MB Creatine Kinase and the Evaluation of Myocardial Injury Following Aortocoronary Bypass Operation

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1 MB Creatine Kinase and the Evaluation of Myocardial Injury Following Aortocoronary Bypass Operation Claude du Cailar, M.D., Jean-Guy Maillk, M.D., William Jones, M.D., B. Charles Solymoss, M.D., Michel Chabot, M.D., Claude Goulet, M.D., Eric Delva, M.D., and Claude M. Grondin, M.D. ABSTRACT Myocardial injury was studied in 104 patients undergoing coronary artery grafting without cold chemical cardioplegia using the quantity of the isoenzyme MB of the creatine kinase liberated as an indicator. This method of evaluation, which is said to permit comparison of different techniques of myocardial protection, allowed us to consider the relative importance of several factors believed to have an influence on intraoperative myocardial injury. Indices of significance were duration of symptoms before operation, presence of chronic arterial hypertension, and the type of antiangina treatment employed. Other operative factors included severity of the arterial lesions, number of anastomoses performed, and duration of extracorporeal circulation and of aortic cross-clamping. Myocardial protection is a current problem. Although the beneficial effects of different forms of myocardial protection can be demonstrated readily in experimental models, it is, in contrast, more difficult to conduct such a study in man. The superiority of one method cannot be based solely on a good :postoperative course or on the incidence of unquestionable myocardial infarction since a large myocardial reserve often allows a myocardial injury of considerable degree (in general, subendocardial) to remain clinically and electrically silent [4]. The object of this study was not to compare the different techniques of myocardial protection but rather to establish a reference baseline for future com- From the Montreal Heart Institute, Montreal, Que, Canada. Accepted for publication Feb 27, Address reprint requests to Dr. Maille, Montreal Heart Institute, 5000 East, Belanger Street, Montreal, Que, HIT 1C8, Canada. parison of such techniques. In addition, the myocardial injury inherent in the technique of coronary artery grafting used in this institution prior to 1977 was calculated. For this purpose, the method of estimation of the size of a myocardial infarct as calculated from successive measurements of the isoenzyme MB of the creatine kinase (CK-MB) [21, 221 was used in patients undergoing coronary artery grafting [81. In the same group of patients, the factors having a potential influence on perioperative myocardial damage were studied. Material and Methods This study involves 105 patients operated on consecutively at the Montreal Heart Institute during Patients undergoing emergency operation were excluded. There was 1 operative death, which reduced the patient population to 104. There were 15 women and 89 men with a mean age of 51.7 years. Ten patients had a single aortocoronary bypass, 41 had two, 37 had three, 15 had four, and 1 patient had five grafts. All were operated on by means of the same technique. A Sarns roller pump and a Travenol bubble oxygenator (model 6LF) were primed with 5% dextrose and Ringer s lactate solution. Moderate hemodilution and hypothermia (mean values: temperature, 24 C; hematocrit, 27) were utilized. Cold chemical cardioplegia was not employed. Mean perfusion pressure was 90 mm Hg and pump flow was 2.08 LI min/m2. Decompression of the left ventricle was assured by a vent introduced through the left atrium. In most instances, the heart was fibrillated and defibrillated electrically. After each distal anastomosis, the aorta was unclamped. Rewarming of the patient was begun during the performance of the aortic anastomoses, during by Claude du Cailar

