University of Cincinnati Medical Center Perioperative Stroke Brian Katz MD Neurovascular Fellow University of Cincinnati Medical Center

Learning Objectives Mechanisms and timing of stroke Procedures and comorbidities associated with perioperative stroke Clinical management options that may reduce the incidence of perioperative stroke Significance of early recognition and treatment of stroke in the postoperative patient

Disclosures No financial Disclosure Pictures/Caricatures: Google Off label medications: IV IA therapy

Outline of Presentation Prevention and Treatment of Stroke Complicating Surgery ? Evidence Answer/Recommendations

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Outline of Presentation

What is the Definition of Perioperative Stroke?

An updated definition of stroke for the 21st century World Health Organization 1970: “neurologic deficit of cerebrovascular cause that persists beyond 24 hours…” AHA/ASA 2013: “CNS infarction is defined as brain, spinal cord or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury.” Society of Neuroscience in Anesthesiology and CC 2014 “Brain infarction of ischemic or hemorrhagic etiology that occurs during surgery or within 30 days after surgery” Sacco RL, et al. Stroke. 2013;44:2064–2089. 1. Perioperative stroke in the noncardiac nonvascular nonneurosurgical patient is fortunately rare (1:1000 cases) but devastating. 2. 1:100 for major vascular surgery, 1:10 for open heart/aortic arch procedures. Incidence roughly equivalent to perioperative MI in this patient population, but most would choose stroke. Perioperative defined as POD’s 1-30. Given advances in neuroimaging our ability to diagnose stroke now not just defined by clinical findings. 1. CNS infarction can occur in much less than 24 hours – histopathology not generally accessible acutely but new MRI sequences highly effective at diagnosing infarcted brain and brain that is still viable. Includes concept of silent infarction or “silent stroke” which is clearly associated with cognitive dysfunction and Alzheimer’s disease. By autopsy up to 18% of general population – silent stroke 10X more common than covert stroke in nonoperative population. Neurovision pilot study: in noncardiac surgery 70 patients ≥ 65 years: 8-15% incidence of covert stroke POD’s 3-10. Stroke recognized recently as a risk factor for other cardiovascular disease (specifically ≥ 20% 10 year risk of atherosclerotic coronary events by AHA/ASA Stroke 2012;43(7):1998 Mashour GA et al. J Neurosurg Anesthesiol 2014;00:000–000.

Perioperative Stroke Definition Catch all definition over a 30 day time period makes it difficult for research/documentation Stroke in the intra-op, immediate post-op, vs. other Not all surgeries are created equal

“Owning” Perioperative Stroke No subspecialty truly “owns” the management of perioperative stroke. Everyone pointing fingers at each other With a poor definition and lack of ownership, most physicians feel extremely uncomfortable with perioperative stroke, amongst all subspecialist. Let us explore this topic this uncharted territory together.

When do most perioperative strokes occur in relation to the operation?

Timing of Stroke in THR Lalmohamed Stroke 2012;43:3225-3229 Because of low incidence of perioperative stroke, neurologists have questioned whether surgery actually increases risk of stroke – answered by large international study Danish national cohort (1990-2007) with 67K THR matched to 200k nonoperative controls. Almost 5 fold increase in risk of ischemic and 4.4 fold increase risk of hemorrhage stroke following THR (in 2 weeks following surgery). Risk elevation extended out 6 weeks for ischemic stroke and 12 weeks for hemorrhagic stroke. Postoperative ASA use protective (70% reduction in HR) against ischemic stroke although those patients receiving ASA were sicker, thus not affecting (and thus emphasizing) protective effect of ASA. Lalmohamed Stroke 2012;43:3225-3229

Timing of stroke in noncarotid major vascular surgery Timing of stroke may also give some insight into mechanism of the stroke. Historically timing of stroke considered to have bimodal distribution with approximately half in first 48 hours post surgery and the remaining half from day 2 onward. Emphysizing that the events occuring during surgery and why they need surgery are equally important to the post-operative care. Unfortunately patients undergoing procedures with highest risk of stroke may be sedated for several to 24 hours post-op. In this noncarotid vascular population only 15 % of strokes occurred in first 24 hours post-op with 60% in first week. Hedbergs group in Sweden has demonstrated that in the cardiac surgery population: Most immediate postoperative strokes are in the right hemisphere whereas late stroke does not have a hemispheric preference suggesting emboli via brachiocephalic trunk. Although all strokes markedly increase 30 day mortality, late strokes are also associated with long-term mortality relative to patients with no stroke or early stroke. This suggests that early and late stroke may represent different processes and that late stroke may be a marker for more significant disease states. These data found to be opposite of Toumpoulis Columbia AM J Cardio l 2008;102(4):411-7 Distribution of stroke in 38k noncarotid major vascular surgery patients (total 228 stroke). Sharifpour, Anesth Analg 2013;116(2):424-34

Recognition of postoperative stroke is frequently delayed Weightman ASA 2012 Abstract A476 # of Strokes N=39 strokes With lack of biomarkers to recognize stroke, left with neurologic examination. Vast majority of strokes with this small study were recognized beyond window during which acute intervention can be performed. Hours post-surgery

Are stroke subtypes different in perioperative stroke than the general population?

Mechanisms of Perioperative Stroke Ischemic Hemorrhagic

Perioperative Strokes “General” Strokes Perioperative Strokes

Classification of Subtypes of Acute Ischemic Stroke Stroke subtypes in postoperative stroke Stroke subtypes in General Population Cardiac Surgery Embolic: 60% Hypoperfuson:12% Thrombotic: 3% Multiple Etiology: 10% Cryptogenic: 15% General Surgery (9) Thrombosis: 0-51% Emboli: 20-57% Hypoperfusion: 0-44% Cryptogenic: 6-25% Trial of Org 10172 in Acute Stroke Treatment Classification of acute stroke subtypes in the nonoperative patient “other” includes carotid or thoracic dissections, low-flow states, PFO and other rare etiologies These distinctions not well understood in the perioperative patient. White, Circulation 2005;111:1327-1331 Julie L et al Anesthesiology 2011; 115:879 –90

What is the incidence of perioperative stroke in the general population?

