- Email: [email protected]
Human cytokine responses to coronary artery bypass grafting with and without cardiopulmonary bypass
Human Cytokine Responses to Coronary Artery Bypass Grafting With and Without Cardiopulmonary Bypass Martin Stru¨ber, MD, Jochen T. Cremer, MD, Bernhard Gohrbandt, MD, Christian Hagl, MD, Michaela Jankowski, MD, Birgit Vo¨lker, MD, Horst Ru¨ckoldt, MD, Michael Martin, PhD, and Axel Haverich, MD Division of Thoracic and Cardiovascular Surgery, Department of Anesthesia, and Department of Pharmacology, Hannover Medical School, Hannover, Germany
Background. Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response. This has been attributed to cytokine release caused by extracorporeal circulation and myocardial ischemia. This study compares the inflammatory response after CABG with cardiopulmonary bypass and after minimally invasive direct coronary artery bypass grafting (MIDCABG) without cardiopulmonary bypass. Methods. Cytokine release and complement activation (interleukin-6 and interleukin-8, soluble tumor necrosis factor receptors 1 and 2, complement factor C3a, and C1 esterase inhibitor) were determined in 24 patients before and after CABG or MIDCABG. The maximum body temperature, chest drainage, and fluid balance were recorded for 24 hours after operation.
Results. Release of interleukin-6, interleukin-8, and tumor necrosis factor receptors 1 and 2 was significantly higher (p < ⴚ 0.005) in the CABG group than the MIDCABG group just after operation. After 24 hours, a significant increase in interleukin-6 was also found in the MIDCABG group (p ⴝ 0.001) compared with preoperative value. Body temperature and fluid balance were significantly higher after CABG (p < 0.001). Conclusions. Minimally invasive direct coronary artery bypass grafting represents a less traumatizing technique of surgical revascularization. The reduction in the inflammatory response may be advantageous for patients with a high degree of comorbidity. (Ann Thorac Surg 1999;68:1330 –5) © 1999 by The Society of Thoracic Surgeons
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(LAD) [3]. Successful use in repeat coronary artery bypass procedures has also been reported [4]. One feature of this technique is the clamping of the LAD for up to 30 minutes for revascularization. Studies of cytokine responses to CPB reveal that cytokine release is triggered by ischemia and reperfusion and that the levels of cytokine release correlate with cardiac ischemia [5]. This study compares the perioperative cytokine release after MIDCABG with that after conventional CABG.
he systemic inflammatory response after coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) contributes substantially to postoperative organ dysfunction and coagulation disorders [1]. Advantages derived from improvement in the biocompatibility of CPB in recent years have been counteracted by the growing demand for surgical revascularization in older and sicker patients. Since the 1967 report by Kolessov [2], only a few surgeons have reported on bypass grafting without CPB. Recent attention has focused on this technique to avoid the adverse effects of CPB on very sick patients and to contain costs. To optimize access to the internal mammary artery (IMA) and improve epicardial stabilization, special retractors were designed (Cardiothoracic Systems, Inc, Cupertino, CA) for minimally invasive direct coronary artery bypass grafting (MIDCABG) through a minithoracotomy without CPB. This technique has been shown to be a safe and reliable method for revascularization of the left anterior descending coronary artery Accepted for publication April 26, 1999. Address reprint requests to Dr Stru¨ber, Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl Neuberg Str 1, 30623 Hannover, Germany; e-mail: [email protected].
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Patients and Methods Cytokine release and complement activation were assessed in 24 patients. Twelve consecutive patients (2 women and 10 men aged 64 ⫾ 9 years) with single-vessel disease underwent MIDCABG. The CABG group comprised 12 consecutive patients (3 women and 9 men aged 61 ⫾ 13 years) with three-vessel disease who received double or triple vein grafts and a left IMA graft with the use of CPB. No patient requiring an emergency procedure, an intraaortic balloon pump preoperatively, or preoperative heparin sodium therapy was included in the study. Consent for the additional blood was obtained from each patient prior to the procedure. The study was approved by the institutional ethics committee. 0003-4975/99/$20.00 PII S0003-4975(99)00729-8
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MIDCABG Procedure A left anterior minithoracotomy of 8 to 10 cm through the fifth intercostal space was performed. With the special retractor system (Cardiothoracic Systems, Inc), the left IMA was dissected as a pedicle up to the second rib. After harvest of the IMA, heparin (100 U/kg of body weight) was administered, and the pericardium was opened. The myocardial surface was stabilized at the site of anastomosis to the LAD with a special “horseshoe” retractor. Before the anastomosis was performed, the LAD was occluded proximally and distally using two tourniquet sutures. The vessel was incised between these sutures, and the IMA anastomosis was constructed in an end-toside fashion. Heparin was not reversed by protamine sulfate. After fixation of the distal pedicle, the chest was closed. The patients were mechanically ventilated in the intensive care unit for 12 to 15 hours and transferred from that unit 24 hours after operation.
CABG Procedure All patients underwent standard surgical revascularization for three-vessel coronary artery disease through a median sternotomy. In every instance, the pedicled left IMA was used as an LAD graft. In addition, two to four vein graft anastomoses were performed. Cardiopulmonary bypass was done with a non-heparin-coated circuit, a roller pump (Sto¨ckert Instrumentation, Munich, Germany), and a membrane oxygenator (Monolyth; Sorin Biomedica, Munich, Germany). During CPB, moderate hypothermia (30° to 32°C) was induced. Prior to CPB, high-dose heparin (300 U/kg) was given, and an activated clotting time of more than 400 seconds was maintained. Heparin was reversed completely after termination of CPB. St. Thomas’ cardioplegic solution, 1 to 1.5 L, was infused through the aortic root to achieve myocardial preservation during cross-clamping.
