T techniques during cardiac operations has been to

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1 Warm Heart Surgery and Results of Operation Recent Myocardial Infarction Samuel V. Lichtenstein, MD, PhD, James G. Abel, MD, and Tomas A. Salerno, MD Division of Cardiovascular Surgery, St. Michael's Hospital and the University of Toronto, Toronto, Ontario, Canada for Revascularization procedures after recent myocardial infarction are associated with higher mortality and morbidity compared with elective coronary artery bypass grafting. Traditional methods of myocardial protection impose a further ischemic insult on already compromised myocardium. Continuous cold blood cardioplegia may eliminate ischemia but may still leave the heart anaerobic. Theoretically, warm aerobic arrest addresses both of these issues and may become an attractive alternative to standard hypothermic ischemic arrest in this setting. In 115 nonrandomized patients undergoing coronary artery bypass grafting within 6 hours to 7 days of an acute myocardial infarction, myocardial protection was provided with continuous cold (4 C) or continuous warm (37 C) blood cardioplegia. Fifty-one patients (after 1988) protected with warm blood cardioplegia were compared with a historical cohort of 64 patients (before 1988) protected with cold blood cardioplegia. Results indicate that the warm cardioplegia group had no mortality versus 1.9% for the cold group (p <.5), a myocardial infarction rate of 2.% in the warm versus 9.3% in the cold group, and use of intraaortic balloon pump of % versus 12.5%, respectively (p <.5). It is concluded that continuous warm aerobic arrest may minimize ischemia and anaerobic metabolism during the operative procedure, and may be of benefit to patients who have a limited tolerance to ischemic insult. (Ann Thorac Surg 1991;52:455-6) he initial, yet on-going, goal of myocardial protective T techniques during cardiac operations has been to prolong safe operating time by minimizing ischemic damage to the heart. This goal ultimately becomes an attempt at maintaining the myocardial energy supply at a level greater than its demand during the time of operation. Cardioplegic preservation therefore strives to optimize the ratio of energy supply to consumption and the capacity of the heart to utilize oxygen and substrate, whether aerobic or anaerobic. This capacity will be determined by the temperature and composition of the perfusate, and the distribution, adequacy, and duration of the infusion. During routine coronary artery bypass grafting procedures, the aorta is cross-clamped and intermittent cold cardioplegia (crystalloid or blood) is administered-cold anaerobic arrest. This allows for a dry and quiet operative field but leaves the myocardium potentially anaerobic for the duration of the cross-clamp period. The ability of blood cardioplegia to deliver and the myocardium to utilize oxygen and substrate is limited at low temperatures resulting in essentially cold, ischemic, anaerobic arrest [l]. It is known that patients who have sustained a recent myocardial infarction have higher morbidity and mortality rates associated with the revascularization procedure, which is directly related to the extent of the preoperative ischemic injury [2]. This is likely due to the fact that the already ischemic (infarcted or infarcting) Presented at the Twenty-seventh Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Feb 1%2, Address reprint requests to Dr Lichtenstein, St. Michael's Hospital #34 B, 3 Bond St, Toronto, Ont, M5B 1W8, Canada. myocardium is subjected to a second ischemic insult during the operative procedure. Continuous warm blood cardioplegia-warm aerobic arrest-has recently been introduced [3, 41 as an alternative method of myocardial protection, which may be of benefit in these high-risk patients. We herein report our initial clinical experience in historical sequential cohorts of patients operated on for angina after a recent myocardial infarction in whom the methods of myocardial protection and systemic perfusion differed only with respect to temperature. Material and Methods Pa tien ts Over a 4-year period, 115 patients underwent coronary artery bypass grafting for angina within 6 hours to 1 week of an acute myocardial infarction. Patients with mechanical defects, such as ischemic mitral insufficency and ventricular septa1 defect, were excluded from this series. Fifty-one of these patients were operated on after 1988 using continuous warm blood cardioplegia. These patients were compared with a historical cohort of 64 patients operated on before 1988 using continuous cold blood cardioplegia. The diagnosis of preoperative myocardial infarction was made by the appearance of a new Q wave on two or more contiguous electrocardiographic leads or elevation in the level of the MB isoenzyme of creatine kinase greater than 5 U/L when associated with prolonged ST elevation, left bundle-branch block, or poor R wave progression. In 1 patient in the cold group and 2 patients in the warm 1991 by The Society of Thoracic Surgeons /91/$3.5

