Neurologic Events After Coronary Bypass Grafting: Further Observations With Warm Cardioplegia

Transcription

1 Neurologic Events After Coronary Bypass Grafting: Further Observations With Warm Cardioplegia Joseph M. Craver, MD, Bradley L. Bufkin, MD, William S. Weintraub, MD, and Robert A. Guyton, MD Division of Cardiothoracic Surgery, Joseph B. Whitehead Department of Surgery, Emory University School of Medicine, Atlanta, Georgia Warm heart surgery has documented myocardial protection benefit, but with an added neurologic threat. It is hypothesized that moderately hypothermic aerobic heart surgery will maintain the myocardial protection and reduce neurologic risk. This study compared 493 patients undergoing coronary artery bypass graft operations with normothermic (35 to 37 C) continuous blood cardioplegia and normothermic perfusion to 379 coronary artery bypass grafting patients with hypothermic (33 to 29 C) continuous blood cardioplegia and hypothermic perfusion to test this hypothesis. There was no difference in age, sex, prior myocardial infarction, hypertension, prior neurologic event, congestive failure, or diabetes. The hypothermic group had more reoperations (24% versus 14%; p = ), class III/IV angina (83% versus 71%; p = 0.002), a trend to more triple-vessel (54% versus 47%; p = 0.10) and left main disease (18% versus 14%; p = 0.10), lower ejection fractions ( versus 0.55 ± 0.13), more grafts placed (3.6 ± 1.1 versus ; p = 0.04), but fewer internal mammary arteries (62% versus 78%; p < ). Postoperative myocardial infarction rate was 1.2% in the hypothermic group and 1.3% in the normothermic group (p = not significant). Intraaortic balloon pump requirement was 3.4% with hypothermic and 1.4% with normothermic groups (p = 0.05). The incidence of postoperative neurologic events was significantly higher in the normothermic group (4.7% versus 1.8%; p = 0.038). The multivariate correlates of stroke were older age and normothermic cardioplegia, whereas the only multivariate correlate of death was older age. In summary, these data suggest that hypothermic continuous blood cardioplegia provides myocardial protection that is equivalent to normothermic continuous blood cardioplegia, whereas hypothermic aerobic heart surgery may lessen the neurologic risk that was observed associated with strict warm heart surgery. (Ann Thorac Surg 1995;59: ) E fforts to reduce neurologic complications of cardiac operations are a priority to maintain patients' quality of life, to eliminate lost patient productivity, and to reduce the overall cost of cardiac surgical care and hospitalization. Normothermic continuous blood cardioplegia combined with normothermic cardiopulmonary bypass (CPB) was identified as a neurologic threat in a randomized prospective study at this institution comparing the technique with cold oxygenated crystalloid cardioplegia [1]. Hypothermic CPB may have provided protection from cerebral ischemia in the oxygenated crystalloid cardioplegia group in that study. This observation provoked reconsideration of normothermic continuous blood cardioplegia and perfusion techniques and the importance of normothermia for the myocardial protection benefit. A controlled laboratory investigation documented maintenance and possible improvement in myocardial protection by combining hypothermia with continuous blood cardioplegia as compared with normothermia [2]. Based on the above theoretical, experimental and clinical Presented at the Forty-first Annual Meeting of the Southern Thoracic Surgical Association, Marco Island, FL, Nov 10-12, Address reprint requests to Dr Craver, The Emory Clinic, 1365 Clifton Rd, Atlanta, GA findings, we applied continuous blood cardioplegia with CPB conducted at moderate hypothermia to reap the myocardial protection benefit and reduce the neurologic risk observed with the normothermic method. In this report, the clinical results of hypothermic and normothermic continuous blood cardioplegia and perfusion are compared. Myocardial protection as measured by the clinical end points of perioperative myocardial infarction, intraaortic balloon pump requirement, and mortality are examined. Neurologic complications determined by fixed neurologic deficit and postoperative delirium/encephalopathy are likewise compared between the two groups. Material and Methods Operative Procedure From August 1992 to April 1994, 379 consecutive patients underwent coronary artery bypass grafting with CPB conducted at moderate hypothermia (33 to 29 C) and myocardial protection provided by continuous blood cardioplegia delivered at similar temperature. Demographic and perioperative clinical data were reviewed in this group of patients. The hypothermic group was compared with a cohort of 493 patients who underwent coronary artery bypass grafting with CPB conducted at 1995 by The Society of Thoracic Surgeons /95/$ (95)00236-E

