Reduction of the Inflammatory Response in Patients Undergoing Minimally Invasive Coronary Artery Bypass Grafting. Patients and Methods Patients

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1 Reduction of the Inflammatory Response in Patients Undergoing Minimally Invasive Coronary Artery Bypass Grafting Y. John Gu, MD, PhD, Massimo A. Mariani, MD, PhD, Willem van Oeveren, PhD, Jan G. Grandjean, MD, PhD, and Piet W. Boonstra, MD, PhD Department of Cardiothoracic Surgery, Thorax Center, University Hospital, Groningen, the Netherlands Background. The aim of this prospective study was to determine whether the inflammation-associated clinical morbidity as well as the subclinical markers of the inflammatory response are reduced in patients who undergo minimally invasive coronary artery bypass grafting without cardiopulmonary bypass. Methods. From June 1995 to June 1996, 62 consecutive patients with isolated stenosis of the left anterior descending coronary artery were assigned randomly to two groups: 31 patients underwent minimally invasive coronary artery bypass grafting and 31 patients underwent conventional coronary artery bypass grafting with cardiopulmonary bypass. In a subgroup of 10 patients in each group, subclinical markers were measured to determine the level of the inflammatory response generated during the operation. Results. In the group that underwent minimally invasive coronary artery bypass grafting, leukocyte elastase, platelet -thromboglobulin, and complement C3a were unchanged at the end of the procedure compared with their baseline concentrations, whereas these inflammatory markers were increased significantly in the group that underwent conventional coronary artery bypass grafting with cardiopulmonary bypass. The patients who underwent minimally invasive coronary artery bypass grafting had a shorter duration of operation ( versus minutes; p < 0.01), less blood loss ( versus ml; p < 0.01), shorter ventilatory support ( versus hours; p < 0.01), and a shorter postoperative hospital stay ( versus days; p < 0.01) than the patients who underwent the conventional procedure. Conclusions. These data suggest that patients who undergo minimally invasive coronary artery bypass grafting have a significant reduction in the systemic inflammatory response, postoperative morbidity, and hospital stay compared with patients who undergo conventional coronary artery bypass grafting with cardiopulmonary bypass. (Ann Thorac Surg 1998;65:420 4) 1998 by The Society of Thoracic Surgeons Patients who have angina caused by an isolated stenosis of the left anterior descending coronary artery (LAD) currently are treated with medication, percutaneous transluminal coronary angioplasty, or coronary artery bypass grafting (CABG) [1 5]. Compared with the other two types of treatment, CABG has several advantages, such as a reduced rate of repeated revascularization and the longest event-free survival [4, 5]. However, CABG has the disadvantage of requiring the use of cardiopulmonary bypass (CPB), which makes patients ill by initiating a systemic inflammatory response [6 9]. Specifically, the use of CPB increases postoperative morbidity, manifested by postoperative bleeding and organ dysfunction [6]. Coronary artery bypass grafting without CPB performed through a median sternotomy reduces postoperative morbidity compared with conventional CABG [10, 11]. This technique has evolved into minimally invasive Accepted for publication Aug 5, Address reprint requests to Dr Boonstra, Department of Cardiothoracic Surgery, University Hospital Groningen, Hanzeplein 1, 9700 RB Groningen, the Netherlands. coronary artery bypass grafting (MICABG), which is performed through a small anterolateral thoracotomy [12, 13] and can reduce postoperative morbidity further. However, there have been few investigations studying the mechanisms and causes of the reduced postoperative morbidity in patients who undergo MICABG. It is known that the systemic inflammatory response induced by CPB contributes to the increased postoperative morbidity observed in cardiac surgical patients [6 9]. Therefore, the aim of this prospective study was to determine whether elimination of the damaging effects of CPB can reduce the inflammation-associated clinical morbidity of CABG and the subclinical markers of the inflammatory response. For this purpose, patients with isolated stenosis of the LAD were assigned randomly to two treatment groups: MICABG without CPB and conventional CABG with CPB. Patients and Methods Patients This prospective study included 62 patients with isolated stenosis of the LAD who underwent operation at the 1998 by The Society of Thoracic Surgeons /98/$19.00 Published by Elsevier Science Inc PII S (97)