Incidence of Perioperative Stroke in Surgical Patients General Surgery: Carotid Surgery: Brooks DC, et al. Perioperative Stroke: Risk Assessment, Prevention and Treatment. Curr Treat Options Cardio Med (2014) 16:282

Incidence of Perioperative Stroke in Surgical Patients Cardiac Surgery: Brooks DC, et al. Perioperative Stroke: Risk Assessment, Prevention and Treatment. Curr Treat Options Cardio Med (2014) 16:282

Incidence of Periopaerative stroke in General Surgery patients Broad surgical population: ~ 1/1000 Excluding cardiac, carotid, major vascular and neurologic surgery Major vascular surgery below the diaphragm: ~6/1000 Mashour GA et al. Anesthesiology. 2011;114:1289–1296. Sharifpour M, Anesth Analg. 2013;116:424–434.

What are the risk factors for perioperative stroke?

Mechanisms of Stroke Comorbidities: Age TIA/stroke Afib Renal disease Female sex Cardiac disease Hypertension Tobacco Perioperative Events: Antiplatelet cessation Statin cessation Afib Hypotension Dehydration Hypercoagulable state Inflammatory response High Risk Procedures: CEA Cardiopulmonary bypass Open heart Aortic Arch Important to note that most co-morbid risk factors are non-modifiable. Although women have lower stroke risk at all ages compared to men (although increased lifetime risk of stroke given longevity), women have been shown to be at increased risk of stroke in multiple surgical populations (Sharifpour, Bateman). Multifactorial but may include ↑cardioembolism, ↓sensitivity to antiplatelet meds, technical factors with small vessels. ?More advanced disease at presentation…. Bateman study Anesthesiology 2009 Atrial fibrillation a co-morbid condition (whether pre-existing or perioperative) in 27.6% of postoperative strokes, making it the most common risk factor in their populations of almost 400k THR, hemicolectomy or lobect Moore, Neurologic Outcomes of Surgery and Anesthesia, Cambridge Press 2013

Cumulative Risk of Stroke 350k noncardiac nonneurologic patients: independent predictors of stroke were age, h/o MI within 6 months, ARF, h/o stroke, h/o TIA, dialysis, hypertension, COPD, current smoker, BMI protective 35-40. Stroke incidence 1.9%, OR 21 Mashour Anesthesiology 2011;114(6): 1289-96

1-2-3 Rule Type of patient Type of Surgery % of Strokes Regular General < 1% “Vasculopath” < 2% Prior Stroke < 3%

Is Perioperative Stroke important to study ?

# of surgical procedures daily at UCMC 100-150 surgeries requiring an OR at UCMC on work day. Not including: endoscopy, catheter lab, dentistry, etc.

Stroke Mortality Facts Yearly Mortality Rate Typical Stroke 8-12.6% Perioperative Stroke 26% Prior stroke w/ periop stroke 10-87% Outcome after perioperative stroke is usually devastating.16 In contrast to the 12.6% mortality rate associated with strokes in the nonsurgical setting,19 mortality from perioperative stroke ranges from 26% after general surgery10 to 87% in patients who have had a previous stroke.9,16 Early mortality from major stroke may result from delayed recognition and diagnosis on surgical services, cerebral edema, and intracranial hypertension, whereas late mortality may be caused by aspiration, pneumonia, metabolic derangement, sepsis, or myocardial infarction.7 

Katz University Bimodal distribution: 48 hours <48 hours -- Only few are time eligible for tPA Mainly Ischemic => Embolic Increase Mortality RF: Surgical type, Prior Stroke, Age, and Atrial Fibrillation

How long should general surgery requiring general anesthesia be delayed after a stroke?

Perioperative stroke Surgical delay Mashour GA, et al. J Neurosug Anesthesiol 2014: 00:000-000

Neurology exam/ evaluation prior to elective surgery How long should general surgery under anesthesia be delayed after a stroke? Neurology exam/ evaluation prior to elective surgery Identify stroke mechanism

Retrospective Evidence How long should general surgery under anesthesia be delayed after a stroke? Delay Surgery Theory Elective surgery 1-3 weeks-months Autoregulation impairment Theoretical Risk Hypotension: Anesthesia or surgical (hemorrhage, anemia, hypotension) Use this time: “Cool off the brain” Discover the mechanism Retrospective Evidence 173 surgical pts w/ a recent & remote stroke found no relationship between timing of stroke history & incidence of perioperative stroke. Orthopedic pt s/p stroke or ACS: stroke w/in 6 months prior to surgery was not a predictor of postop mortality. - Because clinical data are scant, we also consider pathophysiological data in our recommendations. There are theoretical reasons for recommending a delay between ischemic stroke and surgery, so that the brain may recover sufficiently before encountering the hemodynamic stresses associated with surgery and anesthesia. Recovery of cerebral autoregulation after stroke is an important factor that should be considered. - Every patient who has had a stroke should be examined before undergoing elective nonurgent surgery so that the stroke mechanism can be defined and the optimal secondary prevention strategies can be clarified. This should include appropriate vascular imaging (eg, carotid ultrasonography, magnetic resonance angiography and/or computed tomographic angiography), cardiac studies (eg, electrocardiography and/or echocardiography when indicated), and any indicated blood tests.9 - Despite the intuition that delaying surgery after stroke is beneficial, a study of 173 surgical patients with a history of recent and remote stroke found no relationship between timing of stroke history and incidence of perioperative stroke.21 One retrospective study of hip or knee replacement after stroke or acute coronary syndrome found that stroke within six months prior to surgery was not a predictor of postoperative mortality.25 These findings were similar to a recent retrospective study of cardiac surgical patients; the time interval between stroke and coronary artery bypass graft surgery was not found to be a predictor of postoperative stroke or mortality.26 Opinion-based evidence, Category A Category B, Level 2 Blacker DJ Mayo Clin Proc. 2004;79: 223–229. BrownRD Mayo Clin Proc 19494;69:1027-1039 Landercasper J Surg. 1990;125:986–989. Sanders RD, Ann Surg. 2012;255:901–907.

