Despite improvements in cardiopulmonary bypass

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1 On-Pump Versus Off-Pump Coronary Revascularization: Evaluation of Renal Function Raimondo Ascione, MD, Clinton T. Lloyd, FRCS, Malcom J. Underwood, FRCS, Walter J. Gomes, MD, and Gianni D. Angelini, FRCS Bristol Heart Institute, Bristol Royal Infirmary, Bristol, United Kingdom Background. Coronary revascularization with cardiopulmonary bypass has the potential risk of renal dysfunction related to the nonphysiologic nature of cardiopulmonary bypass. Recently, there has been a revival of interest in performing myocardial revascularization on the beating heart and we investigated whether this prevents renal compromise. Methods. A prospective, randomized, controlled trial was performed in 50 patients (45 males, mean age years) undergoing elective coronary artery bypass grafting. Patients were randomly assigned to conventional revascularization with cardiopulmonary bypass (on pump) or beating heart revascularization (off pump). Glomerular and tubular function were assessed up to 48 hours postoperatively. Results. There were no deaths, myocardial infarctions or acute renal failure in either group. Glomerular filtration as assessed by creatinine clearance and the urinary microalbumin/creatinine ratio was significantly worse in the on pump group (p < and , respectively). Renal tubular function was also impaired in the on pump group as assessed by increased N-acetyl glucosaminidase activity (p < ). Conclusions. These results suggest that off pump coronary revascularization offers a superior renal protection when compared with conventional coronary revascularization with cardiopulmonary bypass and cardioplegic arrest in first time coronary bypass patients. (Ann Thorac Surg 1999;68:493 8) 1999 by The Society of Thoracic Surgeons Despite improvements in cardiopulmonary bypass (CPB) technique, anesthesia, and intensive care, perioperative renal dysfunction still represents a significant and potentially lethal complication after cardiac operations [1]. The origin of this condition is multifactorial and includes factors relating to the conduct and management of CPB, such as the systemic inflammatory response, hypoperfusion, and loss of pulsatile perfusion [2 5]. Furthermore, the use of aortic cross-clamping and cardioplegic arrest can result in myocardial dysfunction [6 8], which can lead to renal hypoperfusion and subsequent renal impairment [1]. Recently, there has been a revival of interest in performing coronary artery bypass grafting on a beating heart [8 13], with early results suggesting better preservation of left ventricular contraction compared with conventional techniques in high-risk patients [9, 11]. There are, however, no data on the effects of beating heart operations on renal function from a prospective randomized study of patients who had elective operations. Patients and Methods Fifty patients (45 men, mean age years; 5 women, mean age years) who had first-time coronary artery bypass grafting were enrolled in the Accepted for publication March 16, Address reprint requests to Dr Angelini, Bristol Heart Institute, Bristol Royal Infirmary, Bristol BS2 8HW United Kingdom; g.d.angelini@ bristol.ac.uk. study. Patients were prospectively randomized on the day before their operation into two groups by card allocation. Group A (on pump) had conventional myocardial revascularization with CPB and cardioplegic arrest of the heart, whereas group B (off pump) had beating heart revascularization. Exclusion criteria included impaired left ventricular function as assessed by angiography (ejection fraction 30%), recent myocardial infarction (within the past month), disease involving the distal circumflex artery, diabetes mellitus (insulin or tablet controlled), high serum creatinine level ( 130 mol/l), abnormal results of preoperative urinalysis, concurrent diuretic therapy, reoperation or combined heart operation, respiratory impairment, previous stroke or transient ischemic attack, and coagulopathy. The study was approved by the United Bristol Healthcare Trust Ethics Committee. Anesthetic Technique Anesthetic technique was standardized for all patients and consisted of intravenous anesthesia with propofol infusion at 3 mg/kg per hour combined with remifentanyl infusion at 0.5 to 1 g/kg per minute. Neuromuscular blockade was achieved by 0.1 to 0.15 mg/kg pancuronium bromide or vecuronium, and the lungs were ventilated to normocapnia with air and oxygen (45% to 50%) without positive end-expiratory pressure. In the on-pump group, metaraminol or phentolamine were used to maintain the systemic pressure between 50 to 60 mm Hg. In the off-pump group, mean arterial pressure of 60 mm Hg or 1999 by The Society of Thoracic Surgeons /99/$20.00 Published by Elsevier Science Inc PII S (99)

