Cardiac Enzymes and Autotransfusion of Shed Mediastinal Blood After Myocardial Revascularization

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1 Cardiac Enzymes and Autotransfusion of Shed Mediastinal Blood After Myocardial Revascularization Henrik Schmidt, MD, Poul Erik Mortensen, MD, Soren Lars Folsgaard, MD, and Esther A. Jensen, MD Departments of Anaesthesiology, Cardio-Thoracic Surgery, and Clinical Chemistry, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark Background. Autotransfusion of shed mediastinal blood reduces blood requirement after coronary artery bypass grafting. Recently, two nonrandomized trials indicated that autotransfusion elevates the levels of cardiac enzymes after cardiac operations. Methods. Prospective, randomized controlled studies involving 120 patients (study A) and 15 patients (study B) having elective uncomplicated coronary artery bypass grafting were performed. Autotransfusion of shed mediastinal blood was performed for 18 hours in the patients allocated to autotransfusion. Serum levels of cardiac enzymes were measured. In study B cardiac enzyme levels in shed mediastinal blood and circulating blood were measured 1 hour postoperatively. Results. Cardiac enzyme levels were significantly elevated in the patients receiving autotransfusion. In patients with a perioperative myocardial infarction the level of creatine kinase-mb was much higher than in the autotransfused patients without myocardial infarction. The level of cardiac enzymes was higher in shed mediastinal blood compared with circulating blood. Conclusions. Postoperative autotransfusion of shed mediastinal blood causes elevation of cardiac enzyme levels after coronary artery bypass grafting. (Ann Thorac Surg 1997;63: ) 1997 by The Society of Thoracic Surgeons A utotransfusion of shed mediastinal blood reduces the requirement of blood products after coronary artery bypass grafting (CABG) [1-5]. The inherent benefits from this are evident, but possible drawbacks should also be considered carefully. Cardiac enzymes may be present in high concentrations in shed mediastinal blood [6, 7]. Two recent studies have indicated that autotransfusion of shed mediastinal blood increases the serum levels of cardiac enzymes after CABG [8, 9]. In clinical practice elevated serum levels of cardiac enzymes are often used as an indicator of acute myocardial infarction (AMI) after CABG [10]. It is necessary to establish, in a controlled, randomized setting, whether autotransfusion causes an increase in circulating coronary enzyme levels or not. As part of a prospective, randomized, controlled study of the feasibility and safety of autotransfusion of shed mediastinal blood in CABG patients [5] we examined serum levels of cardiac enzymes after CABG. We also measured cardiac enzyme levels in shed mediastinal blood and in serum before the start of autotransfusion in a separate group of CABG patients. Accepted for publication Nov 13, Address reprint requests to Dr Schmidt, Department of Anaesthesiology, Gentofte Hospital, Niels Andersensvej 65, DK-2900 Hellerup, Denmark. Material and Methods In the main study [5], 120 adult patients undergoing primary, elective CABG entered the study. Informed and written consent was obtained according to the guidelines and approval of the regional Ethics Committee on September 11, Not included in the study were patients with a bleeding time greater than 10 minutes measured by the method of Ivy, left ventricular ejection fraction less than 0.40, diabetes mellitus, or pulmonary or renal disease. Excluded from the study after randomization were 5 patients who underwent hemostatic surgical procedures within the first 18 postoperative hours, and 3 patients in whom technical failures in the autotransfusion reservoir occurred were excluded as well. In the present study (study A) we included 3 patients with low cardiac index who were excluded from the main study [5]. These patients could suffer from perioperative AMI and, therefore, have an elevated concentration of cardiac enzymes, which would be relevant for the present study. Study Protocol The patients were anesthetized and monitored using standard techniques [5]. All operations were performed through a median sternotomy using standard techniques for cardiopulmonary bypass with a crystalloid prime. St. Thomas' cardioplegic solution (4 C) and isotonic saline solution (0 C) in the pericardial sac were used for myo by The Society of Thoracic Surgeons /97/$17.00 Published by Elsevier Science nc PII S (97)