2 9 du Cailar et al: MB Creatine Kinase and Evaluation of Myocardial Injury which the heart was maintained in a state of ventricular fibrillation. Methodology Multiple samples for measurement of CK and its isoenzymes were taken from each patient: prior to the induction of anesthesia, before the start of extracorporeal circulation; 1 hour after the start of extracorporeal circulation; at closure of the chest; 3, 6, and 9 hours later; the following day at 8:OO and 16:OO hours; and once daily at 8:00 hours for seven days. Total CK and its isoenzymes were measured using a method previously described [8]. The CK-MB isoenzyme concentration, expressed in international units per liter, was plotted by computer in the form of a curve illustrating the variations of CK-MB as a function of time [81. Two variables formed the basis of this study: the peak of the CK-MB curve and the total quantity of enzyme liberated. The peak value usually occurs at the third postoperative hour [8]. Therefore, it can be concluded that the height of the individual peak at that particular moment is indicative of the importance of the intraoperative myocardial trauma. The total quantity of CK-MB liberated (Q) is calculated using the formula introduced by Shell and associates [21, 221 in their study of myocardial infarction: Q = K X BW x KdJEdt where K is the constant, BW represents body weight in kilograms, Kd is the coefficient of disappearance of CK-MB which is specific for each patient 1161, and JEdt represents the total serum activity of CK-MB during the first 72 hours and corresponds to the surface described by the curve. Whenever calculation of Kd was rendered difficult, the mean Kd from all patients was used ( ml-l). Calculation of the Kd was not possible in 44 patients due to a reascent of the curve or a plateau in the curve. In some of these instances, the number of points available during the descent of the curve was insufficient (< 5). Measurement of JEdt is done by planimetry and is expressed in international units per milliliter per minute. The degree of myocardial injury is directly proportional to the quantity Q and is expressed in creatine kinase gram-equivalents (CK-gm-Eq). The term myocardial injury seems to better reflect the alterations in surgical patients than the term infarct size used for medical infarct studies. During cardiac operation, infarction represents but one form of myocardial damage. The second part of this work involved the study of several variables associated with the preoperative and perioperative condition of each patient and thought to have an influence on the degree of myocardial damage. In the analysis of each variable, comparisons of total myocardial damage or Q and the peak of the CK-MB curve were performed using the Student t test. Normality of the sample distribution of the means was assumed because of the relatively large number of patients and the usual tendency for this type of variable to follow a normal distribution. The Fisher test of equality of variance was applied before performing the t tests. When the null hypothesis (m12 = ( ~2~) was rejected, the t test was computed based on the separate variance estimates. Results Myocardial lnjury and Peak of the CK-MB Curve All patients studied demonstrated an intraoperative elevation of CK-MB corresponding to a mean myocardial injury of 8.3 f 7.6 CK-gm-Eq. If the 22 patients in whom a perioperative myocardial infarction developed are removed from this group, the mean myocardial damage is 6.5 k 4.7 CK-gm-Eq. The mean CK-MB peak values for the two populations thus defined are k 10 IUL and 158 f 10.9 IUL, respectively. Analysis of Variables Statistical analysis of the different variables studied gave the following results: PREOPERATIVE FACTORS. The 53 patients having angina for more than 3 years demonstrated a greater myocardial injury than those whose symptoms were more recent (< 1 year) (Table 1). Likewise, the group of 20 patients with chronic hypertension had a peak significantly higher than that of normotensive patients. On the other hand, patients treated with propranolol had a lower peak CK-MB level than those receiving other antiangina medications or no treatment. Myocardial injury was significantly greater in the 86 patients with two or

3 10 The Annals of Thoracic Surgery Vol 29 No 1 January 1980 Table 1. Effect of Preoperative Factors on Extent of Myocardial Injury Patients and Time of Myocardial Injury Onset of Symptoms <1 yr >3 yr Arterial Hypertension Propranolol Yes No Yes No Presence of No. of Stenoses Stenosis >So% >80% 1 2 or more Yes No No. of patients Perioperative myocardial injury Intraoperative myocardial injury p = p = p = p = p = p = 0.02 Q = total quantity of the isoenzyme MB of the creatine kinase liberated; CK-gm-Eq = creatine kinase gram-equivalents. Table 2. Effect of lntraoperative Factors on Extent of Myocardial lnjury Duration of Duration of Duration of Cardio- Aortic No. of Cardiopulmonary pulmonary Cross- Aortic Bypass after Duration of Bypass Clamping Cross- Unclamping Anesthesia Patients and 125 (ave, min) (ave, 30 sec) Clampings 48 (ave, min) (ave, 5V4 hr) Time of Myocardial Iniuw <125 >125 <30 >30 0 or 1 2 or more <48 >48 <51/4 >51/4 No. of patients Perioperative myocardial p = p = p = 0.01 p = 0.03 p = 0.04 injury Intraoperative myocardial p = 0.04 p = 0.02 p = 0.01 p = 0.04 p = injury Abbreviations same as for Table 1. more stenoses greater than 5o0/o and in those with at least one stenosis greater than 80%. INTRAOPERATIVE FACTORS. Patients in whom cardiopulmonary bypass time exceeded the average demonstrated a higher peak CK-MB value and an increased myocardial injury (Tables 2, 3). In addition, patients undergoing prolonged cardiopulmonary bypass following aortic unclamping had higher peaks and greater myocardial injury than did those who had either a longer than average aortic cross-clamp time or two or more aortic cross-clamp periods. There was a major difference in the height of the CK-MB peak and myocardial damage between patients who had one or two vein grafts and those who had three or more. These differences remained significant in patients who had a single graft compared with those who had two or more. Moreover, patients with one or more grafts on the circumflex coronary artery had a higher CK-MB peak than those patients receiving grafts to the left anterior descending coronary artery or its branches. NOIGNIFICANT RESULTS. The following variables were not found to have a significant effect on the production of myocardial injury: preoperative electrocardiographic pattern of ischemia, positive exercise treadmill testing at low energy output, anginal threshold corresponding to a low rate-pressure product, occurrence of perioperative hypertensive episodes, duration of reperfusion between aortic crossclamp periods, and graft flow rates above and below 40 ml per minute (Table 4).

