Stroke is responsible for approximately 6.2 million deaths annually, making cerebrovascular disease a leading global cause of premature death and disability.1 Additionally, cerebrovascular disease is projected to be the second leading cause of death worldwide by the year 2030.2 Given the global burden, many efforts have focused on the prevention and treatment of stroke and other sequelae of cerebrovascular disease. One area of particular concern is the perioperative setting where patients may be at particular risk of stroke.3 In the United States alone, significant increases (14-47%) in demand for surgical services are expected over the coming years,4 and it follows that the number of perioperative strokes may increase accordingly. Perioperative stroke in high-risk cardiovascular surgery has been well-documented, with an incidence in the range of approximately 1.9-9.7%.5 Currently, the incidence of perioperative ischemic stroke (IS) in non-cardiac, non-neurologic, and non-major vascular surgery is in the range of approximately 0.1-1.9% depending on associated risk factors.6,7 Pilot data from the Neurovision study, however, suggest that the incidence of covert stroke in high-risk non-cardiac surgery patients may be as high as 10%.8 This is relevant because clinically silent cerebral ischemia has been proportionally correlated with postoperative cognitive impairment in cardiac surgery patients.9 In addition to the potentially underappreciated incidence and significance of perioperative stroke, recent data have shown that mortality from perioperative stroke may be particularly high, with an approximate incidence in the range of 20-60% depending on type of stroke, operation, and patient.10-12 As such, interest has grown in the identification of those at risk for perioperative stroke as well as in potentially modifiable risk factors. This focus has culminated in a consensus statement by the Society for Neuroscience in Anesthesiology and Critical Care (SNACC) for perioperative care of non-cardiac, non-neurological surgery patients at high risk of stroke.13

Figure
figure 1

Ischemic stroke risk as a function of surgical procedure. Stroke incidences are calculated composite averages derived from representative literature from cardiac,5,96,97 vascular,51,97-99 and general surgery.6,7 CABG = coronary artery bypass graft; CEA = carotid endarterectomy

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The SNACC Consensus Statement defines perioperative stroke as a brain infarction of ischemic or hemorrhagic etiology that occurs during surgery or within 30 days after surgery.13 The remainder of this review will focus on stroke based on this definition. Specifically, the pathophysiology and risk factors of perioperative stroke are reviewed, and the recently released SNACC perioperative stroke recommendations are also reviewed. Lastly, directions for future investigations are suggested.

Pathophysiology

Because stroke is caused by a diverse array of etiologies, different stroke subtypes may be a function of varying pathophysiologic pathways. Thus, discussion of the pathophysiology of perioperative stroke first begins with a classification framework for stroke etiology. Though stroke is classified in many different ways (e.g., arterial vs venous and ischemic vs hemorrhagic), for the purpose of this review, perioperative stroke is classified as either ischemic or hemorrhagic.

Ischemic stroke

Categorization of ischemic stroke (IS) based on etiology has been outlined in the Trial of Org 10172 in Acute Stroke Treatment (TOAST).14 The TOAST classification system divides IS subtypes into large-artery atherosclerosis, cardioembolism, small-artery occlusion (lacunar), stroke of other determined etiology, and stroke of undetermined etiology. Much of the recent literature on perioperative stroke focuses on IS, as the incidence of ischemic perioperative stroke seems to be higher than that of hemorrhagic stroke (HS).15,16 As such, pathophysiologic cascades that may facilitate perioperative IS have been considered in this context. Though Ng et al. 17 reviewed major studies that reported the etiologies of perioperative stroke in the non-cardiac surgery setting, estimated incidences of subtypes are difficult to ascertain, as many population-based studies do not analyze stroke subtypes with the required level of granularity.6,7,18 Based on available data, thrombosis, embolism, anemic tissue hypoxia, and cerebral hypoperfusion have all been described as etiologic pathways contributing to perioperative IS.10,19-21 Following is a review of three of the major pathophysiologic mechanisms of IS—thrombosis, cardioembolism, and anemic tissue hypoxia.

