlled trials to confirm our findings and to clarify the peak and maximum rates of oxygen uptake adaptations with CPAP therapy.

A ten-year retrospective analysis of the clinical features and survival of 60 Saudi children with systemic lupus erythematosus (SLE) was made. All the patients fulfilled the 1982 American College of Rheumatologyâs revised criteria for SLE and had had the disease at or before the age of 16 years. The female to male ratio was 5:1, the mean age of onset was 12.1 years (range 1.6-16 years), and the mean duration of follow-up was 4.7 years (range 2.2-11). Thirty-eight patients (63%) were diagnosed correctly before referral to KFSH&RC or KKUH. The mode of presentation was as follows: 55 patients had musculoskeletal involvement (91.6%), 49 patients had skin involvement (81.6%), 40 patients had hematological abnormalities (66.6%), 39 patients had renal disease (65%), 10 patients had pulmonary involvement (16%), 23 patients had cardiovascular disease (38%) and 18 patients had central nervous system involvement. During the study period four patients died (6.6%)âtwo of renal failure, one from meningitis and one from severe sepsis. This is the largest collection of childhood systemic lupus erythematosus from the Middle East and it shows that SLE is more common in Saudis than was hitherto believed, and that it has a high rate of organ involvement.

Patients with severe OSA consume greater amounts of cholesterol, protein, and fat as well as have greater caloric expenditure. However, it is not known whether their activity levels or diet change after treatment with CPAP. To investigate this issue, serial assessments of activity and dietary intake were performed in the Apnea Positive Pressure Long-term Efficacy Study (APPLES); a 6-month randomized controlled study of CPAP vs. sham CPAP on neurocognitive outcomes. Subjects were recruited into APPLES at 5 sites through clinic encounters or public advertisement. After undergoing a diagnostic polysomnogram, subjects were randomized to CPAP or sham if their AHI was ≥ 10. Adherence was assessed using data cards from the devices. At the Tucson and Walla Walla sites, subjects were asked to complete validated activity and food frequency questionnaires at baseline and their 4-month visit. Activity and diet data were available at baseline and after 4 months treatment with CPAP or sham in up to 231 subjects (117 CPAP, 114 Sham). Mean age, AHI, BMI, and Epworth Sleepiness Score (ESS) for this cohort were 55 ± 13 [SD] years, 44 ± 27 /h, 33 ± 7.8 kg/m(2), and 10 ± 4, respectively. The participants lacking activity and diet data were younger, had lower AHI and arousal index, and had better sleep efficiency (p < 0.05). The BMI was higher among women in both CPAP and Sham groups. However, compared to women, men had higher AHI only in the CPAP group (50 vs. 34). Similarly, the arousal index was higher among men in CPAP group. Level of adherence defined as hours of device usage per night at 4 months was significantly higher among men in CPAP group (4.0 ± 2.9 vs. 2.6 ± 2.6). No changes in consumption of total calories, protein, carbohydrate or fat were noted after 4 months. Except for a modest increase in recreational activity in women (268 ± 85 vs. 170 ± 47 calories, p < 0.05), there also were no changes in activity patterns. Except for a modest increase in recreational activity in women, OSA patients treated with CPAP do not substantially change their diet or physical activity habits after treatment. .

Recent studies report a link between obstructive sleep apnea (OSA) syndrome, low vitamin D levels, and high parathyroid hormone (PTH) concentrations. The aim of the current study is to evaluate the effect of 7-night continuous positive airway pressure (CPAP) therapy on serum vitamin D, PTH, and calcium levels in patients with severe OSA syndrome. Patients with severe OSA were enrolled into the study and compared to control subjects. Patients with OSA underwent CPAP therapy for 7 nights and were consequently divided into responders (OSA-R, mean residual AHI < 5/h) and nonresponders (OSA-nR, mean residual AHI > 5/h). Serum vitamin D, PTH, and calcium levels were measured at baseline in patients with severe OSA (apnea-hypopnea index > 30/h) and control subjects. Patients with OSA underwent a final morning blood sample after 7-night CPAP therapy. We enrolled 90 patients with OSA into the study (65 OSA-R and 25 OSA-nR) compared to 32 control subjects. At baseline, lower vitamin D and higher PTH levels were detected in the OSA group compared to controls. After 7-night CPAP therapy, male OSA-R patients showed a significant increase in vitamin D levels. Conversely, female OSA-R patients did not show the same increase in vitamin D levels. It was also observed that OSA-nR subjects did not show modifications of serum markers after nCPAP-therapy. The study demonstrates that short-term nCPAP treatment is able to promote the recovery of vitamin D homeostasis in male patients with OSA. The mediation of sexual hormones in regulating vitamin D is a possible explanation of the lack of recovery of vitamin D homeostasis in female patients with OSA as it often affects postmenopausal women.