4 11 du Cailar et al: MB Creatine Kinase and Evaluation of Myocardial Injury Table 3. Effect of the Number of Bypass Grafts and the Site of the Graft on Myocardial lnjury No. of No. of Bypass Grafts Bypass Grafts Site of Graft Patients and Time of Myo- LAD, Diag Cx, Marg cardial Injury 1 2 or more 1 and 2 3 or more Others Others No. of patients Perioperative myocardial injury p = p = Intraoperative myocardial injury p = p = p = 0.04 LAD = left anterior descending coronary artery; Cx = circumflex coronary artery; Diag = diagonal branch; Marg = marginal branch; other abbreviations same as for Table 1. Comment Following experimental occlusion of coronary arteries, good correlations have been found between the anatomical size of the resulting infarct and that estimated by CK-MB measurements [21]. Similar findings have been described at postmorten examination following myocardial infarction in man [201. The relationship of CK-MB and its isoenzyme to clinical outcome 122, 241, hemodynamic state 12, 141, angiographic findings 1201, and estimated extent of the myocardial necrosis is further evidence of the reliability of this method of measurement of myocardial injury. Thus, the application of this method to explore myocardial damage inherent in coronary artery operations seems justifiable [81. However, the weak point of a similar extrapolation in surgical patients stems from the wide variations in plasma volume that take place during the perioperative period. These variations can arise from modification of the vascular contents such as hemodilution, transfusion, use of blood substitutes, and the administration of diuretics, or they can be secondary to changes in the vasomotor tone. CK is found exclusively in the plasma compartment following its absorption from the lymphatic system. Thus, any modification of the plasma volume could lead to important changes in the concentration of this enzyme. The effects of cardiopulmonary bypass on enzyme clearance by the reticuloendothelial system are unknown at the present time. Because of the limited number of samples taken during the first 12 hours following operation, it is not possible from the present study to define a relationship between the liberation of CK and the different surgical events, in particular the time of aortic unclamping. In spite of these criticisms, it seems justified to extract certain information from each of the variables analyzed in this study. Approximately 3 hours following conclusion of the surgical intervention [81, the peak of the CK-MB curve appears to represent the intensity of the intraoperative myocardial trauma but does not provide evidence for or against the occurrence of a perioperative infarction. Thus, an overly high peak is not synonymous with infarction but merely indicates an important degree of intraoperative myocardial trauma. The quantity Q, which has been associated with total myocardial injury, reflects the global sum of all CK-MB released during the perioperative period irrespective of the mechanism of enzyme release. The determination of the individual Kd used in the calculation of Q has come under some valuable criticism [231. Nevertheless, using the quantity Q or the area of the curve without consideration for the value of Kd yielded comparable results. Intraoperative myocardial injury was found to have occurred in all of our patients. Therefore, knowledge of the mean value for the population studied (or for the subgroup of patients without perioperative myocardial infarction) may be helpful in judging the improve-