Anesthesia Sodium thiopental, fentanyl, and pancuronium bromide were administered to all patients. In the MIDCABG group, hemodynamic monitoring was done with a thermodilution catheter. During the time of harvest of the IMA to completion of the anastomosis, a left bronchial occlusion catheter was used to reduce ventilation of the left lung. In the CABG group, a mean arterial pressure of 50 to 70 mm Hg was maintained during CPB.
Cytokine Measurements Blood samples were obtained on admission, immediately after the surgical procedure, and 2, 8, and 24 hours after arrival in the intensive care unit. Blood was drawn from arterial catheters only. Enzyme-linked immunosorbent assays were used for measurement of soluble tumor necrosis factor (TNF) receptors 1 and 2 (R&D Systems, Wiesbaden, Germany). Levels of interleukin (IL)-6 and IL-8 were also determined by enzyme-linked immunosorbent assay (Immulite, DPC Biermann, Bad Nauheim, Germany). C1 esterase inhibitor activity was measured functionally by a commercially available
Fig 1. Plasma concentration of complement factor C3a in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
amidolytic test (Behring, Marburg, Germany). Complement factor C3a was determined by radioimmunoassay (Amersham International, Inc, Little Chalfont, UK).
Statistical Analysis All data are expressed as the mean ⫾ the standard deviation. Analysis of variance for repeated measures was performed using an SPSS statistical program. A p value of less than 0.05 was considered significant.
Results The MIDCABG procedures were completed in 115 ⫾ 18 minutes. The left bronchial occlusion time was 56 ⫾ 17 minutes, and the LAD was occluded for 17 ⫾ 8 minutes. The duration of operation was significantly shorter ( p ⬍ 0.05) for the MIDCABG group than the CABG group (167 ⫾ 23 minutes). For CABG, the mean cross-clamp time was 47 ⫾ 18 minutes. All patients in both groups were extubated 6 to 12 hours after the operation and were transferred in hemodynamically stable condition from the intensive care unit to a regular ward on the first postoperative day. No sympathomimetic drugs were used during the postoperative course, and no signs of cardiac ischemia as determined by electrocardiographic criteria or creatine kinase or troponin T levels were found. Blood loss within 24 hours after operation was 580 ⫾ 280 mL in the MIDCABG group and 720 ⫾ 350 mL in the CABG group. The concentration of C3a in the CABG group increased fivefold ( p ⫽ 0.001) right after the surgical procedure compared with the preoperative value. The level then decreased steadily until a normal range was reached after 24 hours (Fig 1). In contrast, C3a concentration was unchanged in the MIDCABG group. There was a tendency for the activity of C1 esterase inhibitor to be
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Fig 2. C1 esterase inhibitor (C1-INH) activity in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
Fig 4. Plasma soluble tumor necrosis factor receptor 2 (TNF-R2) concentration in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
reduced ( p ⫽ 0.049) for the first 8 hours after CPB with normal values at 24 hours (Fig 2). No such changes were found in the MIDCABG group. A threefold increase in expression of soluble TNF receptor 1 was measured immediately after operation and 2 hours later in the CABG group. After 8 hours, the values were decreasing (Fig 3). The concentration of soluble TNF receptors followed a similar course in the CABG group with a significant rise postoperatively ( p ⫽ 0.005) that reached its peak at 2 hours. Thereafter, the values decreased more slowly than those for TNF receptor 1 (Fig 4). In the MIDCABG group, the concentrations
of TNF receptors 1 and 2 showed a rising curve up to 8 hours after the procedure and a decreasing curve thereafter. This increase did not reach significance. A high concentration of IL-8 with a large degree of variation was documented right after CABG (Fig 5). The increase was fivefold compared with the preoperative values. During the postoperative course, the concentration decreased to a normal range at 24 hours. There was no increase in IL-8 concentration within the first 24 hours in the MIDCABG group ( p ⫽ 0.004). In contrast to IL-8, the release of IL-6 increased continuously for 2 hours after CABG and had similar values at 2 and 8 hours. At 24
Fig 3. Plasma soluble tumor necrosis factor receptor 1 (TNF-R1) concentration in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
Fig 5. Plasma interleukin-8 (IL8) concentration in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
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balance in those patients revealed a need of fluids, which were infused as crystalloid solutions. The mean fluid balance in the CABG group was 2,600 ⫾ 680 mL versus 480 ⫾ 270 mL in the MIDCABG group ( p ⫽ 0.001).
Comment
Fig 6. Plasma interleukin-6 (IL6) concentration in patients before (pre) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
hours, a reduction from 1,000 pg/mL at 8 hours to about 350 pg/mL was found, which was still significantly higher than the preoperative value (Fig 6). The IL-6 concentration in the MIDCABG group was significantly lower ( p ⫽ 0.001) in the first 8 postoperative hours than the level in the CABG group, but a steady increase was observed during the postoperative course. After 24 hours, the level was comparable to that in the CABG group and significantly higher ( p ⫽ 0.0001) compared with the preoperative control. During the first 24 hours after CABG, all patients had a fever with peak temperatures between 38.6° and 39.1°C (Fig 7). The maximum body temperature of patients in the MIDCABG group was significantly lower ( p ⫽ 0.0001), ranging between 36.5° and 38.0°C. The fluid
Fig 7. Maximum body temperature within 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation.