2 456 LICHTENSTEIN ET AL Ann Thorac Surg 1991;52:455-6 group, the operation was performed early due to an episode of prolonged chest pain at rest with electrocardiographic changes despite maximal medical therapy, and it was not appreciated until later that a preoperative enzyme spike had occurred. Cardiac catheterization was performed in all patients to assess left ventricular function and the extent of coronary artery disease. The left ventricular ejection fraction was estimated from a single-plane contrast left ventriculogram on a scale of 1 to 4 (1, >.6; 2,.4 to.6; 3,.2 to.39; and 4, <.2). The degree of coronary artery narrowing was assessed from at least two views of each vessel and deemed serious if equal to or greater than 5% stenosis of the luminal diameter. Sixty-one percent of the patients in the cold group and 79% of the patients in the warm group underwent urgent revascularization. The urgent group consisted of patients with postinfarction unstable angina or unstable angina with unrecognized non-q-wave infarct (3 patients) who were revascularized within 72 hours of cardiac catheterization. Unstable angina was defined as prolonged (>15 minutes) rest angina with transient changes in the electrocardiogram. These patients normally came to the operating room from the coronary care unit receiving intravenous nitroglycerin, on intraaortic balloon pump counterpulsation, or both. Surgical Technique The technical aspects have been discussed in detail [4, 51. Briefly, standard cardiopulmonary bypass techniques were used through right atrial and aortic cannulation. After institution of cardiopulmonary bypass, systemic core temperature was lowered to 28 C in the cold group and maintained at 37 C in the warm group. The aorta was cross-clamped with the heart empty and beating, and 1.5 L of blood cardioplegia (hematocrit,.22 to.25; KCI, 27 to 3 meq/l) was infused into the ascending aorta at 4 C in the cold group and 37 C in the warm group, which invariably resulted in cardiac arrest within 3 seconds. In the cold group an iced saline pericardial bath was used to keep myocardial temperature at 15 C. Distal anastomoses were performed in order of angiographic importance, and the vein grafts were attached to a perfusion manifold from the cardioplegia line to permit independent control of aortic and graft flow [5]. Low-potassium blood cardioplegia (7 to 1 meq KCI/L) at 37 C or 4 C was infused into the ascending aorta and the bypass grafts when constructed at 5 to 1 mlimin. If blood obscured the operative field when the coronary artery was incised, aortic root cardioplegia was discontinued and the root vented. Similarly, cardioplegia flow in grafts to neighboring territories was interrupted if necessary and local control achieved with saline irrigation. On occasion cardioplegia flow was totally discontinued for up to 15 minutes. When the heart was returned to the pericardial cradle after completion of a distal anastomosis and while the graft was sized, cardioplegia was initially delivered into the aortic root at an accelerated rate, not unlike the standard use of a cardioplegia bolus. The internal mammary artery anastomoses were constructed last and left clamped until completion of all proximal anastomoses and removal of the aortic cross-clamp. Both the distal and proximal anastomoses were constructed during a single aortic cross-clamp period. The aorta was vented during construction of the proximal anastomosis while cardioplegia perfusion continued down the vein grafts, leaving the region at highest risk perfused to the end. Data and Analysis The data were collected in a prospective manner for the coronary surgery database and included information on operative deaths (death from any cause occurring within 3 days of the operation or during the hospital stay), perioperative myocardial infarction (defined as appearance of a new Q wave, left bundle-branch block, or poor R wave progression in association with elevation in level of creatine kinase MB isoenzyme greater than 5 units or exceeding 7% of the total creatine kinase concentration), and low output syndrome (ie, systolic blood pressure <9 mm Hg and cardiac index <2. L * min-' * m-' despite adequate preload and appropriate afterload reduction that required inotropic support or intraaortic balloon pump support). Data are presented as mean 2 standard deviation of the mean. Chi-square analysis without the