Impact of Preoperative Renal Dysfunction on Outcomes of Off-Pump Coronary Artery Bypass Grafting

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1 Impact of Preoperative Renal Dysfunction on Outcomes of Off-Pump Coronary Artery Bypass Grafting Lokeswara Rao Sajja, MD, Gopichand Mannam, FRCS (CT), Rajasekara M. Chakravarthi, MD, Jyothsna Guttikonda, MD, Sriramulu Sompalli, MD, and Joshua Bloomstone, MD Divisions of Cardiothoracic Surgery, Nephrology, and Cardiothoracic Anesthesiology, Star Hospitals, Banjara Hills, Hyderabad; the Division of Nephrology, Care Hospital, The Institute of Medical Sciences, Banjara Hills, Hyderabad, India; and the Department of Anesthesiology and Perioperative Medicine, Banner Thunderbird Medical Center, Glendale, Arizona Background. This study assessed whether preoperative renal insufficiency predisposes patients undergoing offpump coronary artery revascularization to postoperative dialysis. Methods. From August 2004 through June 2009, 2,275 patients undergoing off-pump coronary artery bypass were categorized into five groups (stages) by glomerular filtration rate (GFR). Of these, 1,855 patients had renal insufficiency: stage 2: 1,406; stage 3: 428; stage 4: 21, and 414 had normal renal function, stage 1. Excluded were 6 patients with end-stage renal disease (stage 5). Preoperative variables and postoperative outcomes were compared among groups. Results. Preoperative patient characteristics were similar; however, patients with normal renal function were younger (p 0.001). Serum creatinine rose significantly above baseline on the first postoperative day in the renal insufficiency groups (p 0.001). The GFR groups had similar inotrope use, reexploration rate, duration of postoperative mechanical ventilation, postoperative stroke, wound infection, and mortality rate. Stage 4 patients had a higher incidence of postoperative myocardial infarction (p 0.002). Stage 3 and 4 patients had an increased need for postoperative dialysis vs stage 1 patients (p 0.002). Conclusions. Nonparametric contingency analysis showed patients with low preoperative GFR (stage 3 and 4, p < ) and a history of smoking (p 0.04) were at increased risk for postoperative dialysis. Patients who required postoperative inotropic support tended toward requiring postoperative dialysis (p 0.06). Low preoperative ejection fraction (p 0.83), class III or IV angina (p 0.069), and postoperative blood transfusions were not associated with the need for postoperative dialysis in patients undergoing off-pump revascularization. (Ann Thorac Surg 2011;92:2161 7) 2011 by The Society of Thoracic Surgeons Patients with renal dysfunction who require coronary artery bypass grafting (CABG) represent a complex group of patients with accelerated atherosclerosis and advanced cardiovascular disease[1 3]. CABG is a highly successful surgical treatment for the relief of angina and prolongs life in selected patients. Patients with end-stage renal disease are known to be at higher risk for operative death after CABG using cardiopulmonary bypass [4]. Although several studies have addressed the effect of lesser degrees of renal impairment on patient outcomes after on-pump CABG, the effect of mild to moderate renal impairment after off-pump coronary artery bypass (OPCAB) has not been well studied [2, 5 10]. According to The Society of Thoracic Surgeons National Adult Cardiac Database, 22% of patients undergoing CABG have normal renal function, defined as a glomerular filtration rate (GFR) of 90 ml/min/1.73 m 2 or more. Renal dysfunction is defined as mild in 51% (60 to 89 ml/min/1.73 m 2 ), moderate in 24% (30 to 59 ml/min/ 1.73 m 2 ), severe (without dialysis) in 2% ( 30 ml/min/ 1.73 m 2 ), and 1.5% require dialysis [11]. Preoperative renal dysfunction is thus a powerful, independent predictor of postoperative acute kidney injury; hence, the assessment of preoperative renal function should be incorporated into clinical risk assessment and prediction models. A recently published retrospective study comparing the outcomes of OPCAB among patients with normal and abnormal renal function suggested that the OPCAB technique is an independent, modifiable, and protective factor for acute kidney injury in