Sleep Apnea & Stroke: A Dangerous Liaison Devin Brown, M.D., M.S. Professor of Neurology Stroke Program University of Michigan
Conflict of Interest Disclosures for Speakers x 1. I do not have any relationships with any entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients, OR 2. I have the following relationships with entities producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients. Type of Potential Conflict Details of Potential Conflict Grant/Research Support Consultant Speakers Bureaus Financial support Other 3. The material presented in this lecture has no relationship with any of these potential conflicts, OR 4. This talk presents material that is related to one or more of these potential conflicts, and the following objective references are provided as support for this lecture:
Overview The problem: relationship between OSA and stroke Can we make a difference? CPAP for stroke prevention CPAP for stroke recovery CPAP alternatives
Sleep disordered breathing/osa prevalence after stroke Reference AHI > 10 Broadley et al, 2006 53% Bassetti and Aldrich, 1999 58% Turkington et al., 2002 61% Iranzo et al., 2002 62% Hui et al., 2002 67% Dyken et al., 1996 71% Parra et al., 2000 75%
Prevalence after ischemic stroke, TIA, ICH Johnson and Johnson. J Clin Sleep Med 2010;6:131-137
Is OSA a risk factor for stroke?
CRP, IL-6, E-selectin, oxidative stress (superoxide) SLEEP APNEA Atherosclerosis Autonomics, CO2, endothelial dysfunction Cerebral hemodynamics STROKE Hypercoagualability Platelet activation, increased fibrinogen, EPO
Sleep lab-based study 1022 referred for PSG 697 with OSA (AHI 5) Median follow-up ~3 years Questionnaires to assess for stroke/tia/death medical records reviewed by masked personnel Yaggi et al. NEJM 2005; 353: 2034-2041
Stroke/TIA/death HR = 1.97 (1.12, 3.48) Adjusted for age, sex, race, smoking status, alcohol intake, body-mass index, diabetes, hyperlipidemia, atrial fibrillation, and hypertension Yaggi et al. NEJM 2005; 353: 2034-2041
Trend for severity of OSA and stroke/tia/death risk AHI Hazard Ratio (95% CI) < 3 (referent) 1.00 4-12 1.75 (0.88, 3.49) 13-36 1.74 (0.87, 3.51) > 36 3.30 (1.74, 6.26) Yaggi et al. NEJM 2005; 353: 2034-2041
OSA as Risk Factor for Stroke in the Elderly Vitoria Sleep Project Age 70-100, no stroke Median 4.5 years f/u Variable Stroke No stroke p Male gender, % 85 55.6 0.010 AHI 28 20.1 0.049 AHI 30, % 45 23 0.033 Munoz et al. Stroke 2006; 37: 2317-2321
OSA as Risk Factor for Stroke in the Elderly AHI > 30 Adjusted HR: 2.52 (1.04, 6.10) (adjusted for gender) Munoz et al. Stroke 2006; 37: 2317-2321
Cross-sectional Studies Wisconsin Sleep Cohort Study AHI >20: 3.83 (1.17 12.56) Sleep Heart Health Study Highest quartile AHI: 1.58 (1.02 2.46) Shahar, et al. Am J Respir Crit Care Med 2001;163:19 25. Artz, et al. Am J Resp Crit Care Med 2005; 172: 1447-1451.
Wisconsin Sleep Cohort Study Strokes 14 Unadjusted AHI 20 4.31 (1.31 14.15) 5 to < 20 0.40 (0.05 3.18) Adjusted* AHI 20 3.08 (0.74 12.81) 5 to < 20 0.29 (0.04 2.36) *adjusted for age, sex, BMI Artz, et al. Am J Resp Crit Care Med 2005; 172: 1447-1451.
SHHS: Prospective Cohort Men (n = 2,462) Women (n = 2,960) Strokes 85 108 OAHI* IV quartile (19.13 164.5) 2.86 (1.10, 7.39) 1.21 (0.65, 2.24) III quartile (9.50 <19.13) 1.86 (0.70, 4.95) 1.20 (0.67, 2.16) II quartile (4.05 <9.50) 1.86 (0.67, 5.12) 1.34 (0.76, 2.36) p trend AHI 0.016 0.693 *adjusted for age, BMI, smoking, SBP, use of antihypertensive medications, DM, and race Redline, et al. Am J Respir Crit Care Med. 2010; 182: 269-277
Meta-analysis risk of stroke Li, et al. Int J Cardiol. 2014;172:466-9
Meta-analysis risk of stroke Loke, et al., Circ Cardiovasc Qual Outcomes. 2012;5:720-728
Incident stroke in women AHI 10, untreated (N=268, 17 events) AHI<10 (control group) (N=258, 2 events) Untreated OSA: HR 6.44 (CI: 1.46, 28.34) Adjusted for age, BMI, HTN, DM, AF Campos-Rodriguez, et al. Am J Resp Crit Care Med 2014; 189: 1544-1550
Mortality OSA (AHI 15) Adjusted HR 1.76 (1.05, 2.95) OSA Central SA (AHI 15) Adjusted HR 1.07 (0.65-1.76) Adjusted for: age, sex, BMI, smoking, HTN, diabetes, AF, MMSE, Barthel ADLs. Sahlin et al. Arch Intern Med. 2008;168:297-301
5-year mortality Unadjusted Model *Adjusted Model AHI <10 0.57 (0.30 1.08) 0.79 (0.33 1.85) AHI 10 19 0.68 (0.39 1.2) 0.88 (0.4 1.97) AHI >20 without CPAP 2.12 (1.37 3.3) 1.58 (1.01 2.49) AHI >20 with CPAP 0.76 (0.41 1.41) 1.3 (0.64 2.65) *Adjusted for: age, sex, Barthel index, AHI, and CPAP treatment groups, prior stroke/tia, DM, hypercholesterolemia, BMI, current smoking, HTN, AF, carotid stenosis, fibrinogen. Martinez-Garcia, et al. Am J Respir Crit Care Med 2009; 180: 36 41.