Metabolic Syndrome, Obstructive Sleep Apnea, and Continuous Positive Airway Pressure: A Weighty Issue

What effect on blood pressure can we expect from continuous positive airway pressure treatment in obstructive sleep apnoea?

Resistant hypertension (RH) is a challenging clinical condition characterized by persistently elevated blood pressure despite treatment with at least three antihypertensive medications, including a diuretic. It represents a significant public health concern due to its association with increased cardiovascular morbidity and mortality. The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in the pathophysiology of RH, with abnormalities in plasma renin activity (PRA) and aldosterone levels contributing to sustained hypertension. Understanding RAAS profiles in RH patients can guide therapeutic strategies and improve clinical outcomes. This study aimed to evaluate PRA, plasma aldosterone concentrations, and the aldosterone-to-renin ratio (ARR) in 100 Bangladeshi patients with RH and to explore their clinical implications. A cross-sectional observational study was conducted at the Department of Laboratory Medicine, Department of Biochemistry and Molecular Biology and Department of Cardiology, Bangladesh Medical University, Dhaka, Bangladesh over a period of 1 year from July 2023 to June 2024. Patients aged 18–65 years diagnosed with RH were included. Exclusion criteria encompassed secondary causes of hypertension such as pheochromocytoma, renal artery stenosis, and primary aldosteronism due to adrenal adenoma. Demographic and clinical data, including age, sex, duration of hypertension, comorbidities, and current antihypertensive therapy, were collected. Blood samples were obtained in the morning following overnight fasting, and PRA and plasma aldosterone concentrations were measured using Chemiluminescence immunoassay. ARR was calculated by dividing plasma aldosterone by PRA. The study had a mean age of 58.4 ± 10.2 years, with males comprising 65% of participants. The mean duration of hypertension was 12.5 ± 6.3 years. Comorbidities included diabetes mellitus (45%), chronic kidney disease (30%), and dyslipidemia (40%). The mean PRA was 4.2 ± 3.1 ng/mL/h, and the mean plasma aldosterone level was 238.7 ± 152.3 pg/mL, resulting in a mean ARR of 11.1 ± 8.3. A significant positive correlation between PRA and aldosterone levels was observed (r = 0.68, p &lt; 0.001). Subgroup analysis based on ARR revealed that 60% of patients had low ARR (&lt;10), 25% had intermediate ARR (10–20), and 15% had high ARR (&gt;20). Patients with high ARR exhibited significantly elevated aldosterone levels compared to the low ARR group. These findings demonstrate the heterogeneity of RAAS activation in Bangladeshi patients with RH and highlight the importance of assessing PRA, plasma aldosterone, and ARR for individualized management strategies. Further multicenter and longitudinal studies are warranted to validate these findings and explore targeted RAAS-modulating therapies in resistant hypertension.