2 1430 CRAVER ET AL Ann Thorac Surg WARM HEART SURGERY AND STROKE 1995;59: normothermia (37 to 35 C) and myocardial protection provided by normothermic continuous blood cardioplegia. This normothermic group was a cohort of the prospective, randomized study conducted between March 1990 and July 1992 [1]. Coronary artery bypass operations were conducted similarly in both groups of patients excepting cardioplegia regimens and systemic temperature management. Cardioplegia solution composition was as follows: Hypothermic 4:1 blood:cardioplegia 1,000 ml Plasmalyte 20 meq NaHCO g dextrose High K = 100 meq KCI/L Low K = 30 meq KC1/L Normothermic 4:1 Blood:cardioplegia 1,000 ml 5% dextrose 18 meq MgSO 4 12 meq THAM 20 ml CPD High K = 100 meq KCI/L Low K ~ 30 meq KCI/L There was a higher concentration of glucose in the cardioplegia solution of the warm group as the basic solution for mixing the cardioplegia was changed from 5% dextrose in the warm group to Plasmalyte in the hypothermic group. When elevated blood glucose levels were observed intraoperatively, the patients were treated with supplemental insulin to maintain a serum glucose level less than 200 mg/dl. Cardioplegia was delivered by a 4:1 blood:cardioplegia delivery system with core and cardioplegia temperature maintained at 35 C in the normothermic group and 33 to 29 C in the hypothermic group. In both groups, highpotassium blood cardioplegia (final concentration, 20 meq/l) was infused into the root of the aorta immediately on cross-clamping the aorta at 350 ml/min and a pressure of 100 to 300 mm Hg until diastolic arrest was achieved. Electromechanical arrest was maintained by low-potassium (4 meq/l) cardioplegia delivered continuously into the coronary sinus through a retrograde coronary sinus catheter (Gundry retroplegia cannula; DLP, Inc, Grand Rapids, MI). Coronary sinus pressure was kept near 40 mm Hg and flow rates ranged from 40 to 250 ml/min. In both groups, there were some patients in whom the cardioplegia delivery was stopped for short periods (2 to 5 minutes) to facilitate visualization for construction of the distal coronary anastomoses. All distal anastomoses were performed first. In the hypothermic group, a terminal dose (100 ml) of 37 C high-potassium cardioplegia was administered just before cross-clamp removal to provide the initial warm reperfusion in a state of electromechanical arrest. In both groups, the majority of proximal anastomoses were performed under partial aortic occlusion. Systemic temperature management during CPB was different in the two groups. Systemic temperature was regulated by a water bath heater/cooler (Hematherm; Cincinnati Sub Zero, Cincinnati, OH). In the hypothermic group, core temperatures were reduced (33 to 29 C) before aortic cross-clamping and rewarming occurred during the terminal 15 minutes of the cross-clamp interval. In the normothermic group, core temperatures were maintained in the range of normothermia (35 to 37 C) throughout the CPB run. Cardiopulmonary bypass materials and methods were the same in both groups: roller pumps (Cinco heart-lung machines, Wakefield, MA), membrane oxygenators (COBE Excel, adult membrane lung; COBE Cardiovascular, Arvada, CA), and single aortic and atrial cannulation techniques. Pump flows were maintained at 2.2 to 2.5 L/m 2 during normotherrnic perfusion. At temperatures less than 32 C, flow rates were decreased to as low as 1.8 L/m 2 if in-line venous saturation was greater than 90%. Perfusion pressure was maintained at 50 to 70 mm Hg at temperatures greater than 32 C and 40 to 60 mm Hg less than 32 C. Initial heparinization was accomplished with 4.0 mg/kg and was supplemented as needed to maintain an activated clotting time greater than 300 seconds. Anesthesia was accomplished by high doses of fentanyl citrate supplemented with midazolam hydrochloride, and all patients were paralyzed using vecuronium bromide. Vasoactive and inotropic agents delivered in the operating room were used to maintain acceptable hemodynamic parameters as determined by the operating surgeon and cardiac anesthesiologist. Statistical Methods and Data Collection The database was compiled and analyzed within the Emory Cardiovascular Data Center and consisted of information obtained from patient chart review performed at the end of each individual's hospitalization. All statistical testing was done with BMDP software. Results are reported as the mean _+ the standard deviation or proportions. Continuous measures were compared by