2 Ann Thorac Surg GU ET AL 1998;65:420 4 INFLAMMATORY RESPONSE AND MICABG 421 Table 1. Patients Demographic Data Characteristic MICABG (n 31) CPB- CABG (n 31) p Value Age (y) a Male b 22 (70.9) 19 (61.3) Female b 9 (29.1) 12 (38.7) Preop ejection fraction a Preop LVEDP (mm Hg) a Preop CCS class (grade) Preop hypertension b 6 (19.4) 4 (12.9) History of diabetes b 3 (9.7) 2 (6.5) History of MI b 11 (35.5) 9 (29.0) a Values are mean plus or minus standard deviation. b Values are absolute number, with percentage given in parentheses. CCS Canadian Cardiovascular Society; CPB-CABG conventional coronary artery bypass grafting with cardiopulmonary bypass; LVEDP left ventricular end-diastolic pressure; MI myocardial infarction; MICABG minimally invasive coronary artery bypass grafting; preop preoperative. University Hospital of Groningen between June 1995 and June Inclusion criteria included the presence of isolated stenosis of the LAD (according to the criteria of the American Heart Association). Exclusion criteria included the presence of any associated cardiac disease, such as a left ventricular aneurysm or valvular disease. Patients were assigned randomly to two groups, one of which was operated on without CPB through a small anterolateral thoracotomy (MICABG group, n 31) and the other with CPB (CPB-CABG group, n 31) as a control group. In a subgroup of 10 patients in each group, subclinical biochemical markers were measured to determine the level of inflammatory mediators generated during the operation. All these patients had no signs of severe heart failure or other organ dysfunction and no history of a bleeding diathesis. Administration of platelet-inhibiting drugs such as aspirin was discontinued at least 3 days before operation. Patients were not receiving anticoagulant therapy (ie, heparin infusion) before operation. The study protocol was approved by the institutional medical ethics committee and informed consent was obtained from all patients. The patients demographic information, including age, sex, and preoperative conditions, is provided in Table 1. Anesthesia Anesthesia was induced and maintained by the intravenous infusion of sufentanil citrate (1 to 3 g/kg) and midazolam (0.05 to 0.1 mg/kg). Muscle relaxation was achieved with pancuronium bromide (100 to 140 g/kg). In the CPB-CABG group, dexamethasone, 1 mg/kg, was administered after the induction of anesthesia. Anticoagulation in the MICABG group was achieved by the intravenous administration of 100 IU/kg of bovine lung heparin to increase the activated clotting time to twice the baseline value, whereas in the CPB-CABG group, a loading dose of 300 IU/kg was given before the start of CPB to increase the activated clotting time to more than 400 seconds. Heparin was neutralized only in the CPB- CABG group after the end of CPB by the administration of 3 mg/kg of protamine chloride. Surgical Technique In the MICABG group, the patient s left arm was elevated above the head. A skin incision approximately 8 to 10 cm long was made at the level of the fifth intercostal space, with the medial edge of the incision 3 to 4 cm lateral to the left internal mammary artery. Once the pleural cavity had been opened, the left lung was deflated and the left internal mammary artery was identified by palpation. A specially adapted wound spreader was secured in place and opened. The left internal mammary artery was harvested as a pedicle from the first rib down to the seventh rib space, starting at the level of the skin incision. After the left internal mammary artery was harvested, another spreader carrying a coronary artery stabilizer was placed (CardioThoracic Systems, Cupertino, CA). The LAD was surrounded by two looping 5-0 polypropylene sutures, placed proximal and distal to the chosen site for the anastomosis. To test the tolerance to regional ischemia, the two looping sutures were pulled to occlude the LAD briefly. The LAD then was opened longitudinally and the two looping sutures were pulled up until an adequate hemostasis was provided. The mammary-tocoronary anastomosis was performed with a running 7-0 or 8-0 polypropylene suture. After the anastomosis was completed, the two looping sutures were cut and the mammary pedicle was secured in place by two 5-0 polypropylene stitches. The small thoracotomy wound was closed in layers and one pleural drain was left in place. In the CPB-CABG group, a median sternotomy and standard CPB technique were used. The CPB circuit consisted of roller pumps (Stöckert Instrumentation, Munich, Germany) and a microporous polypropylene membrane oxygenator (CML Excel; Cobe Laboratories Inc, Lakewood, CO). During CPB, moderate hypothermia was induced to maintain the nasopharyngeal temperature between 30 and 32 C. Myocardial preservation during aortic cross-clamping was achieved by 1 L of St.Thomas cardioplegic solution (4 C) infused into the aortic root. The flow rate was set at 2.4 L min 1 min 2 and the mean arterial pressure was maintained at 50 to 60 mm Hg during CPB. After CPB, protamine chloride (3 mg/kg) was administered to neutralize the effect of heparin. Hematologic and Biochemical Measurements For measurement of the inflammatory mediators during operation, a pre-cabg blood sample (baseline) was taken from all patients from the indwelling radial arterial catheter 3 minutes after heparinization. A post-cabg blood sample was taken during wound closure in the MICABG group and after CPB but before protamine administration in the CPB-CABG group. Plasma, obtained by the centrifugation of whole blood at 1,100 g for 10 minutes, was stored at 80 C. Circulating leukocytes

