Clinical manifestations

Presentation and course

Neurologic complications of heart transplantation.

The main neurologic complications of cardiac transplantation are:

• Ischemic stroke • Seizure • Opportunistic infections • Post-transplantation lymphoproliferative disorders

Cerebrovascular events occurring soon after transplantation resemble those seen after valvular or coronary revascularization surgery. The risk factors include hypotension, cardioembolism, seizures, metabolic disturbances, and medication side effects. In a series of 322 patients, preexisting valvular heart disease was associated with ischemic stroke, whereas diabetes and renal failure were associated with seizures (96).

Circulatory support systems, such as left ventricular assist device or total artificial heart used during cardiac transplantation, are thrombogenic and may cause cerebral embolism (126).

Other embolic sources may persist after cardiac transplant, particularly in the aortic arch and the cervical vessels. Neurologic complications in the following weeks to months include opportunistic infections, side effects of immunosuppressants, and post-transplantation lymphoproliferative disorders.

Neurologic complications of coronary artery bypass graft surgery.

	• Central nervous system complications
		- Ischemic stroke and transient ischemic attack - Depressed level of alertness - Altered awareness - Seizure - Asymptomatic embolism
	• Peripheral nervous system complications
		- Brachial plexus injury - Phrenic nerve injury

Ischemic stroke. Experience at a single center including 45,432 patients who underwent coronary artery bypass graft revealed that perioperative stroke rate has declined over the last 30 years. Ischemic stroke occurs more commonly postoperatively than intraoperatively. Intraoperative stroke rates were lowest with off-pump coronary artery bypass graft (0.14%) and on-pump beating-heart coronary artery bypass graft (0%) and highest with on-pump coronary artery bypass graft with hypothermic circulatory arrest (5.3%) (125).

Brain MRI detects more ischemic lesions than head CT. The most common neuroimaging pattern is of multiple embolic punctate infarcts in the cerebral and cerebellar cortex, including in patients with encephalopathy without focal neurologic findings (135).

Microembolic perioperative stroke occurs more often in the border zone areas, but also in subcortical regions resembling lacunar lesions (54; 73; 70).

Lesions in the border between middle cerebral arteries and posterior cerebral arteries can cause visual field defect and transcortical sensory aphasia. Lesions in the border between middle cerebral arteries and anterior cerebral arteries can cause proximal-dominant weakness of extremities (man in the barrel syndrome) and transcortical motor aphasia. Lesions in the border between superficial and deep branches of middle cerebral arteries may present as mutism and rigidity. Watershed infarct of cerebellum can present as dizziness or vertigo, and ataxia (53; 48).

Watershed infarct can also occur in spinal cord, often at the midthoracic level between the spinal arteries territory and artery of Adamkiewicz territory. It can present with acute urinary retention, flaccid paraparesis, and sensory loss with level (48).

Of interest is the timing of surgery in patients with both carotid artery stenosis and coronary artery disease. In simultaneous surgery, the rate of stroke was higher but mortality was similar compared to staged surgery-carotid artery stenosis first, followed by coronary artery bypass graft for myocardial ischemia. However, there were no significant differences in 1-year mortality, and rates of myocardial infarction and transient ischemic attacks (25).

Depressed level of alertness. Decreased consciousness is seen in diffuse encephalopathy. Somnolence occurs if the patient is fully attentive to surroundings while aroused, but alertness decreases rapidly to a sleep-like state. Brief arousal associated with decreased awareness or interest to surroundings is called obtundation. Decreased alertness associated with grimacing or withdrawal from painful stimuli characterizes stupor.

Presence of sleep-wake cycle characterizes the vegetative state. Chewing, teeth grinding, or scratching movements can occur. Persistent vegetative state lasts longer than 4 weeks, and it becomes permanent after 3 months.

The comatose patient is not arousable, but the brainstem reflexes are preserved.

Brain death is characterized by absence of alertness to external stimuli and of all brainstem reflexes.

Nonconvulsive status epilepticus must be excluded in patients with altered alertness. Electrolyte imbalance, acute liver or renal dysfunctions, hypoxia, or hypotension should also be considered. Stroke does not usually affect alertness unless it involves the reticular activating system. Large hemorrhagic or ischemic strokes can decrease alertness by increasing intracranial pressure.

Altered awareness. Confusion is characterized by normal alertness, but altered awareness, orientation, or memory. Restlessness or agitation are typical for delirium. Together, they cause cognitive impairment.