2 494 ASCIONE ET AL Ann Thorac Surg RENAL FUNCTION WITH OFF-PUMP GRAFTING 1999;68:493 8 higher was maintained with increments of metaraminol 0.5 to 1.0 mg or volume as dictated by the hemodynamic condition, in combination with esmolol to maintain a heart rate less than 70 beats per minute. Heparin and Protamine Treatment In the on-pump group, heparin was given at a dose of 300 IU/kg to achieve a target activated clotting time of 480 seconds or above before commencement of CPB. The activated clotting time was monitored during the bypass period (every 15 minutes), and an additional 3,000 IU of heparin were administered if required. In the off-pump group, heparin 100 IU/kg was administered before the start of the first anastomosis. The target activated clotting time in this group was 250 to 350 seconds. Protamine was used at the end of the operation to reverse the effect of heparin and return the activated clotting time to preoperative levels. Surgical Technique Cardiopulmonary bypass was instituted using ascending aortic cannulation and a two-stage venous cannulation in the right atrium. A standard circuit was used, including a bard tubing set, which included a 40- m filter, a Stockert roller pump (Sorin Biomedica, Midhurst, UK), and a hollow fiber membrane oxygenator (Monolyth; Sorin Biomedica, Midhurst, UK). The extracorporeal circuit was primed with 1,000 ml of Hartmann s solution, 500 ml of gelofusine, 0.5g/kg of mannitol, 7 ml of 10% calcium gluconate, and 60 mg of heparin. Nonpulsatile flow was used. The flow rate throughout bypass was 2.4 L/m 2 per minute. Systemic temperature was kept between 34 and 36 C. Myocardial protection was achieved by using intermittent antegrade hyperkalemic warm blood cardioplegia as described by Calafiore and colleagues [14]. Once all distal anastomoses were completed, the aortic cross-clamp was removed and the proximal anastomosis performed with partial clamping. One surgeon completed all procedures. The method of exposure and stabilization used for the anastomosis was a combination of the technique previously described by our group [15] and a CTS retractor (Cardiothoracic Systems Inc, Cupertino, CA). The target vessel was then exposed and snared above the chosen point for anastomosis by using a 4-0 Prolene (Ethicon, Somerville, NJ) suture with a soft plastic snugger to prevent coronary injury. The coronary artery was then opened and the anastomosis performed. Visualization was enhanced using the surgical blower-humidifier (model SSVW-002; Surgical Site Visualization Wand, Research Medical Inc, Midvale, UT) with 1 4-inch polyvinylchloride gas line and fluid administration set connected to a regulated gas source of medical air. An intracoronary shunt (Anastoflo Intravascular Shunt; Research Medical Inc, Midvale, UT) was used only in cases of relative electrocardiographic or hemodynamic instability and excessive bleeding during the anastomosis. Table 1. Preoperative Clinical Data Variable On-Pump (n 25) Off-Pump (n 25) p Value Male Age (y) a Diabetes (diet controlled) Unstable or in hospital Angina class I 2 4 II III 8 9 IV 2 2 Ejection fraction Good ( 50%) Moderate (30% 50%) 5 4 Parsonnet score a a Data are presented as mean standard deviation. Biochemical Markers A selection of noninvasive markers was used to examine both glomerular and tubular function. Creatinine clearance is a well-established indicator of glomerular filtration rate [5] and can be determined by sampling both plasma and urinary creatinine content. Functional alterations were evaluated further by assessing the urinary levels of microalbumin-to-creatinine ratio as an index of glomerular damage. Although many enzymes are excreted into the urine by the kidney, many are unstable and are therefore unsuitable for use in clinical diagnosis [16]. N-acetyl- -glucosaminidase (NAG) is the most widely assayed urinary enzyme for the detection of renal damage because of its stability in urine, its relative molecular mass (M ), which precludes filtration by the glomerulus and its presence in high activity in the tubular lysosomes. Increased NAG activity in urine therefore provides a marker of renal tubular damage [16]. Specimen Collection Urine was collected for creatinine clearance measurement during four intervals, including over a 3-hour period in the evening before the operation, during the entire period of the operation, and then 24 hourly until (and including) the second postoperative day. A blood sample was also taken at the beginning of each period for serum creatinine measurement. Furthermore, 10-mL aliquots of urine were collected at the same stages to assay NAG activity. Laboratory Methods Blood was allowed to clot and centrifuged at 2,000 g for 15 minutes; the serum was separated immediately, and analysis was performed on fresh serum. Serum and urine creatinine values were determined with a commercial reagent kit (HiCo Creatinine; Boehringer Mannheim GmbH Diagnostica, Lewes, UK). Creatinine clearance was determined by the standard formula: creatinine clearance (ml/minute) [urine creatinine concentration (mg/ml) urine volume (ml/min)]/plasma creatinine

