1 Obstructive Sleep Apnea: Poor bedfellowDessislava Ianakieva, MD Sleep Medicine Fellow 5/17/17

2 Objectives Understand the mechanism of sleep apneaKnow factors that increase the incidence of sleep apnea in adults Understand the meaning of “AHI” Understand the effects of sleep apnea on the cardiovascular system Learn the basic treatments of sleep apnea. Understand the risk factors for and symptoms of pediatric sleep apnea. Understand basic treatments of pediatric sleep apnea.

3 Obstructive sleep apnea: The basics

4 Evaluating sleep disorders: PolysomnogramEEG EOG Nasal EtCO2 Nasal Oral Airflow Chin EMG (2) Microphone SaO2 EKG Tech Observer Video Camera Respiratory Effort Leg EMG (2) Records behavior Essentials of Sleep Technology: Pediatrics. Westchester, IL. American Academy of Sleep Medicine, 2006

5 Polysomnogram

6 Obstructive Sleep ApneaComplete or partial upper airway obstruction Often results in reductions in oxygen saturation Often terminated by brief arousals from sleep Duration of each obstruction is at least 10 seconds 20-40% of patients are not obese

7 Respiratory Events: DefinitionsHypopnea

8 Obstructive Apnea EventEKG Airflow Thoracic effort Abd. effort SAO2 Exhale Airway opens Airway obstructs Effort gradually increases Inhale Paradoxing Paradoxing Ends Obstructive Apnea A complete blockage of the airway despite efforts to breath. Notice the effort gradually increasing ending in airway opening. Blood oxygen levels reduce to >3% of baseline value Obstructive Apnea Event

9 Video

10 Normal hypnogram Hypnogram in OSA

11 Obstructive Sleep Apnea in AdultsWisconsin Sleep Cohort study: Estimated prevalence: 9% in women 24% in men

12 Physiologic changes in OSAIntermittent hypoxia Intermittent hypercapnia Increased negative intrathoracic pressure swings Increased arousals from sleep Sleep fragmentation Sympathetic nervous system activation Metabolic dysregulation Endothelial dysfunction Systemic inflammation Hypercoagulability Impaired cardiac function Left atrial enlargement Myocardial ischemia Cardiac remodeling Arrhythmia OSA appeared to be associated with an increased risk of developing heart failure, even after adjustment for potential confounders OSA may be an independent risk factor for VTE and that the risk may be two- to threefold higher than in those without OSA increased hypercoagulable markers including fibrinogen and plasminogen activator inhibitor-1

13 Other consequences of untreated OSAOverall increase in mortality Excessive daytime sleepiness Motor vehicle accidents Mood disorders Decreased quality of life OSA: Sudden cardiac death peaks between 12-6 AM Cardiovascular events occur in the early hours

14 Sleep Apnea and Sudden DeathRespiratory depressants may block the arousal process Alcohol Benzodiazepines Barbiturates Opioids Avoid alcohol within 4 hours of bedtime

15 Symptoms of OSA Middle Age Older > 60 years Pauses in breathingSnoring Nocturia Frequent nocturnal awakenings Morning headache Dry mouth Morning GERD Excessive daytime sleepiness Impaired cognition Older > 60 years A negative intrathoracic pressure is produced by inspiratory effort against a closed airway. Atria mistakenly signals the presence of fluid overload releasing atrial natriuretic peptide. Leading cause of disturbed sleep in older adults

16 Risk factors for OSA Male sex Older age (40-70 years)Postmenopausal status BMI >35 Craniofacial and upper airway abnormalities Resistant hypertension PCOS

17 Diagnosis of OSA In-lab polysomnogram is the gold standardHome sleep apnea test- unattended Apnea Hypopnea Index (AHI)= respiratory events per hour of sleep Apnea (90%obstruction of flow) + hypopnea (30% flow limitation) Normal < 5 Mild: 5-15 Moderate:15-30 Severe > 30

18 Screening questionnaire: STOP-BANGSTOP-Bang score ≥ 3 Sensitivity 89% to detect moderate to severe OSA 93% to detect severe OSA Specificities 30% for moderate to severe 29% for severe OSA

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21 OSA and cardiovascular diseaseHypertension Cardiac arrhythmia Atrial fibrillation Ventricular arrhythmia Coronary artery disease Circulation. 2008;118:

22 OSA and Hypertension ↑ sympathetic nerve activity and catecholamine levels Repetitive hypoxemia and hypercapnia chemoreflex-mediated sympathetic activation and vasoconstriction At the termination of apneas: ↑ cardiac output and severe vasoconstriction BP can rise from 130/60 mm Hg awake to 220/130 mm Hg during apneas Diastolic nocturnal hypertension Loss of nocturnal dipping of blood pressure. From Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96: )

23 OSA And Incident HypertensionSleep Heart Health Study (6424 patients) Linear relationship between the severity of OSA and the risk of systemic hypertension Mild OSA (AHI 5-15): 2 fold increased risk Moderate to severe OSA (AHI >15): 3 fold increased risk Sleep Heart Health Study (6424 patients) Linear relationship between the severity of OSA and the risk of systemic hypertension N Engl J Med 2000; 342:1378.

24 OSA And Hypertension 71% of patients with resistant hypertension have OSA compared to 38% of patients with controlled hypertension. Increased risk of hypertension in patients with OSA who were not compliant with CPAP at 12 years of follow up.

25 OSA and Diabetes OSA is an independent risk factor for the development of T2DM 15%–30% of patients with OSA have T2DM ↑ severity of OSA correlates to increased T2DM incidence and poor glycemic control Sleep Health Heart Study Mild OSA – Diabetes OR=1.27 ( CI 0.98–1.64) Moderate-to-severe OSA- Diabetes OR=1.46 (95% CI 1.09–1.97) OSA severity was associated with increased insulin resistance Nocturnal hypoxemia independently associated with glucose intolerance After adjustment for multiple potential confounders, including age, body mass index (BMI), waist circumference, and self-reported sleep duration

26 Nature and Science of Sleep 2015:7

27 Treatment options for OSA in adults

28 Indications for treatmentAHI >5 events per hour of sleep plus one or more clinical or physiologic sequelae attributable to OSA. AHI ≥15 events per hour of sleep, even in the absence of symptoms Mission critical work (airline pilots, air traffic controllers, locomotive engineers, DOT drivers) with AHI between 5 and 15 events per hour of sleep, even if there are no clinical or physiological symptoms attributable to OSA. Treatment options: Positive airway pressure therapy Oral appliances Positional therapy Bariatric surgery Adenotonsillectomy

29 Positive airway pressure modalities●CPAP delivers positive airway pressure at a level that remains constant throughout the respiratory cycle. It is used most often because it is the simplest, the most extensively studied, and associated with the most clinical experience. A pressure relief setting (ie, lowers the positive airway pressure at the onset of exhalation) is sometimes used to improve comfort and tolerance of the device. ●BPAP delivers a preset inspiratory positive airway pressure (IPAP) and expiratory positive airway pressure (EPAP). The degree of pressure support and consequently tidal volume is related to the difference between the IPAP and EPAP. As an example, the tidal volume is greater using an IPAP of 15 cm H2O and an EPAP of 5 cm H2O (difference of 10 cm H2O), than an IPAP of 10 cm H2O and an EPAP of 5 cm H2O (difference of 5 cm H2O). There is no proven advantage to using BPAP instead of CPAP for the routine management of OSA [58]. BPAP should not be confused with BiPAP, which is the brand name of a single manufacturer and is just one of many devices that can deliver BPAP. ●APAP increases or decreases the level of positive airway pressure in response to a change in airflow, a change in circuit pressure, or a vibratory snore (signs that generally indicate that upper airway resistance has changed). The degree of improvement of major outcomes conferred by APAP and CPAP is similar [59-63]. However, the performance of APAP can be highly variable, the body of evidence supporting its efficacy is more limited than that of fixed CPAP, and direct comparisons with fixed CPAP have not identified definitive benefits. (See "Initiation of positive airway pressure therapy for obstructive sleep apnea in adults", section on 'Auto-titrating CPAP'.) ●Adaptive servo-ventilation (ASV) provides a varying amount of inspiratory pressure superimposed on a low level of CPAP. It can be helpful in patients who have concomitant central apneas, which may occur as a consequence of CPAP (treatment-emergent central apneas), patients on long-acting opioids (narcotic-induced central sleep apnea), and patients who have had a stroke or kidney disease (central sleep apnea due to other conditions). However, based upon the SERVE-HF trial, caution should be exercised when using ASV in patients with heart failure and a Cheyne-Stokes breathing pattern, specifically those with a left ventricular ejection fraction of less than 45 percent, since a higher cardiovascular mortality in association with ASV use was reported in this population [64]. (See "Central sleep apnea: Treatment", section on 'Patients with ejection fraction ≤45 percent'.)