Approximately half of the coronary artery bypass graft procedures result in early cognitive impairment. Improvement occurs within 6 months, but in one third of cases, the deficits may persist up to 12 months (87). Two thirds of patients have complete resolution of neurologic deficits during long-term follow-up (68). Delayed cognitive impairment may occur after 5 years (88).

Prior stroke is a risk factor for delirium after coronary artery bypass surgery (105). MRI imaging in patients with cognitive impairment can reveal multiple small brain lesions (67).

The cognitive impairment may be related to cerebral microembolism, hypoperfusion, edema, inflammation, or metabolic derangements.

The levels of tau protein and neurofilament light protein, specific markers for neuronal injury, may help predict the risk of delirium (107; 23). Tau protein level improves with the clinical status of the patient (06).

Seizure. Incidence of seizures after cardiopulmonary bypass is about 3% (39). Etiology is multifactorial, including stroke, air embolism, atherosclerotic debris, release of inflammatory mediators during surgery, and exposure to potentially epileptogenic medications such as antifibrinolytics and cephalosporin antibiotics.

Asymptomatic embolism. Asymptomatic embolism occurs frequently during coronary artery bypass and endovascular procedures (42). These lesions may not be truly asymptomatic because silent infarcts are associated with memory loss or dementia.

Brachial plexus injury and mononeuropathies. Brachial plexus injury and mononeuropathy may occur after compression or stretching during surgery. The lower trunk of brachial plexus is more vulnerable than the upper trunk. Injury to the phrenic nerves with unilateral or bilateral diaphragmatic paralysis may result from direct manipulation of the nerve, ischemia, or cold cardioplegia (33; 59).

Neurologic complications of left heart catheterization.

	• Central nervous system complications
		- Ischemic stroke and transient ischemic attack - Altered awareness (delirium) - Depressed level of alertness (transient unresponsiveness) - Transient global amnesia - Seizure - Contrast reaction - Migraine
	• Peripheral nervous system complications
		- Lumbosacral plexopathy - Femoral nerve injury

CNS complications after left heart catheterization are rare. Ischemic stroke occurs most commonly (55%), followed by transient ischemic attack (26%), contrast reaction (15%), and neurologic symptoms of unknown etiology (4%). The most common symptom is visual disturbances including diplopia and visual loss. Hemiparesis with or without aphasia, facial weakness with or without aphasia/dysarthria, and paresis in face and arm were also described. Transient unresponsiveness, transient global amnesia, seizures, delirium, and migraine may follow left heart catheterization.

Ischemic stroke caused by large vessel occlusion has worse outcome compared with small vessel occlusion (110). Cerebral embolism likely results from dislodging debris from atheromatous aortic arch or clots forming at the catheter tip.

Femoral nerve injury. Femoral artery puncture can rarely cause pseudoaneurysm, hematoma, arteriovenous fistula, and femoral artery occlusion. Femoral nerve compression (incidence of 0.2%) severity ranges from mild transient sensory neuropathy to disabling paralysis. Average delay from catheterization to recognition of symptoms is 37 hours; severe pain precedes the diagnosis of neuropathy in about half of patients. Although initially disabling, the neuropathy usually resolves completely; surgery is only recommended if there are coexisting complications (62).

Lumbosacral plexopathy. Retroperitoneal hematomas can cause lumbosacral plexopathy, with femoral and obturator nerves being primarily involved. The size of the hematoma does not correlate with the severity of the sensory or motor deficits.

Neurologic complications of other cardiac procedures.

Aortic aneurysm repair.

• Ischemic stroke or transient ischemic attack

Aneurysms of the aortic arch are often treated by surgery. In a series of 284 patients undergoing aortic aneurysm repair, death or stroke occurred in 6.6% (123). Transient neurologic dysfunction occurred in 9.2%. Two patients developed brachial plexus injury from axillary artery cannulation. In another report of 103 patients undergoing total aortic arch replacement, about 9% developed stroke, and approximately 7% had transient neurologic deficits. Four percent also had paraparesis or paraplegia (130).

Hypothermic circulatory arrest and selective cerebral perfusion are used to minimize these complications. In a series of 39 consecutive patients undergoing aortic arch replacement surgery with selective brain perfusion by axillary artery cannulation, only 1 patient had a permanent postoperative neurologic deficit, and 2 patients had temporary deficits (116).