Retrospective Evidence How long should general surgery under anesthesia be delayed after a stroke? Delay Surgery Theory Elective surgery 1-3 weeks-months Autoregulation impairment Theoretical Risk Hypotension: Anesthesia or surgical (hemorrhage, anemia, hypotension) Use this time: “Cool off the brain” Discover the mechanism Retrospective Evidence 173 surgical pts w/ a recent & remote stroke found no relationship between timing of stroke history & incidence of perioperative stroke. Orthopedic pt s/p stroke or ACS: stroke w/in 6 months prior to surgery was not a predictor of postop mortality. - Because clinical data are scant, we also consider pathophysiological data in our recommendations. There are theoretical reasons for recommending a delay between ischemic stroke and surgery, so that the brain may recover sufficiently before encountering the hemodynamic stresses associated with surgery and anesthesia. Recovery of cerebral autoregulation after stroke is an important factor that should be considered. - Every patient who has had a stroke should be examined before undergoing elective nonurgent surgery so that the stroke mechanism can be defined and the optimal secondary prevention strategies can be clarified. This should include appropriate vascular imaging (eg, carotid ultrasonography, magnetic resonance angiography and/or computed tomographic angiography), cardiac studies (eg, electrocardiography and/or echocardiography when indicated), and any indicated blood tests.9 - Despite the intuition that delaying surgery after stroke is beneficial, a study of 173 surgical patients with a history of recent and remote stroke found no relationship between timing of stroke history and incidence of perioperative stroke.21 One retrospective study of hip or knee replacement after stroke or acute coronary syndrome found that stroke within six months prior to surgery was not a predictor of postoperative mortality.25 These findings were similar to a recent retrospective study of cardiac surgical patients; the time interval between stroke and coronary artery bypass graft surgery was not found to be a predictor of postoperative stroke or mortality.26 Opinion-based evidence, Category A Category B, Level 2 Blacker DJ Mayo Clin Proc. 2004;79: 223–229. Brown RD Mayo Clin Proc 19494;69:1027-1039 Landercasper J Surg. 1990;125:986–989. Sanders RD, Ann Surg. 2012;255:901–907.

173 surgical pts w/ a recent and remote stroke How long should general surgery under anesthesia be delayed after a stroke? 173 surgical pts w/ a recent and remote stroke No relationship between timing of stroke history and incidence of perioperative stroke Unclear what prior stroke mechanism 2.9% risk of stroke when patients underwent subsequent general surgeries. Published in 1990… Medicine has come a long way MOST IMPORTLY => CEA, statin, various antiplatelets Antiplatelet, statins, diabetic control, CEA Landercasper J, ArchSurg. 1990;125:986-989.

What is the best time for intervening on a symptomatic ICA stenosis?

Carotid Stenosis Intervention Timing of intervention Historically, the dogma for timing of revascularization in symptomatic patients was to wait 4e6 weeks from the onset of symptoms to avoid recurrent intraoperative stroke and hem- orrhagic stroke conversion. This was supported by literature from the 1960s.58,59 However, a large percentage of the patients treated in these studies had acute carotid thrombosis or were neurologically devastated (i.e. not ideal operative candidates) and this data predated modern therapeutic modalities for prevention of stroke.60 Data from more recent studies has supported CEA within two weeks of symptom onset in patients with >50% carotid stenosis.20,61 This is based on the risk of recurrent stroke in the early period following acute presenta- tion which can be as high as 10e11.2% in the first 7e10days.60,62 According to the data pooled from NASCET and ECST, the ab- solute risk reduction was highest for symptomatic patients undergoing CEA within 2 weeks of symptoms (9.2% vs. 6.4% and 2.9% for time periods of 2e4 weeks and 4e12 weeks).20 This trend was true for patients with 50e69% and >70% stenosis and, for women with 50e69% stenosis, there was no benefit of CEA unless the procedure was performed within 2 weeks. There is also some evidence to support that CEA between 48 h and 7 days after onset of symptoms or emergent intervention in patients with evolving or escalating symptoms is, at the very least, safe and may provide some benefit.63e65 However, these recommendations are offset by limitations in early referral for evaluation of revascularization and development of protocols to prevent delay in treatment may be necessary to improve outcomes in symptomatic carotid stenosis.66,67 In contrast, there appears to be increased risk if CAS is performed early after onset of symptoms.68 A recent analysis of pooled data from the EVA-3S, SPACE and ICSS trials by Ratner et al. supports this assertion.69 The analysis included 2839 patients undergoing CAS (1434) and CEA (1405) and patients were grouped according time e early (<7days), mid (8e14days) and late (>14 days) e from symptoms to revascu- larization. Risk of stroke or death within 30 days of treatment was lowest in the early CEA group (2.8% vs. 9.4% with CAS p 1⁄4 0.03). Stroke and death rate went up in the CEA group with increasing time to intervention (3.5% at 8e14 days and 4.0% at >14 days) although this difference did not reach statistical significance. In the CAS group, the risk of stroke decreased in mid and late time to intervention groups compared to the early group (8.1% at 8e14 days and 7.3% at >14 days compared to 9.4% at <7days), suggesting that in patients undergoing CAS there may be a benefit to waiting. Some limitations of this analysis are the low statistical power of the data to determine relationship of timing to outcome and the lower proportion of patients in the early group who presented with stroke, which could indicate a selection bias.

What are the stroke risks for CEA vs Carotid stenting?

What is the surgical delay for CABG following ischemic stroke?

Timing of Cardiac Surgery after Stroke Delay Surgery Theory Retrospective Evidence Cardiac surgical patients; the time interval between stroke and coronary artery bypass graft surgery was not found to be a predictor of postoperative stroke or mortality. Bottle A, Anesthesiology.2013;118:885–893.

Is Stroke a Contraindication for Urgent Valve Replacement in Acute Infective Endocarditis?

Results The crude incidence of stroke in patients receiving appropriate antimicrobial therapy was 4.82/1000 patient days in the first week of therapy and fell to 1.71/1000 patient days in the second week. This rate continued to decline with further therapy. Stroke rates fell similarly regardless of the valve or organism involved. After 1 week of antimicrobial therapy, only 3.1% of the cohort experienced a stroke. Conclusions TheriskofstrokeinIEfallsdramaticallyaftertheinitiationofeffectiveantimicrobialtherapy.Thefallingrisk of stroke in patients with IE as a whole precludes stroke prevention as the sole indication for valvular surgery after 1 week of therapy. (Am Heart J 2007;154:1086-94.)