OSA and Dependency Logistic regression for dependency: RDI OR 1.06 (1.01, 1.11), p=0.009 Adjusted for stroke subtype, GCS, limb weakness, age, history of stroke, BMI, neck circumference, hypertension, diabetes Turkington et al. Thorax 2004; 59: 367-371
It s difficult to identify
Epworth Sleepiness Scale Scores Arzt, et al. Stroke 2010; 41: e129-e134
BMI Arzt, et al. Stroke 2010; 41: e129-e134
Berlin questionnaire? 68 stroke patients in rehab Berlin questionnaire vs respirography (AHI >15) High risk Berlin score Sensitivity 69% Specificity 15% Area under ROC 0.59 Kotzian et al. Top Stroke Rehabil 2012; 19: 45-53.
Size matters: Oropharyngeal airway
A-B Palatal thickness C-D Retropalatal distance
Palatal length Thickness, retropalatal distance Tongue length/retroglossal space Lat pharyng wall thickness High retropharyngeal Nasopharyngeal area
OSA (n=18) mm (IQR) No OSA (n=9) mm (IQR) p-value Retropalatal distance 3 (2, 5) 6 (5, 7) 0.03 Soft palate length 39 (38, 44) 39 (39, 44) 1.00 Maximum palatal thickness 10 (8, 13) 10 (8, 11) 0.84 Retroglossal space 12 (9, 15) 12 (8, 19) 0.70 Tongue length 67 (60, 73) 61 (58, 74) 0.83 Nasopharygeal airway (in cm 2 ) Total lateral pharyngeal soft tissue thickness High retro pharyngeal airway area 4 (3, 4) 4 (4, 5) 0.27 75 (73, 79) 80 (79, 83) 0.21 2 (1, 2) 2 (1, 2) 0.78 Brown et al, Sleep Medicine 2010; 11: 540-544
Brainstem infarction 355 ischemic stroke Brown, et al., Sleep Med 2014, 15: 887-891
OSA survey post stroke 193 respondents (49% response rate) 9% carried diagnosis 14% had undergone polysomnography 4% were treated with PAP 19% self assessed likely to have OSA 48% scored high risk on Berlin Questionnaire Skolarus et al, Stroke 2012; 43: 1143-1145.
Summary of the problem The brain hates sleep apnea Common after stroke Risk factor for stroke Poor outcomes Difficult to identify No one screened Patients underestimate their risk
Can we help?
CPAP for stroke prevention?
Study: multicenter, open label, RCT Patients: high risk of CVD, mod-severe OSA Outcomes: MI, stroke, CV death
Risk of Cardiov/Cerebrov event Healthy men (n=264) Simple snorers (n=377) OSA tx CPAP (n=372) Untreated mild/mod OSA (n=403) Untreated severe OSA (n=235) AHI 1.2 3.5 42.2 18.2 43.3 Non-fatal adjusted OR Referent 1.32 (0.64, 3.01) 1.42 (0.52, 3.40) 1.57 (0.62, 3.16) 3.17 (1.12, 7.52) Fatal adjusted OR Referent 1.03 (0.31, 1.84) 1.05 (0.39, 2.21) 1.15 (0.34, 2.69) *2.87 (1.17, 7.51) Marin et al. Lancet 2005; 365: 1046-1053
CPAP for stroke recovery?
ACUTE
Tx duration Criteria n Usage Outcomes 1 2 yrs AHI 20; age <75, etc 126 Mean CPAP use 5.3 hours; 14 refused Better functional outcome and neuro outcomes at 1 mos, but not at 3, 12, 24 mos. No diff in CV mortality or CV events. 2 1 mos APAP suggested OSA (AHI 5 or pressure 6 cm H 2 O) 3 1 wk 3 nights, then 4 more if AHI >10 55 Acceptable adherence ( 75% nights for 4 h/night) of 63% in n=16 eligible NIHSS lower at 1 month in intervention group 50 50% excellent use; Day 8 NIHSS nonsignificantly lower 56% some use; 4% no use on night 4 PSG 4 3 mos AHI 5; disabled 19 Days used 16; hours used: 4.5 per night used NIHSS 1 point lower in tx group 1. Parra, et al Eur Respir J 2011; 37: 1128-1136; 2. Bravata, et al Sleep 2011;34:1271-1277; 3. Minnerup, et al Stroke. 2012;43:1137-1139; 4. Brown, et al J Stroke Cerebrovasc Dis. 2013;22:1216-24
Subacute
CPAP After Stroke Ryan et al. Stroke 2011;42:1062-1067.
