Review
Neurological complications of cardiac surgery David L McDonagh, Miles Berger, Joseph P Mathew, Carmelo Graffagnino, Carmelo A Milano, Mark F Newman Lancet Neurol 2014; 13: 490–502 Published Online April 2, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70004-3 See Online for an audio interview with David McDonagh and Mark Newman Department of Anesthesiology (D L McDonagh MD, M Berger MD, Prof J P Mathew MD, Prof M F Newman MD), Department of Neurology (D L McDonagh, Prof C Graffagnino MD), and Department of Surgery (Division of Cardiovascular and Thoracic Surgery) (C A Milano MD), Duke University Medical Center, Durham, NC, USA Correspondence to: Dr David L McDonagh, Department of Anesthesiology, Duke University Medical Center, DUMC Box 3094, Durham, NC 27710, USA [email protected]
For the risk calculator see http://riskcalc.sts.org/ STSWebRiskCalc273/
For the European System for Cardiac Operative Risk Evaluation see http://www. euroscore.org/calc.html
490
As increasing numbers of elderly people undergo cardiac surgery, neurologists are frequently called upon to assess patients with neurological complications from the procedure. Some complications mandate acute intervention, whereas others need longer term observation and management. A large amount of published literature exists about these complications and guidance on best practice is constantly changing. Similarly, despite technological advances in surgical intervention and modifications in surgical technique to make cardiac procedures safer, these advances often create new avenues for neurological injury. Accordingly, rapid and precise neurological assessment and therapeutic intervention rests on a solid understanding of the evidence base and procedural variables.
Introduction Neurological complications have been a major concern throughout the history of cardiac surgery.1 Advances in technology and technique have led to open, minimally invasive, and endovascular therapeutics to repair vascular, valvular, and myocardial pathology. Coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI) are now completed more safely than they ever have been.2–4 Despite these advances, neurological complications, including ischaemic stroke,5 delirium, and cognitive decline, still occur frequently. In this Review, we focus on the neurological complications of cerebral thromboembolism, including risk assessment, comparative risk of cardiac interventions, approaches to minimise perioperative thromboembolic events, and acute stroke therapies. Wherever possible, we have specified the level of evidence available for each intervention according to the joint American College of Cardiology Foundation and American Heart Association classification (level A, B, or C and class I, IIa, or IIb).2 Ischaemic stroke is one of the most feared complications of cardiac surgery and carries high morbidity and mortality; therefore, much of our Review focuses on this topic, but we also discuss hypoxic ischaemic cerebral injury, acute therapy, neurocognitive complications, and future directions in the specialty.
Management of perioperative risk for ischaemic stroke Assessment of risk Ischaemic stroke related to perioperative cerebral thromboembolic or hypoperfusion injury is a wellrecognised complication of cardiovascular surgery. However, advances in perioperative medical and surgical care have progressively reduced stroke rates following primary CABG.3,6 Recent studies report post-CABG stroke rates of 1–5%,3,7–9 although patients with diabetes have a higher post-CABG stroke risk (5·2% at 5 years).8 However, valvular surgery carries an even higher risk for perioperative stroke, which is potentially attributable to increases in particulate and air embolisation.10 In a prospective series of more than 16 000 cardiac surgery patients, which followed up patients for a mean of 11·7 days, the short-term stroke risk was 4·8% after isolated aortic valve replacement, 8·8% after mitral valve replacement, and 9·7% after multivalve
surgery.10 CABG was associated with a 3·8% stroke risk, and CABG plus valve surgery with a 7·4% risk.10 The absence of standardised care across surgeons or institutions could explain the varying neurological complication rates among different studies. Perioperative strokes can be divided into two categories: early perioperative stroke, which is present at extubation (mainly intraoperative); and late perioperative stroke, which occurs postextubation (postoperative). Tarakji and colleagues3 studied more than 45 000 cardiac surgical patients treated over 28 years at the Cleveland Clinic (OH, USA) and reported that some risk factors were associated with both early and late stroke, whereas others were associated with only one type of stroke (panel 1). On-pump procedures with hypothermic circulatory arrest carried the highest early stroke risk, whereas off-pump CABG and onpump beating heart CABG were associated with the lowest risk of early stroke. New-onset postoperative atrial fibrillation was not associated with postoperative stroke in this study.3 Hedberg and colleagues11 also reported unique risk factors associated with intraoperative versus postoperative strokes (panel 1). Although they showed that different risk factors were associated with early and late stroke, these studies suggest that early and late perioperative strokes might arise from different pathophysiological processes. The Society of Thoracic Surgeons has created an online risk calculator for postsurgical complications. This calculator uses three risk models for CABG, valve surgery, and the combination of CABG plus valve surgery. Based on demographics, comorbidities, laboratory and cardiac diagnostic data, and procedural variables, the risk for nine clinical endpoints (mortality, morbidity or mortality, long length of stay, short length of stay, permanent stroke, prolonged ventilation, deep sternal wound infection, renal failure, and reoperation) can be calculated. The European System for Cardiac Operative Risk Evaluation is also used frequently to establish a patient’s mortality risk after cardiac surgery, but it does not specifically assess the risk for neurological injury.
Planning of interventions for coronary artery disease: CABG versus PCI Recent studies have compared the effectiveness of CABG with that of PCI for the treatment of coronary disease, and www.thelancet.com/neurology Vol 13 May 2014
Review
the neurological complication rates after each procedure type. In the SYNTAX trial12,13 investigators randomly allocated patients with three-vessel or left main disease to CABG or PCI with drug-eluting stents. Patients in the CABG group had more strokes, but fewer combined major adverse cardiac and cerebrovascular events (the primary composite endpoint), than did those in the PCI group.13 In the FREEDOM trial, patients with diabetes and multivessel coronary disease were randomly assigned to CABG or PCI.8 This study also showed higher stroke rates in the CABG group than in the PCI group (5·2% vs 2·4%; p=0·03), although the composite primary 5-year endpoint of death, stroke, or myocardial infarction occurred less frequently in the CABG group than in the PCI group. Finally, the ASCERT study retrospectively compared CABG with PCI,14 and recorded lower 4-year mortality with CABG than with PCI (stroke data not yet published). The findings of these three studies are consistent with a previous meta-analysis that showed a trend towards survival benefit from CABG.15 As emphasised in a recent systematic review,16 these studies consistently show that CABG is superior to PCI in terms of mortality and overall composite endpoints, even though CABG is associated with a higher perioperative stroke risk. Nonetheless, the decision to undertake CABG or PCI should be made collaboratively (the so-called heart team approach) by cardiac surgeons and cardiologists16,17 on the basis of an assessment of an individual patient’s coronary disease pattern, comorbidities, and perioperative stroke risk.