30 Continuous Positive Airway Pressure (CPAP) Best Treatment for Significant OSACPAP splints open the airway wherever the obstruction

31 Effect of OSA treatment on comorbid conditions

32 CPAP Treatment And Cardiovascular EventsA prospective cohort study followed 1651 men for a mean of 10 years following polysomnography. Treatment with CPAP reduced incidence of fatal and non-fatal cardiovascular events Lancet. 2005;365(9464):1046. A prospective cohort study followed 449 patients with mild or moderate OSA (~6 years follow up) Treatment of OSA (Primarily CPAP) associated with reduction of likelihood of cardiovascular events Adjusted HR 0.36 (95% CI ) Am J Respir Crit Care Med. 2007;176(12):1274.

33 CPAP Treatment And Cardiovascular EventsReduction in AHI from 29 to 3.7 events per hour No statistically significant effect on cardiovascular events Significant reduction in snoring and daytime sleepiness Improvement in health-related quality of life and mood CAVEAT: Average CPAP use ~ 3.3 hours per night Excluded patients with excessive daytime sleepiness TI CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. AU McEvoy RD, Antic NA, Heeley E, Luo Y, Ou Q, Zhang X, Mediano O, Chen R, Drager LF, Liu Z, Chen G, Du B, McArdle N, Mukherjee S, Tripathi M, Billot L, Li Q, Lorenzi-Filho G, Barbe F, Redline S, Wang J, Arima H, Neal B, White DP, Grunstein RR, Zhong N, Anderson CS, SAVE Investigators and Coordinators SO N Engl J Med. 2016;375(10):919. Epub 2016 Aug 28. BACKGROUND Obstructive sleep apnea is associated with an increased risk of cardiovascular events; whether treatment with continuous positive airway pressure (CPAP) prevents major cardiovascular events is uncertain. METHODS After a 1-week run-in period during which the participants used sham CPAP, we randomly assigned 2717 eligible adults between 45 and 75 years of age who had moderate-to-severe obstructive sleep apnea and coronary or cerebrovascular disease to receive CPAP treatment plus usual care (CPAP group) or usual care alone (usual-care group). The primary composite end point was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for unstable angina, heart failure, or transient ischemic attack. Secondary end points included other cardiovascular outcomes, health-related quality of life, snoring symptoms, daytime sleepiness, and mood. RESULTS Most of the participants were men who had moderate-to-severe obstructive sleep apnea and minimal sleepiness. In the CPAP group, the mean duration of adherence to CPAP therapy was 3.3 hours per night, and the mean apnea-hypopnea index (the number of apnea or hypopnea events per hour of recording) decreased from 29.0 events per hour at baseline to 3.7 events per hour during follow-up. After a mean follow-up of 3.7 years, a primary end-point event had occurred in 229 participants in the CPAP group (17.0%) and in 207 participants in the usual-care group (15.4%) (hazard ratio with CPAP, 1.10; 95% confidence interval, 0.91 to 1.32; P=0.34). No significant effect on any individual or other composite cardiovascular end point was observed. CPAP significantly reduced snoring and daytime sleepiness and improved health-related quality of life and mood. CONCLUSIONS Therapy with CPAP plus usual care, as compared with usual care alone, did not prevent cardiovascular events in patients with moderate-to-severe obstructive sleep apnea and established cardiovascular disease. (Funded by the National Health and Medical Research Council of Australia and others; SAVE ClinicalTrials.gov number, NCT ; Australian New Zealand Clinical Trials Registry number, ACTRN ).