In a metaanalysis of 3000 patients who underwent frozen elephant technique for type A aortic dissection repair aortic, the pooled rates of adverse events were 4.7% for spinal cord stroke, 7.6% for cerebral stroke, and 8.8% for perioperative mortality. Spinal cord ischemia was significantly higher when the length of graft exceeded 15 cm or extended beyond T8 (98).

Cardiac valve surgery.

	• Ischemic stroke or transient ischemic attack
	• Seizure
	• Vasovagal syncope

Heart valve repair and replacement have been performed for several decades. The incidence of neurologic complications after heart valve surgery is less documented in the literature compared to the complications after coronary artery bypass surgery.

Balloon valvuloplasty of the aortic and mitral valves is an effective and safe alternative to open heart surgery. Of 674 patients enrolled in the National Heart Lung and Blood institute (NHLBI) registry who underwent percutaneous aortic balloon valvuloplasty, 2% had strokes, 5% had seizures, 2% had vasovagal syncope, and 0.6% developed transient neurologic deficits in the peri-procedural period (89).

In severe symptomatic aortic stenosis, valve replacement is recommended. In a single center retrospective analysis of 132 patients undergoing aortic valve replacement for aortic stenosis and poor left ventricular function, there were no strokes, suggesting that it is a safe and effective procedure (26).

Transcatheter aortic valve replacement is less invasive and used for symptomatic aortic stenosis with high surgical risk. In a metanalysis and systematic review, in patients with low and intermediate risk, transcatheter aortic valve replacement had a similar rate of neurologic complications and mortality, a lower risk of acute myocardial infarction and acute kidney failure, but a higher risk of arterial complications (131). Similarly, in another matanalysis and systematic review of patients with low risk, transcatheter aortic valve replacement and surgical aortic valve replacement had similar neurologic risks (106).

Mitral valve repair or replacement is indicated if nonfunctional. In a database of 1250 patients, the incidence of stroke after mitral valve surgery was 4.2% to 5% (40; 127).

Balloon mitral valvuloplasty is an alternative to open surgery for mitral stenosis. In a study of 45 patients, only 1 patient had a postprocedural stroke (128). Of 201 consecutive patients undergoing this procedure, 3 developed “thromboembolism.” It is not clear whether these patients developed strokes (136).

Combined procedures such as double-valve replacements or valve replacement with coronary artery bypass graft surgery increase the risk of neurologic complications. In a review of 2008 patients undergoing valve surgery, the overall risk of stroke was 2.2%. However, with combined procedures, the risk was 5.4%. The risk factors were calcified ascending aortic atherosclerosis, advanced age, diabetes, and ejection fraction less than 30%. Stroke increased hospital mortality from 4.6% to 24% (36).

Subcortical lesions were seen on brain MRI after valve replacement surgery and were associated with alteration in memory, attention, and information processing speed. In this study, all cognitive impairments resolved after 4 months (67).

Endovascular valve replacement is increasingly performed in those with high perioperative risks for traditional open-heart surgery, leading to increased incidence of neurologic complications.

New, often multiple, restricted diffusion lesions on MRI of brain were observed in 27 patients (84%) undergoing endovascular aortic valve replacement (57). In another study of high-risk patients, 1-year mortality rate was similar between transcatheter valve replacement group and surgical group, but major vascular complications were more frequent in transcatheter group. Incidence of major stroke at 1 year after procedure was higher in the transcatheter group (5.1% vs. 2.4%) (119).

Recurrent neurologic events may result from paradoxical embolism through patent foramen ovale. Procedure and device related complications included groin and retroperitoneal hematomas, nerve injury, and also atrial fibrillation.

Serious adverse events occurred in 21.6% of the patients in the medical therapy group and 23.0% of the patients in the closure group (P=0.65). Procedure-related or device-related serious adverse events occurred in 4.2% of the patients in closure group.

Radiofrequency ablation for atrial fibrillation.

Atrial fibrillation is an important cause of stroke. Rhythm can be controlled by radiofrequency ablation or long-term antiarrhythmic drugs (65). Atrial fibrillation is more common in older patients. Because ablation is less effective in elderly, those with medium to high risk should continue oral anticoagulant after the procedure (122).

Long-term efficacy of ablation is unclear. The trans-septal puncture required during ablation creates an interatrial shunt, which may create a right to left shunt and paradoxical embolism. Moreover, damage to the endocardium and endothelial surface may activate coagulation.