Off-pump surgery versus cardiopulmonary bypass Neurocognitive complications of cardiac surgery have historically been attributed to embolic events and inflammatory responses related to cardiopulmonary bypass.2 However, a systematic review published in 2005 suggested no difference in stroke or death at 30 days following on-pump compared with off-pump CABG.18 Several studies have since randomly allocated CABG patients to undergo cardiopulmonary bypass or off-pump surgery, and have consistently shown no difference in stroke rates, neurocognitive outcomes, or composite outcomes, including mortality.9,19,20 In fact, the increased cerebral emboli detected during cardiopulmonary bypass have mostly not correlated with neurocognitive injury.2,21 Although undesirable, their clinical significance is unclear. These studies suggest that cardiopulmonary bypass alone does not contribute to perioperative stroke. Since neurological outcomes are similar after on-pump and off-pump CABG, procedure choice should be decided by surgical expertise, vascular anatomy, and patient-related variables. For example, the use of off-pump surgery has technical limitations and it is associated with an increased risk of early coronary revascularisation.19
Pharmacological therapies to reduce risk Aspirin, initiated preoperatively or within 6 h postoperatively, is standard care in cardiac surgery.2 The www.thelancet.com/neurology Vol 13 May 2014
Panel 1: Risk factors for early and late stroke following cardiovascular surgery3,11 Early or intraoperative stroke • Peripheral and carotid vascular disease • Previous cardiac surgery • Poor baseline clinical condition • Left ventricular dysfunction • Circumflex stenosis >70% • On-pump arrested-heart coronary artery bypass grafting • On-pump coronary artery bypass grafting with hypothermic circulatory arrest • Preoperative creatinine elevation • Aortic atherosclerosis • Longer time on cardiopulmonary bypass • Older age Late or postoperative stroke • Left main stenosis • Diabetes • Low use of thoracic artery grafting • Historically earlier date of operation • Female sex • Unstable angina • Postoperative atrial fibrillation • Inotropic support Both early and late stroke • Older age • Lower body surface area • Preoperative atrial fibrillation • Previous stroke • On-pump coronary artery bypass grafting with hypothermic circulatory arrest
Multicenter Study of Perioperative Ischemia reported a 50% reduction in perioperative stroke (1·3% vs 2·6%; p=0·01) if aspirin was given within 48 h of revascularisation.22 A recent meta-analysis23 of preoperative statin therapy trials showed that statin use in CABG surgery (or CABG plus valve surgery) reduces postoperative atrial fibrillation, shortens hospital stay, and, contrary to a smaller meta-analysis in 2012,24 reduces stroke and mortality. Furthermore, concern exists that statin withdrawal after cardiac surgery might be injurious (associated with increased in-hospital mortality).25 Thus, statins should be administered to reduce both perioperative stroke and non-neurological complications (class 1, level A recommendation).2
Atrial fibrillation Atrial fibrillation occurs in up to half of patients after CABG, most often on postoperative day 2.2 Preoperative atrial fibrillation is a risk factor for both early and late postoperative stroke;3,26 postoperative atrial fibrillation is associated with late postoperative stroke.11,26 Notably, the recent analysis by Tarakji and colleagues3 did not associate 491
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postoperative atrial fibrillation with postoperative stroke, which perhaps shows the efficacy of aggressive anticoagulation, early cardioversion treatments, or both, in current practice. Many trials in cardiac surgery have sought to reduce stroke caused by postoperative atrial fibrillation with various interventions, such as posterior pericardiotomy, or pharmacotherapies.27 n-3 polyunsaturated fatty acids have been the focus of many cardiac surgery trials, but neither the largest prospective trial28 nor a meta-analysis of eight randomised trials,29 showed that these fatty acids reduce postoperative atrial fibrillation or adverse outcomes.29 β blockers carry a class I, level B recommendation2 for reducing the incidence of atrial fibrillation; amiodarone is regarded as second-tier therapy. Metoprolol, sotalol, magnesium, amiodarone, statins, atrial pacing, and posterior pericardiotomy all reduce atrial fibrillation rates,24,27 with a non-significant trend towards a reduction in stroke rates.27 Thrombus formation in the left atrial appendage is presumed to be the cause of stroke from atrial fibrillation (appendix).30 Left atrial appendage closure with a range of percutaneous devices is under investigation to reduce stroke in non-surgical patients with atrial fibrillation.30 In cardiac surgery, some surgeons ligate the left atrial appendage if a thrombus is visible on intraoperative transoesophageal echo, or to reduce the stroke risk in patients with chronic (preoperative) atrial fibrillation. In patients with chronic atrial fibrillation, left atrial appendage ligation can also be combined with cryoablation or radiofrequency atrial ablation.31 A prospective trial showed a reduction in persistent postoperative atrial fibrillation, but not stroke rate at 1 year, following left atrial appendage ligation and atrial ablation.31 At present, left atrial appendage closure during cardiac surgery remains experimental.32
Occlusive cerebrovascular disease Concomitant cerebrovascular atherosclerotic disease increases stroke risk for cardiac surgery patients and raises several questions. First, what is the value of screening for atherosclerotic disease? Extracranial carotid disease is a risk factor for stroke after cardiac surgery, and a recent meta-analysis33 found that patients with 50–99% carotid stenosis, or occlusion, had a 7·4% perioperative stroke risk. After exclusion of those with symptomatic disease, carotid occlusion, or both, even asymptomatic patients with 50–99% stenosis had a 3·8% stroke risk. Ipsilateral stroke occurred in 2·0% of patients with an asymptomatic unilateral stenosis, whereas patients with bilateral asymptomatic stenoses had a 6·5% stroke risk. Intracranial cerebral atherosclerosis has been difficult to assess and is understudied. A recent magnetic resonance angiography study suggests that intracranial atherosclerosis independently increases post-CABG stroke risk.34 492
