Cerebrovascular complications of cardiovascular interventions coronary artery bypass graft procedures

Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 2003

Cerebrovascular Complications of Cardiovascular Interventions Coronary Artery Bypass Graft Procedures JAMES D. FLECK, MD* and JOSE´ BILLER, MD** Indianapolis, Indiana and Maywood, Illinois

ABSTRACT Coronary artery bypass surgery is a common surgical procedure. The objective of this article is to discuss the cerebrovascular complications of this surgery. Coronary artery bypass surgery can cause brain injury, typically from emboli or brain hypoperfusion. Ischemic strokes do occur after coronary artery bypass surgery. Techniques have been developed to lessen the chance of brain infarction, including performing the surgery without the use of a cardiopulmonary bypass machine. Neuropsychologic decline can also occur after surgery and is discussed. The clinical presentations of brain infarcts are discussed as well as the evaluation and treatment of these patients. Key words: coronary artery bypass surgery, ischemic stroke, brain infarct, off-pump coronary artery bypass, neuropsychologic decline.

Coronary heart disease (CHD) is an exceedingly prevalent disease, especially in the US. It is estimated that 650,000 Americans per year will have a new coronary attack and 450,000 will have a recurrent attack.1 Coronary heart disease caused more than one of every five deaths in the US in 2000.1 As one of the treatment options for patients with CHD, coronary artery bypass surgery (CABG) is a common procedure. It is estimated that 519,000 of these procedures were performed in the US in 2000.1 Neurologic complications, especially those affecting the brain, are certainly a significant fear of patients and physicians. Cerebral injury in the form of delirium or encephalopathy, stroke, and cognitive dysfunction are not uncommon. The focus of this article will be the cerebrovascular complications of CABG. We will begin by concentrating on strokes, but will also discuss some information on neuropsychologic or cognitive ab-

normalities after CABG. When we discuss stroke in the setting of a CABG, the reader should assume we are referring to ischemic stroke or brain infarcts unless otherwise specified. To understand the potential mechanisms of stroke in patients undergoing CABG using cardiopulmonary bypass (CPB), it is helpful to understand the basic setup of the machine. Blood is taken away from the right atrium of the heart and driven through the machine via a mechanical pump. The second major component of the circuit is the oxygenator, which adds oxygen and removes carbon dioxide from the blood. After flowing through filters and air-bubble detectors, blood is returned to the aorta via a cannula placed distal to the aortic cross-clamping site. The heart is immobilized by temporary interruption of coronary blood flow with the aortic cross clamp. The myocardium is preserved with infusion of high-potassium cardioplegic solution into the aorta proximal to the cross-clamp. A cardiotomy suction line returns blood from the surgical field to the bypass machine. This procedure allows a bloodless and motionless surgical field for the surgeon to make the necessary vascular bypasses of diseased or stenotic coronary vessels. While this is certainly an oversimplification of the process, it does make it easier to see the many sources of

From the *Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, and the **Department of Neurology, Loyola University Medical Center, Maywood, IL. Address reprint requests to James D. Fleck, MD, CL 291, 541 Clinical Drive, Indianapolis, IN 46202. E-mail: [email protected] © 2004 Elsevier Inc. All rights reserved. 1528-9931/03/0304-0004$30.00/0 doi:10.1053/j.scds.2004.02.002

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208 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003

Fig 1. A brain diffusion-weighted MRI scan of a patient after CABG showing evidence of bihemispheric ischemia affecting predominantly the parasagittal region, but also a more predominant region of brain ischemia in the right frontal lobe.