continuity correction was used to compare the differences in number of deaths, perioperative myocardial infarction, spontaneous return to sinus rhythm, low-output syndrome, and the use of intraaortic balloon pump. Nonpaired t test was used to compare cross-clamp times and reperfusion times, defined as the time from removal of the aortic cross-clamp to attempted discontinuation of bypass. Results The demographics of both groups were similar with respect to age, sex distribution, and left ventricular grade (Table 1). There was, however, the tendency to operate on more New York Heart Association class IV patients in the warm group, which was also reflected in the number of urgent operations in this group (79% versus 61%) (Table 2). This is likely due to a more aggressive approach to unstable angina adopted recently, rather than preferring medical stabilization, as was done before There was no mortality in the warm group compared with 7 patients (1.9%) in the cold group ( p <.5). The cause of death in 4 patients was related to perioperative myocardial infarction, systemic hypoperfusion, and arrhythmia. Two patients died intraoperatively and 1 patient died of sepsis due to intraabdominal pathology. The operative mortality associated with a preoperative Q-wave myocardial infarction was 14% as compared with 9% in preoperative non-q-wave infarction. The perioperative myocardial infarction rate was 9.3% in the cold group and 2% in the warm group. One non-q-wave myocardial infarction occurred perioperatively in the warm group. Low-output syndrome occurred in 9 patients (14%) in the cold group and only 4 patients (6.3%) in the warm group. However, the difference in perioperative myocardial infarction and low-output syndrome between the two groups did not achieve statistical signif-

3 Ann Thorac Surg 1991;52:455-6 LICHTENSTEIN ET AL 457 Table 1. Demographic and Angiographic Data Variable Cold Group Warm Group Demographics No. of patients Male/female Age (years t SD) Q-wave MI NYHA class I I1 111 IV Angiographic data LV grade Vessels involved Left main LV = left ventricular; York Heart Association; 64 46/18 63 t (33%) MI = myocardial infarction; SD = standard deviation /12 67 t 1 21 (41%) NYHA = New icance due to the small number of patients. Postoperative intraaortic balloon pump support was needed in 8 patients (12.5%) in the cold group and in no patient in the warm group (p <.5). For those patients coming to the operating room with intraaortic balloon pump support, the need for postoperative support was evaluated by turning the pump off and evaluating the degree of hemodynamic stability. Return to spontaneous normal sinus rhythm was significantly increased in the warm group, Table 2. Operative Data and Results Variable Cold Group Warm Group Operative data Urgent 39 (61%) 4 (78%) Reoperation 8 (13%) 1 (2%) No. of grafts 3.3 t t.7 LIMA 7 (11%) 15 (29%) Cross-clamp (minutes) 58 t t 15.2 Reperfusion (minutes) 37 t k 2.3 Results Mortality 7 (1.9%) (%) Periop MI 6 (9.3%) 1(2%) Low output syndrome 9 (14%) 4 (6.3%) IABP 8 (12.5%) (%). Spontaneous NSR 9 (14%) 5 (98%)b a p <.5; p <.5 IABP = intraaortic balloon pump; LIMA = left internal mammary artery; MI = myocardial infarction; NSR = normal sinus rhythm. and the reperfusion time necessary after removal of the aortic clamp was significantly decreased in the warm group despite similar cross-clamp times in both groups (see Table 2). Although there was an increase in use of the left internal mammary artery as a bypass conduit in the warm group (p <.5), this likely reflects a change in surgical attitude toward this conduit in recent years. Comment Preoperative myocardial infarction has been shown to be an independent predictor of operative mortality in coronary artery bypass grafting after adjustment for other risk variables in several studies [&8]. In a multiinstitutional review, Kirklin and associates [9] demonstrated that a recent myocardial infarction increased the risk for early death after operation. Nevertheless, early operation has been proposed for this high-risk subgroup in the belief that infarct extension, reinfarction, and subsequent death are more common in the medically treated patients [lo, 111. Although initial surgical experience was disappointing with this patient population [7, 121, recently published results are more encouraging, with operative mortality varying between % and 1.5% but certainly exceeding that of elective operation [12, 131. This may be in part due to improvements in myocardial protection and provides an impetus for exploring alternative methods of myocardial protection in this high-risk group of patients. Cold hypothermic arrest, as practiced with intermittent blood or crystalloid cardioplegia, requires a mandatory