unpaired t tests and categoric measures, by )(2 statistical analyses. Multivariate analysis was performed by stepwise logistic regression. Results There were no significant differences in the clinical descriptors of sex, prior myocardial infarction, hypertension, diabetes meuitus, prior neurologic event, or preoperative Canadian class of heart failure between the two groups (Table 1). The hypothermic group was older, had more severe preoperative angina and worse ejection fraction, and included more reoperations. A trend toward more triple-vessel disease and left main disease also was observed in the hypothermic group. The hypothermic group required a shorter aortic crossclamp interval but longer CPB time (Table 2). More grafts were placed in the hypothermic group, but fewer internal mammary arteries were used as conduits. Postoperative myocardial infarction rates were similar in the two

3 Ann Thorac Surg CRAVER ET AL ;59: WARM HEART SURGERY AND STROKE Table 1. Clinical Descriptors Descriptor Hypothermia Normothermia p Value Number Percent Male 72% 74% NS Mean age (y) _ Hypertension 59 % 63 % NS Diabetes mellitus 29% 29% NS Angina--class III/IV 83% 71% CHF 9% 7% NS Prior MI 50% 49% NS Prior CABG 24% 14% Triple-vessel disease 54% 48% 0.10 Left main disease 18% 14% 0.10 Ejection fraction 0.52 _ CABG coronary artery bypass grafting; CHF - congestive heart failure; MI = myocardial infarction; NS = not significant. groups; however, intraaortic balloon pumping was used more often in the hypothermic group (Table 3). The number of patients experiencing perioperative neurologic events was significantly greater in the normothermic group (4.7% versus 1.8%; p = 0.038). Mortality observed was not significantly different but was slightly higher in the hypothermic group. There were no deaths in the patients suffering neurologic injury in the hypothermic group, whereas 30% (7123) of those with stroke in the normothermic group died. Multivariate determinants of stroke were older age and normothermic cardioplegia (odds ratio, 1.10; 95% confidence interval, 1.05 to 1.15 per year of age, p ( ; and odds ratio, 1.76, 95% confidence limits, 1.14 to 2.71 for normothermic group, p = ). Older age was the only multivariate correlate of death (odds ratio, 1.16; p 0.007). When additional clinical variables of diabetes, angina, hypertension, and sex were forced into the multivariate model, the warm cardioplegia group remained a multivariate correlate of stroke with an odds ratio of 1.65 (95% confidence interval, 1.03 to 2.66). Comment Proponents of normothermic continuous blood cardioplegia provide rational arguments for its benefit combined with normothermic perfusion and have coined the term "'warm heart surgery" as a description of the technique [3]. The cornerstone argument for normotherrnic continuous blood cardioplegia focuses on the detri- Table 2. Operative Data Hypothermia Normothermia Variable (n = 379) (n - 493) p Value Number of grafts _ IMA graft 62% 78% Cross-clamp time _ (min) Bypass time (rain) IMA - internal mammary artery. Table 3. Operative Results Hypothermia Normothermia Result (n = 379) (n - 473) p Value Q wave infarct 1.3% 1.2% NS IABP requirement 3.4% 1.4% 0.05 Neurologic event 1.8% 4.7% Stroke 1.6% 3.9% Eneephalopathy 0.2% 0.8% NS Death 2.4% 1.0% 0.11 IABP intraaortic balloon pump; NS = not significant. mental effects of hypothermia on enzyme systems and biochemical reactions in the myocardium and the importance of normothermic aerobic electromechanical arrest for optimal myocardial protection. Additionally, normothermic perfusion is touted to reduce disturbance in the coagulation cascade while avoiding the vasoactive events associated with temperature changes, providing an improved perioperative course [4]. Laboratory investigation has confirmed improved protection by normothermic continuous blood cardioplegia when compared with other hypothermic ischemic regimens [5, 6]. The prospective, randomized Emory Warm Blood Cardioplegia Trial, which was designed to define the clinical myocardial benefits of warm heart surgery, documented effective myocardial protection but uncovered increased neurologic risk with the technique [1]. In elective coronary artery bypass grafting operations, warm heart surgery provided equivalent myocardial protection as determined by postoperative mortality, Q- wave infarct, and intraaortic balloon pump requirement, but displayed a threefold increase in neurologic events when compared with those patients undergoing hypothermic CPB with oxygenated crystalloid cardioplegia for myocardial protection. Progress in myocardial protection must provide better ventricular function preservation at no expense to the remainder