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Effect of intraoperative propranolol on serum creatine kinase MB release in patients having elective cardiac operations
J
THoRAc CARDIOVASC SURG
88:562-566, 1984
Effect of intraoperative propranolol on serum creatine kinase MB release in patients having elective cardiac operations Intraoperative beta blockade has been evaluated as an adjunct to hypothermic cold blood potassium cardioplegia by quantitating semm creatine kinase MB release. RandOmization of 80 patients having coronary artery bypass grafting and 18 patients having valve replacement with or without bypass grafting resulted in 46 of the former andseven of the latter receiving propranolol 0.05 mg/kg 4 to 5 minutes before aortic cross-clamping. Among patients having bypass grafting, infarct size (in gram-equivalents) was 7.9 ± 0.7 gm-Eq for the propranolol group and 10.3 ± 0.8 (p < 0.05) for the control group. Ischemic times were 71.6 ± 2.8 and 78.3 ± 3/4 minutes (p NS~ respectively. In valve replacement, infarct size was 9.9 ± 1.9 gm-Eq for those receiving propranolol and 12.6 ± 2.0 (p = NS) for the control subjects; ischemic times were 99.4 ± 12.5 and 80.5 ± 5.7 minutes, respectively. When the two groups receiving propranolol were combined, infarct size was 8.2 ± 0.6 gm-Eq versus 10.9 ± 0.7 (p < 0.01). When ischemic time was plotted against infarct size, analysis by tinear regression revealed a significant correlation for patients receiving propranolol and having bypass grafting (p < 0.01) and for all patients receiving propranolol (p < 0.01~ These data delllODitrate a modest reduction of infarct size with intraoperative propranolol as an adjunct to our standard management of patients having aortic cross-clamping. Quantitation of creatine kinase MB release is the best clinically available method for assessing alterations in techniques of myocardial preservation.
=
Parinan S. Rao, Ph.D.,* Frances E. Brock, B.S., Kevin Cleary, R.N., Hiltrud Mueller, M.D.,* and Hendrick B. Barner, M.D., St. Louis, Mo.
h e advent of hypothermic potassium cardioplegia and its widespread employment have improved intraoperative myocardial preservation, with a reduction in perioperative myocardial injury and perhaps a decrease in operative mortality. Despite this progress, further improvement in techniques of myocardial preservation is desirable and needed. However, deliberate alterations in myocardial preservation methodology are difficult to assess because operative mortality and the incidence of perioperative infarction are already low. Additionally, the latter may result from technical errors or existing From the Departments of Medicine (Cardiology) and Surgery, St. Louis University, St. Louis, Mo. Received for publication Oct. 17, 1983. Accepted for publication Dec. 27, 1983. Address for reprints: Henrick B. Barner, M.D., Department of Surgery, St. Louis University Medical Center, 1325 South Grand Blvd., St. Louis, Mo. 63104. *Present address: Montefiore Medical Center, III East 210th St., Bronx, N. Y. 10467.
562
coronary disease rather than from the technique of myocardial preservation. Release of creatine kinase MB isoenzyme (CK-MB) has been used to determine perioperative myocardial injury by noting the peak serum level'? or by measuring the quantity released.?" Although infarct sizing from CK-MB release is an accepted technique,":" it is not without controversy." Nevertheless, it would seem to be the best method currently available to assess subtle myocardial injury and to discern effects of alterations in techniques of myocardial preservation,"8,19,20 We report on myocardial injury by serial CK-MB analysis in patients having elective operation who were randomized into Group 1 (propranolol) or Group 2 (no propranolol) and who received cold blood potassium cardioplegia as we have used it since 1977. 21 Methods This study began in October, 1980, and ended in December, 1981. During a 10 month period before the study, we administered propranolol into the pump
Volume 88 Number 4
CK-MB release 5 6 3
October. 1984
