Sleep Apnea: It’s Worse Than You Thought! Clinical Sleep Educator Program

Naresh A. Dewan MD Professor and Program Director Sleep Medicine Creighton University Omaha NE

Sleep Apnea: It’s Worse Than You Thought! Objectives • Sleep Apnea: A Chronic Systemic Disorder? • Morbidity and Mortality Associated with Sleep Apnea: – Cardiovascular – Cognitive – Metabolic – Cancer

Case History • 52 yr old male: snoring, non-restful sleep despite 8 hrs in bed and daytime fatigue and sleepiness (ESS 13) • Medical Hx: HTN on 4 drugs, Diabetes, Atrial Fib, CAD S/P Stent placement • Social Hx: Smokes 1 PPD, 2-3 drinks/day • Accountant: lately not good with numbers

Physical Exam • • • •

BP 140/90 RR 20 HR 100 irregular BMI 40 Neck size 18 inch, Leg edema + Mallampatti Type 4 Data – PSG: AHI 42/h – RDI 52/h ODI 30/h – Percent time < 90% – SaO2 - 12%

Have you encountered such a patient?

What can You tell this patient about his Sleep Apnea and Comorbidities?

Obstructive Sleep Apnea: A Chronic Systemic Disorder with Significant Comorbidity HTN, Angina, Diabetes, MI, CHF, Cardio Metabolic Metabolic Atrial Fib Vascular Syndrome Strokes

Dyslipidemia Obesity

Cancer

OSA

NeuroCognitive Sleepiness, Impaired Executive function Work Safety: Truck Drivers, Pilots Shift Workers, MDs

Link Between OSA and Hypertension

Question #1: Mechanisms that link OSA to hypertension include 1. Increased sympathetic tone 2. Cyclical hypoxia 3. Altered vascular reactivity 4. all of the above

Answer to Question #1: Mechanisms that link OSA to hypertension include 1. Increased sympathetic tone 2. Cyclical hypoxia 3. Altered vascular reactivity 4. All of the above

.

Sleep Apnea and Sympathetic Activity with BP Changes Dempsey J A et al. Physiol Rev 2010;90:47-112

Dempsey J A et al. Physiol Rev 2010;90:47-112

Intermittent Hypoxia and Sympathetic Activity in Human Volunteers Intermittent Hypoxia

OSA 30 sec hypoxia q 2 min

13% oxygen + 2l O2

Tamisier R et al. Eur Resp J 2011, 37: 119-128

Sympathetic Activity

24-h Ambulatory BP Changes with Intermittent Hypoxia Systolic

One Night

13 nights

Recovery

Diastolic Tamisier R et al. Eur Resp J 2011, 37: 119-128

Hypertension in OSA: Epidemiology Link • Wisconsin prospective sleep cohort (n=709; F/u 4 yrs) linear increase with 3 fold greater risk for HTN in severe AHI>30 after all adjustments (1) • Sleep Heart Health Study prospective cohort (n= 2470 middle age and older, F/u 5 yrs) Modest association (OR 1.51) with severe AHI > 30 (2) • Vitoria sleep cohort (n= 2148; age 30-70 yrs; F/u 7.5 yrs) Linear increased risk for HTN with increasing RDI that was not significant after adjustments (3) 1. Peppard PE, NEJM 2000;342:1378-84 2. O’Connor GT, et al. AJRCCM 2009; 179: 1159-64 3. Cano-Pumarega I, et al. AJRCCM 2011; 184: 1299- 1304

Epidemiological Link between OSA and Hypertension: Summary OSA has a modest impact on the development of hypertension with greater effect noted in patients with moderate to severe OSA

Question #2 Choose the correct statement for the effect of CPAP on BP control in OSA patients. 1. CPAP use provides uniform benefit for all patients with OSA on BP control 2. CPAP use provides moderate benefit in controlling BP for all patients 3. CPAP use benefits patients with moderate to severe OSA and who use CPAP effectively

Answer to Question #2 Choose the correct statement for effect of CPAP on BP control in OSA patients. 1. CPAP use provides uniform benefit for all patients with OSA on BP control 2. CPAP use provides moderate benefit in controlling BP for all patients 3. CPAP use benefits patients with moderate to severe OSA and who use CPAP effectively

•

Ambulatory BP in OSA : A Meta-Analysis

12 RCT trials with 572 subjects • Impact of CPAP vs placebo on mean ABP • CPAP decreased mean ABP by 1.69 mm ( 95% CI -2.69- 0.69) • Benefit was greater in patients with severe OSA and effective nightly CPAP use Haenjtjens P, et al. Arch Intern Med 2007; 167: 757-765