patients undergoing CABG when all major preoperative, intraoperative, and postoperative risk factors are considered [12]. Accepted for publication May 3, Address correspondence to Dr Sajja, Division of Cardiothoracic Surgery, Star Hospitals, Rd 10, Banjara Hills, Hyderabad , India; sajjalr@yahoo.com. Dr Bloomstone discloses that he has a financial relationship with Edwards Lifesciences by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 2162 SAJJA ET AL Ann Thorac Surg EFFECT OF PREOP RENAL DYSFUNCTION ON OPCAB 2011;92: Abbreviations and Acronyms ACEI angiotensin converting enzyme inhibitor CABG coronary artery bypass grafting CPB cardiopulmonary bypass CVA cerebrovascular accident GFR glomerular filtration rate LVEF left ventricular ejection fraction MI myocardial infarction NDRI nondialysis-dependent renal insufficiency NS not significant OPCAB off-pump coronary artery bypass grafting RF renal function RI renal insufficiency SCr serum creatinine SD standard deviation Patients and Methods This retrospective study, which was approved by the institutional Ethics Committee, was conducted to compare morbidity and mortality in patients with normal and varying degrees of nondialysis-dependant renal insufficiency (NDRI) undergoing primary CABG using the OPCAB technique. Between August 2004 and June 2009, 4,073 patients underwent primary CABG at our institutions; of these, 2,275 patients underwent OPCAB and their data were extracted from our database. These 2,275 patients were categorized into five groups by GFR according to National Kidney Foundation guidelines: Stage 1: Normal renal function ( 90 ml/min/1.73 m 2 ), 414 patients; Stage 2: Mild renal insufficiency (60 to 89 ml/min/ 1.73 m 2 ), 1,406 patients; Stage 3: Moderate renal insufficiency (30 to 59 ml/min/1.73 m 2 ), 428 patients; Stage 4: Severe renal insufficiency (15 to 29 ml/ min/1.73 m 2 ), 21 patients; and Stage 5: End-stage renal failure ( 15 ml/min/ 1.73 m 2 ), 6 patients, who were excluded from the study Estimation of GFR We estimated GFR by using the Modification of Diet in Renal Disease study equation as suggested by National Kidney Foundation guidelines [13]. The variables included were age, sex, height in cm and weight in kg (for body surface area calculation), blood urea nitrogen (BUN), serum creatinine (SCr), and serum albumin (Alb). The formula is as follows [14]: GFR ml min 1.73 m SCr 0.99 Age BUN Alb for men 170 SCr 0.99 Age BUN Alb for women. Anesthesia Technique The anesthetic technique was standardized for all patients as described earlier [15]. Induction and maintenance of anesthesia was achieved using a propofol bolus, followed by an hourly infusion of 3 mg/kg. Neuromuscular blockade was achieved using vecuronium bromide (0.1 to 0.15 mg/kg). A mean systemic arterial pressure of 65 mm Hg or higher was maintained with dobutamine, norepinephrine, or volume, as directed by the hemodynamic condition. Cell salvage was not used. Heparin and Protamine Management Heparin (100 IU/kg) was administered to achieve an activated clotting time of 300 to 350 seconds. When all distal and proximal anastomoses were completed, protamine sulphate was given to reverse the effect of heparin and to return the activated clotting time to normal. Surgical Technique A median sternotomy was used in all patients. The internal thoracic artery grafts were harvested as pedicles, the saphenous vein grafts were harvested using the open technique, and the radial artery grafts were harvested using the extrafascial technique, as described previously [15]. The distal anastomosis for the internal thoracic artery graft was constructed using 8 0 polypropylene continuous suture, and the saphenous vein and radial artery grafts were constructed with 7 0 polypropylene suture. All proximal anastomoses of the radial artery grafts were constructed with 7 0 polypropylene suture, and those of the saphenous vein grafts were constructed with 6 0 polypropylene suture. OPCAB Technique The method of exposure and stabilization to perform the distal anastomoses consisted of the technique previously described [15]. OPCAB was performed with the Medtronic Octopus 3 or 4 or Evolution stabilizing device (Medtronic Inc, Minneapolis, MN) for target coronary