before cross-clamping. Before the start of the study, five patients received propranolol (0.05 ng/kg) into the reservoir of the extracorporeal circuit and had arterial blood (radial artery) samples drawn 4 to 5 minutes later when the aortic cross-clamp was applied. Propranolol plasma levels were 80 to 100 mg/rnl and as such represented adequate beta adrenergic blockade. Patients included in the study had their operations on Monday or Tuesday of each week so that sampling for serum CK-MB would be complete by the weekend. Patients having coronary bypass grafting (CABG) were included as were patients having valve replacement with or without CABG. Beta blockers were being received by many patients, and these, along with all other cardiovascular-directed medications, were continued through the evening of the day prior to operation. Patients were randomized according to the last digit of the hospital number into the propranolol group (Group 1) or the no propranolol group (Group 2). Propranolol was given as a bolus (0.05 mg/kg) into the reservoir of the extracorporeal circuit at the onset of cooling, which was 4 to 5 minutes before the application of the aortic cross-clamp. Immediately after placement of the cross-clamp, blood at 12° ± 2°C containing potassium chloride 25 mfiq/L was introduced into the aortic root in a volume of 400 ± 100 ml over 2 to 4 minutes. Reinfusion of 300 ± 100 ml was performed every 20 minutes. For aortic valve replacement the initial bolus was given via the aortic root (if the valve was competent), and subsequent boluses were divided between the two coronary ostia. Crushed ice made from sterile lactated Ringer's solution was placed about the heart. The ice was separated from the left phrenic nerve and the diaphragm by an isolation pad (Bjork-Shiley) and renewed with each cardioplegic infusion. Myocardial temperatures were not measured in this study, but when measured in hearts receiving this standard myocardial protection they ranged from 8° to 18° C. Blood for the determination of CK-MB was drawn when the patient arrived in the operating room, 1 hour after the onset of the operation, at the conclusion of the operation (in the operating room), and at postoperative hours 1,2,3,4,6,8, 12, 18,24,30, 36, 42, 48, 66, and 72. Electrocardiograms were obtained preoperatively and on postoperative days 1, 3, and 5. Description of assay and method of calculation. Plasma content of total CK was measured according to the modified Rosalki" method using the Calbiochem CK-Superstat Pak Kit (No. 869414). The normal values (30° C) ranged from 8 to 80 U/L (n = 100). The heart isoenzyme CK-MB was qualitatively visualized by the
electrophoresis method and quantitated by an irnmunoinhibition method using the Eskachem CK-MB Kit (No. 86239). The normal values at 30° C ranged from 0 to 6 U/L (n = 78). The reproducibility of the assay for duplicates in the range of 5 to 50 U/L is 7.1% (n = 10). Infarct size (IS) was calculated according to the formulas of Roberts, Henry, and Sobel":
= ~CK-MB
IS MB (CK.gm-Eq)
. K.I x DV x body weight (gm) p CK-MB . CK-MBnonna l - CK-MBinfa
Values used for the constants are as follows: ~ CK-MB is the area under the serial CK-MB - time (t) curve. K, = 0.0017 (decay constant determined in 10 patients with uncomplicated myocardial infarction). Distribution volume (DV) = 44 ml/kg, PCK-MB = 0.15. CK-MB normal = 136 U/gm wet tissue (300c). CK-MBinfarct ed = 35 U/gm wet tissue (3ooC).
Results Two patients with a perioperative myocardial infarction (new Q wave) were excluded. Of 80 patients having CABG, there were 46 in Group 1 (propranolol) and 34 in Group 2 (no propranolol). Oral beta blockers were being taken by 35 of 46 patients (76%) in Group 1 and 21 of 34 (62%) in Group 2. Of 18 patients having valve replacement with or without CABG, oral beta blockers were being taken by one of seven in Group 3 (propranolol) and one of 11 in Group 4 (no propranolol). Table I summarizes the results. In patients having CABG, infarct size (gram-equivalents of myocardial injury) was 7.9 ± 0.7 gm-Eq in those receiving intraoperative propranolol and 10.3 ± 0.8 gm-Eq (p < 0.05) in the control subjects. Ischemic time was 71.6 ± 2.8 minutes in the propranolol group and 78.3 ± 3.4 minutes (p = NS) in the control group. In patients having valve replacement, infarct size was 9.9 ± 1.9 gm-Eq in the propranolol group versus 12.6 ± 2.0 gm-Eq (p = NS) in the control group. Ischemic time was 99.4 ± 12.5 minutes in the treated group versus 80.5 ± 5.7 (p = NS) in control patients. When data were combined for CABG and valve replacement patients, infarct size was 8.2 ± 0.6 gm-Eq for those receiving propranolol and 10.9 ± 0.7 (p < 0.01) for the control group. Combined ischemic time was 75.3 ± 3.2 minutes for the treatment group versus 78.8 ± 2.9 (p = NS) for the control group. Data were analyzed by linear regression, in which infarct size was plotted against ischemic time. There was a significant correlation for patients having CABG and receiving propranolol (r = 0.4479, P < 0.01) and for all patients receiving propranolol (r = 0.4799, P < 0.01).
The Journal of Thoracic and Cardiovascular Surgery
5 6 4 Roo et al.
