SUSAN RAUSCH, MD, PHD November 10, 2017

SUSAN RAUSCH, MD, PHD November 10, 2017

#1 - Why should we care about diagnosing obstructive sleep apnea? #2 - Does treatment of obstructive sleep apnea make a difference? #3- Is treatment of obstructive sleep apnea cost effective?

Index (events/hour): Apnea index (AI) # Apneas / hour* Apnea Hypopnea Index (AHI) # Apneas + Hypopneas / hour AHI of home study < AHI of in lab study typically Respiratory Disturbance Index (RDI) # Apneas + Hypopneas + RERAs / hour (check definition older literature RDI = AHI) * unit of time varies by sleep study type In lab study total sleep time Home study total recording time (wake + sleep time)

Severity Mild (5 15 EVENTS / HOUR) Moderate (15 30 EVENTS / HOUR) Severe (>30 EVENTS / HOUR)

Why should we care about diagnosing obstructive sleep apnea? Is it associated with other disease(s) that are common? Is it associated with other disease(s) that are costly?

Estimates of 93% women and 82% men not diagnosed who have OSA Young, T et al Sleep 20(9) 1997 US general population 30-70 yoa AHI > 5 with sleepiness - 14% men, 5% women AHI > 15-13% men, 6 % women In last 2 decades increasing prevalence By 14-55% depending on age group Peppard, PE et al 2013

Appears to be associated with increasing the risk of: Cardio-vascular disease Diabetes, insulin resistance Indigestion / heart burn Night time urination / Erectile dysfunction Greater nighttime fall risk (hip fractures) Obesity Earlier death

Increases the risk of Hypertension (systemic and pulmonary) Endothelial dysfunction/accelerated atherosclerosis Arrhythmia Angina Coronary artery disease / myocardial infarction Congestive heart failure Stroke

Common and costly diseases 35% US population with some form of heart disease 2014 CDC and NIH update Up to 50% patients with hypertension have OSA Konecny, T, et al 2014 64%- 83% of patients with resistant HTN have OSA Pedrosa, RP, et al 2011 Logan. J. HTN 19:2271, 2001 Atrial fibrillation 4.8% prevalence with OSA vs 0.9% prevalence without OSA Mehra, R, et al 2006

Sleep normally period of rest for heart NREM 80% of sleep Marked autonomic stability High parasympathetic tone Baroreceptor gain high stability of BP Baroreceptor normally buffers swings in HR and BP during acute perturbations Associated with lower norepinephrine, epinephrine and cortisol levels

Transitions from NREM REM Varying degree of autonomic activation Bursts of vagal tone HR pause or brief frank asystole REM Marked increase in sympathetic tone (greater than wake) Most marked phasic REM BP surges and HR pauses, with reduced Vagal tone and baroreceptor regulation Breathing pattern is irregular Cortisol increased (increase late in sleep period, 5am)

Supply/ demand mismatches REM increased demand related to nocturnal ischemia Increased HR surges, with increased metabolic demands (and reduced O2 delivery) Nowlin, JB, et al, 1965 Patients on beta blockers have less frequent nocturnal ischemia events in REM Andrews, TC, et al 1993 NREM decreased supply (non demand) related ischemia More vulnerable - severe CAD, diabetes, acute coronary artery syndromes Increased PNS tone- more vasodilation (hypotension) Quuyumi, AA et al 1984 Coronary artery under perfused (reduced flow through stenotic vessel) Prothombotic state Mancia, G 1993 Subendocardial MI clustered at time of BP nadir Benhorin J et al 1993 Beta blocker does not reduce non demand ischemia/ MI

Sleep is not a protected state in cardiac disease patients Increased sympathetic (SNS) tone relative to parasympathetic (PNS) tone Post MI Loss of rise in PNS in sleep is characteristic Reduction in parasympathic tone 10 minute before ischemia in sleep Vardas, PE, et al, 1996 Loss of parasympathetic rise in sleep characteristic of patients with residual myocardial ischemia Cerati, D. et al 1997 With Heart failure (high SNS state) More frequent shifts to light sleep stage (less PNS) Arousals (> SNS activity) Increase blood pressure and Heart rate