potential emboli from the heart. The mechanisms by which ischemic stroke may occur in the setting of a CABG procedure are multiple. Many types of embolism can occur including thromboembolism of blood constituents such as fibrin, platelets, leukocytes, cholesterol, air/gas, fat, foreign objects, or combinations of these. Thousands of small capillary and arteriolar dilatations (SCAD) have been reported to occur in patients who died shortly after CPB and are thought to represent fat emboli.2,3 It is not hard to imagine single or multiple macroemboli flowing to the brain to cause focal or multifocal neurologic deficits or, if diffuse enough, a global decline in cognitive functioning, disturbances in consciousness, or coma. Figure 1 demonstrates evidence of multiple areas of brain ischemia on a brain MRI scan of a patient after CABG. Cardiopulmonary bypass machines allow for cardioplegia but can lead to low flow rates or arterial hypotension. Hypoperfusion and/or arterial hypotension can also lead to focal, multifocal, or global areas of brain

ischemia. Cerebrovascular occlusive disease and poor collateral flow within the circle of Willis may predispose patients to more severe effects of brain hypoperfusion. The range of perioperative stroke rates in several case series published after 1990 ranges from 1.4 to 5.7%, typically around 2 to 4%.4-14 The definition of stroke was certainly not consistent across all studies. These numbers reflect stroke rates in patients undergoing only CABG and not combined procedures such as CABG and cardiac valve surgery, repair of other cardiac abnormalities, or carotid endarterectomy. In these patients the risk of stroke is higher.15,16 All patients were placed on cardiopulmonary bypass machines and most surgeries were elective if specified. As would be expected, patients who suffered strokes had higher mortality rates, longer hospitalizations, and a higher rate of discharge to facilities for intermediate- or long-term care.4,6 The risk of stroke associated with preoperative cardiac catheterization, the gold standard by which a diagnosis of ischemic heart

Coronary Bypass Graft ● Fleck and Biller Table 1. Risk Factors for Stroke Associated with CABG Patient-related Increasing age Female gender Previous TIA, stroke, or cerebrovascular disease Carotid artery disease or carotid bruit History of neurologic disease Proximal aortic atherosclerosis or calcified aorta Previous cardiac surgery Preoperative infection Recent myocardial infarction Poor left ventricular ejection fraction Cardiac mural thrombus Peripheral vascular disease Arterial hypertension Diabetes mellitus Chronic obstructive pulmonary disease Cigarette smoking Renal failure Procedure-related Urgent operation Longer duration of cardiopulmonary bypass Use of alpha-adrenergic drugs after bypass High transfusion requirement Need for intraoperative hemofiltration Postoperative arrhythmias Intra-aortic balloon pump

disease is made, should also be taken into consideration. The cerebrovascular complications of cardiac catheterization are discussed elsewhere in this edition. It should be taken into account, however, that in the decade of the 1990’s, patients referred for isolated CABG were significantly older, sicker, and had a higher predicted operative risk as the decade passed. Despite this, the observed operative mortality in the 1,154,486 charts reviewed declined from 3.9% in 1990 to 3.0% in 1999.17 Several of these studies identified risk factors for stroke associated with CABG and these are listed in Table 1.4-14 Many of them seem intuitive as they are risk factors for stroke itself. Increasing age, hypertension, diabetes mellitus, cigarette smoking, and carotid artery disease are known ischemic stroke risk factors. Interestingly, female gender appears to be a risk factor for stroke. In a large study reviewing clinical information on 416,347 patients, the risk of new neurologic events was significantly higher in women undergoing several types of cardiac surgery requiring CPB, including CABG surgery alone (men 2.4% vs women 3.8%).13 This association remained after multivariable analysis, adjusting for many traditional risk factors. Atrial fibrillation is a common complication of cardiac surgery and may be associated with thromboembolic stroke. The likelihood of developing atrial fibrillation after CABG is increased by advancing age, male gender, and the presence of severe right coronary artery disease.18 Aortic atherosclerosis also appears to be a significant risk factor for stroke associated with CABG. Again, this would make sense given the aortic cannulations and