Watchman left atrial appendage closure for atrial fibrillation.

Pericardial effusion requiring either pericardiocentesis or surgical repair occurred in 1.5% to 2.9% and 0.4% to 1.6%, respectively (Holmes et a 2014).

Prognosis and complications

In general, less than one third of patients with stroke have major functional disability at the time of discharge (115; 77; 70).

Several biomarkers that may predict perioperative neurologic complication have been studied. Preoperative serum NMDA antibody levels showed a correlation with perioperative neurologic complications (12). Elevated preoperative serum C-reactive protein level correlated to higher mortality after coronary artery bypass surgery (58).

Postoperatively, prediction of early neurologic complications may accelerate diagnosis as well as early intervention (03).

S100-β, a calcium regulating astroglial protein released by injured brain tissue, may help determine the timing and extent of the brain injury, especially neurocognitive changes (35). However, preoperative S100-β level did not correlate with perioperative neurologic complications (12).

Genetic variants of the C-reactive protein and interleukin-6 genes have been identified to be more common in those who get strokes after cardiac surgery than those who do not (44).

There is no relationship between global cortical beta-amyloid deposition and postoperative cognitive dysfunction in patients undergoing cardiac surgery (66).

Biological basis

The main causes of neurologic complications of cardiac procedures are:

	• Embolism of blood clots, atherosclerotic debris, or originating in the devices used to maintain circulation.
	• Activation of coagulation on contact between blood and cardiopulmonary bypass circuit or left ventricular assist device.
	• Alteration of the cerebral excitability by medication
	• Compression of peripheral nervous fibers
	• Infection
	• Immunosuppression

Etiology and pathogenesis

Ischemic stroke or transient ischemic attack after cardiac procedures. In a retrospective study of 16,184 patients undergoing cardiac surgery, hypertension, diabetes, prior stroke, peripheral vascular disease, preoperative infection, and prolonged cardiopulmonary bypass were independent risk factors for stroke (18). Emboli can be divided into macroemboli, greater than or equal to 200 microns, and microemboli (11).

Macroemboli include air from the heart or open aorta, calcium from the aorta or mitral and aortic valves, and blood clot from the left atrium or ventricle. Depending on size, they may occlude large cerebral arteries and/or their distal branches producing symptoms corresponding to their distribution from stroke to coma (104; 13). Embolization can occur during cannulation/decannulation of the aorta, as well as during application or removal of the cross clamp.

Microembolism plays an important role in cerebral injury after cardiac surgery. Pathological studies reveal dilation of small capillaries and arterioles often at bifurcations. Staining with oil red O and osmium have revealed numerous fat microemboli. The embolic load is higher in patients who remain longer on cardiopulmonary bypass (17).

Other microemboli. Other microemboli may consist of gas from bubble oxygenators, fat from cardiotomy suction, cellular aggregates, and particulate matter of silicone from the bypass pump. The smallest emboli scatter widely and are more likely to cause generalized neuropsychological alterations than hypoxia (48). Acute brain swelling on brain MRI FLAIR sequence in the immediate postoperative period appeared to involve the cortex primarily, which is consistent with the anatomic finding of small capillary and arteriolar dilatations in the cortex and deep gray matter (47). These small capillary and arteriolar dilatations after cardiopulmonary bypass are thought to be caused by embolism (82).

Activation of coagulation by the contact of blood with the surface of the cardiopulmonary bypass circuit leads to platelets and coagulation factors consumption (01; 63). The release of tissue factor is the main trigger of the coagulation system in patients undergoing cardiopulmonary bypass (32).

Cognitive impairment after cardiac procedure. The mechanism of the biphasic cognitive decline after coronary artery bypass graft surgery is unclear. Some early short-term cognitive changes may be multifactorial and reversible (111). Perioperative cerebral ischemic stroke may not always be related to cognitive decline (27). Apolipoprotein E4 genotype is not related to the post-operative cognitive decline (121; 04).

The perioperative burden of hypertension or hypotension affects both short- and long-term outcome in cardiac interventions including stroke, delirium, and death (71).

Cerebral autoregulation in a noninjured brain is diminished perioperatively and may lead to cognitive dysfunction, worse clinical outcome, and even death (72).

