Sleep Apnea: It’s Worse Than You Thought! Naresh A. Dewan MD Professor and Program Director Sleep Medicine Creighton University Omaha NE Clinical Sleep Educator Program
Welcome message from author
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
Sleep Apnea: It’s Worse
Than You Thought!
Naresh A. Dewan MD Professor and Program Director Sleep Medicine
Creighton University Omaha NE
Clinical Sleep Educator Program
Objectives • Sleep Apnea: A Chronic Systemic
Disorder? • Morbidity and Mortality Associated with
Sleep Apnea: – Cardiovascular – Cognitive – Metabolic – Cancer
Sleep Apnea: It’s Worse Than You
Thought!
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
OSA Cancer
Metabolic
Neuro-Cognitive
Cardio
Vascular
Sleepiness, Impaired
Executive function
Work Safety:
Truck Drivers, Pilots
Shift Workers, MDs
HTN, Angina,
MI, CHF,
Atrial Fib
Strokes
Diabetes,
Metabolic
Syndrome
Dyslipidemia
Obesity
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
.
Dempsey J A et al. Physiol Rev 2010;90:47-112
Sleep Apnea and Sympathetic
Activity with BP Changes
Dempsey J A et al. Physiol Rev 2010;90:47-112
Intermittent Hypoxia and Sympathetic
Activity in Human Volunteers Intermittent Hypoxia Sympathetic Activity
Tamisier R et al. Eur Resp J 2011, 37: 119-128
OSA
30 sec hypoxia q 2 min
13% oxygen + 2l O2
24-h Ambulatory BP Changes
with Intermittent Hypoxia
One Night 13 nights Recovery
Tamisier R et al. Eur Resp J 2011, 37: 119-128
Systolic
Diastolic
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
control Duran-Cantolla J et al. BMJ 2010; 341; c5991
Risk of Hypertension in
Treated and Untreated OSA
• 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)
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)
Marin JM, et al. JAMA 2012; 307: 2169-2176
Long-Term Effect of CPAP in
Hypertensive Non-sleepy OSA
• Multicenter RCT in 359 hypertensive (140/90
non-sleepy OSA (AHI>19; ESS <11) patients
• CPAP (n= 178) used for 1 year
• Outcome:
– SBP decreased by 1.89 mm (95% CI -3.89-0.11; P=
0.0654)
– DP decreased by 2.19 mm ( 95% CI, -3.46-.93;
P= 0.0008)
• Greater benefit in CPAP users >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
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
Yaggi, H. N Engl J Med 2005;353:2034-2041
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. Young T. SLEEP 2008;31:1071-78
2. Martinez-Garcia M. AJRCCM 2012;186: 909-16
3. Campos-Rodriquez F. Ann Int Med 2012; 156: 115-22
Link Between OSA
and
Atrial Fibrillation
Copyright ©2004 American Heart Association Gami, A. S. et al. Circulation 2004;110:364-367
Adjusted OR and 95% CI for association between AF and OSA
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
Dempsey J A. Physiol Rev 2010;90:47-112
OSA and Metabolic Dysfunction; Potential Mechanism
Decreased glucose
utilization
Beta-cell proliferation
and cell death
Increased serum cholesterol
Phospholipids
Inhibited cholesterol uptake
Liver inflammation &
fibrosis
Sleep
Apnea Sleep fragmentation Sleep restriction
Intermittent
hypoxia Accumulating
Sleep debt
Increased “S”output
Elevated cortisol level
Insulin resistance
Wt gain &
Diabetes
Potential mechanism
For Sleep Apnea and
Insulin resistance Spiegel K.
J Appl Physol
2005;99:2008
Effect of Sleep Restriction on
Leptin and Ghrelin Levels
Laboratory Study (1)
(n= 12 men; age 22 yrs
2 days of 4 h sleep vs 2
days of 10 h sleep
Sleep Deprivation
Epidemiological Study (2)
N= 1024; 54% men; age
53 yrs
Usual sleep time 5 h
vs 8 h
Change in leptin
(satiety harmone) -18% -16%
Change in ghrelin
(appetite harmone) +28% +15%
1.Spiegel K. Ann Intern Med 2004;141:846 2.Taheri S.PLosmedicine 2004;1:e62
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. Am J Med 2009;122
2. AJRCCM 2010; 181: 507)
Independent Association of OSA
Severity and HbA1C in Non-Diabetic
Adults
Priou P et al.Diabetes Care 2012; 35:1902-06
CS study1599 adults with OSA and no Diabetes.
Increasing hypoxemia also linked to HbA1C > 6%
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
Minville C. CHEST 2014; 145:525-533
Fatty Liver
BMI
NASH
CT 90
BMI
CT 90
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
Sleepiness Mood Changes Cognitive Deficits
Attention and Vigilance
Reduction in working memory
Verbal Memory and Learning
Language fluency
Executive Dysfunction (ED) includes:
Reasoning,
Planning
Problem solving
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.
Lateral PFC Para hippocampal Gyrus
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
Hypoxia, Cognition and MRI
Changes in OSA • Goal: Correlate Cognitive
Impairment with brain
morphology
• 17 OSA CPAP naive: Pre-
post 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 mild-
moderate 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
Sleep 2011; 34: 111-119
Only 50%
Only 30%
No dose response effect
Reaction times unchanged
Cognitive Improvement in Response to
CPAP Sleepiness
Mood Changes
Cognitive Deficits
Attention and Vigilance
Verbal Memory and Learning
Executive Dysfunction (ED) includes
Reasoning, planning and problem solving
Reduced accidents
Improved QOL &
Mood
Respond well to CPAP
Higher level
ED
Respond less well to CPAP
Link Between OSA
and
Cancer
Intermittent Hypoxia Enhances
Cancer Progression : Mouse
Model OSA
Almendros JM et al. ERJ 2012; 39: 215-217
Normoxia
Hypoxic
Tumor Volume and Weight
OSA and Cancer Mortality • Wisconsin Sleep
Cohort (n=1,522) followed over 22 yrs
• OSA severity: AHI and Hypoxemia levels
• After adjustment for age, sex, BMI,& smoking-- total mortality (M)and cancer M associated with OSA in dose dependent fashion
Nieto FJ et al. AJRCCM 2012; 186: 190-194
Adj. Relative Hazards of Cancer Mortality
Absent (AHI<5) 1.0
Mild OSA (AHI 5-15) 1.1
Mod OSA ( AHI 15-30) 2.0
Severe OSA ( AHI >30) 4.8
Hypoxemia Index Adj.RH of Cancer Mortality
% time < 90%
< 0.8% 1.0
0.8-3.6% 1.6 ( 0.6-4.4)
3.6-11.2% 2.9 ( 0.9-9.8)
> 11.2% 8.6 ( 2.6-28.7)
Sleep Apnea and Carcinogenesis:
Proposed Mechanism
• Enhanced angiogenesis in tumor tissue
with aggressive tumor progression
• Postulation: SDB mediated IH with up-
regulation 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
Related Documents