of the biologic system. Hypothermic continuous blood cardioplegia with hypothermic perfusion may avoid these neurologic hazards of normothermia. This study was conducted to compare hypothermic continuous blood cardioplegia and hypothermic perfusion with normothermic continuous blood cardioplegia and normothermic perfusion to establish the benefit of hypothermic aerobic heart surgery. The study examined the two techniques for elective coronary artery bypass grafting operations with antegrade induction and then continu- Ous retrograde cardioplegia for improved distribution of cardioplegia in the setting of proximal coronary occlusion. The two groups displayed similarity in preoperative variables except that there were significantly more older patients, poorer ejection fractions, worse angina, and more reoperations in the hypothermic group. Even though the two study groups were nonrandomized and not concurrently treated, the techniques employed in each group were identical with regard to operation, perfusion, anesthesia, and preoperative and postopera-

4 1432 CRAVER ET AL Ann Thorac Surg WARM HEART SURGERY AND STROKE 1995;59: tive care. The current cold group study was initiated immediately as soon as the Emory Warm Blood Cardioplegia Trial had been completed [1]. The temperature of CPB and of the cardioplegia infusion was the only major variable that was changed for the cold group. The comparison of the data of the two groups we believe is valid. If any bias exists it would be in favor of the warm group as the patient descriptors suggest that the cold group had a higher incidence of factors increasing surgical risks. A change in cardioplegic solution did occur between the normothermic and the hypothermic groups. This was done because of the suggestion that an elevated blood glucose level may lead to an increased susceptibility to injury during transient cerebral ischemia [7]. The normothermic cardioplegia had been based on 5% dextrose whereas the cardioplegia for the hypothermic group was based on Plasmalyte. This led to a lower glucose level in the cardioplegia infusion and consequently lower systemic levels of glucose while on bypass in the hypothermic patients. This was also the case in our previous randomized trials of normothermic versus hypothermic cardioplegia techniques. Systemic glucose levels were monitored in our previous randomized trials, and multivariate analysis revealed that systemic glucose levels were not a multivariate predictor for stroke in this large series [1, 8]. It also should be noted that in the Toronto trial of warm versus cold antegrade continuous blood cardioplegia, 5% dextrose was used as the base cardioplegia solution. This trial (which in fact was performed at very mild hypothermia, not normothermia) had stroke levels that were equivalent to those of the hypothermic groups in the Emory series, despite the use of higher levels of glucose [9]. Systemic glucose levels were not systematically monitored and recorded in the hypothermic group in the current study. Operative data revealed a slightly higher number of grafts in the hypothermic group reflecting the prevalence of more triple-vessel disease. Fewer internal mammary arteries were used for bypass conduits in the hypothermic cohort, which, although it may have long-term implications, did not affect the immediate postoperative course of these patients. The duration of aortic crossclamping and CPB were similar between the groups. Myocardial protection as assessed by Q-wave infarct was similar between the groups; however, a trend to slightly higher mortality in the hypothermic group was observed. An increased incidence of clinical descriptors suggesting more severe disease and increased risk (poorer ejection fraction, worse angina, older age, and higher number of reoperations} were present in the hypothermic group and likely played a role in the slightly increased mortality and more frequent use of intraaortic balloon pumping. Statistical comparison did not reveal a significant difference in mortality among the two groups, and the only multivariate correlate of mortality was older age. In general, differences between myocardial protection regimens are better detected in the setting of metabolically compromised myocardium, when maximal protection of the myocardium is required to ensure adequate postoperative ventricular function [10]. In laboratory investigation of acute myocardial ischemia, hypothermic continuous blood cardioplegia delivery has demonstrated equivalent to improved protection of overall ventricular function when compared with normothermia [2]. Continuous delivery to provide aerobic electromechanical arrest and avoidance of ischemic