The Lung Centre, Vancouver, British Columbia Correspondence: Dr John A Fleetham, The Lung Centre, 7th Floor, 2775 Laurel Street, Vancouver, British Columbia V5Z 1M9. Telephone 604-875-5653, fax 604-875-5587, e-mail john.fleetham@vch.ca In the current issue of the Canadian Respiratory Journal, Rotenberg et al (1) (pages 170-174) report data from a crosssectional survey sent to otolaryngologists, respirologists and family physicians in Ontario, to characterize wait times for obstructive sleep apnea (OSA) care. The major finding was that patients with suspected OSA in Ontario waited a mean of 11.6 months to initiate continuous positive airway pressure (CPAP) treatment and 16.2 months to initiate surgical therapy. This is much longer than the wait time in the Canadian Thoracic Society (CTS) guidelines, which recommend a maximum wait time of two to four weeks for urgent patients with comorbid disease or daytime sleepiness and a critical safety occupation, and six months for all patients with suspected OSA (2,3). Excessive diagnostic wait times frequently lead to inappropriate or incorrect therapy. Wait times for the diagnosis of sleep apnea in Canada have not improved much since Flemons et al (4) reviewed wait times for the diagnosis of OSA in five countries, including Canada, 16 years previously. To paraphrase what Pack (5) wrote in an associated editorial: “It seems inconceivable that we should tell a patient the following: You are highly likely to have severe sleep apnea, a disorder associated with an increased risk of car crashes, high blood pressure, and probably heart attack and stroke. We have an effective treatment for this disorder. We will arrange a study for you in 11.6 months’ time to assess this”. The even longer wait time for surgical treatment of OSA reported by Rotenberg et al also merits comment. The role of corrective upper airway surgery in the treatment of OSA is controversial. The current CTS guidelines conclude that laser-assisted uvulopalatoplasty is not recommended for the treatment of OSA, but that uvulopalatopharyngoplasty may be considered in selected patients with OSA who have failed CPAP and/or oral appliance therapy. The delay in the diagnosis and treatment of OSA in Ontario needs to be put in the context of the rest of Canada, where the diagnosis and treatment of sleep apnea is provided in a very different manner. Ontario has the highest number of sleep laboratories in Canada and most other parts of the world apart from the United States (4). Moreover, Ontario is one of the few provinces, along with Manitoba and Saskatchewan, in which the provincial medical plan funds CPAP treatment. The majority of centres in Canada outside of Ontario use ambulatory sleep monitoring – in addition to polysomnography – to diagnose OSA. After OSA has been diagnosed, there is no additional delay in the provision of CPAP therapy because this is funded by the patient and does not require approval by a funding agency. The majority of respondents to the survey in the article by Rotenberg et al (1) identified ‘not enough sleep laboratories’ as the reason for long wait times. Many would argue that more sleep laboratories are not what is required – what is necessary is a more appropriate diagnostic strategy that uses clinical prediction equations and ambulatory sleep monitoring (6) in conjunction with polysomnography for patients with comorbid disease or who fail to improve with CPAP treatment. Furthermore, if resources for the management of OSA are to be rationed, a higher priority should be given to treatment than to diagnosis. Patients with OSA use health care services at approximately twice the rate of control subjects for up to 10 years before the diagnosis of OSA (7). CPAP treatment has an incremental cost-effectiveness ratio of $2,618 per quality-adjusted life year over no treatment (8). A ratio of less than $10,000 per qualityadjusted life year is generally considered to be extremely cost effective. While CPAP treatment for OSA is funded in many other countries including the United Kingdom (9) and the United States (10), it is not funded in the majority of Canadian provinces. In 2008, The Lung Association and the CTS jointly recommended funding of CPAP treatment under all provincial and federal health insurance plans for adults and children appropriately diagnosed with OSA; however, little progress has been made over the past two years. It is now time to end the postal code differences that currently exist in Canada with regard to access to the diagnosis and treatment of OSA. editorial

Obstructive sleep apnea (OSA) is a common pediatric condition characterized by recurrent partial or complete cessation of airflow during sleep, typically due to inadequate upper airway patency. Continuous positive airway pressure (CPAP) is a therapeutic option that reduces morbidity. Despite efforts to promote use, CPAP adherence is poor in both pediatric and adult populations. We sought to determine whether demographics, insurance status, OSA severity, therapeutic pressure, or comorbid conditions were associated with pediatric CPAP adherence. A retrospective review of adherence download data was performed on all pediatric patients with initiation or adjustment of CPAP treatment over a one-year period with documented in-laboratory CPAP titration. Patients were grouped as CPAP adherent or non-adherent, where adherence was defined as > 70% nightly use and average usage ≥ 4 hours per night. Differences between the groups were analyzed by χ(2) test. Overall, nearly half of participants were CPAP adherent (49%, 69/140). Of the demographic data collected (age, ethnicity, sex, insurance status), only female sex was associated with better adherence (60.9% vs 39.5% of males adherent; odds ratio [OR] = 2.41, 95%CI = 1.20-4.85; p = 0.01). Severity of OSA (diagnostic apnea-hypopnea index [AHI] and degree of hypoxemia), therapeutic pressure, and residual AHI did not impact CPAP adherence (p > 0.05). Patients with developmental delay (DD) were more likely to be adherent with CPAP than those without a DD diagnosis (OR = 2.55, 95%CI = 1.27-5.13; p = 0.007). Female patients with trisomy 21 tended to be more adherent, but this did not reach significance or account for the overall increased adherence associated with female sex. Our study demonstrates that adherence to CPAP therapy is poor but suggests that female sex and developmental delay are associated with better adherence. These findings support efforts to understand the pathophysiology of and to develop adherence-promoting and alternative interventions for pediatric OSA.