artery stabilization. Target arteries were accessed by deep pericardial traction sutures or by the use of a Medtronic Starfish heart positioner (Medtronic Inc). An intracoronary shunt (Medtronic Inc) was used in all vessels measuring more than 1.25 mm in diameter while the coronary anastomosis was constructed. Visualization of the anastomotic area was enhanced by using a humidified carbon dioxide blower/mister (Medtronic Inc) to disperse blood from the anastomotic site while the distal anastomoses were constructed. For safety, a cardiopulmonary bypass machine was kept on standby with a circuit mounted but not primed. All patients received cephazolin intravenously (1 g, 3 times daily) and ofloxacin (200 mg, twice daily) for 2 days. No patients received aprotinin. Cell salvage and reinfusion of shed mediastinal blood was not used during the operation. Strict glycemic control was achieved in all

3 Ann Thorac Surg SAJJA ET AL 2011;92: EFFECT OF PREOP RENAL DYSFUNCTION ON OPCAB 2163 Table 1. Comparison of Variables by Preoperative Stage of Renal Function Patient Groups (Stages) by GFR b Stage 1 Stage 2 Stage 3 Stage 4 p Value Pair-Wise Comparisons Variable a (n 414) (n 1,406) (n 428) (n 21) Stage 1 vs Stage Normal RF Mild RI Moderate RI Severe RI Overall Age, years Mean SD Sex Male 368 (88.9) 1,239 (88.1) 383 (89.5) 15 (71.4) Female 46 (11.1) 167 (11.9) 45 (10.5) 6 (28.6) Preop SCr, mg/dl Mean SD Smoking Yes 32 (7.7) 191 (13.6) 62 (14.4) 1 (4.7) No 382 (92.3) 1,215 (86.4) 366 (85.6) 20 (93.3) Diabetes mellitus Yes 192 (46.4) 728 (51.8) 250 (58.4) 14 (70) No 222 (53.6) 678 (48.2) 178 (41.6) 7 (30) Hypertension, Yes 188 (45.4) 685 (48.7) 207 (48.3) 7 (33.3) No 226 (54.6) 721 (51.3) 221 (51.7) 16 (66.7) Angina class IV Yes 159 (38.4) 532 (37.8) 145 (33.9) 5 (23.8) No 255 (61.6) 874 (62.2) 283 (66.1) 16 (76.2) LVEF ( 0.35) Yes 60 (14.5) 221 (15.7) 63 (14.7) 2 (9.5) No 354 (85.5) 1,185 (84.3) 365 (85.3) 19 (90.5) ACEI preop use Yes 190 (45.9) 587 (41.7) 186 (43.4) 10 (47.6) No 224 (54.1) 819 (58.3) 242 (56.6) 11 (52.4) a Categoric data are expressed as number (%). b GFR stages by ml/min/1.73 m 2 :1 90; 2 60 to 89; 3 30 to 59; 4 15 to 29. ACEI angiotensin converting enzyme inhibitor; GFR glomerular filtration rate; LVEF left ventricular ejection fraction; Preop preoperative; RF renal function; RI renal insufficiency; SCr, serum creatinine; SD standard deviation. patients with continuous intravenous infusion of insulin intraoperatively and postoperatively. Packed red blood cells were transfused for hemoglobin concentrations of less than 9 gm/dl. Other blood products were used as required. Data Collection and Statistical Analysis Perioperative data were extracted from our database and included age, sex, height, weight, diabetes mellitus, hypertension, peripheral vascular disease, left ventricular ejection fraction, number of significantly stenosed coronary arteries, prior myocardial infarction, congestive heart failure, Canadian Cardiovascular Society angina class, serum creatinine, GFR, cerebrovascular accidents, and chronic obstructive pulmonary disease. Intraoperative and postoperative variables were recorded, including the postoperative outcomes for reexploration for bleeding, perioperative myocardial infarction, use of intraaortic balloon pump, incidence of stroke, period of ventilatory support, deep sternal wound infection, and need for blood transfusion. Preoperative variables and postoperative outcomes were compared between normal and renal insufficiency groups. Statistical analyses were performed using SPSS 10.1 software (SPSS Inc, Chicago, IL). Categoric variables were summarized through the calculation of frequency and relative frequency. Continuous variables were summarized through the calculation of mean and standard error. To statistically assess the observed differences among various GFR groups in the distribution of categoric variables, the Pearson 2 or Fisher exact test of association was used. Analysis of variance was applied to all continuous variables to identify differences between groups. In addition to the overall test of group differ-

