Are There Benefits of Exercise in Sleep Apnea?

REVIEW ARTICLE

Are there benefits of exercise in sleep apnea? Existem benefícios do exercício físico na apneia do sono? Roberto Pacheco da Silva1,4, Karlyse Claudino Belli1,2,3,4, Alicia Carissimi1,5, Cintia Zappe Fiori1,4, Christiane Carvalho Faria2,4, Denis Martinez1,4,5

ABSTRACT neia obstrutiva do sono. Foi realizada uma busca na base de dados do Out of the many sleep disorders, obstructive sleep apnea-hypopnea PubMed, utilizando termos MESH e outros relacionados ao exercício syndrome is one of the most harmful. This syndrome is an important físico e à apneia do sono. Das 149 referências encontradas, foram sele- risk factor for the development of cardiovascular disease and patient cionados os ensaios clínicos randomizados ou os estudos de casos, em mortality. Exercise is a way to reduce cardiovascular mortality, which inglês ou português, com amostra de indivíduos adultos portadores de also results in improved sleep quality and may act on the pathogenesis síndrome da apneia-hipopneia obstrutiva do sono. Após seleção dos of obstructive sleep apnea-hypopnea syndrome. However, evidence títulos, resumos e textos completos, foram localizados somente três about the actual role of exercise in this syndrome is still scarce. We estudos que investigaram os efeitos do exercício físico sobre os mar- reviewed the existing literature about the possible benefits of exer- cadores de presença e gravidade dessa síndrome. Nos três artigos, os cise in patients with obstructive sleep apnea-hypopnea syndrome. We grupos submetidos ao exercício evidenciaram redução na gravidade performed a search in the PubMed database using MESH Terms re- da síndrome. Apesar do nível de evidência insuficiente dos artigos, a lated to physical exercise and sleep apnea. Out of the 149 references concordância de resultados positivos dos estudos sugere potencial de identified, we selected randomized controlled trials or case studies benefício do exercício sobre a SAHOS. in English or Portuguese that included patients with OSAHS. After searching titles, abstracts and full texts, we located only three studies Palavras-chave: exercício; síndromes da apneia do sono; doenças that investigated the effects of exercise on the diagnostic and severity cardiovasculares; apneia do sono tipo obstrutiva. indices of obstructive sleep apnea-hypopnea syndrome. In these three papers, groups that exercised showed a reduction in the severity of the INTRODUCTION syndrome. Despite the insufficient level of evidence in the literature, the agreeing positive results of the studies suggest a potential benefit Exercise is a culturally and scientifically accepted non-drug of exercise on obstructive sleep apnea-hypopnea syndrome. intervention that is beneficial to health. There is evidence that it facilitates general wellness1 and sleep, in particular2. Keywords: exercise; sleep apnea syndromes; cardiovascular diseases; During sleep, breathing disorders can occur – in particu- sleep apnea, obstructive. lar, obstructive sleep apnea-hypopnea syndrome (OSAHS), which is assuming epidemic proportions. Over two decades, RESUMO Dentre os distúrbios do sono, a síndrome da apneia-hipopneia obs- reports of the prevalence of OSAHS increased from 4% in 3 4 trutiva do sono é um dos mais deletérios à saúde. Essa síndrome é um men and 2% in women to 32% of the total population . importante fator de risco para o aparecimento de doenças cardiovascu- The prevalence of OSAHS is 95% in the elderly, and more lares, aumentando a taxa de mortalidade dos pacientes. Sabe-se que o than 50 million Brazilians suffer from this syndrome4. exercício físico é uma das formas de reduzir a mortalidade cardiovas- Additionally, OSAHS is an important risk factor for cular, o que também resulta em melhora do sono e pode atuar sobre cardiovascular diseases5, including systemic hypertension6,7 fatores fisiopatológicos da síndrome da apneia-hipopneia obstrutiva 8,9 10 11 do sono. Contudo, evidências sobre o real papel do exercício físico na resistant hypertension , stroke , obesity and metabolic síndrome ainda são escassas. O objetivo dessa revisão foi investigar os syndrome12. American cardiology associations published a possíveis benefícios do exercício físico na síndrome da apneia-hipop- comprehensive document highlighting the need to inves-