Conventional CABG with the use of CPB is a safe and effective procedure. However, CPB induces an inflammatory response that leads to considerable postoperative morbidity, especially in patients with accompanying diseases [6]. Many approaches to reduce the CBP–induced inflammatory reaction have been tried and include heparin-coating of the extracorporeal circuit, depletion of leukocytes [7] or inhibition of their adhesion [8], colloid priming of the CPB circuit [9], and pretreatment with steroids [10]. Nevertheless, CPB triggers an inflammatory response involving proinflammatory cytokines such as TNF-␣, IL-6, and IL-8 [11] and activation of the complement system [6]. This leads clinically to a postperfusion syndrome characterized by fever and fluid accumulation in the interstitium [12]. In addition, low systemic vascular resistance can develop [13]. Postperfusion organ dysfunction has been reported mainly for the lungs [14], the kidneys [15], and the central nervous system. Activation of the complement system by CPB is considered a first step in the inflammatory reaction and a main cause for organ dysfunction [16]. In our study, a significant increase in C3a characterized the activation of the complement system immediately after CABG. This was followed by a moderate decrease in activity of C1 esterase inhibitor, the main inhibitor of activation of the complement system by way of the classic pathway. This decrease may indicate consumption of this factor as a result of overstimulation of the pathway by CPB. In one instance, acquired C1 esterase inhibitor deficiency plus CPB was reported to cause pulmonary edema, circulatory collapse, and hemostatic disorder [17]. Such activation of the complement system by the classic pathway because of exposure of the blood to artificial surfaces was considered the initial step in the CPB–induced inflammatory response [6]. High circulating levels of proinflammatory cytokines such as TNF and IL-6 after cardiac operations are also associated with the postperfusion syndrome and a higher postoperative oxygen consumption [18]. Genes responsible for expression and production of TNF were activated during CPB in all patients and were highest when CPB exceeded 1.5 hours [19]. Reduction in circulating concentrations of complement factors (C3a and C5a) and cytokines (TNF and IL-6) by use of a polysulfone hemofilter during CBP resulted in improved early postoperative oxygenation and hemodynamics [20]. In our study, the soluble TNF receptors were used as a more stable indicator of TNF-␣ release [21, 22]. The postoperative increase in both receptors indicates a substantial release of TNF-␣ during CABG. The increase in the proinflammatory IL-6 and IL-8 follows the same pattern with substantially increased levels after CABG. In contrast, no significant increases in these cytokine levels
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were found after MIDCABG except for IL-6. Steadily increasing concentrations of this cytokine were measured up to 24 hours postoperatively. However, the peak level seen in the CABG group was not reached. This indicates an IL-6 release after the surgical procedure and may be due to anesthesia, blood loss, mechanical ventilation, or pain. Further clinical investigation is necessary to define the factors responsible for IL-6 release. This study demonstrates that the inflammatory response seen with conventional CABG procedures with high circulating concentrations of activated complement products and proinflammatory cytokines is not found after MIDCABG operations. Procedural differences that might influence the inflammatory process include the use of the extracorporeal perfusion system during CABG, the extent of myocardial ischemia (local for MIDCABG and global for CABG), and the use of protamine sulfate and moderate hypothermia for CABG. In a similar study using the same MIDCABG technique, Gu and associates [23] found no activation of the complement system. In addition, they reported the elimination of leukocyte and platelet activation in the MIDCABG group. In our study, no fever was seen clinically after MIDCABG, and the interstitial fluid accumulation evidenced by positive fluid balances in the CABG group was not found after MIDCABG. Other studies [21] report that these advantages may lead to a shorter period of postoperative ventilatory support and a reduction in postoperative hospital stay. These observations were similar to those in a previous study in patients who underwent coronary bypass grafting without CPB [24]. A limitation of this study is that the procedures compared differed in the degree of coronary artery revascularization. In the CABG group, complete revascularization of three-vessel disease was performed. In contrast, with the MIDCABG technique, only coronary arteries of the anterior wall can be accessed. The conventional approach resulted not only in a longer surgical incision and the use of CBP, but also in longer operating and anesthesia times. However, in our experience, the lesser degree of invasiveness of MIDCABG, as evidenced by the elimination of an inflammatory response and the avoidance of a median sternotomy, led to the referral of patients with two- or three-vessel disease for this procedure. These patients had a high degree of comorbidity, such as advanced lung or kidney disease. In this group, the inflammatory response to CABG represents a high risk for postoperative organ dysfunction [25]. After MIDCABG, none of the patients experienced organ dysfunction. The MIDCABG approach offers surgical coronary revascularization to patients who can undergo CPB only at higher risk. Also, MIDCABG with subsequent angioplasty of the remaining lesions (“hybrid procedure”) is applicable particularly for patients with a high degree of comorbidity. In conclusion, this study shows that cytokine release with MIDCABG is significantly lower than that with conventional CABG with CPB. We confirmed other studies revealing high complement activation during CABG that is not found for MIDCABG. In addition, consump-
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tion of C1 esterase inhibitor was found in this study. The absence of complement activation and cytokine release leads to an improved clinical course and no postoperative inflammatory response. These findings are of special importance for patients with associated disease and coronary vessel disease that cannot be treated with angioplasty alone. Minimally invasive direct coronary artery bypass grafting represents another treatment strategy for these patients.