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cross-clamping done in “routine” CABG using CPB. Besides gentle manual palpation of the aorta by the surgeon, other techniques of evaluating for degree of aortic atherosclerosis have been used including epiaortic ultrasound and intraoperative transesophageal echocardiography (TEE).19,20 Techniques for grading the degree of aortic atherosclerosis using both procedures were described in these studies. Severe aortic arch disease discovered by TEE did correlate with a significantly increased risk of stroke. Increasing severity of aortic atherosclerosis as detected by epiaortic ultrasound also correlated with an increasing stroke risk in a large population of patients undergoing cardiac surgeries using CPB. Based on the results of the epiaortic ultrasound, changes in operative technique can be attempted such as using alternative sites for aortic cross-clamping, aortic cannulation, infusion of cardioplegic solutions, and proximal attachments of vein grafts. The authors noted no strokes in 27 patients with moderate to severe aortic atherosclerosis who had ascending aorta replacement as part of their procedure.19 Transcranial Doppler (TCD) monitoring of both middle cerebral arteries has been used to detect high-intensity transient signals (HITS) thought to represent emboli in patients undergoing open-heart valve operations or CABG using CPB.21,22 While emboli were observed at the time of aortic cannulation and at the start of CPB, it appeared that more emboli were detected at the time of cross-clamp release, especially with the heart beating while empty.21 It is not hard to imagine that macroemboli during manipulation of the aorta could lead to single or multiple brain infarctions. Further discussion of microemboli will be discussed in the section on the neuropsychologic effects of CABG. Given the above-mentioned potential morbidity associated with the use of CPB and its attendant significant manipulation of the aorta, there has been increasing interest and use of CABG techniques that do not use the CPB machine, so-called off-pump CABG (OPCABG). The introduction of cardiac stabilization techniques has allowed surgeons to operate on the beating heart. A number of retrospective case series have been published with stroke rates in OPCABG and also comparison of stroke rate in on-pump and OPCABG.23-34 See Table 2 for details. The percentage of patients suffering a perioperative stroke was lower in the off-pump group. This trend also seems to hold for elderly patients. In one study, the stroke rate did not seem to differ in the off-pump group with or without aortic manipulation.33 It is important to realize that all of these case series were retrospective and obviously nonrandomized, which brings up the potential for multiple types of bias. Results from a randomized study showing early outcomes after on-pump versus off-pump CABG was published in 2001 by van Dijk and coworkers35 A total of 281 patients were

210 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003 Table 2. Stroke rate in off-pump CABG Author

Year

Patients

Ricci

2000

All ⬎ 80 yrs

Yokoyama

2000

“High risk”

Hoff

2002

All ⬎ 80 yrs

Demaria

2002

All ⬎ 80 yrs

Bucerius

2003

Hernandez

2001

Cleveland

2001

Patel

2002 Aortic manipulation No aortic manipulation

Stamou

2002

Anyanwu Puskas Hart

2002 2001 2000

CPB

Number of Patients

Stroke (% patients)

Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No No Yes No No No No

172 97 483 242 169 60 63 62 8917 765 6126 1741 106423 11717 1210 520 597 8069 2320 285 200 1582

9.3 0 5 3.3 7.1 0 6.3 0 3.8 2.5 1.8 1.3 1.99 1.25 1.6 0.4 0.5 2.5 1.2 ⬍1 1.5 0.6

P value ⬍0.0005 NS 0.04 0.04 NS NS ⬍0.001

⬍0.01

CPB, cardiopulmonary bypass; NS, not significant.

randomized in the study. The number of strokes measured after 1 month was low in both groups, with only one stroke noted in the off-pump group (142 patients; 0.7%) and two strokes noted in the on-pump group (139 patients; 1.4%), one of which occurred before surgery. This study may have been underpowered to show differences in complication rates.36 These patients were then followed for 1 year and no further strokes occurred in this patient population after the first month.37 In general, it appears that patients undergoing OPCABG have a lower risk of stroke, but this has yet to be definitively proven in a large-scale, randomized study. Neuropsychological dysfunction or cognitive decline does occur following CABG. The incidence reported has varied widely from 3% to more than 50%.4,38 Much of this variation comes from patient selection, the definition of the neuropsychological decline, the timing and type of the neuropsychologic assessment, and likely multiple other factors. The causes of this decline are also likely multiple in nature but one of the most frequently mentioned are microemboli to the brain. As mentioned above, the use of CPB would seemingly increase the chances of more microemboli reaching the brain. Thousands of microemboli have been found in brain specimens from patients who died within 3 weeks of surgery and increasing duration of CPB was associated with an increasing embolic load.39 Also, total embolic load as monitored by TCD was associated with significant early neuropsychologic deficit after CABG using CPB.22 However, assessing the longitudinal impact of any decline in cognitive dysfunction has been a more difficult