34 CPAP treatment and hypertensionCPAP treatment decreases in systolic blood pressure of 2.5 to 3.0 mm Hg Patients with uncontrolled hypertension are likely to gain the largest benefit (reduction in blood pressure) from CPAP CPAP improves blood pressure control more than nocturnal oxygen supplementation prospective cohort study of 1889 participants without hypertension 12 year follow up

35 CPAP and Resistant HypertensionRCT of of 117 patients assessed the effect of continuous positive airway pressure (CPAP) treatment on 24-h urinary aldosterone excretion in patients with Resistant hypertension (RHT) and moderate/severe OSA. Decreased aldosterone excess in resistant hypertensive individuals with OSA Effect was observed with optimal use only (>6hr of use per night) More pronounced in effect: non-dippers, not on spironolactone, less obese, lowest nocturnal oxygen saturation J Hypertens Apr;35(4):

36 Positive Airway Pressure And Heart FailureCanadian Positive Airway Pressure (CANPAP) trial Men with severe OSA (AHI >30 ) were 58 % more likely to develop heart failure Sleep. 2015;38(5):677. Epub 2015 May 1 A meta-analysis (6 RCT) CPAP was associated with a 5% improvement in ejection fraction PLoS One. 2013;8(5):e62298 Canadian Positive Airway Pressure (CANPAP) trial Greater reduction in AHI Improvements in mean nocturnal O2 sat Improvement in left ventricular ejection fraction Improvement in 6 minute walk distance Circulation 2007; 115:3173.

37 Positive Airway Pressure Therapy And Atrial FibrillationRate of recurrent AF after cardioversion: Untreated OSA- 86% Treated OSA 42% Without OSA 53 % CPAP therapy effect on AF: Reduces the structural and electrical remodeling of the left atrium due to OSA Decreases serum markers of oxidative stress (cytokines and free radicals) Heart Rhythm Mar;10(3):331-7.

38 Continuous Positive Airway Pressure Therapy In OSA and Glycemic ControlClinically significant improvement in glycemic control Amelioration of evening fasting glucose metabolism Reduction in the dawn phenomenon Mokhlesi B, Grimaldi D, Beccuti G and Van Cauter E. Effect of one week of CPAP treatment of obstructive sleep apnoea on 24-hour profiles of glucose, insulin and counter-regulatory hormones in type 2 diabetes 24-hour profiles of glucose, insulin and counter-regulatory hormones in 12 subjects with type 2 diabetes and OSA before and after 1 week of effective in-laboratory CPAP therapy over an entire 8-hour night thus ensuring optimal CPAP compliance. Monitored in lab Largest reduction in morning fasting levels Reduced the late-night increase in glucose levels dawn phenomenon, a late-night glucose increase not adequately tx by oral medications no significant effect on the 24-hour or overnight profiles of GH and cortisol but norepinephrine levels decreased significantly Diabetes Obes Metab, 2016.

39 Oral appliance: Mandibular repositioning devisesIndicated for mild-moderate OSA 50% reduction in the AHI Discontinuation rates of14–63% after 4-5 years Advancement to the maximum tolerable distance or 65% of the maximum protrusion Med Oral Patol Oral Cir Bucal Sep 1;20(5):e605-15

40 Bariatric surgery and OSAHigher prevalence of OSA among the morbidly obese: 55% in women and 80% in men .2 50% reduction in AHI with 10%-15% reduction in body weight This study is part of a non-randomized, controlled clinical trial; the MOBIL-study (Morbid Obesity treatment, Bariatric surgery versus Intensive Lifestyle intervention Study) 133 morbidly obese patients, Intensive lifestyle vs Gastric bypass surgery Remission of OSA (AHI < 5 events/h) at 1 year follow up: 66% RYGB patients vs 40% ILI patients Journal of Clinical Sleep Medicine, Vol. 9, No. 5, 201

41 Pediatric Obstructive Sleep Apnea

42 Snoring in children 10% of children snore1-5 % have sleep disordered breathing Snoring > 3 times per week associated with increased risk of OSA Peak prevalence: 2 and 8 years of age Chronic nasal congestion Adenotonsillar hypertrophy

44 Video

45 OSA Risk factors in childrenTonsillar and adenoidal hypertrophy History of prematurity and multiple gestation Family history of OSA Craniofacial abnormalities Neuromuscular disorders Myelomeningocele History of low birth weight Uncontrolled epilepsy Obesity Adenotonsillar hypertrophy and obesity are the major risk factors for OSA. Other conditions that reduce upper airway size, affect the neural control of the upper airway, or impact the collapsibility of the upper airway are also risk factors for OSA 46.6% of obese children in the community had an obstructive apnea hypopnea index (POAHI) >1/hr

46 Syndromes associated with OSATrisomy 21 (Down Syndrome) Prader-Willi Robin sequence Treacher Collins Beckwith-Wiedemann Achondroplasia Smith Magenis Turner Syndrome Strickler Syndrome Fetal Alcohol Syndrome Arnold-Chiari malformation