References 1. Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61:1714–20. 2. Kolessov VI. Mammary artery-coronary artery anastomosis as method of treatment for angina pectoris. J Thorac Cardiovasc Surg 1967;54:535– 44. 3. Cremer J, Stru¨ber M, Wittwer T, et al. Off-bypass coronary bypass grafting via minithoracotomy using mechanical epicardial stabilization. Ann Thorac Surg 1997;63:S79 – 83. 4. Boonstra PW, Grandjean JG, Mariani MA. Reoperative coronary bypass grafting without cardiopulmonary bypass through a small thoracotomy. Ann Thorac Surg 1997;63: 405–7. 5. Wan S, LeClerc J-L, Vincent J-L. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation. Ann Thorac Surg 1997;63:269–76. 6. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–57. 7. Gu YJ, de Vries AJ, Boonstra PW, van Oeveren W. Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996;112:494 –500. 8. Gillinov AM, Redmond JM, Zehr KJ, et al. Inhibition of neutrophil adhesion during cardiopulmonary bypass. Ann Thorac Surg 1994;57:126–33. 9. Jansen PG, de Velthuis H, Wildevuur WR, et al. Cardiopulmonary bypass with modified fluid gelatin and heparincoated circuits. Br J Anaesth 1996;76:13–9. 10. Wan S, DeSmet J-M, Antoine M, Goldman M, Vincent J-L, LeClersk J-L. Steroid administration in heart and heart-lung transplantation: is the timing adequate? Ann Thorac Surg 1996;61:674– 8. 11. Wan S, Marchant A, DeSmet JM, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996;111:469–77. 12. Olthof CG, Jansen PG, de Vries JP, et al. Interstitial fluid volume during cardiac surgery measured by means of a non-invasive conductivity technique. Acta Anaesthesiol Scand 1995;39:508–12. 13. Christakis GT, Fremes SE, Koch J-P, et al. Determinants of low systemic vascular resistance during cardiopulmonary bypass. Ann Thorac Surg 1994;58:1040–9. 14. Ranucci M, Cirri S, Conti D, et al. Beneficial effects of Duraflo II heparin-coated circuits on postperfusion lung function. Ann Thorac Surg 1996;61:76– 81. 15. Zanardo G, Michielon P, Paccagnella A, et al. Acute renal failure in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:1489–95. 16. Plotz FB, van Oeveren W, Bartlett RH, Wildevuur CR. Blood activation during neonatal extracorporeal life support. J Thorac Cardiovasc Surg 1993;105:823–32. 17. Bonser RS, Dave J, Morgan J, et al. Complement activation during bypass in acquired C1 esterase inhibitor deficiency. Ann Thorac Surg 1991;52:541–3.
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18. Oudemans-van Straaten HM, Jansen PG, te Velthuis H, et al. Increased oxygen consumption after cardiac surgery is associated with the inflammatory response to endotoxemia. Intensive Care Med 1996;22:294 –300. 19. Hattler BG, Zeevi A, Oddis CV, Finkel MS. Cytokine induction during cardiac surgery: analysis of TNF-alpha expression pre- and postcardiopulmonary bypass. J Cardiac Surg 1995;10(4 Suppl):418–22. 20. Journois D, Pouard P, Greeley WJ, Mauriat P, Vouhe´ P, Safran D. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines, and complement components. Anesthesiology 1994;81: 1181–9. 21. Vey E, Burger D, Dayer JM. Expression and cleavage of tumor necrosis factor-␣ and tumor necrosis factor receptors
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by human monocytic cell lines upon direct contact with stimulated T cells. Eur J Immunol 1996;26:2404–9. Radoux D, DeGroote D. The total cytokine concept: the influence of soluble receptors in the cytokine measurement. In: Bergmann L, Mirou PS, eds. Cytokines in cancer therapy. Basel: Karger, 1994:251–9. Gu YJ, Mariani MA, van Oeveren W, Grandjean J-G, Boonstra PW. Reduction of the inflammatory response in patients undergoing minimally invasive coronary artery bypass grafting. Ann Thorac Surg 1998;65:420– 4. Buffolo E, de Andrade JCS, Branco JNR, Teles CA, Aguiar LF, Gomes W J. Coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg 1996;61:63– 6. Cremer J, Stru¨ber M, Wittwer T, et al. Morbidity of cardiopulmonary bypass and potential benefits of minimally invasive coronary surgery. Cor Europaeum 1997;6:164–7.
INVITED COMMENTARY The study of Dr Stru¨ber and associates brings to the focus of less invasive coronary surgery an important subject. We did almost the same design as the authors did, and our results were exactly the same (Ann Thorac Surg 1998:67:56 –9). We observed in 60% of patients operated on with cardiopulmonary bypass TNF-␣ factor and IL-6 release contrasting with 0% in the off-pump group. Thus, it appears that among possible factors, something happens when blood circulates out of its natural endothelium. Probably the complement activation is the initial step in CPB-induced inflammation—the main cause for organ dysfunction after extracorporeal circulation— but it is still to be proved that complement blockade eliminates ad-
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
verse effects of cardiopulmonary bypass. However, we really think, based on our 18 years of experience of myocardial revascularization without pump, that the incidence of clinical inflammatory response and vasoplegic syndrome can be dramaticaly reduced, avoiding the cardiopulmonary circuit. Enio Buffolo, MD Cardiovascular Surgery UNIFESP-EPM Rua Botucatu 740, 3rd Fl Sa˜o Paulo SP CEP 04023-900, Brazil e-mail: [email protected].