Study carried out at Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre (RS), Brazil. 1 Interdisciplinary Sleep Research Laboratory, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre (RS), Brazil. 2 Exercise Pathophysiology Research Laboratory, Cardiology Division, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre (RS), Brazil. 3 Research on Research Group – Duke University, Durham, USA; Department of Medicine, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre (RS), Brazil. 4 Graduate Program in Cardiology and Cardiovascular Sciences, Cardiology Unit, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre (RS), Brazil; Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre (RS), Brazil. 5 Graduate Program in Medical Sciences, Cardiology Unit, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre (RS), Brazil; Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre (RS), Brazil. Financial support: none. Conflict of interests: nothing to declare. Corresponding author: Roberto Pacheco da Silva – Cardiology Unit, Hospital de Clínicas Porto Alegre – Rua Ramiro Barcelos, 2.350 – CEP 90035-002 - Porto Alegre (RS), Brazil – E-mail: [email protected] Received: February 8, 2011 – Accepted: June 6, 2011

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tigate sleep apnea in cardiopathies13,14. Patient mortality ed by consensus of the authors. The following information is increased with OSAHS and its comorbidities15,16, while was extracted from articles: (1) authors; (2) years of publica- treatment for OSAHS reverses the consequences17 and re- tion; (3) type of study; (4) sample size; (5) age of the sample; duces mortality18,19. (6) weight; (7) body mass index (BMI); (8) intervention; (9) Exercise reduces cardiovascular mortality20-22 and may apnea-hypopnea index (AHI) pre- and post-treatment and modify the deleterious effects of OSAHS on the circulatory (10) statistical significance of change with treatment. These system23-26. However, evidence about the role of exercise in data are shown in Table 1. OSAHS is still scarce. Thus, this review reports the direct The references obtained for the other topics described be- and indirect benefits of exercise in OSAHS. low in this paper, were based non-systematic reviews.

METHODOLOGY OF THE REVIEW ON EXERCISE Obstructive sleep apnea-hypopnea AS TREATMENT OF OSAHS syndrome Studies of exercise and OSAHS included in this review There are two types of sleep apnea: central, which is caused were randomized clinical trials or case studies written in by the central nervous system, and obstructive, which in- English or Portuguese and examined adult human patients volves physical changes in the pharynx27. In central apnea, with OSAHS. which is caused by failure of the ventilatory drive, there is The search strategy is described in Appendix A and was no movement of the thorax and abdomen. Regardless of the conducted on December 16, 2010. For the search, we used cause, episodes of airflow reduction to 10% or less of basal the Medical Subject Headings (MeSH) terms “sleep apnea value for 10 seconds or more are called apneas. Reductions of syndromes”, “sleep apnea, central”, “sleep apnea, obstructive” 50% or more of ventilatory flow, associated with a decrease and “exercise” with their respective entry terms and Boolean of at least 3% in oxygen saturation or an arousal, are called operators in PubMed. Using these terms resulted in 149 re- hypopneas. This situation normalizes rapidly after an arousal sults. One of the investigators (RPS) reviewed the results of interrupts the apnea, resulting in the recovery of ventilation this search, first by title, then by the abstract and full text. and normalization of arterial blood oxygen28. Finally, we selected 45 potentially relevant articles for review The severity of OSAHS is determined by the apnea-hy- and discussed these with the other authors. After reading the popnea index (AHI). The total number of apneas and hypo- full texts, three articles were chosen, as described in Table 1. pneas of the individual is divided by the number of hours of sleep. Normal values are below 5/hour; OSAHS is diagnosed Data collection process as mild if AHI is between 5 and 14, moderate if AHI is Data extraction was conducted by the first author and re- between 15 and 29 and severe if AHI ≥30. Patients with viewed by the second author. Any discrepancies were correct- OSAHS (AHI >5) present additional symptoms, including

Table 1. Studies describing exercise effects on apnea-hypopnea index (AHI). First Year of Sample Age BMI AHI AHI Design Weight (kg) Intervention P Author publication analyzed (n) (years) (kg/m2) Pre Post 6 months, 3 times/ week; Aerobic exercise, Norman 2000 Case study 9 48±9 111±11 35±4 30-45 minutes, 50-80% 22±9 12±7 < 0.01 VO2max; and resistance exercise 6-months, 2 times/ week; Aerobic exercise, Giebelhaus 2000 Case study 11 52±6 80* 27±3 120 minutes; and power 33±22 24* < 0.05 exercise (repetitive light weight-lifting) 3-months, 3 times/ week; Aerobic exercise, Randomized Sengul 2009 10 54±7 86±8 30±3 45-60 minutes, 60-70% 15±5 11±5 0.02 controled trial VO2max; and breathing exercise, 15-30min 10 Control group 18±6 17±11 0.58 Data presented as mean±standard deviation. AHI: apnea-hypopnea index; BMI: body mass index; VO2max: peak oxygen uptake. * This study did not report standard deviation for this variable.