Cardiac Surgery Mechanical Heart valve thrombus Stroke Risk of hemorrhagic conversion

Katz University Timing of Surgery Neurologist => Stroke Mechanism ? Autoregulation post stroke ? General Surgery and CABG Carotid: < 2 weeks (prefer <1 week) IE: No Hemorrhage < 1 week Hemorrhage > 4 weeks

RECOMMENDATION: Screen for risk factors of perioperative stroke, most notably remote or recent history of stroke, and communicate such risk to patients and providers (Category B, Level 2). Discuss surgical timing with a neurologist and consider delaying elective surgical cases in patients with recent stroke until the etiology is investigated and the peak of autoregulatory disturbances has passed (likely at one month) (Opinion-based evidence, Category A). However, observational studies to date do not suggest a clear relationship between timing of past stroke history and incidence of postoperative stroke (Category B, Level 2)

What should we do about anti-platelets prior to surgery?

Aspirin following cardiac surgery Mangano NEJM 2002;347:1309

Management of Anti-platelet Rx in General Surgery Rebound Hypercoagulability Bleeding Complications (prothrombotic state induced by surgery) Limited data to guide management of this situation that pertain specifically to perioperative stroke.

Management of Anti-platelet Rx in General Surgery Bleeding Complications (prothrombotic state induced by surgery) Limited data to guide management of this situation that pertain specifically to perioperative stroke.

Management of Anti-Anti-platet Rx in General Surgery 2012 Chest Guidelines grouped surgical risk into 4 groups. This was primarily based on surgical observations case-series; which are known to be biased given that they are authored by surgeons. Darvish-Kazem S, Semin Thromb Hemost. 2012;38:652–660.

If only someone did a RCT

Management of Anti-platelet Rx in General Surgery 10,000 patients POISE-2 was a randomized, controlled, multicentre, international trial conducted from 2010 to 2013, enrolling 10 010 patients undergoing noncardiac surgery. Inclusion criteria were: known CV disease, major vascular surgery and the meeting of at least three of nine prespecified vascular risk criteria. (granted not all vascular risk factors are the same– such as HTN and stroke); were stratified into two groups based on whether they were prior users of aspirin (continuation stratum (CS)) or not on regular aspirin (initiation stratum (IS)). Each of these groups were randomised into aspirin or placebo groups, resulting in four study groups: IS-placebo (no aspirin), IS-aspirin (Aspirin preoperatively for 3 days then aspirin for 30 days), CS-placebo (no aspirin/ for at least 3 days preoperatively then placebo for 7 days, followed by usual dose), and CS-aspirin (no aspirin for at least 3 days preoperatively then apirin 7 days before returning to usual dose). Patients with a recent percutaneous coronary intervention were excluded. April, 2014

Management of Anti-platelet Rx in General Surgery 10,010 On ASA 4998 Cont. ASA Placebo No ASA 5012 Initiated ASA “Vascular” Patients Baseline DB RCT Study Drug Timing: 3 days prior to surgery to 30 days post-surgery 1:1 Randomization 5% Stroke 10,000 patients POISE-2 was a randomized, controlled, multicentre, international trial conducted from 2010 to 2013, enrolling 10 010 patients undergoing noncardiac surgery. Inclusion criteria were: known CV disease, major vascular surgery and the meeting of at least three of nine prespecified vascular risk criteria. (granted not all vascular risk factors are the same– such as HTN and stroke); were stratified into two groups based on whether they were prior users of aspirin (continuation stratum (CS)) or not on regular aspirin (initiation stratum (IS)). Each of these groups were randomised into aspirin or placebo groups, resulting in four study groups: IS-placebo (no aspirin), IS-aspirin (Aspirin preoperatively for 3 days then aspirin for 30 days), CS-placebo (no aspirin/ for at least 3 days preoperatively then placebo for 7 days, followed by usual dose), and CS-aspirin (no aspirin for at least 3 days preoperatively then apirin 7 days before returning to usual dose). Patients with a recent percutaneous coronary intervention were excluded. Devereaux J. POISE 2. NEJM 2014

Management of Anti-platelet Rx in General Surgery (prothrombotic state induced by surgery) Devereaux J. POISE 2. NEJM 2014

Management of Anti-platelet Rx in General Surgery 81.7% 82.9% Devereaux J. POISE 2. NEJM 2014

Management of Anti-platelet Rx in General Surgery 10,010 On ASA 4998 Cont. ASA Placebo No ASA 5012 Initiated ASA Vascular Patients Baseline DB RCT Outcomes: Neutral: Mortality and non-fatal MI All Incidence Stroke: ASA: 16 (0.3) None: 19 (0.4) p= 0.62 5% Stroke All-cause mortality or non-fatal MI 7.0% vs. 7.1% (HR 0.99; 95% CI 0.86-1.15; P=0.92) Initiation: 6.5% vs. 6.6% (HR 0.99; 95% CI 0.81-1.21; P=0.92) Continuation: 7.7% vs. 7.8% (HR 1.00; 95% CI 0.81-1.23; P=0.97)Secondary Outcomes All-cause mortality, non-fatal MI, or non-fatal stroke 7.2% vs. 7.4% (HR 0.98; 95% CI 0.85-1.13; P=0.80) Initiation: 6.6% vs. 6.9% (HR 0.95; 95% CI 0.78-1.17; P=0.64) Continuation: 8.1% vs. 8.0% (HR 1.01; 95% CI 0.82-1.25; P=0.90) All-cause mortality, non-fatal MI, cardiac revascularization, non-fatal PE, non-fatal DVT 8.0% vs. 8.1% (HR 0.99; 95% CI 0.86-1.14; P=0.90) Initiation: 7.3% vs. 7.6% (HR 0.97; 95% CI 0.80-1.17; P=0.73) Continuation: 9.0% vs. 8.8% (HR 1.02; 95% CI 0.83-1.24; P=0.86) Adverse Events Bleeding Life-threatening: 1.7% vs. 1.5% (HR 1.19; 95% CI 0.88-1.63; P=0.26) Initiation: 1.7% vs. 1.7% (HR 1.05; 95% CI 0.70-1.56; P=0.82) Continuation: 1.7% vs. 1.2% (HR 1.46; 95% CI 0.89-2.41; P=0.13) Fatal bleed or led to hypotension requiring inotrope/vasopressor support, emergent surgery, or ICH. Major: 4.6% vs. 3.8% (HR 1.23; 95% CI 1.01-1.49; P=0.04) Initiation: 4.6% vs. 3.5% (HR 1.34; 95% CI 1.03-1.74; P=0.03) Continuation: 4.6% vs. 4.1% (HR 1.11; 95% CI 0.84-1.48; P=0.47) P-value for interaction 0.35 Stroke 16 (0.3) 19 (0.4) 0.84 (0.43–1.64) 0.62 Devereaux J. POISE 2. NEJM 2014