Effect of CPAP on Systemic Hypertension in OSA

• Multicenter RCT in 340 patients with OSA (AHI > • • •

• •

15/h) and HTN (140/90) CPAP use (n= 169) vs Sham CPAP (n=171) Outcome: Change in mean 24 hr BP Result: CPAP decreased mean BP by 1.5 (95% CI, 0.4-2.7; P= 0.01) Statistically significant but less than 3 mm difference the trial was powered to detect Conclusion: Modest benefit of CPAP on BP Duran-Cantolla J et al. BMJ 2010; 341; c5991 control

Risk of Hypertension in Treated and Untreated OSA Marin JM, et al. JAMA 2012; 307: 2169-2176

Prospective FU of 1899 cases over 10 yrs Incident HTN in 705 cases (37.3%) Adjusted Hazard Ratio for HTN in Untreated and Treated OSA as compared to controls ( After all adjustments) • CPAP Declined : 1.96 ( 95% CI, 1.44-2.96) • CPAP Nonadherent: 1.78 (95% CI 1.2-2.6) • CPAP Treated: 0.71 ( 95% CI, 0.53-0.94)

Long-Term Effect of CPAP in Hypertensive Non-sleepy OSA • Multicenter RCT in 359 hypertensive (140/90 non-sleepy OSA (AHI>19; ESS 5.6 hrs Barbe F, et al. AJRCCM 2010; 181: 718-726

Association of Severe OSA and Resistant Hypertension • 284 participants in Heart Biomarker Evaluation in Apnea Treatment (HeartBEAT) study • Severe OSA (23.6%) associated with 4 fold increased risk of resistant HTN (poor BP control despite 3 or more drugs) • Conclusion: Untreated severe OSA contributes to poor BP control and increased cardiovascular risk despite intensive antihypertensive therapy Walia HK. JCSM 2014; 10(8):835-843

Effect of CPAP in OSA and Resistant Hypertension: HIPARCO Study • 194 subjects with Drug Resistant HTN (DRH) (>3 drugs) randomized to CPAP (n=98) for 12 weeks and control (n=96) • Incidence of OSA 89% • CPAP use ( mean 5 +/- 1.9 hrs) reduced mean 24 h BP by 3.1 mm (CI 0.6 to 5.6;p=0.02) Nocturnal dipping ( 35.9% vs 21.6%; p= 0.02) CPAP use > 4 hrs subgroup: 4.4 mm decline in 24 BP Positive linear correlation between BP decline and CPAP use (1.3 mm mean BP decline for each additional hour) Martinez-Garcia M, et al. JAMA 2013; 310: 2407

OSA and Hypertension: Take Home Message

• Both Untreated and Severe OSA are associated with increased risk for new incident HTN • Long-term CPAP treatment has moderate benefit in BP control in both symtomatic sleepy and nonsleepy patients and is related to CPAP adherence > 4 hrs • CPAP use provides greater benefit in DRH but BP decline is still limited to 3-4 mm

Obstructive Sleep Apnea as a Risk Factor for Stroke and Death 

 

Yaggi, H. N Engl J Med 2005;353:2034-2041

Observational cohort study 1022 pts ( 68% had mean AHI 35/hr) OSA associated with stroke or any cause death (adjusted HR 1.97) OSA significantly increased risk of stroke or any cause death independent of all risk factors including HTN

Cardiovascular Outcomes in OSA with and without CPAP: 10 Year Observational Study Healthy n=264

Snorers n=377

UnT Mild-Mod OSA N=403

UnT Severe OSA N=235

Treated Severe OSA N=372

Non-fatal CV events

12

22

36

50

24

Events/100 person yrs

0.45

0.58

0.89

2.13

0.64

Fatal CV events

8

13

22

25

13

Events/100 person yrs

0.3

0.34

0.55

1.06

0.35

Marin JM. Lancet 2005;365:1046

Mortality in OSA • Wisconsin Sleep cohort (n=1522; F/u18 yr) - All cause (HR 3.8) and CV ( HR 5.2) mortality greater in severe untreated OSA vs no SDB (1) • Spanish prospective observational cohort (939 elderly subjects; median f/u 69 months) (2) CV mortality greater in Untreated Severe OSA (HR 2.25 ) vs. treated OSA ( HR 0.93) • CV mortality also higher in women ( n=1116) with unTx severe OSA (HR 3.50) vs CPAP Tx (HR 0.55) (3) 1. 2. 3.