task. Newman and coworkers evaluated 261 patients who underwent CABG using CPB with a battery of cognitive tests before surgery, and at intervals up to 5 years after surgery.38 The incidence of cognitive decline at discharge, 6 weeks, 6 months, and 5 years was 53, 36, 24 and 42%, respectively. Cognitive function at discharge was a significant predictor of long-term function. It is interesting that the incidence seems to decline over time except at the 5-year mark, where a jump in the incidence is noted. The exact mechanism of this finding is not known. A late cognitive decline at 1 year after CABG with CPB has been noted in some patients by others.40 On the other hand, not all have found a significant decline in neuropsychological test performance in those undergoing CABG with CPB.41 Selnes and coworkers attempted to compare neuropsychologic assessments of patients undergoing CABG with CPB to a control group of patients with comparable risk factors for coronary artery disease who did not have surgery.42 In these two groups, the neuropsychological performance did not differ at 3 months or 1 year. The patients were not studied earlier, for example, at discharge or 1 month. Advanced MRI techniques, especially diffusion-weighted imaging (DWI), allow earlier detection of ischemic brain than conventional MRI techniques. DWI has certainly shown new ischemic lesions in patients after CABG with CPB that did not seem to have any new significant bedside evidence of focal neurologic deficits. In one study, the patients with new lesions on DWI had a larger neurocognitive decline than those with stable MRIs.43 However, in the other study the presence of an ischemic

Coronary Bypass Graft ● Fleck and Biller

lesion was not related to impaired postoperative test performance.44 Both of these studies included a relatively small number of patients. If the number of microemboli reaching the brain during CABG with CPB is in some way related to postoperative neuropsychologic performance, it would seem reasonable to consider OPCABG to be an alternative to decrease the embolic load. However, the results in this area of study have been conflicting also. Diegeler and coworkers assessed the neurocognitive status preoperatively and postoperatively in patients undergoing CABG either on-pump or off-pump. The median value of HITS noted on intraoperative TCD was higher in the on-pump group and cognitive impairment was strongly associated with CPB and the occurrence of microemboli.45 A randomized trial of cognitive outcome after off-pump and on-pump CABG was performed by Van Dijk and colleagues.46 This is essentially the same group of patients discussed above in the stroke section. Cognitive outcome was assessed at 3 and 12 months with a set of 12 tests. The off-pump group of patients had improved cognitive outcomes 3 months after the procedure but the differences became negligible by 12 months. Protein S-100 is a protein found in high concentrations in glial and Schwann cells. The appearance of this protein in serum is thought to represent both neuronal damage and increased permeability of the blood– brain barrier. In a prospective study of patients undergoing on-pump or off-pump CABG, S-100 was measured at intervals up to 24 hours postoperatively and neuropsychologic performance was assessed preoperatively and at 12 weeks after CABG.47 Significantly higher levels of serum S-100 were noted in the on-pump group 30 minutes after the surgery but there was no significant difference in neuropsychologic performance between the two groups at 12 weeks. Neuropsychologic decline or cognitive decline certainly does occur after CABG, especially early after surgery. It is likely a multifactorial process with several potential risk factors that are patient-related, exacerbated by the pathophysiologic stress of a major operation, metabolic derangements, and microemboli from the CABG surgery itself almost certainly play some role. The goal of further research is to further define risk factors, improve anesthetic and operative risks, and lessen the risk of cognitive decline. Consensus statements on defining and measuring neurobehavioral outcomes after cardiac surgery have been published.48,49 Because of the multiple potential causes noted above and the potential for multiple areas of brain to be affected, the clinical presentation of patients with cerebrovascular events associated with CABG will vary. The location and extent of neuronal injury will also play a significant role in the clinical presentation. Focal motor or sensory deficits most often occur with focal brain ischemia. Behavioral or cognitive abnormalities may oc-