3 422 GU ET AL Ann Thorac Surg INFLAMMATORY RESPONSE AND MICABG 1998;65:420 4 and platelets were counted by an automatic cell counter (Cell-Dyn 610; Sequoia-Turner, Mountain View, CA) from whole blood. Activation of leukocytes was indicated by concentrations of plasma elastase in complex with 1 -proteinase inhibitor as assessed by an enzyme-linked immunosorbent assay (Merck, Darmstadt, Germany). Activation of platelets was indicated by the release of -thromboglobulin as determined by a radioimmunoassay (Amersham International Inc, Amersham, UK). Complement activation was indicated by the release of C3a as determined by a radioimmunoassay (Amersham International Inc). Clinical Parameters Postoperative blood loss was calculated during the first 24 hours after operation in the intensive care unit. Donor blood transfusion was performed when the hematocrit was less than 25%. Patients were extubated when they had stable hemodynamics, were awake, and were breathing on their own without respiratory acidosis or hypoxemia. Patients were discharged from the hospital when they had achieved a stable and good overall condition and had the ability to perform basic daily activities. Statistical Analysis All the hematologic and biochemical data are expressed as mean and standard error of the mean. Clinical data are expressed as mean and standard deviation. Categorical data are expressed as numbers with percentages. Hematologic and biochemical data obtained during operation are corrected for hemodilution. Data processing and statistical testing were performed with Statistical Package for the Social Sciences software (SPSS Inc, Chicago, IL). The nonparametric Mann-Whitney test was used to determine the differences between the two groups and the Wilcoxon test was used for the within-group differences. The 2 test was used to compare categorical variables between groups. A p value of less than 0.05 was considered statistically significant. Results Systemic Inflammatory Response The circulating leukocyte count increased significantly in the CPB-CABG group at the end of CPB compared with the baseline count (from to /L; p 0.01), whereas no increase occurred in the MICABG group (from to /L). The plasma elastase concentration rose significantly in the CPB- CABG group at the end of CPB compared with the baseline value (from to ng/ml; p 0.01), but did not rise in the MICABG group (from to ng/ml) (Fig 1A). The platelet count was similar in both groups at the end of the CABG procedure (from to /L in the CPB-CABG group, and from to /L in the MICABG group). However, platelet degranulation, indicated by the release of -thromboglobulin, was found in the CPB-CABG group (from to 1, ng/ml; p 0.01), but not in the MICABG group (from Fig 1. Inflammatory mediators derived from leukocytes (A), platelets (B), and complement activation (C) in patients undergoing minimally invasive coronary artery bypass grafting (MICABG) and conventional coronary artery bypass grafting (CABG) with cardiopulmonary bypass (CPB-CABG). (**p 0.01 compared with pre- CABG values.) to ng/ml) (Fig 1B). Complement activation, identified by C3a, increased significantly in the CPB-CABG group at the end of CPB compared with the baseline concentration (from 1, to 3, ng/ml; p 0.01), but did not increase in the MICABG group (from to ng/ml) (Fig 1C). The postoperative leukocyte count did not differ between the groups on the first postoperative day, but was significantly less in the MICABG group on the second postoperative day and before hospital discharge (Table 2). Clinical Outcome There was no hospital mortality in this patient population. The mean duration of operation was significantly shorter in the MICABG group than in the CPB-CABG group ( versus minutes). The mean blood loss was significantly less in the MICABG group than in the CPB-CABG group ( versus ml) (Fig 2A). No patient in the MICABG group received donor red blood cell transfusion, whereas 3 patients (9.7%) in the CPB-CABG group received 1 unit of donor red blood cells, 5 patients (16.1%) received 2 units, 2 patients (6.5%) received 3 units, and 1 patient (3.2%) received 6 units within 24 hours after the operation. The

4 Ann Thorac Surg GU ET AL 1998;65:420 4 INFLAMMATORY RESPONSE AND MICABG 423 Table 2. Postoperative Hematologic Measurements, Morbidity, and Hospital Stay Parameter MICABG (n 31) CPB- CABG (n 31) p Value Leukocytes (10 9 /L) POD POD Discharge Hematocrit (%) POD POD Discharge Blood loss (ml) RBC transfusion (ml) Postoperative ventilation (h) Hospital stay (d) CPB-CABG conventional coronary artery bypass grafting with cardiopulmonary bypass; MICABG minimally invasive coronary artery bypass grafting; POD postoperative day; RBC red blood cell. hematocrit level was significantly higher in the MICABG group during their postoperative hospital stay, although they did not receive donor red blood cells (Table 2). In the MICABG group, mean postoperative ventilatory support was significantly shorter than in the CPB-CABG group ( versus hours) (Fig 2B). In