Young T. SLEEP 2008;31:1071-78 Martinez-Garcia M. AJRCCM 2012;186: 909-16 Campos-Rodriquez F. Ann Int Med 2012; 156: 115-22

Link Between OSA and Atrial Fibrillation

Adjusted OR and 95% CI for association between AF and OSA

Gami, A. ©2004 S. etAmerican al. Circulation 2004;110:364-367 Copyright Heart Association

Link Between OSA and Diabetes

Question #3 Contributing factors linking OSA and Diabetes include: 1. Sleep fragmentation 2. Intermittent hypoxia 3. Sleep duration 4. All of the above

Answer to Question #3 Contributing factors linking OSA and Diabetes include: 1. Sleep fragmentation 2. Intermittent hypoxia 3. Sleep duration 4. All of the above

OSA and Metabolic Dysfunction; Potential Mechanism Decreased glucose utilization Beta-cell proliferation and cell death

Dempsey J A. Physiol Rev 2010;90:47-112

Increased serum cholesterol Phospholipids Inhibited cholesterol uptake Liver inflammation & fibrosis

Sleep Apnea

Intermittent hypoxia

Sleep fragmentation Sleep restriction

Accumulating Sleep debt Increased “S”output Elevated cortisol level

Potential mechanism For Sleep Apnea and Insulin resistance

Insulin resistance Wt gain & Diabetes

Spiegel K. J Appl Physol 2005;99:2008

Effect of Sleep Restriction on Leptin and Ghrelin Levels

1.Spiegel K. Ann Intern Med 2004;141:846 2.Taheri S.PLosmedicine 2004;1:e62

Laboratory Study (1) (n= 12 men; age 22 yrs

Epidemiological Study (2) N= 1024; 54% men; age 53 yrs

2 days of 4 h sleep vs 2 Usual sleep time 5 h days of 10 h sleep vs 8 h

Sleep Deprivation Change in leptin (satiety harmone)

-18%

-16%

Change in ghrelin (appetite harmone)

+28%

+15%



Sleep Apnea and Insulin Resistance

Two studies (Ip n=185 &Punjabi n=156) showed independent association of SDB and Insulin Resistance(IR)  IR also noted in non-obese OSA (Ip study)  IR linked to severity of nocturnal desaturation( 4%) and respiratory events: OR 1.99 ( Punjabi study)  Increased “S” activity proposed as causal link between IR and OSA I

Ip et,al. AJRCCM 2002;165:670-76. Punjabi et,al. AJRCCM 2002;165:677-82

Relationship between OSA and Diabetes

• Several cross sectional epidemiological studies have shown a link between OSA and Diabetes. • Wisconsin Sleep Cohort: 987 subjects with 4 yrs prospective follow up • Prevalence of diabetes greater with AHI>15 (OR 2.3) • No independent association after adjustment of abdominal girth Reichmuth-Am J Crit Care Med 2005;172:1590

Relationship between Severity of OSA and Diabetes

• 544 non diabetic patients and OSA with prospective follow up (1) • Risk of diabetes increased by 43% for every quartile increase in severity of OSA • CS study of 60 OSA and diabetes: Higher HbA1C with increasing OSA severity (2) Mild ( 1.49%) Mod ( 1.93%) Severe ( 3.69%) 1. 2.

Am J Med 2009;122 AJRCCM 2010; 181: 507)

Independent Association of OSA Severity and HbA1C in Non-Diabetic Adults CS study1599 adults with OSA and no Diabetes. Increasing hypoxemia also linked to HbA1C > 6%

Priou P et al.Diabetes Care 2012; 35:1902-06

OSA and Diabetic Neuropathy • CS study in Type 2 Diabetes (n=234) and OSA • OSA noted in 65% Mod-severe 40% • Diabetic Neuropathy (DN) prevalence higher in OSA ( 60% vs 27%, P < 0.001) • OSA independently associated with DN ( OR 2.82, 95% CI, 1.44-5.52; P= 0.0034) • Potential Link: Nitrosative/oxidative stress and impaired microvascular regulation Tahrani AA, etal. AJRCCM 2012; 186: 434-441

CPAP Impact on Metabolic Function and Insulin Resistance • Two RCT evaluating metabolic outcomes with therapeutic CPAP vs sham CPAP in diabetic and non diabetic patients • Both studies showed no benefit in obese patients 1 , 2 • Another RCT in moderately obese subjects showed improvement in insulin sensitivity at 1 and 12 weeks with CPAP 3 • Insulin resistance (IR) in obese OSA patients likely to be determined by obesity rather than CPAP treatment but more studies are needed to address this issue 1. Coughlin et al. Eur Respir J 2007; 29: 720-727 2. West SD et al. Thorax 2007; 62: 969-974 3. Lam JCM et al. Eur Respir J 2010; 35: 138-145

OSA, Hypoxemia and NAFLD NASH

Fatty Liver

CT 90

BMI

CT 90

BMI Minville C. CHEST 2014; 145:525-533

Link Between OSA and Cognitive Impairment

Question #4 Cognitive changes in OSA are associated with: 1. Sleep fragmentation 2. Intermittent hypoxia 3. Executive dysfunction 4. All of the above

Answer to Question #4 Cognitive changes in OSA are associated with: 1. Sleep fragmentation 2. Intermittent hypoxia 3. Executive dysfunction 4. All of the above

Cognitive Changes in OSA Cognitive Deficits

Sleepiness

Attention and Vigilance Reduction in working memory Verbal Memory and Learning Language fluency Executive Dysfunction (ED) includes: Reasoning, Planning Problem solving

Mood Changes

OSA and Cognitive Dysfunction: Mechanism

Beebe DW and Gozal. J Sleep research 2002; 11: 1-16

Regional Reduction in Gray Matter Volume in Moderate to Severe OSA Patients CHEST. 2012;141(6):1601-1610.