47 OSA symptoms in childrenCommon signs and symptoms during sleep: Common signs and symptoms during wakefulness: Snoring Pauses in breathing Chocking or gasping Increased work of breathing Enuresis Excessive sweating Hyperextended neck Frequent awakenings Poor school performance Aggressive behavior Hyperactivity Excessive daytime sleepiness Morning headaches Failure to thrive Hyperactivity and/or attention deficits; Bizarre and/or aggressive behavior; Learning, developmental, discipline, and/or behavioral problems; Poor school performance; Developmental delay; May briefly improve following nap; Poor appetite, decreased intake, slow eating, difficulty swallowing and growth retardation. Only 9-13% exhibit daytime sleepiness

49 Effects Of Untreated Pediatric OSAFailure to thrive Increased energy expenditure due to increased work of breathing Decreased nocturnal growth hormone secretion may be decreased in children with increased upper airway resistance Improvement in growth hormone secretion after adenotonsillectomy Cadiovascular effects in children with POAHI >5 Lower RV ejection fraction Increased LV diastolic dysfunction Remodeling with larger interventricular septal thickness index on echocardiogram Effects noted were independent of the effect of obesity OBJECTIVE The pathophysiological mechanisms of growth impairment frequently associated with the obstructive sleep apnea syndrome (OSAS) in children are poorly defined. The main objective of this study was to evaluate whether nighttime upper airway obstruction attributable to adenotonsillar hypertrophy and subsequent surgical treatment affect the circulating concentrations of insulin-like growth factor-I (IGF-I) and IGF-binding protein 3 (IGFBP-3) along with other growth parameters in children. PATIENTS AND METHODS We initially studied 70 children (mean age: 5.8 years; range: years) admitted to a university hospital because of clinical symptoms of OSAS. Their sleep was monitored with a 6-channel computerized polygraph. Data on anthropometry and circulating concentrations of IGF-I and IGFBP-3 were generated and compared with corresponding characteristics in control children (N = 35). Thirty children with an obstructive apnea-hypopnea index (OAHI) of 1 or more were categorized as children with OSAS (mean OAHI: 5.4 [95% confidence interval for mean (CI): ]), whereas 40 children with an OAHI of<1 were considered as primary snorers (PS) (mean OAHI 0.13 [95% CI: ]). Nineteen children with OAHI>2 underwent adenotonsillectomy attributable to OSAS and were reassessed 6 months later together with 34 nonoperated children with OAHI<2. RESULTS There were no initial differences in relative height and weight for height between the 3 groups of children. No differences were observed in peripheral IGF-I concentrations, but both OSAS and PS children had reduced peripheral IGFBP-3 levels. The operated children with initial OSAS experienced a highly significant reduction in their OAHI from 7.1 (95% CI: ) to 0.37 (95% CI: ). Weight-for-height, body mass index, body fat mass, and fat-free mass increased during the follow-up in the operated children with OSAS, whereas only fat-free mass and relative height increased in the PS children. Both the IGF-I and the IGFBP-3 concentrations increased significantly in the operated children, whereas no significant changes were seen in the PS children.

50 Effects Of Untreated Pediatric OSAEndothelial dysfunction Metabolic dysregulation Impaired glucose tolerance Hyperlipidemia NASH Impairment of neurocognitive development Poor school performance Behavioral problems

51 Grey matter volume reductions superior frontal, prefrontal, superior and lateral parietal cortices that control of cognition and mood

54 Effects of treatment of pediatric sleep apneaImprovement of: Behavior Attention span Quality of life Neurocognitive functioning Enuresis Parasomnias Restless sleep Reversal of associated cardiovascular sequelae Improvement in cardiac function Decrease in average heart rate and blood pressure Improvement in endothelial function

55 Adenotonsillectomy Success rate of adenotonsillectomy is 75%-85%Poor prognostic factors: Obesity Severe OSA pre-surgery with an POAHI of >20/hr Cildren aged >7 years High Mallampati score African-American ethnicity Craniofacial abnormalities (e.g., Pierre Robin syndrome) Chromosomal abnormalities (e.g., trisomy 21) Neuromuscular disease |