2 Ann Thorac Surg SCHMIDT ET AL ;63: CK-MB AND AUTOTRANSFUSION cardial protection. Anticoagulation was established with heparin, 300 IU per kg, and maintained with additional heparin guided by coagulation parameters during cardiopulmonary bypass. After cardiopulmonary bypass, heparin was neutralized with protamine sulfate. Blood remaining in the cardiopulmonary bypass circuit at the conclusion of the procedure was collected for later transfusion. At the end of the operation all patients had their mediastinal and pleural tubes attached to the inlet port of the Bard Cardiotomy/Autotransfusion reservoir (C.R. Bard Inc, Tewksbury, MA). The shed mediastinal blood was filtered through the 40-~m micrometer filter in the cardiotomy reservoir before transfusion. Upon arrival in the intensive care unit the patients were randomly allocated either to autotransfusion of shed mediastinal blood (autotransfusion group) or no autotransfusion (control group). Autotransfusion was terminated after 18 hours. The blood from the cardiopulmonary bypass circuit was given to all patients during the first postoperative hour. Blood samples were drawn preoperatively and 1, 6, and 18 hours postoperatively, and on the second and seventh postoperative days. After the blood samples were drawn 1 hour postoperatively, autotransfusion was started. The samples were analyzed for levels of lactate dehydrogenase (LDH), aspartate aminotransferase (ASAT), and creatine kinase (CK) MB activity (CK-MB) measured as mass concentration (IMx STAT CK-MB, Abbott Laboratories, Abbott Park, IL). Twelve-lead electrocardiograms were obtained before the operation and 1 hour and 18 hours postoperatively. The electrocardiograms were interpreted without knowledge of the serum enzyme levels or randomization. The patients were categorized into two groups: group 1, patients having definite perioperative AMI indicated by the appearance of new Q waves after the operation; and group 2, patients without Q-wave AMI. In a separate study (study B) of fifteen consecutive CABG patients the shed mediastinal blood and the circulating blood were analyzed for levels of ASAT, LDH, CK, CK-MB, plasma hemoglobin, and hematocrit I hour postoperatively. Statistical Methods All data are presented as means -+ standard deviation. Statistical analysis was performed using parametric statistical tests (t test, paired t test, and analyses of variance for repeated measurements). A p value (type I error) less than 0.05 was considered significant. Results Of the 120 patients enrolled in study A, 112 patients (54 in the autotransfusion group and 58 in the control group) completed the study protocol and form the basis for this report. There was no difference between the autotransfusion and the control group regarding preoperative or operative data (Table 1). All patients received the left internal mammary artery as a graft. There was no difference in the number of grafts (see Table 1). Postoperative Table 1. Preoperative and Operative Data of the Two Patient Groups ~ Variable Autotransfusion Control Group Group (n = 54) (n = 58) Age (y) Male/female 46/8 53/5 Left ventricular ± 0.11 ejection fraction Height (cm) Weight (kg) 82 ± ± 13 Time on extracorporeal 106 _ _+ 43 circulation (rain) Aortic cross-clamp ± 36 time (min) No. of grafts b Blood loss (ml) 473 _ a There were no statistically significant differences between the groups. 6 All patients received the left internal mammary artery as a graft. blood loss during the first 18 hours was ml (range, 295 to 2,065 ml) in the autotransfused group and 857 _+ 394 ml (range, 300 to 2,670 ml) in the control group. Ninety-five percent (740 _+ 403 ml; range, 215 to 2,015 ml) of the shed mediastinal blood was retransfused in the autotransfusion group. In both the autotransfusion group and the control group a rise in enzyme levels was seen postoperatively. Postoperatively the enzyme levels were significantly higher in the autotransfusion group than in controls (Table 2). A total of 10 patients had a perioperative AMI, 4 of 54 in the autotransfusion group and 6 of 58 in the control group (not significant). In patients without AMI, the CK-MB level was higher when autotransfusion was performed (Table 3). The patients with AMI had significantly higher levels of CK-MB at 1, 6, and 18 hours postoperatively and on the second postoperative day compared with the autotransfusion group without AMI (see Table 3). The maximum level of CK-MB for each patient during the study and the minimum level for the patients with AMI are shown as a scatter plot in Figure 1. The maximum level of CK-MB was 61 _+ 28/zg/L in the autotransfusion group without AMI and /~g/L in the control group without AMI (p < 0.01). The levels of cardiac enzymes in the 15 patients in study B are shown in Table 4. The ASAT, LDH, and CK-MB levels were markedly increased in the shed mediastinal blood compared with the circulating blood. One of the patients had a perioperative AMI. Comment This prospective, randomized trial investigated the effect of autotransfusion of shed mediastinal blood on cardiac enzyme levels after CABG. The study shows that autotransfusion causes elevation in the serum levels of cardiac enzymes. In 1992 Wahl and co-workers [8] suggested that autotransfusion of shed mediastinal blood might contribute