Table I. Ischemic time and infarct size for control and treated patients Coronary bypass Group I: Propranolol No. Ischemia time (mean ± 1 SEM) Infarct size (gm-Eq ± 1 SEM) Correlation coefficient
)
46 71.6 ± 2.8 7.9 ± 0.7* 0.4479t
Valve replacement!
Group 2: No propranolol
Group 3: Propranolol
34 78.3 ± 3.4 10.3 ± 0.8* 0.0328
7 99.4 ± 12.5 9.9 ± 1.9 0.5830
I
Group 4: No propranolol 11 80.5 5.7 12.6 ± 2.0 0.5313
*p < 0.05. tp <0.01. :j:Three patients in the propranolol group and one patient in the control group had associated coronary bypass.
Discussion Release of CK-MB from the myocardium in association with cardiac operation has been related to the technique of cardioplegia,II the duration of ischemia, 11.12 and myocardial temperature." Significantly greater quantities of enzyme were released in patients who had a perioperative myocardial infarction (new Q wave). Furthermore, an intermediate group has been identified in which less enzyme is released than for the infarct group but more than is noted for patients having optimal myocardial preservation. 5, 9 Careful sampling has determined that CK-MB will be released in all patients having cardiac operations,8.II.13,14 although it has been concluded by some that this does not always occur.l" It is also apparent that even with minimal (13 minutes) myocardial ischemia and what would be acknowledged by many as optimal myocardial protection (hypothermic crystalloid cardioplegia with a myocardial temperature of 15° C), there is an infarct size of 2.3 ± 1.2 gm-Eq." Five to 15 minutes of warm ischemia in the experimental animal is thought to be the minimal insult capable of inducing detectable but reversible myocardial injury, but has not been correlated with CK-MB release.>" Although hypothermia should increase the duration of injury-free ischemia, there may be injury related to the use of hyperkalemic cardioplegia which may damage some myocytes and cause release of CK-MB. The fact that there was a myocardial injury of 2.3 gm-Eq despite an ischemic time of only 13 minutes would suggest that all cardiac operations in which there is aortic cross-clamping are associated with myocardial injury, and even when both coronary arteries are perfused with blood during aortic cross-clamping there is CK-MB detectable in the serum." The time course of release of CK-MB is significant in that it reaches a peak 2 ± 0 hours postoperatively in the patient who has an uncomplicated course and is free of conventional criteria for myocardial infarction. By contrast, in the patient with acute myo-
cardial infarction presenting to a coronary care unit, the peak serum level is attained 17 ± 1 hours after the onset of symptoms." Postoperative patients having Q-wave evidence of myocardial infarction have a greater peak and longer duration of serum CK-MB release than patients without additional evidence of infarction.t'" 14 Thus, this would seem to be the best method currently available for assessing subtle myocardial injury and discerning improvement in techniques of myocardial
preservation.v 25.26
We have found an infarct size of 7.9 ± 0.7 gm-Eq with a mean cross-clamp time of 71.6 ± 2.8 minutes, which compares with 6.1 ± 1.3 gm-Eq during 67 minutes of ischemia in patients having isolated CABG with hypothermic crystalloid cardioplegia.'? This represents a comparison of our patients receiving propranolol and their patients having "rapid" pressurized cardioplegia. Our patients not receiving propranolol had 10.3 ± 0.8 gm-Eq of injury with a mean ischemic time of 78.3 ± 3.4 minutes, whereas their patients having less rapid cardioplegic infusion had 9.2 ± 0.4 gm-Eq of injury with a mean cross-clamp time of 65 minutes." Comparison of data between institutions lacks validity because of differences in and continuing evolution of laboratory methods for measuring serum CK-MB. The importance of determining perioperative infarct size with CK-MB determinations lies in the use of this approach for assessment of alterations in techniques of myocardial preservation, as exemplified by the use of high-flow cardioplegia lO, 1I or intraoperative beta blockade. Preoperative therapy with beta blockers has been found to reduce intraoperative infarct size (defmed as the peak level of serum CK-MB) but not perioperative infarct size (defmed as the total gram-equivalents of myocardial injury)." It can be argued that because more patients in Group 1 than Group 2 were receiving oral beta blockers, this may have reduced infarct size and therefore the two groups are not comparable. On the
Volume 88 Number 4 October, 1984
other hand, this would support the position that beta blockade is advantageous whether it is preoperative or intraoperative. Groups 3 and 4 are more comparable in this regard, as one patient in each group received oral beta blockers. Beta blockade has reduced ischemic myocardial injury associated with experimental coronary artery occlusion.>" Recovery from global myocardial ischemia was improved by preischemic propranolol, regardless of whether the myocardium was normothermic or hypothermic." There is evidence to suggest that reduction of myocardial contractility through beta blockade, in addition to the use of hypothermic potassium cardioplegia may promote the preservation of myocardial energy reserves." Beta blockade has been employed to prevent myocardial contracture in association with ischemia.'>" These experimental data support the use of beta blockade for preservation of ischemic myocardium and provide a perspective for beta blockade as an adjunct to hypothermic potassium cardioplegia. The failure of infarct size to correlate with ischemia time in the non propranolol patients would suggest that within a certain time range there are other important factors that determine the extent of myocardial injury. The use of beta blockade must obviate some of these factors and allow ischemic time to become a relatively more important determinant of infarct size. Dr. John Standeven provided the statistical analysis, and Kathy Illyes typed the manuscript.