Management of Anti-platelet Rx in General Surgery 10,010 On ASA 4998 Cont. ASA Placebo No ASA 5012 Initiated ASA Vascular Patients Baseline DB RCT Outcomes: Site and Major Bleeding (life threatening bleeding was neutral) 5% Stroke All-cause mortality or non-fatal MI 7.0% vs. 7.1% (HR 0.99; 95% CI 0.86-1.15; P=0.92) Initiation: 6.5% vs. 6.6% (HR 0.99; 95% CI 0.81-1.21; P=0.92) Continuation: 7.7% vs. 7.8% (HR 1.00; 95% CI 0.81-1.23; P=0.97)Secondary Outcomes All-cause mortality, non-fatal MI, or non-fatal stroke 7.2% vs. 7.4% (HR 0.98; 95% CI 0.85-1.13; P=0.80) Initiation: 6.6% vs. 6.9% (HR 0.95; 95% CI 0.78-1.17; P=0.64) Continuation: 8.1% vs. 8.0% (HR 1.01; 95% CI 0.82-1.25; P=0.90) All-cause mortality, non-fatal MI, cardiac revascularization, non-fatal PE, non-fatal DVT 8.0% vs. 8.1% (HR 0.99; 95% CI 0.86-1.14; P=0.90) Initiation: 7.3% vs. 7.6% (HR 0.97; 95% CI 0.80-1.17; P=0.73) Continuation: 9.0% vs. 8.8% (HR 1.02; 95% CI 0.83-1.24; P=0.86) Adverse Events Bleeding Life-threatening: 1.7% vs. 1.5% (HR 1.19; 95% CI 0.88-1.63; P=0.26) Initiation: 1.7% vs. 1.7% (HR 1.05; 95% CI 0.70-1.56; P=0.82) Continuation: 1.7% vs. 1.2% (HR 1.46; 95% CI 0.89-2.41; P=0.13) Fatal bleed or led to hypotension requiring inotrope/vasopressor support, emergent surgery, or ICH. Major: 4.6% vs. 3.8% (HR 1.23; 95% CI 1.01-1.49; P=0.04) Initiation: 4.6% vs. 3.5% (HR 1.34; 95% CI 1.03-1.74; P=0.03) Continuation: 4.6% vs. 4.1% (HR 1.11; 95% CI 0.84-1.48; P=0.47) P-value for interaction 0.35 Stroke 16 (0.3) 19 (0.4) 0.84 (0.43–1.64) 0.62 Devereaux J. POISE 2. NEJM 2014

Management of Anti-platelet Rx in General Surgery Major bleeding, which occurred mostly at the surgical site, was greater in the aspirin group (4.6% vs 3.8%, p=0.04). Devereaux J. POISE 2. NEJM 2014

Management of Anti-platelet Rx in General Surgery 10,010 On ASA 4998 Cont. ASA Placebo No ASA 5012 Initiated ASA Vascular Patients Baseline DB RCT Secondary Endpoints: New AKI -> Dialysis Decrease stroke 5% Stroke AKI requiring HD 0.7% vs. 0.4% (HR 1.75; 95% CI 1.00-3.09; P=0.05) Initiation: 0.5% vs. 0.4% (HR 1.28; 95% CI 0.58-2.83; P=0.54) Continuation: 0.9% vs. 0.4% (HR 2.41; 95% CI 1.05-5.51; P=0.04) P-value for interaction 0.28 Devereaux J. POISE 2. NEJM 2014

Before you raise your hand Just published=> no spin-off publications yet! No specifics about: Risks/bleed % for individual surgery types Prior stroke and TIA patients and their outcomes.

Pts on antiplatelet undergoing general surgery Post-surgical Aspirin One Case-Control Study of THR in 2012 70% reduction in the HR Lalmohamed Stroke 2012;43:3225-3229

Before you raise your hand Just published=> no spin-off publications yet! No specifics about: Risks/bleed % for individual surgery types Prior stroke and TIA patients and their outcomes. SNACC 2014 Guidelines: No Evidence to suggest that continuation of ASA in patients at risk for vascular complication reduces the risk of stroke after noncardiac surgeries (Category A, Level A) Is this applicable to our stroke pts????

Management of Anti-platelet Rx in General Surgery Rebound Hypercoagulability (prothrombotic state induced by surgery) Limited data to guide management of this situation that pertain specifically to perioperative stroke.

Effects of antiplatelet therapy withdrawal Population-based ~5% of ischemic strokes are ~ w/ withdrawal of AT w/in 60 days of onset. Antiplatelet vs Warfarin withdrawal ?Stroke risk in Withdrawal of only Antiplatelet ? EASIER SAID THAN DONE Exact contribution of ASA withdrawal to perioperative stroke incidence unknown In a non-operative population, withdrawal of antiplatelet and antithrombolitc medications was associated with a 5.2% incidence of stroke within 60 days of drug cessation. Furthermore, non-operative patient having stroke while off antiplatelets and antithrombotics drugs have greater morbidity and mortality compared to patients who continuedt aking them. In contrast to the much greater use of antiplatelet agents than warfarin in the general population, over half of ischemic strokes in our study population occurred in patients who had withdrawal of warfarin. 5% probably underestimate as patients reporting may be cognitively impaired or aphasic (Neurology 2004;62:1187-1189) 70% reduction in the risk of postoperative stroke on patients receiving post-surgical ASA although this patient subset was sicker overall. Lalmohamed Stroke 2012;43:3225-3229 Timeframe for stroke following ASA cessation important as mirroring duration of action of ASA on platelet inhibition Patients on warfarin at even greater risk of stroke from warfarin withdrawal Rebound in platelet activity with abrupt cessation Broderick JP Stroke 2012

For patients on warfarin who should receive bridging therapy? This is very controversial – no good evidence either way. Patients in atrial fibrillation with h/o of stroke or TIA within 6 months