Sleep Sci. 2011;4(2):��–67 63 Silva RP, Belli KC, Carissimi A, Fiori CZ, Faria CC, Martinez D excessive daytime sleepiness and snoring. Although not all orders are obese41. This risk factor also contributes to the snorers have OSAHS, untreated snoring can have cardiovas- onset of cardiovascular and metabolic disease in this popula- cular consequences29. tion35. The risk of developing moderate to severe sleep disor- In obstructive sleep apnea, there are several mechanisms ders is increased by six times with a 10% increment in body of airway occlusion. These include fat accumulation in the mass. Each 1% increase in body mass is associated with a 3% neck, anatomic abnormalities, disorders of the upper airway increase in AHI42. muscles and unbalances in respiratory control, all of which Patients with higher BMI show a higher prevalence of contribute to airway obstruction during sleep30. most types of severe OSAHS40. The increase in body fat and intra-abdominal pressure reduces functional residual capac- OSAHS AND CARDIOVASCULAR INJURY ity. Combined with the increased consumption of oxygen in The main cardiovascular consequences arising from OSAHS tissues, it results in faster depletion of oxygen stocks during are generated by cyclic intermittent hypoxia and arousals31. apnea43. Due to more intense oxygen desaturation in obese Intermittent hypoxia and arousals result in chronic hyperac- individuals as compared with non-obese individuals, strate- tivity of the sympathetic nervous system, increased heart rate, gies for weight loss, including exercise, have been suggested blood pressure, sensitivity of central and peripheral chemore- as an alternative to reduce the severity of OSAHS35. ceptors and decreased baroreceptor activation31,32. They can Weight loss via increased physical activity and changes also result in oxidative stress, inflammation, endocrine -dis in diet and lifestyle has been studied as a treatment for orders and endothelial dysfunction23,33,34. These changes are sleep disorders44. Therefore, increasing physical activity mechanisms that underlie the onset of cardiovascular and could reduce the body mass of these patients, improve their metabolic diseases35. Concomitantly, patients present a reduc- sleep disturbance and be considered an important goal for tion in exercise capacity associated with reduced peak oxygen treatment45. consumption (peak VO2), chronotropic incompetence and al- tered blood pressure response and heart rate24. BENEFITS OF EXERCISE ON SLEEP

The potential mechanism for the reduction of peak VO2 Although sleep and exercise act in diametrically opposed in patients with OSAHS is related to the patient’s base pa- ways from the physiological point of view, the benefits of thology. During exercise, peak VO2 increases in response to these two states are related. Advances in knowledge have metabolic demand by muscle activation. For this, the car- revealed new associations between the mechanisms that act diovascular system is responsible for optimizing the deliv- on exercise and sleep2,46. Therefore, promoting or improv- ery of blood and oxygen to working muscles and increasing ing sleep through exercise is believed to be healthy, safe and cardiac output (CO). Any factor that limits CO (filling pres- simple and might even be an alternative in the treatment sure, ventricular compliance, heart rate, contractility, blood of insomnia2. Both aerobic and resistance exercises improve pressure and/or afterload) can interfere with the exercise ca- sleep quality47. Gary and Lee48 reported that a 12-week pacity of the individual25. walking program increased the total sleep time for patients OSAHS affects left ventricular function26. The increased by 20%, improving their quality of life. ventricular afterload results from the increase in negative in- The elderly population seems to benefit the most from trathoracic pressure during airway obstruction. As a result physical activity. Besides improved quality of sleep, older of the larger intrathoracic pressure swings, there are fluc- adults also show improvements in their chronic pain and tuations in the ejection fraction, heart rate, and CO. The functional capacity. Compared to the elderly, young adults rapid increase in CO and the increase in coronary vascular and children need longer and more intense exercise to obtain tone during the apnea cycle can cause episodes of myocardial similar benefits47. ischemia. Other factors that can affect left ventricular func- The facilitation of sleep induction after exercise supports tion include a reduction in vagal activity, increased platelet the role of sleep in the conservation of energy, in muscle aggregation, and insulin resistance36. recovery and body temperature regulation2. Exercise causes The intermittent hypoxia associated with OSAHS reduces energy depletion, muscle micro-damage, body temperature the production of nitric oxide (NO)37 and impairs endothelial elevation and changes in melatonin levels46, all of which are function25,38. Nitric oxide-dependent mechanisms may reduce restored during sleep2. the exercise capacity of patients with the disease39. The reduction of body temperature is part of the process of inducing sleep. Melatonin, produced by the pineal gland OSAHS AND OBESITY in darkness, shortens sleep latency and reduces body tem- The main risk factor for development of OSAHS is obesity40, perature. The hypothesis that exercise downregulates tem- and about 70% of patients with breathing-related sleep dis- perature explains the increase in deep sleep after exercise.