Large- and small-vessel occlusion: thrombosis

Surgery precipitates systemic inflammation and hypercoagulability,22-24 and this state may contribute to thrombogenesis and vessel plaque rupture in the perioperative setting. Further, patients receiving anticoagulation or antiplatelet therapy preoperatively may be at risk for rebound hypercoagulation25 and subsequent IS upon withdrawal.26 Taken together, this indicates that some patients—especially those on preoperative anticoagulation or antiplatelet therapy—may be at an increased risk for perioperative thromboembolic events via a hypercoagulable state that may be driven by both surgical intervention and rebound hypercoagulation. This hypercoagulable state may be exacerbated by systemic inflammation, which is also increased perioperatively.22,23,27 An elevation of inflammatory biomarkers has been shown to predict future stroke,28-30 and it follows that anti-inflammatory measures may conceivably reduce the risk of stroke. One such possible anti-inflammatory intervention is statin administration, which has been associated with decreased perioperative stroke across multiple surgical populations.31,32 Though statins act through various pathways, there is evidence to suggest that the anti-inflammatory effects, in particular, confer stroke protection.33-37 Given the clinical evidence, inflammatory and hypercoagulable factors may indeed combine to increase the risk of perioperative thrombogenic stroke.

Cardioembolism

Ischemic stroke of embolic origin is often due to cardioembolism. In this review, cardioembolism refers to any embolic phenomenon originating from the heart, including both valvular and non-valvular sources. In the perioperative setting, atrial fibrillation combined with a hypercoagulable state (as discussed above) may be a source of cardioembolic phenomena. Atrial fibrillation has indeed been a consistent risk factor for perioperative stroke across various surgical populations.5,6,38,39 An additional source of cardioembolic stroke is cardiovascular manipulation of the heart and aortic arch, both of which occur during major cardiac and some vascular surgery (e.g., endovascular stent grafting). In fact, these surgeries have been linked with a relatively high incidence of perioperative stroke, with embolic stroke representing a relatively high proportion of these events.5,38

Other determined stroke etiologies—anemia-associated tissue hypoxia

One potential mechanism by which IS may occur involves cerebral hypoxia in the setting of hemodilution and anemia.40 With anemic states, increased cardiac output (CO) and cerebral blood flow act as compensatory mechanisms to preserve oxygenation.41-46 In the setting of use of a non-specific beta-blocker (i.e., metoprolol) and anemia, both CO and cerebral vasodilation become impaired, which may result in cerebral tissue hypoxia.46-48 Mechanistically, animal models have shown that the β2-mediated reduction in cerebral vasodilatory function may be integral to the reduction in cerebral oxygenation.47,48 In animal studies, minimizing β2-mediated cerebrovascular antagonism improved cerebral oxygenation in the setting of anemia.49 Ultimately, this aberrant physiology may render vulnerable brain regions at risk for ischemia and stroke. Indeed, clinical data have shown an increased risk of stroke in surgical patients on beta-blockade with hemoglobin levels below 9 g·dL−1; those taking metoprolol were at highest risk.20 The risk of stroke also increased in the Perioperative Ischemic Evaluation (POISE) trial in patients who experienced significant bleeding.21

Hemorrhagic stroke

According to the American Heart Association and American Stroke Association (AHA/ASA), stroke of hemorrhagic etiology can be attributed to a focal collection of blood within the brain parenchyma, subarachnoid space, or ventricular system that is not caused by trauma.50 Perioperatively, this may plausibly occur via factors such as uncontrolled hypertension, cerebral vascular malformations, and administration of anticoagulant or antiplatelet therapy. Fortunately, however, this seems to be an infrequent occurrence, as HS represents approximately only 1-4% of all perioperative strokes as shown by incidence data.15,16 As such, much of the research into the mechanisms of perioperative stroke to date centres on IS, which remains the focus for the rest of this review.