3 1290 SCHMIDT ET AL Ann Thorac Surg CK-MB AND AUTOTRANSFUSION 1997;63: Table 2. Serum Cardiac Enzyme Levels in the Two Patient Groups Autotransfusion Group (n - 54) Control Group (n - 58) ASAT LDH CK-MB ASAT LDH CK-MB Time (U/L) (U/L) (/xg/l) (U/L) (U/L) (/zg/l) Preop ± ± h _ ± z ± h 88 _+ 25 ~ " 58 _+ 29 b h 120 ± 187' 1129 ± 291" ± ± 47 2nd day 77 ± ± ± th day ± ± "p < between the autotransfusion group and the control group, b p < 0.05 between the autotransfusion group and the control group. ASAT = aspartate aminotransferase; CK-MB - creatine kinase MB activity; LDH - lactate dehydrogenase; Preop - preoperative; 1 h 1 hour postoperatively before start of autotransfusion; 6 h - 6 hours after start of autotransfusion; 18 h 18 hours after start of autotransfusion; 2nd day - second postoperative day; 7th day = seventh postoperative day. to the elevation of cardiac enzyme levels and might mimic or mask the presence of perioperative AMI. They found an increase in CK, LDH, and glutamic-oxaloacetic transaminase levels, but no elevation of the CK-MB fraction in the autotransfusion group compared with the control group. The study was not randomized and contained only 16 autotransfused patients and 4 in the control group. No comments were made on the selection of patients for the control group. Recently, Hannes and co-workers [9] studied the effect of autotransfusion of shed mediastinal blood on cardiac enzymes. They reported an immediate increase in serum levels of CK-MB, LDH, glutamic-oxaloacetic transaminase, troponin T, and myoglobin after the start of autotransfusion. Their study [9] was not randomized, and the control group consisted of the patients with postoperative bleeding less than 300 rnl. Patients with signs of acute cardiac ischemia or acute infarction in the postoperative period were excluded from the study. There was no information about postoperative bleeding in the two groups and no information on cardiac enzyme levels in the patients with acute signs of cardiac ischemia or AMI in the postoperative period. In both studies [8, 9] the Table 3. Creatine Kinase-MB Values (#g/l) in Patients Without and With Perioperative Acute Myocardial Infarction During the First 18 Hours Time Patients Without Perioperative AMI Control Autotransfusion Patients With Group Group Perioperative AMI (n - 52) (n 50) (n = 10) Preop lh 38± 17 44_ ± 85 b 6 h " 106 ~ 67 t' 18 h l J ~ =~p < 0.05 between control group and autotransfusion group without AMI. b p < 0.05 between autotransfusion group without AMI and the group of patients with AML AMI = acute myocardial infarction; Preop ~ preoperative; 1 h - 1 hour postoperative before start of autotransfusion; 6 h - 6 hours after start of autotransfusion; 18 h - 18 hours after start of autotransfusion. enzyme levels in the shed mediastinal blood were very high compared with the levels in circulating blood. In our study autotransfusion of shed mediastinal blood caused increased serum levels of ASAT, LDH, and CK- MB, with a maximum CK-MB level after 5 hours of autotransfusion. The CK-MB level was back to normal on the second postoperative day. The peak level and the time of elevation correspond well with the results found by Hannes and co-workers [9]. In the shed mediastinal blood, we likewise found increased levels of cardiac enzymes. Baur and associates [10] used peak CK-MB levels to discriminate patients with perioperative myocardial infarction from those without infarction. In patients with definite perioperative transmural infarction the peak values appeared 12 to 18 hours postoperatively. Like Baur and associates [10] and others [11, 12], we found the 5O /Jg/L Z ± L Group C Group A Minimum Maximum Group AMI Fig 1. Maximum level of creatine kinase-mb in each patient and the minimum level of creatine kinase-mb of the patients with acute myocardial infarction (AMI) during the first 18 postoperative hours. (Group A = patients without AMI in the autotransfusion group; Group AM1 - patients with AMI; Group C - patients without AMI in the control group.)