CPAP After Stroke Ischemic/hemorrhagic stroke CPAP: 19.7+/-16.8 days, control: 21.5+/-8.7 days AHI >15, >80% obstructive Primary outcome results (between group differences): Canadian Neurological scale (+) 6-minute walk test (-) Sustained attention to response test (-) Digit span and visual spatial span-backward (-) Ryan et al. Stroke 2011;42:1062-1067.
CPAP After Stroke MMSE, delirium, Barthel no change Depression +26% vs -8.1% (p=0.004) No difference in outcomes (functional, neurological, depression/anxiety, BP) 80 days or 6 months post stroke. Sandberg et al. Eur Respir J. 2001; 18:630-634 Hsu et al. JNNP 2006; 77: 1143:1149
CPAP Use Why? 8: problems with machine or mask (4) 8: upper airway symptoms (3) 9: stroke related (confusion, etc) 2: lack of belief in treatment Other Aphasia, low functional status, delirium, depression, urinary incontinence Hsu et al. JNNP 2006; 77: 1143:1149
Palombini 06 Hsu 06 Bassetti 06 Broadley 06 Martinez- Garcia 05 M G 09 qualified 32 PSG 21 titration 14 sent home tolerated 12 1 week 7 1 month 8 weeks 7
Palombini 06 Hsu 06 Bassetti 06 Broadley 06 Martinez- Garcia 05 M G 09 qualified 32 PSG 21 titration 14 sent home tolerated 12 1 week 7 1 month 8 weeks 7
Palombini 06 Hsu 06 Bassetti 06 Broadley 06 Martinez - Garcia 05 M-G 09 PSG+ 70 16 51 96 titration 14 15 48 13 51 96 sent home tolerated 12 36 8 1 week 7 1 month 15 8 weeks 7 7 6 months 53 5 years 28
Acute/subacute CPAP conclusions Trials inefficient need to screen many Many of patients not interested Drop out rate high Adherence not good Sham CPAP a reasonable placebo
Acute management guidelines 2013 Supplemental oxygen should be provided to maintain oxygen saturation >94% (Class I; Level of Evidence C). Supplemental oxygen is not recommended in nonhypoxic patients with acute ischemic stroke (Class III; Level of Evidence B). Stroke. 2013;44:870-947
Secondary prevention guidelines 2014 A sleep study might be considered for patients with an ischemic stroke or TIA on the basis of the very high prevalence of sleep apnea in this population and the strength of the evidence that the treatment of sleep apnea improves outcomes in the general population (Class IIb; Level of Evidence B). Treatment with CPAP might be considered for patients with ischemic stroke or TIA and sleep apnea given the emerging evidence in support of improved outcomes (Class IIb; Level of Evidence B). Stroke. 2014;45:2160-236
CPAP alternatives
30 pts with attended nocturnal polysomnography Sleep position
Sleep studies Median (IQR) or N (%) AHI 23 (IQR: 6, 47) Minimal oxygen saturation % 88 (IQR: 82, 91) OSA 22 (73) Total record time 415 minutes (IQR: 384, 447) Total sleep time 262 minutes (IQR: 218, 322) Sleep time supine 209 minutes (IQR: 131, 270) % time of sleep supine 100 (62, 100) Brown et al. Stroke 2008; 39:2511-2514.
Positional therapy Proof of concept trial Randomized, controlled, crossover study Outcomes: Supine time, AHI N=18; 14 days of stroke Portable respiratory monitoring system Night 1 Night 2 Positional therapy Usual care Usual care Positional therapy Svatikova et al, Sleep Medicine 2011; 12: 262-266.
Positional therapy
Raw data Sleep Apnea Study Characteristics No Positional Therapy Median (IQR) Positional Therapy Median (IQR) Supine time, as % of recording 39 (12, 90) 8 (1, 20) Time supine, minutes 142 (31, 295) 30 (3, 66) AHI, events/hour 39 (21, 54) 27 (22,47) Oxygen Desaturation Index 7 (4, 14) 6 (3, 13) Mean oxygen saturation, % 95 (93, 97) 95 (95, 97) Svatikova et al, Sleep Medicine 2011; 12: 262-266.
Accounting for repeated Supine sleep % measures Reduced by absolute 36% (95% CI: 18 55%, (P<0.001)) AHI Reduced by relative 19.5% (95% CI: 4.9 31.9%, (P=0.011)) Svatikova et al, Sleep Medicine 2011; 12: 262-266.
Unanswered questions Does CPAP prevent incident or recurrent stroke? Does CPAP improve stroke recovery? How can we improve tolerance to CPAP? What CPAP alternatives are best for stroke patients?