0003-4975/99/$20.00 PII S0003-4975(99)00769-9
Background. Coronary artery bypass grafting (CABG) is associated with a systemic inflammatory response. This has been attributed to cytokine release caused by extracorporeal circulation and myocardial ischemia. This study compares the inflammatory response after CABG with cardiopulmonary bypass and after minimally invasive direct coronary artery bypass grafting (MIDCABG) without cardiopulmonary bypass. Methods. Cytokine release and complement activation (interleukin-6 and interleukin-8, soluble tumor necrosis factor receptors 1 and 2, complement factor C3a, and C1 esterase inhibitor) were determined in 24 patients before and after CABG or MIDCABG. The maximum body temperature, chest drainage, and fluid balance were recorded for 24 hours after operation.
Results. Release of interleukin-6, interleukin-8, and tumor necrosis factor receptors 1 and 2 was significantly higher (p < ⴚ 0.005) in the CABG group than the MIDCABG group just after operation. After 24 hours, a significant increase in interleukin-6 was also found in the MIDCABG group (p ⴝ 0.001) compared with preoperative value. Body temperature and fluid balance were significantly higher after CABG (p < 0.001). Conclusions. Minimally invasive direct coronary artery bypass grafting represents a less traumatizing technique of surgical revascularization. The reduction in the inflammatory response may be advantageous for patients with a high degree of comorbidity. (Ann Thorac Surg 1999;68:1330 –5) © 1999 by The Society of Thoracic Surgeons
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(LAD) [3]. Successful use in repeat coronary artery bypass procedures has also been reported [4]. One feature of this technique is the clamping of the LAD for up to 30 minutes for revascularization. Studies of cytokine responses to CPB reveal that cytokine release is triggered by ischemia and reperfusion and that the levels of cytokine release correlate with cardiac ischemia [5]. This study compares the perioperative cytokine release after MIDCABG with that after conventional CABG.
he systemic inflammatory response after coronary artery bypass grafting (CABG) using cardiopulmonary bypass (CPB) contributes substantially to postoperative organ dysfunction and coagulation disorders [1]. Advantages derived from improvement in the biocompatibility of CPB in recent years have been counteracted by the growing demand for surgical revascularization in older and sicker patients. Since the 1967 report by Kolessov [2], only a few surgeons have reported on bypass grafting without CPB. Recent attention has focused on this technique to avoid the adverse effects of CPB on very sick patients and to contain costs. To optimize access to the internal mammary artery (IMA) and improve epicardial stabilization, special retractors were designed (Cardiothoracic Systems, Inc, Cupertino, CA) for minimally invasive direct coronary artery bypass grafting (MIDCABG) through a minithoracotomy without CPB. This technique has been shown to be a safe and reliable method for revascularization of the left anterior descending coronary artery Accepted for publication April 26, 1999. Address reprint requests to Dr Stru¨ber, Division of Thoracic and Cardiovascular Surgery, Hannover Medical School, Carl Neuberg Str 1, 30623 Hannover, Germany; e-mail: [email protected].
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
Patients and Methods Cytokine release and complement activation were assessed in 24 patients. Twelve consecutive patients (2 women and 10 men aged 64 ⫾ 9 years) with single-vessel disease underwent MIDCABG. The CABG group comprised 12 consecutive patients (3 women and 9 men aged 61 ⫾ 13 years) with three-vessel disease who received double or triple vein grafts and a left IMA graft with the use of CPB. No patient requiring an emergency procedure, an intraaortic balloon pump preoperatively, or preoperative heparin sodium therapy was included in the study. Consent for the additional blood was obtained from each patient prior to the procedure. The study was approved by the institutional ethics committee. 0003-4975/99/$20.00 PII S0003-4975(99)00729-8
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MIDCABG Procedure A left anterior minithoracotomy of 8 to 10 cm through the fifth intercostal space was performed. With the special retractor system (Cardiothoracic Systems, Inc), the left IMA was dissected as a pedicle up to the second rib. After harvest of the IMA, heparin (100 U/kg of body weight) was administered, and the pericardium was opened. The myocardial surface was stabilized at the site of anastomosis to the LAD with a special “horseshoe” retractor. Before the anastomosis was performed, the LAD was occluded proximally and distally using two tourniquet sutures. The vessel was incised between these sutures, and the IMA anastomosis was constructed in an end-toside fashion. Heparin was not reversed by protamine sulfate. After fixation of the distal pedicle, the chest was closed. The patients were mechanically ventilated in the intensive care unit for 12 to 15 hours and transferred from that unit 24 hours after operation.
CABG Procedure All patients underwent standard surgical revascularization for three-vessel coronary artery disease through a median sternotomy. In every instance, the pedicled left IMA was used as an LAD graft. In addition, two to four vein graft anastomoses were performed. Cardiopulmonary bypass was done with a non-heparin-coated circuit, a roller pump (Sto¨ckert Instrumentation, Munich, Germany), and a membrane oxygenator (Monolyth; Sorin Biomedica, Munich, Germany). During CPB, moderate hypothermia (30° to 32°C) was induced. Prior to CPB, high-dose heparin (300 U/kg) was given, and an activated clotting time of more than 400 seconds was maintained. Heparin was reversed completely after termination of CPB. St. Thomas’ cardioplegic solution, 1 to 1.5 L, was infused through the aortic root to achieve myocardial preservation during cross-clamping.
Anesthesia Sodium thiopental, fentanyl, and pancuronium bromide were administered to all patients. In the MIDCABG group, hemodynamic monitoring was done with a thermodilution catheter. During the time of harvest of the IMA to completion of the anastomosis, a left bronchial occlusion catheter was used to reduce ventilation of the left lung. In the CABG group, a mean arterial pressure of 50 to 70 mm Hg was maintained during CPB.