4 2164 SAJJA ET AL Ann Thorac Surg EFFECT OF PREOP RENAL DYSFUNCTION ON OPCAB 2011;92: Fig 1. Mean preoperative (dark bars) and postoperative (light bars) serum creatinine levels are shown among the groups with different glomerular filtration rates, calculated as ml/min/1.73 m 2 : stage 1 90; stage 2 60 to 89; stage 3 30 to 59; stage 4 15 to 29. ences, pair-wise comparisons were made between the group with normal renal function and each of the other three groups with abnormal renal function. These tests were made in conjunction with Bonferroni adjustments. A nominal significance level of 0.05 was used for all hypothesis testing. Renal Function Baseline serum creatinine and GFR were measured at the time of hospitalization. Serum creatinine was measured on postoperative days 1, 2, 3, and 5. Postoperative GFR was not estimated because results would be erroneous in the presence of fluid imbalance, changes in serum albumin, and patient weight. Fluid intake and urine output were measured daily in all patients during the intensive care unit stay. A positive fluid balance was observed in the lower GFR groups (stage 3 and 4), and furosemide was given (0.5 to 1 mg/kg per dose) as required. All patients with a GFR of less than 60 ml/min received 600 mg of N-acetylcysteine orally once daily, immediately before revascularization, and for the first 5 postoperative days. No patients received perioperative aminoglycosides or nonsteroidal antiinflammatory agents. Results In the study population of 2,275, 414 patients (18.2%) had normal renal function (stage 1: GFR 90 ml/min per 1.73 m 2 ), 1,406 (61.8%) had mild renal dysfunction (stage 2: GFR 60 to 89 ml/ min per 1.73 m 2 ), 428 (18.8%) had moderate renal dysfunction (stage 3: GFR 30 to 59 ml/ min per 1.73 m 2 ), and 21 (0.92%) had severe renal dysfunction (stage 4: GFR 30 ml/ min per 1.73 m 2 ). We excluded 6 patients (0.26%) with stage 5 renal failure. A greater number of patients in the renal insufficiency groups were older (p 0.001) and smokers (p 0.006). The groups did not differ in gender distribution, hypertensive use, preoperative angina class, poor left ventricular function, and preoperative use of angiotensinconverting enzyme inhibitors (Table 1); however, more diabetic patients were in stage 2 (p 0.05) and stage 3 (p 0.001) than in stage 1. There was no difference in the mean number of grafts per patient or in the index of completeness of revascularization among the groups (p 0.894). Requirement for postoperative inotropic support was similar among the groups (p 0.73). Association With Early Outcomes In univariate analysis, worsening renal function was associated with a rise in serum creatinine in the immediate postoperative period (p 0.001), a higher incidence of postoperative myocardial infarction (p 0.013), and an increased need for dialysis (p 0.001; Fig 1). NDRI was not associated with an increased risk of reexploration for excessive mediastinal bleeding, postoperative incidence of cerebrovascular accident, deep sternal wound infection, or death compared with the group with normal renal function group (Table 2). Nonparametric contingency analysis demonstrated that patients with low preoperative GFR (stage 3 and 4, p ) and a history of smoking (p 0.04) were at an increased risk for postoperative dialysis. Patients who required postoperative inotropic support tended toward requiring postoperative dialysis (p 0.06). A low preoperative ejection fraction (p 0.83), class III or IV angina (p 0.069), and postoperative blood transfusions were not associated with the need for postoperative dialysis in patients undergoing OPCAB. Comment Dialysis-dependent renal dysfunction is a widely recognized risk factor for increased morbidity and death after conventional CABG [16 19]. NDRI also predisposes patients to adverse outcomes after conventional CABG [6, 9]. Several studies have recently demonstrated that OPCAB provides better outcomes than conventional CABG in patients with renal dysfunction [10 12]. We have evaluated the effect of various stages of renal