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Physical activities may upregulate the body’s ability to lose The authors observed a 46% reduction in AHI, with a 5% heat, facilitating the sleep-related temperature drop46. reduction in BMI from 31 to 30 kg/m2 and of cervical cir- The optimum benefit of exercise is obtained when it is cumference from 43 to 41 cm. Five patients treated with a practiced 4-8 hours before bedtime. However, exercise at continuous positive airway pressure (CPAP) device showed a any time of day enhances sleep. In addition to aerobic and reduction in AHI from 21 to 11/h, much like the group with- resistance exercises, Tai Chi Chuan also improves the sleep out the equipment, whose AHI was reduced from 22 to 12/h. of practitioners47. In both cases, there was a change in the OSAHS classification, from moderate to light, irrespective of the use of CPAP57. POTENTIAL CARDIOVASCULAR BENEFITS OF Due to the 5% reduction in BMI, it is difficult to attri- PHYSICAL ACTIVITY IN OSAHS bute the reduction in AHI exclusively to the direct effect of Cardiovascular function is also affected by OSAHS. During exercise. However, one can infer that the reduction in AHI cardiopulmonary exercise testing (CPET), 35% of OSAHS was greater than expected by simple weight loss, using as patients have a hypertensive response and 45% show abnor- a basis the data of Young et al., which showed a 3% reduc- 49 58 mal VO2 peaks (84% below expected values) . tion in AHI for each 1% reduction in weight . In that case, During CPET, chronotropic incompetence and a delay in the expected drop in AHI for that magnitude of weight loss HR recovery may predict cardiovascular events and mortal- would be approximately 15%, which is quite different from ity in OSAHS patients24,50. Resistance training affects HR in the 46% reported. the long run, through adjustments in the autonomic nervous Giebelhaus et al.59 showed that exercising just 2 days a system. These adjustments are represented by a reduction in week also improves AHI. The physical training program, last- sympathetic activation and increased parasympathetic activ- ing 6 months, consisted of 120 minutes of aerobic exercise ity, resulting in a decrease in resting HR50. and 120 minutes of weight training on separate days. Ten men Nitric oxide is the most potent vasodilator produced in and one woman with a mean age of 52 years were evaluated. the body. During exercise, the shear stress (the tangential All study subjects were treated with a CPAP machine for a force that blood flow exerts on the vessel wall) stimulates period of 3-12 months (6±1.4 months). The authors observed the endothelium, increasing NO production and the vaso- a 27% reduction in AHI from 33 to 24/h, i.e., from severe to dilatory response. This causes increased blood flow, trig- moderate OSAHS. In that sample, the change in body weight gering acute, subacute and chronic adaptive responses to of the patients from 79.7 to 80.4 kg was not significant, leav- exercise throughout the entire cardiovascular and muscular ing no doubt about the isolated effect of exercise. systems51,52. Exercise may have a hypotensive effect of vari- Sengul et al.60 performed a randomized controlled study able magnitude according to the type, intensity and duration that evaluated aerobic performance and AHI after 3 months of exercise52,53. Activities with an intensity between 40 and of physical exercise in patients with mild OSAHS who were