3 Ann Thorac Surg ASCIONE ET AL 1999;68:493 8 RENAL FUNCTION WITH OFF-PUMP GRAFTING 495 Table 2. Surgical Data Variable On-Pump (n 25) Off-Pump (n 25) p Value Cardiopulmonary bypass time a Cross-clamp time (min) a Grafts per patient (n) a Graft distribution IMA to LAD graft (n) Diag graft (n) 10 7 RCA/PDA graft (n) Proximal circumflex artery 10 7 graft (n) BIMA graft (n) 4 3 Radial artery graft (n) 1 3 Metaraminol dose (mg) a Fluid balance at 24 hr (ml) a 1, , a Data are presented as mean standard deviation. BIMA bilateral internal mammary artery; Diag Diagonal branch of LAD; IMA internal mammary artery; LAD left anterior descending coronary artery; PDA posterior descending artery; RCA right coronary artery. concentration (mg/ml). Serum creatinine level at the start of each period was used to determine the creatinine clearance during that period. Urine microalbumin levels (mg/l) were determined by immunoturbidimetry on the Cobas Mira (Koni Inst, Sweden) calibrated for albumin, an assay designed to quantify concentrations of urinary albumin less than 100 mg/l. N-acetyl- -glucosaminidase activity was measured as reported by Horak and associates [17]. Statistical Analysis Data are presented as mean standard deviation. Comparisons between preoperative variables were made using Fisher s exact test. Repeated measures analysis of variance was used to assess differences over time between groups, and the Bonferroni test was used to assess differences within a group. Analyses were performed using Statview (SAS Institute Inc, Cary, NC) Results The randomization sequence was strictly adhered to, and no patients allocated to the off-pump group were crossed over to the on-pump group. The preoperative clinical and surgical data are shown in Tables 1 and 2, respectively. The groups were similar with respect to age, gender, severity of coronary disease, diabetes mellitus, New York Heart Association functional class, and surgical data such as number of distal anastomoses. Seven patients in the on-pump group and 8 in the off-pump group were unstable, in-hospital patients treated with lowmolecular-weight heparin and aspirin. There were no instances of acute renal failure, death, or myocardial infarction in either group. For creatinine clearance over time, the use of cardiopulmonary bypass had a significant effect ( p ). Creatinine clearance improved significantly in the onpump group compared with the off-pump group from a mean of ml/minute preoperatively to ml/minute during the operative period ( p ). However, it then deteriorated during the first postoperative 24 to 48 hour period to ml/minute and ml/minute, respectively, which was significantly worse than the on-pump group ( p ) (Fig 1). Cardiopulmonary bypass also had a significant overall effect with respect to urinary albumin-to-creatinine ratios ( p ). Perioperatively the ratio increased significantly in the on-pump group ( to ) compared with the off-pump group ( to ) ( p ), decreasing to levels similar to those of the off-pump group over the next 24 to 48 hours (Fig 2). Fig 1. Changes in creatinine clearance (mean standard deviation) during periods 1 through 4 in the on-pump group (n 25) and in the off-pump group (n 25). *p on versus offpump.

4 496 ASCIONE ET AL Ann Thorac Surg RENAL FUNCTION WITH OFF-PUMP GRAFTING 1999;68:493 8 Fig 2. Changes in albuminto-creatinine ratio (mean standard deviation) during periods 1 through 4 in the on-pump group (n 25), and in the off-pump group (n 25). *p on versus off-pump. Urinary NAG activity was comparable in both groups preoperatively. It increased significantly from preoperatively to at the end of the operation in the on-pump group and from to in the off-pump group (p ). The urinary NAG activity values remained significantly higher in the postoperative 24 and 48 hour periods in the on-pump group compared with the off-pump group (Fig 3). Means and standard deviations for all groups are shown in Table 3. The postoperative clinical data are given in Table 4. There was no significant difference between the two groups with respect to complications, such as lung infections, stroke, or transient ischemic attacks. Blood loss and transfusion requirements were significantly greater in the on-pump group. Intensive care unit and hospital length of stay was longer in the on-pump group. Comment The cause of renal dysfunction after cardiac operation is multifactorial and usually attributed to several factors, such as the use of CPB, perioperative cardiovascular compromise, or toxic insults to the kidneys [1, 5, 18]. Free plasma hemoglobin, elastase and endothelin, and free radicals including superoxide, hydrogen peroxide, and Fig 3. Changes in n-acetyl- -glucosamine levels (mean standard deviation) during periods 1 through 4 in the on-pump group (n 25) and in the off-pump group (n 25). *p on versus off-pump.