SNS activation leads to: Increased SVR, LV afterload, vasoconstriction Increased right heart afterload, Increased myocardial contractility and hypertrophy Arrhythmia often tachyarrhythmia Increased myocardial NE myocyte toxicity and apoptosis Groups at higher risk for nocturnal MI older, low EF, Diabetes Treatment plan to include exercise even adding moderate exercise to plan improves autonomic status and sleep continuity

Hypoxia and hypercapnia (during apnea) Activates sympathetic nervous system Vasoconstriction, BP and HR surges Via Peripheral and central chemoreceptor Hypocapnia (hyperventilation in recovery) May contribute to arrhythmogenesis May impair myocardial O2 delivery Coronary artery vasoconstriction Shift O2 dissociation curve to left

Decreased oxygen delivery (esp with CAD) O2 Supply and demand mismatch vulnerability REM: higher demand (Tachycardia) NREM: lower supply (Hypoperfusion) May further impair myocardial contractility May lead to angina, MI, arrhythmia, heart failure, sudden death Funiyoshi et al 2008 Hemodynamics Systemic Central Gami et al, 2005

Cyclical changes in blood pressure Increases wall stress [plaque rupture] Reduces delivery of O2 [ischemia] Promotes further endothelial dysfunction, atherosclerosis, LV dysfunction Rise in intrapleural pressure, can lead to arrhythmogenic atrial stretch

Pulmonary vasoconstriction 4 studies, subjects with no pulmonary disease Mild pulmonary HTN seen in 17-42% Severe Pulmonary HTN (cor pulmonale) may be seen in patients with severe OSA Right heart afterload challenge and myocardial O2 consumption Pre capillary (hypoxic vasoconstriction) Post capillary (LV dysfunction) CPAP effective in reducing pulmonary pressures if delivered before remodeling occurs

American Heart Association and American College of Cardiology Joint Statement recommendation: PSG should be done to r/o OSA in all patients with pulmonary HTN Targeted OSA treatment should be provided to improve/ prevent further deterioration in central hemodynamics McLoughlin, VV, et al 2009

Associated with biochemical and cellular changes Neuro-humoral activation Endothelial dysfunction as indicated by: Vasoconstriction favored state Inflammatory mediator release Pro-thrombotic state Oxidative stress Adverse Lipid profiles Hemodynamic change Genetic susceptibility

CPAP treatment can reverse these biochemical and cellular changes Especially in drug resistant hypertension with compliant CPAP use Small drops in BP can lead to reduced cardiovascular disease 2-10 mm Hg DBP 10-56% reduction in stroke 7-37 % reduction in heart disease

Breathing reduces sympathetic outflow Apnea potentiates SNS activation Increases in blood pressure with sleep apnea can be astounding, particularly when they occur at altitude Morgan, Chest 122:398, 2002 Patients must use CPAP at altitude! (Tis the Season)

Nighttime SNS activation can carry over to daytime function In healthy subjects 2 week exposure to repetitive hypoxia increased chemoreceptor gain and blunted BR protection Tamisier et al, 2011

Humans, increased peroneal muscle SNA (msna) In healthy subjects Increased msna during apnea and return to baseline after event Hedner, J HTN 6:S529,1988 With successive 40 sec exposure to HPO, greater duration of time to recovery after event Xie, Appl. Physiol. 89:1333,1999 OSA subjects In wake, increased msna present Increased msna correlated with elevated plasma catechols, in both normotensive and hypertensive subjects Carlson, Chest 103:1763, 1993

Vasoactive changes- favor vasoconstiction Vasodilators decreased (Nitric oxide, prostacyclin) Vasoconstrictors increased (endothelin-1, angiotension II, thromboxane, Serotonin) Phelan, MW, et al 1996 Yu AY, et al 1999; Koong, AC, et al 1994

Inflammatory mediator markers of increased oxidative stress seen in OSA subjects Increased CRP, IL-6, TNF-alpha, IL-18, MMP-9 May / not be related to obesity (studies differ) Is related to OSA severity Lavie,P, et al 2009; Schultz, R, et al 2000; IP, MSM et al, 2000; Kato, M, et al 2001; Jelic, s, etal 2008;Foster, GE, etal 2006; Shamuzzaman, A, et al 2014; Hoyos, CM, et al, 2015 ; Sanner BM, et al 2000; Yokoe,T, et al 2003; Ryan, S et al 2005 Excellent review Budhiraja, J Clin Sleep Med 3(4): 409, 2007