70% of peak VO2, longer than 30 minutes in duration and not using CPAP. Twenty subjects were studied, 10 participat- repeated 5 to 7 times per week lowers blood pressure54,55. ing in the intervention group and 10 in the control group. Meta-analysis of more than a dozen studies on the effect Only the mean age was significantly different among groups: of resistance exercises, such as weight training, revealed that 54 years in the intervention group and 48 years in the con-

increases in peak VO2 and the metabolic equivalent of task trol group. Both groups predominantly included individuals (MET) caused a 2% (-3±3 mmHg) and 4% (-3±2 mmHg) not practicing regular physical activity. The training applied reduction in systolic and diastolic pressure at rest, respec- to the intervention group consisted of aerobic exercises, per- tively, in hypertensive subjects56. For each MET increase in formed three times per week on a treadmill and ergometric

peak VO2 of the individual, there is a reduction between 8 bike for 45-60 minutes with an intensity of 60-70% of peak 20,22 and 17% in cardiovascular mortality . VO2. Breathing exercises were also performed for 15 to 30 minutes. The controls remained without intervention. EXERCISE AS TREATMENT OF OSAHS In the same study60, after 3 months, the authors observed The three studies that investigated the effect of exercise on that the controls maintained constant anthropometric and AHI are summarized in Table 1. Norman et al.57 studied 8 AHI variables. The intervention group showed a decrease in men and 1 woman with a mean age of 49 years who under- AHI from 15 to 11 events per hour of sleep, or a reduction went exercise 3 times a week for 6 months. Their exercise of 27%, with no reduction in anthropometric variables such sessions consisted of 30-45 minutes of walking on a tread- as BMI and neck circumference. In this study, the effects of mill and riding a stationary bicycle with an intensity equiv- exercise and weight loss on AHI were also confounded. There 2 alent to 50-80% of the subject’s peak VO2. Bodybuilding was a 2% drop in BMI from 29.8 to 29.2 kg/m , which would exercises were used to complement each training session. explain a 6% reduction in AHI but not the 27% observed.

Sleep Sci. 2011;4(2):��–67 65 Silva RP, Belli KC, Carissimi A, Fiori CZ, Faria CC, Martinez D