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cur with focal ischemic lesions of the temporal, parietal, or frontal lobes. Delirium or encephalopathy may be a manifestation of smaller areas of multifocal brain ischemia in patients that do not show obvious focal motor or sensory deficits. Coma can occur in patients with brainstem or notable bihemispheric ischemia. Severe global hypoperfusion can obviously lead to severe brain injury, coma, or brain death. Cerebral infarcts are often multiple and frequently involve posterior parts of the brain.50 Hemispheric syndromes also occur, and patients may have cortical visual disorientation, field deficits, alexia, and constructional apraxia. Ischemia in the borderzone territory between the middle and posterior cerebral arteries may initially result in cortical blindness that improves but leaves a dyslexia, dyscalculia, dysgraphia, and memory defect for verbal and nonverbal material. Ischemia in the borderzone territory of all three major arteries supplying the hemispheres (anterior, middle, and posterior cerebral arteries) may result in bilateral lower altitudinal visual field defects, difficulty in judging size, distance, and movements. These deficits may be more difficult to detect without a more detailed neurologic examination. Bilateral ischemia between the anterior and middle cerebral arteries can result in bilateral arm sensory and motor impairments. Pituitary apoplexy has also been described as a complication of cardiac surgery.51 Spinal cord infarction is also possible during CABG and may also occur with placement of an intraaortic balloon pump. When evaluating patients postoperatively with suspected stroke, a careful preoperative history, especially regarding vascular risk factors, is helpful. A review of the intraoperative record and postoperative course looking at the duration of CPB and also looking for complications such as periods of hypotension or cardiac rhythm disturbance is useful. A thorough general and neurologic examination is the next step. A review of pertinent laboratory data is necessary to look for metabolic derangements that can mimic subtle focal deficits or cause delirium or encephalopathy. If there is still a strong suspicion for brain ischemia, the next step in the evaluation process is typically a brain imaging study. While performing a head CT without intravenous contrast is typically easier and quicker to perform and may be more sensitive for acute intracranial bleeding, its sensitivity for acute ischemia is somewhat limited. An MRI of the brain, including diffusion-weighted images, is a much more sensitive tool to look for ischemic lesions, especially smaller ones and those located in the brainstem or posterior fossa. We will next discuss some treatment approaches for ischemic stroke after CABG. Obviously, prevention of stroke would be the ideal treatment. Minimizing sources of air or particulate emboli, minimizing aortic manipulation, and prevention of arterial hypotension and hypoperfusion will lessen the chances of intraoperative

