Perioperative Stroke Laurel Moore Associate Professor Will discuss management of acute stroke on Thursday Laurel Moore Associate Professor Director, Division of Neuroanesthesiology University of Michigan

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

Outline of Presentation Brief Review of Perioperative Stroke Preoperative risk reduction Intraoperative risk reduction Postoperative recognition and possible treatment options

Why care about perioperative stroke? Perioperative Complication Incidence (range)% Myocardial infarction 0.0005-5.1 Stroke 0.1-3.0 Postoperative visual loss 0.1-0.2 Neurovision Trial – 10% incidence in patients > 65 years and low risk procedures As no equivalent biomarkers such as ECG or troponins, we probably grossly underestimate incidence. Clearly associated with up to 10 fold increase in perioperative mortality

Incidence of stroke by procedure Surgical Procedure Incidence (%) Noncardiac nonneurologic1 0.1 Total hip arthroplasty2 0.2 Vascular noncarotid3, 20 0.4-0.8 Vascular carotid27 0.9 Coronary artery bypass19, 60 2.0-3.1 Double and triple valve replacement61 9.7 Aortic arch procedures with DHA4 19.2

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.” 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

Mechanisms of Perioperative Stroke Ischemic Perioperative strokes: < 1% are hemorrhagic, vast majority ischemic. Nonoperative strokes: 10-20% hemorrhagic (5% SAH), remainder are ischemic Hemorrhagic

Classification of Subtypes of Acute Ischemic Stroke (TOAST Stroke 1993;24:35-41) 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

Watershed Infarction Bijker, Can J Anaesth 2013;60(2):159-67 Watershed infarcts common in the cardiac surgery patient compared to nonoperative stroke patients – incidence of 47% bilateral watershed infarcts by MRI in patients with s/o of postoperative stroke. Intraoperative hypotension, relative to baseline BP, appears to be contributory to watershed infarctions in cardiac surgery patients (Gottesman Stroke 2006). Mechanism appears to involve both hypotension and poor wash-out of emboli. Unclear if low-flow states result in platelet activation and microemboli formation or emboli produce low-flow states in addition to possible hypotension. In any case, patients with bilateral watershed infarctions have poor prognosis. Bijker, Can J Anaesth 2013;60(2):159-67

Mechanisms of Stroke Comorbidities: Age TIA/stroke Renal disease Female sex Cardiac disease Hypertension Afib 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. High Risk ≥ 5 risk factors Stroke incidence 1.9%, OR 21 Mashour Anesthesiology 2011;114(6): 1289-96

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. 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

Outline of Presentation Brief Review of Stroke and Perioperative Stroke Preoperative risk reduction Intraoperative risk reduction Postoperative recognition and possible treatment options Antiplatelet therapy Statin therapy Will speak re: β blockers on intraoperative section: with the exception of in combination with statins, no evidence preoperative beta blockers protect against perioperative stroke and probably increases risk (POISE). Patients on βblockers chronically, however, should continue them due to risks of cardiovascular complications with their withdrawal.

Aspirin following cardiac surgery Mangano NEJM 2002;347:1309

Should ASA be discontinued preoperatively? Cerebrovascular Complications Bleeding Complications ASA is standard therapy for primary and secondary stroke prevention Surgical acceptance of continuation of anti-platelet therapy significantly helped by the advent of coronary stents and the cardiac literature associated with this. In the non-surgical literature when discussing ASA therapy the # frequently quoted is that ASA causes a 1.5 fold increase in bleeding complications without significant changes in outcome with the exception of intracranial procedures and some urologic procedures (Burger J Intern Med 2005;257(5):399-414) Much of medical literature also relates to low-risk procedures such as endoscopy, ERCP and not major surgery Abrupt cessation of antiplatelet therapy can cause rebound increases in platelet activity (Blood coagul fibinolysis 1996;7:80-84

Effects of antiplatelet therapy withdrawal Rebound in platelet activity with abrupt cessation 5% of nonoperative ischemic stroke associated with withdrawal of antiplatelet therapy Strokes generally occur within 2 weeks of antiplatelet cessation Exact contribution of ASA withdrawal to perioperative stroke incidence unknown 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 5% probably underestimate as patients reporting may be cognitively impaired or aphasic (Neurology 2004;62:1187-1189) 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