Prothrombotic state induced by hypoxia through redox sensitive gene activation. Leading to: 1) Prothrombotic state Via increases in Endothelin 1, vascular endothelial GF, platelet derived GF Reduction in fibrinolytic activity (nadir in sleep) 2) Via increases in cellular adhesion molecules With subsequent leucocyte endothelial attachment and transmigration ICAM- 1, v-cam1, monocyte chemo attractant protein-1 Lavie,P, et al 2009; Schultz, R, et al 2000; IP, MSM et al, 2000; Kato, M, et al 2001; Jelic, s, etal 2008;Foster, GE, etal 2006; Shamuzzaman, A, et al 2014; Hoyos, CM, et al, 2015 ; Sanner BM, et al 2000; Yokoe,T, et al 2003; Ryan, S et al 2005; Bridges, AB, et al 1993 Excellent review Budhiraja, J Clin Sleep Med 3(4): 409, 2007

Oxidative stress Free radical generation with reoxygenation With repetitive swings in saturation more free radical generation, more deleterious than sustained hypoxia Prabhaker Nr, 2001, and 2002 May occur 100 s of times/ night with OSA reperfusion injury May promote vascular inflammation and remodeling

Adverse changes in lipid metabolism with increased AHI Increased LDL oxidation Decreased HDL Increased apoe levels Increased homocysteine levels

Rats with 12 week exposure to intermittent hypoxia Normoxia with high cholesterol diet no atherosclerotic aorta lesions Hypoxia without high cholesterol diet no atherosclerotic aorta lesions Hypoxia with high cholesterol diet atherosclerotic aorta lesions Increased LDL and decreased HDL Twofold increased in lipid peroxidation Hypoxia and high cholesterol diet interact to accelerate atherosclerosis Savransky, AJRCCM 175: 1290, 2007

Obstructive Sleep Apnea and Hypertension

Obstructive sleep apnea is an independent risk factor for the development of HTN Demonstrated in Cross sectional, case controlled studies Longitudinal studies Animal studies with induced intermittent hypoxia Drug resistant hypertension If 3 or more anti-hypertensive medications are needed to treat hypertension, there is an 83% chance patient with OSA As defined by AHI > 10 Logan. J. HTN 19:2271, 2001

Sleep normally period of rest for heart NREM Decreased sympathetic contribution Increased parasympathetic contribution End result: Decreased BP (>10% BP drop in dipper) Decreased HR (normal 40-90 bpm) Dipping is normal Non dipping not normal

Case Matched control study ODI 29 and 2 N=45 each group Untreated OSA pts, and 24 hr ambulatory BP Reduced nocturnal dip Higher waking diastolic BP Davies, Thorax 55:736, 2000

Non dipper with greater: All cause and CV mortality Fagard, RJ, et al 2008 All CV disease endpoints Staessen, JA et al 1999 Frequency and complexity of ventricular arrhythmias Schillaci, G, et al 1996 Risk of MI Piedomenico, SD, et al et al 1998 Cerebrovascular insult Schwartz, GL, et al 2007 Increased end organ damage and heart failure Cardiac hypertrophy Verdecchia, P, et al 1990 Remodeling and Diastolic dysfunction T wave Alternans (may predict lethal arrhythmia) Verrier RL, et al, 2011; Takasugi N, et al 2009 Blunted endothelial vasodilator dependent response implicated

Demographics Gender women under diagnosed and undertreated Less aggressive evaluation and treatment Potential survival disadvantage Race -? Age HTN OR decreases with older age, above 70 yoa AHI not predict HTN Bixler, EO, et al 2000 Should not conclude older patients do not have risk of higher morbidity associated with OSA (? survival bias) Weight OSA and obesity independently impact HTN risk OSA more strongly predictive of HTN in Leaner patients Young, T, et al 1997

Suggested dose response between moderate OSA and HTN Severe OSA flatten risk, may be survival bias Severe OSA HTN myocardial dysfunction and heart failure lower blood pressure Nieto, FJ, et al 2000 Wisconsin Cohort Study, Middle aged employees with HTN SBP >140, DBP >90, no anti HTN treatment At 4 yrs compared with AHI < 5 AHI 5-15 (mild OSA), OR 2x for developing HTN AHI > 15 (moderate severe OSA), OR 3x for developing HTN Peppard, PE, et al 2000 Sleep Heart Health Study 5 yrs, 50% increased risk of HTN with OSA patients Dose response with AHI and Heart failure Shahar, E, et al 2001

Does adequacy of treating Obstructive Sleep Apnea impact management of hypertension?