period of ischemic arrest between infusions of the cardioplegia and also invokes the detrimental effects of hypothermia. Theoretical considerations and potential advantages of continuous warm blood cardioplegia have been discussed in detail elsewhere [4, 141. Briefly, electromechanical arrest alone [15] accounts for nearly all of the oxygen consumption of the heart, with little further benefit gained even with profound hypothermia [16]. Continuous aerobic perfusion of the arrested heart is, therefore, theoretically an ideal protected state of the heart that maximizes the oxygen supply and minimizes demand. Yau and colleagues [17] have shown that with average flow rates greater than 8 ml/min, warm blood cardioplegia keeps the heart relatively aerobic, inhibits lactate production, and spares energy stores. The technical constraints of coronary artery operation may, however, on occasion necessitate local vessel control or the interruption of global perfusion, resulting in a transient period of normothermic regional or global ischemia, and potential reperfusion injury. Intuitively this would seem particularly detrimental. However, as already discussed, there is only a slight further decrease in myocardial oxygen consumption in cold arrested hearts compared with those arrested warm [16]. Therefore, as originally demonstrated by Melrose and co-workers [15], an equal period of ischemia (<15 minutes) should be tolerated as safely with warm electromechanical arrest as with intermittent hypothermic cardioplegia. The mortality reported in the continuous cold car-

4 458 LICHTENSTEIN ET AL Ann Thorac Surg 1991;52:4554 dioplegia group in this study is comparable with that in the literature [6, 71. However, the reduced mortality in the warm cardioplegia group, most likely due to reduced and limited perioperative myocardial infarction (non-qwave), suggests that there may be advantages to this method of myocardial protection that are not as yet clearly understood. It is interesting to speculate that maintenance of the integrity of basal cardiac metabolism with normothermia may enhance the tolerance to ischemia, as well as the ability to shift from aerobic to anaerobic metabolism, and the capacity to deal with reperfusion after short periods of ischemia. Given that continuous perfusion cannot be achieved in all types of cardiac procedures, there may be a benefit conferred during ischemia at 37 C that offsets the slightly higher oxygen consumption. Opie [18] has suggested that the rate of anaerobic metabolism during ischemia ultimately determines cellular viability. We would postulate that perhaps intermittent normothermic ischemia permits the highest rate of anaerobic glycolysis and is the best adaptive state of the myocardium. Shaper and associates [19] have calculated that in the absence of electromechanical activity, anaerobic energy-producing pathways and cellular energy stores should be able to maintain the viability of myocardial tissues for many hours. Alternatively, intermittent warm ischemia and reperfusion may precondition the myocardium, improving the tolerance to ischemia [2, 211. The mechanisms responsible for this tolerance are likely temperature dependent. Many improvements in preoperative and postoperative care, anesthetic management, and the conduct of cardiopulmonary bypass have taken place over the time frame of this study. Therefore, the proof of a definitive clinical advantage of continuous warm blood cardioplegia awaits the results of randomized trials. It is suggested, however, that continuous warm aerobic arrest may confer an advantage on patients with limited tolerance to ischemia and anaerobic metabolism. Supported by grant MA 844 from the Medical Research Council. References 1. Magovern GJ Jr, Flaherty JT, Gott VL, Bulkley BH, Gardner TJ. Failure of blood cardioplegia to protect myocardium at lower temperatures. Circulation 1982;62(Suppl 1): Teoh KH, Christakis GT, Weisel RD, et al. Increased risk of urgent revascularization. J Thorac Cardiovasc Surg 1987;93: Lichtenstein SV, El-Dalati H, Panos A, Slutsky AS. Long cross clamp time with warm heart surgery. Lancet 1989;1: Lichtenstein SV, Ashe KA, El-Dalati H, Cusimano RJ, Panos A, Slutsky AS. Warm heart surgery. J Thorac Cardiovasc Surg 1991;11: Lichtenstein SV, Fremes SE, Abel JG, Christakis GT, Salerno TA. Technical aspects of warm heart surgery. J Cardiac Surg 199 1;6: Fremes SE, Goldman BS, Weisel RD, et al. Recent preoperative myocardial infarction increases the risk of surgery for unstable angina. J Cardiac Surg 1991;6:2-12. Dawson JT, Hall RJ, Hallman GL, Cooley DA. Mortality in patients undergoing coronary artery bypass surgery after myocardial infarction. Am J Cardiol 1974;33: Floten HS, Ahmad A, Swanson