212 Seminars in Cerebrovascular Diseases and Stroke Vol. 3 No. 4 December 2003 strokes. It would also seem reasonable to protect the brain from the effects of ischemia but to date no medications have been proven to do so in the setting of CABG. Hyperbaric oxygen therapy is a potential treatment option for those with proven air emboli. Intravenous thrombolysis with tissue plasminogen activator (tPA) has been proven to be beneficial if given to patients with acute ischemic stroke within 3 hours of the onset of symptoms. However, a major surgery such as CABG is a contraindication to intravenous tPA. Intraarterial thrombolysis typically uses a lower dose of thrombolytic with direct local delivery of the agent to the vascular occlusion via an endovascular approach. It has been attempted with some success in a few selected patients suffering an ischemic stroke after CABG without excessive severe bleeding risks.52 For those patients with concomitant need for CABG and severe extracranial carotid artery disease indicating a potential need for carotid endarterectomy (CEA), a clear consensus of opinion on how to surgically deal with these patients has not been reached.16 Depending on the patient and the surgeon, the CEA and CABG may be performed separately or concurrently. With regard to the general care of patients who have suffered an ischemic stroke, it is optimal to do the following: maintain normal body temperature, maintain adequate oxygenation, avoid hypotension/brain hypoperfusion, maintain normal serum glucose, avoid hypotonic intravenous fluids, prevent deep venous thrombosis, and avoid aspiration pneumonia by carefully evaluating the swallowing capabilities of those considered for oral feeding. In summary, we would like to offer the following statements. CABG surgery is a relatively commonly performed procedure. Over the last decade, the rate of cerebrovascular complications associated with CABG has not increased despite more operations on patients who are older with more potential risk factors. This is likely due to the improved operative procedures and care delivered by the teams performing the procedure, which include nurses, surgeons, anesthesiologists, and perfusionists, along with improved postoperative care. Given the recognition that cerebrovascular complications can occur and can be devastating, there is continued interest in decreasing the complication rate of this potentially life-saving procedure.

References 1. Heart Disease and Stroke Statistics: 2003 Update, American Heart Association 2. Challa VR, Moody DM, Troost BT: Brain embolic phenomena associated with cardiopulmonary bypass. J Neurol Sci 117:(1-2):224-231, 1993 3. Moody DM, Bell MA, Challa VR, et al: Brain microemboli

4.

5.

6.

7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

during cardiac surgery or aortography. Ann Neurol 28(4): 477-486, 1990 Roach GW, Kanchuger M, Mangano CM, et al: Adverse cerebral outcomes after coronary bypass surgery. Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation Investigators. N Engl J Med 335(25):1857-1863, 1996 Puskas JD, Winston AD, Wright CE, et al: Stroke after coronary artery operation: incidence, correlates, outcome, and cost. Ann Thorac Surg 69(4):1053-1056, 2000 McKhann GM, Grega MA, Borowicz LM, et al: Encephalopathy and stroke after coronary artery bypass grafting: incidence, consequences, and prediction. Arch Neurol 59(9):1422-1428, 2002 Frye RL, Kronmal R, Schafff HV, et al: Stroke in coronary artery bypass graft surgery: an analysis of the CASS experience. The participants in the Coronary Artery Surgery Study. Int J Cardiol 36(2):213-221, 1992 Tuman KJ, McCarthy RJ, Najafi H, et al: Differential effects of advanced age on neurologic and cardiac risks of coronary artery operations. J Thorac Cardiovasc Surg 104(6):1510-1517, 1992 Borger MA, Ivanov J, Weisel RD, et al: Stroke during coronary bypass surgery: principal role of cerebral macroemboli. Eur J Cardiothorac Surg 19(5):627-632, 2001 Lynn GM, Stefanko K, Reed JF III, et al: Risk factors for stroke after coronary artery bypass. J Thorac Cardiovasc Surg 104(6):1518-1523, 1992 McKhann GM, Goldsborough MA, Borowicz LM Jr, et al: Predictors of stroke risk in coronary artery bypass patients. Ann Thorac Surg 63(2):516-521, 1997 Ricotta JJ, Faggioli GL, Castilone A, et al: Risk factors for stroke after cardiac surgery: Buffalo Cardiac-Cerebral Study Group. J Vasc Surg 21(2):359-363, 1995 Hogue CW Jr, Barzilai B, Pieper S, et al: Sex differences in neurological outcomes and mortality after cardiac surgery: a Society of Thoracic Surgery National Database report. Circulation 103(17):2133-2137, 2001 John R, Choudhri AF, Weinberg AD, et al: Multicenter review of preoperative risk factors for stroke after coronary artery bypass grafting. Ann Thorac Surg 69(1):30-35, 2001 Wolman RL, Nussmeier NA, Aggarwal A, et al: Cerebral injury after cardiac surgery: identification of a group at extraordinary risk. Multicenter Study of Perioperative Ischemia Research Group (McSPI) and the Ischemia Research Education Foundation (IREF) Investigators. Stroke 30(3):514-522, 1999 Fleck JD, O’Donnell JA, Biller J: Cardiac evaluation of patients with carotid artery stenosis and treatment strategies for coexisting disease. in Loftus CM, Kresowik TF (eds): Carotid Artery Surgery. New York, Thieme, 2000, pp 121-129 Ferguson TB Jr, Hammill BG, Peterson ED, et al: A decade of change—risk profiles and outcomes for isolated coronary artery bypass grafting procedures, 1990-1999: a report from the STS National Database Committee and the Duke Clinical Research Institute. Society of Thoracic Surgeons. Ann Thorac Surg 73(2):480-489, 2002 Mendes LA, Connelly GP, McKenney PA, et al: Right coronary artery stenosis: an independent predictor of atrial