Mild Obstructive Sleep Apnea Syndrome Should Not Be Treated

Obstructive sleep apnea syndrome (OSAS) is a serious medical condition that occurs during sleep and consists of episodes of complete (respiratory pauses) or partial obstruction (hypoventilation) of the upper airway. Approximately 80% of persons diagnosed with OSAS are prescribed nasal Continuous Positive Airway Pressure (CPAP) treatment, which has proven to be the treatment of choice for OSAS. However, noncompliance with CPAP treatment in OSAS patients is a widely recognized problem, and many persons refuse CPAP as a treatment option or fail to use it reliably. Investigations of CPAP use in OSAS patients have generally found that nightly use averages less than five hours. Few interventions have been scientifically evaluated for improving CPAP compliance. The current study evaluated a method of introducing OSAS patients to CPAP prior to the administering CPAP titration in the laboratory. Participants in the treatment groups underwent a 30-minute CPAP habituation trial, with a range of pressures, prior to the polysomnography with CPAP. It was hypothesized that the participants who experienced CPAP habituation would have better sleep quality during CPAP, would be more likely to accept CPAP, and would use CPAP more on a nightly basis than control participants who experienced the usual laboratory procedures for introducing CPAP (CPAP education) to OSAS patients. There were no statistically significant differences for any of the dependent variables between participants who experienced CPAP habituation and participants who experienced CPAP education. Men were found to use CPAP 1.61 hours more on a nightly basis than women (p = .03). This difference is most likely attributable to severity, as men were observed to have an A+HI that was twice the observed A+HI of women participants. Overall, CPAP acceptance and compliance for the complete sample was comparable to what has been reported in the CPAP treatment literature.

Obstructive sleep apnea (OSA) is a prevalent and debilitating condition that is significantly underdiagnosed. The majority of adults sleep with someone-a partner. Partners can play a significant role in the patient's OSA diagnosis. The goal of this work is to describe facilitators and barriers to OSA diagnosis as discussed by patients with OSA and their partners. This was a qualitative secondary analysis with results drawn from 20 dyadic interviews, conducted 1 couple at a time, in 20 newly diagnosed adult patients with OSA and their partners. Qualitative interview data were analyzed using conventional content analysis. Facilitators of OSA diagnosis were partners pushing patients to seek care, patients actively seeking care, and care providers identifying the patient's risk of OSA. Barriers to OSA diagnosis were patients' lack of serious attention to symptoms, patients' negative perceptual framing of diagnosis and treatment of OSA, and poor coordination of health care services. We recommend engaging partners in the OSA diagnosis and developing educational and behavioral interventions to raise public awareness about OSA. It is important to educate clinicians on atypical presentations of OSA. Further investigation is needed to evaluate the impact of health care services on OSA diagnosis. Ye L, Li W, Willis DG. Facilitators and barriers to getting obstructive sleep apnea diagnosed: perspectives from patients and their partners. J Clin Sleep Med. 2022;18(3):835-841.

Obstructive sleep apnea (OSA) is a major risk factor for hypertension and has been associated with increased risk for cardiovascular morbidity. A dysregulated renin-angiotensin-aldosterone system may contribute to excess sodium retention and hypertension and may be activated in OSA. We tested the hypothesis that serum levels of aldosterone and plasma renin activity (PRA) are increased by apneic sleep in subjects without cardiovascular disease, compared to healthy control subjects. Plasma aldosterone level was measured in 21 subjects with moderate to severe OSA and was compared to 19 closely matched healthy subjects. Plasma renin activity (PRA) was measured in 19 OSA patients and in 20 healthy controls. Aldosterone and PRA were measured before sleep (9 pm), after 5 hrs of untreated OSA ( 2am) and in the morning after awakening (6 am). There were no baseline (9pm) differences in serum aldosterone levels and PRA between the healthy controls and OSA patients (aldosterone: 55.2 +/- 9 vs 56.0 +/- 9 pg/mL; PRA: 0.99 +/- 0.15 vs. 1.15 +/- 0.15 ng/mL/hr). Neither several hours of untreated severe OSA nor CPAP treatment affected aldosterone levels and PRA in OSA patients. Diurnal variation of both aldosterone and PRA was observed in both groups, in that morning renin and aldosterone levels were higher than those measured at night before sleep. Our study shows that patients with moderate to severe OSA without co-existing cardiovascular disease have plasma aldosterone and renin levels similar to healthy subjects. Neither untreated OSA nor CPAP treatment acutely affect plasma aldosterone or renin levels.