Second, does this increased stroke risk justify carotid intervention? If so, should carotid atherosclerotic disease be treated in advance of cardiac surgery or as part of a combined operative procedure? In the CREST trial35 patients (not undergoing cardiac surgery) with carotid atherosclerosis were randomly allocated to carotid artery stenting or endarterectomy; no difference in the primary composite endpoint of stroke, myocardial infarction, or death was recorded. The endarterectomy group had fewer strokes but more myocardial infarctions than the carotid artery stenting group. Prospective data are not available for cardiac surgery patients. Stenting necessitates dual antiplatelet therapy, and is typically not done as a combined procedure with cardiac surgery. However, its feasibility as a combined procedure has been reported.36 A retrospective study37 assessed 27 084 patients who underwent carotid stenting before CABG or carotid endarterectomy combined with CABG. Postoperative stroke occurred more often in the combined procedure group, although no significant difference in the composite risk for stroke and death was recorded between the two groups after adjustment for baseline comorbidities. Carotid endarterectomy can be done either before the cardiac surgery (ie, staged) or as a combined procedure with CABG as mentioned above. Shishehbor and colleagues38 analysed three groups of patients who had undergone staged carotid endarterectomy and CABG, combined carotid endarterectomy and CABG, or staged carotid artery stenting and CABG at one treatment centre. The patients who underwent staged carotid endarterectomy and CABG had the poorest outcomes because of myocardial infarction after the carotid endarterectomy. Staged carotid artery stenting and CABG and combined carotid endarterectomy and CABG had similar early outcomes, whereas the patients who underwent staged carotid artery stenting and CABG had better outcomes after 1 year than the other groups. A larger retrospective analysis39 of the Nationwide Inpatient Sample database showed no difference between staged versus combined carotid endarterectomy and CABG in terms of neurological complications or mortality. For now, the longstanding approach that the most symptomatic atherosclerotic vascular bed should be treated first still holds true, but prospective trials are needed. Existing guidelines recommend multidisciplinary assessment of patients with substantial carotid disease before cardiac surgery (class I, level C), carotid duplex screening for high-risk patients (class IIa, level C), and consideration of simultaneous or staged combined carotid and coronary revascularisation in patients with symptomatic carotid disease (class IIa, level C).2 In asymptomatic patients without previous stroke and with bilateral high-grade stenoses, or with unilateral high-grade stenosis and contralateral occlusion, carotid revascularisation “may be considered” (class IIa, level C). www.thelancet.com/neurology Vol 13 May 2014
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Aortic valve surgery Aortic valve replacement can be done as an open, minimally invasive, or catheter-based procedure. For transcatheter aortic valve implantation, the transcatheter device is inserted with a percutaneous endovascular approach or a cardiac transapical approach. This procedure is typically used in patients judged to be too high risk for conventional open replacement.40 The PARTNER trial41 compared patients randomised to transcatheter aortic valve implantation or open aortic valve replacement. The occurrence of all transient ischaemic attacks or strokes at 1 year was 8·7% for transcatheter aortic valve implantation and 4·3% for open aortic valve replacement (p=0·03); at 2 years, the frequency was 11·2% for transcatheter aortic valve implantation versus 6·5% for open aortic valve replacement (p=0·05). The occurrence of stroke alone was not statistically different between groups: 6·0% for transcatheter aortic valve implantation and 3·2% for open aortic valve replacement at 1 year (p=0·08). Mortality was roughly 25% at 1 year and 35% at 2 years in this high-risk patient population. Nonetheless, specific procedural strategies, such as implantation without valvuloplasty, and cerebral embolic protection devices have been proposed to decrease transcatheter aortic valve implantation-associated stroke risk.42 Patients are also typically treated with dual antiplatelet therapy after transcatheter aortic valve implantation, but comparative effectiveness data for various antithrombotic strategies are scarce at present.40 For valvular surgeries undertaken with minimally invasive or robotic techniques, outcomes are judged acceptable when compared with traditional techniques; however, few comparative data are available.43
Intraoperative management to minimise stroke Optimisation of blood pressure Several studies have attempted to define the optimum blood pressure that would result in the fewest neurological complications after cardiac surgery. Cardiac surgery patients randomised to a higher mean arterial pressure (80–100 mm Hg vs 50–60 mm Hg) had fewer neurological complications than the lower mean arterial pressure group in one trial.44 Indeed, in a subsequent trial,45 investigators recorded an association between intraoperative hypotension and the occurrence of neurological complications. Aronson and colleagues46 did a post-hoc analysis of perioperative blood pressure variability in more than 1500 patients from the ECLIPSE cardiac surgery trials—a combination of three prospective randomised parenteral antihypertensive drug treatment trials. They noted that systolic blood pressure variability was associated with 30-day mortality in proportion to the time spent outside a 75–135 mm Hg range intraoperatively and outside 85–145 mm Hg postoperatively, but whether these haemodynamic derangements actually contributed to increased mortality or whether they were merely surrogate markers for sicker patients is unclear. Another study showed less early cognitive dysfunction in cardiac www.thelancet.com/neurology Vol 13 May 2014
surgery patients randomly allocated to high (vs low) pressure cardiopulmonary bypass,47 but the small sample size limits definitive conclusions.48 Taken together, these studies suggest that maintenance of an intraoperative mean arterial pressure higher than 80 mm Hg might reduce neurological complications in cardiac surgery patients. Larger randomised trials will be needed to confirm this finding and to assess the occurrence of other complications associated with higher blood pressure during cardiopulmonary bypass. We discuss approaches to individualise cerebral perfusion pressure targets in the following sections.