4 Ann Thorac Surg SCHMIDT ET AL ;63: CK-MB AND AUTOTRANSFUSION Table 4. Values of Cardiac Enzymes in Shed Mediastinal Blood and Circulating Blood 1 Hour After the Operation (Study B) Circulating Blood Shed Mediastinal Enzyme (n = 15) Blood (n - 15) ASAT (U/L) 58 ~ ± 812 LDH (U/L) ,293 _+ 1,290 "1 CK (U/L) 1,008 ± 215 4,627 _+ 2,203 ~ CK-MB (/~g/l) 35 _ _+ 112" Plasma hemoglobin 32 _ ± 95 ~ (/~mol/l) a p < compared with circulating blood. ASAT = aspartate aminotransferase; CK - creatine kinase; CK- MB - creatine kinase MB activity; LDH - lactate dehydrogenase. maximum CK-MB level after 18 hours in patients with AMI. The patients with AMI had a significantly higher level of CK-MB even when compared with autotransfused patients without AML The CK-MB level is an important diagnostic tool in the assessment of myocardial injury during the course of CABG. The increase in CK-MB level in the 10 patients with Q-wave infarction was significantly higher than in the patients with autotransfusion and no electrocardiographic changes. There was a substantial overlap between the mean CK-MB values of the 10 patients with Q-wave infarction and the mean CK-MB values of the patients in the autotransfusion group without AMI. The number of patients with Q-wave infarctions in this study is small, so calculation of sensitivity and specificity of the use of mean CK-MB values will be imprecise. However, when looking at the maximum values of CK-MB measured during the first 18 hours postoperatively, we saw almost no overlap between the AMI group and the corresponding maximum CK-MB values in the patients without AMI. Using a CK-MB value of 100 p,g/l as cutoff point for diagnosing AMI would yield a sensitivity of 92% and a specificity of 100%. This indicates that only serial measurements of CK-MB or very high values of CK-MB are useful in the diagnosis of AMI by the CK-MB values. The precise determination of the degree to which autotransfusion influences the diagnosis of transmural AMI will require a far larger study than ours. In clinical practice we believe that serial measurements of CK-MB levels still are useful together with other parameters like electrocardiograms and cardiac performance to give the final diagnosis of AMI. The influence of autotransfusion on CK-MB levels in patients with other myocardial damage like subendocardial infarction or prolonged ischemia was not investigated in our study. We cannot fully explain why the autotransfusion of shed mediastinal blood increases the cardiac enzyme levels after CABG operation. Skeletal muscles of the chest wall contains high levels of CK with a CK-MB fraction of 5% to 9% [7]. This could explain the high level of CK-MB in shed mediastinal blood. Hemolysis may be enhanced in shed mediastinal blood [13], and this may interfere with analysis of CK-MB [14-16]. Hemolysis may also cause falsely high CK-MB activity due to myokinase from the erythrocytes [14]. However, the product specification of IMx STAT CK-MB [17] states that free hemoglobin in a concentration up to 465 t~mol/l (750 mg/dl) does not interfere with the specificity of measurement. The median values of free hemoglobin in our patients was 31 ptmol/l (range, 9 to 156/~mol/L). The sensitivity of the IMx STAT CK-MB assay has been determined to be 0.7 ~zg/l [17]. The specificity of the IMx STAT CK-MB assay was not influenced by bilirubin, hemoglobin, or triglycerides. And the cross-reactivity for CK-BB (10,000 t~g/l) was % and that for CK-MM (5,000 p,g/l) was 0.002% [17]. We believe that the high content of CK-MB, ASAT, and LDH in shed mediastinal blood is responsible for the elevated serum levels in autotransfused patients. In conclusion, postoperative autotransfusion of shed mediastinal blood causes elevation of levels of cardiac enzymes after CABG. Normal ranges of postoperative values of CK-MB after CABG have to be adjusted when using autotransfusion of shed mediastinal blood. We would suggest a normal value of CK-MB after CABG to be 29 to 79 ~g/l. References 1. Schaff HV, Hauer JM, Bell WR, et al. Autotransfusion of shed mediastinal blood after cardiac surgery: a prospective study. J Thorac Cardiovasc Surg 1978;75: Eng J, Kay PH, Murday AJ, et al Postoperative autologous transfusion in cardiac surgery. A prospective, randomised