Epidemiology

The main complications of cardiac procedures are:

	• Stroke
	• Encephalopathy
	• Cognitive impairment
	• Headache
	• Seizures
	• Infections

Neurologic complications of heart transplantation. Experience from a single center including 200 patients revealed that 23% had neurologic complications that included ischemic stroke, seizures, diffuse encephalopathy, headache, and cerebral infections. Preoperative mechanical circulatory support requirement was the most important predictor of poor neurologic outcome (137). The risk factors for ischemic stroke after cardiac transplant are history of prior stroke and dilated cardiomyopathy (56; 09).

Neurologic complications of coronary artery bypass graft surgery. In prospective studies, the incidence of stroke after coronary artery bypass surgery was 1.5% to 5.2% (78; 113; 19).

In a large study of 2985 patients who underwent coronary artery bypass surgery, the incidence of stroke was 1.6% (37). More than three quarters were large embolic infarcts. Previous stroke, extensive aortic calcification, female gender, and congestive heart failure were predictors of stroke in these patients. The in-hospital mortality and long-term survival rate were affected by perioperative stroke.

In another single center study of 4335 coronary artery bypass graft surgery patients with or without aortic valve replacement, stroke was detected in 1.8%. The combination of coronary artery bypass graft surgery with carotid endarterectomy increased the risk of perioperative stroke significantly (15.1% vs. 0%) (69).

Neurologic complications of percutaneous coronary intervention (PCI). Almost two thirds of coronary revascularization procedures are percutaneous coronary intervention, an increasingly popular approach. The incidence of stroke was 0.08% to 0.4% (55; 74). However, many perioperative embolic events are clinically silent. Using diffusion-weighted MRI, 15% of individuals undergoing cardiac catheterization had asymptomatic ischemic cerebral lesions (20).

Prevention

Prevention of perioperative neurologic complications includes:

	• Preoperative evaluation should look for history of stroke, large vessel atherosclerosis, valvular disease, and atrial fibrillation.
	• Treatment of hyperglycemia, hypotension, and hyperthermia is recommended.
	• Dexmedetomidine administered perioperatively does not prevent perioperative delirium.

Thorough preoperative evaluation of risk factors, including prior stroke, carotid stenosis, and aortic atherosclerotic plaques may help prevent complications after coronary artery bypass graft surgery (22).

Preoperative statin has been shown to reduce mortality of coronary artery bypass graft surgery but not the risk of stroke (93). In a retrospective study, beta-blockers and statins reduced the number of perioperative strokes (14).

Control of atrial fibrillation, intraoperative quantitation of aortic atherosclerosis by ultrasound, and treatment of hyperthermia, hyperglycemia, and hypotension are also recommended (43; 120; 79).

In a small clinical trial, perioperative administration of dexmedetomidine lowered the incidence of delirium in patients 60 and older (134). However, a systematic review found that after excluding the trials at high risk of bias, dexmedetomidine is no longer associated with decreased delirium (94).

Neurologic complication risk factors associated with general cardiac surgery. Several studies have attempted to identify the subset of patients at high risk preoperatively.

	A. Factors predicting postoperative neurologic complications (103)
		1. Preoperative factors
			a. Carotid stenosis greater than 50% b. Prior heart surgery c. Prior stroke
		2. Intraoperative factors
			a. Valve surgery
	B. Factors predicting higher postoperative mortality (70)
		1. Preoperative factors
			a. Carotid stenosis greater than 50% b. Prior heart surgery c. Peripheral vascular disease d. Hypercholesterolemia
		2. Intraoperative factors
			a. Longer cardiopulmonary bypass
	C. Factors predicting perioperative stroke (78)
		1. Preoperative factors
			a. Age b. Previous stroke c. Presence of carotid bruit d. History of hypertension e. History of diabetes mellitus
		2. Intraoperative factors
			a. Longer cardiopulmonary bypass
	D. Factors predicting postoperative delirium (18)
		1. Preoperative factors
			a. Prior cerebrovascular disease b. Peripheral vascular disease c. Atrial fibrillation d. Diabetes mellitus e. Ejection fraction less than 30% f. Urgent operation
		2. Intraoperative factors
			a. Need for massive blood transfusion b. Operation time greater than 3 hours
	E. Factors predicting postoperative neurologic complications (112)
		1. Preoperative factors
			a. Hypertension b. Diabetes c. Prior stroke d. Smoking e. Aortic atherosclerosis
		2. Intraoperative factors
			a. Severe hypotension b. Manipulation of the atherosclerotic aorta c. Prolonged bypass time
		3. Postoperative factors
			a. Occurrence of atrial fibrillation
	F. Factors predicting postoperative seizure (75)
		1. Preoperative factors
			a. Renal dysfunction b. Advanced age c. Prior cardiac surgery d. Peripheral vascular disease e. Cardiac arrest
		2. Intraoperative factors
			a. Open heart surgery b. Prolonged cardiopulmonary bypass time (less than 120 minutes) c. Exposure to high dose tranexamic acid (less than 100 mg/kg)