intervals appears to be the element responsible for observed benefit of aerobic myocardial protection with temperature exerting only mild significance. The effectiveness of hypotherrnic continuous aerobic blood cardioplegia for myocardial protection was demonstrated in this investigation because results similar to those of the normothermia group were achieved in higher risk patients. Also, hypothermia may provide a second tier of protection when cardioplegia must be interrupted to improve visibility for construction of distal anastomoses. Hypothermia allows such ischemic intervals to occur under more favorable metabolic circumstances. Postoperative neurologic complications remain an important concern for cardiac surgeons. A reduced incidence of neurologic injury was identified in the hypothermic group in this study in comparison to a similar population in the Emory Warm Blood Cardioplegia Trial [1]. Multivariate analysis demonstrated an odds ratio of 1.76 for neurologic events in the normothermic group and also identified old age as a correlate for stroke. In addition, the warm heart surgery and warm cardioplegia were found to be independent of other correlates of stroke previously reported from this institution [11]. The majority of neurologic events presented as focal deficit on neurologic examination, suggesting an embolic nature of perioperative cerebral embarrassment. Including the observed difference in incidence of neurologic complications, a difference in the impact of these events on survival was observed with 1 in 3 of the normothermic stroke victims dying in the postoperative period. Neurologic injury related to CPB is often thought to be due to embolization into the cerebral vasculature during the operation. Embolic events that can occur during CPB can arrive from microscopic debris contained in the CPB circuit, atheroemboli from native atherosclerotic aorta, intracardiac thrombi, and air within the CPB circuit. All these and others can be etiologic agents of embolic cerebral injury during CPB. Cardiopulmonary bypass at normothermia produces substantially higher cerebral blood flow when compared with extracorporeal circulation at moderate hypothermia [12, 13]. Such a circumstance could produce increased exposure to a larger number of embolic events over a given time in the normothermic group, thereby increasing the probability of neurologic injury. Intracerebral vascular occlusive disease and perfusion pressure variations while on CPB also can produce areas of focal intracerebral ischemic injury. Hypotherrnia has long been established as a neuroprotective agent [14]. Cerebral ischemic injury is attenuated even with mild degrees of hypothermia as measured clinically, morphologically, and biochemically [15, 16]. The neurologic risk of CPB and the neuroprotection of

5 Ann Thorac Surg CRAVER ET AL ;59: WARM HEART SURGERY AND STROKE hypothermia provide a framework for understanding different neurologic outcomes after normothermic perfusion. The neurologic hazards of normothermic CPB initially were unappreciated in the earlier reports on application of warm heart surgery [3]. It is likely that several factors are responsible for the poorer cerebral tolerance of CPB at normothermia. Cerebral ischemic injuries produced at normothermia display larger zones of infarction, more severe cellular acidosis, and higher concentrations of neuronal injury markers when compared with equivalent injuries produced at hypothermia [15-17]. These investigations have demonstrated that cerebral ischemic events, whether embolic or occlusive, produce less cerebral injury when the brain temperature is lowered at the time the ischemic insult is incurred [15]. This observation is particularly true if the current ischemia is transient in nature [18]. This likely explains the clinical improvement to normalcy often observed after some early "strokes" when air embolization or hypoperfusion is suspected as the cause rather than in strokes due to larger particulate or thrombus embolization. It is likely that less well tolerated cerebral ischemia at normothermia and possibly an increased cerebral perfusion/emboli burden combined are responsible for the difference in neurologic complications observed with warm heart surgery. In conclusion, this study suggests that reducing the systemic perfusion temperature while on CPB may lessen the neurologic risk that has been observed with strict warm heart surgery. It also suggests that continuous hypothermic blood cardioplegia can provide myocardial protection that is equivalent to that observed with continuous normothermic blood cardioplegia. The clinical recommendation of this report is that as a patient's