JS, et al. Long term survival after postinfarction bypass operation. Early versus late operation. Ann Thorac Surg 1989;48: Kirklin JW, Naftel DC, Blackstone EH, Pohost GM. Summary of a consensus concerning death and ischemic events after coronary artery bypass grafting. Circulation 1989;79(Suppl 1): Ochsner JL. Early bypass operation after acute myocardial infarction. Ann Thorac Surg 1989;48:75-1. Weisman HF, Healy B. Myocardial infarct expansion, infarct extension and reinfarction: Pathophysiologic concepts. Prog Cardiovasc Dis 1987;3: Hill JD, Kerth WJ, Kelly JJ, et al. Emergency aortocoronary bypass for impending or extending myocardial infarction. Circulation 1971;44(Suppl 1):lOEilO. Kouchoukos NT, Murphy S, Philpott T, et al. Coronary artery bypass grafting for post infarction angina pectoris. Circulation 1989;79(Suppl 1):6&%72. Lichtenstein SV, Salerno TA, Slutsky AS. Warm continuous cardioplegia versus intermittent hypothermic protection during cardiopulmonary bypass: pro and con. J Cardiothorac Anesth 199;4: Melrose DG, Dreyer 8, Bentall HH, Baker JBE. Elective cardiac arrest: preliminary communication. Lancet 1955;2:21-2. Bernhard WF, Schwarz HF, Malick NP. Selective hypothermic cardiac arrest in normothermic animals. Ann Surg 1961; 153: Yau TM, Weisel RD, Mickle DAG, et al. Optimal delivery of blood cardioplegia. Circulation (in press). Opie LH. Importance of glycolytically produced ATP for the integrity of the threatened myocardial cell. In: Piper HM, ed. Pathophysiology of severe ischemic myocardial injury. Dordrecht: Kluwer Academic Publishers, 199: Schaper W, Binz K, Sass S, Winkler B. Influence of collateral blood flow and of variations in MVO, on tissue-atp content in ischemic and infarcted myocardium. J Mol Cell Cardiol 1987;19: Murray CE, Vincent RJ, Reiner KA, Jennings RB. Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res 199;66: Schott RJ, Rohmann S, Braun ER, Schaper W. Ischemic preconditioning reduces infarct size in swine myocardium. Circ Res 199;66: DISCUSSION DR RICHARD M. ENGELMAN (Springfield, MA): Thanks to the authors, I have had the opportunity to read the manuscript, which was highly beneficial in formulating a rational discussion. What they have shown in a retrospective analysis is that normo- thermic perfusion and normothermic blood cardioplegic preservation provided significantly improved mortality and morbidity compared with hypothermic perfusion and preservation. During this 4-year time frame they used only antegrade, not retrograde

5 Ann Thorac Surg 1991;52:455-6 LICHTENSTEIN ET AL 459 cardioplegia, thus missing the presumed benefits of immediate perfusion of ischemic, stunned, or infarcted myocardium. Regardless of this, they had zero mortality and one perioperative infarct in the 51 warm patients, 1 of whom were undergoing reoperations, and all of whom were having postinfarction angina from 6 hours to 1 week after infarction. We must therefore consider what is so special about normothermia versus hypothermia. With hypothermia, there is a marked shift to the left of the oxyhemoglobin dissociation curve. This means that cold blood will have to come to a very low oxygen tension to release its oxygen into the myocardium. This is not true at normothermic levels, where the oxygen content of arterial blood in the pump is greater than 15 ml of oxygen per 1 ml of blood, most of which oxygen is available for aerobic metabolism. In our own prospective analysis of three cardioplegic approaches using antegrade for arrest and retrograde for maintenance cardioplegia, my colleagues and I were unable to distinguish cold blood from warm blood preservation but found that there was increased malonaldehyde generation during reperfusion only in the cold crystalloid group. Further, we found that there was increased creatine kinase-mb generation during the first 24 hours after operation only in the cold crystalloid group, whereas cold blood and warm blood preservation were essentially identical. Dr Lichtenstein, first, could you please elaborate on your thoughts, which were briefly mentioned in the manuscript, regarding warm preservation and myocardial preconditioning? If indeed the process of warm preservation leads to preconditioning, a feature of this reported by Dr Shaper s laboratory from Germany could be increased messenger RNA, a reflection of altered gene expression, leading to improved myocardial energy levels and sarcolemmal membrane integrity, clearly a beneficial effect of warm preservation. Second, could you possibly explain how you and Dr Salerno avoided infarction in the warm group when only antegrade cardioplegia was administered and the left internal mammary artery, which was used in 15 patients, was allowed to remain clamped until all