Risk factors

Many risk factors for perioperative stroke have been elucidated over the years, and several of those factors seem to fit well within the pathophysiologic framework as outlined above. These risk factors have been derived largely from case series and large database studies, 5-7,51 as the rarity of perioperative stroke makes it difficult to collect and analyze prospective data. In particular, factors that reflect pre-existing vascular disease or propagation of vascular disease have been consistently shown across studies. Examples include advanced age, previous stroke or transient ischemic attacks, coronary artery disease, and renal disease (Table 1).6,7,51 These factors may reflect less cerebrovascular reserve and thus higher susceptibility to deleterious cerebral thromboembolic phenomena. Major cardiovascular surgery has a relatively high incidence of perioperative stroke (Figure),5,52 as these surgeries carry the additional risk of cardioembolism from cardiac and vascular manipulation. Along similar lines, atrial fibrillation serves as a risk factor for perioperative embolic stroke.5,6,38,39 Recently, in fact, patients with new-onset atrial fibrillation after non-cardiac surgery were shown to be at increased risk of IS beyond the perioperative setting alone.53

Table 1 Stroke risk factors across various surgical populations
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Perioperative beta-blockade has emerged as a risk factor for stroke across the general surgical population.16,20,21,54 Both prospective randomized controlled trials and retrospective observational studies have shown an increased risk of stroke in patients taking beta-blockers in the perioperative setting.16,20,21 Further, there may be a differentially increased risk with relatively non-selective beta-blockers.16,20 As previously outlined, this may be due to impaired cerebral vasodilation and CO in the setting of malperfusion and non-selective beta-blockade.46-48

The SNACC Consensus Statement

In 2014, the SNACC released the first set of recommendations regarding care for patients at high risk for perioperative stroke in the setting of non-cardiac non-neurologic surgery.13 Based on a review of the literature as well as expert opinion, recommendations to minimize the risk of perioperative stroke in the preoperative, intraoperative, and postoperative periods were presented. Considerations for prevention and management of stroke across the perioperative spectrum are reviewed below. These factors are derived from both the SNACC Consensus Statement as well as from other subsequent influential studies.55-57

Preoperative management

Phenotype of the high-risk patient

Prevention of perioperative stroke begins with the identification of high-risk patients in the preoperative setting. By initially stratifying risk based on the type of surgery, non-cardiac, non-neurologic, and non-major vascular surgery are all associated with the lowest incidence of perioperative stroke—approximately 1 per 1,000 cases (0.1%).7 The SNACC Consensus Statement focuses largely on this population. The incidence then climbs with major vascular and cardiac surgery, with reported incidences as high as 5.6% and 9.7%, respectively.5,58 In addition to the type of surgery, patient-specific risk factors also play a role. Across major epidemiologic studies examining risk factors for stroke in the general surgical population, advanced age, history of renal failure, history of stroke, and cardiac disease all confer an increased risk of perioperative stroke.6,7 The existence of such conditions in a patient’s medical history should alert the perioperative physician to an increased risk of cerebrovascular compromise and raise the index of suspicion for stroke in the setting of postoperative neurologic changes. Thus, the phenotype of the high-risk patient may appear as someone presenting for major surgery (especially cardiovascular) with comorbidities such as advanced age, renal dysfunction, history of cerebrovascular compromise, and history of cardiac disease.

Identifying modifiable risk factors

Although many risk factors for perioperative stroke are largely non-modifiable, the discussion below encompasses elements that the perioperative physician may be able to modulate for risk reduction. As may become evident, there are noticeably few large-scale randomized prospective trials available to help guide management for the factors below. Possible modifiable risk factors, along with proposed strategies for minimizing the risk of perioperative stroke, are outlined in the sections below and presented in Table 2.

Table 2 Proposed perioperative modifiable risk factors
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Recent stroke