study. Eur J Cardiothorac Surg 1990;4: Page R, Russell GN, Fox MA, Fabri BM, Lewis I, Williets T. Hardshell cardiotomy reservoir for reinfusion of shed mediastinal blood. Ann Thorac Surg 1989;48: Lepore V, Radegran K. Autotransfusion of mediastinal blood in cardiac surgery. Scand J Thorac Cardiovasc Surg 1989;23: Schmidt H, Mortensen PE, Folsgaard SL, Jensen EA. Autotransfusion after coronary artery bypass grafting halves the number of patients needing blood transfusion. Ann Thorac Surg 1996;61: Adoumie R, Lockanathan R, Yen A, Chiu R-C. Character of shed blood in cardiac and thoracic surgery patients: implications for reinfusion. Can J Surg 1994;37: Graeber GM, Caffertv PJ, Wolf RE, Zajtchuk R. Creatine kinase and lactate dehydrogenase in the muscles encountered during median sternotomy and in myocardium of the cardiac chambers. J Thorac Cardiovasc Surg 1985;89: Wahl CW, Feins RH, Alfieres G, Blixby K. Reinfusion of shed blood after coronary operation causes elevation of cardiac enzyme levels. Ann Thorac Surg 1992;53: Hannes W, Keilich M, Koster W, Seitelberger R, Fasol R. Shed blood autotransfusion influences ischemia-sensitive laboratory parameters after coronary operations. Ann Thorac Surg 1994;57: Baur HR, Steele BW, Preimesberger KF, Goberl FL. Serum myocardial creatine kinase (CK-MB) after coronary bypass surgery. Am J Cardiol 1979;44: Shell WE, Kjekshus JK, Sobel 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 1971;50: Grande P, Hansen BF, Christiansen C. Estimation of acute myocardial infarct size in man by serum CK-MB measurements. Circulation 1982;65: Kongsgaard UE, Tollofsrud S, Brosstad F, Ovrum E, Bjornskau L. Autotransfusion after open heart surgery: characteristics of shed mediastinal blood and its influence on the

5 1292 SCHMIDT ET AL Ann Thorac Surg CK-MB AND AUTOTRANSFUS1ON 1997;63: plasma proteases in circulating blood. Acta Anaesthesiol Scand 1991;35: Sonntag O. Haemolysis as an interference factor in clinical chemistry. J Clin Chem Clin Biochem 1986;24: Hombrouckx RO, De Vos JY, Gilbert BH. Creatine phosphokinase increase during dialysis by red-cell fragmentation. Nephrol Dial Transplant 1992;7: Wellstein A, Schmidt EW. Einfluss der Hamolyse auf die Aktivitatsbestimmung des herzmuskelspezifischen CK- Isoenzymes MB [Influence of haemolysis on myocardiumspecific CK-isoenzyme MB activity]. Arztl Lab 1977;23: Product specification of IMx STAT CK-MB. Abbott Park IL: Abbott Laboratories, The Society of Thoracic Surgeons: Thirty-fourth Annual Meeting Mark your calendars for the Thirty-fourth Annual Meeting of The Society of Thoracic Surgeons, which will be held at the Ernest N. Morial Convention Center in New Orleans, Louisiana, January 26-28, Members may register for the Scientific Sessions at no charge. There will be a $250 registration fee for nonmember physicians except for Scientific and Poster Session presenters and residents. Registration for the Postgraduate Course is separate from the Annual Meeting. There will be a $70 registration fee for attendees of the Postgraduate Program, which will be held Sunday, January 25. The Postgraduate Course will provide in-depth coverage of thoracic surgical topics selected to enhance and broaden the knowledge of practicing thoracic and cardiac surgeons. Advance registration forms, hotel reservation forms, and details regarding transportation arrangements, as well as the complete meeting program, will be mailed to Society members this fall (1997). Also, complete meeting information will be available as early as possible on The Society's Web site located at Nonmembers wishing to receive information on attending the meeting should write to the Society's Secretary, Peter C. Pairolero. The abstract submission form for the Thirty-fourth Annual Meeting will be sent to all Society members in May and July, will be published in the May, June, and July issues of The Annals, and will also be available as early as possible on the STS Web site. The abstracts will be due on August 4, Films will be due on July 31, Peter C. Pairolero, MD Secretary The Society of Thoracic Surgeons 401 N Michigan Ave Chicago, IL (312) Fax: (312) by The Society of Thoracic Surgeons Ann Thorac Surg 1997;63: /97/$17.00 Published by Elsevier Science Inc PII S (97)