risk of perioperative stroke is increased, especially in the elderly, the systemic temperature of CPB should be lowered appropriately, which could reduce the incidence of perioperative stroke. References 1. Martin TD, Craver JM, Gott JP, et al. Prospective, randomized trial of retrograde warm blood cardioplegia: myocardial benefit and neurologic threat. Ann Thorac Surg 1994;57: Bufkin BL, Mellitt RJ, Gott JP, et al. Aerobic blood cardioplegia for revascularization of acute infarct: effects of delivery temperature. Ann Thorac Surg 1994;58: Lichtenstein SV, Ashe KA, EI-Daliti H, et al. Warm heart surgery. J Thorac Cardiovasc Surg 1991;101: Vaughn CC, Opie JC, Florendo FT, et al. Warm blood cardioplegia. Ann Thorac Surg 1993;55: Horsley WS, Whitlark JD, Hall JD, et al. Revascularization for acute myocardial infarction: superiori~ of myocardial protection with warm blood cardioplegia. Ann Thorac Surg 1993;56: Brown WM, Jay JL, Gott JP, et al. Warm aerobic blood cardioplegia: superior protection during revascularization for acute myocardial ischemia. Ann Thorac Surg 1993;55: Lanier WL. Glucose management during cardiopulmonary bypass: cardiovascular and neurologic implications. Anesth Analg 1991;72: Mellitt RJ, Weintraub WS, Craver JM, et al. The interrelationship of age and normothermic blood vs cold crystalloid cardioplegia on the incidence of stroke in elective coronary artery bypass grafting: results of the Emory Randomized Trial. Circulation 1993;88(Suppl 1): Naylor DC, Lichtenstein SV, Fremes SE, et al. Randomized trial of normothermic versus hypothermic coronary bypass surgery. Lancet 1994;343: Olinger GN, Po J, Maloney JV, et al. Coronary revascularization in high versus low-risk patients: the role of myocardial protection. Ann Thorac Surg 1975;182: Weintraub WS, Craver JM, Cohen CL, et al. Influence of age on results of coronary surgery. Circulation 1991;84(Suppl 3): Murkin JM. Anesthesia, the brain, and cardiopulmonary bypass. Ann Thorac Surg 1993;56: Schell RM, Kern FH, Greeley WJ, et al. Cerebral blood flow and metabolism during cardiopulmonary bypass. Anesth Analg 1993;76: Hoff JT. Cerebral protection. J Neurosurg 1986;65: Kuluz JW, Gregory GA, Yu ACH, et al. Selective brain cooling during and after prolonged global ischemia reduces cortical damage in rats. Stroke 1992;23: Moyer DJ, Welsh FA, Zager EL. Spontaneous cerebral hypothermia diminishes focal infarction in rat brain. Stroke 1992;23: Busto AU, Globus MY, Dietrich WD, et al. Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 1989;20: Ridenour TR, Warner DS, Todd MM, et al. Mild hypothermia reduces infarct size resulting from temporary but not permanent focal ischemia in rats. Stroke 1992;23: DISCUSSION DR DUKE E. CAMERON (Baltimore, MD): I enjoyed your paper very much. I have a question that concerns how well matched these two groups were. You cite in the abstract a number of variables, saying that both groups were well matched, but you did not cite one of the most important in terms of predicting stroke, that is whether or not there is a history of stroke. Are these two groups the same in terms of previous stroke or was previous stroke an exclusion criteron? DR CRAVER: No, we looked at that. There was no significant difference in their incidence of prior cerebral events or risk factors for cerebral events. DR CAMERON: Similarly, carotid bruits were not mentioned as to whether or not they played a role. DR CRAVER: We have really not paid a whole lot of attention to asymptomatic carotid bruits in terms of documenting them. We have taken the clinical tack that if patients are not symptomatic at the time, we do not work up asymptornatic carotid bruits. If they have had a previous event or if they have ongoing cerebral symptoms, then we do work those up. With findings of significant lesions, we electively have the vascular surgeons perform a carotid endarterectomy under local anesthesia, usually 2 days

6 1434 CRAVER ET AL Ann Thorac Surg WARM HEART SURGERY AND STROKE 1995;59: before the coronary bypass operation. With that we have had no increase in perioperative strokes. DR CAMERON: Finally, did you evaluate neurocognitive function, and how did you define stroke? DR CRAVER: We evaluated the neurocognitive function very carefully. Christine Morrow, who is an anesthesiologist with a special interest in this area, in the first group had 150 randomized patients picked with detailed neurologic examination involving psychometric testing by trained people preoperatively, immediately postoperatively in the hospital, and at 4 weeks postoperatively in the follow-up visit, and there was no significant difference. In the latter group, that degree of neuropsychometric testing