In 2014, Jorgensen et al. presented observational cohort data regarding postoperative risk of major adverse cardiovascular events (MACE) after recent IS.55 The data come from the Danish National Patient Register—a national registry of prospectively collected data from patients in the Danish healthcare system. In this study, patients who had a recent history of IS also showed an increased risk of MACE and mortality within 30 days of the operation. Further, patients were also at risk for postoperative IS, and this risk progressively decreased the longer the duration of time between stroke and subsequent surgery: stroke < three months previously (odds ratio [OR], 67.6; 95% confidence interval [CI], 52.27 to 87.42), stroke three to < six months previously (OR, 24.02; 95% CI, 15.03 to 38.39), and stroke six to < 12 months previously (OR, 10.39; 95% CI, 6.18 to 17.44). The increased risk of perioperative stroke appeared to return to that of patients with a remote history of stroke in the preceding nine to 12 months. One criticism was the lack of a non-surgery control group.59 Indeed, an increased risk of stroke recurrence has been shown within 12 months of incident stroke without surgery.60,61 Nonetheless, probing for history of recent stroke seems reasonable. As time from the onset of stroke symptoms to intervention is critical, any conditions that obscure the ability to evaluate for stroke symptoms (e.g., recovery from general anesthesia) may place patients at higher risk. As such, elective cases should be delayed and a risk/benefit analysis should be conducted in these scenarios given 1) the challenges present with the diagnosis and management of stroke after surgery and anesthesia and 2) the eightfold increase in mortality with perioperative stroke.7 Further investigation into the optimal timing of surgery after stroke is certainly warranted.

Perioperative beta-blockade

Evidence shows a reduced risk of MACE with perioperative beta-blockade, though this may come at the expense of an increased risk of stroke in non-cardiac surgery patients.54,62 In the 2014 American College of Cardiology/American Heart Association (ACC/AHA) Guidelines, the authors recommend a risk-benefit analysis for perioperative beta-blockade on a case-by-case basis.62 Specifically, the suggestion is made to weigh the risk of MACE against the risk of perioperative stroke to guide the decision-making with regard to management of perioperative beta-blockade. In cases where the risk of MACE may be higher than that of perioperative stroke, perioperative beta-blockade may be beneficial, whereas in cases where the risk of stroke is higher than that of MACE, a strategy involving aggressive beta-blockade may be harmful. This distinction is certainly not always easy to delineate clinically. An initial step may be to identify patients on beta-blockade who are at high risk for cerebrovascular ischemia based on patient- and surgery-specific risk factors. For example, as mentioned above, the combination of anemia and beta-blockade may place patients at risk for stroke. As such, patients on preoperative beta-blockade presenting for surgery with a high risk of major hemorrhage may be at increased risk. Further investigation may be informative.

Anticoagulant and antiplatelet therapy

In general, the risk of excessive perioperative bleeding is weighed against the risk of thromboembolism, though a clear diametric clinical distinction is not always present. For patients on anticoagulation for conditions such as atrial fibrillation, the ACC/AHA Guidelines recommend discontinuation of anticoagulation for ≥ 48 hr for major surgery.62 The American College of Chest Physicians recommends continued perioperative anticoagulation for patients at high risk for venous thromboembolism.63 At this point, it is unclear if aggressive perioperative anticoagulation would reduce the risk of postoperative stroke,39 and further investigation would be of benefit for clinical decision-making. With regard to antiplatelet therapy, both observational and interventional data have shown a cerebroprotective effect of acetylsalicylic acid in cardiac surgery patients.64,65 In non-cardiac surgery patients, the POISE-2 trial showed a reduced incidence of stroke in patients who started acetylsalicylic acid therapy during the course of the study,66 though this benefit was not seen in patients who had already been on acetylsalicylic acid therapy. Further, the authors reported that this was likely a spurious subgroup effect in the initiation stratum due to the combination of small sample size, an unexpectedly large benefit of acetylsalicylic acid, benefits not previously shown in other studies, and a hypothesized direction opposite to the observed finding.66,67

Intraoperative management

From the perspective of the anesthesiologist, an evidence-based intraoperative strategy to minimize the risk of stroke may indeed sound appealing. To that end, different intraoperative anesthetic techniques and pharmacologic and physiologic strategies have been studied with the intent of minimizing postoperative risk of stroke. Below, we review some of the major studies examining intraoperative considerations that may impact the risk of perioperative stroke.