Pt w/ A fib on anticoagulation undergoing general surgery Warfarin Opinion-based evidence Category A BRIDGE Study Enrollment stopped PERIOP 2 Study Almost done enrolling The American College of Chest Physicians recommends that heparin therapy be considered for postoperative atrial fibrillation in patients with a history of stroke or transient ischemic attack. Medically manage atrial fibrillation and continue anticoagulation in patients with atrial fibrillation for minor surgeries or those in which high blood loss is unlikely. Discontinue anticoagulation in surgical patients at high risk of bleeding (with appropriate bridging strategies as indicated), but resume as soon as the risk of surgical bleeding is considered to be low (Opinion-based evidence, Category A). Darvish-Kazem S, Semin Thromb Hemost. 2012;38:652–660. Douketis JD, Chest. 2012;141:e326S–e350S. Baron TH, N Engl J Med. 2013;368:2113–2124

Katz University Surgery type => Talk to Surgeon Acutely stopping Rx => Rebound hypercoag Aspirin Stroke patients => Stay on aspirin Respect aspirin’s bleeding risk Warfarin I follow bridging guidelines; mostly. Watch for those 2 RCT

Does Asymptomatic Carotid Artery Stenosis Predict Perioperative Stroke After Non-cardiac Surgery?

Carotid Revascularization prior to General Surgery ??? # of surgical procedures daily at UCMC 100-150 surgeries requiring an OR at UCMC on work day Prevalence of Asymptomatic Carotid Stenosis Moderate Severe Age- and sex-specific prevalence estimates of moderate (A) and severe ACAS (B) in men and women. Brooks DC, et al. Perioperative Stroke: Risk Assessment, Prevention and Treatment. Curr Treat Options Cardio Med (2014) 16:282

Carotid Revascularization prior to General Surgery??? 2005 RCT CCF 5 year experience “Major Vascular” Surgeries 40 per-op CEA vs. 39 control Results: 30 day follow up No perioperative strokes or death “noncardiac surgery” 5-year period 2110 pts Carotid U/S 13% >70% stenosis 37%: >50-69% 50%: <50% No association of carotid artery stenosis and periop Stroke No stenosis cut off Carotid artery stenosis was not associated with postoperative MI Ballotta E, et al. Prospective randomized study on asymptomatic severe carotid stenosis and perioperative stroke risk in patients undergoing major vascular surgery: prophylactic or deferred carotid endarterectomy? Ann Vasc Surg. 2005 Nov;19(6):876-81. We compared the perioperative (30-day) stroke risk in asymptomatic patients with severe carotid stenosis who underwent carotid endarterectomy (CEA) before or after major vascular surgery. Seventy-nine patients with asymptomatic severe carotid lesion were randomly assigned to group I (n = 40) or group II (n = 39) to receive prophylactic CEA (within 1 week before major surgery) or deferred CEA (between 30 days and 6 months after major surgery), respectively. All procedures were eversion CEAs performed under deep general anesthesia and cerebral protection involving continuous electroencephalographic monitoring for selective shunting. There were no perioperative deaths or strokes relating to the major surgical procedure in either group. All group II patients underwent deferred CEA as planned (median 47 days, range 38-94) with no subsequent perioperative deaths or strokes. Two of these patients (5.1%) suffered a minor stroke, however, 65 and 78 days after their major surgical procedure, while awaiting carotid revascularization. Although data emerging from this analysis indicate that severe asymptomatic carotid disease may be safely postponed in patients undergoing major noncarotid vascular surgery, only a multicenter prospective study could determine the most appropriate management of this subset of patients. Ballotta E, et al Ann Vasc Surg. 2005 Nov;19(6):876-81. Sony, A et al. Anesthesiology. 2014 Nov;12

Does Symptomatic Intracranial Stenosis Predict Perioperative Stroke After Non-Cardiac Surgery?

N= 38 50 operations w/ gen anesthesia 3 ischemic strokes - Prolonged hypotension - SBP <100 mmHg for > 10 min 6.0% stroke risk / surgery

Katz University Asymptomatic => No Touch Symptomatic => Treat underlying mechanism Avoid Hypotension (easier said than done)

Intraoperative Recommendations

Does the type of anesthesia change your stroke risk?

Stroke reduced with Neuroaxial Anesthesia in THR & TKR Not going to talk about GA as a neuroprotectant Retrospective observational study with N=382K patients, 11% done under straight neuroaxial, 89% done under GA or combined GA/neuroaxial – out of hospital for special surgery Cornell University Rothman et al out of Jefferson found for almost 19k consecutive joint replacements that GA was an independent predictor of stroke with OR of 3.5 (Mortazavi J Bone Joint Surg Am 2010;92:2095 Still no data in a more general surgical population to support regional over general anesthesia Wife thinks induction blood pressure fluctuations Memtsoudis, Anesthesiology 2013;118(5):1046-1058

Types of Anesthetics for Carotid Surgery? The multicentre GALA trial studied 3526 patients pre- senting for carotid surgery with general anaesthesia or local anaesthesia with sedation.67 The risk of stroke was ~4% in each group suggesting that, at least for carotid endarterectomy, general anaesthesia is not a risk factor for perioperative stroke.

What about intraoperative medications and stroke risk?

Intraoperative Beta-Blockers (metoprolol) in General Surgery Large prospective multi-center study done in which metoprolol was administered acutely to patients undergoing non-cardiac surgery. While metoprolol administration reduced the risk of composite cardiac complications and specifically myocardial infarction, There was an increased risk of stroke (HR 2.17) and death (1.3) POISE prompted the American College of Cardiology and the AHA to revise their recommendations for perioperative beta blockade, limiting their use to patients on ongoing beta blockade and patients at high risk for cardiac events (inducible ischemia or multiple risk factors undergoing vascular surgery) and recommending against acute administration of beta blockers for cardioprotection. Effect of article additionally focused attention on association between perioperative beta blockers and hypotension and stroke. Lancet 2008;371(9627):1839-47

Perioperative metoprolol and perioperative stroke Following POISE series of editorials and clinical studies that a. POISE may not be representative due to the very large dose, associated hypotension and bradycardia and b. Conflicting results whether beta blockers associated with stroke and whether there are distinctions between beta blockers and their risk of stroke. Mashour study 2013: Single center retrospective study of almost 60,000 anesthetics. These data not adjusted for co-morbidities but preoperative metoprolol also with greater stroke incidence compared to atenolol in a matched cohort. Intraoperative hypotension also associated with stroke in this study but no colinearity between metoprolol use and hypotension Mashour Anesthesiology 2013

Perioperative Stroke with various Beta Blockers Metoprolol Atenolol What is mechanism of variations in beta blockers Comparison of the effect of lowest recorded hemoglobin (within 72 hours of surgery) on postoperative stroke. Single center, 44k noncardiac and noneurologic patients The relationship shows that metoprolol has a higher baseline risk of stroke, whereas atenolol has a baseline stroke risk similar to bisoprolol. The risk of stroke increases for all [beta]-blockers at a postoperative hemoglobin level of 9 gm/dl. A spline curve refers to a smoothing process. Suggest (and animal data would support) that cardioselective agents may be preferable to noncardioselective as they may not inhibit B2 mediated cerebral vasodilation, for example in response to anemia. Bisoprolol Ashes, Anesthesiology 2013;119(4):777-787

Why Metoprolol? ?