was not done. The strokes we identified as focal neurologic deficits or psychological aberrations, confusional states, et cetera. In the warm group the incidence of focal deficits was 3.3%, which was significant. The others were 1.2%. In the cold group the incidence of focal deficits was 1.1% with virtually no confusional states. DR CHRISTOPHER J. KNOTT-CRAIG (Oklahoma City, OK): I enjoyed your paper very much. Do you have any suggestions or recommendations to make with regard to the temperature to which you rewarm your patients? In other words, do you think it is beneficial to rewarm them to a lower core temperature based on the findings that you presented today? DR CRAVER: We rewarm them slowly. We do not let the perfusate exceed 38 C, and we try to get them to 36 C systemically before coming off bypass, but it was a matter of warming patients slowly internally. And we are willing to take the time to do it, which was demonstrated by extended bypass interval. DR CHARLES C. CANVER (Madison, WI): Your results are somewhat surprising. In the warm and cold group of patients your cross-clamp time was essentially similar (40 minutes versus 46 minutes). If one agrees with your conclusion, 46 minutes on cardiopulmonary bypass would make a significant difference in cerebral protection between warm and cold groups. In our practice, we do not see any significant neurologic dysfunction in cold or warm cardioplegia patients when the bypass time is 60 minutes or less. However, we see increasing numbers of neurologic complications in patients undergoing combined coronary bypass and valve operations, redo procedures, and operations where prolonged cardiopulmonary bypass was required. My question is, do you have any data that show the incidence of neurologic events in isolated coronary artery bypass grafting, aortic valve replacement, mitral valve replacement, or combined operations in reference with the cold and warm temperatures? I think if you can show that there is significant difference among those subsets of patients, that would be more convincing evidence for your conclusion. DR CRAVER: Initially we tried to apply the warm cardioplegia program to everybody. In using warm techniques in the patients who have combined aortic valve disease and coronary disease (who I think are at increased risk for stroke) I had 2 patients of the first 20 who had no reason in the world to have a stroke but had a devastating stroke. So, I stopped, and it is just not something I think is good. I agree with the point you made: as patients have ischemic intervals that extend longer, to an hour, hour and a hall 2 hours, it is certainly more important during that time to lower the temperature. I think the incidence of strokes occurs related to bypass. It is increased by the lengthening of bypass. The longer bypass is the more risk you have; the emboli from the perfusion tubing, the atheroemboli from whatever source, air, et cetera. You have some degree of exposure no matter how long or short patients are on the pump, and the longer it is, the more the exposure. I think what we are demonstrating and what we feel is the case is that a brain that is warm is more subject to injury from these incidental events, whereas a brain that is cooler can tolerate them better. This was also brought out in that 7 of the 23 patients who had strokes in the warm group died of their stroke or died of complications of stroke, whereas of the 6 patients in the cold group who had strokes, none of them died. They all had focal deficits that got better; they went to rehabilitation and are improving. The devastating nature of the ischemic injury that occurs to a warm brain is truly magnified. Laboratory data suggest that too. DR RICHARD E. MICHALIK (Kingsport, TN): I know that there have been a lot of different approaches to neurologic evaluation of patients at Emory before operation. Did you go back and look at the people who had stroke and do some duplex scans or anything like that? The fact that there seems to be an older group here makes me sort of wonder. And the other thing was, was I right, the patient who spends a few days way, way out in left field, is that defined as a neurologic event? DR CRAVER: When we looked at the cold group versus the warm group in Dr Martin's paper, there was no difference in the neurologic risk or work-ups in either groups. In the latter group that we did, we would screen them ahead of time. If they had a symptomatic carotid bruit, they had those worked up and dealt with, and then they were entered in the trial just as though they were the elective bypass patients, and those were all included. Patients were not removed if they had a neurologic risk.