5 Ann Thorac Surg SAJJA ET AL 2011;92: EFFECT OF PREOP RENAL DYSFUNCTION ON OPCAB 2165 Table 2. Comparison of Intraoperative and Postoperative Variables in Patients Grouped by Preoperative Glomerular Filtration Patient Groups (Stages) by GFR b p Value Variable a Stage 1 Stage 2 Stage 3 Stage 4 For Pair-Wise Comparison (n 414) (n 1,406) (n 428) (n 21) Stage 1 vs Stage Normal RF Mild RI Moderate RI Severe RI Overall Grafts per patient, No. Mean SD Inotrope use Yes 163 (39.4) 518 (36.8) 151 (35.3) 9 (42.9) No 251 (60.6) 888 (63.2) 277 (64.7) 12 (57.1) Postop SCr, mg/dl Mean SD Postop MI Yes 1 (0.2) 6 (0.43) 5 (1.16) 1 (4.76) No 413 (99.8) 1400 (99.57) 423 (98.84) 20 (95.24) Postop dialysis Yes 1 (0.2) 5 (0.36) 11 (2.6) 1 (4.76) No 413 (99.8) 1401 (99.64) 417 (97.4) 20 (95.24) Reexploration Yes 3 (0.7) 18 (1.3) 4 (0.93) 1 (4.8) No 411 (99.3) 1388 (98.7) 424 (99.07) 20 (96.2) Postop CVA Yes 2 (0.5) 14 (1.0) 0 (0) 0 (0) No 412 (99.5) 1392 (99.0) 428 (100) 21 (100) Mechanical ventilation, hrs Mean SD Wound infection Yes 5 (1.2) 10 (0.7) 2 (0.46) 0 (0) No 409 (98.8) 1396 (99.3) 426 (99.54) 21 (100) Mortality Yes 2 (0.5) 10 (0.7) 4 (0.9) 0.95 (00) No 412 (99.5) 1396 (99.3) 424 (99.1) 21 (100) a Categoric data are expressed as number (%). b GFR stages by ml/min/1.73 m 2 :1 90; 2 60 to 89; 3 30 to 59; 4 15 to 29. CVA cerebrovascular accident; GFR glomerular filtration rate; MI myocardial infarction; Postop postoperative; RF renal function; RI renal insufficiency; SCr serum creatinine; SD standard deviation. dysfunction compared with normal renal function on the need for postoperative dialysis in patients undergoing OPCAB. This study adds to the growing body of evidence documenting the effects of mild to moderate renal insufficiency on the need for postoperative dialysis after OPCAB. The association between renal dysfunction and worse outcome after CABG for patients who do not require dialysis has multiple possible explanations: First, the greater frequency of triple-vessel disease and left main coronary artery involvement among patients with renal disease suggests that these patients have more extensive coronary artery disease than those with normal kidney function [20]. Second, increased risk may also be attributed to a multitude of comorbidities common to patients with renal insufficiency, including older age, poor left ventricular function, diabetes, hypertension, and peripheral vascular disease. In addition to these known risk factors for post-cabg dialysis, our study demonstrates that GFR is an important risk factor beyond these traditionally assessed predictors. Third, and perhaps most probable, renal function is likely a direct risk factor for intraoperative and postoperative adverse events and for complications that lead to longer operative times and prolonged postoperative ventilation. Indeed, the reoperation rate is twice as common among nondialysis patients with severe renal dysfunc-

6 2166 SAJJA ET AL Ann Thorac Surg EFFECT OF PREOP RENAL DYSFUNCTION ON OPCAB 2011;92: tion as among patients with GFRs within normal reference ranges [11]. Several studies suggest that the OPCAB technique is an independent protective factor for acute kidney injury in patients undergoing CABG [10, 12]. Several preoperative, intraoperative, and postoperative risk factors, including older age, diabetes, peripheral vascular disease, cardiogenic shock, C reactive protein, length of intensive care unit stay, and maximum serum creatinine, have been repeatedly identified as non-modifiable risk factors for acute kidney injury. Many studies have shown that NDRI is an independent predictor of increased morbidity, mortality, and reduced long-term survival [6, 9, 21]. Owing to simultaneous advances in anesthesiology and intensive care, cardiac operative outcomes after CABG in low-risk patients have improved significantly. These advances, however, have had little effect on the outcome of patients with NDRI, as evidenced by morbidity rates of 5% to 19% and mortality rates of 29% to 80% [9, 22, 23]. Several publications have confirmed that patients with NDRI have a higher incidence of cardiovascular risk factors, including hypertension, diabetes, prior myocardial infarction, left ventricular dysfunction, peripheral vascular disease, and dyslipidemia. In addition, several studies have shown that renal insufficiency is a predictor of cardiovascular morbidity and death after acute myocardial infarction, acute coronary syndrome, and revascularization by surgical or percutaneous techniques [24]. Angiographic evidence of greater severity of atherosclerosis and calcification of coronary vessels in NDRI patients has been published previously [24]. Weerasinghe and colleagues [9] showed that an elevated preoperative serum creatinine level is a significant risk factor for worsening postoperative renal dysfunction as evidenced by further elevations in serum creatinine. Other studies have demonstrated that mild to moderate renal insufficiency is a risk factor for ventilator-associated complications after on-pump CABG [9, 25]. Anderson and colleagues [5] suggested that limited elimination of fluid volume and decreased excretion of sedatives and analgesics because of impaired kidney function might have resulted in impaired alveolar gaseous exchange, impaired ventilatory drive, and increased ventilatory complications. Chirumamilla and colleagues [25] attributed a higher incidence of postoperative respiratory failure to renal-induced congestive heart failure. Our study demonstrates that most of the early outcomes of OPCAB in patients with renal dysfunction were comparable to those with normal renal function except (1) there was a significant rise of serum creatinine above baseline in the renal insufficiency groups (p 0.05), (2) the incidence of postoperative myocardial infarction was higher in patients with stage 4 renal dysfunction (GFR 15 to 29 ml/min/1.73 m 2 ; p 0.002), and (3) there was a greater requirement for postoperative dialysis in the moderate (stage 3) and severe (stage 4) renal insufficiency groups (p 0.002) compared with the group with normal renal function. There were no statistically significant Table 3. Comparative Data of Clinical Outcomes of Patients Undergoing Off-Pump and On-Pump Coronary Artery Bypass Grafting OPCAB CABG Variable a (n 3,028) (n 3,040) p Value Hospital mortality 11 (0.36) 52 (1.71) 0.01 Postoperative MI 32 (1.05) 28 (0.92) 0.6 Intraaortic balloon pump 36 (1.19) 41 (1.35) 0.65 Reentry for bleeding 34 (1.12) 46 (1.51) 0.22 Grafts Mean SD Postoperative stroke 26 (0.86) 46 (1.51) 0.02 Postoperative dialysis 24 (0.79) 32 (1.05) 0.35 Sternal wound infection 12 (0.39) 18 (0.59) 0.36 Blood transfusion received 1999 (66) 3040 (100) a Categoric data are shown as number (%). CABG coronary artery bypass grafting; MI myocardial infarction; OPCAB off-pump coronary artery bypass grafting; SD standard deviation. differences in operative mortality rates between the normal and abnormal renal function groups. We have compared the early outcomes of off-pump vs contemporaneous on-pump CABG patients at our institution (Table 3). In the OPCAB group, the operative mortality was lower (p 0.01), the number of grafts per patient was less (p 0.001), the incidence of postoperative cerebrovascular accident was less (p 0.02), and the need for postoperative dialysis between the two groups was not statistically significant (p 0.35). The insignificant difference in the requirement for postoperative dialysis in our series may be because most of our patients with high serum creatinine values and low GFR selectively underwent OPCAB since January In conclusion, our study demonstrates that patients with low preoperative GFR (stage 3 and 4, p ) and a history of smoking (p 0.04) were at an increased risk for postoperative dialysis. Patients who required postoperative inotropic support tended to require postoperative dialysis (p 0.06). Low preoperative ejection fraction (p 0.83), class III or IV angina (p 0.069), and postoperative blood transfusions were not associated with the need for postoperative dialysis in patients undergoing OPCAB. We thank A. Nadamuni Naidu, MS (stat), Head, Department of Statistics (Retired), National Institute of Nutrition, ICMR, Hyderabad, India, for statistical advice and analysis for this study, and V. Srikanth Jalakam, MS (Biotechnology), Clinical Research Coordinator, Star Hospitals, Hyderabad, for help in preparing the manuscript. We thank Dinkar Malladi, MD, Phoenix, Arizona, for help in revising the manuscript. References 1. Liu JY, Birkmeyer JO, Sanders JH, et al. Risks of morbidity and mortality in dialysis patients undergoing coronary artery bypass surgery. Circulation 2000;102:

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