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REFERENCES Balderman SC, Bhayana IN, Steinbach JJ, Masud ARZ, Michalek S: Perioperative myocardial infarction. A diagnostic dilemma. Ann Thorac Surg 30:370, 1980 Bleese N, Doring V, Kalmar P, Pokar H, Polonius MJ, Steiner D, Rodewald G: Intraoperative myocardial protection by cardioplegia in hypothermia. J THORAC CARDIavASC SURG 75:405, 1978 Pyle RB, Blomber DJ, Burke MD, Lindsay WG, Nicoloff DM: CPK-MB isoenzyme. Use in diagnosis of acute myocardial infarction in the early postoperative period. J THORAC CARDIOVASC SURG 71:884, 1976 Roberts AJ, Combes JR, Jacobstein JG, Alonso DR, Post MR, Subramanian VA, Abel RM, Brachfeld NR, Hine SA, Gay WA: Perioperative myocardial infarction associated with coronary artery bypass graft surgery. Improved sensitivity in the diagnosis within 6 hours after operation. 99"'Tc-Glucoleptonate myocardial imaging and myocardial-specific isoenzymes. Ann Thorac Surg 27:42, 1979 Rucker CM, Dugall HC, Ganter EL, Kartub MG: The detection of perioperative myocardial infarction in aortocoronary bypass surgery. Chest 75:300, 1979 Bomfim V: Myocardial protection during aortic valve
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replacement. Scand J Thorac Cardiovasc Surg Supp1 29:1-26, 1981 7 Delva E, Maille JG, Solymoss BC, Chabot M, Grondin CM, Bourassa MG: Evaluation of myocardial damage during coronary artery grafting with serial determinations of serum CPK MB isoenzyme. J THORAC CARDIOVASC SURG 75:467, 1978 8 duCailar C, Maille JG, Jones W, Solymoss M, Chabot M, Goulet C, Delva E, Grondin CM: MB creatine kinase and the evaluation of myocardial injury followingaortocoronary bypass operation. Ann Thorac Surg 29:8, 1980 9 Gray RJ, Shell WE, Conklin C, Ganz W, Shah Pk, Miyamoto AT, Matloff JM, Swan HJC: Quantification of myocardial injury during coronary artery bypass graft. Circulation 58:Suppl 1:38, 1978 10 Molina JE, Gani KS, Voss DM: Pressurized rapid cardioplegia versus administration of exogenous substrate and topical hypothermia. Ann Thorac Surg 33:434, 1982 11 Molina JE, Gani KS, Voss DM: How should clear cardioplegia be administered? A method of rapid arrest with high flow and pressure. J THORAC CARDIOVASC SURG 84:762, 1982 12 Strom S, Bendz R, Olin C: Myocardial injury and CK-MB release during aortic valve surgery with selective coronary perfusion. Clin Cardiol 4:155, 1981 13 Strom S, Mogensen L, Bendz R: Serum CK-MB.kinetics in acute myocardial infarction and after coronary bypass operation. Scand J Thorac Cardiovasc Surg 13:61, 1979 14 Weisel RD, Lipton IH, Lyall RN, Baird RJ: Cardiac metabolism and performance following cold potassium cardioplegia. Circulation 58:Suppl 1:217, 1978 15 Roberts R, Henry PD, Sobel BE: An improved basis for enzymatic estimation of infarct size. Circulation 52:743, 1975 16 Shell WE, Kjekshus JK, Sobol BE: Quantitative assessment of the extent of myocardial infarction in the conscious dog by means of analysis of serial changes in serum creatine phosphokinase activity. J Clin Invest 50:2614, 1971 17 Sobel BE, Bresnahan GF, Shell WE, Yoder RD: Estimation of infarct size in man and its relation to prognosis. Circulation 46:640, 1972 18 Roe CR, Cobb FR, Starmer CG: The relationship between enzymatic and histologic estimates of the extent of myocardial infarction in conscious dogs with permanent coronary occlusion. Circulation 55:438, 1977 19 Raabe DS Jr, Morise A, Sbarbaro JA, Gundel WD: Diagnostic criteria for acute myocardial infarction in patients undergoing coronary artery bypass surgery. Circulation 62:869, 1980 20 Tamaki S, Nakajima H, Murakami T, Yui Y, Kamgara H, Kadota K, Yoshida A, Kawai C, Tamaki N, Mukai T, Ishii Y, Turizuka K: Estimation of infarct size by myocardial emission computed tomography with thallium-201 and its relation to creatine kinase-MB release after myocardial infarction in man. Circulation 66:994, 982 21 Barner HB, Kaiser GC, Codd JE, Tyras DH, Pennington