British Journal of Urology International 2011 “We should cease offering TURP in favour of alternative surgery options for anticoagulated patients” In response to small study of patients undergoing transurethral resection of prostate 10% of patients suffered cardiac or cerebrovascular complications following cessation of anticoagulant therapy including anti-platelet agents. British Journal of Urology International 2011

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

Primary and Secondary Stroke Prevention with Statins Primary stroke prevention HMG–coA reductase inhibitors Unlike aspirin – no downside to continuing statins in patients on statin therapy Secondary stroke prevention Nassief Stroke 2008;39:1042-1048

AF Stalenhoef, J Vasc Surg 2009;49(4):1091 As regards perioperative statins: “Prospective randomized trials…cannot be performed anymore…because all vascular patients should receive statin treatment as secondary prevention of cardiovascular disease.” Eric Heyer Stroke 2013;44:1150-1152 demonstrated asymptomatic patients undergoing CEA statins not only reduced incidence of stroke but also POCD Standard practice to begin vascular patients on statins preoperatively. No data to support this recommendation in more generalized surgical population Statins should be continued perioperatively and for patients who will remain NPO a long-acting drug such as fluvastatin should be considered. AF Stalenhoef, J Vasc Surg 2009;49(4):1091

Outline of Presentation Brief Review of Perioperative Stroke Preoperative risk reduction Intraoperative risk reduction Postoperative recognition and possible treatment options Despite what neurology consults say, Stroke recognized at emergence from anesthesia represents only approximately 10% of strokes, therefore most strokes are perioperative and not necessarily intraoperative events. Specifically not going to refer to “neuroprotection” because the patients we’re discussing aren’t being subjected to planned cerebral ischemia such as HCA or aneurysm surgery. Anesthetic technique Use of β-blockers Blood pressure management

Anesthetics as Neuroprotectants Not going to talk about GA as a neuroprotectant

Stroke reduced with Neuroaxial Anesthesia in THR and TKR 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 Memtsoudis, Anesthesiology 2013;118(5):1046-1058

POISE Trial 2008 Lancet 2008;371(9627):1839-47 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

Association of 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

Stroke incidence with anemia 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

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

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.

Bijker and Gelb Can J Anaesth 2013;60(2):159-67 “Unusually low blood pressure will eventually result in neurological damage; however, the threshold and duration at which an association might be found between a perioperative stroke and hypotension have not been well investigated. Thus, 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

Outline of Presentation Brief Review of Perioperative Stroke Preoperative risk reduction Intraoperative risk reduction Postoperative recognition and possible treatment options

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

“Time is Brain” Kidwell Stroke 2004;35:2662-2665 Definition of stroke has changed from clinical exam lasting beyond 24 hours now to include neuroimaging. This slide demonstrates the distinction between areas of completed infarction vs. brain that is salvageable Depending on volume and significance of brain that is salvageable patients may be eligible for intervention beyond the usual 4.5 hours accepted for intravenous thrombolytic therapy Kidwell Stroke 2004;35:2662-2665

Mechanical Thrombolysis Several recent studies have demonstrated the lack of benefit of endovascular intervention over IV tPA for acute ischemic stroke The postoperative patient who is felt to be too high risk for system thrombolysis may be the exception to these findings We need to improve our recognition of stroke postoperatively before we can offer acute intervention.

Suggestions for clinical management Stroke is more common than you think When possible continue anti-platelet rx Statins and β-blockers should continue However, no evidence yet that statins should be initiated for non-vascular surgery as stroke-prevention measure.

Suggestions for Intraoperative management Blood pressure goals should be assessed as % variance from baseline Prolonged hypotension probably bad Normocapnia probably good Induced hypotension for beach chair position definitely bad Nitrous oxide okay

Intraop management cont. Patients on β-blockers may be more sensitive to anemia Short-acting or β1-selective β-blockers when possible Glucose levels 80-150 mg/dL

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

SNACC Task Force on Perioperative Stroke Perioperative Care of Patients at High Risk for Stroke after Non-Cardiac, Non-Neurologic Surgery: Guidelines from the Society for Neuroscience in Anesthesiology and Critical Care SNACC Task Force on Perioperative Stroke George A. Mashour MD PhD, Laurel E. Moore MD, Abhijit V. Lele MD, Steven A Robicsek MD PhD, Adrian W. Gelb MBChB http://www.snacc.org/