Left Temporal

Frontal

Neurochemical abnormalities associated with CI Decreased neuronal metabolite ratio of N-acetyl aspartate (myelin synthesis) and Choline (neuronal cell degradation) Marker of neuronal injury

Lateral PFC

Para hippocampal Gyrus

Hypoxia, Cognition and MRI Changes in OSA

• Goal: Correlate Cognitive Impairment with brain morphology • 17 OSA CPAP naive: Prepost CPAP & 15 controls • CI linked to reduction in grey-matter volume in L hippocampus, L PPC and R Frontal C that improved with CPAP ( 12 weeks) • Conclusion: Early Diagnosis and Treatment helpful

Canessa N. et al. AJRCCM 2011: 183: 1419-26

OSA and Motor Vehicle Accident Risk • OSA with EDS: MVA risk 6 x greater than other drivers (1) • Severe OSA: MVA risk 2 x greater than mildmoderate OSA • Sleepiness: MWT < 33 min had more line crossings in real driving test than normals (2) • Sleep restriction (< 4 hrs) and alcohol (BAC 0.05 gm/dl) in OSA exacerbate MVA risk (3) 1.Ward KL. JCSM 2013; 9:1013; 2. Philip P. Ann Neuro 2008; 64: 410 3. Vakulin A. Ann Intern Med 2009; 151: 447

Impact of CPAP Treatment on MVA Risk • Meta-analysis of 15 studies (n= 1300 patients) • CPAP use was associated with marked reduction in the incidence of: – Real crashes ( OR 0.21; 95% CI 0.04-0.21)

– Near misses ( OR 0.09; 95% CI 0.04-0.21) – Simulator crashes (SMD – 1.20 events; 95% CI – .75 to – 0.064) • NNT: Real crashes 1 in 5; Near misses 1 in 2 Antonopoulos CN. Sleep Med Review 2011; 15: 301-310

Impact of 3 months CPAP Use on Daytime Sleepiness and Cognition No dose response effect

Only 50%

Only 30%

Reaction times unchanged

Sleep 2011; 34: 111-119

Cognitive Improvement in Response to CPAPRespond well to CPAP Sleepiness

Mood Changes

Reduced accidents Improved QOL & Mood

Cognitive Deficits Respond less well to CPAP

Attention and Vigilance Higher level Verbal Memory and Learning ED Executive Dysfunction (ED) includes Reasoning, planning and problem solving

Link Between OSA and Cancer

Intermittent Hypoxia Enhances Cancer Progression : Mouse Model OSA Tumor Volume and Weight

Normoxia

Hypoxic

Almendros JM et al. ERJ 2012; 39: 215-217

OSA and Cancer Mortality • Wisconsin Sleep Cohort (n=1,522) followed over 22 yrs • OSA severity: AHI and Hypoxemia Adj. Relative Hazards of Cancer Mortality levels Absent (AHI30) 4.8 age, sex, BMI,& Hypoxemia Index Adj.RH of Cancer Mortality smoking-- total % time < 90% mortality (M)and < 0.8% 1.0 cancer M associated 0.8-3.6% 1.6 ( 0.6-4.4) 3.6-11.2% 2.9 ( 0.9-9.8) with OSA in dose > 11.2% 8.6 ( 2.6-28.7) dependent fashion Nieto FJ et al. AJRCCM 2012; 186: 190-194

Sleep Apnea and Carcinogenesis: Proposed Mechanism • Enhanced angiogenesis in tumor tissue with aggressive tumor progression • Postulation: SDB mediated IH with upregulation of vascular endothelial growth factor (VEGF) • Observed association of cancer needs further definition: higher cancer rates vs aggressive tumor biology

Sleep Apnea: Worse than you Thought

• Sleep Apnea is chronic systemic disorder • Severity of sleep apnea is related to AHI and extent of desaturation (IH) • Morbidity and mortality is related to cardiovascular, metabolic, cognitive and cancer • CPAP benefits are linked to effective use of CPAP

Two Patients with OSA Patient data

Patient A

Patient B

Age/BMI

54 yrs/ 42

53 yrs/ 30

PSG: AHI

32

32

RDI

38

50

ODI 4%

30

20

Sao2% Min

65

85

Percent time < 90%

20

3