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DG, Laks H, Willman VL: Clinical experience with cold blood as the vehicle for hypothermic potassium cardioplegia. Ann Thorac Surg 29:224, 1980 Rosa1ki SB: An improved procedure for serum creatine phosphokinase determination. J Lab Clin Med 69:696, 1967 Hatt RY, Moravec J: Acute hypoxia of myocardium. Ultrastructural changes. Cardiology 56:73, 1971 Jennings RB, Baum HG, Herdson PB: Find structural changes in myocardial ischemic injury. Arch Pathol 79:135, 1965 Lichtig C, Brooks H: Myocardial ultrastructure and function during progressive early ischemia in the intact heart. J THORAC CARDIOVASC SURG 70:309, 1975 Kloner RA, Fishbein MC, Cotran RS: The effect of propranolol on microvascular injury in acute myocardial ischemia. Circulation 55:872, 1977 Maroko PR, Kjeksus JK, Sobel BE, Watanabe T, Covell VW, Ross J, Braunwald E: Factors influencing infarct size following experimental coronary artery occlusions. Circulation 53:67, 1971 Rasmussen MM, Reimer KA, Kloner RA, Jennings RB: Infarct size reduction by propranolol before and after coronary ligation in dogs. Circulation 56:794, 1977 Reimer KA, Rasmussen MM, Jennings RB: Reduction by propranolol of myocardial necrosis following temporary coronary artery occlusion in dogs. Circ Res 33:353, 1973 Reimer KA, Rasmussen MM, Jenning RB: On the nature of protection by propranolol against myocardial necrosis
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after temporary coronary artery occlusion in dogs. Am J Cardiol 37:520, 1976 Shell WE, Lavell JR, Covell JW, Sobel BE: Early estimation of myocardial damage in conscious dogs and patients with evolving acute myocardial infarction. J Clin Invest 52:2579, 1973 Sommers HM, Jennings RB: Ventricular fibrillation and myocardial necrosis after transient ischemia. Effect of treatment with oxygen, procainamide, reserpine and propranolol. Arch Intern Med 129:780, 1972 Magee PG, Gardner TJ, Flaherty JT, Bulkley BH, Goldman RA, Gott VL: Improved myocardial protection with propranolol during drug induced ischemia. Circulation 62:Suppl 1:49, 1980 Butchart EG, McEnany MT, Strich G, Sbokos C, Austen WG: The influence of prearrest factors on the preservation of left ventricular function during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 79:812, 1980 Baroldi G, Milan JD, Wukasch DC, Sandiford FM, Romagnoli A, Cooley DA: Myocardial cell damage in "stone hearts." J Mol Cell Cardiol 6:395, 1974 MacGregor DC, Wilson GJ, Tanaka S, Holness DE, Lixfield W, Silver MD, Rubis LJ, Goldstein LJ, Gunstensen W: Ischemic contracture of the left ventricular. J THORAC CARDIOVASC SURG 70:945, 1975 Ruel GJ, Romagnoli A, Sandiford FM, Wukasch DC, Cooley DA, Norman JC: Protective effect of propranolol on the hypertrophied heart during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 68:283, 1974
THoRAc CARDIOVASC SURG
88:562-566, 1984
Effect of intraoperative propranolol on serum creatine kinase MB release in patients having elective cardiac operations Intraoperative beta blockade has been evaluated as an adjunct to hypothermic cold blood potassium cardioplegia by quantitating semm creatine kinase MB release. RandOmization of 80 patients having coronary artery bypass grafting and 18 patients having valve replacement with or without bypass grafting resulted in 46 of the former andseven of the latter receiving propranolol 0.05 mg/kg 4 to 5 minutes before aortic cross-clamping. Among patients having bypass grafting, infarct size (in gram-equivalents) was 7.9 ± 0.7 gm-Eq for the propranolol group and 10.3 ± 0.8 (p < 0.05) for the control group. Ischemic times were 71.6 ± 2.8 and 78.3 ± 3/4 minutes (p NS~ respectively. In valve replacement, infarct size was 9.9 ± 1.9 gm-Eq for those receiving propranolol and 12.6 ± 2.0 (p = NS) for the control subjects; ischemic times were 99.4 ± 12.5 and 80.5 ± 5.7 minutes, respectively. When the two groups receiving propranolol were combined, infarct size was 8.2 ± 0.6 gm-Eq versus 10.9 ± 0.7 (p < 0.01). When ischemic time was plotted against infarct size, analysis by tinear regression revealed a significant correlation for patients receiving propranolol and having bypass grafting (p < 0.01) and for all patients receiving propranolol (p < 0.01~ These data delllODitrate a modest reduction of infarct size with intraoperative propranolol as an adjunct to our standard management of patients having aortic cross-clamping. Quantitation of creatine kinase MB release is the best clinically available method for assessing alterations in techniques of myocardial preservation.