addition, the mean postoperative hospital stay was significantly shorter in the MICABG group than in the CPB-CABG group ( versus days) (Fig 2C). this study, however, no increase of C3a was observed during operation in the MICABG group compared with the CPB-CABG group, which suggests that the MICABG procedure eliminates complement activation and thus also the triggering of the systemic inflammatory response. The circulating leukocyte count usually increases during and after operation in patients undergoing CPB [6 8]. This systemic leukocytosis is thought to be a combined effect of CPB and complement activation resulting in the mobilization of leukocytes from the marginating pool and bone marrow [22]. In this study, the circulating leukocyte count did not increase at the end of the operation in the MICABG group, suggesting that the MICABG operation prevents or at least delays leukocytosis. However, a low number of circulating leukocytes often is viewed negatively as a sign of complement activation during operation [23]. Although it is well stated in the literature that complement activation may induce leukocyte sequestration in the lung, causing systemic leukopenia [6 8, 22], other factors, such as hemodynamic changes, rewarming, and complement activation during CPB, may dominantly induce leukocyte release from bone marrow, leading to a systemic leukocytosis [22, 24]. A stable leukocyte count together with low C3a and elastase concentrations in patients who undergo MICABG most likely is due to the absence of all these processes. Comment In the past, reduction of the CPB-induced inflammatory response in patients undergoing CABG has been achieved partially by pretreatment with corticosteroids [14, 15], the use of heparin-coated extracorporeal circuits [16, 17], the depletion of leukocytes [18, 19], and other methods [20, 21]. This study demonstrates that the MI- CABG procedure reduces the systemic inflammatory response and subsequently reduces the postoperative morbidity in patients with isolated stenosis of the LAD. The reduced systemic inflammatory response in the MICABG group was evidenced by the elimination of complement, leukocyte, and platelet activation during operation, and was associated with less blood loss, shorter postoperative ventilatory support, and a shorter postoperative hospital stay than in the CPB-CABG group. Complement activation is considered a trigger of CPB-induced inflammatory response in patients undergoing cardiac operations [6]. Exposure of blood to the artificial surface in the CPB circuit activates complement and subsequently results in leukocyte activation that stimulates a systemic inflammatory response [6 8]. Usually, complement activation is associated with a strong release of C3a during CPB. High levels of C3a have been found even after pretreatment of patients with corticosteroids and the use of heparin-coated circuits [15, 16]. In Fig 2. Postoperative blood loss (A), ventilatory support (B), and hospital stay (C) in patients undergoing minimally invasive coronary artery bypass grafting (MICABG) and conventional coronary artery bypass grafting with cardiopulmonary bypass (CPB-CABG). (**p 0.01 in comparison between the two groups.)

5 424 GU ET AL Ann Thorac Surg INFLAMMATORY RESPONSE AND MICABG 1998;65:420 4 It is possible that factors other than the elimination of CPB contribute to the reduction in the inflammatory response seen in patients who undergo MICABG. First, the loading dose of heparin was reduced to 100 IU/kg in these patients. It is known that heparin in a dose range of clinical CPB activates granulocytes, platelets, and fibrinolysis [25, 26]. Second, MICABG involves a smaller surgical wound area than conventional CABG with CPB. Exposure of blood to the surgical wound is known to cause blood activation, as does CPB [27]. Finally, the effects of heparin were not reversed with protamine in patients who underwent MICABG. The avoidance of protamine also may contribute to the reduced inflammatory response in these patients. Conventional CABG with CPB is an effective therapy for patients with isolated stenosis of the LAD [4, 5]. However, the accompanying CPB-induced inflammatory response contributes significantly to postoperative morbidity [6]. As demonstrated in this study as well as in previous studies [10, 11], patients who undergo MICABG or CABG through a median sternotomy without CPB have a significantly shorter hospital stay compared with those who undergo conventional CABG with CPB. These observations suggest that the reduced postoperative morbidity and hospital stay noted in patients who undergo MICABG may offset the disadvantages of CABG for patients with isolated stenosis of the LAD. We conclude that patients with isolated stenosis of the LAD who undergo MICABG have a significant reduction in the systemic inflammatory response, postoperative morbidity, and hospital stay compared with those who undergo conventional CABG with CPB. We thank Heleen Los for her support in preparing the manuscript and Johan Haan for performing the biochemical assays. References 1. 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