The first-choice therapy for adults with moderate/severe obstructive sleep apnea is continuous positive airway pressure (CPAP). However, studies evaluating whether the therapeutic CPAP level obtained from a titration is affected by sex are surprisingly scarce. Our main objective was to verify if sex influenced the optimal CPAP measurement obtained during a titration. This cross-sectional study was conducted in adults diagnosed with moderate/severe obstructive sleep apnea [baseline apnea-hypopnea index (AHI) ≥ 15.0 events/h] who underwent auto-adjusting CPAP titration (S9 or S10 AutoSet ResMed) in a sleep laboratory setting. All participants used a nasal mask during the titration. The optimal pressure, leak, and residual AHI values were registered. Multiple linear regression was used to evaluate if clinical and polysomnographic data influenced the therapeutic CPAP level setting (95th percentile pressure). A total of 1,006 adults were enrolled: 354 women and 652 men. There were no statistically significant sex-related differences in the CPAP requirements and leak values delineated during the titration; all P-values > .005. However, the median residual AHI was significantly higher in males vs females: 2.7 events/h vs 2.2 events/h (P = .008). Body mass index (β: 0.292, P < .001), baseline AHI (β: 0.167, P < .001), and age (β: 0.065, P = .035) were independent predictors of the therapeutic CPAP level settings. Sex does not significantly influence the therapeutic CPAP settings. However, age, BMI, and baseline AHI emerge as independent predictors of the 95thpercentile CPAP requirement during an auto-adjusting CPAP titration. Duarte RLM, Magalhães-da-Silveira FJ, Gozal D. Are there sex-related differences in therapeutic CPAP levels in adults undergoing in-laboratory titration? JClin Sleep Med. 2021;17(9):1815-1820.

Rationale: Nasal masks are first-line options for obstructive sleep apnea (OSA) treatment with continuous positive airway pressure (CPAP). Unintentional leak during nasal CPAP is a common side-effect that is associated with reduced adherence. Mouth leak episodes are often terminated by arousals and mouth closing. Mouth and mask leak have different graphical profiles. While mouth leak leads to repetitive episodes of abrupt leak reduction, mask leak is associated with sustained excessive leak. The distinction between mask and mouth leak has important clinical significance as they require different treatment approaches. We hypothesized that mouth leak is common and independently associated with age and CPAP level. Methods: CPAP and patient demographic data from a cohort of OSA patients under CPAP treatment were retrieved from the online CPAP data platform. Subjects that were using oronasal masks or a chinstrap and those that were not using CPAP during any of the last 30 days were excluded. Thirty-day CPAP data summary and detailed CPAP data of the last 7 nights were retrieved from each subject. Unintentional leak, residual apnea-hypopnea index and 30-day adherence were recorded. Mouth leak (ML) episodes were determined by the identification of abrupt leak reductions (&amp;gt;10L/min drop) during each overnight leak profile graph. ML index was defined by the total number of ML episodes divided by hours of CPAP use. Excessive leak was defined as a 95th leak percentile ≥15L/min. Mask leak was defined as ML index&amp;lt;1/h and the presence of excessive sustained leak. Mouth leak was defined as ML index ≥1/h in the absence of sustained excessive leak. Mixed leak was defined as ML index ≥1/h and the presence of sustained excessive leak. A multiple linear regression model was used to test age and CPAP level as independent predictors of ML index. Results: Demographic, OSA severity and CPAP data of 101 included patients are presented in Table 1. Age was higher in the mixed leak as compared to no leak groups. ML index was higher in the mouth and mixed groups as compared to the no-leak group. ML index was predicted by age and CPAP level (R2=0.233; P&amp;lt;0.001). Conclusions: Mouth leak is common among nasal CPAP users and can be predicted by age and CPAP level. The recognition of the different air leak phenotypes and its determinants allow the design of trials aimed to prevent and control mouth leak during nasal CPAP.