Age. Advanced age is a major risk factor for stroke and postoperative cognitive dysfunction following cardiac surgery (41). In a study of 2000 patients undergoing cardiopulmonary bypass, the incidence of neurologic deficits after surgery was 10 times higher in those 75 years or older than in those younger than 65 years of age. Mortality rate was 9 times higher (35.7% vs. 4.0%) in patients with perioperative neurologic deficits (81). Fortunately, with innovations in surgical techniques, more elderly patients have been successfully operated with lower rates of complications nowadays (102).

Sex. Women, for unknown reason, have higher mortality and increased risk of perioperative neurologic complications compared to men (50).

Previous stroke. History of stroke is a risk factor for perioperative complications (100) or stroke (51). These patients take longer to awaken or be extubated, and are more likely to be confused or reintubated. They also experience more focal neurologic deficits, new strokes, and reappearance or worsening of previous stroke symptoms.

Open heart surgery. Open heart surgery carries the added risk of intracardiac air embolism. Leaflet and annulus calcification may lead to embolism in cardiac valve replacement surgeries as demonstrated by a higher number of high intensity transient signals (HITS) by transcranial Doppler (TCD) than coronary artery bypass graft surgery. A higher number of HITS correlates with worse neuropsychological outcomes (99).

Ascending aorta atheroma. Atheroma of ascending aorta in cardiac surgical patients predicts neurologic events, stroke, prolonged hospitalization, and mortality (29; 30; 07; 101). Embolism is reduced by avoiding aortic manipulation during surgery (132).

A significantly lower incidence of stroke was seen in off-pump patients (0.4%) compared to the on-pump group (3.9%) (95). The off-pump, no-touch surgical technique avoids aortic manipulation and the effects of cardiopulmonary bypass and (101; 21). Intraoperative ultrasound of the proximal aorta helps to avoid the area of plaque before clamp placement and may reduce the incidence of perioperative stroke (81; 91).

Cardiopulmonary bypass. Cardiac surgery with cardiopulmonary bypass is associated with more frequent and severe complications. The duration of the cardiopulmonary bypass is an important risk factor of the perioperative neurologic complications (81; 70).

In a small study, cardiac surgery performed without cardiopulmonary bypass, the off-pump technique, has reduced overall morbidity and mortality compared with on-pump surgery (02). However, another study, enrolling 2203 patients who underwent coronary artery bypass graft, did not find a significant difference in the composite outcome, stroke, or neuropsychological decline between the 2 groups at 30 days (117).

The cardiopulmonary bypass circuit may trigger the coagulation in contact with blood. Coating the bypass circuits with phosphoryl-choline or heparin seems to reduce the thromboembolic complications (31; 49).

Perioperative mean arterial pressure. Cerebral blood flow must be constant in order to sustain the brain metabolism. Cerebral blood flow can be defined as cerebral perfusion pressure over cerebrovascular resistance. Autoregulation is maintenance of cerebral blood relatively constant at cerebral perfusion pressure values between 50 to 130 mmHg.

Cerebral perfusion pressure is defined as mean arterial pressure minus intracranial pressure. Under normal circumstances, intracranial pressure is constant around 10 mmHg. Therefore, theoretically, mean arterial pressure must be maintained between 60 to 140 mmHg throughout the procedure.

Initial studies suggested maintenance of mean arterial pressure at greater than 50 mmHg to prevent cerebral dysfunction. Subsequent studies did not confirm these findings (38; 81; 118).

Carotid artery stenosis. The incidence of hemodynamically significant carotid stenosis is 11% to 20% in patients undergoing cardiac operations (124).

In a retrospective review of 1022 coronary artery bypass surgery patients, the overall rate of perioperative stroke was 2.2%. The rate was increased with severity of extracranial carotid stenosis, from 4.7% in less than 70% stenosis, 5% in 70% to 99% stenosis to 8% in total occlusion (28).