Coronary Bypass Graft ● Fleck and Biller

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

fibrillation after coronary artery bypass surgery. J Am Coll Cardiol 25(1):198-202, 1995 Wareing TH, Davila-Roman VG, Daily BB, et al: Strategy for the reduction of stroke incidence in cardiac surgical patients. Ann Thorac Surg 55(6):1400-1407, 1993 Marschall K, Kanchuger M, Kessler K, et al: Superiority of transesophageal echocardiography in detecting aortic arch atheromatous disease: identification of patients at increased risk of stroke during cardiac surgery. J Cardiothorac Vasc Anesth 8(1):5-13, 1994 van der Linden J, Casimir-Ahn H: When do cerebral emboli appear during open heart operations? A transcranial Doppler study. Ann Thorac Surg 51(2):237-241, 1991 Sylivris S, Levi C, Matalanis G, et al: Pattern and significance of cerebral microemboli during coronary artery bypass grafting. Ann Thorac Surg 66(5):1674-1678, 1998 Ricci M, Karamanoukian HL, Abraham R, et al: Stroke in octogenarians undergoing coronary artery surgery with and without cardiopulmonary bypass. Ann Thorac Surg 69(5): 1471-1475, 2000 Yokoyama T, Baumgartner FJ, Gheissari A, et al: Offpump versus on-pump coronary bypass in high-risk subgroups. Ann Thorac Surg 70(5):1546-1550, 2000 Bucerius J, Gummert JF, Borger MA, et al: Stroke after cardiac surgery: a risk factor analysis of 16,184 consecutive adult patients. Ann Thorac Surg 75(2):472-478, 2003 Hoff SJ, Ball SK, Coltharp WH, et al: Coronary artery bypass in patients 80 years and over: is off-pump the operation of choice? Ann Thorac Surg 74(4):S1340-S1343, 2002 Demaria RG, Carrier M, Fortier A, et al: Reduced mortality and strokes with off-pump coronary artery bypass grafting surgery in octogenarians. Circulation 106(12 Suppl 1): I5–I10 (12 Suppl 1), 2002 Anyanwu AC, Al-Ruzzeh S, George SJ, et al: Conversion to off-pump coronary bypass without increased morbidity or change in practice. Ann Thorac Surg 73(3):798-802, 2002 Hernandez F, Cohn WE, Baribeau YR, et al: In-hospital outcomes of off-pump versus on-pump coronary artery bypass procedures: a multicenter experience. Ann Thorac Surg 72(5):1528-1533; 1533-1534, 2001 Puskas JD, Thourani VH, Marshall JJ, et al: Clinical outcomes, angiographic patency, and resource utilization in 200 consecutive off-pump coronary bypass patients. Ann Thorac Surg 71(5):1477-1483, 2001 Hart JC, Spooner TH, Pym J, et al: A review of 1,582 consecutive Octopus off-pump coronary bypass patients. Ann Thorac Surg 70(3):1017-1020, 2000 Cleveland JC Jr, Shroyer AL, Chen AY, et al: Off-pump coronary artery bypass grafting decreases risk-adjusted mortality and morbidity. Ann Thorac Surg 72(4):12821288, 2001 Patel NC, Deodhar AP, Grayson AD, et al: Neurological outcomes in coronary surgery: independent effect of avoiding cardiopulmonary bypass. Ann Thorac Surg 74(2):400405, 2002 Stamou SC, Jablonski KA, Pfister AJ, et al: Stroke after conventional versus minimally invasive coronary artery bypass. Ann Thorac Surg 74(2):394-399, 2002 van Dijk D, Nierich AP, Jansen WL, et al: Early outcome after off-pump versus on-pump coronary bypass surgery:

36. 37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

213

results from a randomized study. Circulation 104(15): 1761-1766, 2001 Rose EA: Off-pump coronary-artery bypass surgery. N Engl J Med 348(5):379-380, 2003 Nathoe HM, van Dijk D, Jansen EW, et al: A comparison of on-pump and off-pump coronary bypass surgery in low-risk patients. N Engl J Med 348(5):394-402, 2003 Newman MF, Kirchner JL, Phillips-Bute B, et al: Longitudinal assessment of neurocognitive function after coronary-artery bypass surgery. N Engl J Med 344(6):395-402, 2001 Brown WR, Moody DM, Challa VR, et al: Longer duration of cardiopulmonary bypass is associated with greater numbers of cerebral microemboli. Stroke 31(3):707-713, 2000 McKhann GM, Goldsborough MA, Borowicz LM Jr, et al: Cognitive outcome after coronary artery bypass: a one-year prospective study. Ann Thorac Surg 63(2):510-515, 1997 Mullges W, Babin-Ebell J, Reents W, et al: Cognitive performance after coronary artery bypass grafting: a follow-up study. Neurology 59(5):741-743, 2002 Selnes OA, Grega MA, Borowicz LM Jr, et al: Cognitive changes with coronary artery disease: a prospective study of coronary artery bypass graft patients and nonsurgical controls. Ann Thorac Surg 75(5):1377-1384, 2003 Restrepo L, Wityk RJ, Grega MA, et al: Diffusion- and perfusion-weighted magnetic resonance imaging of the brain before and after coronary artery bypass grafting surgery. Stroke 33(12):2909-2915, 2002 Bendszus M, Reents W, Franke D, et al: Brain damage after coronary artery bypass grafting. Arch Neurol 59(7): 1090-1095, 2002 Diegeler A, Hirsch R, Schneider F, et al: Neuromonitoring and neurocognitive outcome in off-pump versus conventional coronary bypass operation. Ann Thorac Surg 69(4): 1162-1166, 2000 Van Dijk D, Jansen EW, Hijman R, et al: Cognitive outcome after off-pump and on-pump coronary artery bypass graft surgery: a randomized trial. JAMA 287(11):14051412, 2002 Lloyd CT, Ascione R, Underwood MJ, et al: Serum S-100 protein release and neuropsychologic outcome during coronary revascularization on the beating heart: a prospective randomized study. J Thorac Cardiovasc Surg 119(1):148154, 2000 Murkin JM, Newman SP, Stump DA, et al: Statement of consensus on assessment of neurobehavioral outcomes after cardiac surgery. Ann Thorac Surg 59(5):1289-1295, 1995 Murkin JM, Stump DA, Blumenthal JA, et al: Defining dysfunction: group means versus incidence analysis—a statement of consensus. Ann Thorac Surg 64(3):904-905, 1997 Barbut D, Grassineau D, Lis E, et al: Posterior distribution of infarcts in strokes related to cardiac operations. Ann Thorac Surg 65(6):1656-1659, 1998 Cooper DM, Bazaral MG, Furlan AJ, et al: Pituitary apoplexy: a complication of cardiac surgery. Ann Thorac Surg 41(5):547-550, 1986 Chalela JA, Katzan I, Liebeskind DS, et al: Safety of intra-arterial thrombolysis in the postoperative period. Stroke 32(6):1365-1369, 2001