5 Ann Thorac Surg ASCIONE ET AL 1999;68:493 8 RENAL FUNCTION WITH OFF-PUMP GRAFTING 497 Table 3. Changes in Creatinine Clearance Levels, Urinary Albumin-to-Creatinine Ratio, and N-acetyl- -glucosamine Levels Preoperative Operative Postoperative Day 1 Postoperative Day 2 Creatinine clearance (ml/min) Group A a b Group B Urine albumin-to-creatinine ratio Group A a c Group B N-acetyl- -glucosamine levels Group A a Group B a p between operative and preoperative levels with on-pump. b p between day 1 and operative levels with on-pump. c p between day 1 and operative levels with on-pump. the hydroxyl radicals can be generated during CPB and can induce injury in the renal brush-border membrane [5]. Nonpulsatile flow, renal hypoperfusion, hypothermia, and duration of CPB are also thought to have adverse effects on renal function [4, 5, 19]. Operation on a beating heart is a relatively new surgical procedure and can be considered the best model of pulsatile perfusion, which also avoids the use of CPB and its side effects. In the present study we used beating heart operations in elective patients who needed myocardial revascularization (excluding patients with involvement of the distal branch of the circumflex artery) to clarify the impact of this procedure on renal function as part of a prospective randomized study. The exclusion criteria attempted to avoid exposing the two groups to concomitant renal risk factors. In agreement with previous reports [5, 20], this study found a marked improvement in creatinine clearance, a reliable indicator of glomerular filtration rate, during CPB in the on-pump group. The off-pump group also showed a significant increase in this marker at the end of the operation. This improvement is probably made possible by the well documented ability of the kidney to increase its glomerular filtration capacity under a variety Table 4. General Perioperative Data Variable On-Pump (n 26) Off-Pump (n 25) p Value Acute renal failure Lung infection Stroke Transitory ischemic attack Reopened for bleeding Total blood loss (ml) a 1, Transfusion requirement (units) a Whole blood or packed cells Fresh frozen plasma Platelets Intensive therapy unit stay (days) a Hospital length of stay (days) a a Data are presented as mean standard deviation. of conditions, so called renal functional reserve [21]. Nevertheless, at 24 and 48 hours postoperatively the creatinine clearance values decreased significantly in the on-pump group, reaching levels markedly lower than preoperative levels. Conversely, in the off-pump group the values returned to preoperative levels at both 24 and 48 hours postoperatively. Functional alteration of the glomerular and tubular parts of the nephron can be evaluated further by assessing microalbuminuria and NAG activity, respectively. When the normal tubular protein absorption mechanism is near saturation, a small increase in glomerular permeability results in a large increase in proteinuria. Therefore, concentrations of urinary albumin can be used reliably as an index of glomerular damage [5]. More recently, urinary NAG activity has emerged as the most widely assayed urinary enzyme for detection of renal damage because of its stability in urine, its relative molecular mass which precludes filtration by the glomerulus, and its presence in high activity in the tubular lysosomes. The marked increases in urinary albumin-to-creatinine ratio and NAG activity levels in the current study confirm the potential deleterious effect of the CPB on renal function. Furthermore, changes in these markers appeared to be significantly lower in the off-pump group, suggesting better functional preservation. This study also showed a significantly higher requirement for vasoconstrictors in the on-pump group to keep the perfusion pressure at the predefined level during normothermic CPB compared with the need for vasoconstrictors to keep the mean blood pressure at a predefined level in the off-pump group. However, in previous reports that did not appear to have any effect on the degree of renal dysfunction or the impact on proteinuria [5, 22]. It is important that the above results were obtained despite the advantageous effect of hemodilution on blood viscosity and improved renal plasma flow secondary to pump priming [23] and the use of mannitol in the prime in the on-pump group. This is reported to maintain glomerular capillary pressure [24] and prevent tubular obstruction, protect against free radical induced injury to the renal brush border membrane, reduce ischemia-

6 498 ASCIONE ET AL Ann Thorac Surg RENAL FUNCTION WITH OFF-PUMP GRAFTING 1999;68:493 8 induced protein leakage across kidney vessel walls, and reduce plasma hydrogen peroxide free radicals [24]. The current study also showed a significantly higher blood loss and transfusion requirement in the on-pump group. Although this loss seems high, 28% of those patients were unstable and treated preoperatively with aspirin and low-molecular-weight heparin. Furthermore, these losses concur with other recently published data [25, 26]. Lung infections were defined as lung collapse and pyrexia requiring prolonged antibiotic therapy. Although the on-pump group had more infections, the difference was not significant. In conclusion, this study clearly showed that off-pump coronary revascularization is a safe surgical technique that provides better protection of renal function compared with conventional operations that use cardiopulmonary bypass and cardioplegic arrest. 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