proximal and distal vein grafts were completed? It is remarkable to me that you were able to avoid infarction in this group of patients, particularly in patients who were so critically ill. DR GEORGE E. CIMOCHOWSKI (Wilkes-Barre, PA): I rise to congratulate Lichtenstein and associates on their innovative thinking. Actually, I got involved in this procedure about 3 months ago in a patient with a very high level of cold agglutinins, with my associate, John Anderson. We commenced a small, prospective, consecutive series of patients at Wilkes-Barre General Hospital over the past couple of months. We have only been there about 6 months, so we compared our first 93 patients receiving antegrade cold cardioplegia with 52 patients receiving retrograde warm cardioplegia. They were a group similar to that of Dr Lichtenstein: 68 years of age, 29% female, 26% diabetic, 26% with a recent myocardial infarction, and 37% with left ventricular hypertrophy. We used 4 ml of antegrade warm cardioplegia to stop the heart and then used continuous retrograde in each case, occasionally turning it off for a distal, maintained a pressure of 18 to 22 mm Hg, which is about half of what you would see with cold. We had flow rates easily of 1 to 15 ml/min, and there were no venous injuries using the retrograde cardioplegia. Now, we used blood cardioplegia for both. In the retrograde group we used 22 meq of potassium for the high dose of 4 ml antegrade, and then continuous at 7 meq retrograde. One thing we did notice, when we took the cross-clamp off, the potassium level was 5.7 meqil, and that was substantially higher than what we are used to. And, if fact, when you take the clamp off, there are very bizarre electrocardiographic complexes (Some of our perfusionists call them tombstone electrocardiograms). These are due to the hyperkalemia, but within a few minutes this washes out. In only 1 patient out of 52 did we have to treat that, as within a few minutes you see a normal-looking electrocardiogram. The mean time to stop the heart is 38 seconds, just like that of Lichtenstein and associates. Finally, we vented the aortic root, used no topical saline solution, and maintained systemic perfusion at 34 C in case there was a perfusion accident. The warm cardioplegia was going in at 37 C. We prospectively evaluated 52 patients. Forty-six were undergoing isolated coronary artery bypass grafting, 6 valve operations, double valve, and valve coronaries. It is interesting that with this technique we were able to use internal mammary arteries in all of the coronary cases. In fact, we are averaging 1.4 arterial grafts per patient. We compared the two groups. The mortality was low in both, 1.1% and %. Perioperative myocardial infarction rate is about the same in each group. There was significantly less phrenic nerve paralysis in the warm group, as one would guess because we were not cooling. Inotropic usage dropped from 52% to 11%. We counted using inotropes as little as 5 minutes coming off the pump. So 89% of the warm group came off with only a nitroglycerin drip. Atrial fibrillation was markedly reduced from 21% to 5.7%. If you like to do arterial vascularization, this facilitates it. We had a patient with a free gastroepiploic artery graft to the obtuse marginal, a left internal mammary artery graft to the left anterior descending, a free right internal mammary artery graft to the right coronary artery, and one vein graft. Now, we found it particularly useful on a difficult case such as was described this morning with proximal dissections. We had a patient with a large left hypertrophic ventricle from aortic stenosis. I created a serious iatrogenic complication. Early in the series, I gave warm antegrade cardioplegia into the aortic root. I perforated the left main, dissected it, and dehisced the aorta off the annulus. This was in a 3-year-old man whose father worked in our hospital. We took down the left internal mammary artery graft to the left anterior descending on the pump, placed a vein graft to the circumflex artery, and fixed the aorta. After 5% hours on the pump and a cross-clamp time of 4% hours with continuous warm retrograde cardioplegia, he came off bypass with only a nitroglycerin drip. I have a few questions for Dr Lichtenstein. Is warm retrograde cardioplegia better distributed because we do not have a cold vasospastic phenomenon? We think there are no contraindications. Do you think there are any? Atrial activity occurs; we have ignored it. What is your experience? How do you minimize hyperkalemia after removal of the aortic cross-clamp? Finally, would you comment on the thought of this being a superior way to protect the donor heart for heart transplants? DR LICHTENSTEIN: I thank Dr Engelman and Dr Cimochowski for their kind comments. Dr Engelman asked me to comment on the issue of potential preconditioning. It is certainly of interest to us. As I mentioned, if one can run warm blood cardioplegia continuously, it is hard to argue with that as representing a near-ideal state of protection. This is usually easily achieved in valvular operations; however, in coronary bypass operations technical constraints necessitate repeatedly interrupting the flow. There is evidence in the literature, as Dr Engelman alluded to, that suggests that short periods of intermittent normothermic ischemia actually precondition the heart and seem to protect against a greater insult at a later period of time. In other words,