What about intraoperative hypotension and stroke risk?

The role of intraoperative hypotension in postoperative stroke Role of hypotension in perioperative stroke poorly defined: stroke apparent at emergence rare. Bijker et al demonstrated a small but significant relationship between duration of intraoperative hypotension (> 30% below baseline preoperative blood pressure) and postoperative stroke in 48K consecutive noncardiac patients. Stroke risk increases 1.3% per minute of hypotension, therefore effect size very small Primary analysis was stroke within 10 days, but difficult to relate intraoperative hypotension to stroke 10 days later. Subsequently did post-hoc analysis on patients with stroke within 24 hours (red) Shaded areas 99.9% confidence intervals Authors conclude that postoperative hypotension probably comparable in effect to IOH and that IOH may be important as a marker for patients at risk for postoperative hypotension and stroke rather than a primary determinant of postoperative stroke. Add N’s!!!! Bijker Anesthesiology 2012;116(3):658-64

“Unusually low blood pressure will eventually result in neurological damage …” Threshold and duration at which an association might be found between a perioperative stroke and hypotension have not been well investigated… “The exact role of hypotension in the etiology of perioperative stroke is still largely unknown.” Bijker and Gelb Can J Anaesth 2013;60(2):159-67

A word about the dangers of the beach chair position… For every 1 cm increase in height, there is a 0.8 mmHg drop in blood pressure. Therefore with a 20 cm difference between brainstem and brachial artery, there can be a 15 mmHg drop in perfusion pressure Cuff on leg is even worse Recent article in orthopedic journal supporting HYPOTENSION in seated position. Suggesting 6% incidence of EEG changes is acceptable.

Katz University Avoid introducing Beta Blockers in surgery Use Regional Anesthesia if possible Avoid Intraoperative Hypotension General Population vs. Complex Stroke Patient

Ventilation Strategies and Risk of Perioperative Stroke There are no data on which to base recommendations regarding intraoperative ventilation strategies and the incidence of perioperative stroke (Category D, Silent).

Intraoperative Hemorrhage and Blood Transfusion Therapy In a retrospective study of 651,775 patients undergoing noncardiac, noncarotid and nonneurologic surgery, patients receiving more than four units of packed red blood cells (as a surrogate for major hemorrhage) had an approximately 2.5 fold increased risk for stroke or Q-wave myocardial infarction The POISE trial also found “significant bleeding” to be an independent predictor of postoperative stroke (adjusted OR 2.18, 95% CI 1.45-8.52) in the population of high risk patients undergoing noncardiac surgery

For noncardiac, nonneurologic surgical patients already taking a beta blocker, a hemoglobin <9.0 gm/dl should be avoided in order to minimize risk of stroke (Category B, Level 1).

What acute treatments can we provide for acute ischemic strokes in the perioperative state?

Recognition of postoperative stroke is frequently delayed Weightman ASA 2012 Abstract A476 # of Strokes N=39 strokes With lack of biomarkers to recognize stroke, left with neurologic examination. Vast majority of strokes with this small study were recognized beyond window during which acute intervention can be performed. Hours post-surgery

Acute Revascularization Tools Risks and benefits Bleeding risk Cataract, compressible, Recent history of a major surgical procedure poses systemic bleeding risk in the setting of intravenous rtPA and may represent another group for consideration of intra-arterial fibrinolysis. Several small case series of postoperative car- diac surgery cases suggest reasonable safety of intra-arterial fibrinolysis.551–553 In addition, a retrospective case series of 36 ischemic stroke patients from 6 academic centers treated with intra-arterial fibrinolysis after surgical procedures, including open heart surgery (n=18), CEA (n=6), and urologic-gynecologic surgery (n=4), suggested that intra-arterial rtPA is reasonably safe in the postoperative setting, with the exception of neurosurgical procedures (n=3).554 Major systemic bleeding occurred in 4 cases, including 3 postcraniotomy ICHs and 1 post–coronary artery bypass graft hemopericardium. The intra-arterial approach is thought to be more efficacious for recanalization of proximal arterial occlusions than intravenous fibrinolysis, but the evidence for this is limited. Supportive evidence comes primarily from a cohort study by Mattle et al.245 They compared stroke outcomes at 2 stroke units, each of which treated exclusively with either intravenous rtPA or intra-arterial urokinase. Favorable outcomes (mRS score 0–2) were seen in 29 (53%) of 55 intra-arterial cases and 13 (23%) of 57 intravenous cases (P=0.001). In addition, a small feasibility study by Sen et al549 randomized consecutive patients with proximal arterial occlusions on CTA scan within 3 hours of stroke symptom onset to standard intravenous rtPA (0.9 mg/kg) versus intra-arterial rtPA (up to 22 mg over 2 hours). Median NIHSS scores were 17 and 16 and mean ages were 71 and 66 years for the intravenous and intraarterial arms, respectively. Fibrinolysis was initiated at a mean of 95 minutes for the intravenous arm and 120 minutes for the intra-arterial arm (P=0.4). The intravenous group had 1 sICH, and the intra-arterial group had 1 asymptomatic ICH. All intra-arterial cases had recanalization, and none of the intravenous cases had recanalization (P=0.03). Neurological improvement (a 4-point decrease in NIHSS score at 90 days) was seen in 3 of 4 patients treated with intravenous rtPA and 2 of 3 treated with intra-arterial rtPA. On the basis of the premise that intra-arterial therapy may be more effective for recanalization of larger thrombi, severe neurological deficits (NIHSS score ≥10) that suggest a proximal arterial occlusion and radiographic evidence of occlusion of a major intracranial vessel have been considered potential indications for the use of intra-arterial therapy. However, this clinical benefit may be counterbalanced by delay to treatment initiation with the intra-arterial approach and consequent late reperfusion, potential risks of periprocedural sedation, and treatment-related complications. Definitive data from randomized controlled trials delineating the relative efficacy of intra-arterial therapy versus intravenous rtPA treatment are lacking at this time. Intra-arterial fibrinolysis is a consideration for patients ineligible for intravenous rtPA. For example, the PROACT II trial may be applicable to patients eligible for treatment within 6 hours; more definitive data for patients in the extended time window from randomized controlled trials are needed.550 Recent history of a major surgical procedure poses systemic bleeding risk in the setting of intravenous rtPA and may represent another group for consideration of intra-arterial fibrinolysis. Several small case series of postoperative cardiac surgery cases suggest reasonable safety of intra-arterial fibrinolysis.551–553 In addition, a retrospective case series of 36 ischemic stroke patients from 6 academic centers treated with intra-arterial fibrinolysis after surgical procedures, including open heart surgery (n=18), CEA (n=6), and urologic-gynecologic surgery (n=4), suggested that intra-arterial rtPA is reasonably safe in the postoperative setting, with the exception of neurosurgical procedures (n=3).554 Major systemic bleeding occurred in 4 cases, including 3 postcraniotomy ICHs and 1 post–coronary artery bypass graft hemopericardium. Rates of good clinical outcome after intra-arterial fibrinolysis are likely to be highly time dependent, as is the case with intravenous rtPA treatment.92,93,555 If intra-arterial fibrinolysis treatment is planned, an emphasis should be placed on rapid triage, patient transport, and clinical team mobilization.