Intraoperative cerebral monitoring Continuous global cerebral blood flow monitoring is not routinely available in the operating room; therefore, various surrogates for cerebral blood flow have been used in cardiac surgery. Continuous electroencephalographic monitoring, used to detect ischaemia-induced changes in brain electrical activity, can monitor large areas of the cortex but cannot detect focal cerebral ischaemia and is confounded by temperature effects during intraoperative hypothermia.49 However, the use of continuous electroencephalographic monitoring in critical care is increasing and could prove to be beneficial for ongoing monitoring of cerebral perfusion or subclinical seizures after cardiac surgery. Near-infrared spectroscopy, based on the differential absorption of light by oxygenated versus deoxygenated haemoglobin, is an attractive option for intraoperative cerebral perfusion monitoring.50,51 Cerebral desaturation events measured by near-infrared spectroscopy are associated with cognitive decline after cardiac surgery.52 In another study, investigators randomly allocated CABG patients to receive cerebral oximetry monitoring with an active treatment protocol for desaturation events, or to a control group with masked monitors.53 A lower occurrence of the composite endpoint of major morbidity or mortality was recorded in the active treatment group than in the control group, and a non-significant trend towards stroke reduction was also noted in the active treatment group. Ono and colleagues54 reported impaired cerebral autoregulation in 20% of cardiac surgery patients using combined monitoring with transcranial doppler and nearinfrared spectroscopy. These patients had increased perioperative stroke rates compared with those with intact autoregulation. The same group subsequently reported the validation of a standalone near-infrared spectroscopy monitor in measuring autoregulation,55 and recorded an association between time below the lower limit of autoregulation and perioperative morbidity after cardiac surgery.56 Although larger studies are needed to establish whether near-infrared spectroscopy perfusion or autoregulation monitoring, with personalised treatment protocols, decreases stroke or neurocognitive outcomes in cardiac surgery, the use of near-infrared spectroscopy might better guide us as to what would be the optimum blood pressure management for these patients. 493
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Hypothermic versus normothermic cardiopulmonary bypass Despite its frequent use, no proven benefit has been shown for cooling to below 32–34°C (mild hypothermia) during cardiopulmonary bypass.57–59 Several trials have shown that moderate hypothermia (28–32°C) during cardiopulmonary bypass does not change the rate of intraoperative cerebral emboli58 (as measured by transcranial Doppler) or the rate of stroke or cognitive decline.59 However, rewarming might be a source of cerebral injury, and recommendations are to rewarm slowly with avoidance of overshoot hyperthermia intraoperatively or postoperatively.60
Transoesophageal echocardiography and epiaortic ultrasound The amount of aortic atherosclerosis is strongly associated with perioperative stroke in cardiac surgery patients.2 Epiaortic ultrasound assessment of the aorta is superior to manual palpation or transoesophageal echocardiography assessment for detection of aortic atherosclerosis.61 Epiaortic ultrasound is an intuitive approach to detect and avoid embolising aortic atheroma, and it has a class IIa, level B recommendation from the American Heart Association.2 However, whether its use improves neurological outcomes is unclear because randomised trials are scarce.61 Such trials will be difficult to undertake in this area because of an absence of clinical equipoise; epiaortic ultrasound evaluation is believed to decrease stroke risk, and few risks are associated with its use.
Neuraxial analgesia Epidural analgesia has been shown to decrease thromboembolism and improve outcomes after noncardiac surgery.62 These findings have led to additional studies to establish whether epidural analgesia also improves outcomes in cardiac surgery. A meta-analysis indicated that thoracic epidural analgesia reduced supraventricular arrhythmias and respiratory complications in cardiac surgery patients, but did not reduce neurocognitive complications.63 However, the largest randomised trial so far showed no clinically relevant benefit of thoracic epidural analgesia in 654 cardiac surgery patients.64 Overall, thoracic epidural analgesia is used rarely in cardiac surgery because of the risk of epidural haematoma formation following high-dose heparinisation for cardiopulmonary bypass, and because of insufficient evidence for its benefit over routine care.
inferior to a liberal strategy targeting a level of 30% or higher; a 6% incidence of neurological complications was recorded in both groups.67 Current Society of Thoracic Surgeons guidelines68 recommend maintenance of haemoglobin concentration higher than 60 g/L (or 6 g/dL) on cardiopulmonary bypass and at least 70 g/L (or 7 g/dL) postoperatively (class IIa, level C), with individual adjustment as clinically indicated.2
Glycaemic control Impaired perioperative glycaemic control is associated with postoperative morbidity and mortality in some cardiac surgery trials.2 Recent data suggested that high preoperative glycosylated haemoglobin concentrations (≥6·5%) correlated with postoperative glycaemic variability after CABG.69 Furthermore, this postoperative glycaemic variability was associated with a composite of poor outcomes, including stroke, in a prospective cohort of 1461 patients.69 A prospective randomised trial showed that tight glycaemic control in patients in intensive care units (many of whom underwent cardiac surgery) resulted in a reduction in morbidity and mortality.70 Similarly, intraoperative hyperglycaemia has been associated with increased risk for neurocognitive injury in non-diabetic patients.71 Despite the consistent association between poor glycaemic control and morbidity and mortality after cardiac surgery, the aggregate tight glycaemic control studies have shown more harm than benefit. Lazar and colleagues showed that tight glycaemic control yields no demonstrable benefit and actually increases hypoglycaemic events.72 Two other studies also showed that tight glycaemic control during cardiac surgery does not improve neurological outcomes,73,74 and the NICE-SUGAR trial of more than 6000 critical care patients showed an association between hypoglycaemic episodes (because of tight glycaemic control) and increased mortality.75 Existing recommendations therefore suggest that blood glucose should be maintained at less than 9·99 mmol/L during and after cardiac surgery (class I, level B).2
Treatment of acute ischaemic stroke in the perioperative setting Existing stroke guidelines recommend avoidance of systemic thrombolysis within 14 days of major surgery,76 thus precluding the use of intravenous alteplase in most cases of stroke after cardiovascular surgery. Localised intraarterial thrombolysis has been described with acceptable safety in this setting in one small case series77 (panel 2).