=
Parinan S. Rao, Ph.D.,* Frances E. Brock, B.S., Kevin Cleary, R.N., Hiltrud Mueller, M.D.,* and Hendrick B. Barner, M.D., St. Louis, Mo.
h e advent of hypothermic potassium cardioplegia and its widespread employment have improved intraoperative myocardial preservation, with a reduction in perioperative myocardial injury and perhaps a decrease in operative mortality. Despite this progress, further improvement in techniques of myocardial preservation is desirable and needed. However, deliberate alterations in myocardial preservation methodology are difficult to assess because operative mortality and the incidence of perioperative infarction are already low. Additionally, the latter may result from technical errors or existing From the Departments of Medicine (Cardiology) and Surgery, St. Louis University, St. Louis, Mo. Received for publication Oct. 17, 1983. Accepted for publication Dec. 27, 1983. Address for reprints: Henrick B. Barner, M.D., Department of Surgery, St. Louis University Medical Center, 1325 South Grand Blvd., St. Louis, Mo. 63104. *Present address: Montefiore Medical Center, III East 210th St., Bronx, N. Y. 10467.
562
coronary disease rather than from the technique of myocardial preservation. Release of creatine kinase MB isoenzyme (CK-MB) has been used to determine perioperative myocardial injury by noting the peak serum level'? or by measuring the quantity released.?" Although infarct sizing from CK-MB release is an accepted technique,":" it is not without controversy." Nevertheless, it would seem to be the best method currently available to assess subtle myocardial injury and to discern effects of alterations in techniques of myocardial preservation,"8,19,20 We report on myocardial injury by serial CK-MB analysis in patients having elective operation who were randomized into Group 1 (propranolol) or Group 2 (no propranolol) and who received cold blood potassium cardioplegia as we have used it since 1977. 21 Methods This study began in October, 1980, and ended in December, 1981. During a 10 month period before the study, we administered propranolol into the pump
Volume 88 Number 4
CK-MB release 5 6 3
October. 1984
before cross-clamping. Before the start of the study, five patients received propranolol (0.05 ng/kg) into the reservoir of the extracorporeal circuit and had arterial blood (radial artery) samples drawn 4 to 5 minutes later when the aortic cross-clamp was applied. Propranolol plasma levels were 80 to 100 mg/rnl and as such represented adequate beta adrenergic blockade. Patients included in the study had their operations on Monday or Tuesday of each week so that sampling for serum CK-MB would be complete by the weekend. Patients having coronary bypass grafting (CABG) were included as were patients having valve replacement with or without CABG. Beta blockers were being received by many patients, and these, along with all other cardiovascular-directed medications, were continued through the evening of the day prior to operation. Patients were randomized according to the last digit of the hospital number into the propranolol group (Group 1) or the no propranolol group (Group 2). Propranolol was given as a bolus (0.05 mg/kg) into the reservoir of the extracorporeal circuit at the onset of cooling, which was 4 to 5 minutes before the application of the aortic cross-clamp. Immediately after placement of the cross-clamp, blood at 12° ± 2°C containing potassium chloride 25 mfiq/L was introduced into the aortic root in a volume of 400 ± 100 ml over 2 to 4 minutes. Reinfusion of 300 ± 100 ml was performed every 20 minutes. For aortic valve replacement the initial bolus was given via the aortic root (if the valve was competent), and subsequent boluses were divided between the two coronary ostia. Crushed ice made from sterile lactated Ringer's solution was placed about the heart. The ice was separated from the left phrenic nerve and the diaphragm by an isolation pad (Bjork-Shiley) and renewed with each cardioplegic infusion. Myocardial temperatures were not measured in this study, but when measured in hearts receiving this standard myocardial protection they ranged from 8° to 18° C. Blood for the determination of CK-MB was drawn when the patient arrived in the operating room, 1 hour after the onset of the operation, at the conclusion of the operation (in the operating room), and at postoperative hours 1,2,3,4,6,8, 12, 18,24,30, 36, 42, 48, 66, and 72. Electrocardiograms were obtained preoperatively and on postoperative days 1, 3, and 5. Description of assay and method of calculation. Plasma content of total CK was measured according to the modified Rosalki" method using the Calbiochem CK-Superstat Pak Kit (No. 869414). The normal values (30° C) ranged from 8 to 80 U/L (n = 100). The heart isoenzyme CK-MB was qualitatively visualized by the
electrophoresis method and quantitated by an irnmunoinhibition method using the Eskachem CK-MB Kit (No. 86239). The normal values at 30° C ranged from 0 to 6 U/L (n = 78). The reproducibility of the assay for duplicates in the range of 5 to 50 U/L is 7.1% (n = 10). Infarct size (IS) was calculated according to the formulas of Roberts, Henry, and Sobel":
= ~CK-MB
IS MB (CK.gm-Eq)
. K.I x DV x body weight (gm) p CK-MB . CK-MBnonna l - CK-MBinfa
Values used for the constants are as follows: ~ CK-MB is the area under the serial CK-MB - time (t) curve. K, = 0.0017 (decay constant determined in 10 patients with uncomplicated myocardial infarction). Distribution volume (DV) = 44 ml/kg, PCK-MB = 0.15. CK-MB normal = 136 U/gm wet tissue (300c). CK-MBinfarct ed = 35 U/gm wet tissue (3ooC).
Results Two patients with a perioperative myocardial infarction (new Q wave) were excluded. Of 80 patients having CABG, there were 46 in Group 1 (propranolol) and 34 in Group 2 (no propranolol). Oral beta blockers were being taken by 35 of 46 patients (76%) in Group 1 and 21 of 34 (62%) in Group 2. Of 18 patients having valve replacement with or without CABG, oral beta blockers were being taken by one of seven in Group 3 (propranolol) and one of 11 in Group 4 (no propranolol). Table I summarizes the results. In patients having CABG, infarct size (gram-equivalents of myocardial injury) was 7.9 ± 0.7 gm-Eq in those receiving intraoperative propranolol and 10.3 ± 0.8 gm-Eq (p < 0.05) in the control subjects. Ischemic time was 71.6 ± 2.8 minutes in the propranolol group and 78.3 ± 3.4 minutes (p = NS) in the control group. In patients having valve replacement, infarct size was 9.9 ± 1.9 gm-Eq in the propranolol group versus 12.6 ± 2.0 gm-Eq (p = NS) in the control group. Ischemic time was 99.4 ± 12.5 minutes in the treated group versus 80.5 ± 5.7 (p = NS) in control patients. When data were combined for CABG and valve replacement patients, infarct size was 8.2 ± 0.6 gm-Eq for those receiving propranolol and 10.9 ± 0.7 (p < 0.01) for the control group. Combined ischemic time was 75.3 ± 3.2 minutes for the treatment group versus 78.8 ± 2.9 (p = NS) for the control group. Data were analyzed by linear regression, in which infarct size was plotted against ischemic time. There was a significant correlation for patients having CABG and receiving propranolol (r = 0.4479, P < 0.01) and for all patients receiving propranolol (r = 0.4799, P < 0.01).
The Journal of Thoracic and Cardiovascular Surgery
5 6 4 Roo et al.
Table I. Ischemic time and infarct size for control and treated patients Coronary bypass Group I: Propranolol No. Ischemia time (mean ± 1 SEM) Infarct size (gm-Eq ± 1 SEM) Correlation coefficient
)
46 71.6 ± 2.8 7.9 ± 0.7* 0.4479t
Valve replacement!
Group 2: No propranolol
Group 3: Propranolol
34 78.3 ± 3.4 10.3 ± 0.8* 0.0328
7 99.4 ± 12.5 9.9 ± 1.9 0.5830
I
Group 4: No propranolol 11 80.5 5.7 12.6 ± 2.0 0.5313
*p < 0.05. tp <0.01. :j:Three patients in the propranolol group and one patient in the control group had associated coronary bypass.