Anesthetic and monitoring techniques

Various anesthetic and neuromonitoring techniques have been studied in patients undergoing surgical procedures associated with a high risk of stroke, e.g., carotid endarterectomy (CEA). In over 3,000 patients presenting for CEA, the GALA trial randomized patients to general anesthesia (GA) vs local anesthesia in a multicentre randomized controlled format.68 The trial could not show any definitive difference in stroke outcomes between those two groups. A secondary analysis of this trial did not show an increased risk of stroke in patients exposed to nitrous oxide69 despite the known increase in plasma homocysteine levels associated with its use.70 This finding was reaffirmed in patients undergoing major non-cardiac surgery, where the use of nitrous oxide did not confer an increased risk of stroke.71 In patients who are indeed undergoing high-risk procedures like CEA under GA, neuromonitoring techniques, such as electroencephalography and somatosensory-evoked potential monitoring (SSEP), allow detection of intraoperative ischemia.72,73 Electroencephalography, however, may allow for faster and more sensitive detection of ischemia than SSEP in these cases.72,74 A review of these techniques as well as a discussion of their respective benefits and drawbacks can be found elsewhere.74-76 Assessment of regional cerebral oxygenation (rSO2) is an additional intraoperative neuromonitoring technique where near-infrared spectroscopy is used to measure cerebral tissue oxygenation indirectly.77,78 In cardiac surgery patients, preliminary data indicate that intraoperative rSO2 monitoring may reduce the risk of perioperative stroke,79,80 though further studies are needed to confirm or refute these findings.

Lastly, investigators have recently assessed rates of perioperative stroke in orthopedic surgery patients receiving either general or neuraxial anesthesia for various joint arthroplasty procedures.81,82 In both studies, general anesthesia was associated with a higher risk of perioperative stroke. Based on study design—a large retrospective database study82 and a prospective observational cohort study81—no inferences regarding causality can be drawn. Nonetheless, the notion that anesthetic technique may modulate the risk of perioperative stroke in certain patient populations certainly deserves further investigative consideration.

Physiologic management

Optimal intraoperative physiologic management may play a role in stroke prevention. Maintaining blood pressure near preoperative baseline values may help lower the risk of stroke, though supporting evidence is limited. Two large retrospective database studies were carried out to examine the relationship between intraoperative blood pressure and postoperative stroke.16,83 Bijker et al. showed an association between intraoperative hypotension and postoperative stroke when mean arterial pressure (MAP) was reduced by 30% (per minute) compared with baseline (OR, 1.01; 99.9% CI, 1.00 to 1.03).83 This OR expresses the increase in the risk of stroke per minute of defined intraoperative hypotension (i.e., a 30% MAP reduction). In a subsequent retrospective database study, Mashour et al. found associations between postoperative stroke and intraoperative hypotension 20% below baseline for both systolic blood pressure (SBP) and MAP (median values measured over ten-minute intervals).16 Reasons for the discrepancy between these studies are unclear, but they might relate to differences in the definition of baseline blood pressure as well as the duration of hypotension. Indeed, definitions of intraoperative hypotension and baseline blood pressure vary widely in the literature, as does the studied duration of perioperative hypotension.84 As an additional consideration, Bijker et al. also noted significant variance in the intervals used to record postoperative blood pressure and lack of a detailed characterization of the severity of postoperative hypotension.83 For these reasons, data regarding postoperative blood pressure were excluded from their analysis. Studying the effects of the outcomes of hypotension and perioperative stroke thus becomes difficult when considering the rarity of stroke, the lack of standardized definitions for baseline blood pressure and intraoperative hypotension, and the time period during which hypotension may be most deleterious (i.e., intraoperative vs postoperative).

Avoiding extremes in plasma glucose concentration may also help reduce the risk of stroke. Ghandi et al. found an increased risk of postoperative stroke with tight intraoperative glucose control in cardiac surgery patients.85 Conversely, Doenst et al. showed an increased risk of composite adverse events—including stroke—with hyperglycemia during cardiac surgery.86 At present, few data are otherwise available to guide intraoperative glucose management, especially in the non-cardiac surgery literature.