6 46 LICHTENSTEIN ET AL Ann Thorac Surg 1991; in animal experiments short periods of ischemia at normothermia before ligation of the left anterior descending coronary artery results in a smaller infarct than acute ligation of the left anterior descending coronary artery. This phenomenon is being looked at in Dr Slutsky's laboratory in Toronto, and preliminary results suggest that normothermic ischemia gives rise to potentially protective heat shock proteins, a nonspecific stress-induced protein. I really cannot comment any further on that other than it is an interesting and likely important finding. There was no significant difference in the perioperative infarct rate in the warm group over the cold continuous group, although the trend for reduction was certainly there and with larger numbers it may very well prove to be significant. Those of us who use a semicontinuous method of cardioplegia, whether it be down vein grafts or retrograde coronary sinus perfusion, have long ago come to realize that blood is ubiquitous and distributes everywhere in the vasculature. The question in terms of protecting against perioperative infarct really becomes one of adequate amount of perfusion for the electromechanically arrested state. Whenever possible we like to graft a diagonal or a posterior descending artery feeding the left anterior descending coronary artery territory if an internal mammary artery is being used with the antegrade approach. Although there are theoretical advantages of distribution beyond stenosis to retrograde cardioplegia, many of these are clinically unimportant and are counterbalanced by the drawbacks related to retrograde perfusion itself. Dr Cimochowski asked a number of pertinent questions. Since we started using continuous warm cardioplegia both antegrade and retrograde we noted a reduced coronary vascular resistance, which may possibly be due to the absence of cold vasospasm. In fact, with warm retrograde cardioplegia our coronary sinus pressures rarely get above 2 mm Hg even at flow rates in excess of 15 ml/min, which initially caused us great concern regarding the position and location of the cannula. The only contraindication to retrograde warm cardioplegia would be a congenital anomaly such as an unroofed coronary sinus, in which case very little of the cardioplegia would be delivered into the coronary vasculature. It was actually Dr Engelman who called and made us aware of this potential problem with retrograde warm perfusion, which he unfortunately experienced in one of his patients. One would of course not use retrograde cold cardioplegia in that situation either. When atrial activity occasionally occurs we too have ignored it. We have not seen any clinical sequelae attributable to intraoperative atrial activity, with most patients spontaneously reverting to normal sinus rhythm after removal of the cross-clamp. Hyperkalemia has not been a problem for us thanks to the interest and involvement of our anesthetists, who pretreat with glucose and insulin or diuretics if the systemic potassium level is elevated before the removal of the cross-clamp. In terms of donor heart protection, Dr Feindel in Toronto and Dr Murphy in Halifax frequently perfuse the donor heart with warm blood cardioplegia as soon as it comes into the operating room. Drs Feindel and Fremes in Toronto are looking at a normothermic perfusion system in arrested hearts for long-term preservation. Unfortunately, at the present time it still remains cumbersome and not clinically practical. I think a major advantage of warm blood cardioplegia, particularly if it can be run nearly continuously, is in the problematic cases with prolonged cross-clamp times and in complex high risk procedures, as in the case presented by Dr Cimochowski. As his experience and ours have shown, ischemic time is relatively independent of cross-clamp time. The cross-clamp can be on for 4% hours and the true ischemic time can in fact be only minutes. I think that is a major technical advantage of this conceptual framework.