Haemodilution and transfusion Extreme intraoperative haemodilution (haematocrit
Neurological complications of cardiac surgery David L McDonagh, Miles Berger, Joseph P Mathew, Carmelo Graffagnino, Carmelo A Milano, Mark F Newman Lancet Neurol 2014; 13: 490–502 Published Online April 2, 2014 http://dx.doi.org/10.1016/ S1474-4422(14)70004-3 See Online for an audio interview with David McDonagh and Mark Newman Department of Anesthesiology (D L McDonagh MD, M Berger MD, Prof J P Mathew MD, Prof M F Newman MD), Department of Neurology (D L McDonagh, Prof C Graffagnino MD), and Department of Surgery (Division of Cardiovascular and Thoracic Surgery) (C A Milano MD), Duke University Medical Center, Durham, NC, USA Correspondence to: Dr David L McDonagh, Department of Anesthesiology, Duke University Medical Center, DUMC Box 3094, Durham, NC 27710, USA [email protected]
For the risk calculator see http://riskcalc.sts.org/ STSWebRiskCalc273/
For the European System for Cardiac Operative Risk Evaluation see http://www. euroscore.org/calc.html
490
As increasing numbers of elderly people undergo cardiac surgery, neurologists are frequently called upon to assess patients with neurological complications from the procedure. Some complications mandate acute intervention, whereas others need longer term observation and management. A large amount of published literature exists about these complications and guidance on best practice is constantly changing. Similarly, despite technological advances in surgical intervention and modifications in surgical technique to make cardiac procedures safer, these advances often create new avenues for neurological injury. Accordingly, rapid and precise neurological assessment and therapeutic intervention rests on a solid understanding of the evidence base and procedural variables.
Introduction Neurological complications have been a major concern throughout the history of cardiac surgery.1 Advances in technology and technique have led to open, minimally invasive, and endovascular therapeutics to repair vascular, valvular, and myocardial pathology. Coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI) are now completed more safely than they ever have been.2–4 Despite these advances, neurological complications, including ischaemic stroke,5 delirium, and cognitive decline, still occur frequently. In this Review, we focus on the neurological complications of cerebral thromboembolism, including risk assessment, comparative risk of cardiac interventions, approaches to minimise perioperative thromboembolic events, and acute stroke therapies. Wherever possible, we have specified the level of evidence available for each intervention according to the joint American College of Cardiology Foundation and American Heart Association classification (level A, B, or C and class I, IIa, or IIb).2 Ischaemic stroke is one of the most feared complications of cardiac surgery and carries high morbidity and mortality; therefore, much of our Review focuses on this topic, but we also discuss hypoxic ischaemic cerebral injury, acute therapy, neurocognitive complications, and future directions in the specialty.
Management of perioperative risk for ischaemic stroke Assessment of risk Ischaemic stroke related to perioperative cerebral thromboembolic or hypoperfusion injury is a wellrecognised complication of cardiovascular surgery. However, advances in perioperative medical and surgical care have progressively reduced stroke rates following primary CABG.3,6 Recent studies report post-CABG stroke rates of 1–5%,3,7–9 although patients with diabetes have a higher post-CABG stroke risk (5·2% at 5 years).8 However, valvular surgery carries an even higher risk for perioperative stroke, which is potentially attributable to increases in particulate and air embolisation.10 In a prospective series of more than 16 000 cardiac surgery patients, which followed up patients for a mean of 11·7 days, the short-term stroke risk was 4·8% after isolated aortic valve replacement, 8·8% after mitral valve replacement, and 9·7% after multivalve
surgery.10 CABG was associated with a 3·8% stroke risk, and CABG plus valve surgery with a 7·4% risk.10 The absence of standardised care across surgeons or institutions could explain the varying neurological complication rates among different studies. Perioperative strokes can be divided into two categories: early perioperative stroke, which is present at extubation (mainly intraoperative); and late perioperative stroke, which occurs postextubation (postoperative). Tarakji and colleagues3 studied more than 45 000 cardiac surgical patients treated over 28 years at the Cleveland Clinic (OH, USA) and reported that some risk factors were associated with both early and late stroke, whereas others were associated with only one type of stroke (panel 1). On-pump procedures with hypothermic circulatory arrest carried the highest early stroke risk, whereas off-pump CABG and onpump beating heart CABG were associated with the lowest risk of early stroke. New-onset postoperative atrial fibrillation was not associated with postoperative stroke in this study.3 Hedberg and colleagues11 also reported unique risk factors associated with intraoperative versus postoperative strokes (panel 1). Although they showed that different risk factors were associated with early and late stroke, these studies suggest that early and late perioperative strokes might arise from different pathophysiological processes. The Society of Thoracic Surgeons has created an online risk calculator for postsurgical complications. This calculator uses three risk models for CABG, valve surgery, and the combination of CABG plus valve surgery. Based on demographics, comorbidities, laboratory and cardiac diagnostic data, and procedural variables, the risk for nine clinical endpoints (mortality, morbidity or mortality, long length of stay, short length of stay, permanent stroke, prolonged ventilation, deep sternal wound infection, renal failure, and reoperation) can be calculated. The European System for Cardiac Operative Risk Evaluation is also used frequently to establish a patient’s mortality risk after cardiac surgery, but it does not specifically assess the risk for neurological injury.
Planning of interventions for coronary artery disease: CABG versus PCI Recent studies have compared the effectiveness of CABG with that of PCI for the treatment of coronary disease, and www.thelancet.com/neurology Vol 13 May 2014
Review
the neurological complication rates after each procedure type. In the SYNTAX trial12,13 investigators randomly allocated patients with three-vessel or left main disease to CABG or PCI with drug-eluting stents. Patients in the CABG group had more strokes, but fewer combined major adverse cardiac and cerebrovascular events (the primary composite endpoint), than did those in the PCI group.13 In the FREEDOM trial, patients with diabetes and multivessel coronary disease were randomly assigned to CABG or PCI.8 This study also showed higher stroke rates in the CABG group than in the PCI group (5·2% vs 2·4%; p=0·03), although the composite primary 5-year endpoint of death, stroke, or myocardial infarction occurred less frequently in the CABG group than in the PCI group. Finally, the ASCERT study retrospectively compared CABG with PCI,14 and recorded lower 4-year mortality with CABG than with PCI (stroke data not yet published). The findings of these three studies are consistent with a previous meta-analysis that showed a trend towards survival benefit from CABG.15 As emphasised in a recent systematic review,16 these studies consistently show that CABG is superior to PCI in terms of mortality and overall composite endpoints, even though CABG is associated with a higher perioperative stroke risk. Nonetheless, the decision to undertake CABG or PCI should be made collaboratively (the so-called heart team approach) by cardiac surgeons and cardiologists16,17 on the basis of an assessment of an individual patient’s coronary disease pattern, comorbidities, and perioperative stroke risk.