FINAL Considerations 9. Gus M, Gonçalves SC, Martinez D, de Abreu Silva EO, Mor- Despite being a less controllable form of therapy, changes eira LB, Fuchs SC, et al. Risk for obstructive sleep apnea by in lifestyle are part of the medical prescription. Exercise has Berlin Questionnaire, but not daytime sleepiness, is associated with resistant hypertension: a case-control study. Am J been shown in the three reviewed trials to be an effective Hypertens. 2008;21(7):832-5. Comment in: Am J Hypertens. intervention for reduction of OSAHS severity. Furthermore, 2008;21(7):728. exercise can play an important role in treating the main 10. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, OSAHS factors, through reduction of both the cardiovas- Mohsenin V. Obstructive sleep apnea as a risk factor for stroke cular risk factors and the body mass of patients. Preventing and death. N Engl J Med. 2005;353(19):2034-41. Com- weight gain through exercise can prevent the emergence or ment in: N Engl J Med. 2005;353(19):2070-3. N Engl J Med. worsening of OSAHS. Physical training reduces cardiovas- 2006;354(10):1086-9; author reply 1086-9. N Engl J Med. 2006;354(10):1086-9; author reply 1086-9. cular events and OSAHS severity, regardless of the use of 11. Shah N, Roux F. The relationship of obesity and obstructive sleep other therapies such as CPAP or decreasing BMI. The lim- apnea. Clin Chest Med. 2009;30(3):455-65, vii. ited number of studies requires additional investigation of 12. Mugnai G. Pathophysiological links between obstructive sleep the effectiveness of the role of exercise in OSAHS before this apnea syndrome and metabolic syndrome. G Ital Cardiol (Rome). treatment modality can be universally recommended. Nev- 2010;11(6):453-9. Article in Italian. ertheless, the agreement among the reviewed articles sug- 13. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, Daniels S, Floras JS, Hunt CE, Olson LJ, Pickering TG, Rus- gests a potential benefit of exercise on OSAHS. sell R, Woo M, Young T; American Heart Association Council for High Blood Pressure Research Professional Education Commit- FINANCIAL SUPPORT tee, Council on Clinical Cardiology; American Heart Association Students received grants from the Brazilian government through Stroke Council; American Heart Association Council on Cardiovas- Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) cular Nursing; American College of Cardiology Foundation. Sleep and National Council of Technological and Scientific Develop- apnea and cardiovascular disease: an American Heart Association/ American College Of Cardiology Foundation Scientific Statement ment (CNPq). 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APPENDIX A Strategy of literature search performed on December 16, 2010. Legend Most recent queries Time Result #10 Search (#8) AND #9 12:16:00 149 #9 Search (exercise[MeSH Terms]) OR (Exercises[Text Word]) OR Exercise, Physical[Text 12:13:49 94.477 INTERVENTION Word]) OR (Exercises, Physical[Text Word]) OR (Physical Exercise[Text Word]) OR (Physical Exercises[Text Word]) OR Exercise, Isometric[Text Word]) OR (Exercises, Isometric[Text Word]) OR (Isometric Exercises[Text Word]) OR (Isometric Exercise[Text Word]) OR (Warm-Up Exercise[Text Word]) OR (Exercise, Warm-Up[Text Word]) OR (Exercises, Warm-Up[Text Word]) OR (Warm Up Exercise[Text Word]) OR Warm-Up Exercises[Text Word]) OR (Exercise, Aerobic[Text Word]) OR (Aerobic Exercises[Text Word]) OR (Exercises, Aerobic[Text Word]) OR (Aerobic Exercise[Text Word]) OR (Exercise Therapy[MeSH Terms]) OR (Therapy, Exercise[Text Word]) OR (Exercise Therapies[Text Word]) OR (Therapies, Exercise[Text Word]) OR (Resistance Training[Text Word]) OR (Training, Resistance[Text Word]) OR (Strength Training[Text Word]) OR (Training, Strength[Text Word]) OR (Weight-Lifting Strengthening Program[Text Word]) OR (Strengthening Program, Weight-Lifting[Text Word]) OR (Strengthening Programs, Weight-Lifting[Text Word]) OR (Weight Lifting Strengthening Program[Text Word]) OR (Weight-Lifting Strengthening Programs[Text Word]) OR (Weight-Lifting Exercise Program[Text Word]) OR (Exercise Program, Weight-Lifting[Text Word]) OR Exercise Programs, Weight- Lifting[Text Word]) OR (Weight Lifting Exercise Program[Text Word]) OR (Weight-Lifting Exercise Programs[Text Word]) OR (Weight-Bearing Strengthening Program[Text Word]) OR (Strengthening Program, Weight-Bearing[Text Word]) OR (Strengthening Programs, Weight-Bearing[Text Word]) OR (Weight Bearing Strengthening Program[Text Word]) OR (Weight-Bearing Strengthening Programs[Text Word]) OR (Weight-Bearing Exercise Program[Text Word]) OR (Exercise Program, Weight-Bearing[Text Word]) OR (Exercise Programs, Weight-Bearing[Text Word]) OR (Weight Bearing Exercise Program[Text Word]) OR (Weight-Bearing Exercise Programs[Text Word]) #8 Search (Sleep Apnea, Obstructive OR Apnea, Obstructive Sleep OR Apneas, Obstructive Sleep 12:12:59 22.975 PATIENTS OR Obstructive Sleep Apneas OR Sleep Apneas, Obstructive OR Obstructive Sleep Apnea Syndrome OR Syndrome, Sleep Apnea, Obstructive OR Syndrome, Obstructive Sleep Apnea OR Obstructive Sleep Apnea OR Sleep Apnea Syndrome, Obstructive OR Upper Airway Resistance Sleep Apnea Syndrome OR Syndrome, Upper Airway Resistance, Sleep Apnea OR Sleep Apnea Syndromes OR Apnea Syndrome, Sleep OR Apnea Syndromes, Sleep OR Sleep Apnea Syndrome OR Apnea, Sleep OR Apneas, Sleep OR Sleep Apnea OR Sleep Apneas OR Sleep Hypopnea OR Hypopnea, Sleep OR Hypopneas, Sleep OR Sleep Hypopneas OR Sleep- Disordered Breathing OR Breathing, Sleep-Disordered OR Sleep Disordered Breathing OR Sleep Apnea, Mixed Central and Obstructive OR Mixed Central and Obstructive Sleep Apnea OR Sleep Apnea, Mixed OR Mixed Sleep Apnea OR Mixed Sleep Apneas OR Sleep Apneas, Mixed OR Hypersomnia with Periodic Respiration)

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