In patients with asymptomatic carotid stenosis undergoing CABG, the risk of in-hospital stroke or death was similar regardless of the degree of carotid stenosis (109).

Summary. Common risk factors are advanced age, carotid artery stenosis, prior heart surgery, prior stroke, peripheral vascular disease, hypertension, diabetes mellitus, aortic atheroma, open heart surgery, and prolonged cardiopulmonary bypass time.

Risk factors associated with left heart catheterization.

Risk factors of CNS complication. Risk factors include female sex, peripheral vascular disease, left ventricular hypertrophy, severe coronary disease, poor left ventricular ejection fraction, concomitant peripheral vascular disease, performance of percutaneous coronary intervention, longer fluoroscopy times, and protruding aortic atheromas (129; 68; 110). Lack of aspirin prior to percutaneous coronary intervention has been associated with increased risk of in-hospital mortality and stroke (61).

Risk factors of peripheral nervous system complication. Thrombocytopenia, female sex, and excessive anticoagulation (aPTT > 150 seconds) are strong predictors of retroperitoneal hemorrhage. There is no strong correlation between the size of hematoma and the severity of the sensory or motor deficits. Most patients are treated by transfusion alone (an average of 4 units). Urgent surgery is needed if hypotension is refractory to fluid administration (62). Neurologic complications during intra-aortic balloon pump include peripheral nerve injuries and rarely paraplegia related to spinal cord infarction (08).

Differential diagnosis

Perioperative neurologic dysfunction following cardiac catheterization and surgery are generally due to surgical and catheter manipulations. However, other nonsurgical factors such as drugs, infection, posttransplantation lymphoproliferative disorders, and metabolic derangements may also play a role, particularly in cardiac transplantation patients.

Diagnostic workup

The key tests used in patients who experience complications following cardiac procedures are:

	• Head CT
	• Brain MRI. There is increasing evidence of safety in patients with cardiac pacemakers and defibrillators.
	• Coagulation profile
	• Blood and fungal cultures
	• Lumbar puncture
	• EEG

CT is the first-line brain imaging modality in patients with suspected stroke. Diffusion-weighted MRI is more sensitive to ischemic lesions that are small or in unsuspected locations (20). Concern persists in patients with cardiac pacemakers and defibrillators (10). However, several studies have demonstrated the safety of cerebral MRI in these patients (92; 108; 83). Patients with pulmonary artery catheters that include pacing or thermistor wires should not undergo MRI (90). Coagulation intensity is monitored with APTT and PT/INR in patients on heparin and coumadin, respectively. Fever should prompt blood cultures and in some cases CSF examination.

Electrographic seizures occur infrequently after cardiac surgery and are generally associated with a good prognosis. Hence prophylactic cEEG monitoring is unlikely to be cost-effective in this population (39).

Management

	• Intravenous thrombolysis may be contraindicated in patients who underwent a recent surgical procedure.
	• Intra-arterial thrombolysis has been used successfully in strokes following cardiac catheterization.
	• Mechanical thrombectomy is an option if a large cerebral artery is occluded.
	• Perfusion studies may help selection of patients with large arterial occlusion up to 24 hours from onset of stroke.
	• Permissive hypertension should be used cautiously in unstable cardiac patients.
	• The risk of death or severe cardiovascular morbidity is high, but there is no significant difference between synchronous and staged carotid artery revascularization and coronary artery bypass graft surgery.

Management of peri-procedural stroke. Treatment of periprocedural stroke is similar to that of ischemic stroke. Urgent head CT is needed to exclude intracerebral hemorrhage. Intravenous t-PA can be given within 4.5 hours from last time normal unless contraindicated by coagulopathy or recent surgical procedure. Large vessel occlusion with salvageable penumbra, less likely to respond to t-PA, may be treated, up to 24 hours in selected cases, with endovascular thrombectomy. Perfusion scans (eg, CT perfusion scan with CT angiogram, MR perfusion scan with DWI sequence) may help with selection for endovascular treatment of large vessel occlusions by quantifying the mismatch between penumbra and the infarct core (DAWN Trial Investigators 2018; 76).

In acute period, permissive hypertension should be avoided in certain cardiac conditions like pulmonary edema, aortic dissection, and acute myocardial infarction, or when organ injury is suspected.

During cardiac catheterization. There is anecdotal evidence of successful intra-arterial thrombolysis for ischemic stroke during or after cardiac catheterization (64).