Discussion Release of CK-MB from the myocardium in association with cardiac operation has been related to the technique of cardioplegia,II the duration of ischemia, 11.12 and myocardial temperature." Significantly greater quantities of enzyme were released in patients who had a perioperative myocardial infarction (new Q wave). Furthermore, an intermediate group has been identified in which less enzyme is released than for the infarct group but more than is noted for patients having optimal myocardial preservation. 5, 9 Careful sampling has determined that CK-MB will be released in all patients having cardiac operations,8.II.13,14 although it has been concluded by some that this does not always occur.l" It is also apparent that even with minimal (13 minutes) myocardial ischemia and what would be acknowledged by many as optimal myocardial protection (hypothermic crystalloid cardioplegia with a myocardial temperature of 15° C), there is an infarct size of 2.3 ± 1.2 gm-Eq." Five to 15 minutes of warm ischemia in the experimental animal is thought to be the minimal insult capable of inducing detectable but reversible myocardial injury, but has not been correlated with CK-MB release.>" Although hypothermia should increase the duration of injury-free ischemia, there may be injury related to the use of hyperkalemic cardioplegia which may damage some myocytes and cause release of CK-MB. The fact that there was a myocardial injury of 2.3 gm-Eq despite an ischemic time of only 13 minutes would suggest that all cardiac operations in which there is aortic cross-clamping are associated with myocardial injury, and even when both coronary arteries are perfused with blood during aortic cross-clamping there is CK-MB detectable in the serum." The time course of release of CK-MB is significant in that it reaches a peak 2 ± 0 hours postoperatively in the patient who has an uncomplicated course and is free of conventional criteria for myocardial infarction. By contrast, in the patient with acute myo-
cardial infarction presenting to a coronary care unit, the peak serum level is attained 17 ± 1 hours after the onset of symptoms." Postoperative patients having Q-wave evidence of myocardial infarction have a greater peak and longer duration of serum CK-MB release than patients without additional evidence of infarction.t'" 14 Thus, this would seem to be the best method currently available for assessing subtle myocardial injury and discerning improvement in techniques of myocardial
preservation.v 25.26
We have found an infarct size of 7.9 ± 0.7 gm-Eq with a mean cross-clamp time of 71.6 ± 2.8 minutes, which compares with 6.1 ± 1.3 gm-Eq during 67 minutes of ischemia in patients having isolated CABG with hypothermic crystalloid cardioplegia.'? This represents a comparison of our patients receiving propranolol and their patients having "rapid" pressurized cardioplegia. Our patients not receiving propranolol had 10.3 ± 0.8 gm-Eq of injury with a mean ischemic time of 78.3 ± 3.4 minutes, whereas their patients having less rapid cardioplegic infusion had 9.2 ± 0.4 gm-Eq of injury with a mean cross-clamp time of 65 minutes." Comparison of data between institutions lacks validity because of differences in and continuing evolution of laboratory methods for measuring serum CK-MB. The importance of determining perioperative infarct size with CK-MB determinations lies in the use of this approach for assessment of alterations in techniques of myocardial preservation, as exemplified by the use of high-flow cardioplegia lO, 1I or intraoperative beta blockade. Preoperative therapy with beta blockers has been found to reduce intraoperative infarct size (defmed as the peak level of serum CK-MB) but not perioperative infarct size (defmed as the total gram-equivalents of myocardial injury)." It can be argued that because more patients in Group 1 than Group 2 were receiving oral beta blockers, this may have reduced infarct size and therefore the two groups are not comparable. On the
Volume 88 Number 4 October, 1984
other hand, this would support the position that beta blockade is advantageous whether it is preoperative or intraoperative. Groups 3 and 4 are more comparable in this regard, as one patient in each group received oral beta blockers. Beta blockade has reduced ischemic myocardial injury associated with experimental coronary artery occlusion.>" Recovery from global myocardial ischemia was improved by preischemic propranolol, regardless of whether the myocardium was normothermic or hypothermic." There is evidence to suggest that reduction of myocardial contractility through beta blockade, in addition to the use of hypothermic potassium cardioplegia may promote the preservation of myocardial energy reserves." Beta blockade has been employed to prevent myocardial contracture in association with ischemia.'>" These experimental data support the use of beta blockade for preservation of ischemic myocardium and provide a perspective for beta blockade as an adjunct to hypothermic potassium cardioplegia. The failure of infarct size to correlate with ischemia time in the non propranolol patients would suggest that within a certain time range there are other important factors that determine the extent of myocardial injury. The use of beta blockade must obviate some of these factors and allow ischemic time to become a relatively more important determinant of infarct size. Dr. John Standeven provided the statistical analysis, and Kathy Illyes typed the manuscript.
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