Intraoperative beta-blockade

As discussed previously, the findings of the POISE trial led many to rethink the approach to perioperative beta-blockade. At the time, few data existed relating risk of perioperative stroke to specific beta-blockers, dosing regimens, and, notably, effects of intraoperative beta-blockade. In a retrospective investigation of 57,218 patients, Mashour et al.16 found a 3.3-fold (95% CI, 1.4 to 7.8; P = 0.003) unadjusted increased risk of perioperative stroke in patients who received intraoperative metoprolol. This finding was not shown with other beta-blockers studied. Postulated mechanisms for this association include impaired cerebral tissue oxygen delivery via decreased cerebral vasodilation and impaired CO in the setting of hemodilution.46-48 At present, few other data exist regarding intraoperative beta-blockade and cerebrovascular outcomes. Decisions regarding intraoperative beta-blockade may be made on a case-by-case basis depending on the patient, type of surgical intervention, and ongoing physiologic considerations as previously described.

Postoperative management

In general, only approximately 5-15% of perioperative strokes occur intraoperatively or in the immediate (i.e., apparent in the postanesthesia care unit) postoperative setting.16,51 Indeed, most postoperative strokes present at least 24 hr after surgery.16,51 Given this timeline, continued clinical vigilance for stroke symptoms along with timely neurology consultation is paramount for successful diagnosis and management of postoperative stroke. Emergent neuroimaging should be obtained in parallel with activation of the stroke rapid response team, if available. A multidisciplinary discussion involving neurology and the primary surgical service should ensue with input from interventional neuroradiology and anesthesiology as needed. Providers should seek expeditious evaluation and mobilization of resources, as in-hospital stroke may be associated with worse outcomes compared with community-onset stroke.57 Indeed, Saltman et al. reported delayed recognition of symptoms, delayed neuroimaging, lower rates of thrombolysis, and exceptionally severe stroke with in-hospital stroke patients compared with those with community-onset stroke.57 Surgical patients represented nearly 50% of all in-hospital strokes in this study. Thus, timely and optimal management of perioperative stroke may be crucial in these high-risk patients. Glucose should be checked, as both hypo- and hyperglycemia have been associated with worse stroke outcomes.85,87 Acetylsalicylic acid should be considered prior to discharge if surgically feasible, given improved outcomes when used for secondary prevention.88 A proposed management checklist for perioperative stroke is outlined in Table 3.

Table 3 Perioperative ischemic stroke management
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Treatment for postoperative stroke remains a source of ongoing active discussion. According to the 2013 AHA/ASA Guidelines, patients who have undergone recent major surgery may be candidates for intravenous fibrinolysis, though a careful risk-benefit analysis should first be conducted.89 These guidelines also speculate that selective intra-arterial thrombolysis may be warranted in a select group of surgical patients who may be at high risk for systemic hemorrhage. Several case series have shown a favourable safety profile of intra-arterial intervention across diverse surgical populations.90-92 Catheter-based mechanical interventions may also be appropriate in these select populations, especially given recent data showing improved functional outcomes and reduction in mortality among select patients.93 Ultimately, further investigation is warranted.

In terms of blood pressure management in IS patients, the 2013 AHA/ASA Guidelines recommend permissive hypertension up to 220/120 mmHg if not being considered for thrombolytic reperfusion therapy and if not contraindicated by coexisting medical conditions (i.e., acute aortic dissection, acute myocardial infarction, etc.).89 If intravenous thrombolytic therapy is being considered, however, recommendations are for controlled blood pressure reduction to < 185/110 mmHg.89 Since the release of these Guidelines, the results of the China Antihypertensive Trial in Acute Ischemic Stroke (CATIS) have been released. From a starting mean [standard deviation (SD)] SBP of 166.7 (17.3) mmHg, there was no clinical benefit in reducing blood pressure to 144.7 (15.0) mmHg at 24 hr or to 137.3 (11.8) mmHg at seven days.56 Thus, at present, a SBP goal of approximately 140-185 mmHg may be reasonable. Certainly, avoiding extremes of blood pressure may help avoid further neurologic insult, as has been observed in patients after receiving thrombolysis.94

Conclusions

Perioperative stroke has attracted renewed attention over the past few years, as associated morbidity and mortality remain high and potentially modifiable risk factors have been identified. Significant investigative work remains to be done in the areas of perioperative beta-blockade, anticoagulation, antiplatelet management, and intraoperative management. The SNACC Consensus Statement represents a succinct yet thorough review of the current literature supporting preventative and management approaches to perioperative stroke.