After coronary artery bypass surgery. Recent surgery is a contraindication to intravenous t-PA. The is anecdotal evidence of benefit from intra-arterial thrombolysis (60). Permissive hypertension may be used cautiously after surgery to prevent bleeding from an unhealed surgical site.

After cardiac transplantation. Typically, patients waiting for cardiac transplantation with a left ventricular assist device need anticoagulation, a contraindication for intravenous tPA (84). Mechanical thrombectomy is an alternative for large vessel occlusion. Permissive hypertension should be cautiously used in patients with heart failure.

Management of potential stroke risk factors that are commonly found during preprocedural screening.

Patent foramen ovale. Patent foramen ovale has been associated with paradoxical embolism. Larger right-to-left shunts are linked to higher rates of embolism. Patent foramen ovale closure may be considered in selected patients without other risk factors for stroke, which is not the case in most perioperative strokes (80).

Carotid artery stenosis. Carotid endarterectomy (CEA) may benefit carefully selected patients with symptomatic and asymptomatic carotid stenosis (46). As coronary artery disease and carotid stenosis may coexist, optimal timing of CEA in relation to coronary artery bypass graft surgery has been of interest. Carotid duplex ultrasound screening is reasonable before elective coronary artery bypass graft surgery in patients older than 65 years of age and in those with left main coronary stenosis, peripheral arterial disease, a history of cigarette smoking, a history of stroke or transient ischemic attack, or carotid bruit.

A systematic review of 97 studies of combined carotid endarterectomy and coronary artery bypass graft surgery did not find a significant difference between the synchronous and staged procedures. The risk of stroke or major cardiovascular morbidity was 10% to 12% (85). In a metaanalysis of 12 studies including coronary artery bypass graft patients with asymptomatic unilateral carotid stenosis, the lowest risk of stroke or death was observed in synchronous carotid endarterectomy plus off-pump coronary artery bypass graft surgery group (2.2%), whereas the risk of the other groups was 7% to 8% (34).

Carotid artery stenting (CAS) is an alternative to carotid endarterectomy (16). A metaanalysis of 11 studies examined the overall operative risk of cardiovascular events in patients undergoing staged carotid artery stenting plus coronary artery bypass graft surgery. In a cohort of predominantly asymptomatic unilateral carotid disease patients, the 30-day risk of death/any stroke was 9.1% (86).

Additionally, carotid revascularization by endarterectomy or stenting with embolic protection before or concurrent with myocardial revascularization surgery is reasonable in symptomatic patients with stenosis more than 80%. However, safety and efficacy of carotid revascularization in patients with asymptomatic carotid stenosis, even if severe, are not well established (15).

General management of cardiac transplanted patients. Usually, opportunistic CNS infections occur after 3 weeks from surgery. Post-transplantation lymphoproliferative disorder may be confined to the nervous system or disseminated. The response to treatment is poor (97).

Some antiepileptic drugs may reduce immunosuppressant levels in post-transplantation patients (24). Newer agents are not subject to this interaction.

Outcomes

In a series of 100 patients who underwent heart valve procedures, 24 had focal deficits of which 92% recovered completely at 5 months (118). Vocal cord dysfunction due to direct trauma or recurrent laryngeal nerve injury can lead to partial laryngeal obstruction and may necessitate reintubation (114).

Cognitive decline after cardiac surgery may affect 7% to 49% of patients at 3 months and up to 33% after 1 year (133). Of concern was also late decline in cognitive function due to cardiac procedures. However, this is most likely related to progression of preexisting vascular disease, other neurodegenerative disease, or new neurologic events (79).

Special considerations

Anesthesia

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST), an international, multicenter, randomized, controlled trial is ongoing to study effects of subanesthetic dose of intraoperative ketamine on postoperative delirium and other neurologic and psychiatric outcomes in cardiac and noncardiac surgeries. Smaller randomized controlled trials have shown significant reduction in postoperative delirium from 31% to 3%; beneficial effects have been attributed to ketamine’s antiinflammatory and antiexcitotoxic actions (05).

Studies have shown the correlation between low cortical oxygen saturation and cognitive dysfunction, and prolonged hospitalization and perioperative cerebrovascular accidents in patients undergoing cardiopulmonary bypass. A randomized trial has demonstrated higher intraoperative cortical oxygen saturation in the patients undergoing anesthesia with sevoflurane compared to total intravenous anesthesia with midazolam and fentanyl during cardiopulmonary bypass (45).