Ambulatory BP before and after treatment n=60 each group Similar age, baseline anthropomorphics Similar AHI (35-39) Similar hours of use 4 wks of CPAP-therapeutic or subtherapeutic More severely elevated AHI with greater BP in sleep (greater nondip) BP fall independent of baseline BP Conclusion after 1 month of treatment CPAP produces a clinically significant lowering of BP Pepperell, Lancet 359:204, 2001 (it is not enough to diagnose, also shows importance of appropriate treatment pressure)

Obstructive Sleep Apnea and Arrhythmia

Incidence of malignant arrhythmia usually reduced in sleep Not so with OSA NREM complex changes in vagal tone / increase adrenergic tone with OSA Change atrial refractoriness, repolarization, intra-atrial conduction Josephson, ME 2002 REM associated surge in SNS Direct - effect on electrical substrate excitability Indirect raise BP and HR

Atrial fibrillation 2.5 million patients in US 10-25% facilitated by vagal influence 2x greater risk if patient has OSA Monahan, K, et al, 2009 SNS activity pressor surge with atrial stretch / hypoxia Otto, ME, et al, 2007 Orban M, et al, 2008 Drager, LF, et al, 2010 Nocturnal peak of AFib between MN- 6 AM Rostagno, C, et al 1993 Yamashito, T, et al, 1998 Gillis, AM, et al 2001 Anti- arrhythmic refractory period 4-5 am occurs during REM Gillis, AM, et al 2001

Ventricular tachycardia Desaturations increase VT risk after MI Galatius Jensen, S., et al 1994 Desaturations increase VT risk with greater age Asplund,R. 1994 Treatment stabilizes underlying EP substrate Beta blockers, avoid hypotension (r/o white coat HTN), treat OSA

Cardioversion for afib Effective if OSA treated, limited effectiveness if OSA is not treated Fein, AS, et al 2013 At 12 months - 82% recurrence with ineffective CPAP - vs 42% recurrence with effective CPAP Pharmacologic management of afib Untreated OSA less likely to respond to anti-arrhythmic treatment Monahan K, et al 2012 Recommendation presence of nocturnal afib should prompt evaluation and treatment of OSA

Obstructive Sleep Apnea and Nocturnal Angina

OSA in 9/10 patients with coronary artery disease who had nocturnal angina CPAP treatment reversed angina Franklin, KA, et al 1995 Silent nocturnal ischemia in 31% of 226 patients More frequent with more severe OSA Mooe, T, et al 2000

Obstructive Sleep Apnea and Coronary Artery Disease

Risk of unstable angina, acute MI, sudden cardiac deathincreased in late sleep / upon wake OSA - independent increased risk of sudden cardiac death OSA with cardiac disease- retrospective study More sudden death during sleep in OSA patients Vs patients with cardiac disease and no OSA, and controls Muller, JE, et al, 1989 10,701 consecutive adult patients, 5.3 yr follow up, 142 resuscitated or sudden cardiac death AHI >20, Hazard ratio 1.6 Mean nocturnal sat < 93%, Hazard ratio 2.93 Nadir sat < 78%, Hazard ratio 2.6S Gami, AS, et al 2005 Incidence of MI with AHI > 15, adjusted OR 2 Nakashima, H, et al 2013

Study of PSG and EKG- nocturnal ischemia common with OSA and CAD mainly in REM, during apnea and sustained HPO Koehler, U, et al 1991 ST segment depression seen in patients with OSA and no known CAD resolved with cpap Hanly, P, et al 1993 Compared to controls (angiographic +CAD, OSA = AI > 10) CAD 2x > in men Mooe, T, et al 1996 CAD 3x> in women < 70 yoa Mooe, T, et al 1996 Sleep Cohort Study, n = 386, CAD present in 20% of patients with OSA Akasaka, K, et al, 1997 25% of OSA patients, higher incidence with moderate and severe OSA Maekawa, M,et al 1998 OSA (AHI > 5), 6 yr follow up in patients with h/o MI OR 5 for recurrent MI in OSA patients, compared to controls Use of CPAP (> 3.5 hrs) reduced MI and revascularization Garcia-Rio, G, et al 2013