Cytokine Measurements Blood samples were obtained on admission, immediately after the surgical procedure, and 2, 8, and 24 hours after arrival in the intensive care unit. Blood was drawn from arterial catheters only. Enzyme-linked immunosorbent assays were used for measurement of soluble tumor necrosis factor (TNF) receptors 1 and 2 (R&D Systems, Wiesbaden, Germany). Levels of interleukin (IL)-6 and IL-8 were also determined by enzyme-linked immunosorbent assay (Immulite, DPC Biermann, Bad Nauheim, Germany). C1 esterase inhibitor activity was measured functionally by a commercially available
Fig 1. Plasma concentration of complement factor C3a in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
amidolytic test (Behring, Marburg, Germany). Complement factor C3a was determined by radioimmunoassay (Amersham International, Inc, Little Chalfont, UK).
Statistical Analysis All data are expressed as the mean ⫾ the standard deviation. Analysis of variance for repeated measures was performed using an SPSS statistical program. A p value of less than 0.05 was considered significant.
Results The MIDCABG procedures were completed in 115 ⫾ 18 minutes. The left bronchial occlusion time was 56 ⫾ 17 minutes, and the LAD was occluded for 17 ⫾ 8 minutes. The duration of operation was significantly shorter ( p ⬍ 0.05) for the MIDCABG group than the CABG group (167 ⫾ 23 minutes). For CABG, the mean cross-clamp time was 47 ⫾ 18 minutes. All patients in both groups were extubated 6 to 12 hours after the operation and were transferred in hemodynamically stable condition from the intensive care unit to a regular ward on the first postoperative day. No sympathomimetic drugs were used during the postoperative course, and no signs of cardiac ischemia as determined by electrocardiographic criteria or creatine kinase or troponin T levels were found. Blood loss within 24 hours after operation was 580 ⫾ 280 mL in the MIDCABG group and 720 ⫾ 350 mL in the CABG group. The concentration of C3a in the CABG group increased fivefold ( p ⫽ 0.001) right after the surgical procedure compared with the preoperative value. The level then decreased steadily until a normal range was reached after 24 hours (Fig 1). In contrast, C3a concentration was unchanged in the MIDCABG group. There was a tendency for the activity of C1 esterase inhibitor to be
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Fig 2. C1 esterase inhibitor (C1-INH) activity in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
Fig 4. Plasma soluble tumor necrosis factor receptor 2 (TNF-R2) concentration in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
reduced ( p ⫽ 0.049) for the first 8 hours after CPB with normal values at 24 hours (Fig 2). No such changes were found in the MIDCABG group. A threefold increase in expression of soluble TNF receptor 1 was measured immediately after operation and 2 hours later in the CABG group. After 8 hours, the values were decreasing (Fig 3). The concentration of soluble TNF receptors followed a similar course in the CABG group with a significant rise postoperatively ( p ⫽ 0.005) that reached its peak at 2 hours. Thereafter, the values decreased more slowly than those for TNF receptor 1 (Fig 4). In the MIDCABG group, the concentrations
of TNF receptors 1 and 2 showed a rising curve up to 8 hours after the procedure and a decreasing curve thereafter. This increase did not reach significance. A high concentration of IL-8 with a large degree of variation was documented right after CABG (Fig 5). The increase was fivefold compared with the preoperative values. During the postoperative course, the concentration decreased to a normal range at 24 hours. There was no increase in IL-8 concentration within the first 24 hours in the MIDCABG group ( p ⫽ 0.004). In contrast to IL-8, the release of IL-6 increased continuously for 2 hours after CABG and had similar values at 2 and 8 hours. At 24
Fig 3. Plasma soluble tumor necrosis factor receptor 1 (TNF-R1) concentration in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
Fig 5. Plasma interleukin-8 (IL8) concentration in patients before (prae) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
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balance in those patients revealed a need of fluids, which were infused as crystalloid solutions. The mean fluid balance in the CABG group was 2,600 ⫾ 680 mL versus 480 ⫾ 270 mL in the MIDCABG group ( p ⫽ 0.001).
Comment
Fig 6. Plasma interleukin-6 (IL6) concentration in patients before (pre) and 0, 2, 8, and 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation. The p value represents an intergroup comparison.
hours, a reduction from 1,000 pg/mL at 8 hours to about 350 pg/mL was found, which was still significantly higher than the preoperative value (Fig 6). The IL-6 concentration in the MIDCABG group was significantly lower ( p ⫽ 0.001) in the first 8 postoperative hours than the level in the CABG group, but a steady increase was observed during the postoperative course. After 24 hours, the level was comparable to that in the CABG group and significantly higher ( p ⫽ 0.0001) compared with the preoperative control. During the first 24 hours after CABG, all patients had a fever with peak temperatures between 38.6° and 39.1°C (Fig 7). The maximum body temperature of patients in the MIDCABG group was significantly lower ( p ⫽ 0.0001), ranging between 36.5° and 38.0°C. The fluid
Fig 7. Maximum body temperature within 24 hours after minimally invasive direct coronary artery bypass (MIDCAB) (n ⫽ 12) and coronary artery bypass grafting (CABG) (n ⫽ 12). Data are expressed as the mean ⫾ the standard deviation.