56 Risk Factors For Complications Following AdenotonsillectomyIncreased severity of OSA with increased obesity Evaluate for atlantoaxial instability and Likely to require adjuvant surgical procedures Severity and sites of airway obstruction Likely to require adjuvant surgical procedures At risk for significant hypoventilation At risk for pulmonary and cardiac dysfunction Increased adenoid and tonsil size Increased risk for respiratory complications

57 The Childhood Adenotonsillectomy Trial (CHAT)Surgical treatment did not significantly improve attention or executive function as measured by neuropsychological testing Surgical treatment did: Reduce symptoms Improve behavior and quality of life Normalization of polysomnographic findings 79% vs. 46% Evaluate the efficacy of early adenotonsillectomy versus watchful waiting A randomized trial of adenotonsillectomy for childhood sleep apnea. AU Marcus CL, Moore RH, Rosen CL, Giordani B, Garetz SL, Taylor HG, Mitchell RB, Amin R, Katz ES, Arens R, Paruthi S, Muzumdar H, Gozal D, Thomas NH, Ware J, Beebe D, Snyder K, Elden L, Sprecher RC, Willging P, Jones D, Bent JP, Hoban T, Chervin RD, Ellenberg SS, Redline S, Childhood Adenotonsillectomy Trial (CHAT) SO N Engl J Med. 2013;368(25):2366. BACKGROUND Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes. METHODS We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months. RESULTS The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [±SD]improvement, 7.1±13.9 in the early-adenotonsillectomy group and 5.1±13.4 in the watchful-waiting group; P=0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%). CONCLUSIONS As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT ). n engl j med 368;25 june 20, 2013

58 Mandibular DistractionBilateral corticotomy of the mandible Insertion of either internal or external metal distractors Gradual distraction of the mandible while new bone fills in the gap Indicated in children with significant micrognathia and severe sleep apnea Paediatr Respir Rev June ; 16(3): 189–196.

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61 References: Durán-CantollaJ et al. Efficacy of mandibular advancement device in the treatment of obstructive sleep apnea syndrome: A randomized controlled crossover clinical trial. Med Oral Patol Oral Cir Bucal Sep 1;20(5) Marin JM et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet. 2005;365(9464):1046. Buchner NJ et al. Continuous positive airway pressure treatment of mild to moderate obstructive sleep apnea reduces cardiovascular risk. Am J Respir Crit Care Med. 2007;176(12):1274. Marie-Françoise Vecchierini et al. A custom-made mandibular repositioning device for obstructive sleep apnoea–hypopnoea syndrome: the ORCADES study. Sleep Medicine. Volume 19, March 2016, Pages 131–140 McEvoy RD et. Al. CPAP for Prevention of Cardiovascular Events in Obstructive Sleep Apnea. N Engl J Med. 2016;375(10):919. Epub 2016 Aug 28. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378. Tomas Konecny et al.Obstructive Sleep Apnea and Hypertension Hypertension. 2014;63: Marin JM et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012;307(20):2169. Kanagala R et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation. 2003;107(20):2589. Epub 2003 May 12. Holmqvist F et al. Impact of obstructive sleep apnea and continuous positive airway pressure therapy on outcomes in patients with atrial fibrillation-Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF). Am Heart J May;169(5): e2. Epub 2015 Feb 7. Hla KM et al. Coronary heart disease incidence in sleep disordered breathing: the Wisconsin Sleep Cohort Study. Sleep. 2015;38(5):677. Epub 2015 May 1. Mansfield DR et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med. 2004;169(3):361. Sun H et al. Impact of continuous positive airway pressure treatment on left ventricular ejection fraction in patients with obstructive sleep apnea: a meta-analysis of randomized controlled trials. PLoS One. 2013;8(5):e Epub 2013 May 1 Nieminen P et al. Growth and biochemical markers of growth in children with snoring and obstructive sleep apnea. Pediatrics. 2002;109(4):e55. Chan JY et al. Cardiac remodelling and dysfunction in children with obstructive sleep apnoea: a community based study. Thorax. 2009;64(3):233. Gozal D et al. Obstructive sleep apnea and endothelial function in school-aged nonobese children: effect of adenotonsillectomy. Circulation Nov;116(20): Epub 2007 Oct 29. Marcus CL et al. A randomized trial of adenotonsillectomy for childhood sleep apnea. N Engl J Med. 2013;368(25):2366. Waters KA et al. Obstructive sleep apnea: the use of nasal CPAP in 80 children. Am J Respir Crit Care Med. 1995;152(2):780.

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