With MI 33% patients had OSA (AHI > 15) vs 4% patients with AHI < 5 Hung, J, et al 1990 Case controlled CAD study With h/o MI, OR 2 that OSA present (AHI >20) Schager, H, et al 1999 With CAD, OR 3 that OSA present (AHI >10) Peker, Y, et al 1999

Uncontrolled studies OSA defined as AI >10, with CAD OSA present in 35-66% of patients Andreas, S, et al 1996; Koehler, U, et al 1996; Yumino, D, et al 2007; Mehra, R, et al 2006 OSA defined as AHI >15, with CAD, undergoing percutaneous intervention OSA present in 43%- 66% Nakashima, H, et al 2006 Lee, CH et al 2009 Retrospective study Suspected 12 % but found 41% with AHI >15 Konecny, T, et al 2010 Randomized Control trial, 662 revascularized patients 64% with AHI >15, most with no daytime sleepiness Glantz, H, et al 2013

Longitudinal studies no OSA treatment: At 10 yrs, n = 1300, severe OSA 3-4 x fatal / non fatal cv events compared to snorer Marin, JM et al 2005 At 3 yrs, n = 1436, with AHI >5, CAD event or death, Adjusted Hazard ratio - 2 Shah, NA, et al 2010 At 8.7 yrs SHHS n = 1927 men, n = 2495 women AHI >30 in men (not women) CAD adjusted Hazard ratio 1.7 Gottlieb, DJ, et al 2010 At 10 yrs Spanish study, n = 1116 women, untreated severe OSA Adjusted Hazard ratio- 3.5 cv mortality compared to AHI <10 Adjusted Hazard ratio - 2.8 CAD and stroke in AHI > 10 compared to AHI < 10 Campos - Rodriguez,F, et al 2012

Does treatment of obstructive sleep apnea make a difference? Can we impact cardiovascular disease by treating obstructive sleep apnea?

Retrospective studies At 7.3 yr follow up, n = 55, h/o CAD CPAP compliant patients had lower incidence of cv death, acute coronary artery syndrome, cardiac failure, revascularization Milleron, O, et al, 2004 At 7.5 yr follow up, n = 168, h/o CAD In CPAP treated patients cardiovascular death less, compared to untreated patients Doherty, LS, et al 2005

10 year prospective study N=1600, men Severe OSAH (AHI> 30) significantly increases the risk of nonfatal and fatal c-v events Treatment with CPAP reduces CV Mortality and morbidity Marin, Lancet 365:1046, 2005

OSA (or surrogate symptoms-- EDS) associated with reduced survival treatment improves survival At 7 yrs - Untreated OSA 25% developed CAD vs Treated OSA 4% vs Untreated snorers 6% Peker, Y, et al, 2006 At 18 yrs (Wisconsin cohort n = 1522) AHI > 30, if not using CPAP, adjusted HR 5.2 for cardiovascular disease mortality c/w no OSA Young, T, et al 2008 At 4-14 yrs, 444 pts with CPAP 95% survival, without treatment 60% survival (Marti) At 2-11 yrs, 5669 pts pts died more frequently with poorer compliance with OSA treatment (Veulx) 1600 men, followed 10 yrs pts died >> without CPAP (Marin) 8 yr study in pts with ischemic heart disease without treatment 13% died, with treatment 5% died (Doherty)

After percutaneous coronary intervention N=78 OSA patients associated with lumen loss and restenosis at 7 months Steiner, S, et al 2008 Adverse cardiac events at 6 months in patients acute coronary syndrome (n=89), psg done OSA (AHI > 10) in 57% of patients adverse event (death/ reinfarct / revascularization) in 24% with untreated OSA, 5% with no underlying OSA Greater lumen loss and higher restenosis (37% vs 15%) in OSA pts Yumino, D, et al 2007

Is treatment of obstructive sleep apnea cost effective? What impact does OSA have on health care utilization? Does treatment reduce costs?