Conventional CABG with the use of CPB is a safe and effective procedure. However, CPB induces an inflammatory response that leads to considerable postoperative morbidity, especially in patients with accompanying diseases [6]. Many approaches to reduce the CBP–induced inflammatory reaction have been tried and include heparin-coating of the extracorporeal circuit, depletion of leukocytes [7] or inhibition of their adhesion [8], colloid priming of the CPB circuit [9], and pretreatment with steroids [10]. Nevertheless, CPB triggers an inflammatory response involving proinflammatory cytokines such as TNF-␣, IL-6, and IL-8 [11] and activation of the complement system [6]. This leads clinically to a postperfusion syndrome characterized by fever and fluid accumulation in the interstitium [12]. In addition, low systemic vascular resistance can develop [13]. Postperfusion organ dysfunction has been reported mainly for the lungs [14], the kidneys [15], and the central nervous system. Activation of the complement system by CPB is considered a first step in the inflammatory reaction and a main cause for organ dysfunction [16]. In our study, a significant increase in C3a characterized the activation of the complement system immediately after CABG. This was followed by a moderate decrease in activity of C1 esterase inhibitor, the main inhibitor of activation of the complement system by way of the classic pathway. This decrease may indicate consumption of this factor as a result of overstimulation of the pathway by CPB. In one instance, acquired C1 esterase inhibitor deficiency plus CPB was reported to cause pulmonary edema, circulatory collapse, and hemostatic disorder [17]. Such activation of the complement system by the classic pathway because of exposure of the blood to artificial surfaces was considered the initial step in the CPB–induced inflammatory response [6]. High circulating levels of proinflammatory cytokines such as TNF and IL-6 after cardiac operations are also associated with the postperfusion syndrome and a higher postoperative oxygen consumption [18]. Genes responsible for expression and production of TNF were activated during CPB in all patients and were highest when CPB exceeded 1.5 hours [19]. Reduction in circulating concentrations of complement factors (C3a and C5a) and cytokines (TNF and IL-6) by use of a polysulfone hemofilter during CBP resulted in improved early postoperative oxygenation and hemodynamics [20]. In our study, the soluble TNF receptors were used as a more stable indicator of TNF-␣ release [21, 22]. The postoperative increase in both receptors indicates a substantial release of TNF-␣ during CABG. The increase in the proinflammatory IL-6 and IL-8 follows the same pattern with substantially increased levels after CABG. In contrast, no significant increases in these cytokine levels
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were found after MIDCABG except for IL-6. Steadily increasing concentrations of this cytokine were measured up to 24 hours postoperatively. However, the peak level seen in the CABG group was not reached. This indicates an IL-6 release after the surgical procedure and may be due to anesthesia, blood loss, mechanical ventilation, or pain. Further clinical investigation is necessary to define the factors responsible for IL-6 release. This study demonstrates that the inflammatory response seen with conventional CABG procedures with high circulating concentrations of activated complement products and proinflammatory cytokines is not found after MIDCABG operations. Procedural differences that might influence the inflammatory process include the use of the extracorporeal perfusion system during CABG, the extent of myocardial ischemia (local for MIDCABG and global for CABG), and the use of protamine sulfate and moderate hypothermia for CABG. In a similar study using the same MIDCABG technique, Gu and associates [23] found no activation of the complement system. In addition, they reported the elimination of leukocyte and platelet activation in the MIDCABG group. In our study, no fever was seen clinically after MIDCABG, and the interstitial fluid accumulation evidenced by positive fluid balances in the CABG group was not found after MIDCABG. Other studies [21] report that these advantages may lead to a shorter period of postoperative ventilatory support and a reduction in postoperative hospital stay. These observations were similar to those in a previous study in patients who underwent coronary bypass grafting without CPB [24]. A limitation of this study is that the procedures compared differed in the degree of coronary artery revascularization. In the CABG group, complete revascularization of three-vessel disease was performed. In contrast, with the MIDCABG technique, only coronary arteries of the anterior wall can be accessed. The conventional approach resulted not only in a longer surgical incision and the use of CBP, but also in longer operating and anesthesia times. However, in our experience, the lesser degree of invasiveness of MIDCABG, as evidenced by the elimination of an inflammatory response and the avoidance of a median sternotomy, led to the referral of patients with two- or three-vessel disease for this procedure. These patients had a high degree of comorbidity, such as advanced lung or kidney disease. In this group, the inflammatory response to CABG represents a high risk for postoperative organ dysfunction [25]. After MIDCABG, none of the patients experienced organ dysfunction. The MIDCABG approach offers surgical coronary revascularization to patients who can undergo CPB only at higher risk. Also, MIDCABG with subsequent angioplasty of the remaining lesions (“hybrid procedure”) is applicable particularly for patients with a high degree of comorbidity. In conclusion, this study shows that cytokine release with MIDCABG is significantly lower than that with conventional CABG with CPB. We confirmed other studies revealing high complement activation during CABG that is not found for MIDCABG. In addition, consump-
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tion of C1 esterase inhibitor was found in this study. The absence of complement activation and cytokine release leads to an improved clinical course and no postoperative inflammatory response. These findings are of special importance for patients with associated disease and coronary vessel disease that cannot be treated with angioplasty alone. Minimally invasive direct coronary artery bypass grafting represents another treatment strategy for these patients.