Off-pump surgery versus cardiopulmonary bypass Neurocognitive complications of cardiac surgery have historically been attributed to embolic events and inflammatory responses related to cardiopulmonary bypass.2 However, a systematic review published in 2005 suggested no difference in stroke or death at 30 days following on-pump compared with off-pump CABG.18 Several studies have since randomly allocated CABG patients to undergo cardiopulmonary bypass or off-pump surgery, and have consistently shown no difference in stroke rates, neurocognitive outcomes, or composite outcomes, including mortality.9,19,20 In fact, the increased cerebral emboli detected during cardiopulmonary bypass have mostly not correlated with neurocognitive injury.2,21 Although undesirable, their clinical significance is unclear. These studies suggest that cardiopulmonary bypass alone does not contribute to perioperative stroke. Since neurological outcomes are similar after on-pump and off-pump CABG, procedure choice should be decided by surgical expertise, vascular anatomy, and patient-related variables. For example, the use of off-pump surgery has technical limitations and it is associated with an increased risk of early coronary revascularisation.19
Pharmacological therapies to reduce risk Aspirin, initiated preoperatively or within 6 h postoperatively, is standard care in cardiac surgery.2 The www.thelancet.com/neurology Vol 13 May 2014
Panel 1: Risk factors for early and late stroke following cardiovascular surgery3,11 Early or intraoperative stroke • Peripheral and carotid vascular disease • Previous cardiac surgery • Poor baseline clinical condition • Left ventricular dysfunction • Circumflex stenosis >70% • On-pump arrested-heart coronary artery bypass grafting • On-pump coronary artery bypass grafting with hypothermic circulatory arrest • Preoperative creatinine elevation • Aortic atherosclerosis • Longer time on cardiopulmonary bypass • Older age Late or postoperative stroke • Left main stenosis • Diabetes • Low use of thoracic artery grafting • Historically earlier date of operation • Female sex • Unstable angina • Postoperative atrial fibrillation • Inotropic support Both early and late stroke • Older age • Lower body surface area • Preoperative atrial fibrillation • Previous stroke • On-pump coronary artery bypass grafting with hypothermic circulatory arrest
Multicenter Study of Perioperative Ischemia reported a 50% reduction in perioperative stroke (1·3% vs 2·6%; p=0·01) if aspirin was given within 48 h of revascularisation.22 A recent meta-analysis23 of preoperative statin therapy trials showed that statin use in CABG surgery (or CABG plus valve surgery) reduces postoperative atrial fibrillation, shortens hospital stay, and, contrary to a smaller meta-analysis in 2012,24 reduces stroke and mortality. Furthermore, concern exists that statin withdrawal after cardiac surgery might be injurious (associated with increased in-hospital mortality).25 Thus, statins should be administered to reduce both perioperative stroke and non-neurological complications (class 1, level A recommendation).2
Atrial fibrillation Atrial fibrillation occurs in up to half of patients after CABG, most often on postoperative day 2.2 Preoperative atrial fibrillation is a risk factor for both early and late postoperative stroke;3,26 postoperative atrial fibrillation is associated with late postoperative stroke.11,26 Notably, the recent analysis by Tarakji and colleagues3 did not associate 491
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postoperative atrial fibrillation with postoperative stroke, which perhaps shows the efficacy of aggressive anticoagulation, early cardioversion treatments, or both, in current practice. Many trials in cardiac surgery have sought to reduce stroke caused by postoperative atrial fibrillation with various interventions, such as posterior pericardiotomy, or pharmacotherapies.27 n-3 polyunsaturated fatty acids have been the focus of many cardiac surgery trials, but neither the largest prospective trial28 nor a meta-analysis of eight randomised trials,29 showed that these fatty acids reduce postoperative atrial fibrillation or adverse outcomes.29 β blockers carry a class I, level B recommendation2 for reducing the incidence of atrial fibrillation; amiodarone is regarded as second-tier therapy. Metoprolol, sotalol, magnesium, amiodarone, statins, atrial pacing, and posterior pericardiotomy all reduce atrial fibrillation rates,24,27 with a non-significant trend towards a reduction in stroke rates.27 Thrombus formation in the left atrial appendage is presumed to be the cause of stroke from atrial fibrillation (appendix).30 Left atrial appendage closure with a range of percutaneous devices is under investigation to reduce stroke in non-surgical patients with atrial fibrillation.30 In cardiac surgery, some surgeons ligate the left atrial appendage if a thrombus is visible on intraoperative transoesophageal echo, or to reduce the stroke risk in patients with chronic (preoperative) atrial fibrillation. In patients with chronic atrial fibrillation, left atrial appendage ligation can also be combined with cryoablation or radiofrequency atrial ablation.31 A prospective trial showed a reduction in persistent postoperative atrial fibrillation, but not stroke rate at 1 year, following left atrial appendage ligation and atrial ablation.31 At present, left atrial appendage closure during cardiac surgery remains experimental.32
Occlusive cerebrovascular disease Concomitant cerebrovascular atherosclerotic disease increases stroke risk for cardiac surgery patients and raises several questions. First, what is the value of screening for atherosclerotic disease? Extracranial carotid disease is a risk factor for stroke after cardiac surgery, and a recent meta-analysis33 found that patients with 50–99% carotid stenosis, or occlusion, had a 7·4% perioperative stroke risk. After exclusion of those with symptomatic disease, carotid occlusion, or both, even asymptomatic patients with 50–99% stenosis had a 3·8% stroke risk. Ipsilateral stroke occurred in 2·0% of patients with an asymptomatic unilateral stenosis, whereas patients with bilateral asymptomatic stenoses had a 6·5% stroke risk. Intracranial cerebral atherosclerosis has been difficult to assess and is understudied. A recent magnetic resonance angiography study suggests that intracranial atherosclerosis independently increases post-CABG stroke risk.34 492