5 12 The Annals of Thoracic Surgery Vol 29 No 1 January 1980 Table 4. Factors without a Significant Effect on Production of Myocardial lnjury Patients and Time of Myocardial Iniurv Metabolic Preoperative Equivalents Ischemic ECG (0, consumption) Changes Exercise Testing (ave, 5 mets) Yes No + - c5 >5 No. of patients 37 44= Perioperative myocardial injury Intraoperative myocardial injury =Excluded Q waves. ECG = electrocardiographic; other abbreviations same as for Table 1. - ment of techniques for myocardial protection in coronary artery grafting. In the present study, analysis of the factors responsible for myocardial injury showed that certain variables played little role. However, their involvement in the perioperative trauma could not be excluded. Patients who display an ischemic pattern on preoperative electrocardiogram or who have a positive exercise treadmill test at low energy output or an abnormally low rate-pressure product [7, 191 appear more susceptible to intraoperative myocardial injury. Hypertensive episodes secondary to hypersecretion of catecholamines or activation of the renin-angiotensin system are particularly frequent in coronary artery operations [MI. Increases in afterload and in myocardial contractility secondary to adrenergic stimulation may create imbalance in the oxygen supply and demand ratio, leading to ischemia in more vulnerable areas such as the subendocardium. Prompt treatment of these episodes by infusion of nitroprusside or by nitroglycerin certainly aided in masking their effects in this study. Reperfusion between two periods of aortic clamping during at least half of the clamping time was used to repay suspected oxygen debt in this series. Rigid adherence to this principle did not permit the finding of a significant effect of the length of reperfusion 1101 on the release of CK-MB. A recent study has shown that such a reperfusion can eliminate electrical signs of ischemia after cross-clamping [9]. No signifi- cant difference was found in the myocardial injury following bypass grafting with graft flows greater than or less than 40 ml per minute. This suggests that, in certain instances, the changes in the myocardium occurred before the anastomosis became functional and that a good graft flow is not necessarily synonymous with myocardial integrity. Documentation of myocardial infarction within the territory of patent grafts [l, 51 reinforces this hypothesis. When there is preexisting arterial hypertension, the extremely high CK-MB peak may be the result of left ventricular, hypertrophy plus ventricular fibrillation, an association which is known to further jeopardize the subendocardial perfusion [12]. Several studies have shown the protective effect of propranolol on the myocardium during periods of ischemia [13, 171. Propranolol may also counteract the secondary effects due to the release of catecholamines in the perioperative period [3]. This may explain the differences in the peak CK-MB values noted in this study with the various types of antiangina medical treatment employed in the preoperative period. No difference was noted between a sudden stoppage of propranolol before operation or its continuation to the time of operation. In the presence of moderate or critical experimental coronary stenoses, either cardiopulmonary bypass or induction of ventricular fibrillation alone may account for some ischemic phenomena [6, 111. Thus, the greater vulnerability of the myocardium noted in the

6 13 du Cailar et al: MB Creatine Kinase and Evaluation of Myocardial Injury Table 4. Continued Rate Pressure Product (ave, 22 x lo3) Perioperative Hypertension c22 >22 Yes No Short Reperfusion Graft Flow (mumin) Yes No <40 > presence of stenoses greater than 80% or multiple stenoses greater than 50% represents the clinical counterpart of this phenomenon. Increased myocardial injury in relation to the duration of cardiopulmonary bypass was also demonstrated. This may result from the abnormal tissue perfusion inherent to the nonpulsatile flow during cardiopulmonary bypass and to hemodilution and hypothermia. Furthermore, during hypothermia, the maintenance in a normal physiological state of certain variables such as blood ph may not be desirable. A certain degree of alkalosis seems preferable under these conditions [151. The influence of the number and duration of aortic cross-clamps on myocardial injury is logical. A few seconds following aortic crossclamping, the oxygen store at the tissue level is depleted. This triggers the immediate onset of anaerobic metabolism with its undesirable effects. The increase in myocardial injury with respect to the length of cardiopulmonary bypass following the last aortic clamping may stem from extended reperfusion of a fibrillating heart. The number of arteries bypassed enters the statistically significant list of variables through the necessarily greater frequency or duration of aortic cross-clampings. Maneuvers necessary for proper exposition of the circumflex coronary artery and the malfunction of venting mechanisms under these circumstances may cause a net increase in myocardial injury. References 1. Assad-Morel1 JL, Frye RL, Connolly DC, et al: Relation of intraoperative or early postoperative transmural myocardial infarction to patency of aortocoronary bypass grafts and to diseased ungrafted coronary arteries. Am J Cardiol 35:767, Bleifeld W, Mathey D, Hanrath P, et al: Infarct size estimated from serial serum creatine phosphokinase in relation to left ventricular hemodynamics. Circulation 55:303, Boudoulas H, Snyder GL, Lewis RP, et al: Safety and efficacy of continued propranolol administration through coronary bypass surgery (abstract). Am J Cardiol41:359, Buckberg GD: Left ventricular subendocardial necrosis (collective review). Ann Thorac Surg 24~379, Bulkley BH, Hutchins GM: Myocardial consequences of coronary artery bypass graft surgery: the paradox of necrosis in areas of revascularization. Circulation 56:906, Ciardullo RC, Shaff HV, Flaherty JT, et al: Myocardial ischemia during cardiopulmonary bypass: the hazards of ventricular fibrillation in the presence of a critical coronary stenosis. J Thorac Cardiovasc Surg 73:746, Cokkinos DV, Voridis EM: Constancy of pressure-rate product in pacing-induced angina pectoris. Br Heart J 38:39, Delva E, Maille J-G, Solymoss BC, et al: Evaluation of myocardial damage during coronary artery grafting with serial determinations of serum CPK MB isoenzyme. J Thorac Cardiovasc Surg 75:467, Engelman RM: Discussion of Koster JK Jr, Cohn LH, Collins JJ Jr, et al: Continuous hypothermic arrest versus intermittent ischemia for myocardial protection during coronary revascularization. Ann Thorac Surg 24:330, 1977

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