Perioperative stroke Bleeding Mashour GA, et al. J Neurosug Anesthesiol 2014: 00:000-000

Acute Revascularization Tools ? Risks and benefits Bleeding risk Cataract, compressible, Recent history of a major surgical procedure poses systemic bleeding risk in the setting of intravenous rtPA and may represent another group for consideration of intra-arterial fibrinolysis. Several small case series of postoperative car- diac surgery cases suggest reasonable safety of intra-arterial fibrinolysis.551–553 In addition, a retrospective case series of 36 ischemic stroke patients from 6 academic centers treated with intra-arterial fibrinolysis after surgical procedures, including open heart surgery (n=18), CEA (n=6), and urologic-gynecologic surgery (n=4), suggested that intra-arterial rtPA is reasonably safe in the postoperative setting, with the exception of neurosurgical procedures (n=3).554 Major systemic bleeding occurred in 4 cases, including 3 postcraniotomy ICHs and 1 post–coronary artery bypass graft hemopericardium. The intra-arterial approach is thought to be more efficacious for recanalization of proximal arterial occlusions than intravenous fibrinolysis, but the evidence for this is limited. Supportive evidence comes primarily from a cohort study by Mattle et al.245 They compared stroke outcomes at 2 stroke units, each of which treated exclusively with either intravenous rtPA or intra-arterial urokinase. Favorable outcomes (mRS score 0–2) were seen in 29 (53%) of 55 intra-arterial cases and 13 (23%) of 57 intravenous cases (P=0.001). In addition, a small feasibility study by Sen et al549 randomized consecutive patients with proximal arterial occlusions on CTA scan within 3 hours of stroke symptom onset to standard intravenous rtPA (0.9 mg/kg) versus intra-arterial rtPA (up to 22 mg over 2 hours). Median NIHSS scores were 17 and 16 and mean ages were 71 and 66 years for the intravenous and intraarterial arms, respectively. Fibrinolysis was initiated at a mean of 95 minutes for the intravenous arm and 120 minutes for the intra-arterial arm (P=0.4). The intravenous group had 1 sICH, and the intra-arterial group had 1 asymptomatic ICH. All intra-arterial cases had recanalization, and none of the intravenous cases had recanalization (P=0.03). Neurological improvement (a 4-point decrease in NIHSS score at 90 days) was seen in 3 of 4 patients treated with intravenous rtPA and 2 of 3 treated with intra-arterial rtPA. On the basis of the premise that intra-arterial therapy may be more effective for recanalization of larger thrombi, severe neurological deficits (NIHSS score ≥10) that suggest a proximal arterial occlusion and radiographic evidence of occlusion of a major intracranial vessel have been considered potential indications for the use of intra-arterial therapy. However, this clinical benefit may be counterbalanced by delay to treatment initiation with the intra-arterial approach and consequent late reperfusion, potential risks of periprocedural sedation, and treatment-related complications. Definitive data from randomized controlled trials delineating the relative efficacy of intra-arterial therapy versus intravenous rtPA treatment are lacking at this time. Intra-arterial fibrinolysis is a consideration for patients ineligible for intravenous rtPA. For example, the PROACT II trial may be applicable to patients eligible for treatment within 6 hours; more definitive data for patients in the extended time window from randomized controlled trials are needed.550 Recent history of a major surgical procedure poses systemic bleeding risk in the setting of intravenous rtPA and may represent another group for consideration of intra-arterial fibrinolysis. Several small case series of postoperative cardiac surgery cases suggest reasonable safety of intra-arterial fibrinolysis.551–553 In addition, a retrospective case series of 36 ischemic stroke patients from 6 academic centers treated with intra-arterial fibrinolysis after surgical procedures, including open heart surgery (n=18), CEA (n=6), and urologic-gynecologic surgery (n=4), suggested that intra-arterial rtPA is reasonably safe in the postoperative setting, with the exception of neurosurgical procedures (n=3).554 Major systemic bleeding occurred in 4 cases, including 3 postcraniotomy ICHs and 1 post–coronary artery bypass graft hemopericardium. Rates of good clinical outcome after intra-arterial fibrinolysis are likely to be highly time dependent, as is the case with intravenous rtPA treatment.92,93,555 If intra-arterial fibrinolysis treatment is planned, an emphasis should be placed on rapid triage, patient transport, and clinical team mobilization.

Katz University S/P “Major Surgery” IV tPA is contraindicated If Large Vessel Occlusion (NIHSS >10) strongly consider IA treatments. Generally Safe (except in post-craniotomy pts)

Conclusions Perioperative stroke is rare but potentially devastating Associated co-morbidities are well-defined Intraoperative associations are not well-defined Improved recognition of postoperative stroke is necessary before acute intervention can be considered

Questions