Second, does this increased stroke risk justify carotid intervention? If so, should carotid atherosclerotic disease be treated in advance of cardiac surgery or as part of a combined operative procedure? In the CREST trial35 patients (not undergoing cardiac surgery) with carotid atherosclerosis were randomly allocated to carotid artery stenting or endarterectomy; no difference in the primary composite endpoint of stroke, myocardial infarction, or death was recorded. The endarterectomy group had fewer strokes but more myocardial infarctions than the carotid artery stenting group. Prospective data are not available for cardiac surgery patients. Stenting necessitates dual antiplatelet therapy, and is typically not done as a combined procedure with cardiac surgery. However, its feasibility as a combined procedure has been reported.36 A retrospective study37 assessed 27 084 patients who underwent carotid stenting before CABG or carotid endarterectomy combined with CABG. Postoperative stroke occurred more often in the combined procedure group, although no significant difference in the composite risk for stroke and death was recorded between the two groups after adjustment for baseline comorbidities. Carotid endarterectomy can be done either before the cardiac surgery (ie, staged) or as a combined procedure with CABG as mentioned above. Shishehbor and colleagues38 analysed three groups of patients who had undergone staged carotid endarterectomy and CABG, combined carotid endarterectomy and CABG, or staged carotid artery stenting and CABG at one treatment centre. The patients who underwent staged carotid endarterectomy and CABG had the poorest outcomes because of myocardial infarction after the carotid endarterectomy. Staged carotid artery stenting and CABG and combined carotid endarterectomy and CABG had similar early outcomes, whereas the patients who underwent staged carotid artery stenting and CABG had better outcomes after 1 year than the other groups. A larger retrospective analysis39 of the Nationwide Inpatient Sample database showed no difference between staged versus combined carotid endarterectomy and CABG in terms of neurological complications or mortality. For now, the longstanding approach that the most symptomatic atherosclerotic vascular bed should be treated first still holds true, but prospective trials are needed. Existing guidelines recommend multidisciplinary assessment of patients with substantial carotid disease before cardiac surgery (class I, level C), carotid duplex screening for high-risk patients (class IIa, level C), and consideration of simultaneous or staged combined carotid and coronary revascularisation in patients with symptomatic carotid disease (class IIa, level C).2 In asymptomatic patients without previous stroke and with bilateral high-grade stenoses, or with unilateral high-grade stenosis and contralateral occlusion, carotid revascularisation “may be considered” (class IIa, level C). www.thelancet.com/neurology Vol 13 May 2014
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Aortic valve surgery Aortic valve replacement can be done as an open, minimally invasive, or catheter-based procedure. For transcatheter aortic valve implantation, the transcatheter device is inserted with a percutaneous endovascular approach or a cardiac transapical approach. This procedure is typically used in patients judged to be too high risk for conventional open replacement.40 The PARTNER trial41 compared patients randomised to transcatheter aortic valve implantation or open aortic valve replacement. The occurrence of all transient ischaemic attacks or strokes at 1 year was 8·7% for transcatheter aortic valve implantation and 4·3% for open aortic valve replacement (p=0·03); at 2 years, the frequency was 11·2% for transcatheter aortic valve implantation versus 6·5% for open aortic valve replacement (p=0·05). The occurrence of stroke alone was not statistically different between groups: 6·0% for transcatheter aortic valve implantation and 3·2% for open aortic valve replacement at 1 year (p=0·08). Mortality was roughly 25% at 1 year and 35% at 2 years in this high-risk patient population. Nonetheless, specific procedural strategies, such as implantation without valvuloplasty, and cerebral embolic protection devices have been proposed to decrease transcatheter aortic valve implantation-associated stroke risk.42 Patients are also typically treated with dual antiplatelet therapy after transcatheter aortic valve implantation, but comparative effectiveness data for various antithrombotic strategies are scarce at present.40 For valvular surgeries undertaken with minimally invasive or robotic techniques, outcomes are judged acceptable when compared with traditional techniques; however, few comparative data are available.43
Intraoperative management to minimise stroke Optimisation of blood pressure Several studies have attempted to define the optimum blood pressure that would result in the fewest neurological complications after cardiac surgery. Cardiac surgery patients randomised to a higher mean arterial pressure (80–100 mm Hg vs 50–60 mm Hg) had fewer neurological complications than the lower mean arterial pressure group in one trial.44 Indeed, in a subsequent trial,45 investigators recorded an association between intraoperative hypotension and the occurrence of neurological complications. Aronson and colleagues46 did a post-hoc analysis of perioperative blood pressure variability in more than 1500 patients from the ECLIPSE cardiac surgery trials—a combination of three prospective randomised parenteral antihypertensive drug treatment trials. They noted that systolic blood pressure variability was associated with 30-day mortality in proportion to the time spent outside a 75–135 mm Hg range intraoperatively and outside 85–145 mm Hg postoperatively, but whether these haemodynamic derangements actually contributed to increased mortality or whether they were merely surrogate markers for sicker patients is unclear. Another study showed less early cognitive dysfunction in cardiac www.thelancet.com/neurology Vol 13 May 2014
surgery patients randomly allocated to high (vs low) pressure cardiopulmonary bypass,47 but the small sample size limits definitive conclusions.48 Taken together, these studies suggest that maintenance of an intraoperative mean arterial pressure higher than 80 mm Hg might reduce neurological complications in cardiac surgery patients. Larger randomised trials will be needed to confirm this finding and to assess the occurrence of other complications associated with higher blood pressure during cardiopulmonary bypass. We discuss approaches to individualise cerebral perfusion pressure targets in the following sections.