References 1. Cremer J, Martin M, Redl H, et al. Systemic inflammatory response syndrome after cardiac operations. Ann Thorac Surg 1996;61:1714–20. 2. Kolessov VI. Mammary artery-coronary artery anastomosis as method of treatment for angina pectoris. J Thorac Cardiovasc Surg 1967;54:535– 44. 3. Cremer J, Stru¨ber M, Wittwer T, et al. Off-bypass coronary bypass grafting via minithoracotomy using mechanical epicardial stabilization. Ann Thorac Surg 1997;63:S79 – 83. 4. Boonstra PW, Grandjean JG, Mariani MA. Reoperative coronary bypass grafting without cardiopulmonary bypass through a small thoracotomy. Ann Thorac Surg 1997;63: 405–7. 5. Wan S, LeClerc J-L, Vincent J-L. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation. Ann Thorac Surg 1997;63:269–76. 6. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J Thorac Cardiovasc Surg 1983;86:845–57. 7. Gu YJ, de Vries AJ, Boonstra PW, van Oeveren W. Leukocyte depletion results in improved lung function and reduced inflammatory response after cardiac surgery. J Thorac Cardiovasc Surg 1996;112:494 –500. 8. Gillinov AM, Redmond JM, Zehr KJ, et al. Inhibition of neutrophil adhesion during cardiopulmonary bypass. Ann Thorac Surg 1994;57:126–33. 9. Jansen PG, de Velthuis H, Wildevuur WR, et al. Cardiopulmonary bypass with modified fluid gelatin and heparincoated circuits. Br J Anaesth 1996;76:13–9. 10. Wan S, DeSmet J-M, Antoine M, Goldman M, Vincent J-L, LeClersk J-L. Steroid administration in heart and heart-lung transplantation: is the timing adequate? Ann Thorac Surg 1996;61:674– 8. 11. Wan S, Marchant A, DeSmet JM, et al. Human cytokine responses to cardiac transplantation and coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996;111:469–77. 12. Olthof CG, Jansen PG, de Vries JP, et al. Interstitial fluid volume during cardiac surgery measured by means of a non-invasive conductivity technique. Acta Anaesthesiol Scand 1995;39:508–12. 13. Christakis GT, Fremes SE, Koch J-P, et al. Determinants of low systemic vascular resistance during cardiopulmonary bypass. Ann Thorac Surg 1994;58:1040–9. 14. Ranucci M, Cirri S, Conti D, et al. Beneficial effects of Duraflo II heparin-coated circuits on postperfusion lung function. Ann Thorac Surg 1996;61:76– 81. 15. Zanardo G, Michielon P, Paccagnella A, et al. Acute renal failure in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1994;107:1489–95. 16. Plotz FB, van Oeveren W, Bartlett RH, Wildevuur CR. Blood activation during neonatal extracorporeal life support. J Thorac Cardiovasc Surg 1993;105:823–32. 17. Bonser RS, Dave J, Morgan J, et al. Complement activation during bypass in acquired C1 esterase inhibitor deficiency. Ann Thorac Surg 1991;52:541–3.
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18. Oudemans-van Straaten HM, Jansen PG, te Velthuis H, et al. Increased oxygen consumption after cardiac surgery is associated with the inflammatory response to endotoxemia. Intensive Care Med 1996;22:294 –300. 19. Hattler BG, Zeevi A, Oddis CV, Finkel MS. Cytokine induction during cardiac surgery: analysis of TNF-alpha expression pre- and postcardiopulmonary bypass. J Cardiac Surg 1995;10(4 Suppl):418–22. 20. Journois D, Pouard P, Greeley WJ, Mauriat P, Vouhe´ P, Safran D. Hemofiltration during cardiopulmonary bypass in pediatric cardiac surgery. Effects on hemostasis, cytokines, and complement components. Anesthesiology 1994;81: 1181–9. 21. Vey E, Burger D, Dayer JM. Expression and cleavage of tumor necrosis factor-␣ and tumor necrosis factor receptors
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by human monocytic cell lines upon direct contact with stimulated T cells. Eur J Immunol 1996;26:2404–9. Radoux D, DeGroote D. The total cytokine concept: the influence of soluble receptors in the cytokine measurement. In: Bergmann L, Mirou PS, eds. Cytokines in cancer therapy. Basel: Karger, 1994:251–9. Gu YJ, Mariani MA, van Oeveren W, Grandjean J-G, Boonstra PW. Reduction of the inflammatory response in patients undergoing minimally invasive coronary artery bypass grafting. Ann Thorac Surg 1998;65:420– 4. Buffolo E, de Andrade JCS, Branco JNR, Teles CA, Aguiar LF, Gomes W J. Coronary artery bypass grafting without cardiopulmonary bypass. Ann Thorac Surg 1996;61:63– 6. Cremer J, Stru¨ber M, Wittwer T, et al. Morbidity of cardiopulmonary bypass and potential benefits of minimally invasive coronary surgery. Cor Europaeum 1997;6:164–7.
INVITED COMMENTARY The study of Dr Stru¨ber and associates brings to the focus of less invasive coronary surgery an important subject. We did almost the same design as the authors did, and our results were exactly the same (Ann Thorac Surg 1998:67:56 –9). We observed in 60% of patients operated on with cardiopulmonary bypass TNF-␣ factor and IL-6 release contrasting with 0% in the off-pump group. Thus, it appears that among possible factors, something happens when blood circulates out of its natural endothelium. Probably the complement activation is the initial step in CPB-induced inflammation—the main cause for organ dysfunction after extracorporeal circulation— but it is still to be proved that complement blockade eliminates ad-
© 1999 by The Society of Thoracic Surgeons Published by Elsevier Science Inc
verse effects of cardiopulmonary bypass. However, we really think, based on our 18 years of experience of myocardial revascularization without pump, that the incidence of clinical inflammatory response and vasoplegic syndrome can be dramaticaly reduced, avoiding the cardiopulmonary circuit. Enio Buffolo, MD Cardiovascular Surgery UNIFESP-EPM Rua Botucatu 740, 3rd Fl Sa˜o Paulo SP CEP 04023-900, Brazil e-mail: [email protected].
0003-4975/99/$20.00 PII S0003-4975(99)00769-9