3 studies Analyzed global costs in years before / after diagnosis Compared with controls matched for confounding factors

Health care costs in year preceding diagnosis No treatment assessment Washington state, Group Health Co-operative of Puget Sound OSA pts (n = 238) Greater chronic disease score (HTN, CAD, DM, Depression, asthma/copd) Controls n = 476, age and gender matched Costs for OSA patients 2x greater True after adjustment for chronic disease score Costs rose with AHI Kapur Sleep 22(6), 1999

Comparison of costs 1 year before diagnosis Dose response between OSA severity and medical costs OSA pt $2720 vs control $1384 (annual costs for depression and anxiety $2390) 1.7 million people with moderate severe OSA x $2000 = $3.4 billion/yr Kapur Sleep 22(6), 1999

Health care expenditure in women in 10 years prior to OSA diagnosis (n=344) Obese with sleep apnea (Obese with) Obese without sleep apnea (obese without) In normal weight (normal control) Year before dx fees office visit Obese with OSA $C548 13 Obese no OSA $C247 7 Normal control $C 130 4 Banno sleep 32(2), 249, 2009

Canadian study, n = 414, women only 5 years before, 2 years after diagnosis CPAP compliant, CPAP non compliant Control group for each n = 1404 Yearly MD claims 3 years before were up $C123 (rising trend) First year after treatment were down $C38 (falling trend) (controls up $C16, CPAP noncompliant up $C25 respectively) Yearly clinic visits 2 years before: 11 13 visits -up 2.33 visits First 2 years after treatment started - down 1.5 visits (no change in controls) Banno, et al Sleep 29(10), 2009

Improved MD costs and clinic visits in 2 years with CPAP compliant subjects Reduced testing (50% decrease) Treatment of respiratory disease (59% decrease) Treatment of ill defined complaint (91% decrease) Treatment of injuries and poisoning (68% decrease) Reduced rate of clinic visits (Increase 2.3/2 yr decrease 1.5/2yr) Banno, et al Sleep 29(10), 2009

Male Canadian subjects Matched for age, gender, postal code Patients n= 344, controls n= 1324 Costs 5 year before/ 2 year after Diagnostic costs included in year 1 after diagnosis Before diagnosis, costs approx 2x greater in patients Compared with controls in 10 years preceding Costs decrease after diagnosis and treatment Bahamman Sleep 22(6):740, 1999

OSA patients with absolute higher costs With diagnosis -reduced MD costs (C$260 C$174 at 2 years) Included with and without treatment adherence Reduced hospital stays at 2 year after treatment Costs examined by compliance (CPAP) Compliant n = 282 (MD and hospital lower costs) Noncompliant n = 62 (costs not lower) Bahamman Sleep 22(6): 740, 1999

Cost of Treatment Machine US$ 800 / 5 years, + 1 MD visit/yr Consumables US$ 100-200/yr Total US$ 350 /yr Comparison (meds) Simple HTN US$ 360/yr Angina with Rx US$ 570/yr COPD, with exacerbations, US$ 954/yr

Summary

Great burden of disease to patients and society Occurs in sleep Insidious process, patients can not take corrective action Findings in sleep cannot be detected by daytime tests Night time findings have predictive value in overall prognosis Common in patients with cardiovascular disease The more severe the CV disease, the higher the prevalence of OSA OSA is common and often unrecognized in patients with CAD Treatment with CPAP is associated with Improvement in cv disease burden Improved treatment efficacy

Regarding hypertension Biologically plausible that OSA is an important factor contributing to HTN Studies tend to show treating OSA leads to reduction in Blood pressure (both systemic and pulmonary) From public heath perspective reduction of 2 mmg Hg 10% fewer strokes 7% reduction in Heart disease related mortality Treatment with CPAP is associated with: Improvement in cv disease burden Improved treatment efficacy

#1 - We should care about diagnosing Obstructive Sleep Apnea. OSA has associated impact on other common and costly disease processes and management #2- Treatment of Obstructive Sleep Apnea does make a clinical difference Efficacy of cardiac interventions and treatment are also impacted Need to have effective OSA treatment #3- Treatment of obstructive sleep apnea is cost effective. Need to use treatment

Consider Obstructive Sleep Apnea a modifiable risk factor for cardiovascular disease Pursue the diagnosis and treatment OSA cv disease (if you think of 1 think of the other) If CPAP isn t worn it will not work Benefits are not sustained if CPAP is stopped or not at an effective dose

The undiagnosed Children, women, elderly The sub-therapeutic treatment In terms of duration of use and pressure used There is no ceiling for duration of use (longer is better) The untreated Untreated will not see a benefit

Treatment with CPAP can be frustrating Don t Give Up