Intraoperative cerebral monitoring Continuous global cerebral blood flow monitoring is not routinely available in the operating room; therefore, various surrogates for cerebral blood flow have been used in cardiac surgery. Continuous electroencephalographic monitoring, used to detect ischaemia-induced changes in brain electrical activity, can monitor large areas of the cortex but cannot detect focal cerebral ischaemia and is confounded by temperature effects during intraoperative hypothermia.49 However, the use of continuous electroencephalographic monitoring in critical care is increasing and could prove to be beneficial for ongoing monitoring of cerebral perfusion or subclinical seizures after cardiac surgery. Near-infrared spectroscopy, based on the differential absorption of light by oxygenated versus deoxygenated haemoglobin, is an attractive option for intraoperative cerebral perfusion monitoring.50,51 Cerebral desaturation events measured by near-infrared spectroscopy are associated with cognitive decline after cardiac surgery.52 In another study, investigators randomly allocated CABG patients to receive cerebral oximetry monitoring with an active treatment protocol for desaturation events, or to a control group with masked monitors.53 A lower occurrence of the composite endpoint of major morbidity or mortality was recorded in the active treatment group than in the control group, and a non-significant trend towards stroke reduction was also noted in the active treatment group. Ono and colleagues54 reported impaired cerebral autoregulation in 20% of cardiac surgery patients using combined monitoring with transcranial doppler and nearinfrared spectroscopy. These patients had increased perioperative stroke rates compared with those with intact autoregulation. The same group subsequently reported the validation of a standalone near-infrared spectroscopy monitor in measuring autoregulation,55 and recorded an association between time below the lower limit of autoregulation and perioperative morbidity after cardiac surgery.56 Although larger studies are needed to establish whether near-infrared spectroscopy perfusion or autoregulation monitoring, with personalised treatment protocols, decreases stroke or neurocognitive outcomes in cardiac surgery, the use of near-infrared spectroscopy might better guide us as to what would be the optimum blood pressure management for these patients. 493
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Hypothermic versus normothermic cardiopulmonary bypass Despite its frequent use, no proven benefit has been shown for cooling to below 32–34°C (mild hypothermia) during cardiopulmonary bypass.57–59 Several trials have shown that moderate hypothermia (28–32°C) during cardiopulmonary bypass does not change the rate of intraoperative cerebral emboli58 (as measured by transcranial Doppler) or the rate of stroke or cognitive decline.59 However, rewarming might be a source of cerebral injury, and recommendations are to rewarm slowly with avoidance of overshoot hyperthermia intraoperatively or postoperatively.60
Transoesophageal echocardiography and epiaortic ultrasound The amount of aortic atherosclerosis is strongly associated with perioperative stroke in cardiac surgery patients.2 Epiaortic ultrasound assessment of the aorta is superior to manual palpation or transoesophageal echocardiography assessment for detection of aortic atherosclerosis.61 Epiaortic ultrasound is an intuitive approach to detect and avoid embolising aortic atheroma, and it has a class IIa, level B recommendation from the American Heart Association.2 However, whether its use improves neurological outcomes is unclear because randomised trials are scarce.61 Such trials will be difficult to undertake in this area because of an absence of clinical equipoise; epiaortic ultrasound evaluation is believed to decrease stroke risk, and few risks are associated with its use.
Neuraxial analgesia Epidural analgesia has been shown to decrease thromboembolism and improve outcomes after noncardiac surgery.62 These findings have led to additional studies to establish whether epidural analgesia also improves outcomes in cardiac surgery. A meta-analysis indicated that thoracic epidural analgesia reduced supraventricular arrhythmias and respiratory complications in cardiac surgery patients, but did not reduce neurocognitive complications.63 However, the largest randomised trial so far showed no clinically relevant benefit of thoracic epidural analgesia in 654 cardiac surgery patients.64 Overall, thoracic epidural analgesia is used rarely in cardiac surgery because of the risk of epidural haematoma formation following high-dose heparinisation for cardiopulmonary bypass, and because of insufficient evidence for its benefit over routine care.
inferior to a liberal strategy targeting a level of 30% or higher; a 6% incidence of neurological complications was recorded in both groups.67 Current Society of Thoracic Surgeons guidelines68 recommend maintenance of haemoglobin concentration higher than 60 g/L (or 6 g/dL) on cardiopulmonary bypass and at least 70 g/L (or 7 g/dL) postoperatively (class IIa, level C), with individual adjustment as clinically indicated.2
Glycaemic control Impaired perioperative glycaemic control is associated with postoperative morbidity and mortality in some cardiac surgery trials.2 Recent data suggested that high preoperative glycosylated haemoglobin concentrations (≥6·5%) correlated with postoperative glycaemic variability after CABG.69 Furthermore, this postoperative glycaemic variability was associated with a composite of poor outcomes, including stroke, in a prospective cohort of 1461 patients.69 A prospective randomised trial showed that tight glycaemic control in patients in intensive care units (many of whom underwent cardiac surgery) resulted in a reduction in morbidity and mortality.70 Similarly, intraoperative hyperglycaemia has been associated with increased risk for neurocognitive injury in non-diabetic patients.71 Despite the consistent association between poor glycaemic control and morbidity and mortality after cardiac surgery, the aggregate tight glycaemic control studies have shown more harm than benefit. Lazar and colleagues showed that tight glycaemic control yields no demonstrable benefit and actually increases hypoglycaemic events.72 Two other studies also showed that tight glycaemic control during cardiac surgery does not improve neurological outcomes,73,74 and the NICE-SUGAR trial of more than 6000 critical care patients showed an association between hypoglycaemic episodes (because of tight glycaemic control) and increased mortality.75 Existing recommendations therefore suggest that blood glucose should be maintained at less than 9·99 mmol/L during and after cardiac surgery (class I, level B).2
Treatment of acute ischaemic stroke in the perioperative setting Existing stroke guidelines recommend avoidance of systemic thrombolysis within 14 days of major surgery,76 thus precluding the use of intravenous alteplase in most cases of stroke after cardiovascular surgery. Localised intraarterial thrombolysis has been described with acceptable safety in this setting in one small case series77 (panel 2).
Haemodilution and transfusion Extreme intraoperative haemodilution (haematocrit
![[Psychiatric and neurological complications associated with cardiac surgery (author's transl)].](/assets/img/hold.png)
